Patent Document

[0001]    This application claims the benefit of priority to International Application No. PCT/CN2015/070967, filed Jan. 19, 2015, the contents of which are incorporated herein by reference. 
     
    
       [0002]    SCY-078 (or “compound 1”) is a glucan synthase inhibitor useful as an antifungal compound. SCY-078 is useful for treating, among other things,  Invasive Candidiasis  and  Invasive Aspergillosis . Other antimicrobial utilities of SCY-078 are disclosed, for example, in U.S. Pat. No. 8,188,085, the relevant portions of which are incorporated herein by reference. SCY-078 has the following chemical structure: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0003]    The present disclosure is directed to, among other things, pharmaceutically acceptable salts of SCY-078 and polymorphs of those salts. In another embodiment, the salts and polymorphs thereof exhibit certain kinetic solubilities. Higher kinetic solubilities can be importance in formulations, such as intravenous formulations. In yet another embodiment, the salts and polymorphs thereof exhibit certain hygroscopicities. Hygroscopity has been found to play an important role in the preparation of solid dosage forms and the selection of excipients. The present disclosure is further directed to, among other things, methods of preparing pharmaceutically acceptable salts of SCY-078 and polymorphs thereof. 
         [0004]    The present disclosure is additionally directed to, among other things, pharmaceutical compositions comprising pharmaceutically acceptable salts of SCY-078 and polymorphs thereof. In another embodiment, the disclosure relates to methods of preparing pharmaceutical compositions comprising pharmaceutically acceptable salts of SCY-078 and polymorphs thereof suitable for injection or intravenous administration. In yet another embodiment, the present disclosure relates to method of treating fungal infections by administering pharmaceutically acceptable salts of SCY-078 and polymorphs thereof. 
     
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         [0005]      FIG. 1  is an X-ray Powder Diffraction “XRPD” pattern of SCY-078 phosphate from Example 1. 
           [0006]      FIG. 2  is a DSC curve and a TGA curve of SCY-078 phosphate from Example 1. 
           [0007]      FIG. 3  is an XRPD of SCY-078 crystalline freebase (MeOH desolvate), batch 1 from Example 2. 
           [0008]      FIG. 4  is a DSC curve and a TGA curve of SCY-078 crystalline freebase (MeOH desolvate), batch 1 from Example 2. 
           [0009]      FIG. 5  is an XRPD of SCY-078 crystalline freebase (MeOH desolvate), batch 2 from Example 2. 
           [0010]      FIG. 6  is a DSC curve and a TGA curve of SCY-078 amorphous freebase from Example 3. 
           [0011]      FIG. 7  is an XRPD of SCY-078 HCl Type A from Example 7. 
           [0012]      FIG. 8  is a DSC curve and a TGA curve of SCY-078 HCl Type A from Example 7. 
           [0013]      FIG. 9  is an XRPD of SCY-078 citrate Type A from Example 8. 
           [0014]      FIG. 10  is a DSC curve and a TGA curve of SCY-078 citrate Type A from Example 8. 
           [0015]      FIG. 11  is an XRPD of SCY-078 hippurate Type A from Example 9. 
           [0016]      FIG. 12  is a DSC curve and a TGA curve of SCY-078 hippurate Type A from Example 9. 
           [0017]      FIG. 13  is an XRPD of SCY-078 hippurate Type B from Example 10 overlaid on an XRPD of SCY-078 hippurate Type A from Example 9. 
           [0018]      FIG. 14  is a DSC curve and a TGA curve of SCY-078 hippurate Type B from Example 10. 
           [0019]      FIG. 15  is an XRPD of SCY-078 hippurate Type C from Example 11 overlaid on the XPRDs of SCY-078 hippurate Type A, hippurate Type B, and hippurate Type B heated to 175° C. 
           [0020]      FIG. 16  is a cycle DSC curve of SCY-078 hippurate Type B and SCY-078 hippurate Type C from Example 11. 
           [0021]      FIG. 17  is an XRPD of SCY-078 fumarate Type A from Example 12. 
           [0022]      FIG. 18  is a DSC curve and a TGA curve of SCY-078 fumarate Type A from Example 12. 
           [0023]      FIG. 19  is an XRPD of SCY-078 fumarate Type B from Example 13. 
           [0024]      FIG. 20  is a DSC curve and a TGA curve of SCY-078 fumarate Type B from Example 13. 
           [0025]      FIG. 21  is an XRPD of SCY-078 glycolate Type A from Example 14. 
           [0026]      FIG. 22  is a DSC curve and a TGA curve of SCY-078 glycolate Type A from Example 14. 
           [0027]      FIG. 23  is an XRPD of SCY-078 mesylate Type A from Example 15. 
           [0028]      FIG. 24  is a DSC curve and a TGA curve of SCY-078 mesylate Type A from Example 15. 
           [0029]      FIG. 25  is an XRPD of SCY-078 calcium Type A from Example 16. 
           [0030]      FIG. 26  is a DSC curve and a TGA curve of SCY-078 calcium Type A from Example 16. 
           [0031]      FIG. 27  is an XRPD of scaled-up SCY-078 hippurate Type B from Example 17. 
           [0032]      FIG. 28  is a DSC curve and a TGA curve of scaled-up SCY-078 hippurate Type B from Example 17. 
           [0033]      FIG. 29  is a DVS isotherm plot of scaled-up SCY-078 hippurate Type B from Example 17. 
           [0034]      FIG. 30  is an XRPD of scaled-up SCY-078 hippurate Type B before DVS, after DVS, and compared to hippurate Type A from Example 17. 
           [0035]      FIG. 31  is an XRPD of scaled-up SCY-078 fumarate Type A from Example 18. 
           [0036]      FIG. 32  is a DSC curve and a TGA curve of scaled-up SCY-078 fumarate Type A from Example 18. 
           [0037]      FIG. 33  is a DVS isotherm plot of scaled-up SCY-078 fumarate Type A from Example 18. 
           [0038]      FIG. 34  is an XRPD of scaled-up SCY-078 mesylate Type A from Example 19. 
           [0039]      FIG. 35  is a DSC curve and a TGA curve of scaled-up SCY-078 mesylate Type A from Example 19. 
           [0040]      FIG. 36  is a DVS isotherm plot of scaled-up SCY-078 mesylate Type A from Example 19. 
           [0041]      FIG. 37  is an XRPD of scaled-up SCY-078 phosphate Type A from Example 20. 
           [0042]      FIG. 38  is a DSC curve and a TGA curve of scaled-up SCY-078 phosphate Type A from Example 20. 
           [0043]      FIG. 39  is a DVS isotherm plot of scaled-up SCY-078 phosphate Type A from Example 20. 
           [0044]      FIG. 40  is an XRPD of scaled-up SCY-078 citrate Type A from Example 21. 
           [0045]      FIG. 41  is a DSC curve and a TGA curve of scaled-up SCY-078 citrate Type A from Example 21. 
           [0046]      FIG. 42  is a DVS isotherm plot of scaled-up SCY-078 citrate Type A from Example 21. 
           [0047]      FIG. 43  is an XRPD of scaled-up SCY-078 citrate Type A from Example 26. 
           [0048]      FIG. 44  is a DSC curve and a TGA curve of scaled-up SCY-078 citrate Type A from Example 26. 
           [0049]      FIG. 45  is an XRPD of SCY-078 citrate Type A from Example 38. 
           [0050]      FIG. 46  is a DSC curve and a TGA curve of SCY-078 citrate Type A from Example 38. 
           [0051]      FIG. 47  is a DVS isotherm plot of SCY-078 citrate Type A from Example 38. 
           [0052]      FIG. 48  is an XRPD of SCY-078 citrate Type A after process development from Example 38. 
           [0053]      FIG. 49  is a DSC curve and a TGA curve of SCY-078 citrate Type A after process development from Example 38. 
           [0054]      FIG. 50  is a DVS isotherm plot of SCY-078 citrate Type A after process development from Example 38. 
           [0055]      FIG. 51  is an XRPD of SCY-078 citrate Type B from Example 39. 
           [0056]      FIG. 52  is a DSC curve and a TGA curve of SCY-078 citrate Type B from Example 39. 
           [0057]      FIG. 53  is an XRPD of SCY-078 citrate Type E from Example 40. 
           [0058]      FIG. 54  is an XRPD of SCY-078 citrate Type E from Example 40 before and after storage. 
           [0059]      FIG. 55  is an XRPD of SCY-078 citrate Type F from Example 41. 
           [0060]      FIG. 56  is a DSC curve and a TGA curve of SCY-078 citrate Type F from Example 41. 
           [0061]      FIG. 57  is an XRPD of SCY-078 citrate Type M from Example 42. 
           [0062]      FIG. 58  is a DSC curve and a TGA curve of SCY-078 citrate Type M from Example 42. 
           [0063]      FIG. 59  is a DVS isotherm plot of SCY-078 citrate Type M from Example 42. 
           [0064]      FIG. 60  is an XRPD of SCY-078 citrate Type M from Example 42 at variable temperatures. 
           [0065]      FIG. 61  is an XRPD of SCY-078 citrate Type N from Example 43. 
           [0066]      FIG. 62  is an XRPD of SCY-078 citrate Type N from Example 43 before and after drying. 
           [0067]      FIG. 63  is an XRPD of SCY-078 citrate Type 0 from Example 44. 
           [0068]      FIG. 64  is an XRPD of SCY-078 citrate Type Q from Example 45. 
           [0069]      FIG. 65  is an XRPD of SCY-078 citrate Type Q from Example 45 before and after drying. 
           [0070]      FIG. 66  is an XRPD of SCY-078 citrate Type R from Example 46. 
           [0071]      FIG. 67  is an XRPD of SCY-078 citrate Type R from Example 46 before and after drying. 
           [0072]      FIG. 68  is an XRPD of SCY-078 citrate Type S from Example 47. 
           [0073]      FIG. 69  is a DSC curve and a TGA curve of SCY-078 citrate Type S from Example 47. 
           [0074]      FIG. 70  is a DVS isotherm plot of SCY-078 citrate Type S from Example 47. 
           [0075]      FIG. 71  is an XRPD of SCY-078 citrate Type S from Example 47 at variable temperatures. 
           [0076]      FIG. 72  shows XRPD patterns of SCY-078 citrate Types C, I, J, and P from Example 48. 
           [0077]      FIG. 73  shows XRPD patterns of slurry conversion of SCY-078 citrate Type A or Type B to Type N from Example 50. 
           [0078]      FIG. 74  shows XRPD patterns of SCY-078 citrate Type Q after drying from Example 50. 
           [0079]      FIG. 75  shows XRPD patterns of SCY-078 citrate Types R, E, and M from Example 51. 
           [0080]      FIG. 76  shows XRPD patterns of SCY-078 citrate Type M slurry in acetone from Example 51. 
           [0081]      FIG. 77  shows XRPD patterns of SCY-078 citrate Type M slurry in acetonitrile from Example 51. 
           [0082]      FIG. 78  shows XRPD patterns of SCY-078 citrate Type M slurry in MeOH/IPAc from Example 51. 
           [0083]      FIG. 79  shows XRPD patterns of SCY-078 citrate Type M slurry in heptane from Example 51. 
           [0084]      FIG. 80  shows XRPD patterns of SCY-078 citrate Type M after stability testing from Example 52. 
           [0085]      FIG. 81  shows XRPD patterns of SCY-078 citrate Type S after stability testing from Example 52. 
           [0086]      FIG. 82  is an XRPD of SCY-078 citrate Type A from Example 53. 
           [0087]      FIG. 83  is a DSC curve and a TGA curve of SCY-078 citrate Type A from Example 53. 
           [0088]      FIG. 84  is a DSC curve and a TGA curve of SCY-078 citrate Type A from Example 53. 
           [0089]      FIG. 85  is an XRPD of SCY-078 Trifluoroacetate Type A from Example 54. 
           [0090]      FIG. 86  is a DSC curve and a TGA curve of SCY-078 Trifluoroacetate Type A from Example 54. 
           [0091]      FIG. 87  is an XRPD of SCY-078 Trifluoroacetate Type A before and after storage from Example 54. 
           [0092]      FIG. 88  is an XRPD of SCY-078 Trifluoroacetate Type B from Example 55. 
           [0093]      FIG. 89  is a DSC curve and a TGA curve of SCY-078 Trifluoroacetate Type B from Example 55. 
           [0094]      FIG. 90  is a DVS curve of SCY-078 Trifluoroacetate Type B from Example 55. 
           [0095]      FIG. 91  is an XRPD overlay of SCY-078 Trifluoroacetate Type B before and after DVS from Example 55. 
           [0096]      FIG. 92  is an XRPD overlay of SCY-078 Trifluoroacetate Type B at varying relative humidity from Example 55. 
           [0097]      FIG. 93  is a VT-XRPD overlay of SCY-078 Trifluoroacetate Type A from Example 55. 
           [0098]      FIG. 94  is an XRPD of SCY-078 HCl Type I from Example 56. 
           [0099]      FIG. 95  is a DSC curve and a TGA curves of SCY-078 HCl Type I from Example 56. 
           [0100]      FIG. 96  is a DVS curve of SCY-078 HCl Type I from Example 56. 
           [0101]      FIG. 97  is an XRPD overlay of SCY-078 HCl Type I before and after DVS from Example 56. 
           [0102]      FIG. 98  is an XRPD of SCY-078 HCl Type II from Example 57. 
           [0103]      FIG. 99  is a DSC curve and TGA curve of SCY-078 HCl Type II from Example 57. 
           [0104]      FIG. 100  shows the kinetic solubility curves of SCY-078 Trifluoroacetate Types A and B and SCY-078 HCl Type I in SGF from Example 58. 
           [0105]      FIG. 101  is an XRPD overlay of SCY-078 Trifluoroacetate Type A in SGF from Example 58. 
           [0106]      FIG. 102  is an XRPD overlay of SCY-078 Trifluoroacetate Type B in SGF from Example 58. 
           [0107]      FIG. 103  is an XRPD overlay of SCY-078 HCl Type I in SGF from Example 58. 
           [0108]      FIG. 104  shows the kinetic solubility curves of SCY-078 Trifluoroacetate Types A and B and SCY-078 HCl Type I from Example 59. 
           [0109]      FIG. 105  is an XRPD overlay of SCY-078 Trifluoroacetate Type A from Example 59. 
           [0110]      FIG. 106  is an XRPD overlay of SCY-078 Trifluoroacetate Type B from Example 59. 
           [0111]      FIG. 107  is an XRPD overlay of SCY-078 HCl Type I from Example 59. 
           [0112]      FIG. 108  shows the kinetic solubility curves of SCY-078 Trifluoroacetate Types A and B and SCY-078 HCl Type I from Example 60. 
           [0113]      FIG. 109  is an XRPD overlay of SCY-078 Trifluoroacetate Type A from Example 60. 
           [0114]      FIG. 110  is an XRPD overlay of SCY-078 Trifluoroacetate Type B from Example 60. 
           [0115]      FIG. 111  is an XRPD overlay of SCY-078 HCl Type I from Example 60. 
           [0116]      FIG. 112  shows the kinetic solubility curves of SCY-078 Trifluoroacetate Types A and B and SCY-078 HCl Type I from Example 61. 
           [0117]      FIG. 113  is an XRPD overlay of SCY-078 Trifluoroacetate Type A from Example 61. 
           [0118]      FIG. 114  is an XRPD overlay of SCY-078 Trifluoroacetate Type B from Example 61. 
           [0119]      FIG. 115  is an XRPD overlay of SCY-078 HCl Type I from Example 61. 
           [0120]      FIG. 116  shows the kinetic solubility curves of SCY-078 Trifluoroacetate Types A and B and SCY-078 HCl Type I from Example 62. 
           [0121]      FIG. 117  is an XRPD overlay of SCY-078 Trifluoroacetate Type A from Example 62. 
           [0122]      FIG. 118  is an XRPD overlay of SCY-078 Trifluoroacetate Type B from Example 62. 
           [0123]      FIG. 119  is an XRPD overlay of SCY-078 HCl Type I from Example 62. 
           [0124]      FIG. 120  is an XRPD overlay of SCY-078 Trifluoroacetate Type A under 25° C./60% RH from Example 63. 
           [0125]      FIG. 121  is an XRPD overlay of SCY-078 Trifluoroacetate Type A under 40° C./75% RH from Example 63. 
           [0126]      FIG. 122  is an XRPD overlay of SCY-078 Trifluoroacetate Type A under 60° C. from Example 63. 
           [0127]      FIG. 123  is an XRPD overlay of SCY-078 Trifluoroacetate Type B under 25° C./60% RH from Example 63. 
           [0128]      FIG. 124  is an XRPD overlay of SCY-078 Trifluoroacetate Type B under 40° C./75% RH from Example 63. 
           [0129]      FIG. 125  is an XRPD overlay of SCY-078 Trifluoroacetate Type B under 60° C. from Example 63. 
           [0130]      FIG. 126  is an XRPD overlay of SCY-078 HCl Type I under 25° C./60% RH from Example 63. 
           [0131]      FIG. 127  is an XRPD overlay of SCY-078 HCl Type I under 40° C./75% RH from Example 63. 
           [0132]      FIG. 128  is an XRPD overlay of SCY-078 HCl Type I under 60° C. from Example 63. 
       
    
    
     DETAILED DESCRIPTION 
       [0133]    All numbers used herein, including those in the examples and claims, should be understood as being modified by the term “about” unless otherwise stated, such as with a specified precision. Unless expressly stated to the contrary, all ranges cited herein are inclusive. 
         [0134]    As used herein, the singular forms “a,” “an,” and “the” include plural reference unless the context dictates otherwise. 
         [0135]    The terms “SCY-078” and “compound 1” refer to the compound shown below, and refer to the freebase form unless otherwise indicated. Another name for SCY-078 is (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2-amino-2,3,3-trimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-1445-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-4a-propano-2H -phenanthro[1,2-c]pyran-7-carboxylic acid. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0136]    The term “HCl” refers to hydrochloric acid. The term “Ca” refers to calcium. 
         [0137]    The terms “pharmaceutically acceptable salt” and the like should be understood to include, but not limited to, citrate salts, hippurate salts, fumarate salts, glycolate salts, mesylate salts, and calcium salts. 
         [0138]    As used here, phrases such as “SCY-078 salt,” “SCY-078 salts,” “salt of SCY-078,” “salts of SCY-078,” “pharmaceutically acceptable salt of SCY-078,” and “pharmaceutically acceptable salts thereof” should be understood to be salts in various forms, for example, the polymorphs disclosed herein. In addition, as used here, phrases such as “SCY-078 phosphate,” “SCY-078 citrate,” “SCY-078 hippurate,” “SCY-078 glycolate,” “SCY-078 mesylate,” “SCY-078 fumarate,” and “SCY-078 calcium” should be understood to be salts in various forms, for example, the polymorphs disclosed herein. 
         [0139]    The term “solvent” and the like refer to any appropriate aqueous or organic solvent. Solvents include, but are not limited to, methanol, acetic acid, tetrahydrofuran, 2 methyl-tetrahydrofuran, 1,4-dioxane, n-methyl-2-pyrrolidone, dimethyl sulfoxide, dimethylacetamide, isopropyl alcohol, acetonitrile, acetone, ethyl acetate, water and mixtures thereof. 
         [0140]    The term “pharmaceutically acceptable carrier” and the like refer to an ingredient that is compatible with SCY-078 and is not harmful to a patient&#39;s health. Pharmaceutically acceptable carriers include, but are not limited to, one or more of the following: aqueous vehicles and solvents, such as water, saline solutions, and alcohols; buffers; surface active agents; dispersing agents; inert diluents; preservatives; suspending agents; emulsifying agents; demulcents; thickening agents; emulsifying agents; antioxidants; and stabilizing agents. Other additional ingredients that may be included in the pharmaceutical compositions of the disclosure are generally known in the art and may be described, for example, in  Remington&#39;s Pharmaceutical Sciences , Mack Publishing Co., Easton, Pa., which is incorporated by reference herein. 
         [0141]    The term “injection” and the like refer to the insertion of a composition into the body by syringe, hollow needle, or the like. The term “injection” and the like include, but are not limited to, intravenous injections, including those entailing administering using an IV bag containing a diluent. 
         [0142]    The term “effective amount” refers to an amount of the active ingredient that, when administered to a subject, alleviates at least some of the symptoms or stops the progression of the identified disease or condition. The terms “disease” or “condition” include, but are not limited to, infections such as fungal infections. Exemplary dosage amounts can be found, for example, in U.S. Pat. No. 8,188,085, the relevant portions of which are incorporated herein by reference. 
         [0143]    The term “Å” refers to angstroms. Terms such as “2θ” or “2 Th.” refer to degrees 2 theta. 
         [0144]    The XRPD peaks recited herein should be understood to reflect a precision of ±0.2 for the 2 theta peaks, and the equivalent precision for d-spacings as per Bragg&#39;s law. The present disclosure also fully incorporates section 941 of the United States Pharmacopeia. The National Formulary from 2014 (USP 37/NF 32, volume 1) relating to characterization of crystalline and partially crystalline solids by X-ray Powder Diffraction. 
         [0145]    The present disclosure relates to, among other things, pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, glycolate, mesylate, fumarate, and calcium. In one embodiment, the salt is selected from citrate, hippurate, mesylate, and fumarate. In a further embodiment, the SCY-078 salt is selected from SCY-078 hippurate Type A, SCY-078 hippurate Type B, and SCY-078 hippurate Type C. In another embodiment, the SCY-078 salt is selected from SCY-078 fumarate Type A and SCY-078 fumarate Type B. In yet another embodiment, the salt is a SCY-078 citrate salt. In yet a further embodiment, the salt is SCY-078 citrate Type A. 
         [0146]    The present disclosure further relates to pharmaceutically acceptable salts of SCY-078 that have a chemical purity of at least 90%. In another embodiment, pharmaceutically acceptable salts of SCY-078 have a chemical purity of at least 95%. In a further embodiment, pharmaceutically acceptable salts of SCY-078 have a chemical purity of at least 98%. In yet another embodiment, pharmaceutically acceptable salts of SCY-078 have a chemical purity of at least 99%. In still another embodiment, the present disclosure relates to pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the salt has a chemical purity of at least 90%, at least 95%, at least 98%, or at least 99%. 
         [0147]    The present disclosure additionally relates to pharmaceutically acceptable salts of SCY-078 that have a kinetic solubility of at least 2 mg/mL at 4 hours in dextrose buffer at pH 5.5. In one embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of at least 4 mg/mL at 4 hours in dextrose buffer at pH 5.5. In another embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of from 2 mg/mL to 5 mg/mL at 4 hours in dextrose buffer at pH 5.5. In yet another embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of from 4 mg/mL to 5 mg/mL at 4 hours in dextrose buffer at pH 5.5. In still another embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility greater than SCY-078 (as a freebase) at 4 hours in dextrose buffer at pH 5.5. 
         [0148]    The present disclosure additionally relates to pharmaceutically acceptable salts of SCY-078 that have a kinetic solubility of at least 2 mg/mL at 24 hours in dextrose buffer at pH 5.5. In one embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of at least 4 mg/mL at 24 hours in dextrose buffer at pH 5.5. In another embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of at least 8 mg/mL at 24 hours in dextrose buffer at pH 5.5. In a further embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of from 2 mg/mL to 9 mg/mL at 24 hours in dextrose buffer at pH 5.5. In yet another embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of from 4 mg/mL to 9 mg/mL at 24 hours in dextrose buffer at pH 5.5. In still another embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of from 8 mg/mL to 9 mg/mL at 24 hours in dextrose buffer at pH 5.5. 
         [0149]    The present disclosure additionally relates to pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the salt has a kinetic solubility of from 2 mg/mL to 5 mg/mL at 4 hours in dextrose buffer at pH 5.5. In one embodiment, the disclosure relates to pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the salt has a kinetic solubility of from 4 mg/mL to 5 mg/mL at 4 hours in dextrose buffer at pH 5.5. 
         [0150]    In yet another embodiment, the disclosure relates to pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the salt has a kinetic solubility of from 2 mg/mL to 9 mg/mL at 24 hours in dextrose buffer at pH 5.5. In still another embodiment, the disclosure also relates to pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the salt has a kinetic solubility of from 4 mg/mL to 9 mg/mL at 24 hours in dextrose buffer at pH 5.5. In another embodiment, the disclosure relates to pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the salt has a kinetic solubility of from 8 mg/mL to 9 mg/mL at 24 hours in dextrose buffer at pH 5.5. 
         [0151]    The present disclosure additionally relates to pharmaceutically acceptable salts of SCY-078 that have a kinetic solubility of at least 2 mg/mL at 4 hours in phosphate buffer at pH 6.0. In one embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of at least 4 mg/mL at 4 hours in phosphate buffer at pH 6.0. In another embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of from 2 mg/mL to 5 mg/mL at 4 hours in phosphate buffer at pH 6.0. In yet another embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of from 4 mg/mL to 5 mg/mL at 4 hours in phosphate buffer at pH 6.0. 
         [0152]    In still another embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of at least 4.5 mg/mL at 24 hours in phosphate buffer at pH 6.0. In one embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of at least 7 mg/mL at 24 hours in phosphate buffer at pH 6.0. In another embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of from 4.5 mg/mL to 8 mg/mL at 24 hours in phosphate buffer at pH 6.0. In yet another embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of from 7 mg/mL to 8 mg/mL at 24 hours in phosphate buffer at pH 6.0. 
         [0153]    The present disclosure additionally relates to pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the salt has a kinetic solubility of from 1 mg/mL to 5 mg/mL at 4 hours in phosphate buffer at pH 6.0. In one embodiment, the disclosure relates to pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the salt has a kinetic solubility of from 4 mg/mL to 5 mg/mL at 4 hours in phosphate buffer at pH 6.0. 
         [0154]    In another embodiment, the disclosure relates to pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the salt has a kinetic solubility of from 4 mg/mL to 8 mg/mL at 24 hours in phosphate buffer at pH 6.0. In yet another embodiment, the disclosure relates to pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the salt has a kinetic solubility of from 7 mg/mL to 8 mg/mL at 24 hours in phosphate buffer at pH 6.0. 
         [0155]    The present disclosure additionally relates to pharmaceutically acceptable salts of SCY-078 that have a kinetic solubility of at least 16 mg/mL at 1 hour in SGF media. In one embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of at least 17 mg/mL at 1 hour in SGF media. In another embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of at least 18 mg/mL at 1 hour in SGF media. In yet another embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of at least 20 mg/mL at 1 hour in SGF media. 
         [0156]    The present disclosure additionally relates to pharmaceutically acceptable salts of SCY-078 that have a kinetic solubility of from 17 mg/mL to 21 mg/mL at 1 hour in SGF media. In another embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of from 18 mg/mL to 21 mg/mL at 1 hour in SGF media. In yet another embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of from 20 mg/mL to 21 mg/mL at 1 hour in SGF media. 
         [0157]    The present disclosure additionally relates to pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the salt has a kinetic solubility of from 12 mg/mL to 21 mg/mL at 1 hour in SGF media. In one embodiment, the disclosure relates to pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the salt has a kinetic solubility of from 13 mg/mL to 21 mg/mL at 1 hour in SGF media. In another embodiment, the disclosure relates to pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the salt has a kinetic solubility of from 18 mg/mL to 21 mg/mL at 1 hour in SGF media. In yet another embodiment, the disclosure relates to pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the salt has a kinetic solubility of from 20 mg/mL to 21 mg/mL at 1 hour in SGF media. 
         [0158]    The present disclosure additionally relates to pharmaceutically acceptable salts of SCY-078 that have a kinetic solubility of at least 17 mg/mL at 24 hours in FaSSIF media. In one embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of at least 22 mg/mL at 24 hours in FaSSIF media. In another embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of from 17 mg/mL to 22 mg/mL at 24 hours in FaSSIF media. In yet another embodiment, the pharmaceutically acceptable salts of SCY-078 have a kinetic solubility of from 21 mg/mL to 22 mg/mL at 24 hours in FaSSIF media. 
         [0159]    The present disclosure additionally relates to pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the salt has a kinetic solubility of from 17 mg/mL to 22 mg/mL at 24 hours in FaSSIF media. In one embodiment, the disclosure relates to pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the salt has a kinetic solubility of from 21 mg/mL to 22 mg/mL at 24 hours in FaSSIF media. 
         [0160]    The present disclosure additionally relates to pharmaceutically acceptable salts of SCY-078 having any of the disclosed kinetic solubilities and having a water sorption of not greater than 7% at 25° C. and 80% relative humidity as determined by DVS. In one embodiment, the pharmaceutically acceptable salts of SCY-078 have a water sorption of from 2% to 7% at 25° C. and 80% relative humidity as determined by DVS. In another embodiment, the pharmaceutically acceptable salts of SCY-078 have a water sorption of from 3% to 7% at 25° C. and 80% relative humidity as determined by DVS. In yet another embodiment, the pharmaceutically acceptable salts of SCY-078 have a water sorption of from 6% to 7% at 25° C. and 80% relative humidity as determined by DVS. 
         [0161]    The present disclosure additionally relates to pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the salt has a water sorption of from 2% to 7% at 25° C. and 80% relative humidity as determined by DVS. In one embodiment, the disclosure relates to pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the salt has a water sorption of from 3% to 7% at 25° C. and 80% relative humidity as determined by DVS. In one embodiment, the disclosure relates to pharmaceutically acceptable salts of SCY-078, wherein the salt is selected from citrate, hippurate, mesylate, and fumarate, and wherein the salt has a water sorption of from 6% to 7% at 25° C. and 80% relative humidity as determined by DVS. 
         [0162]    The present disclosure further relates to hippurate salts of SCY-078, such as SCY-078 hippurate Type A, SCY-078 hippurate Type B, and SCY-078 hippurate Type C. In one embodiment, the SCY-078 hippurate Type A has an XRPD pattern comprising peaks at one or more of the following locations: 
         [0000]                                                          TABLE A                       FWHM               Pos. [°2Th.]   Height [cts]   Left [°2Th.]   d-spacing [Å]   Rel. Int. [%]                                6.276484   353.472400   0.102336   14.08226   12.90       7.023845   139.782300   0.307008   12.58545   5.10       7.900725   1475.766000   0.127920   11.19048   53.85       8.241444   302.522300   0.102336   10.72859   11.04       9.723080   945.921800   0.089544   9.09681   34.52       11.283030   414.659200   0.102336   7.84238   15.13       11.492390   300.886600   0.076752   7.69998   10.98       12.610210   2740.558000   0.089544   7.01982   100.00       12.910370   765.158500   0.063960   6.85728   27.92       13.561180   243.791900   0.153504   6.52963   8.90       14.149930   371.812900   0.102336   6.25924   13.57       15.182550   1607.490000   0.102336   5.83577   58.66       15.806230   690.955800   0.179088   5.60688   25.21       16.673670   482.323700   0.179088   5.31709   17.60       17.068480   365.833300   0.127920   5.19498   13.35       18.200570   206.779900   0.153504   4.87432   7.55       18.933070   395.979900   0.153504   4.68736   14.45       19.293830   277.037400   0.102336   4.60052   10.11       19.924160   251.428800   0.204672   4.45638   9.17       20.583290   158.800000   0.204672   4.31514   5.79       21.951230   220.614300   0.153504   4.04923   8.05       23.477450   72.922780   0.409344   3.78934   2.66       24.511240   99.987140   0.255840   3.63181   3.65       24.954920   117.325600   0.153504   3.56824   4.28       25.993010   108.058000   0.204672   3.42804   3.94       28.257860   72.489400   0.409344   3.15822   2.65       31.063590   95.037750   0.179088   2.87907   3.47       31.653730   62.090590   0.307008   2.82673   2.27                    
For example, the SCY-078 hippurate Type A has an XRPD pattern comprising one or more peaks at d-spacings of 11.20, 7.02, and 5.84 A. In another example, the SCY-078 hippurate Type A has an XRPD pattern comprising one or more peaks at degrees 2 theta of 7.90, 12.6, and 15.18.
 
         [0163]    In one embodiment, the SCY-078 hippurate Type B has an XRPD pattern comprising peaks at one or more of the following locations: 
         [0000]                                                          TABLE B                       FWHM               Pos. [°2Th.]   Height [cts]   Left [°2Th.]   d-spacing [Å]   Rel. Int. [%]                                5.887601   118.925500   0.102336   15.01151   9.56       6.889384   462.675400   0.063960   12.83077   37.19       7.277837   251.176000   0.051168   12.14678   20.19       8.767134   927.066800   0.076752   10.08643   74.52       9.945603   1143.995000   0.102336   8.89377   91.96       10.843500   681.448200   0.102336   8.15925   54.78       11.822440   140.502200   0.127920   7.48575   11.29       12.417990   1244.014000   0.089544   7.12805   100.00       13.714490   435.466500   0.089544   6.45698   35.00       14.608760   1242.496000   0.102336   6.06367   99.88       15.050420   474.015800   0.102336   5.88670   38.10       16.071560   476.890000   0.127920   5.51491   38.33       16.476910   708.831400   0.102336   5.38014   56.98       16.857150   185.689200   0.102336   5.25963   14.93       17.289970   422.781900   0.127920   5.12893   33.99       17.612420   996.474200   0.089544   5.03575   80.10       18.405510   186.288500   0.153504   4.82051   14.97       19.118560   303.851800   0.127920   4.64230   24.43       19.623870   158.474700   0.153504   4.52389   12.74       20.218430   314.377200   0.153504   4.39218   25.27       21.746130   200.050600   0.153504   4.08695   16.08       23.075880   129.668200   0.204672   3.85436   10.42       23.853540   106.856400   0.204672   3.73044   8.59       25.372290   96.670350   0.204672   3.51048   7.77       29.216870   66.396300   0.230256   3.05670   5.34       32.714200   31.053470   0.614016   2.73748   2.50                    
For example, the SCY-078 hippurate Type B has an XRPD pattern comprising one or more peaks at d-spacings of 8.90, 7.13, and 6.10 A. In another example, the SCY-078 hippurate Type B has an XRPD pattern comprising one or more peaks at degrees 2 theta of 9.95, 12.42, and 14.61.
 
         [0164]    In one embodiment, the SCY-078 hippurate Type C has an XRPD pattern comprising peaks at one or more of the following locations: 
         [0000]                                                          TABLE C               Pos.       FWHM               [°2Th.]   Height [cts]   Left [°2Th.]   d-spacing [Å]   Rel. Int. [%]                                3.027072   11818.150000   0.051168   29.18766   100.00       5.916137   351.270000   0.102336   14.93916   2.97       6.916698   947.910600   0.102336   12.78016   8.02       7.251646   624.847700   0.076752   12.19059   5.29       8.761702   1828.733000   0.076752   10.09268   15.47       9.962105   2404.236000   0.102336   8.87907   20.34       10.897800   1593.408000   0.102336   8.11872   13.48       11.868550   552.254500   0.102336   7.45677   4.67       12.432300   2880.441000   0.127920   7.11988   24.37       12.857840   525.634600   0.076752   6.88518   4.45       13.091360   511.764400   0.115128   6.76288   4.33       13.709840   1112.219000   0.102336   6.45916   9.41       14.555290   3086.294000   0.153504   6.08582   26.11       14.984610   1215.693000   0.102336   5.91241   10.29       15.341160   506.870800   0.153504   5.77579   4.29       16.136210   1315.742000   0.089544   5.49296   11.13       16.453540   1710.358000   0.153504   5.38772   14.47       16.897030   606.324900   0.102336   5.24730   5.13       17.280760   1171.798000   0.127920   5.13164   9.92       17.591700   2258.867000   0.102336   5.04163   19.11       18.190770   538.754800   0.127920   4.87692   4.56       18.425670   516.831300   0.179088   4.81528   4.37       19.151570   950.084500   0.102336   4.63437   8.04       19.602330   487.956400   0.127920   4.52881   4.13       20.234760   861.917600   0.153504   4.38867   7.29       20.860030   424.598600   0.153504   4.25851   3.59       21.725360   459.496200   0.307008   4.09081   3.89       22.532320   498.240700   0.102336   3.94610   4.22       23.078810   380.947900   0.127920   3.85388   3.22       23.551950   208.488500   0.409344   3.77752   1.76       23.874020   377.598600   0.102336   3.72728   3.20       25.381750   351.553600   0.102336   3.50919   2.97       25.844490   207.070300   0.204672   3.44740   1.75       27.188450   192.463400   0.153504   3.27997   1.63       27.681830   144.369000   0.307008   3.22262   1.22       29.319670   172.870900   0.511680   3.04622   1.46       30.833510   86.432220   0.307008   2.90002   0.73       34.979000   90.330020   0.204672   2.56525   0.76       35.588330   69.479680   0.307008   2.52271   0.59       37.270360   55.666410   0.307008   2.41264   0.47                    
For example, the SCY-078 hippurate Type C has an XRPD pattern comprising one or more peaks at d-spacings of 29.19, 8.88, 7.12, and 6.09 Å. In another example, the SCY-078 hippurate Type C has an XRPD pattern comprising one or more peaks at degrees 2 theta of 3.03, 9.96, 12.43, and 14.56.
 
         [0165]    The present disclosure further relates to fumarate salts of SCY-078, such as SCY-078 fumarate Type A and SCY-078 fumarate Type B. In one embodiment, the SCY-078 fumarate Type A has an XRPD pattern comprising peaks at one or more of the following locations: 
         [0000]                                                          TABLE D                       FWHM               Pos. [°2Th.]   Height [cts]   Left [°2Th.]   d-spacing [Å]   Rel. Int. [%]                                7.747007   167.350400   0.153504   11.41218   2.00       8.493147   8373.572000   0.102336   10.41119   100.00       9.346397   181.715800   0.204672   9.46257   2.17       9.931064   167.355100   0.153504   8.90676   2.00       10.442940   371.960600   0.089544   8.47130   4.44       10.706620   463.482500   0.076752   8.26326   5.54       11.231160   490.618200   0.153504   7.87848   5.86       13.030860   311.426800   0.102336   6.79415   3.72       13.700070   569.254300   0.102336   6.46374   6.80       14.895760   234.024600   0.153504   5.94748   2.79       15.204970   269.752200   0.153504   5.82722   3.22       16.350790   434.953000   0.127920   5.42135   5.19       16.976580   3015.489000   0.115128   5.22289   36.01       17.726110   1152.135000   0.230256   5.00370   13.76       18.205910   303.920500   0.102336   4.87290   3.63       18.863510   267.939100   0.153504   4.70449   3.20       20.164360   63.804870   0.409344   4.40383   0.76       20.898390   184.877000   0.102336   4.25078   2.21       21.419940   168.417300   0.102336   4.14844   2.01       22.228150   318.867400   0.127920   3.99940   3.81       23.936960   77.330220   0.307008   3.71763   0.92       25.533030   318.681700   0.089544   3.48874   3.81       26.114530   59.303240   0.204672   3.41236   0.71       26.883130   111.136200   0.204672   3.31652   1.33       30.876670   38.684340   0.614016   2.89607   0.46                    
For example, the SCY-078 fumarate Type A has an XRPD pattern comprising one or more peaks at d-spacings of 10.41, 5.22, and 5.00 A. In another example, the SCY-078 fumarate Type A has an XRPD pattern comprising one or more peaks at degrees 2 theta of 8.49, 16.98, and 17.73.
 
         [0166]    In one embodiment, the SCY-078 fumarate Type B has an XRPD pattern comprising peaks at one or more of the following locations: 
         [0000]                                                          TABLE E                       FWHM               Pos. [°2Th.]   Height [cts]   Left [°2Th.]   d-spacing [Å]   Rel. Int. [%]                                5.449312   94.567020   0.307008   16.21786   19.92       6.318422   110.456500   0.409344   13.98888   23.26       9.799620   153.670200   0.614016   9.02593   32.36       10.577440   403.264100   0.255840   8.36388   84.93       10.995710   322.682700   0.089544   8.04665   67.96       11.970210   133.555200   0.307008   7.39367   28.13       13.136230   472.855300   0.102336   6.73989   99.58       13.551710   408.076200   0.102336   6.53417   85.94       14.201760   320.510900   0.204672   6.23651   67.50       15.712210   472.732700   0.076752   5.64022   99.56       16.216750   474.828900   0.076752   5.46586   100.00       16.849640   211.687300   0.204672   5.26195   44.58       20.391740   103.586500   0.358176   4.35524   21.82       21.343910   97.997770   0.409344   4.16305   20.64       28.564840   34.739620   0.614016   3.12498   7.32                    
For example, the SCY-078 fumarate Type B has an XRPD pattern comprising one or more peaks at d-spacings of 8.36, 6.74, 6.53, 5.64, and 5.47 Å. In another example, the SCY-078 fumarate Type B has an XRPD pattern comprising one or more peaks at degrees 2 theta of 10.58, 13.14, 13.55, 15.71, and 16.22.
 
         [0167]    The present disclosure further relates to glycolate salts of SCY-078. In one embodiment, the SCY-078 glycolate has an XRPD pattern comprising peaks at one or more of the following locations: 
         [0000]                                                          TABLE F                       FWHM               Pos. [°2Th.]   Height [cts]   Left [°2Th.]   d-spacing [Å]   Rel. Int. [%]                                7.879599   291.814000   0.127920   11.22044   54.74       8.983378   233.086200   0.204672   9.84412   43.72       9.855934   117.677600   0.153504   8.97448   22.07       11.483230   269.580500   0.204672   7.70610   50.56       12.311460   163.106800   0.358176   7.18949   30.59       14.259570   285.813400   0.179088   6.21136   53.61       14.651000   437.366100   0.102336   6.04628   82.04       15.433320   533.138100   0.102336   5.74151   100.00       16.892280   103.441500   0.614016   5.24877   19.40       18.826490   177.863500   0.204672   4.71365   33.36       20.401140   101.236100   0.307008   4.35325   18.99       21.743970   54.436950   0.614016   4.08735   10.21       24.981860   29.298130   0.614016   3.56445   5.50                    
For example, the SCY-078 glycolate has an XRPD pattern comprising one or more peaks at d-spacings of 11.22, 6.21, 6.05, and 5.74 A. In another example, the SCY-078 glycolate has an XRPD pattern comprising one or more peaks at degrees 2 theta of 7.88, 14.26, 14.65, and 15.43.
 
         [0168]    The present disclosure further relates to mesylate salts of SCY-078. In one embodiment, the SCY-078 mesylate has an XRPD pattern comprising peaks at one or more of the following locations: 
         [0000]                                                          TABLE G                       FWHM               Pos. [°2Th.]   Height [cts]   Left [°2Th.]   d-spacing [Å]   Rel. Int. [%]                                5.321569   44.016770   0.307008   16.60688   3.75       6.654286   233.467600   0.076752   13.28355   19.89       8.041747   243.835400   0.204672   10.99455   20.77       9.224843   236.712900   0.153504   9.58698   20.16       10.179890   547.128100   0.089544   8.68960   46.60       10.532080   592.551800   0.089544   8.39980   50.47       11.692820   225.932500   0.409344   7.56843   19.24       12.670270   361.926000   0.102336   6.98668   30.83       14.316750   537.652200   0.102336   6.18668   45.80       14.751260   1174.011000   0.102336   6.00541   100.00       15.645660   347.928600   0.204672   5.66406   29.64       16.537910   485.586600   0.179088   5.36043   41.36       17.477180   328.731900   0.127920   5.07441   28.00       18.838670   252.134300   0.307008   4.71063   21.48       19.613670   351.448500   0.153504   4.52622   29.94       21.008230   254.102200   0.204672   4.22880   21.64       22.068870   130.646600   0.307008   4.02791   11.13       23.475460   151.601600   0.204672   3.78965   12.91       25.592960   130.952000   0.153504   3.48071   11.15                    
For example, the SCY-078 mesylate has an XRPD pattern comprising one or more peaks at d-spacings of 10.99, 6.99, and 6.01 Å. In another example, the SCY-078 mesylate has an XRPD pattern comprising one or more peaks at degrees 2 theta of 8.04, 12.67, and 14.75.
 
         [0169]    The present disclosure further relates to calcium salts of SCY-078. In one embodiment, the SCY-078 Calcium has an XRPD pattern comprising peaks at one or more of the following locations: 
         [0000]                                                          TABLE H                       FWHM               Pos. [°2Th.]   Height [cts]   Left [°2Th.]   d-spacing [Å]   Rel. Int. [%]                                5.330948   1222.647000   0.063960   16.57768   100.00       8.684942   82.143680   0.307008   10.18170   6.72       9.624508   215.229600   0.127920   9.18975   17.60       10.625810   286.722000   0.153504   8.32591   23.45       13.358050   110.336200   0.307008   6.62846   9.02       14.092620   101.325400   0.307008   6.28456   8.29       15.952080   1188.492000   0.153504   5.55594   97.21       16.282720   334.685300   0.153504   5.44386   27.37       17.853110   104.842700   0.153504   4.96839   8.58       19.638160   74.407610   0.307008   4.52063   6.09       29.434800   171.668200   0.204672   3.03457   14.04       30.178030   59.353870   0.153504   2.96150   4.85       31.428330   37.765730   0.307008   2.84648   3.09                    
For example, the SCY-078 calcium has an XRPD pattern comprising one or more peaks at d-spacings of 16.58, 5.56, and 5.44 A. In another example, the SCY-078 calcium has an XRPD pattern comprising one or more peaks at degrees 2 theta of 5.33, 15.95, and 16.28.
 
         [0170]    The present disclosure further relates to citrate salts of SCY-078, such as SCY-078 citrate Type A, Type B, Type E, Type F, Type M, Type N, Type 0, Type Q, Type R, and Type S. In one embodiment, the citrate salt of SCY-078 comprises at least one of Type A, Type B, Type E, Type F, Type M, Type N, Type 0, Type Q, Type R, and Type S. 
         [0171]    The present disclosure further relates to a citrate salt of SCY-078 comprising Type A. In one embodiment, the citrate salt of SCY-078 consists essentially of Type A. In another embodiment, the citrate salt of SCY-078 comprises at least 98% Type A. In a further embodiment, the citrate salt of SCY-078 comprises at least 99% Type A. 
         [0172]    In one embodiment, the SCY-078 citrate Type A is stable for at least 1 week when stored at 60° C. In another embodiment, the SCY-078 citrate Type A is stable for at least 1 week when stored at 25° C. and 60% relative humidity. In a further embodiment, the SCY-078 citrate Type A is stable for at least 1 week when stored at 40° C. and 75% relative humidity. 
         [0173]    In a further embodiment, the SCY-078 citrate Type A has an equilibrium solubility of 38 mg/mL in non-buffered water at ambient temperature. In yet another embodiment, the SCY-078 citrate Type A has an approximate solubility of from 40 mg/mL to 42 mg/mL at room temperature in at least one solvent selected from methanol, isopropyl alcohol, acetic acid, tetrahydrofuran, 2 methyl-tetrahydrofuran, 1,4-dioxane, n-methyl-2-pyrrolidone, dimethyl sulfoxide, and dimethylacetamide. In still another embodiment, the SCY-078 citrate Type A has a water sorption of 6% at 25° C. and 80% relative humidity as determined by DVS. 
         [0174]    In one embodiment, the SCY-078 citrate Type A has a kinetic solubility of 4 mg/mL at 4 hours in dextrose buffer at pH 5.5. In another embodiment, the SCY-078 citrate Type A has a kinetic solubility of 8 mg/mL at 24 hours in dextrose buffer at pH 5.5. In a further embodiment, the SCY-078 citrate Type A has a kinetic solubility of 5 mg/mL at 4 hours in phosphate buffer at pH 6.0. In still another embodiment, the SCY-078 citrate Type A has a kinetic solubility of 8 mg/mL at 24 hours in phosphate buffer at pH 6.0. 
         [0175]    In one embodiment, the SCY-078 citrate Type A has a kinetic solubility of 21 mg/mL at 1 hour in SGF media. In another embodiment, the SCY-078 citrate Type A has a kinetic solubility of 4 mg/mL at 24 hours in FeSSIF media. In yet another embodiment, the SCY-078 citrate Type A has a kinetic solubility of 10 mg/mL at 1 hour in FaSSIF media. In a further embodiment, the SCY-078 citrate Type A has a kinetic solubility of 21 mg/mL at 4 hours in FaSSIF media. 
         [0176]    The present disclosure further relates to a citrate salt of SCY-078 comprising SCY-078 citrate Type A. In one embodiment, the SCY-078 citrate Type A has an XRPD pattern comprising peaks at one or more of the following locations: 
         [0000]                                                          TABLE I               Pos.       FWHM               [°2Th.]   Height [cts]   Left [°2Th.]   d-spacing [Å]   Rel. Int. [%]                                5.400273   434.322700   0.102336   16.36502   3.34       7.453872   13000.820000   0.191880   11.86031   100.00       9.201639   691.948300   0.204672   9.61110   5.32       10.831710   404.555000   0.153504   8.16811   3.11       11.485080   936.115200   0.179088   7.70486   7.20       12.491050   954.805500   0.179088   7.08652   7.34       13.191360   1776.320000   0.204672   6.71184   13.66       15.020350   1342.537000   0.204672   5.89842   10.33       15.664830   532.278900   0.179088   5.65717   4.09       15.955570   613.057500   0.127920   5.55474   4.72       16.751250   951.729000   0.153504   5.29264   7.32       17.978130   170.323300   0.204672   4.93412   1.31       19.591770   472.971000   0.204672   4.53123   3.64       22.213400   146.982900   0.204672   4.00202   1.13       23.845740   34.469910   0.614016   3.73164   0.27       25.160050   117.741100   0.307008   3.53961   0.91       28.761350   129.234400   0.255840   3.10407   0.99       30.356250   332.945100   0.230256   2.94452   2.56       32.317870   87.151140   0.307008   2.77014   0.67       34.725480   74.664570   0.511680   2.58339   0.57                    
For example, the SCY-078 citrate Type A has an XRPD pattern comprising one or more peaks at d-spacings of 11.86, 7.70, 7.09, 6.71, 5.90, and 5.29 Å. In another example, the SCY-078 citrate Type A has an XRPD pattern comprising one or more peaks at degrees 2 theta of 7.45, 11.49, 12.49, 13.19, 15.02, and 16.75.
 
         [0177]    The present disclosure further relates to a citrate salt of SCY-078 comprising SCY-078 citrate Type B. In one embodiment, the SCY-078 citrate Type B has an XRPD pattern comprising peaks at one or more of the following locations: 
         [0000]                                                          TABLE J                       FWHM               Pos. [°2Th.]   Height [cts]   Left [°2Th.]   d-spacing [Å]   Rel. Int. [%]                                5.561437   214.772000   0.127920   15.89114   18.87       6.920576   1138.274000   0.115128   12.77301   100.00       9.319721   77.009080   0.307008   9.48959   6.77       11.144180   155.075600   0.153504   7.93978   13.62       11.729970   201.281900   0.153504   7.54455   17.68       13.405240   187.402700   0.358176   6.60523   16.46       15.225970   237.746900   0.204672   5.81923   20.89       16.813690   449.144100   0.153504   5.27312   39.46       18.219030   148.764600   0.204672   4.86942   13.07       19.324790   108.017600   0.153504   4.59322   9.49       20.531330   143.254500   0.127920   4.32594   12.59       23.721410   34.728650   0.307008   3.75092   3.05       26.000800   68.151450   0.204672   3.42703   5.99       29.343000   18.852780   0.614016   3.04385   1.66                    
For example, the SCY-078 citrate Type B has an XRPD pattern comprising one or more peaks at d-spacings of 15.89, 12.77, 7.54, 5.82, and 5.27 Å. In another example, the SCY-078 citrate Type B has an XRPD pattern comprising one or more peaks at degrees 2 theta of 5.56, 6.92, 11.73, 15.23, and 16.81.
 
         [0178]    The present disclosure further relates to a citrate salt of SCY-078 comprising SCY-078 citrate Type E. In one embodiment, the SCY-078 citrate Type E has an XRPD pattern comprising peaks at one or more of the following locations: 
         [0000]                                                          TABLE K                       FWHM               Pos. [°2Th.]   Height [cts]   Left [°2Th.]   d-spacing [Å]   Rel. Int. [%]                                5.524293   92.779970   0.307008   15.99790   5.74       7.256628   1616.341000   0.179088   12.18224   100.00       11.438900   216.111400   0.281424   7.73586   13.37       14.135060   246.012400   0.255840   6.26579   15.22       15.755470   336.295500   0.255840   5.62483   20.81       16.331430   208.920100   0.255840   5.42773   12.93       17.088060   99.712520   0.409344   5.18907   6.17       21.127980   46.130650   0.614016   4.20511   2.85       31.562360   23.421260   0.614016   2.83470   1.45                    
For example, the SCY-078 citrate Type E has an XRPD pattern comprising one or more peaks at d-spacings of 12.18, 7.74, 6.27, 5.62, and 5.43 A. In another example, the SCY-078 citrate Type E has an XRPD pattern comprising one or more peaks at degrees 2 theta of 7.26, 11.44, 14.14, 15.76, and 16.33.
 
         [0179]    The present disclosure further relates to a citrate salt of SCY-078 comprising SCY-078 citrate Type F. In one embodiment, the SCY-078 citrate Type F has an XRPD pattern comprising peaks at one or more of the following locations: 
         [0000]                                                          TABLE L                       FWHM               Pos. [°2Th.]   Height [cts]   Left [°2Th.]   d-spacing [Å]   Rel. Int. [%]                                3.633823   273.473300   0.204672   24.31535   100.00       8.094996   83.291080   0.307008   10.92235   30.46       14.004250   57.266020   0.818688   6.32402   20.94       17.742840   88.241520   0.307008   4.99902   32.27                    
For example, the SCY-078 citrate Type F has an XRPD pattern comprising one or more peaks at d-spacings of 24.32 and 5.00 Å. In another example, the SCY-078 citrate Type F has an XRPD pattern comprising one or more peaks at degrees 2 theta of 3.63 and 17.74.
 
         [0180]    The present disclosure further relates to a citrate salt of SCY-078 comprising SCY-078 citrate Type M. In one embodiment, the SCY-078 citrate Type M has an XRPD pattern comprising peaks at one or more of the following locations: 
         [0000]                                                          TABLE M                       FWHM               Pos. [°2Th.]   Height [cts]   Left [°2Th.]   d-spacing [Å]   Rel. Int. [%]                                5.572099   251.586000   0.179088   15.86076   9.89       7.341430   2543.546000   0.332592   12.04171   100.00       9.506812   193.442600   0.307008   9.30326   7.61       11.507120   612.058600   0.281424   7.69016   24.06       12.151790   217.504900   0.255840   7.28359   8.55       14.166310   475.291100   0.179088   6.25204   18.69       15.796090   798.112100   0.255840   5.61046   31.38       16.373100   704.236700   0.179088   5.41401   27.69       17.342680   236.560600   0.511680   5.11346   9.30       18.264100   127.099200   0.307008   4.85751   5.00       20.028560   111.330700   0.307008   4.43338   4.38       21.230190   166.125100   0.255840   4.18509   6.53       22.124240   151.032300   0.358176   4.01795   5.94       23.019390   107.550400   0.307008   3.86369   4.23       25.286220   144.601600   0.511680   3.52223   5.69       27.656070   79.447100   0.358176   3.22556   3.12       28.430390   56.622940   0.409344   3.13945   2.23       29.646340   75.432070   0.614016   3.01339   2.97       32.376530   74.417430   0.307008   2.76525   2.93       36.534050   34.760060   0.614016   2.45955   1.37       38.139080   26.017290   0.614016   2.35966   1.02                    
For example, the SCY-078 citrate Type M has an XRPD pattern comprising one or more peaks at d-spacings of 12.04, 7.69, 6.25, 5.61, and 5.41 A. In another example, the SCY-078 citrate Type M has an XRPD pattern comprising one or more peaks at degrees 2 theta of 7.34, 11.51, 14.17, 15.80, and 16.37.
 
         [0181]    The present disclosure further relates to a citrate salt of SCY-078 comprising SCY-078 citrate Type N. In one embodiment, the SCY-078 citrate Type N has an XRPD pattern comprising peaks at one or more of the following locations: 
         [0000]                                                          TABLE N                       FWHM               Pos. [°2Th.]   Height [cts]   Left [°2Th.]   d-spacing [Å]   Rel. Int. [%]                                5.410849   486.098000   0.076752   16.33306   9.13       7.067553   5326.844000   0.089544   12.50771   100.00       10.838060   670.175200   0.063960   8.16333   12.58       11.383920   1260.568000   0.089544   7.77310   23.66       11.924900   315.766000   0.153504   7.42166   5.93       12.367310   352.822800   0.153504   7.15714   6.62       12.923310   1574.956000   0.089544   6.85044   29.57       14.132120   1282.157000   0.102336   6.26708   24.07       15.162450   1604.350000   0.102336   5.84346   30.12       16.256930   1496.153000   0.089544   5.45244   28.09       16.676790   891.116500   0.115128   5.31610   16.73       16.898590   608.961300   0.102336   5.24682   11.43       17.769210   633.106100   0.127920   4.99166   11.89       18.512560   1119.245000   0.102336   4.79287   21.01       20.764100   264.835400   0.102336   4.27797   4.97       21.599360   277.781400   0.127920   4.11439   5.21       22.726850   204.007000   0.102336   3.91276   3.83       23.066060   336.013100   0.153504   3.85598   6.31       24.489610   243.365100   0.127920   3.63497   4.57       28.491330   175.736200   0.179088   3.13287   3.30       30.668850   84.372280   0.307008   2.91522   1.58       33.097360   34.363080   0.614016   2.70666   0.65       36.308500   40.510880   0.716352   2.47431   0.76                    
For example, the SCY-078 citrate Type N has an XRPD pattern comprising one or more peaks at d-spacings of 12.51, 7.77, 6.85, 6.27, 5.84, 5.45, and 4.79 Å. In another example, the SCY-078 citrate Type N has an XRPD pattern comprising one or more peaks at degrees 2 theta of 7.07, 11.38, 12.92, 14.13, 15.16, 16.26, and 18.51.
 
         [0182]    The present disclosure further relates to a citrate salt of SCY-078 comprising SCY-078 citrate Type O In one embodiment, the SCY-078 citrate Type O has an XRPD pattern comprising peaks at one or more of the following locations: 
         [0000]                                                          TABLE O                       FWHM               Pos. [°2Th.]   Height [cts]   Left [°2Th.]   d-spacing [Å]   Rel. Int. [%]                                3.214240   359.101800   0.409344   27.48844   9.56       5.562890   564.632100   0.102336   15.88699   15.03       7.082335   3757.717000   0.115128   12.48164   100.00       11.908250   1208.103000   0.089544   7.43200   32.15       14.197590   602.552700   0.115128   6.23833   16.04       16.178670   447.137400   0.179088   5.47864   11.90       16.755170   956.290800   0.115128   5.29141   25.45       28.567280   48.759020   0.307008   3.12472   1.30                    
For example, the SCY-078 citrate Type 0 has an XRPD pattern comprising one or more peaks at d-spacings of 12.48, 7.43, and 5.29 A. In another example, the SCY-078 citrate Type O has an XRPD pattern comprising one or more peaks at degrees 2 theta of 7.08, 11.91, and 16.76.
 
         [0183]    The present disclosure further relates to a citrate salt of SCY-078 comprising SCY-078 citrate Type Q. In one embodiment, the SCY-078 citrate Type Q has an XRPD pattern comprising peaks at one or more of the following locations: 
         [0000]                                                          TABLE P                       FWHM Left               Pos. [°2Th.]   Height [cts]   [°2Th.]   d-spacing [Å]   Rel. Int. [%]                                5.686347   449.970600   0.102336   15.54234   13.51       6.300879   3329.599000   0.140712   14.02779   100.00       6.890776   1871.585000   0.076752   12.82818   56.21       8.441730   95.233120   0.153504   10.47449   2.86       9.785571   136.396600   0.153504   9.03885   4.10       11.334590   1386.986000   0.140712   7.80682   41.66       11.733060   826.632000   0.102336   7.54257   24.83       12.939760   265.781600   0.409344   6.84177   7.98       13.691820   190.778000   0.153504   6.46762   5.73       14.156830   332.781500   0.153504   6.25620   9.99       14.496570   455.453300   0.102336   6.11034   13.68       15.135910   594.105600   0.153504   5.85365   17.84       15.903400   540.737100   0.127920   5.57284   16.24       17.010910   1588.263000   0.127920   5.21243   47.70       17.296950   476.914900   0.127920   5.12687   14.32       18.962100   570.585000   0.204672   4.68025   17.14       20.190720   395.466100   0.102336   4.39814   11.88       20.646480   601.591200   0.153504   4.30207   18.07       21.298380   208.197100   0.153504   4.17185   6.25       22.025220   160.183700   0.307008   4.03579   4.81       22.719750   205.611500   0.204672   3.91397   6.18       23.633070   128.288000   0.307008   3.76474   3.85       25.991160   157.744000   0.204672   3.42828   4.74       27.462080   37.389280   0.307008   3.24790   1.12       28.950740   597.140100   0.140712   3.08419   17.93       34.085010   29.835660   0.511680   2.63046   0.90                    
For example, the SCY-078 citrate Type Q has an XRPD pattern comprising one or more peaks at d-spacings of 14.03, 12.83, 7.81, 7.54, and 5.21 Å. In another example, the SCY-078 citrate Type Q has an XRPD pattern comprising one or more peaks at degrees 2 theta of 6.30, 6.89, 11.33, 11.73, and 17.01.
 
         [0184]    The present disclosure further relates to a citrate salt of SCY-078 comprising SCY-078 citrate Type R. In one embodiment, the SCY-078 citrate Type R has an XRPD pattern comprising peaks at one or more of the following locations: 
         [0000]                                                          TABLE Q                       FWHM Left               Pos. [°2Th.]   Height [cts]   [°2Th.]   d-spacing [Å]   Rel. Int. [%]                                6.143884   611.904200   0.153504   14.38589   100.00       11.248800   143.606900   0.255840   7.86616   23.47       14.059410   351.488100   0.204672   6.29933   57.44       14.636960   372.993000   0.204672   6.05205   60.96       16.413500   550.672100   0.102336   5.40078   89.99       17.742000   362.377400   0.614016   4.99926   59.22       19.697290   248.048100   0.307008   4.50719   40.54       22.159300   133.589200   0.409344   4.01167   21.83       30.197650   27.706020   0.614016   2.95963   4.53                    
For example, the SCY-078 citrate Type R has an XRPD pattern comprising one or more peaks at d-spacings of 14.39, 6.05, 5.40, and 5.00 Å. In another example, the SCY-078 citrate Type R has an XRPD pattern comprising one or more peaks at degrees 2 theta of 6.14, 14.64, 16.41, and 17.74.
 
         [0185]    The present disclosure further relates to a citrate salt of SCY-078 comprising SCY-078 citrate Type S. In one embodiment, the SCY-078 citrate Type S has an XRPD pattern comprising peaks at one or more of the following locations: 
         [0000]                                                          TABLE R                       FWHM Left               Pos. [°2Th.]   Height [cts]   [°2Th.]   d-spacing [Å]   Rel. Int. [%]                                5.512446   1020.013000   0.089544   16.03226   16.16       7.296105   6310.710000   0.153504   12.11641   100.00       8.443163   252.219900   0.230256   10.47272   4.00       11.057440   582.228600   0.179088   8.00186   9.23       12.004950   2714.326000   0.166296   7.37235   43.01       14.346070   536.999100   0.204672   6.17410   8.51       16.812800   1626.861000   0.127920   5.27340   25.78       19.482230   106.142000   0.358176   4.55646   1.68       22.188280   88.048920   0.409344   4.00650   1.40       24.046320   53.183810   0.818688   3.70096   0.84                    
For example, the SCY-078 citrate Type S has an XRPD pattern comprising one or more peaks at d-spacings of 16.03, 12.12, 7.37, and 5.27 A. In another example, the SCY-078 citrate Type S has an XRPD pattern comprising one or more peaks at degrees 2 theta of 5.51, 7.30, 12.00, and 16.81.
 
         [0186]    The present disclosure further relates to a method for preparing a pharmaceutically acceptable salt of SCY-078 comprising combining at least components: (i) a free base of SCY-078; (ii) a weak organic acid; and (iii)a liquid carrier. The weak organic acid may be chosen from those known in the art. In one embodiment, the weak organic acid is selected from citric acid, fumaric acid, methanesulfonic acid, and hippuric acid. In another embodiment, the weak organic acid is citric acid. In a further embodiment, the liquid carrier is a solvent or solvent mixture, and at least one of the free base of SCY-078 and the weak organic acid is soluble in the solvent or solvent mixture. In still another embodiment, the liquid carrier comprises at least one of ethanol, isopropyl alcohol, acetonitrile, acetone, ethyl acetate, and tetrahydrofuran/water mixture. In yet another embodiment, the liquid carrier comprises ethanol. In one embodiment, the method further comprises combining (iv) an anti-solvent. In another embodiment, the anti-solvent comprises N-heptane. 
         [0187]    In one embodiment, the method further comprises agitating the combination of at least components (i)-(iii). In a further embodiment, the method further comprises agitating the combination of at least components (i)-(iii) for at least 24 hours. In another embodiment, the method further comprises agitating and heating the combination of at least components (i)-(iii). In a further embodiment, the method further comprises agitating and heating the combination of at least components (i)-(iii) to a temperature of from 40° C. to 60° C. In still another embodiment, the method further comprises agitating and heating the combination of at least components (i)-(iii) to a temperature of from 40° C. to 60° C. for at least 60 minutes. 
         [0188]    In one embodiment, the method further comprises agitating and heating the combination of at least components (i)-(iii) and adding to the combination of at least components (i)-(iii) an anti-solvent after at least 14 hours. In yet another embodiment, the anti-solvent is N-heptane. 
         [0189]    In one embodiment, the method further comprises agitating and heating the combination of at least components (i)-(iii); adding to the combination of at least components (i)-(iii) an anti-solvent after at least 14 hours; and cooling the combination of at least components (i)-(iii). In a further embodiment, the cooling is from 0° C. to 20° C. In another embodiment, the cooling is from 0° C. to 20° C. at a rate of 0.25° C./min. 
         [0190]    The present disclosure further relates to methods for preparing citrate Type A salt of SCY-078. In one embodiment, the method comprises desolvating at least one of Type B, Type N, and Type Q citrate salt of SCY-078. In a further embodiment, the desolvating comprises drying under nitrogen. In yet another embodiment, the desolvating comprises drying under vacuum filtration. 
         [0191]    The present disclosure additionally relates to pharmaceutical compositions comprising a pharmaceutically acceptable salt of SCY-078, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be chosen from, among other things, one or more of the following: water, saline solutions, buffers, and alcohols. In one embodiment, the pharmaceutically acceptable salt in the pharmaceutical composition is selected from citrate, hippurate, mesylate, and fumarate. In yet another embodiment, the pharmaceutically acceptable salt is a citrate salt. In still another embodiment, the pharmaceutically acceptable salt of SCY-078 is SCY-078 citrate Type A. 
         [0192]    According to certain embodiments, the pharmaceutically acceptable salt of SCY-078 may consist essentially of a specified crystal form. According to certain embodiments, the pharmaceutically acceptable salt of SCY-078 may comprise a specified crystal in combination with one or more other crystal forms. The pharmaceutically acceptable salt of SCY-078 may, for example, contain a specified crystal form together with less than 10% of another crystal form(s), such as less than 5%, less than 2%, or less than 1%. 
         [0193]    In one embodiment, the pharmaceutical composition is made by dissolving the pharmaceutically acceptable salt of SCY-078 in a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be chosen from, among other things, one or more of the following: water, saline solutions, buffers, and alcohols. In another embodiment, the pharmaceutical composition is suitable for injection into a human. In a further embodiment, the pharmaceutical composition is suitable for intravenous injection into a human. In another embodiment, the pharmaceutically acceptable salt is a citrate salt. In still another embodiment, the pharmaceutically acceptable salt of SCY-078 is SCY-078 citrate Type A. 
         [0194]    The present disclosure further relates to methods of preparing a pharmaceutical composition comprising pharmaceutically acceptable salts of SCY-078, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be chosen from, among other things, one or more of the following: water, saline solutions, buffers, and alcohols. In one embodiment, the pharmaceutically acceptable salt of SCY-078 is dissolved in the pharmaceutically acceptable carrier within 1 hour. In another embodiment, the pharmaceutically acceptable salt of SCY-078 is dissolved in the pharmaceutically acceptable carrier within 24 hours. In a further embodiment, the pharmaceutically acceptable salt is a citrate salt. In still another embodiment, the pharmaceutically acceptable salt of SCY-078 is SCY-078 citrate Type A. 
         [0195]    The present disclosure additionally relates to methods of treating a fungal infection in a patient in need thereof. For example, the methods include treating  Invasive Candidiasis  and  Invasive Aspergillosis . In one embodiment, the method comprises administering to the patient in need thereof a pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable salt of SCY-078. In another embodiment, the pharmaceutically acceptable salt is a citrate salt. In a further embodiment, the pharmaceutically acceptable salt of SCY-078 is SCY-078 citrate Type A. In another embodiment, the pharmaceutical composition is suitable for injection into a human. In yet another embodiment, the pharmaceutical composition is suitable for intravenous injection into a human. 
       EXAMPLES 
       [0196]    Methods and Materials 
         [0197]    The following describes the materials and methods used for all examples unless otherwise stated. 
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                   
                 Abbreviation/ 
                   
               
               
                 Type 
                 Acronym 
                 Full Name/Description 
               
               
                   
               
             
             
               
                 Solvent 
                 ACN 
                 Acetonitrile 
               
               
                   
                 DCM 
                 Dichloromethane 
               
               
                   
                 DMA 
                 Dimethylamine 
               
               
                   
                 DMAc 
                 Dimethylacetamide 
               
               
                   
                 DMSO 
                 Dimethyl sulfoxide 
               
               
                   
                 EtOH 
                 Ethanol 
               
               
                   
                 EtOAc 
                 Ethyl Acetate 
               
               
                   
                 IPA 
                 Isopropyl alcohol 
               
               
                   
                 IPAc 
                 Isopropyl acetate 
               
               
                   
                 MeOH 
                 Methanol 
               
               
                   
                 MIBK 
                 Methyl isobutyl ketone 
               
               
                   
                 MTBE 
                 Methyl tert-butyl ether 
               
               
                   
                 NMP 
                 N-methyl-2-pyrrolidone 
               
               
                   
                 THF 
                 Tetrahydrofuran 
               
               
                 Bio-Relevant 
                 SGF 
                 Simulated gastric fluid 
               
               
                 Media 
                 FaSSIF 
                 Fasted state simulated intestinal fluid 
               
               
                   
                 FeSSIF 
                 Fed state simulated intestinal fluid 
               
               
                 Techniques 
                 DSC 
                 Differential scanning calorimetry 
               
               
                   
                 DVS 
                 Dynamic Vapor Sorption 
               
               
                   
                 HPLC 
                 High Performance Liquid 
               
               
                   
                   
                 Chromatography 
               
               
                   
                 TGA 
                 Thermogravimetric analysis 
               
               
                   
                 XRPD 
                 X-ray power diffraction 
               
               
                 Other 
                 FB 
                 Freebase 
               
               
                   
                 NF 
                 New form 
               
               
                   
                 RH 
                 Relative humidity 
               
               
                   
                 RT 
                 Room temperature 
               
               
                   
               
             
          
         
       
     
         [0198]    X-Ray Powder Diffraction (XRPD)—To perform XRPD analysis, a PANanalytical Empryean X-ray powder diffractometer was used. The typical XRPD parameters used are listed below. Data Viewer (version 1.4a) from PANanalytic was used for analysis. 
         [0000]    
       
         
               
               
             
           
               
                   
               
             
             
               
                 X-Ray Wavelength 
                 Cu, kα, Kα1 (Å): 1.540598, Kα2 (Å): 1.544426 
               
               
                   
                 Kα2/Kα1 intensity ratio: 0.50 
               
               
                 X-Ray tube setting 
                 45 kV, 40 mA 
               
               
                 Divergence split 
                 Automatic 
               
               
                 Scan mood 
                 Continuous 
               
               
                 Scan range (°2 TH) 
                 3°-40° 
               
               
                 Step size (°2 TH) 
                 0.0130 or 0.0170 
               
               
                 Scan speed (°/min) 
                 ~10 
               
               
                   
               
             
          
         
       
     
         [0199]    Differential Scanning Calorimetry (DSC)—DSC was performed with a TA Q2000 DSC from TA Instruments. To perform DSC, the sample was ramped from room temperature to the desired temperature at a heating rate of 10° C./min, using N 2  as the purge gas and with the pan crimped. Universal Analysis 2000 (TA Instruments) was used to analyze the results. 
         [0200]    Thermogravimetric Analysis (TGA)—TGA was performed with a TA Q500/Q5000 TGA from TA Instruments. To perform TGA, the sample was ramped from room temperature to the desired temperature at a heating rate of 10° C./min, using N 2  as the purge gas. Universal Analysis 2000 (TA Instruments) was used to analyze the results. The temperature was calibrated using nickel and the weight using TA-supplied standard weights and verified against calcium oxalate monohydrate dehydration and decomposition. 
         [0201]    Dynamic Vapor Sorption (DVS)—The term “DVS” means the procedure described in below. The relative humidity at 25° C. was calibrated against deliquescence point of LiCl, Mg(NO 3 ) 2  and KCl. 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 Temperature 
                 25° C. 
               
               
                   
                 Gas Flow and Rate 
                 N 2 , 200 mL/min 
               
               
                   
                 dm/dt 
                 0.002%/min 
               
               
                   
                 Min. dm/dt stability duration 
                 10 min 
               
               
                   
                 Max. equilibrium time 
                 180 min 
               
               
                   
                 RH range 
                 95% RH-0% RH-95% RH 
               
               
                   
                 RH step size 
                 10% (90% RH-0% RH-90% RH) 
               
               
                   
                   
                 5% (90% RH-95% RH-90% RH) 
               
               
                   
                   
               
             
          
         
       
     
         [0202]    The DVS of SCY-078 salts were tested according to the above method, using a 10-20 mg sample size. The DVS was measured using a Surface Measurement Systems (SMS) DVS Intrinsic. 
         [0203]    High Power Liquid Chromatography (HPLC) Method—An Agilent 1260 HPLC with DAD detector was utilized to test solubility or to test purity and stability. For all compounds tested other than the trifluoroacetate salts (Type A and B) and the HCl Type I and II salts, the conditions and parameters used for measuring solubility are shown in Table 2A and for measuring stability are showing in Table 3A. The conditions and parameters used for the solubility of the trifluoroacetate salts (Type A and B) and the HCl Type I and II salts are shown in Table 2B and for stability are shown in Table 3B. System suitability was tested by injecting standard solutions five times in each sample sequence, and the relative standard deviation of the peak areas was less than 2%. 
         [0000]    
       
         
               
               
             
               
               
               
               
             
               
               
               
             
               
               
             
           
               
                 TABLE 2A 
               
               
                   
               
             
             
               
                 Column 
                 53#: Eclipse plus C18, 4.6 * 150 mm, 3.5 μm 
               
               
                 Mobile Phase 
                 A: 0.1% HClO 4  in H 2 OB: ACN 
               
               
                   
               
             
          
           
               
                   
                 Time (mins) 
                 % A 
                 % B 
               
               
                   
               
               
                 Gradient Table 
                 0 
                 70 
                 30 
               
               
                   
                 1 
                 70 
                 30 
               
               
                   
                 7 
                 5 
                 95 
               
               
                   
                 8 
                 5 
                 95 
               
               
                   
                 8.1 
                 70 
                 30 
               
               
                   
                 12 
                 70 
                 30 
               
               
                   
               
             
          
           
               
                 Flow Rate 
                 1.0 
                 mL/min 
               
               
                 Injection Volume 
                 10 
                 μL 
               
               
                 Detector Wavelength 
                 255 
                 nm 
               
               
                 Run Time 
                 12 
                 min 
               
               
                 Column Temperature 
                 40° 
                 C. 
               
             
          
           
               
                 Autosampler 
                 RT 
               
               
                 Temperature 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
             
               
               
             
           
               
                 TABLE 2B 
               
               
                   
               
             
             
               
                 Column 
                 Waters C18 110A, 4.6 * 150 mm, 5 μm 
               
               
                 Mobile Phase 
                 A: 0.1% TFA in H 2 O; B: 0.1% TFA in 
               
               
                   
                 acetonitrile 
               
               
                   
               
             
          
           
               
                   
                 Time (mins) 
                 % B 
               
               
                   
               
               
                 Gradient Table 
                 0 
                 5 
               
               
                   
                 1 
                 5 
               
               
                   
                 9 
                 95 
               
               
                   
                 11 
                 95 
               
               
                   
                 11.1 
                 5 
               
               
                   
                 15 
                 5 
               
               
                   
               
             
          
           
               
                 Flow Rate 
                 1.0 
                 mL/min 
               
               
                 Injection Volume 
                 10 
                 μL 
               
               
                 Detector Wavelength 
                 UV at 255 
                 nm 
               
               
                 Run Time 
                 15 
                 min 
               
               
                 Column Temperature 
                 40° 
                 C. 
               
             
          
           
               
                 Autosampler Temperature 
                 RT 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
             
               
               
               
               
             
               
               
               
             
               
               
             
           
               
                 TABLE 3A 
               
               
                   
               
             
             
               
                 Column 
                 Phenomenex, Gemini C18, 4.6 × 150 mm, 3 mm 
               
               
                 Mobile Phase 
                 A: 0.1% HClO 4  in H 2 O B: ACN 
               
               
                   
               
             
          
           
               
                   
                 Time (mins) 
                 % A 
                 % B 
               
               
                   
               
               
                 Gradient Table 
                 0.0 
                 63 
                 37 
               
               
                   
                 5.0 
                 43 
                 57 
               
               
                   
                 15.0 
                 38 
                 62 
               
               
                   
                 20.0 
                 10 
                 90 
               
               
                   
                 30.0 
                 10 
                 90 
               
               
                   
                 31.0 
                 63 
                 37 
               
               
                   
                 36.0 
                 63 
                 37 
               
               
                   
               
             
          
           
               
                 Flow Rate 
                 1.0 
                 mL/min 
               
               
                 Injection Volume 
                 10 
                 μL 
               
               
                 Detector Wavelength 
                 UV at 210 
                 min 
               
               
                 Run Time 
                 36.0 
                 min 
               
               
                 Column Temperature 
                 40° 
                 C. 
               
             
          
           
               
                 Sampler Temperature 
                 RT 
               
               
                 Diluent 
                 ACN 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
             
               
               
               
               
             
               
               
               
               
             
               
               
               
             
           
               
                   
                 TABLE 3B 
               
               
                   
                   
               
             
             
               
                   
                 Column 
                 Waters C18 110A, 
               
               
                   
                   
                 4.6 * 150 mm, 5 μm 
               
               
                   
                 Mobile Phase 
                 A: 0.1% TFA in H 2 O; B: 0.1% 
               
               
                   
                   
                 TFA in acetonitrile 
               
               
                   
                   
               
             
          
           
               
                   
                   
                 Time (mins) 
                 % B 
               
               
                   
                   
               
               
                   
                 Gradient Table 
                 0.0 
                 5 
               
               
                   
                   
                 23 
                 95 
               
               
                   
                   
                 27 
                 95 
               
               
                   
                   
                 27.1 
                 5 
               
               
                   
                   
                 30 
                 5 
               
               
                   
                   
               
             
          
           
               
                   
                 Flow Rate 
                 1.0 
                 mL/min 
               
               
                   
                 Injection Volume 
                 10 
                 μL 
               
               
                   
                 Detector Wavelength 
                 270 
                 min 
               
               
                   
                 Run Time 
                 30.0 
                 min 
               
               
                   
                 Column Temperature 
                 40° 
                 C. 
               
             
          
           
               
                   
                 Sampler Temperature 
                 RT 
               
               
                   
                   
               
             
          
         
       
     
         [0204]    SGF Media Preparation—The term “SGF media” means a solution prepared according to the following method. Sodium chloride (0.2 g) and Triton X-100 (0.1 g) were combined in a 100 mL flask. Then deionized water was added. The mixture was stirred until all solids were dissolved. Then 12 N HCl (200 μL) was added and the pH value was checked with a pH meter. The pH was adjusted to 1.8 with 1N HCl or 1N NaOH. Once the desired pH was established, the solution was diluted to volume with deionized water. 
         [0205]    FaSSIF Media Preparation—The term “FaSSIF media” means a solution prepared according to the following method. A FaSSIF Dissolving Buffer was prepared by dissolving maleic acid (0.222 g) in 45 mL of purified water. The pH was adjusted to exactly 6.4 using 1N NaOH. 
         [0206]    FaSSIF media was prepared by adding sodium taurocholate (0.161 g), sodium chloride (0.398 g), and lecithin (0.0156 g) into a 100-mL volumetric flask. Then 40 mL of deionized water was added. The solution was sonicated until clear. Next 45 mL of the FaSSIF Dissolving Buffer was added. The pH was adjusted to 6.5 with 1N NaOH or 1N HCl. Once the desired pH was reached, the solution was diluted to volume with deionized water. 
         [0207]    An alternative media (“FaSSIF alternative media”) was used to study the trifluoroacetate salts (Type A and B) and the HCl Type I salt. More specifically, the media was prepared by weighing 0.17 g of sodium phosphate monobasic (NaH2PO4, anhydrous), 0.021 g of sodium hydroxide, and 0.31 g of sodium chloride into a 50-mL volumetric flask and was dissolve with approximately 48 mL of purified water. The pH was adjusted to exactly 6.5 using 1 M HCl or 1 M NaOH and diluted to volume with purified water. 0.11 g of SIF powder was then added, stirred and sonicated until all the powder was completely dissolved. The solution was equilibrated for 2 hours at RT before use. The solution can be stored at RT for 48 hours or 4° C. for 7 days and should be equilibrated to RT before use 
         [0208]    FeSSIF Preparation—The term “FeSSIF media” means a solution prepared according to the following method. A FeSSIF Dissolving Buffer was prepared by dissolving maleic acid (0.638 g) and NaCl (0.728 g) in 100 mL of purified water. The pH was adjusted to exactly 5.8 using 1N NaOH or 1N HCl. 
         [0209]    FeSSIF media was prepared by adding sodium taurocholate (0.269 g), lecithin (0.078 g), sodium oleate (0.012 g), and glyceryl monooleate (0.089) into a 50-mL flask. Then 2.5 mL of the FeSSIF Dissolving Buffer was added. The solution was sonicated. An additional 12.5 mL of the FeSSIF Dissolving Buffer was then added 1 mL stepwise forming an emulsion. The solution was transferred to a 50-mL volumetric flask and diluted to volume with the FeSSIF Dissolving Buffer. 
         [0210]    An alternative media (“FeSSIF alternative media”) was used to study the trifluoroacetate salts (Type A and B) and the HCl Type I salt. More specifically, the media was prepared by transferring 0.41 mL of glacial acid and weighing 0.20 g of sodium hydroxide, 0.59 g of sodium chloride into a 50-mL volumetric flask. This was dissolved with approximately 48 mL of purified water. The pH was adjusted to exactly 5.0 using 1 M HCl or 1 M NaOH and diluted to volume with purified water. 0.56 g of SIF powder was added, stirred and sonicated until all the powder is completely dissolved. The solution can be stored at RT for 48 hours or 4° C. for 7 days and should be equilibrated to RT before use. 
         [0211]    Dextrose Buffer (pH 5.5) Preparation—The terms “dextrose buffer at pH 5.5” and “dextrose buffer (pH 5.5)” mean a solution prepared according to the following method. Dextrose (0.5 g) was added to a 100-mL volumetric flask. Then 1M HCl or 1M NaOH was added to adjust the pH of the buffer to pH 5.5. 
         [0212]    Acetate Buffer (pH 5.5) Preparation—The acetate buffer (pH 5.5) used for the trifluoroacetate salts (Type A and B) and the HCl Type I salt was prepared by placing 0.60 g sodium acetate (NaC 2 H 3 O 2 .3H 2 O) in a 100-mL volumetric flask, adding 3 mL of 2 M acetic acid solution, and then adding purified water to volume. 
         [0213]    Phosphate Buffer (pH 6.0) Preparation—The terms “phosphate buffer at pH 6.0” and “phosphate buffer (pH 6.0)” mean a solution prepared according to the following method. A solution of 0.2 M KH 2 PO 4  (25 mL) and 0.2 M NaOH (5.6 mL) was prepared in a 100-mL volumetric flask. The pH was checked by pH meter. Then water was added to volume. 
         [0214]    An alternative media (“phosphate (pH 6.0) alternative media”) was used to study the trifluoroacetate salts (Type A and B) and the HCl Type I salt. More specifically, the media was prepared by dissolving 2.72 g of 0.2 M monobasic potassium phosphate (KH 2 PO 4 ) in purified water, and diluting with purified water to 100 mL. 0.8 g of 0.2 M sodium hydroxide in purified water was diluted with purified water to 100 mL. Then 50 mL of the 0.2 M monobasic potassium phosphate solution was placed in a 200-mL volumetric flask, 5.6 mL of 0.2 M sodium hydroxide solution was added, and then purified water was added to volume. 
         [0215]    Phosphate Buffer (pH 7.5) Preparation—The terms “phosphate buffer at pH 7.5” and “phosphate buffer (pH 7.5)”mean a solution prepared according to the following method. A solution of 0.2 M KH 2 PO 4  (25 mL) and 0.2 M NaOH (40.2 mL) was prepared in a 100-mL volumetric flask. The pH was checked by pH meter. Then water was added to volume. 
         [0216]    Kinetic Solubility of SCY-078 Salts—The term “kinetic solubility” with respect to SCY-078 salts means the following procedure. First, 15 mg, 50 mg, or 100 mg of one of the SCY-078 salts was placed into a 4-mL plastic centrifuge tubes along with 1.7 mL of relevant media or 2.0 mL of water. For dextrose buffer at pH 5.5, phosphate buffer at pH 6.0, and phosphate buffer at pH 7.5, 15 mg of the SCY-078 salt was used. For SGF media, FeSSIF media, and FaSSIF media, 50 mg of the SCY-078 salt was used. For water, 100 mg of the SCY-078 salt was used. The actual weight of each sample was recorded. The tube was subsequently capped and the suspension samples were stirred on a rolling incubator (25 rpm) at room temperature. Samples were taken at 1 hour, 4 hours, and 24 hours respectively. For each sample, a 0.5 mL aliquot of the suspension was transferred into a 1.5-mL centrifuge filtration tube and centrifuged. The samples were then filtered through the centrifuge filtration tube (0.45 μm) at 8,000 rpm at room temperature for 3 minutes. 
         [0217]    The trifluoroacetate salts (Type A and B) and the HCl Type I salt were tested using the following alternative procedure. First, 15 mg, 36 mg or 90 mg solid was weighted into a 4-mL plastic tube, and 3 mL of relevant media was added before leaving the suspension on a rolling incubator (25 r/min). For SCF, 90 mg of solid was used. For FaSSIF, acetate buffer (pH 5.5), and phosphate buffer (pH 6.0), 15 mg solid was used. For FeSSIF, 36 mg of solid was used. 1.0 mL aliquot of the suspension was sampled for centrifugation with the supernatant submitted for HPLC and pH measurement and solid for XRPD characterization at 1 hr, 4 hr and/or 24 hrs. 
         [0218]    Approximate solubility of SCY-078 salts—The term “approximate solubility” with respect to SCY-078 salts means the procedure described in this paragraph. To conduct each experiment, a sample of a SCY-078 salt (˜2 mg) was added into a 3-mL glass vial. Then a solvent was added step-wise (100 μL per step) into the vials until the solids were dissolved or a total volume of 2 mL was reached. 
         [0219]    Equilibrium solubility of SCY-078 salts—The term “equilibrium solubility” with respect to SCY-078 salts means the procedure described in this paragraph. The equilibrium solubility of a SCY-078 salt was evaluated in water at room temperature. First, the SCY-078 salt (˜50 mg) was weighed into a 1.5-mL vial followed by addition of 1.0 mL water, and then the sample was stirred (800 rpm) at room temperature for 24 hours. The sample was centrifuged with the residual solid analyzed by XRPD and supernatant concentration measured by HPLC. 
         [0220]    Polarized light microscopic imaging—Polarized light microscopic (PLM) images was captured at room temperature using Axio Lab A1 upright microscope equipped with ProgRes® CT3 camera. The sample was sandwiched between a glass slide and a top cover before placed under the polarized light microscopy for imaging. 
       Example 1 
       [0221]    SCY-078 Phosphate: The phosphate salt of SCY-078 was prepared from SCY-078 freebase, which was prepared using known procedures. See, e.g., U.S. Pat. No. 8,188,085. SCY-078 freebase (10.0 g) was placed in a 250 mL reactor. Ethanol (50 mL), ethyl acetate (30 mL), acetic acid (1.5 mL) and water (1 mL) were added and the mixture was stirred at room temperature over 10 minutes. The resulting homogeneous solution was heated to 50° C. and phosphoric acid (1.74 g) solution in ethyl acetate was slowly added to the solution at 50° C. for 1 hour. The resulting slurry was slowly cooled to room temperature and stirred overnight at room temperature. The slurry was filtered, and the wet cake was washed with 20 mL mixed solvents (ethanol:ethyl acetate:water=5:5:0.1) two times, then twice with ethyl acetate (1 mL). The wet cake was dried under vacuum with nitrogen sweep over three hours, and then dried in a vacuum oven overnight to obtain 11.08 g of an off-white crystal. The retention time of the compound was 4.08 minutes, as measured by HPLC using an Ascentis Express C18 column with standard gradient: 10-95% of B in 6 minutes (A=0.1% phosphoric acid, B=acetonitrile), 2 minute hold 2 minute post; flow rate: 1.8mL/minute (UV detection at 245 nm, 40° C.). 
         [0222]    SCY-078 phosphate was characterized by XRPD, which evidenced that the compound is crystalline ( FIG. 1 ). The 2 theta and d-spacing values are summarized in Table 4. The DSC curve of SCY-078 phosphate exhibited two endothermic peaks at 48.1° C. and 267° C. ( FIG. 2 ). A weight loss of 6.6% was observed up to 155.4° C. in the TGA curve ( FIG. 2 ). 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
               
                   
                   
                 FWHM Left 
                   
                   
               
               
                 Pos. [°2Th.] 
                 Height [cts] 
                 [°2Th.] 
                 d-spacing [Å] 
                 Rel. Int. [%] 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 3.446579 
                 121.838400 
                 0.153504 
                 25.63591 
                 8.36 
               
               
                 6.002339 
                 410.263500 
                 0.127920 
                 14.72481 
                 28.14 
               
               
                 6.926787 
                 321.574500 
                 0.153504 
                 12.76157 
                 22.05 
               
               
                 7.923199 
                 635.487400 
                 0.179088 
                 11.15879 
                 43.58 
               
               
                 9.163023 
                 1458.149000 
                 0.230256 
                 9.65152 
                 100.00 
               
               
                 9.949172 
                 420.112200 
                 0.153504 
                 8.89059 
                 28.81 
               
               
                 10.395180 
                 355.706200 
                 0.204672 
                 8.51011 
                 24.39 
               
               
                 11.606700 
                 1098.847000 
                 0.179088 
                 7.62440 
                 75.36 
               
               
                 11.998390 
                 742.370400 
                 0.153504 
                 7.37637 
                 50.91 
               
               
                 12.509650 
                 1152.457000 
                 0.230256 
                 7.07603 
                 79.04 
               
               
                 14.390130 
                 1325.262000 
                 0.179088 
                 6.15529 
                 90.89 
               
               
                 15.561700 
                 1295.270000 
                 0.230256 
                 5.69443 
                 88.83 
               
               
                 16.742160 
                 847.559600 
                 0.230256 
                 5.29549 
                 58.13 
               
               
                 17.427190 
                 694.495600 
                 0.179088 
                 5.08885 
                 47.63 
               
               
                 18.989620 
                 584.788500 
                 0.204672 
                 4.67353 
                 40.10 
               
               
                 19.700330 
                 472.891400 
                 0.204672 
                 4.50650 
                 32.43 
               
               
                 20.641180 
                 788.029700 
                 0.153504 
                 4.30316 
                 54.04 
               
               
                 22.864060 
                 331.310800 
                 0.204672 
                 3.88959 
                 22.72 
               
               
                 24.026930 
                 187.756700 
                 0.307008 
                 3.70391 
                 12.88 
               
               
                 25.365620 
                 208.707200 
                 0.358176 
                 3.51139 
                 14.31 
               
               
                 28.405150 
                 77.468630 
                 0.614016 
                 3.14218 
                 5.31 
               
               
                 30.814330 
                 70.380370 
                 0.818688 
                 2.90179 
                 4.83 
               
               
                   
               
             
          
         
       
     
       Example 2 
       [0223]    SCY-078 Crystalline Freebase (MeOH desolvate): The MeOH desolvate was prepared as follows. SCY-078 phosphate salt (10.0 g) was charged into a 250 mL reactor. Sodium carbonate (50 mL of a 10% solution) was added at 20° C. and agitated. 2-methyltetrahydrofuan (100 mL) was added and agitated strongly at 20° C. until all the solids dissolved. The mixture was left to stand for 30 minutes to leave two clear layers which were separated and the organic layer was washed twice with deionized water (40 mL). The washed organic layer was transferred to a 125-mL reaction vessel and agitated at 500 rpm, heated to 50° C. and distilled under partial vacuum at 50° C. down to 40 mL volume. Methanol (80 mL) was added to the reaction vessel at 50° C., which was then cooled to 40° C.; after 2 hours, crystals formed. The volume was then distilled down to 50 mL at 40° C. under partial vacuum over 16 hours. There was then constant volume distillation at 40° C. while adding methanol (40 mL) over 2 hours. Water (20 mL) was then added over 2 hours. The reaction vessel was then cooled to 20° C. over 2 hours and then slurry aged at 20° C. for 2 hours. The mixture was then filtered and the resulting wet cake washed with 20 mL of a 4:1 solution of methanol and water. The wet cake was dried under nitrogen sweep at room temperature for 16 hours. XRPD analysis confirmed that the dry cake is desolvated methanol solvate (yield 89%, purity: 99.1%). 
         [0224]    Two batches of MeOH desolvate were prepared and characterized by XRPD, DSC, and TGA ( FIGS. 3-5 ). XRPD patterns evidenced that the compound is crystalline. The 2 theta and d-spacing values from Batch 1 and Batch 2 are summarized in Tables 5a and 5b, respectively. The DSC curve of MeOH desolvate Batch 1 exhibited an endotherm at ˜55.0° C. and an exotherm at ˜281.5° C. The DSC curve of MeOH desolvate Batch 2 exhibited an endotherm at ˜56.1° C. and an exotherm at ˜279.2° C. The TGA curve of Batch 1 showed a weight loss of 4.7% before 120° C. The TGA curve of Batch 1 showed a weight loss of 6.6% before 120° C. The TGA curve of Batch 2 showed a weight loss of 4.9% before 120° C. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 5a 
               
               
                   
               
               
                   
                   
                 FWHM Left 
                   
                   
               
               
                 Pos. [°2Th.] 
                 Height [cts] 
                 [°2Th.] 
                 d-spacing [Å] 
                 Rel. Int. [%] 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 6.763088 
                 656.275900 
                 0.153504 
                 13.07009 
                 7.96 
               
               
                 7.007256 
                 762.055000 
                 0.127920 
                 12.61520 
                 9.24 
               
               
                 7.747366 
                 5938.858000 
                 0.179088 
                 11.41165 
                 72.02 
               
               
                 8.156786 
                 1751.303000 
                 0.179088 
                 10.83975 
                 21.24 
               
               
                 9.712988 
                 1115.822000 
                 0.153504 
                 9.10623 
                 13.53 
               
               
                 10.141860 
                 2106.808000 
                 0.076752 
                 8.72210 
                 25.55 
               
               
                 12.584090 
                 950.310500 
                 0.153504 
                 7.03433 
                 11.52 
               
               
                 13.014360 
                 1356.119000 
                 0.127920 
                 6.80272 
                 16.45 
               
               
                 13.486330 
                 1749.145000 
                 0.102336 
                 6.56570 
                 21.21 
               
               
                 13.729600 
                 2433.802000 
                 0.076752 
                 6.44991 
                 29.52 
               
               
                 14.005940 
                 8245.783000 
                 0.166296 
                 6.32326 
                 100.00 
               
               
                 14.405120 
                 4246.837000 
                 0.140712 
                 6.14892 
                 51.50 
               
               
                 14.876760 
                 4956.689000 
                 0.127920 
                 5.95503 
                 60.11 
               
               
                 15.210400 
                 2019.649000 
                 0.089544 
                 5.82515 
                 24.49 
               
               
                 15.545740 
                 4247.989000 
                 0.153504 
                 5.70024 
                 51.52 
               
               
                 15.924930 
                 1123.799000 
                 0.127920 
                 5.56535 
                 13.63 
               
               
                 16.357440 
                 911.992900 
                 0.102336 
                 5.41916 
                 11.06 
               
               
                 16.653970 
                 1230.506000 
                 0.153504 
                 5.32333 
                 14.92 
               
               
                 17.281780 
                 1476.632000 
                 0.115128 
                 5.13134 
                 17.91 
               
               
                 18.290550 
                 2584.896000 
                 0.127920 
                 4.85054 
                 31.35 
               
               
                 18.910970 
                 2762.926000 
                 0.089544 
                 4.69279 
                 33.51 
               
               
                 19.423650 
                 3792.983000 
                 0.166296 
                 4.57006 
                 46.00 
               
               
                 20.154410 
                 631.061700 
                 0.153504 
                 4.40598 
                 7.65 
               
               
                 21.211700 
                 1085.950000 
                 0.153504 
                 4.18870 
                 13.17 
               
               
                 22.103930 
                 642.381300 
                 0.153504 
                 4.02160 
                 7.79 
               
               
                 22.813500 
                 357.089200 
                 0.153504 
                 3.89809 
                 4.33 
               
               
                 23.851840 
                 485.307900 
                 0.204672 
                 3.73070 
                 5.89 
               
               
                 24.372350 
                 254.224300 
                 0.153504 
                 3.65219 
                 3.08 
               
               
                 25.127990 
                 631.886600 
                 0.204672 
                 3.54405 
                 7.66 
               
               
                 25.582260 
                 817.763400 
                 0.230256 
                 3.48214 
                 9.92 
               
               
                 25.946780 
                 361.733700 
                 0.127920 
                 3.43404 
                 4.39 
               
               
                 27.215450 
                 399.894700 
                 0.204672 
                 3.27677 
                 4.85 
               
               
                 31.598700 
                 117.418900 
                 0.358176 
                 2.83152 
                 1.42 
               
               
                 34.043420 
                 360.328100 
                 0.179088 
                 2.63357 
                 4.37 
               
               
                 35.453150 
                 228.142700 
                 0.204672 
                 2.53202 
                 2.77 
               
               
                 37.397760 
                 89.968660 
                 0.204672 
                 2.40471 
                 1.09 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 5b 
               
               
                   
               
               
                   
                   
                 FWHM Left 
                   
                   
               
               
                 Pos. [°2Th.] 
                 Height [cts] 
                 [°2Th.] 
                 d-spacing [Å] 
                 Rel. Int. [%] 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 6.689568 
                 495.508900 
                 0.076752 
                 13.21357 
                 7.10 
               
               
                 6.958760 
                 795.039300 
                 0.076752 
                 12.70301 
                 11.39 
               
               
                 7.719929 
                 6977.127000 
                 0.102336 
                 11.45214 
                 100.00 
               
               
                 8.113519 
                 1569.148000 
                 0.076752 
                 10.89746 
                 22.49 
               
               
                 9.660554 
                 883.585800 
                 0.089544 
                 9.15554 
                 12.66 
               
               
                 10.105090 
                 1377.370000 
                 0.063960 
                 8.75376 
                 19.74 
               
               
                 12.511740 
                 551.167400 
                 0.076752 
                 7.07485 
                 7.90 
               
               
                 12.972470 
                 906.794200 
                 0.102336 
                 6.82459 
                 13.00 
               
               
                 13.432450 
                 898.612700 
                 0.051168 
                 6.59191 
                 12.88 
               
               
                 13.698610 
                 1280.818000 
                 0.063960 
                 6.46442 
                 18.36 
               
               
                 13.963580 
                 6943.854000 
                 0.102336 
                 6.34235 
                 99.52 
               
               
                 14.354450 
                 3936.292000 
                 0.102336 
                 6.17051 
                 56.42 
               
               
                 14.833880 
                 3242.652000 
                 0.102336 
                 5.97215 
                 46.48 
               
               
                 15.161830 
                 1072.948000 
                 0.102336 
                 5.84370 
                 15.38 
               
               
                 15.499310 
                 3840.597000 
                 0.115128 
                 5.71721 
                 55.05 
               
               
                 15.870270 
                 694.539900 
                 0.063960 
                 5.58440 
                 9.95 
               
               
                 16.294450 
                 561.885100 
                 0.102336 
                 5.43997 
                 8.05 
               
               
                 16.589520 
                 716.170000 
                 0.076752 
                 5.34387 
                 10.26 
               
               
                 17.231620 
                 1048.768000 
                 0.089544 
                 5.14616 
                 15.03 
               
               
                 18.228150 
                 1455.529000 
                 0.089544 
                 4.86701 
                 20.86 
               
               
                 18.853630 
                 2320.288000 
                 0.102336 
                 4.70693 
                 33.26 
               
               
                 19.358690 
                 2769.789000 
                 0.127920 
                 4.58525 
                 39.70 
               
               
                 20.105050 
                 319.040400 
                 0.153504 
                 4.41669 
                 4.57 
               
               
                 21.158160 
                 854.556900 
                 0.089544 
                 4.19918 
                 12.25 
               
               
                 22.060990 
                 457.091300 
                 0.127920 
                 4.02933 
                 6.55 
               
               
                 22.755630 
                 189.699300 
                 0.153504 
                 3.90788 
                 2.72 
               
               
                 23.818130 
                 259.770000 
                 0.102336 
                 3.73590 
                 3.72 
               
               
                 24.629730 
                 250.065300 
                 0.153504 
                 3.61461 
                 3.58 
               
               
                 25.034030 
                 415.901700 
                 0.102336 
                 3.55714 
                 5.96 
               
               
                 25.544070 
                 535.863500 
                 0.179088 
                 3.48726 
                 7.68 
               
               
                 25.883800 
                 303.412800 
                 0.102336 
                 3.44225 
                 4.35 
               
               
                 27.200370 
                 321.682800 
                 0.102336 
                 3.27856 
                 4.61 
               
               
                 27.597540 
                 179.014900 
                 0.102336 
                 3.23227 
                 2.57 
               
               
                 28.068430 
                 126.035900 
                 0.409344 
                 3.17911 
                 1.81 
               
               
                 29.974950 
                 124.045000 
                 0.153504 
                 2.98110 
                 1.78 
               
               
                 31.402190 
                 89.293980 
                 0.614016 
                 2.84879 
                 1.28 
               
               
                 32.603460 
                 118.588300 
                 0.204672 
                 2.74652 
                 1.70 
               
               
                 33.988800 
                 247.854700 
                 0.179088 
                 2.63768 
                 3.55 
               
               
                 35.391040 
                 161.830400 
                 0.153504 
                 2.53632 
                 2.32 
               
               
                   
               
             
          
         
       
     
       Example 3 
       [0225]    SCY-078 Amorphous Freebase: To prepare SCY-078 amorphous freebase, MeOH desolvate (50 mg) was added to a 3-mL vial. Then DCM (0.5 mL) was added to the vial of MeOH desolvate. The resulting solution of MeOH desolvate and DCM formed a clear solution. The solution was evaporated to dryness from an open vial at 50° C. 
         [0226]    The solid obtained after evaporation was characterized by XRPD, TGA, DSC, and DVS. The XRPD pattern evidenced that the tested sample is amorphous. The DSC and TGA curves of the amorphous sample exhibited a glass transition at ˜189.1° C. ( FIG. 6 ). The TGA curve demonstrated a weight loss of 4.2% before 150° C. The DVS curve demonstrated that the sample is hygroscopic with a water uptake of ˜4.8% at 80% RH, 25° C. An XRPD pattern performed after DVS demonstrated no form change. 
       Example 4 
       [0227]    Kinetic Solubility of SCY-078 Freebase: The kinetic solubility of SCY-078 MeOH desolvate and SCY-078 amorphous freebase was evaluated in SGF media, FaSSIF media, FeSSIF media, dextrose buffer (pH 5.5), phosphate buffer (pH 6.0), and phosphate buffer (pH 7.5) at room temperature. First, solid SCY-078 MeOH desolvate or SCY-078 amorphous freebase (˜15 mg) was weighed into a 4-mL vial. Then the relevant media (3.0 mL) was added and the suspensions were stirred on a rolling incubator (25 rpm) at room temperature for 1 hour, 4 hours, and 24 hours respectively. After stirring, 0.5 mL of suspension was centrifuged and filtered (0.45 μm). The residual solids were analyzed by XRPD, and the supernatant was measured by HPLC and pH meter. 
         [0228]    The results (Table 6) suggested that both the MeOH desolvate and the amorphous freebase display high solubility in SGF and FeSSIF. The results also showed that both the MeOH desolvate and the amorphous freebase are only sparingly soluble in FaSSIF and pH 5.5, pH 6.0, and pH 7.5 buffers. 
         [0229]    Solid form change was observed during the solubility measurements of the MeOH desolvate in FeSSIF, FaSSIF, pH 5.5 and 6.0 buffers. Additionally, three new crystal forms were discovered (Table 6). The three new forms are identified as New Form 1, 2, and 3. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 Kinetic solubility of SCY-078 freebase 
               
             
          
           
               
                   
                 Starting 
                 Time 
                 Solubility 
                   
                   
               
               
                 Solvent 
                 Form 
                 (hours) 
                 (mg/mL) 
                 pH 
                 Form 
               
               
                   
               
             
          
           
               
                 SGF 
                 Desolv. $   
                 1 
                 &gt;5.3* 
                 2.8 
                 N/A 
               
               
                   
                   
                 4 
                 &gt;5.3* 
                 2.8 
                 N/A 
               
               
                   
                   
                 24 
                 &gt;5.3* 
                 2.8 
                 N/A 
               
               
                   
                 Amorph. 
                 1 
                 &gt;5.2* 
                 2.1 
                 N/A 
               
               
                   
                   
                 4 
                 &gt;5.2* 
                 2.2 
                 N/A 
               
               
                   
                   
                 24 
                 &gt;5.2* 
                 2.2 
                 N/A 
               
               
                 FeSSIF 
                 Desolv. 
                 1 
                 3.3 
                 5.1 
                 NF 1 
               
               
                   
                   
                 4 
                 3.5 
                 5.1 
                 NF 1 
               
               
                   
                   
                 24 
                 3.5 
                 5.1 
                 NF 1 
               
               
                   
                 Amorph. 
                 1 
                 3.0 
                 5.1 
                 Amorph. 
               
               
                   
                   
                 4 
                 3.7 
                 5.1 
                 Amorph. 
               
               
                   
                   
                 24 
                 3.8 
                 5.1 
                 Amorph. 
               
               
                 FaSSIF 
                 Desolv. 
                 1 
                 ND 
                 6.6 
                 NF 1 
               
               
                   
                   
                 4 
                 ND 
                 6.6 
                 NF 1 
               
               
                   
                   
                 24 
                 ND 
                 6.6 
                 NF 1 
               
               
                   
                 Amorph. 
                 1 
                 0.017 
                 6.6 
                 Amorph. 
               
               
                   
                   
                 4 
                 &lt;0.51 μg/mL 
                 6.6 
                 Amorph. 
               
               
                   
                   
                 24 
                 ND 
                 6.6 
                 Amorph. 
               
               
                 pH 5.5 
                 Desolv. 
                 1 
                 N/A 
                 N/A 
                 N/A 
               
               
                 buffer 
                   
                 4 
                 0.0008 
                 7.2 
                 NF 2 
               
               
                   
                   
                 24 
                 ND 
                 7.1 
                 NF 2 
               
               
                   
                 Amorph. 
                 1 
                 N/A 
                 N/A 
                 N/A 
               
               
                   
                   
                 4 
                 ND 
                 6.8 
                 Amorph. 
               
               
                   
                   
                 24 
                 ND 
                 6.9 
                 Amorph. 
               
               
                 pH 6.0 
                 Desolv. 
                 1 
                 N/A 
                 N/A 
                 N/A 
               
               
                 buffer 
                   
                 4 
                 0.045 
                 6.2 
                 NF 1 
               
               
                   
                   
                 24 
                 0.60 
                 6.1 
                 NF 3 
               
               
                   
                 Amorph. 
                 1 
                 N/A 
                 N/A 
                 N/A 
               
               
                   
                   
                 4 
                 &lt;0.51 μg/mL 
                 6.1 
                 Amorph. 
               
               
                   
                   
                 24 
                 0.0024 
                 6.1 
                 Amorph, 
               
               
                 pH 7.5 
                 Desolv. 
                 1 
                 N/A 
                 N/A 
                 N/A 
               
               
                 buffer 
                   
                 4 
                 0.0024 
                 7.3 
                 Desolv. 
               
               
                   
                   
                 24 
                 0.0025 
                 7.4 
                 Desolv. 
               
               
                   
                 Amorph. 
                 1 
                 N/A 
                 N/A 
                 N/A 
               
               
                   
                   
                 4 
                 ND 
                 7.4 
                 Amorph. 
               
               
                   
                   
                 24 
                 ND 
                 7.4 
                 Amorph. 
               
               
                   
               
               
                 *Clear solution was obtained 
               
               
                 NF: New Form 
               
               
                 ND: Not Detected 
               
               
                   $ MeOH desolvate 
               
               
                 N/A: Not available 
               
               
                 Desolv.: Desolvate 
               
               
                 Amorph.: Amorphous 
               
             
          
         
       
     
       Example 5 
       [0230]    Approximate Solubility of SCY-078 MeOH Desolvate: The approximate solubility of SCY-078 MeOH desolvate was measured in 20 solvents at room temperature (25±3° C.). First, MeOH desolvate (˜2 mg) was added to a 3-mL glass vial. Then the corresponding solvent was added step wise (100 μL) until the solution was visually clear or a total volume of 2 mL was reached. The results appear in Table 7. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                 Approximate solubility of SCY-078 
               
               
                 freebase at RT 
               
             
          
           
               
                   
                 Solvent 
                 Solubility (mg/mL) 
               
               
                   
                   
               
               
                   
                 MeOH 
                 5.4 &lt; S &lt; 6.3 
               
               
                   
                 EtOH 
                 2.6 &lt; S &lt; 3.0 
               
               
                   
                 IPA 
                 7.0 &lt; S &lt; 11.0 
               
               
                   
                 Acetic Acid 
                 S &gt;25.0 
               
               
                   
                 ACN 
                 2.6 &lt; S &lt; 2.9 
               
               
                   
                 Acetone 
                 8.3 &lt; S &lt; 12.5 
               
               
                   
                 MIBK 
                 S &gt;29.0 
               
               
                   
                 EtOAc 
                 S &gt;23.0 
               
               
                   
                 iPrOAc 
                 10.5 &lt; S &lt; 21.0 
               
               
                   
                 MTBE 
                 S &gt;23.0 
               
               
                   
                 THF 
                 S &gt;23.0 
               
               
                   
                 2-MeTHF 
                 S &gt;25.0 
               
               
                   
                 1,4-Dioxane 
                 S &gt;37.0 
               
               
                   
                 NMP 
                 S &gt;45.0 
               
               
                   
                 DMSO 
                 S &gt;32.0 
               
               
                   
                 CHCl 3   
                 S &gt;33.0 
               
               
                   
                 Toluene 
                 6.8 &lt; S &lt; 8.5 
               
               
                   
                 Heptane 
                 S &lt;2.2 
               
               
                   
                 DMA 
                 S &gt;40.0 
               
               
                   
                 H 2 O 
                 S &lt;1.9 
               
               
                   
                   
               
             
          
         
       
     
       Example 6 
       [0231]    Salt Study of SCY-078 Freebase: A salt study of the SCY-078 MeOH desolvate freebase was performed using 108 different conditions developed through 18 acids in 6 solvents (Table 8). The salt study was performed by first preparing a solution of SCY-078 MeOH desolvate freebase and mixing with an equi-molar acid solution. This solution was stirred at room temperature overnight. 
         [0232]    For precipitates, the solids were isolated and analyzed by XRPD. Clear solutions were evaporated slowly to dryness at room temperature. 
         [0233]    The salt study (Table 8) showed that seven crystalline salts (eight crystal forms) of SCY-078 were found: HCl Type A, citrate Type A, hippurate Type A, fumarate Type A, fumarate Type B, glycolate Type A, mesylate Type A, and Ca salt Type A. Four crystal forms of SCY-078 freebase were discovered during the salt study and were identified as freebase (“FB”) Type A, B, C, and D. 
         [0000]    
       
         
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                   
                 Solvent 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 THF/H 2 O 
               
               
                 Acid 
                 EtOH (A) 
                 IPA (B) 
                 ACN (C) 
                 Acetone (D) 
                 EtOAc (E) 
                 (19:1, v/v) (F) 
               
               
                   
               
               
                 HCl 
                 oil 
                 oil 
                 HCl salt 
                 HCl salt 
                 amorphous 
                 oil 
               
               
                   
                   
                   
                 Type A 
                 Type A 
                   
                   
               
               
                 H 2 PO 4   
                 oil 
                 oil 
                 oil 
                 oil 
                 oil 
                 oil 
               
               
                 Maleic Acid 
                 amorphous 
                 amorphous 
                 FB 
                 amorphous 
                 amorphous 
                 amorphous 
               
               
                   
                   
                   
                 Type A 
                   
                   
                   
               
               
                 Citric Acid 
                 amorphous 
                 amorphous 
                 Citrate 
                 amorphous 
                 FB 
                 amorphous 
               
               
                   
                   
                   
                 Type A 
                   
                 Type A 
                   
               
               
                 Hippuric Acid 
                 FB 
                 FB 
                 Hippurate 
                 Hippurate 
                 Hippurate 
                 Low 
               
               
                   
                 Type B 
                 Type B 
                 Type A 
                 Type A 
                 Type A 
                 crystallinity 
               
               
                 Adipic Acid 
                 amorphous 
                 FB 
                 FB 
                 FB 
                 amorphous 
                 amorphous 
               
               
                   
                   
                 Type A 
                 Type A 
                 Type C 
                   
                   
               
               
                 Fumaric Acid 
                 amorphous 
                 amorphous 
                 Fumarate 
                 FB 
                 Fumarate 
                 amorphous 
               
               
                   
                   
                   
                 Type A 
                 Type D 
                 Type B 
                   
               
               
                 Glutaric Acid 
                 amorphous 
                 FB 
                 FB 
                 FB 
                 FB 
                 amorphous 
               
               
                   
                   
                 Type A 
                 Type A 
                 Type C 
                 Type A 
                   
               
               
                 Glycolic Acid 
                 FB 
                 FB 
                 FB 
                 FB 
                 FB 
                 Glycolate 
               
               
                   
                 Type B 
                 Type B 
                 Type B 
                 Type C 
                 Type B 
                 Type A 
               
               
                 D-Glutamic 
                 MeOH 
                 FB 
                 FB 
                 FB 
                 FB 
                 amorphous 
               
               
                 Acid 
                 desolvate + acid 
                 Type A 
                 Type A 
                 Type C 
                 Type A 
                   
               
               
                 Acetic Acid 
                 oil 
                 oil 
                 amorphous 
                 amorphous 
                 amorphous 
                 oil 
               
               
                 Mucic Acid 
                 amorphous 
                 amorphous 
                 FB 
                 FB 
                 FB 
                 amorphous 
               
               
                   
                   
                   
                 Type D 
                 Type D 
                 Type D 
                   
               
               
                 L-Malic Acid 
                 amorphous 
                 amorphous 
                 FB 
                 FB 
                 FB 
                 amorphous 
               
               
                   
                   
                   
                 Type A 
                 Type C 
                 Type A 
                   
               
               
                 Benzoic acid 
                 MeOH 
                 FB 
                 FB 
                 FB 
                 FB 
                 amorphous 
               
               
                   
                 Desolvate 
                 Type A 
                 Type A 
                 Type C 
                 Type A 
                   
               
               
                 Methanesulfonic 
                 amorphous 
                 amorphous 
                 FB 
                 Mesylate 
                 FB 
                 amorphous 
               
               
                 Acid 
                   
                   
                 Type B 
                 Type A 
                 Type B 
                   
               
               
                 Malonic Acid 
                 amorphous 
                 amorphous 
                 FB 
                 amorphous 
                 FB 
                 amorphous 
               
               
                   
                   
                   
                 Type A 
                   
                 Type A 
                   
               
               
                 Ethanesulfonic 
                 amorphous 
                 oil 
                 FB 
                 FB 
                 FB 
                 amorphous 
               
               
                 Acid 
                   
                   
                 Type B 
                 Type B 
                 Type B 
                   
               
               
                 Ca(OH) 2   
                 Ca(OH) 2   
                 Ca(OH) 2   
                 FB 
                 FB 
                 Ca(OH) 2   
                 Ca salt 
               
               
                   
                   
                   
                 Type D 
                 Type C 
                   
                 Type A 
               
               
                   
               
               
                 All the above salt formation experiments were performed at RT using 1.0 mole equivalency of acid. 
               
               
                 FB: freebase 
               
             
          
         
       
     
       Example 7 
       [0234]    SCY-078 HCl Type A: SCY-078 HCl Type A prepared from the salt study in Example 6 was characterized by XRPD, DSC, and TGA ( FIGS. 7-8 ). The resulting XRPD pattern evidenced that SCY-078 HCl Type A is weakly crystalline and has a unique form as compared to the freebase MeOH desolvate. The 2 theta and d-spacing values are summarized in Table 9. The DSC curve displayed an endotherm at 48.5° C. (onset temperature). The TGA curve showed a weight loss of 14.4% before 130° C. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 9 
               
               
                   
               
               
                 Pos. 
                 Height 
                 FWHM Left 
                 d-spacing 
                 Rel. Int. 
               
               
                 [°2Th.] 
                 [cts] 
                 [°2Th.] 
                 [Å] 
                 [%] 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 5.635436 
                 167.080400 
                 0.153504 
                 15.68264 
                 21.28 
               
               
                 9.023307 
                 62.106750 
                 0.307008 
                 9.80065 
                 7.91 
               
               
                 11.313240 
                 785.111500 
                 0.179088 
                 7.82150 
                 100.00 
               
               
                 14.217720 
                 329.207600 
                 0.179088 
                 6.22955 
                 41.93 
               
               
                 16.983670 
                 169.700900 
                 0.204672 
                 5.22073 
                 21.61 
               
               
                 18.224350 
                 96.247500 
                 0.409344 
                 4.86801 
                 12.26 
               
               
                 32.709530 
                 91.332090 
                 0.153504 
                 2.73786 
                 11.63 
               
               
                   
               
             
          
         
       
     
       Example 8 
       [0235]    SCY-078 Citrate Type A (Molar Equivalency—counter ion/API 1): SCY-078 citrate Type A prepared from the salt study in Example 6 was characterized by XRPD, DSC, and TGA ( FIGS. 9-10 ). The resulting XRPD pattern evidenced that SCY-078 citrate Type A is crystalline and is a unique form compared to the freebase MeOH desolvate. The 2 theta and d-spacing values are summarized in Table 10. The DSC curve displayed two endotherms at 36.2° C. and 194.8° C. (onset temperature). The TGA curve demonstrated 5.1% before 100° C. 
         [0236]    A sample was heated to 100° C. and then cooled to room temperature. XRPD was performed after heating and cooling to room temperature. The resulting XRPD pattern showed that there was no change in form. DSC and TGA characterization was also performed after heating and cooling. The DSC curve demonstrated two endotherms at 39.9° C. and 194.8° C. (onset temperatures). The TGA curve showed a weight loss of 5.3% before 100° C. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 10 
               
               
                   
               
               
                 Pos. 
                 Height 
                 FWHM Left 
                 d-spacing 
                 Rel. Int. 
               
               
                 [°2Th.] 
                 [cts] 
                 [°2Th.] 
                 [Å] 
                 [%] 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 5.448309 
                 886.677500 
                 0.140712 
                 16.22084 
                 29.56 
               
               
                 7.551316 
                 2999.844000 
                 0.153504 
                 11.70747 
                 100.00 
               
               
                 9.280401 
                 338.350200 
                 0.204672 
                 9.52971 
                 11.28 
               
               
                 10.933390 
                 532.481900 
                 0.102336 
                 8.09237 
                 17.75 
               
               
                 11.525650 
                 1003.802000 
                 0.140712 
                 7.67783 
                 33.46 
               
               
                 12.550580 
                 416.868300 
                 0.204672 
                 7.05304 
                 13.90 
               
               
                 13.236060 
                 1150.251000 
                 0.153504 
                 6.68928 
                 38.34 
               
               
                 15.063710 
                 476.465200 
                 0.153504 
                 5.88154 
                 15.88 
               
               
                 16.766510 
                 1157.775000 
                 0.204672 
                 5.28786 
                 38.59 
               
               
                 18.032270 
                 212.464400 
                 0.153504 
                 4.91943 
                 7.08 
               
               
                 19.686700 
                 214.063600 
                 0.307008 
                 4.50959 
                 7.14 
               
               
                 22.220460 
                 123.975800 
                 0.153504 
                 4.00077 
                 4.13 
               
               
                 30.421720 
                 65.589230 
                 0.358176 
                 2.93833 
                 2.19 
               
               
                 34.915250 
                 28.764450 
                 0.614016 
                 2.56979 
                 0.96 
               
               
                   
               
             
          
         
       
     
       Example 9 
       [0237]    SCY-078 Hippurate Type A (Molar equivalency counter ion/API 2.0): SCY-078 hippurate Type A prepared from the salt study in Example 6 was characterized by XRPD, DSC, and TGA ( FIGS. 11-12 ). The XRPD pattern of SCY-078 hippurate Type A indicated that the sample is crystalline and has a unique form as compared to the freebase MeOH desolvate. The DSC curve displayed three endotherms at 36.3° C., 104.6° C., and 165.5° C. (onset temperatures) and one exotherm at 201.9° C. (onset temperature). The TGA curve showed a weight loss of 4.9% before 150° C. 
       Example 10 
       [0238]    SCY-078 Hippurate Type B: SCY-078 hippurate Type B is produced from heating hippurate Type A to 150° C. and then cooling the sample to room temperature. SCY-078 hippurate Type B was characterized by XRPD, DSC, and TGA ( FIGS. 13-14 ). The XRPD pattern showed that the sample is crystalline and a unique form compared to SCY-078 hippurate Type A. The DSC curve displayed two endotherms at 39.6° C. and 166.4° C. (onset temperatures) and one exotherm at 201.4° C. (onset temperature). The TGA curve demonstrated a weight loss of 1.8% before 150° C. 
       Example 11 
       [0239]    SCY-078 Hippurate Type C: Cycle DSC and XRPD were performed to investigate the phase transition events during the heating-cooling process of SCY-078 hippurate Type B ( FIGS. 15-16 ). The XRPD overlay and DSC curve suggested the melting point of SCY-078 hippurate Type B at 163.9° C. followed by amorphous phase recrystallizing at 208.8° C. and a new anhydrate phase being formed. The new anhydrate phase is SCY-078 hippurate Type C. 
       Example 12 
       [0240]    SCY-078 Fumarate Type A (Molar equivalency counter ion/API 1.0): SCY-078 fumarate Type A prepared from the salt study in Example 6 was characterized by XRPD, DSC, and TGA ( FIGS. 17-18 ). The XRPD pattern indicated that the sample is crystalline and a unique form compared to the freebase MeOH desolvate. The DSC curve of SCY-078 fumarate Type A showed an endotherm at 33.1° C. and a melting point at 207.3° C. (onset temperature). The TGA curve displayed a weight loss of 2.4% before 120° C. 
         [0241]    A sample of SCY-078 fumarate Type A was heated to 120° C. and then allowed to cool to room temperature. Characterization by XRPD, DSC, and TGA were then repeated. The XRPD pattern displayed no form change after heating and cooling. The DSC curve of heated-cooled SCY-078 fumarate Type A exhibited two endotherms at 38.4° C. and 207.1° C. (onset temperatures). The TGA curve of heated-cooled SCY-078 fumarate Type A showed a weight loss of 2.0% before 120° C. 
       Example 13 
       [0242]    SCY-078 Fumarate Type B (Molar equivalency counter ion/API 0.8): SCY-078 fumarate Type B prepared from the salt study in Example 6 was characterized by XRPD, DSC, and TGA ( FIGS. 19-20 ). The XRPD pattern of SCY-078 fumarate Type B indicated that the sample is weakly crystalline and that it is a unique form compared to the freebase MeOH desolvate. The DSC curve of SCY-078 fumarate Type B showed two endotherms at 37.9° C. and 178.5° C. (onset temperature). The TGA curve demonstrated a weight loss of 13.4% before 300° C. 
       Example 14 
       [0243]    SCY-078 Glycolate Type A (Molar equivalency counter ion/API 2.0): SCY-078 glycolate Type A prepared from the salt study in Example 6 was characterized by XRPD, DSC, and TGA ( FIGS. 21-22 ). The XRPD pattern of SCY-078 glycolate Type A indicated that the sample is crystalline and a unique form compared to the freebase MeOH solvate. The DSC curve of the sample displayed two endotherms at 35.9° C. and 159.6° C. (onset temperatures). The TGA curve showed a weight loss of 6.6% before 100° C. 
       Example 15 
       [0244]    SCY-078 Mesylate Type A (Molar equivalency counter ion/API 1.0): SCY-078 mesylate Type A prepared from the salt study in Example 6 was characterized by XRPD, DSC, and TGA ( FIGS. 23-24 ). The XRPD pattern indicated that the sample is crystalline and a unique form compared to the freebase MeOH desolvate. The DSC curve displayed an endotherm at 44.2° C. and a melting point at 260.0° C. (onset temperatures). The TGA showed a weight loss of 4.5% before 120° C. 
         [0245]    Next, a sample of SCY-078 mesylate Type A was heated to 120° C. and then allowed to cool to room temperature. Characterization by XRPD, DSC, and TGA was then repeated. The XRPD pattern displayed no form change after heating and cooling. The DSC curve of the heated-cooled SCY-078 mesylate Type A exhibited an endotherm at 59.7° C. and a melting point at 257.4° C. (onset temperatures). The TGA curve of the heated-cooled SCY-078 mesylate Type A showed a weight loss of 9.4% before 120° C. 
       Example 16 
       [0246]    SCY-078 Calcium Type A: SCY-078 calcium Type A prepared from the salt study in Example 6 was characterized by XRPD, DSC, and TGA ( FIGS. 25-26 ). The XRPD pattern indicated that the sample is crystalline and a unique form compared to the freebase MeOH desolvate. The DSC curve displayed two endotherms at 147.3° C. and 230.8° C. (onset temperatures). The TGA curve showed a weight loss of 5.3% before 170° C. 
       Example 17 
       [0247]    Preparation and Characterization of Scaled-Up SCY-078 Hippurate Type B: To scale-up SCY-078 hippurate Type B, a solution of hippuric acid (122.8 mg) and SCY-078 MeOH desolvate (500.3 mg) in ACN (5.0 mL) was prepared. The suspension was then stirred (500 rpm) at room temperature for 28 hours. Following stirring, some slurry was filtered and the isolated solid was checked by XRPD to confirm SCY-078 hippurate Type A. The suspension was filtered and dried at 150° C. for 1 hour before characterization. Finally, the solid was check by XRPD to confirm to SCY-078 hippurate Type B. 
         [0248]    The scaled-up SCY-078 hippurate Type B was analyzed by XRPD, DSC, TGA, and DVS ( FIGS. 27-30 ). The resulting XRPD pattern evidenced that SCY-078 hippurate Type B was successfully scaled up. The 2 theta and d-spacing values are summarized in Table 11. The DSC curve showed two endotherms at 34.5° C. and 164.4° C. and one exotherm at 205.2° C. (onset temperatures). The TGA curve showed a weight loss of 0.9% before 130° C. The DVS curve showed that the sample is hygroscopic with a water uptake of -3.5% at 25° C. and 80% RH. A second XRPD pattern performed after DVS showed SCY-078 hippurate Type B converted to SCY-078 hippurate Type A after DVS experiment. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 11 
               
               
                   
               
               
                 Pos. 
                 Height 
                 FWHM Left 
                 d-spacing 
                 Rel. Int. 
               
               
                 [°2Th.] 
                 [cts] 
                 [°2Th.] 
                 [Å] 
                 [%] 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 3.027072 
                 11818.150000 
                 0.051168 
                 29.18766 
                 100.00 
               
               
                 5.916137 
                 351.270000 
                 0.102336 
                 14.93916 
                 2.97 
               
               
                 6.916698 
                 947.910600 
                 0.102336 
                 12.78016 
                 8.02 
               
               
                 7.251646 
                 624.847700 
                 0.076752 
                 12.19059 
                 5.29 
               
               
                 8.761702 
                 1828.733000 
                 0.076752 
                 10.09268 
                 15.47 
               
               
                 9.962105 
                 2404.236000 
                 0.102336 
                 8.87907 
                 20.34 
               
               
                 10.897800 
                 1593.408000 
                 0.102336 
                 8.11872 
                 13.48 
               
               
                 11.868550 
                 552.254500 
                 0.102336 
                 7.45677 
                 4.67 
               
               
                 12.432300 
                 2880.441000 
                 0.127920 
                 7.11988 
                 24.37 
               
               
                 12.857840 
                 525.634600 
                 0.076752 
                 6.88518 
                 4.45 
               
               
                 13.091360 
                 511.764400 
                 0.115128 
                 6.76288 
                 4.33 
               
               
                 13.709840 
                 1112.219000 
                 0.102336 
                 6.45916 
                 9.41 
               
               
                 14.555290 
                 3086.294000 
                 0.153504 
                 6.08582 
                 26.11 
               
               
                 14.984610 
                 1215.693000 
                 0.102336 
                 5.91241 
                 10.29 
               
               
                 15.341160 
                 506.870800 
                 0.153504 
                 5.77579 
                 4.29 
               
               
                 16.136210 
                 1315.742000 
                 0.089544 
                 5.49296 
                 11.13 
               
               
                 16.453540 
                 1710.358000 
                 0.153504 
                 5.38772 
                 14.47 
               
               
                 16.897030 
                 606.324900 
                 0.102336 
                 5.24730 
                 5.13 
               
               
                 17.280760 
                 1171.798000 
                 0.127920 
                 5.13164 
                 9.92 
               
               
                 17.591700 
                 2258.867000 
                 0.102336 
                 5.04163 
                 19.11 
               
               
                 18.190770 
                 538.754800 
                 0.127920 
                 4.87692 
                 4.56 
               
               
                 18.425670 
                 516.831300 
                 0.179088 
                 4.81528 
                 4.37 
               
               
                 19.151570 
                 950.084500 
                 0.102336 
                 4.63437 
                 8.04 
               
               
                 19.602330 
                 487.956400 
                 0.127920 
                 4.52881 
                 4.13 
               
               
                 20.234760 
                 861.917600 
                 0.153504 
                 4.38867 
                 7.29 
               
               
                 20.860030 
                 424.598600 
                 0.153504 
                 4.25851 
                 3.59 
               
               
                 21.725360 
                 459.496200 
                 0.307008 
                 4.09081 
                 3.89 
               
               
                 22.532320 
                 498.240700 
                 0.102336 
                 3.94610 
                 4.22 
               
               
                 23.078810 
                 380.947900 
                 0.127920 
                 3.85388 
                 3.22 
               
               
                 23.551950 
                 208.488500 
                 0.409344 
                 3.77752 
                 1.76 
               
               
                 23.874020 
                 377.598600 
                 0.102336 
                 3.72728 
                 3.20 
               
               
                 25.381750 
                 351.553600 
                 0.102336 
                 3.50919 
                 2.97 
               
               
                 25.844490 
                 207.070300 
                 0.204672 
                 3.44740 
                 1.75 
               
               
                 27.188450 
                 192.463400 
                 0.153504 
                 3.27997 
                 1.63 
               
               
                 27.681830 
                 144.369000 
                 0.307008 
                 3.22262 
                 1.22 
               
               
                 29.319670 
                 172.870900 
                 0.511680 
                 3.04622 
                 1.46 
               
               
                 30.833510 
                 86.432220 
                 0.307008 
                 2.90002 
                 0.73 
               
               
                 34.979000 
                 90.330020 
                 0.204672 
                 2.56525 
                 0.76 
               
               
                 35.588330 
                 69.479680 
                 0.307008 
                 2.52271 
                 0.59 
               
               
                 37.270360 
                 55.666410 
                 0.307008 
                 2.41264 
                 0.47 
               
               
                   
               
             
          
         
       
     
       Example 18 
       [0249]    Preparation and Characterization of Scaled-Up SCY-078 Fumarate Type A: To scale-up SCY-078 fumarate Type A, a solution of fumaric acid (79.8 mg) and SCY-078 MeOH desolvate (501.9 mg) in ACN (15.0 mL) was prepared. The suspension was then stirred (500 rpm) at room temperature for 28 hours. Following stirring, some slurry was filtered and the isolated solid was checked by XRPD to confirm SCY-078 fumarate Type A. Finally, the suspension was filtered and dried at 30° C. for 4 hours in vacuum before characterization. 
         [0250]    Characterization of scaled-up SCY-078 fumarate Type A included XRPD, DSC, TGA, and DVS ( FIGS. 31-33 ). The resulting XRPD pattern evidenced that SCY-078 fumarate Type A was successfully scaled up. The 2 theta and d-spacing values are summarized in Table 12. The DSC curve showed an endotherm at 39.9° C. and a melting endotherm at 208.4° C. (onset temperatures). The TGA curve showed a weight loss of 1.7% before 150° C. The DVS curve showed that the sample is hygroscopic with a water uptake of 2.5% at 80% RH, 25° C. A second XRPD pattern performed after DVS showed SCY-078 fumarate Type A had no form change. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 12 
               
               
                   
               
               
                 Pos. 
                 Height 
                 FWHM Left 
                 d-spacing 
                 Rel. Int. 
               
               
                 [°2Th.] 
                 [cts] 
                 [°2Th.] 
                 [Å] 
                 [%] 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 6.708362 
                 290.801200 
                 0.153504 
                 13.17659 
                 2.14 
               
               
                 7.779830 
                 2540.992000 
                 0.102336 
                 11.36410 
                 18.74 
               
               
                 8.490587 
                 13558.710000 
                 0.127920 
                 10.41433 
                 100.00 
               
               
                 9.362659 
                 1986.519000 
                 0.102336 
                 9.44617 
                 14.65 
               
               
                 9.964151 
                 661.033600 
                 0.127920 
                 8.87725 
                 4.88 
               
               
                 10.417770 
                 2882.948000 
                 0.115128 
                 8.49171 
                 21.26 
               
               
                 10.694630 
                 3478.282000 
                 0.127920 
                 8.27250 
                 25.65 
               
               
                 11.221780 
                 3785.363000 
                 0.140712 
                 7.88504 
                 27.92 
               
               
                 11.875520 
                 519.613200 
                 0.153504 
                 7.45241 
                 3.83 
               
               
                 12.271310 
                 357.834700 
                 0.127920 
                 7.21292 
                 2.64 
               
               
                 13.008060 
                 5831.607000 
                 0.140712 
                 6.80600 
                 43.01 
               
               
                 13.729940 
                 1780.661000 
                 0.127920 
                 6.44975 
                 13.13 
               
               
                 14.640000 
                 1169.640000 
                 0.076752 
                 6.05080 
                 8.63 
               
               
                 14.888350 
                 2319.347000 
                 0.078000 
                 5.94549 
                 17.11 
               
               
                 14.955620 
                 2471.802000 
                 0.076752 
                 5.92381 
                 18.23 
               
               
                 15.225230 
                 1608.774000 
                 0.089544 
                 5.81951 
                 11.87 
               
               
                 16.171470 
                 1276.652000 
                 0.076752 
                 5.48106 
                 9.42 
               
               
                 16.429100 
                 2604.447000 
                 0.140712 
                 5.39569 
                 19.21 
               
               
                 16.942700 
                 6000.498000 
                 0.140712 
                 5.23326 
                 44.26 
               
               
                 17.442280 
                 1878.502000 
                 0.063960 
                 5.08448 
                 13.85 
               
               
                 17.749440 
                 3552.116000 
                 0.140712 
                 4.99718 
                 26.20 
               
               
                 18.202980 
                 2297.875000 
                 0.127920 
                 4.87368 
                 16.95 
               
               
                 18.928920 
                 1597.690000 
                 0.140712 
                 4.68838 
                 11.78 
               
               
                 20.028870 
                 591.031400 
                 0.127920 
                 4.43332 
                 4.36 
               
               
                 20.258840 
                 480.204800 
                 0.102336 
                 4.38351 
                 3.54 
               
               
                 20.868380 
                 1498.769000 
                 0.127920 
                 4.25683 
                 11.05 
               
               
                 21.397940 
                 1555.987000 
                 0.089544 
                 4.15266 
                 11.48 
               
               
                 21.879750 
                 1130.218000 
                 0.127920 
                 4.06229 
                 8.34 
               
               
                 22.217300 
                 1475.131000 
                 0.102336 
                 4.00133 
                 10.88 
               
               
                 22.591130 
                 913.600300 
                 0.102336 
                 3.93596 
                 6.74 
               
               
                 23.385000 
                 425.684600 
                 0.153504 
                 3.80411 
                 3.14 
               
               
                 23.950880 
                 915.135300 
                 0.204672 
                 3.71550 
                 6.75 
               
               
                 24.627720 
                 245.047100 
                 0.153504 
                 3.61490 
                 1.81 
               
               
                 25.499420 
                 1445.187000 
                 0.089544 
                 3.49326 
                 10.66 
               
               
                 26.148510 
                 509.814300 
                 0.179088 
                 3.40800 
                 3.76 
               
               
                 26.502880 
                 512.161300 
                 0.127920 
                 3.36323 
                 3.78 
               
               
                 26.881710 
                 614.926800 
                 0.153504 
                 3.31669 
                 4.54 
               
               
                 27.716900 
                 269.647600 
                 0.255840 
                 3.21862 
                 1.99 
               
               
                 28.552140 
                 414.549300 
                 0.153504 
                 3.12634 
                 3.06 
               
               
                 29.217330 
                 471.259100 
                 0.153504 
                 3.05666 
                 3.48 
               
               
                 29.558860 
                 525.910500 
                 0.204672 
                 3.02211 
                 3.88 
               
               
                 30.043740 
                 270.781000 
                 0.204672 
                 2.97444 
                 2.00 
               
               
                 30.962340 
                 570.115500 
                 0.307008 
                 2.88825 
                 4.20 
               
               
                 33.133860 
                 264.449500 
                 0.179088 
                 2.70376 
                 1.95 
               
               
                 33.967430 
                 212.730600 
                 0.179088 
                 2.63929 
                 1.57 
               
               
                 34.456190 
                 314.358700 
                 0.179088 
                 2.60297 
                 2.32 
               
               
                 35.316070 
                 163.009400 
                 0.179088 
                 2.54153 
                 1.20 
               
               
                 35.928310 
                 161.442300 
                 0.307008 
                 2.49962 
                 1.19 
               
               
                 37.556590 
                 162.885200 
                 0.153504 
                 2.39491 
                 1.20 
               
               
                   
               
             
          
         
       
     
       Example 19 
       [0251]    Preparation and Characterization of Scaled-Up SCY-078 Mesylate Type A: To scale up SCY-078 mesylate Type A, a solution of methanesulfonic acid (66.7 mg) and SCY-078 MeOH desolvate (500.00 mg) in ACN (6.0 mL) was prepared. The suspension was then stirred (500 rpm) at room temperature for 28 hours. Following stirring, some slurry was filtered and the isolated solid was checked by XRPD to confirm to SCY-078 mesylate Type A. Finally, the suspension was filtered and dried at 30° C. for 4 hours in vacuum before characterization. 
         [0252]    Characterization of scaled-up SCY-078 mesylate Type A included XRPD, DSC, TGA, and DVS ( FIGS. 34-36 ). The resulting XRPD pattern evidenced that SCY-078 mesylate Type A was successfully scaled up. The 2 theta and d-spacing values are summarized in Table 13. The DSC curve showed an endotherm at 45.1° C. and a melting endotherm at 252.5° C. (onset temperatures). The TGA curve showed a weight loss of 5.5% before 150° C. The DVS curve showed that the sample is hygroscopic with a water uptake of 11.5% at 25° C. and 80% RH. A second XRPD pattern performed after DVS showed SCY-078 mesylate Type A had no form change. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 13 
               
               
                   
               
               
                 Pos. 
                 Height 
                 FWHM Left 
                 d-spacing 
                 Rel. Int. 
               
               
                 [°2Th.] 
                 [cts] 
                 [°2Th.] 
                 [Å] 
                 [%] 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 3.460873 
                 6386.923000 
                 0.076752 
                 25.53007 
                 100.00 
               
               
                 5.977580 
                 779.662100 
                 0.063960 
                 14.78574 
                 12.21 
               
               
                 7.966391 
                 2528.494000 
                 0.089544 
                 11.09839 
                 39.59 
               
               
                 9.108506 
                 1390.758000 
                 0.089544 
                 9.70916 
                 21.78 
               
               
                 9.950825 
                 1211.786000 
                 0.102336 
                 8.88911 
                 18.97 
               
               
                 11.611990 
                 1031.845000 
                 0.076752 
                 7.62094 
                 16.16 
               
               
                 11.923410 
                 791.823600 
                 0.102336 
                 7.42258 
                 12.40 
               
               
                 12.425240 
                 1268.865000 
                 0.089544 
                 7.12391 
                 19.87 
               
               
                 13.944550 
                 688.156900 
                 0.102336 
                 6.35096 
                 10.77 
               
               
                 14.380410 
                 848.725700 
                 0.102336 
                 6.15943 
                 13.29 
               
               
                 14.769580 
                 2671.218000 
                 0.089544 
                 5.99800 
                 41.82 
               
               
                 15.556400 
                 1399.797000 
                 0.102336 
                 5.69636 
                 21.92 
               
               
                 15.933420 
                 664.503200 
                 0.102336 
                 5.56241 
                 10.40 
               
               
                 16.662350 
                 540.586700 
                 0.102336 
                 5.32067 
                 8.46 
               
               
                 17.361270 
                 955.468500 
                 0.127920 
                 5.10802 
                 14.96 
               
               
                 18.265030 
                 453.378300 
                 0.153504 
                 4.85726 
                 7.10 
               
               
                 18.734480 
                 812.380000 
                 0.102336 
                 4.73660 
                 12.72 
               
               
                 19.019690 
                 850.304100 
                 0.102336 
                 4.66621 
                 13.31 
               
               
                 19.260210 
                 762.325000 
                 0.153504 
                 4.60847 
                 11.94 
               
               
                 19.645310 
                 613.773700 
                 0.127920 
                 4.51900 
                 9.61 
               
               
                 20.566280 
                 436.518500 
                 0.127920 
                 4.31867 
                 6.83 
               
               
                 21.974920 
                 571.254200 
                 0.127920 
                 4.04491 
                 8.94 
               
               
                 22.483420 
                 374.000100 
                 0.255840 
                 3.95457 
                 5.86 
               
               
                 24.101950 
                 210.447500 
                 0.153504 
                 3.69255 
                 3.29 
               
               
                 25.009440 
                 137.497300 
                 0.204672 
                 3.56058 
                 2.15 
               
               
                 26.043990 
                 151.416700 
                 0.204672 
                 3.42144 
                 2.37 
               
               
                 27.012060 
                 72.724460 
                 0.307008 
                 3.30098 
                 1.14 
               
               
                 28.443410 
                 214.270100 
                 0.153504 
                 3.13804 
                 3.35 
               
               
                 34.283540 
                 45.493190 
                 0.511680 
                 2.61568 
                 0.71 
               
               
                   
               
             
          
         
       
     
       Example 20 
       [0253]    Preparation and Characterization of Scaled-Up SCY-078 Phosphate Type A: To scale up SCY-078 phosphate Type A, a solution of phosphoric acid (87.2 mg) and SCY-078 MeOH desolvate (501.1 mg) in EtOH/EtOAc/acetic acid/H 2 O (6.0 mL, 5:3:0.15:0.1; v/v/v/v) was prepared. The suspension was then stirred (500 rpm) at room temperature for 28 hours. Following stirring, some slurry was filtered and the isolated solid was checked by XRPD and named as SCY-078 phosphate Type A. Finally, the suspension was filtered and dried at 30° C. for 4 hours in vacuum before characterization. 
         [0254]    Characterization of scaled-up SCY-078 phosphate Type A included XRPD, DSC, TGA, and DVS ( FIGS. 37-39 ). The XRPD pattern of the scaled-up SCY-078 phosphate Type A was compared with another phosphate sample. The comparison XRPD pattern evidenced certain peak shifts, which are signaled with an asterisk. The 2 theta and d-spacing values of SCY-078 phosphate Type A are summarized in Table 14. The DSC curve showed two endotherms at 43.5° C. and 261.6° C. (onset temperatures). The TGA curve showed a weight loss of 5.7% before 100° C. The DVS curve showed that the sample is hygroscopic with a water uptake of 12.5% at 25° C. and 80% RH. A second XRPD pattern performed after DVS showed SCY-078 phosphate Type A had no form change. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 14 
               
               
                   
               
               
                 Pos. 
                 Height 
                 FWHM Left 
                 d-spacing 
                 Rel. Int. 
               
               
                 [°2Th.] 
                 [cts] 
                 [°2Th.] 
                 [Å] 
                 [%] 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 3.510749 
                 3822.958000 
                 0.063960 
                 25.16747 
                 100.00 
               
               
                 3.777221 
                 1538.172000 
                 0.089544 
                 23.39256 
                 40.24 
               
               
                 6.351771 
                 817.179700 
                 0.089544 
                 13.91551 
                 21.38 
               
               
                 6.974826 
                 213.577600 
                 0.153504 
                 12.67379 
                 5.59 
               
               
                 7.884021 
                 2248.860000 
                 0.089544 
                 11.21415 
                 58.83 
               
               
                 8.064520 
                 922.909900 
                 0.076752 
                 10.96356 
                 24.14 
               
               
                 9.551988 
                 811.444000 
                 0.179088 
                 9.25936 
                 21.23 
               
               
                 9.893185 
                 731.339200 
                 0.127920 
                 8.94077 
                 19.13 
               
               
                 11.410930 
                 713.463600 
                 0.153504 
                 7.75476 
                 18.66 
               
               
                 11.807790 
                 1002.811000 
                 0.127920 
                 7.49500 
                 26.23 
               
               
                 12.234010 
                 806.819600 
                 0.153504 
                 7.23483 
                 21.10 
               
               
                 12.657670 
                 895.228700 
                 0.127920 
                 6.99361 
                 23.42 
               
               
                 14.562960 
                 1550.900000 
                 0.102336 
                 6.08263 
                 40.57 
               
               
                 15.413370 
                 939.681700 
                 0.204672 
                 5.74889 
                 24.58 
               
               
                 15.841220 
                 831.733000 
                 0.307008 
                 5.59457 
                 21.76 
               
               
                 17.560630 
                 1113.197000 
                 0.409344 
                 5.05048 
                 29.12 
               
               
                 18.775820 
                 475.510700 
                 0.153504 
                 4.72626 
                 12.44 
               
               
                 20.576380 
                 320.212100 
                 0.307008 
                 4.31657 
                 8.38 
               
               
                 22.143260 
                 373.653900 
                 0.204672 
                 4.01454 
                 9.77 
               
               
                   
               
             
          
         
       
     
       Example 21 
       [0255]    Preparation and Characterization of Scaled-Up SCY-078 Citrate Type A (Molar Equivalency—counter ion/API 1.0): To scale up SCY-078 citrate Type A, a solution of citric acid (130.7 mg) and SCY-078 MeOH desolvate (501.6 mg) in ACN (15.0 mL) was prepared. The suspension was then stirred (500 rpm) at room temperature for 30 hours. Following stirring, some slurry was filtered and the isolated solid was checked by XRPD to confirm SCY-078 citrate Type A. Finally, the suspension was filtered and dried at 30° C. for 4 hours in vacuum before characterization. 
         [0256]    Characterization of scaled-up SCY-078 citrate Type A included XRPD, DSC, TGA, and DVS ( FIGS. 40-42 ). XRPD pattern evidenced that SCY-078 citrate Type A was successfully scaled up. The 2 theta and d-spacing values are summarized in Table 15. The DSC curve showed an endotherm at 38.5° C. and a melting endotherm at 183.7° C. (onset temperatures). The TGA curve showed a weight loss of 4.1% before 110° C. The DVS curve showed that the sample is hygroscopic with a water uptake of 6.4% at 80% RH, 25° C. A second XRPD pattern performed after DVS showed SCY-078 citrate Type A had no form change. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 15 
               
               
                   
               
               
                 Pos. 
                 Height 
                 FWHM Left 
                 d-spacing 
                 Rel. Int. 
               
               
                 [°2Th.] 
                 [cts] 
                 [°2Th.] 
                 [Å] 
                 [%] 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 5.448098 
                 1112.016000 
                 0.102336 
                 16.22147 
                 25.78 
               
               
                 7.430264 
                 4314.252000 
                 0.153504 
                 11.89794 
                 100.00 
               
               
                 8.687142 
                 329.877800 
                 0.153504 
                 10.17913 
                 7.65 
               
               
                 9.219851 
                 511.870400 
                 0.153504 
                 9.59216 
                 11.86 
               
               
                 9.657531 
                 424.140300 
                 0.255840 
                 9.15840 
                 9.83 
               
               
                 10.883410 
                 1078.439000 
                 0.051168 
                 8.12942 
                 25.00 
               
               
                 11.515250 
                 2094.987000 
                 0.115128 
                 7.68474 
                 48.56 
               
               
                 13.187380 
                 2396.469000 
                 0.089544 
                 6.71386 
                 55.55 
               
               
                 14.126680 
                 799.280200 
                 0.255840 
                 6.26949 
                 18.53 
               
               
                 14.845300 
                 757.431100 
                 0.230256 
                 5.96758 
                 17.56 
               
               
                 16.818410 
                 2913.176000 
                 0.127920 
                 5.27165 
                 67.52 
               
               
                 18.364160 
                 492.518400 
                 0.153504 
                 4.83127 
                 11.42 
               
               
                 19.381840 
                 490.181800 
                 0.307008 
                 4.57983 
                 11.36 
               
               
                 20.774420 
                 185.062500 
                 0.307008 
                 4.27587 
                 4.29 
               
               
                 22.213250 
                 308.712600 
                 0.204672 
                 4.00205 
                 7.16 
               
               
                 23.587350 
                 109.338400 
                 0.818688 
                 3.77193 
                 2.53 
               
               
                 29.871450 
                 85.095400 
                 0.307008 
                 2.99120 
                 1.97 
               
               
                   
               
             
          
         
       
     
       Example 22 
       [0257]    Chemical Characterization of SCY-078 Salts: The chemical purity of each of the scaled-up salts of SCY-078 (hippurate Type B, fumarate Type A, mesylate Type A, phosphate Type A, and citrate Type A) was tested using HPLC chromatographs. The chromatographs of the five compounds indicated that each compound has purity greater than 99% (Table 16). 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 16 
               
             
             
               
                   
               
               
                 Chemical Characterization of SCY-078 Salts 
               
             
          
           
               
                   
                 Compound 
                 Purity 
               
               
                   
                   
               
               
                   
                 Hippurate Type B 
                 99.19 
               
               
                   
                 Fumarate Type A 
                 99.90 
               
               
                   
                 Mesylate Type A 
                 99.91 
               
               
                   
                 Phosphate Type A 
                 99.91 
               
               
                   
                 Citrate Type A 
                 99.89 
               
               
                   
                   
               
             
          
         
       
     
       Example 23 
       [0258]    Evaluation of the pH Value of SCY-078 Salts in Water: The pH value for the saturated salt solutions of SCY-078 (i.e., hippurate Type B, fumarate Type A, mesylate Type A, phosphate Type A, and citrate Type A) was tested. To test the pH, a solution of each compound was equilibrated at room temperature using a rolling incubator (25 rpm) for 1 hour and 24 hours before measurement. The results (Table 17) suggested that the pH values of each of the salts tested is in the range of 3.0 to 5.0. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 17 
               
             
             
               
                   
               
               
                 pH value of saturated SCY-078 salt solutions in H 2 O 
               
             
          
           
               
                   
                 Salt Form 
                 pH 1 hr 
                 pH 24 hrs 
               
               
                   
                   
               
               
                   
                 Hippu rate Type B 
                 4.6 
                 4.2 
               
               
                   
                 Fumarate Type A 
                 4.4 
                 3.8 
               
               
                   
                 Mesylate Type A 
                 3.4 
                 3.6 
               
               
                   
                 Phosphate Type A 
                 3.4 
                 3.6 
               
               
                   
                 Citrate Type A 
                 3.5 
                 3.8 
               
               
                   
                   
               
             
          
         
       
     
       Example 24 
       [0259]    Evaluation of the Kinetic Solubility of SCY-078 Salts: The kinetic solubilities of SCY-078 hippurate Type B, SCY-078 fumarate Type A, SCY-078 mesylate Type A, SCY-078 phosphate Type A, and SCY-078 citrate Type A were measured in dextrose buffer at pH 5.5, phosphate buffer at pH 6.0, phosphate buffer at pH 7.5, SGF media, FeSSIF media, and FaSSIF media according to the method described above. After filtration, 0.2 mL of supernatant was collected for HPLC quantification. The remaining solution was collected for pH measurement. The remaining solid was collected for XRPD characterization. The results appear in Table 18. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 18 
               
             
             
               
                   
               
               
                 Kinetic Solubility (mg/mL) of SCY-078 salts 
               
             
          
           
               
                   
                   
                 Hippu- 
                 Fuma- 
                 Mesy- 
                 Phos- 
                 Cit- 
               
               
                   
                 Time 
                 rate 
                 rate 
                 late 
                 phate 
                 rate 
               
               
                 Media 
                 (hours) 
                 Type B 
                 Type A 
                 Type A 
                 Type A 
                 Type A 
               
               
                   
               
             
          
           
               
                 dextrose 
                 1 
                 hr 
                 0.54 
                 0.05 
                 1.4 
                 0.10 
                 0.67 
               
               
                 buffer 
                 4 
                 hrs 
                 1.7 
                 0.46 
                 2.5 
                 0.09 
                 4.2 
               
               
                 (pH 5.5) 
                 24 
                 hrs 
                 4.4 
                 2.1 
                 4.3 
                 0.04 
                 8.3 
               
               
                 phosphate 
                 1 
                 hr 
                 &lt;LOQ 
                 0.07 
                 0.16 
                 &lt;LOQ 
                 0.75 
               
               
                 buffer 
                 4 
                 hrs 
                 0.04 
                 1.2 
                 0.13 
                 &lt;LOQ 
                 4.7 
               
               
                 (pH 6.0) 
                 24 
                 hrs 
                 0.47 
                 4.7 
                 0.04 
                 &lt;LOQ 
                 7.5 
               
               
                 phosphate 
                 1 
                 hr 
                 &lt;LOQ 
                 &lt;LOQ 
                 &lt;LOQ 
                 &lt;LOQ 
                 &lt;LOQ 
               
               
                 buffer 
                 4 
                 hrs 
                 &lt;LOQ 
                 &lt;LOQ 
                 &lt;LOQ 
                 &lt;LOQ 
                 &lt;LOQ 
               
               
                 (pH 7.5) 
                 24 
                 hrs 
                 &lt;LOQ 
                 &lt;LOQ 
                 &lt;LOQ 
                 &lt;LOQ 
                 &lt;LOQ 
               
               
                 SGF 
                 1 
                 hr 
                 12.4 
                 13.4 
                 17.8 
                 9.2 
                 20.6 
               
               
                   
                 4 
                 hrs 
                 15.0 
                 17.7 
                 20.5 
                 16.0 
                 21.4 
               
               
                   
                 24 
                 hrs 
                 21.8 
                 23.4 
                 22.5 
                 21.2 
                 21.1 
               
               
                 FeSSIF 
                 1 
                 hr 
                 3.4 
                 2.2 
                 1.2 
                 0.89 
                 0.39 
               
               
                   
                 4 
                 hrs 
                 &lt;LOQ 
                 0.51 
                 1.5 
                 1.3 
                 2.5 
               
               
                   
                 24 
                 hrs 
                 0.003 
                 0.02 
                 1.6 
                 1.5 
                 4.2 
               
               
                 FaSSIF 
                 1 
                 hr 
                 &lt;LOQ 
                 &lt;LOD 
                 &lt;LOQ 
                 0.006 
                 9.5 
               
               
                   
                 4 
                 hrs 
                 0.0007 
                 2.8 
                 0.29 
                 0.17 
                 20.7 
               
               
                   
                 24 
                 hrs 
                 &lt;LOQ 
                 17.0 
                 0.44 
                 1.0 
                 21.6 
               
               
                   
               
               
                 LOD: 0.07 μg/mL 
               
               
                 LOQ: 0.22 μg/mL 
               
             
          
         
       
     
       Example 25 
       [0260]    Evaluation of the Stability of SCY-078 Salts: To test the chemical and physical stability of the salts, samples of the salts were placed under three different conditions for one week: (1) open dish at 25° C. with 60% RH; (2) open dish at 40° C. with 75% RH; and (3) closed dish at 60° C. with no humidity control. 
         [0261]    The chemical and physical stability of SCY-078 fumarate Type A and SCY-078 citrate Type A were tested as described above (Table 19). XRPD indicated that neither SCY-078 fumarate Type A nor SCY-078 citrate Type A experienced form change during assessment. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 19 
               
             
             
               
                   
               
               
                 Stability result of SCY-078 salts 
               
             
          
           
               
                   
                   
                   
                 Impurity % 
               
               
                   
                 Sample 
                 Condition 
                 by HPLC 
               
               
                   
                   
               
               
                   
                 Citrate 
                 Initial 
                 0.34 
               
               
                   
                 Type A 
                 25° C./60% RH - 1 week 
                 0.09 
               
               
                   
                   
                 40° C./75% RH - 1 week 
                 0.10 
               
               
                   
                   
                 60° C. - 1 week 
                 0.17 
               
               
                   
                 Fumarate 
                 Initial 
                 0.12 
               
               
                   
                 Type A 
                 25° C./60% RH - 1 week 
                 0.09 
               
               
                   
                   
                 40° C./75% RH - 1 week 
                 0.10 
               
               
                   
                   
                 60° C. - 1 week 
                 0.10 
               
               
                   
                   
               
             
          
         
       
     
       Example 26 
       [0262]    Scaled-up SCY-078 Citrate Type A: A second scale-up of SCY-078 Citrate Type A was carried out to obtain 2.5 g via reactive ACN. To scale-up, SCY-078 MeOH desolvate (2.5 g) and citric acid (660 mg) were dissolved in ACN (80 mL). The resulting solution was stirred at a rate of 1000 rpm at room temperature for 30 hours and then the solid was isolated. The solid obtained was dried at 50° C. under vacuum overnight. 
         [0263]    An XRPD pattern ( FIG. 43 ) showed that SCY-078 citrate Type A was successfully scaled up and that it is highly crystalline. The 2 theta and d-spacing values are summarized in Table 20. DSC curve ( FIG. 44 ) exhibited two endothermic peaks at 56.7° C. and 187.1° C. (onset temperatures). TGA curve ( FIG. 44 ) showed 7.9% weight loss before 150° C. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 20 
               
               
                   
               
               
                 Pos. 
                 Height 
                 FWHM Left 
                 d-spacing 
                 Rel. Int. 
               
               
                 [°2Th.] 
                 [cts] 
                 [°2Th.] 
                 [Å] 
                 [%] 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 5.400273 
                 434.322700 
                 0.102336 
                 16.36502 
                 3.34 
               
               
                 7.453872 
                 13000.820000 
                 0.191880 
                 11.86031 
                 100.00 
               
               
                 9.201639 
                 691.948300 
                 0.204672 
                 9.61110 
                 5.32 
               
               
                 10.831710 
                 404.555000 
                 0.153504 
                 8.16811 
                 3.11 
               
               
                 11.485080 
                 936.115200 
                 0.179088 
                 7.70486 
                 7.20 
               
               
                 12.491050 
                 954.805500 
                 0.179088 
                 7.08652 
                 7.34 
               
               
                 13.191360 
                 1776.320000 
                 0.204672 
                 6.71184 
                 13.66 
               
               
                 15.020350 
                 1342.537000 
                 0.204672 
                 5.89842 
                 10.33 
               
               
                 15.664830 
                 532.278900 
                 0.179088 
                 5.65717 
                 4.09 
               
               
                 15.955570 
                 613.057500 
                 0.127920 
                 5.55474 
                 4.72 
               
               
                 16.751250 
                 951.729000 
                 0.153504 
                 5.29264 
                 7.32 
               
               
                 17.978130 
                 170.323300 
                 0.204672 
                 4.93412 
                 1.31 
               
               
                 19.591770 
                 472.971000 
                 0.204672 
                 4.53123 
                 3.64 
               
               
                 22.213400 
                 146.982900 
                 0.204672 
                 4.00202 
                 1.13 
               
               
                 23.845740 
                 34.469910 
                 0.614016 
                 3.73164 
                 0.27 
               
               
                 25.160050 
                 117.741100 
                 0.307008 
                 3.53961 
                 0.91 
               
               
                 28.761350 
                 129.234400 
                 0.255840 
                 3.10407 
                 0.99 
               
               
                 30.356250 
                 332.945100 
                 0.230256 
                 2.94452 
                 2.56 
               
               
                 32.317870 
                 87.151140 
                 0.307008 
                 2.77014 
                 0.67 
               
               
                 34.725480 
                 74.664570 
                 0.511680 
                 2.58339 
                 0.57 
               
               
                   
               
             
          
         
       
     
       Example 27 
       [0264]    Approximate Solubility of SCY-078 Citrate Type A: The approximate solubility of SCY-078 citrate Type A from Example 26 was determined in 19 solvents at room temperature (25±3° C.) according to the procedure described above and is reported in Table 21 below. 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                 TABLE 21 
               
               
                   
                   
               
               
                   
                 Solvent 
                 Solubility (mg/mL) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 MeOH 
                 &gt;42.4 
               
               
                   
                 EtOH 
                 &lt;1.0 
               
               
                   
                 IPA 
                 &gt;40.0 
               
               
                   
                 Acetic Acid 
                 &gt;41.0 
               
               
                   
                 ACN 
                 &lt;1.1 
               
               
                   
                 Acetone 
                 1.6 &lt; S &lt; 1.7 
               
               
                   
                 MIBK 
                 &lt;1.0 
               
               
                   
                 EtOAc 
                 &lt;1.0 
               
               
                   
                 IPAc 
                 &lt;1.1 
               
               
                   
                 MTBE 
                 &lt;1.0 
               
               
                   
                 THF 
                 &gt;41.0 
               
               
                   
                 2-MeTHF 
                 &gt;41.8 
               
               
                   
                 1,4-Dioxane 
                 &gt;41.0 
               
               
                   
                 NMP 
                 &gt;40.6 
               
               
                   
                 DMSO 
                 &gt;40.6 
               
               
                   
                 DCM 
                 &lt;1.0 
               
               
                   
                 Toluene 
                 &lt;1.0 
               
               
                   
                 Heptane 
                 &lt;1.1 
               
               
                   
                 DMAc 
                 &gt;40.8 
               
               
                   
                   
               
             
          
         
       
     
       Example 28 
       [0265]    Kinetic Solubility of SCY-078 Citrate Type A in Water: The kinetic solubility of SCY-078 citrate Type A from Example 26 was evaluated according to the procedure described above. After the samples were centrifuged, the residual solids analyzed by XRPD and the supernatant concentration measured by HPLC. Results (Table 22) indicated that SCY-078 citrate Type A partially converted to amorphous in water after 24 hours, and exhibited a slow rate of dissolution and increasing solubility in water from 1 hour to 24 hours. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 22 
               
             
             
               
                   
               
               
                 Kinetic Solubility of SCY-078 citrate Type A in Water 
               
             
          
           
               
                   
                 Initial 
                 1 hr 
                 4 hrs 
                 24 hrs 
               
               
                   
                   
               
             
          
           
               
                 pH 
                 8.0 
                  3.3 
                  3.3 
                  3.4 
               
               
                 Solubility (mg/mL) 
                   
                 18.6 
                 26.7 
                 41.4 
               
               
                 Form 
                 Citrate 
                 Citrate 
                 Citrate 
                 Citrate Type A + 
               
               
                   
                 Type A 
                 Type A 
                 Type A 
                 amorphous 
               
               
                   
               
             
          
         
       
     
         [0266]    Then the kinetic solubility of SCY-078 citrate Type A was compared with a mixture of SCY-078 amorphous freebase/citric acid. The kinetic solubility comparison was conducted in water at room temperature and was measured at 1 hour, 4 hours, and 24 hours with a ratio of solute to solvent of 20 mg/mL and 50 mg/mL. Results (Table 23) indicated that SCY-078 citrate Type A shows higher dissolution rate and equilibrium solubility in water than the mixture of SCY-078 amorphous freebase/citric acid. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 23 
               
             
             
               
                   
               
               
                 Kinetic solubility comparison between mixture of SCY-078 
               
               
                 freebase/citric acid and SCY-078 citrate Type A 
               
             
          
           
               
                   
                   
                   
                   
                 Solubility 
               
               
                 Starting Material 
                 Time 
                 pH 
                 XRPD Form 
                 (mg/ML) 
               
               
                   
               
             
          
           
               
                 Freebase Citric Acid 
                 1 
                 hr 
                 2.7 
                 Amorphous 
                 3.0 
               
               
                 20 mg/mL 
                 4 
                 hrs 
                 2.9 
                 Amorphous 
                 5.1 
               
               
                   
                 24 
                 hrs 
                 3.5 
                 Amorphous 
                 10.1 
               
               
                 Freebase Citric Acid 
                 1 
                 hr 
                 2.7 
                 Amorphous 
                 2.9 
               
               
                 50 mg/mL 
                 4 
                 hrs 
                 2.8 
                 Amorphous 
                 16.8 
               
               
                   
                 24 
                 hrs 
                 3.2 
                 Amorphous 
                 28.1 
               
               
                 Citrate Type A 20 mg/mL 
                 1 
                 hr 
                 3.5 
                 Citrate Type A 
                 3.5 
               
               
                   
                 4 
                 hrs 
                 3.4 
                 Citrate Type A 
                 8.3 
               
               
                   
                 24 
                 hrs 
                 3.3 
                 Citrate Type A 
                 17.0 
               
               
                 Citrate Type A 50 mg/mL 
                 1 
                 hr 
                 3.4 
                 Citrate Type A 
                 6.5 
               
               
                   
                 4 
                 hrs 
                 3.3 
                 Citrate Type A 
                 14.5 
               
               
                   
                 24 
                 hrs 
                 3.2 
                 Citrate Type A 
                 33.9 
               
               
                   
               
             
          
         
       
     
         [0267]    The remaining solids from the solubility measurement of physical mixture of freebase:citric acid at 1:1 molar ratio in water were amorphous. To determine the form of the amorphous, liquid NMR was performed on a Bruker 400M NMR Spectrometer using CD 3 OD. The spectrum showed the number of hydrogen atoms assigned to citric acid as 3.12, corresponding to 0.78 equivalent of citric acid. This is less than 1:1 for mono-citrate and suggests it is a mixture that comprises a majority of amorphous citrate salt with a small quantity of amorphous freebase. 
       Example 29 
       [0268]    Equilibrium Solubility of SCY-078 Salts in Water: Equilibrium solubility of SCY-078 citrate Type A from Example 26 in water was determined using the method described above. Results showed that SCY-078 citrate Type A exhibits 38.1 mg/mL solubility in water with the undissolved material having become amorphous after stirring in water for 24 hours. 
         [0269]    Then to further study the solubility of SCY-078 citrate Type A in water, citrate Type A was tested for 24 hours at three ratios of solute to solvent: 0.3 mg/mL, 2.0 mg/mL, and 50.6 mg/mL. Each test used magnetic stirring and began with an initial pH of 8.0. The results (Table 24) indicated that SCY-078 citrate Type A exhibits a concentration-dependent solubility in water. 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE 24 
               
             
             
               
                   
               
               
                 Concentration dependent solubility of SCY-078 
               
               
                 citrate Type A in water 
               
             
          
           
               
                 Ratio of 
                   
                   
               
               
                 Solid/Solvent 
                 Solubility after 24 hrs 
               
               
                 (mg/mL) 
                 (mg/mL) 
                 Final pH 
               
               
                   
               
             
          
           
               
                 0.3 
                 &lt;0.3 
                 5.1 
               
               
                   
                 (suspension) 
               
               
                 2.0 
                 &gt;2.0 
                 4.2 
               
               
                   
                 (clear) 
               
               
                 50.6 
                 38.1 
                 3.4 
               
               
                   
               
             
          
         
       
     
       Example 30 
       [0270]    Kinetic Solubility of SCY-078 Citrate Amorphous in Water: SCY-078 citrate amorphous was prepared under various conditions, including lyophilization from phosphate buffer (pH 6.0), lyophilization from water, and fast evaporation in THF. The results appear in Table 25. Where the table indicates “limited solid,” there was not sufficient solid for XRPD analysis of the solid form. 
         [0271]    Lyophilization in phosphate buffer (pH 6.0)—For lyophilization in phosphate buffer (pH 6.0), SCY-078 citrate amorphous was prepared by first preparing 50 mM pH 6.0 buffer. Then citrate Type A (30 mg) was weighed into a 20-mL vial. Then pH 6.0 buffer (20 mL) was added to the vial and was stirred at room temperature for 24 hours. The samples were filtered and the supernatant was cooled to −15° C. for 2 hours. Finally, the frozen samples were lyophilized at −50° C. for 12 hours. A larger batch (150 mg) was prepared using the same procedure noted above. The kinetic solubility of the second batch of the lyophilized product in water was measured according to the above procedure except that ˜150 mg of solid and 1.0 mL of water were used. After the samples were centrifuged, the residual solids were analyzed by XRPD and the supernatant concentration was measured by HPLC. 
         [0272]    Lyophilization in water—For lyophilization in water, amorphous citrate was prepared by first weighing citrate Type A (˜150 mg) into a 20-mL vial. Then 10 mL of water was added to dissolve the solid completely. The solution was filtered and put in a condition of −20° C. until it froze. Finally, the sample was lyophilized under -50° C. for 24 hours. The kinetic solubility of the lyophilized product in water was measured according to the above procedure except that ˜120 mg of solid and 1.5 mL of water were used. After the samples were centrifuged, the residual solids were analyzed by XRPD and the supernatant concentration was measured by HPLC. 
         [0273]    Fast Evaporation in THF—For fast evaporation in THF, amorphous citrate was prepared by first weighing citrate Type A from Example 26 (˜150 mg) into a 20-mL vial. Then THF (3 mL) was added to dissolve the solid completely. The solution was filtered under a fume hood for performance of fast evaporation. The kinetic solubility in water of the product in water was measured according to the above procedure except that ˜120 mg of solid and 1.5 mL of water were used. After the samples were centrifuged, the residual solids were analyzed by XRPD and the supernatant concentration was measured by HPLC. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 25 
               
             
             
               
                   
               
               
                 Kinetic solubility of amorphous SCY-078 citrate in water 
               
             
          
           
               
                   
                   
                 Solubility 
                   
                   
               
               
                 Starting Solid 
                 Time 
                 (mg/mL) 
                 pH 
                 Form 
               
               
                   
               
             
          
           
               
                 Lyophilization in pH 6.0 buffer 
                  1 hr 
                 0.14 
                 5.1 
                 Amorphous 
               
               
                   
                  4 hrs 
                 0.39 
                 5.1 
                 Amorphous 
               
               
                   
                 24 hrs 
                 1.5 
                 5.1 
                 Amorphous 
               
               
                 Lyophilization in water (pH 8.0) 
                  1 hr 
                 55.4 
                 3.1 
                 Amorphous 
               
               
                   
                  4 hrs 
                 54.7 
                 3.3 
                 NA 
               
               
                   
                 24 hrs 
                 55.5 
                 3.2 
                 NA 
               
               
                 Fast evaporation in THF 
                  1 hr 
                 44.5 
                 3.2 
                 Amorphous 
               
               
                 (pH 8.0) 
                  4 hrs 
                 50.2 
                 3.2 
                 NA 
               
               
                   
                 24 hrs 
                 52.8 
                 3.2 
                 NA 
               
               
                   
               
               
                 NA: Limited solid for XRPD 
               
             
          
         
       
     
       Example 31 
       [0274]    Slow Evaporation of SCY-078 Citrate Type A: Slow evaporation experiments were performed in 12 different solvent systems. SCY-078 citrate Type A from Example 26 (10 mg) was dissolved with solvent (0.05 mL −0.25 mL) for each sample in a 3-mL glass vial. The visually clear solutions were subjected to slow evaporation at room temperature to dryness. The solids obtained were then isolated for XRPD analysis, which showed that no crystalline form was obtained. The results appear in Table 26. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 26 
               
             
             
               
                   
               
               
                 Slow evaporation experiments 
               
             
          
           
               
                   
                 Solvent 
                 Form 
               
               
                   
                   
               
               
                   
                 MeOH 
                 Amorphous 
               
               
                   
                 IPA 
                 Amorphous 
               
               
                   
                 Acetic Acid 
                 Amorphous 
               
               
                   
                 THF 
                 Amorphous 
               
               
                   
                 MeOH/ACN, 9/1 
                 Amorphous 
               
               
                   
                 IPA/Acetone, 9/1 
                 Amorphous 
               
               
                   
                 THF/EtOAc, 9/1 
                 Amorphous 
               
               
                   
                 MeOH/H 2 O, 9/1 
                 Amorphous 
               
               
                   
                 THF/Acetone, 9/1 
                 Amorphous 
               
               
                   
                 IPA/DCM, 9/1 
                 Amorphous 
               
               
                   
                 MeOH/MTBE, 9/1 
                 Amorphous 
               
               
                   
                 THF/EtOH, 9/1 
                 Amorphous 
               
               
                   
                   
               
             
          
         
       
     
       Example 32 
       [0275]    Slurry Conversion of SCY-078 Citrate Type A: Slurry conversion experiments were conducted under 50 conditions. SCY-078 citrate Type A from Example 26 (˜10 mg) was suspended in each solvent (0.5 mL). The suspensions were stirred for 3 days at either room temperature (Table 27) or 50° C. (Table 28). After stirring, the solids were isolated for XRPD analysis. If the suspensions turned into clear solutions upon slurry, the clear solutions were subjected to slow evaporation at room temperature. The results revealed that SCY-078 citrate Type B and mixtures of SCY-078 citrate Type A and SCY-078 citrate Type B were discovered. All SCY-078 citrate Type C that was discovered was identified as freebase form. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 27 
               
             
             
               
                   
               
               
                 Slurry conversion experiments at RT 
               
             
          
           
               
                   
                 Solvent 
                 Form 
               
               
                   
                   
               
               
                   
                 EtOH 
                 Type B 
               
               
                   
                 ACN 
                 Type B 
               
               
                   
                 Acetone 
                 Type B 
               
               
                   
                 MIBK 
                 Type B 
               
               
                   
                 EtOAc 
                 Type B 
               
               
                   
                 IPAc 
                 Type B 
               
               
                   
                 MTBE 
                 Amorphous 
               
               
                   
                 1,4-Dioxane 
                 Amorphous via slow 
               
               
                   
                   
                 evaporation 
               
               
                   
                 DCM 
                 Type B 
               
               
                   
                 Toluene 
                 Type B 
               
               
                   
                 Heptane 
                 Type B 
               
               
                   
                 MeOH/Acetone, 1/19 
                 Type B 
               
               
                   
                 IPA/Heptane, 1/19 
                 Type B 
               
               
                   
                 THF/Toluene, 1/19 
                 Type B 
               
               
                   
                 NMP/EtOH, 1/19 
                 Amorphous 
               
               
                   
                 NMP/Acetone, 1/19 
                 Amorphous 
               
               
                   
                 NMP/IPAc, 1/19 
                 Amorphous 
               
               
                   
                 NMP/DCM, 1/19 
                 Type C 
               
               
                   
                 DMSO/ACN, 1/19 
                 Type C 
               
               
                   
                 DMSO/MIBK, 1/19 
                 Type C 
               
               
                   
                 DMSO/EtOAc, 1/19 
                 Type C 
               
               
                   
                 DMSO/Toluene, 1/19 
                 Type C 
               
               
                   
                 DMAc/EtOH, 1/19 
                 Type C 
               
               
                   
                 DMAc/Acetone, 1/19 
                 Type C 
               
               
                   
                 DMAc/MTBE, 1/19 
                 Type C 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 28 
               
             
             
               
                   
               
               
                 Slurry conversion experiments at 50° C. 
               
             
          
           
               
                   
                 Solvent 
                 Form 
               
               
                   
                   
               
               
                   
                 EtOH 
                 Type B 
               
               
                   
                 ACN 
                 Type B 
               
               
                   
                 Acetone 
                 Type A + B 
               
               
                   
                 MIBK 
                 Type B 
               
               
                   
                 EtOAc 
                 Amorphous 
               
               
                   
                 IPAc 
                 Type B 
               
               
                   
                 MTBE 
                 Amorphous 
               
               
                   
                 1,4-Dioxane 
                 Amorphous via slow 
               
               
                   
                   
                 evaporation 
               
               
                   
                 DCM 
                 Type B 
               
               
                   
                 Toluene 
                 Type A + B 
               
               
                   
                 Heptane 
                 Type B 
               
               
                   
                 MeOH/Acetone, 1/19 
                 Type A + B 
               
               
                   
                 IPA/Heptane, 1/19 
                 Type B 
               
               
                   
                 THF/Toluene, 1/19 
                 Type A + B 
               
               
                   
                 NMP/EtOH, 1/19 
                 Amorphous 
               
               
                   
                 NMP/Acetone, 1/19 
                 Amorphous 
               
               
                   
                 NMP/IPAc, 1/19 
                 Amorphous 
               
               
                   
                 NMP/DCM, 1/19 
                 Amorphous 
               
               
                   
                 DMSO/ACN, 1/19 
                 Type C 
               
               
                   
                 DMSO/MIBK, 1/19 
                 Type C 
               
               
                   
                 DMSO/EtOAc, 1/19 
                 Type C 
               
               
                   
                 DMSO/Toluene, 1/19 
                 Type C 
               
               
                   
                 DMAc/EtOH, 1/19 
                 Amorphous 
               
               
                   
                 DMAc/Acetone, 1/19 
                 Type C 
               
               
                   
                 DMAc/MTBE, 1/19 
                 Type C 
               
               
                   
                   
               
             
          
         
       
     
       Example 33 
       [0276]    Reverse Anti-solvent addition of SCY-078 citrate Type A: Reverse anti-solvent addition experiments were conducted under 14 conditions. SCY-078 citrate Type A from Example 26 (˜10 mg) was dissolved in each solvent (0.1 mL) to obtain a clear solution. This solution was added drop-wise into a glass vial containing 2.0 mL of each anti-solvent at room temperature. The precipitate was isolated for XRPD analysis. Slow evaporation experiments were conducted for the clear solutions. The results, which appear in Table 29, suggested that SCY-078 citrate Type E and SCY-078 citrate Type F were obtained. SCY-078 citrate Type D and SCY-078 citrate Type J were identified as freebase form. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 29 
               
             
             
               
                   
               
               
                 Reverse anti-solvent addition experiments at RT 
               
             
          
           
               
                   
                 Anti- 
                   
                   
               
               
                 Solvent 
                 solvent 
                 Observation 
                 Form 
               
               
                   
               
               
                 MeOH 
                 IPAc 
                 Precipitation 
                 Type E 
               
               
                 MeOH 
                 DCM 
                 Clear 
                 Amorphous via slow 
               
               
                   
                   
                   
                 evaporation 
               
               
                 IPA 
                 EtOH 
                 Clear 
                 Clear solution after slow 
               
               
                   
                   
                   
                 evaporation RT for 2 weeks 
               
               
                 IPA 
                 MTBE 
                 Precipitation 
                 Amorphous 
               
               
                 IPA 
                 Toluene 
                 Precipitation 
                 Type F 
               
               
                 THF 
                 ACN 
                 Precipitation 
                 Type D 
               
               
                 THF 
                 MIBK 
                 Precipitation 
                 Amorphous 
               
               
                 THF 
                 Heptane 
                 Precipitation 
                 Amorphous 
               
               
                 NMP 
                 ACN 
                 Clear 
                 Clear solution after slow 
               
               
                   
                   
                   
                 evaporation at RT for 2 weeks 
               
               
                 NMP 
                 Toluene 
                 Clear 
                 Clear solution after slow 
               
               
                   
                   
                   
                 evaporation at RT for 2 weeks 
               
               
                 DMSO 
                 EtOH 
                 Clear 
                 Type J 
               
               
                 DMSO 
                 DCM 
                 Clear 
                 Amorphous via slow 
               
               
                   
                   
                   
                 evaporation 
               
               
                 DMAc 
                 DCM 
                 Clear 
                 Amorphous via slow 
               
               
                   
                   
                   
                 evaporation 
               
               
                 DMAc 
                 Toluene 
                 Clear 
                 Clear solution after slow 
               
               
                   
                   
                   
                 evaporation at RT for 2 weeks 
               
               
                   
               
             
          
         
       
     
       Example 34 
       [0277]    Solid vapor diffusion of SCY-078 Citrate Type A: Solid vapor diffusion experiments were conducted using four solvents at room temperature. SCY-078 citrate Type A from Example 26 (˜10 mg) was placed into a 3-mL glass vial. Then the vial was sealed into a 20-mL glass vial with a solvent (3 mL). The system was kept at room temperature for six days, which was sufficient time for organic vapor to interact with the solids. The solids were characterized by XRPD to identify crystalline forms. The results (Table 30) indicated that SCY-078 citrate Type A and SCY-078 citrate Type B were generated. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 30 
               
             
             
               
                   
               
               
                 Solid vapor diffusion experiments 
               
             
          
           
               
                   
                 Solvent 
                 Form 
               
               
                   
                   
               
               
                   
                 EtOH 
                 Type A 
               
               
                   
                 EtOAc 
                 Type B 
               
               
                   
                 Acetone 
                 Type A 
               
               
                   
                 DCM 
                 Type A 
               
               
                   
                   
               
             
          
         
       
     
       Example 35 
       [0278]    Solution vapor diffusion of SCY-078 Citrate Type A: Solution vapor diffusion experiments were conducted under 5 conditions at room temperature. SCY-078 citrate Type A from Example 26 (˜10 mg) was dissolved in a solvent to obtain a clear solution in a 3-mL glass vial. The vial was then sealed into a 20-mL glass vial with a volatile anti-solvent (3 mL). The system was kept at room temperature for six days, which allowed sufficient time for precipitation. As no precipitation was observed, the samples were evaporated slowly to dryness at room temperature. The solids were separated and analyzed by XRPD. The results (Table 31) indicated that no crystalline form was obtained. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 31 
               
             
             
               
                   
               
               
                 Solution vapor diffusion experiments 
               
             
          
           
               
                   
                 Anti- 
                   
                   
               
               
                 Solvent 
                 solvent 
                 Observation 
                 Form 
               
               
                   
               
               
                 Acetic Acid 
                 EtOH 
                 Clear 
                 Amorphous via slow 
               
               
                   
                   
                   
                 evaporation 
               
               
                 DMSO 
                 Acetone 
                 Clear 
                 Amorphous via slow 
               
               
                   
                   
                   
                 evaporation 
               
               
                 DMAc 
                 IPAc 
                 Clear 
                 Clear solution after slow 
               
               
                   
                   
                   
                 evaporation at RT for 2 weeks 
               
               
                 IPA 
                 DCM 
                 Clear 
                 Amorphous via slow 
               
               
                   
                   
                   
                 evaporation 
               
               
                 NMP 
                 MTBE 
                 Clear 
                 Clear solution after slow 
               
               
                   
                   
                   
                 evaporation at RT for 2 weeks 
               
               
                   
               
             
          
         
       
     
       Example 36 
       [0279]    Polymer Induced Crystallization of SCY-078 Citrate Type A: Polymer induced crystallization experiments were performed under four conditions. SCY-078 citrate Type A from Example 26 (˜10 mg) was dissolved in a solvent (0.1 mL -0.8 mL) in a 3-mL glass vial. A mixed polymer (-1.0 mg) was added into the visually clear solutions. The “mixed polymer” was a mixture of six polymers (polyvinyl alcohol, polyvinylchloride, polyvinyl pyrrolidone, polyvinyl acetate, hypromellose, and methyl cellulose) at the mass ration of 1.0. All the samples were then evaporated slowly at room temperature to dryness. The solids obtained were isolated for XRPD analysis. The results (Table 32) showed that no crystalline form was observed. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 32 
               
             
             
               
                   
               
               
                 Polymer induced crystallization experiments 
               
             
          
           
               
                   
                 Solvent 
                 Form 
               
               
                   
                   
               
               
                   
                 MeOH 
                 Amorphous 
               
               
                   
                 THF 
                 Amorphous 
               
               
                   
                 1,4-Dioxane 
                 Amorphous 
               
               
                   
                 MeOH/EtOH, 9/1 
                 Amorphous 
               
               
                   
                 MeOH/Acetone, 9/1 
                 Amorphous 
               
               
                   
                   
               
             
          
         
       
     
       Example 37 
       [0280]    Slow cooling of SCY-078 Citrate Type A: Slow cooling experiments were conducted under 10 conditions (Table 33). SCY-078 citrate Type A from Example 26 (˜10 mg) was suspended in a solvent (0.1 mL -0.2 mL) at 50° C. Suspensions were filtered at 50° C., and the filtrates were collected and cooled from 50° C. to 5° C. at a rate of 0.1° C./min. All solutions were clear and subjected to slow evaporation at room temperature to induce precipitation. The solids were isolated for XRPD analysis. The results (Table 33) indicated that SCY-078 citrate Type C and SCY-078 citrate Type J were produced and that both SCY-078 citrate Type C and SCY-078 citrate Type J are freebase forms. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 33 
               
             
             
               
                   
               
               
                 Slow Cooling Experiments 
               
             
          
           
               
                   
                   
                 Observation 
                   
               
               
                   
                 Solvent, v/v 
                 (5° C.) 
                 Form 
               
               
                   
                   
               
               
                   
                 MeOH/Toluene, 
                 Clear 
                 Amorphous 
               
               
                   
                 9/1 
               
               
                   
                 IPA/ACN, 9/1 
                 Clear 
                 Amorphous 
               
               
                   
                 IPA/EtOAc, 9/1 
                 Clear 
                 Amorphous 
               
               
                   
                 THF/Toluene, 9/1 
                 Clear 
                 Amorphous 
               
               
                   
                 THF/DCM, 9/1 
                 Clear 
                 Amorphous 
               
               
                   
                 NMP/MTBE, 9/1 
                 Clear 
                 Amorphous 
               
               
                   
                 DMSO/Acetone, 
                 Clear 
                 Type C 
               
               
                   
                 9/1 
               
               
                   
                 DMAc/IPAc, 9/1 
                 Clear 
                 Type J 
               
               
                   
                 DMAc/ACN, 9/1 
                 Clear 
                 Type J 
               
               
                   
                   
               
             
          
         
       
     
       Example 38 
       [0281]    SCY-078 Citrate Type A via Reactive Crystallization: SCY-078 citrate Type A was obtained by reactive crystallization in ACN. The XRPD pattern showed distinctive diffraction peaks ( FIG. 45 ). DSC curve showed two endothermic peaks at 56.7° C. and 187.1° C. (onset temperatures) ( FIG. 46 ). TGA curve displayed a 7.9% weight loss up to 150° C. ( FIG. 46 ). DVS plot showed a water uptake of 7.0% at 80% RH ( FIG. 47 ). There was no form change after DVS analysis. 
         [0282]    SCY-078 citrate Type A was also tested with variable temperature XRPD analysis. No form change was observed upon heating SCY-078 citrate Type A to 120° C. and then cooling back to 25° C., indicating that SCY-078 citrate Type A is an anhydrate. 
         [0283]    After crystallization process development, SCY-078 citrate Type A exhibited higher crystallinity and less surface moisture adsorption was produced ( FIG. 49 ). DSC curve showed two endothermic peaks at 41.7° C. and 194.8° C. (onset temperatures). TGA curve displayed 2.9% weight loss up to 150° C. DVS analysis showed a water uptake of 6.5% at 25° C. and 80% RH. No form change was observed after DVS analysis.  1 H-NMR spectrum in CD 3 OD showed the molar ration of freebase and citric acid is 1:1, indicating that SCY-078 citrate Type A is mono-citrate. 
       Example 39 
       [0284]    SCY-078 Citrate Type B: SCY-078 citrate Type B was obtained by slurry conversion at room temperature in ACN. SCY-078 citrate Type B can also be obtained by slurrying SCY-078 citrate Type A in various organic solvents such as EtOH, ACN, acetone, MIBK, EtOAc, IPAc, DCM, toluene, heptane, MeOH/acetone (1/19, v/v), IPA/heptane (1/19, v/v), and THF/toluene (1/19, v/v). SCY-078 citrate Type B converts to Type A rapidly under vacuum or upon N 2  flow at room or elevated temperature. 
         [0285]    The XRPD pattern of SCY-078 citrate Type B showed distinctive diffraction peaks ( FIG. 51 ). DSC curve exhibited three endothermic peaks at 70.8° C., 190.6° C., and 202.9° C. (peak temperatures) ( FIG. 52 ). TGA curve displayed 10.3% weight loss up to 150° C. ( FIG. 52 ). 
       Example 40 
       [0286]    SCY-078 Citrate Type E: SCY-078 citrate Type E was obtained by drying a metastable solvate SCY-078 citrate Type R from MeOH/IPAc. The XRPD pattern shows the crystalline form of the sample ( FIG. 53 ).SCY-078 citrate Type E is not stable at ambient conditions, since it rapidly converts to a new form (SCY-078 citrate Type M) after exposing to air for 2 days ( FIG. 54 ). 
       Example 41 
       [0287]    SCY-078 Citrate Type F: SCY-078 citrate Type F was obtained by reverse anti-solvent addition in IPA/toluene according to the process described in Example 33 and Table 29. The XRPD pattern indicated that SCY-078 citrate Type F is weakly crystalline ( FIG. 55 ). DSC curve exhibited a wide endothermic peak at 37.3° C. (onset temperature)( FIG. 56 ). TGA curve displayed a weight loss of 11.8% up to 120° C. ( FIG. 56 ). 
       Example 42 
       [0288]    SCY-078 Citrate Type M: SCY-078 citrate Type M was obtained by storing SCY-078 citrate Type E in ambient conditions for 2 days. The XRPD pattern of SCY-078 citrate Type M displayed distinctive diffraction peaks ( FIG. 57 ). DSC curve exhibited two endothermic peaks at 125.8° C. and 193.3° C. (onset temperatures) ( FIG. 58 ). TGA curve displayed a 11.4% weight loss up to 150° C. ( FIG. 58 ). DVS plot showed 11.0% water uptake at 25° C. and 80% RH ( FIG. 59 ). After DVS, SCY-078 citrate Type M converts to partially amorphous. 
         [0289]    XRPD analysis was also performed at variable temperatures wherein XRPD patterns were produced at 25° C., then at 150° C., and finally, again at 25° C. ( FIG. 60 ). A shift in diffraction peaks was observed, indicating that Type M is probably a channel hydrate. 
       Example 43 
       [0290]    SCY-078 Citrate Type N: SCY-078 citrate Type N was obtained by slurrying SCY-078 citrate Type B in EtOH at room temperature for two weeks. SCY-078 citrate Type N can also be obtained by exposing SCY-078 citrate Type A in EtOH vapor for 8 days or slurrying SCY-078 citrate Type A in EtOH for 2 hours. The XRPD pattern of SCY-078 citrate Type N indicates that it is highly crystalline ( FIG. 61 ). SCY-078 citrate Type N converts to SCY-078 citrate Type A after vacuum drying at room temperature ( FIG. 62 ), indicating SCY-078 citrate Type N is a metastable EtOH solvate, which rapidly converts to SCY-078 citrate Type A under vacuum or upon air/N 2  drying at ambient temperature or elevated temperature. 
       Example 44 
       [0291]    SCY-078 Citrate Type O: SCY-078 citrate Type O was obtained by slurrying SCY-078 citrate Type M in acetone at room temperature for 19 hours. The XRPD pattern of SCY-078 citrate Type O indicated that it is highly crystalline with distinctive diffraction peaks ( FIG. 63 ). SCY-078 citrate Type O converts to SCY-078 citrate Type S under ambient or vacuum conditions. 
       Example 45 
       [0292]    SCY-078 Citrate Type Q: SCY-078 citrate Type Q was obtained when performing reactive crystallization of freebase and citric acid (1:1) in EtOH without seeds. SCY-078 citrate Type N was consistently obtained when the reactive crystallization was performed using SCY-078 citrate Type N or SCY-078 citrate Type A seeds. The XRPD pattern showed SCY-078 citrate Type Q is highly crystalline with distinctive diffraction peaks ( FIG. 64 ). SCY-078 citrate Type Q can convert to SCY-078 citrate Type A after vacuum drying at room temperature, indicating that SCY-078 citrate Type Q is a metastable EtOH solvate ( FIG. 65 ). 
         [0293]    The stability of the two EtOH solvates, SCY-078 citrate Type N and SCY-078 citrate Type Q, was evaluated by measuring their solubility at 5° C. and 20° C. (Table 34). The solubility was measured by slurrying SCY-078 citrate Type N and SCY-078 citrate Type Q samples in EtOH for 24 hours with a magnetic stirring rate of 1000 rpm. SCY-078 citrate Type Q exhibited lower solubility than SCY-078 citrate Type N in EtOH at 5° C. and 20° C., indicating that SCY-078 citrate Type Q is thermodynamically more stable in EtOH from 5° C. to 20° C. XRPD analysis of the remaining wet cakes from the solubility experiments showed no form change for both SCY-078 citrate Type Q and SCY-078 citrate Type N. 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE 34 
               
             
             
               
                   
               
               
                 Solubility (mg/mL) of SCY-078 citrate Type N and SCY-078 citrate 
               
               
                 Type Q in EtOH at different temperatures 
               
             
          
           
               
                 Temperature (° C.) 
                 Type N 
                 Type Q 
               
               
                   
               
             
          
           
               
                 5 
                 24.4 
                 17.4 
               
               
                 20 
                 27.1 
                 25.9 
               
               
                   
               
             
          
         
       
     
       Example 46 
       [0294]    SCY-078 Citrate Type R: SCY-078 citrate Type R was obtained by slurrying SCY-078 citrate Type M in MeOH/IPAc (1/14, v/v) for 17 hours. SCY-078 citrate Type R can also be obtained by reverse anti-solvent addition in MeOH/IPAc. The XRPD pattern indicated that SCY-078 citrate Type R is weakly crystalline ( FIG. 66 ). XRPD analysis also indicated that SCY-078 citrate Type R is a metastable solvate that can easily convert to SCY-078 citrate Type S upon air drying and to SCY-078 citrate Type M after vacuum drying ( FIG. 67 ). 
       Example 47 
       [0295]    SCY-078 Citrate Type S: SCY-078 citrate Type S can be obtained by drying SCY-078 citrate Type O sample under ambient or vacuum condition. The XRPD patterns showed shift of diffraction peaks after conversion from SCY-078 citrate Type O to SCY-078 citrate Type S ( FIG. 68 ). DSC curve exhibited two endothermic peaks at 35.7° C. and 188.0° C. (onset temperatures) ( FIG. 69 ). TGA curve displayed 6.6% weight loss up to 100° C. ( FIG. 69 ). DVS plot showed 8.2% water uptake at 25° C. and 80% RH for SCY-078 citrate Type S ( FIG. 70 ). XRPD analysis after DVS showed peak shifts. XRPD analysis was further performed at variable temperatures 30° C. to 120° C. and back to 40° C., which showed a shift of diffraction peaks ( FIG. 71 ). 
       Example 48 
       [0296]    Disproportionation of SCY-078 Citrate Salt: Crystalline forms of SCY-078 citrate named Type C, Type I, Type J, and Type P were observed either during polymorph study or when investigating the inter-conversion relationship of different SCY-078 citrate forms. XRPD patterns of the four forms ( FIG. 72 ) demonstrated that SCY-078 citrate Type C and SCY-078 citrate Type J are freebase forms and that SCY-078 citrate Type I and SCY-078 citrate Type P are likely freebase forms. 
         [0297]    SCY-078 citrate Type I was obtained in DMSO/EtOH system. SCY-078 citrate Type P was obtained by slurrying SCY-078 citrate Type M in acetone/H 2 O system. SCY-078 citrate Type A disproportionated to the freebase (SCY-078 citrate Type C, which converts to SCY-078 citrate Type J upon drying) when slurrying in EtOH/H 2 O, acetone/H 2 O, and BuOH/H 2 O systems. Slurrying SCY-078 citrate Type A or evaporating the citrate solution in DMSO, DMAc and DCM-related co-solvents also resulted in disproportionation. 
       Example 49 
       [0298]    Inter-conversion Between SCY-078 Citrate Type A and Citrate Type B: Slurry experiments were performed with SCY-078 citrate Type A in different organic solvents in order to understand the inter-conversion between SCY-078 citrate Type A and SCY-078 citrate Type B. SCY-078 citrate Type A (-20 mg) was suspended into a solvent (0.5 mL) in a 1.5-mL glass vial. After the suspensions were ultrasonicated for 1 hour or stirred for 6 hours at room temperature, the remaining solids were isolated for XRPD analysis. The results (Table 35) indicated that SCY-078 citrate Type B can be obtained from various organic solvents. SCY-078 citrate Type B was also prepared from SCY-078 citrate Type A by slurry in EtOH, ACN, acetone, MIBK, EtOAc, IPAc, DCM, toluene, heptane, MeOH/acetone (1/19), IPA/heptane (1/19), THF/toluene (1/19) or by solid vapor diffusion in EtOAc. SCY-078 citrate Type B can convert to SCY-078 citrate Type A via drying under N 2  or vacuum at room temperature. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 35 
               
             
             
               
                   
               
               
                 Summary of preparation methods of SCY-078 citrate Type B 
               
             
          
           
               
                   
                   
                   
                 Form, 
                   
               
               
                   
                   
                   
                 Vacuum 
               
               
                   
                   
                 Form, Wet 
                 filtered 
                 Form after N 2   
               
               
                 Solvent 
                 Preparation 
                 Slurry 
                 slurry 
                 drying at RT 
               
               
                   
               
               
                 ACN 
                 Ultrasonication for 1 hr 
                 Type B 
                 Type A 
                 Type A 
               
               
                 DCM 
                 Ultrasonication for 1 hr 
                 Type B 
                 Type A 
                 Type A 
               
               
                 EtOAc 
                 Stirring for 6 hrs 
                 Type B 
                 Type B 
                 Type A 
               
               
                   
               
             
          
         
       
     
       Example 50 
       [0299]    Inter-conversion between SCY-078 citrate Type A and SCY-078 citrate Type N and SCY-078 citrate Type Q: SCY-078 citrate Type N can be obtained by slurrying SCY-078 citrate Type A (or SCY-078 citrate Type B) in EtOH with ultrasonication or at room temperature for 1 hour. SCY-078 citrate Type N rapidly converts to SCY-078 citrate Type A via vacuum filtration ( FIG. 73 ). 
         [0300]    SCY-078 citrate Type Q was obtained by reactive crystallization of freebase MeOH desolvate and citric acid (1:1) in EtOH without seeds. After drying in vacuum at room temperature, SCY-078 citrate Type Q converts to SCY-078 citrate Type A ( FIG. 74 ). The study of the inter-conversion between SCY-078 citrate Type A and SCY-078 citrate Type N and SCY-078 citrate Type Q is summarized below in Table 36. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 36 
               
             
             
               
                   
               
               
                 Slurry conversion of SCY-078 citrate Type A or 
               
               
                 SCY-078 citrate Type B to SCY-078 citrate Type N 
               
             
          
           
               
                   
                   
                   
                 Form, 
                 Form, 
               
               
                 Starting Material 
                 Method 
                 Solvent 
                 Wet Slurry 
                 Vacuum Dry 
               
               
                   
               
               
                 Type A 
                 Ultrasonication 
                 EtOH 
                 Type N 
                 Type A 
               
               
                 Type B 
                 Ultrasonication 
                 EtOH 
                 Type N 
                 Not 
               
               
                   
                   
                   
                   
                 Measured 
               
               
                 MeOH 
                 Reactive 
                 EtOH 
                 Type Q 
                 Type A 
               
               
                 desolvate/citric 
                 crystallization 
               
               
                 acid (1:1) 
               
               
                   
               
             
          
         
       
     
       Example 51 
       [0301]    Inter-conversion Relationship Around Channel Hydrate SCY-078 Citrate Type M: Metastable solvate SCY-078 citrate Type R was obtained by reverse anti-solvent addition in MeOH/IPAc. SCY-078 citrate Type R converted to SCY-078 citrate Type E after drying in vacuum at room temperature, and then SCY-078 citrate Type M was obtained by storing SCY-078 citrate Type E under ambient conditions for 2 days ( FIG. 75 ). SCY-078 citrate Type R was found to convert to SCY-078 citrate Type M directly upon vacuum drying at room temperature. 
         [0302]    Slurry experiments were performed on SCY-078 citrate Type M in selected organic solvents. The results (Table 37) indicated that SCY-078 citrate Type M converted to SCY-078 citrate Type 0 after slurrying in acetone for 17 hours, and SCY-078 citrate Type 0 converted to SCY-078 citrate Type S after air drying ( FIG. 76 ). SCY-078 citrate Type M converted to SCY-078 citrate Type A when slurried in ACN ( FIG. 77 ), and converted to metastable solvate SCY-078 citrate Type R in MeOH/IPAc co-solvent ( FIG. 78 ). SCY-078 citrate Type R converted to SCY-078 citrate Type S upon air drying and converted back to SCY-078 citrate Type M through vacuum drying at room temperature. No form change was observed by slurrying SCY-078 citrate Type M in heptane ( FIG. 79 ). 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 37 
               
             
             
               
                   
               
               
                 Slurry experiments result of SCY-078 citrate Type M in 
               
               
                 organic solvents 
               
             
          
           
               
                   
                 Solvent 
                 Condition 
                 Solid Form 
               
               
                   
                   
               
               
                   
                 Acetone 
                 10 mins 
                 Amorphous 
               
               
                   
                   
                 ultrasonication/wet 
               
               
                   
                   
                 17 hrs (slurry) wet 
                 Type O 
               
               
                   
                   
                 17 hrs (slurry) dry under 
                 Type S 
               
               
                   
                   
                 ambient conditions 
               
               
                   
                 ACN 
                 10 mins 
                 Type M 
               
               
                   
                   
                 ultrasonication/wet 
               
               
                   
                   
                 17 hrs (slurry) wet 
                 Type B 
               
               
                   
                   
                 17 hrs (slurry) dry under 
                 Type A 
               
               
                   
                   
                 ambient conditions 
               
               
                   
                 Heptane 
                 10 mins 
                 Type M 
               
               
                   
                   
                 ultrasonication/wet 
               
               
                   
                   
                 17 hrs (slurry) wet 
                 Type M 
               
               
                   
                   
                 17 hrs (slurry) dry under 
                 Type M 
               
               
                   
                   
                 ambient conditions 
               
               
                   
                 MeOH/IPAc 
                 10 mins 
                 Type M 
               
               
                   
                 (5/70, v/v) 
                 ultrasonication/wet 
               
               
                   
                   
                 17 hrs (slurry) wet 
                 Type R* 
               
               
                   
                   
                 17 hrs (slurry) dry under 
                 Type S 
               
               
                   
                   
                 ambient conditions 
               
               
                   
                   
               
               
                   
                 *Type R converts to Type M after vacuum drying at RT 
               
             
          
         
       
     
       Example 52 
       [0303]    Stability Study of SCY-078 Citrate Type A, SCY-078 Citrate Type M, and SCY-078 Citrate Type S: As described in Example 25 and Table 19, SCY-078 citrate Type A is physically/chemically stable at the tested conditions for at least 1 week. To test the physical and chemical stability of SCY-078 citrate Type M and SCY-078 citrate Type S, each was placed under three different conditions: (1) open dish at 25° C. with 60% RH; (2) open dish at 40° C. with 75% RH; and (3) closed dish at 60° C. with no humidity control. SCY-078 citrate Type M was tested for 4 days and SCY-078 citrate Type S was tested for 1 week ( FIGS. 80-81 ). 
         [0304]    The results (Table 38) showed that SCY-078 citrate Type M was physically and chemically stable at 25° C. and 60% RH for at least 4 days. One diffraction peak change and partial crystallinity loss was observed in the XRPD pattern of SCY-078 citrate Type M after storage at 40° C. and 75% RH. This is consistent with the previous observation in Example 42 that SCY-078 citrate Type M partially converts to amorphous after DVS analysis. The impurity of SCY-078 citrate Type M increased under closed conditions at 60° C. for 4 days. 
         [0305]    SCY-078 citrate Type S is physically and chemically stable under 60° C. closed conditions for one week. Diffraction peak shifts were observed for the samples stored at 25° C. and 60% RH and 40° C. and 75% RH. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 38 
               
             
             
               
                   
               
               
                 Physical and Chemical Stability of SCY-078 citrate Type M 
               
               
                 and SCY-078 citrate Type S 
               
             
          
           
               
                   
                   
                   
                 Impurity % 
                 Solid 
               
               
                   
                 Sample 
                 Condition 
                 by HPLC 
                 Form 
               
               
                   
                   
               
               
                   
                 Type M 
                 Initial 
                 0.42 
                 Type M 
               
               
                   
                 (4 days) 
                 25° C./60% 
                 0.39 
                 Type M 
               
               
                   
                   
                 RH 
               
               
                   
                   
                 40° C./75% 
                 0.00 
                 Type M* 
               
               
                   
                   
                 RH 
               
               
                   
                   
                 60° C. closed 
                 0.63 
                 Type M 
               
               
                   
                 Type S 
                 Initial 
                 0.10 
                 Type S 
               
               
                   
                 (1 week) 
                 25° C./60% 
                 0.03 
                 Type S** 
               
               
                   
                   
                 RH 
               
               
                   
                   
                 40° C./75% 
                 0.03 
                 Type S** 
               
               
                   
                   
                 RH 
               
               
                   
                   
                 60° C. closed 
                 0.11 
                 Type S 
               
               
                   
                   
               
               
                   
                 *One peak change was observed for the sample 
               
               
                   
                 **Peak shifts were observed for the samples 
               
             
          
         
       
     
       Example 53 
       [0306]    Alternative Preparation of SCY-078 Citrate Type A: A 10-L reactor was charged with SCY-078 phosphate (450 g; freebase content in phosphate was 85.6% by HPLC). 2-MeTHF (2.25 L) was charged into the same reactor. A 10% Na 2 CO 3  water solution (2.25 L) at 20° C. was charged into the reaction in 25 min. The suspension was stirred at 20° C. for 20 min and then allowed to settle for 30 min. The organic layer was collected and washed with 1.8 L of saturated NaCl water solution twice, and then further washed with 1.8 L deionized water once. 
         [0307]    The organic layer was transferred to a 4-L crystallizer. The reactor was rinsed with 250 mL 2-MeTHF and the liquid was transferred into the crystallizer containing the organic layer. The solution was concentrated in the crystallizer to 900 mL at 50° C. The crystallizer was charged with 900 mL methanol and the mixture was cooled to 40° C. The mixture was stirred at 40° C. for 1 hour (clear). 4.5 g of seeds were added to the crystallizer and the suspension was aged at 40° C. for 1 hour. The mixture was then concentrated to 900 mL at 40° C. The crystallizer was then charged with 900 mL methanol and again concentrated to 900 mL at 40° C. This step was repeated twice more and the mother liquor was assayed by gas chromatography. The mixture was cooled to 10° C. in 2 hours and then aged at 10° C. for no less than three hours. The mother liquor was sampled for solution concentration by HPLC. The suspension was filtered and the cake was dried in a vacuum over at 35° C. for 12 hours. 
         [0308]    To generate the citrate salt, a 10-L jacketed crystallizer with a twin-impeller over-head agitator was used. The diameter of the impeller is 13 cm. First, EtOH (500 mL) was added into a 10-L crystallizer (Crystallizer 1) and was agitated (300 rpm). The temperature of Crystallizer 1 was maintained at 25° C. The SCY-078 freebase (242.09 g) was added to Crystallizer 1. Another volume of EtOH (500 mL) was charged into Crystallizer 1. Crystallizer 1 was heated to 50° C. A citric acid solution, prepared by dissolving citric acid (58.22 g) into EtOH (758 mL), was charged into Crystallizer 1 in 35 min. Crystallizer 1 was heated to 55° C. and stirred for 20 minutes. Then Crystallizer 1 was cooled to 50° C. for 20 minutes. 
         [0309]    After cooling, the extraneous matter was filtered (pore size of 30˜50 μm) and the filtrate was transferred to another 10-L crystallizer (Crystallizer 2). The filter was washed with EtOH (5 mL) and transferred into Crystallizer 2. The mixture in Crystallizer 2 was stirred at 50° C. for 30 minutes. Next a seed slurry, which was prepared from seeds (13.22 g) that were sonicated and dispersed in 50/50 EtOH/n-heptane (68 mL), was rapidly charged into Crystallizer 2. The mixture in Crystallizer 2 was aged at 50° C. for 2 hours. Crystallizer 2 was then charged with n-heptane (1758 mL) for 12 hours at 50° C. The mixture was again aged at 50° C. for 2 hours. From the resulting mixture, a sample was taken for XRPD analysis and microscopy. 
         [0310]    The mixture was cooled to 20° C. in 2 hours and then stirred at 20° C. for 3 hours. The batch was filtered and the cake was washed with a solution of 1:1 EtOH/n-heptune (500 mL). The cake was blown with N 2  for 60 minutes. Finally, the cake was dried at 45-55° C. with N 2  blowing. 
         [0311]    Ultimately 241 grams of product was obtained with a 86.4% yield. XRPD analysis showed that the product was highly crystalline SCY-078 citrate Type A ( FIG. 82 ). TGA curve showed a weight loss of 2.2% before 150° C. ( FIG. 83 ). The DSC curve showed a melting point of 197.8° C. (onset temperature) ( FIG. 83 ). The resulting crystals were rod-like with an average size of 34.2 pm ( FIG. 84 ). 
       Example 54 
       [0312]    Preparation and characterization of SCY-078 Trifluoroacetate Type A: SCY-078 amorphous freebase (994.3 mg) and trifluoroacetic acid (freebase/acid molar ratio—1/1) were weighted into a 5-mL vial, followed by addition of 5 mL acetonitrile. The mixture was slurried at RT with a magnetic stirring rate of 1000 rpm for 4 days. The suspension was centrifuged and vacuum dried at RT overnight. 
         [0313]    SCY-078 Trifluoroacetate Type A is highly crystalline as shown in the XRPD ( FIG. 85 ). A weight loss of 1.1% is observed up to 120° C. in the TGA curve ( FIG. 86 ). The DSC ( FIG. 86 ) shows two endothermic peaks, one at 65.8° C. and 229.8° C. Trifluoroacetate Type A converted to Type B after stored under ambient conditions for 2 days ( FIG. 87 ). The molar ratio of trifluoroacetate Type A (acid: freebase) was determined to be 1:1 via HPLC-IC confirmation. 
       Example 55 
       [0314]    Preparation and characterization of SCY-078 Trifluoroacetate Type B: Trifluoroacetic acid (331.5 mg) was added into acetonitrile (8 mL) in a 20-mL glass vial, followed by addition of amorphous SCY-078 freebase Type A (freebase/acid molar ratio =1/1). The mixture was stirred at RT with a magnetic stirring rate of 600 rpm for 24 hours. The suspension was vacuum filtered and dried at RT for 20 hours. Trifluoroacetate Type A was obtained (2.18 g), which converted to Trifluoroacetate Type B after storage at ambient conditions for almost 1 month. 
         [0315]    SCY-078 Trifluoroacetate Type B is highly crystalline as shown in the XRPD ( FIG. 88 ). A weight loss of 4.7% is observed up to 120° C. in the TGA curve ( FIG. 89 ). The DSC ( FIG. 89 ) shows two endothermic peaks, one at 92.8° C. and 230.0° C. Due to the reversible conversation of Trifluoroacetate Type A and Type B, the molar ratio of Trifluoroacetate Type B (acid:freebase) is postulated to be 1:1, same as Type A. 
         [0316]    From the DVS ( FIG. 90 ), 3.4 wt % of water uptake was observed at 25° C. 80% RH, indicating that Type B is moderately hygroscopic. The DVS revealed potential form change with respect to RH, estimated to be between 30% RH and 40% RH. SCY-078 Trifluoroacetate Type B converted to Type A after DVS as shown in  FIG. 91 . 
         [0317]    To investigate transition relationship of trifluoroacetate Type A and Type B, both samples were stored in chambers with varying relative humidity to monitor any form change. Summary of trifluoroacetate Type B stored at varying relative humidity is listed in Table 39, and XRPD patterns overlay is displayed in  FIG. 92 . Trifluoroacetate Type B converted to Type A only at high relative humidity (97% RH) while Type B is stable at low relative humidity (&lt;22% RH). Varying temperature (VT)-XRPD of trifluoroacetate Type A was performed. VT-XRPD patterns overlay is displayed in  FIG. 93 . Type A converted to Type B after heated to 120° C. 
         [0000]    
       
         
               
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 39 
               
             
             
               
                   
                   
               
               
                   
                 Relativity Humidity 
               
             
          
           
               
                   
                 0% 
                 22% 
                 97% 
               
               
                   
                   
               
             
          
           
               
                   
                 TFA Type B 
                 Type B 
                 Type B 
                 Type A 
               
               
                   
                   
               
               
                   
                 The XRPD patterns were collected after storage for 24 hours. 
               
             
          
         
       
     
       Example 56 
       [0318]    Preparation and characterization of SCY-078 HCl Type I: 342.7 μL of concentrated HCl (37.5%) was dispersed in 40 mL of acetone. 2.0 mg of SCY-078 freebase Type A (freebase/acid molar ratio=1/1.5) was added. The suspension was settled in a biochemical incubator to perform heat-cooling cycles (50° C.˜20° C.) with a magnetic stirring rate of 600 rpm. The suspension was cooled to 5° C. at a rate of 0.1° C./min and aged at 5° C. for 17 hours. The wet cake was vacuum filtered and dried at RT for 20 hours. SCY-078 HCl Type I (2.06 g) was obtained. 
         [0319]    SCY-078 HCl Type I is highly crystalline as shown in the XRPD ( FIG. 94 ). A weight loss of 4.2% is observed up to 120° C. in the TGA curve ( FIG. 95 ). The DSC ( FIG. 95 ) shows three endothermic peaks, one at 46.2° C., one at 115.5° C. and one at 274.3° C. The molar ratio of SCY-078 HCl Type I (acid:freebase) was determined to be 1.5:1 via HPLC-IC. 
         [0320]    From the DVS ( FIG. 96 ), 6.1 wt % of water uptake was observed at 25° C./80% RH, indicating HCl Type I is moderately hygroscopic. No form change was observed after DVS characterization as shown in  FIG. 97 . 
       Example 57 
       [0321]    Preparation and characterization of SCY-078 HCl Type II: SCY-078 HCl Type II was obtained by suspending HCl Type I in acetate buffer (pH 5.5) for 4 hours. The XRPD pattern ( FIG. 98 ) indicates Type II is highly crystalline. The TGA shows that HCl Type II exhibits a weigh loss of 6.9% up to 150° C. and the DSC shows an endothermic peak at 48.3° C. (onset temperature), as shown in  FIG. 99 . 
       Example 58 
       [0322]    The solubility of trifluoroacetate Type A, Type B and HCl Type I was measured in SGF at ambient temperature. Approximately 90 mg of solid sample was weighted into a 4-mL centrifuge tube, and 3 mL of SGF buffer was added before leaving the suspension on a rolling incubator (25 r/min). 1.0 mL aliquot of the suspension was sampled for centrifugation (10000 rpm, 3 mins) the supernatant was analyzed by HPLC and pH measurement and solid by XRPD characterization at 1 hr, 4 hr and 24 hrs, respectively. The results are summarized in Table 40 and the solubility curves are displayed in  FIG. 100 . All three salts exhibit high solubility in SGF (&gt;20 mg/mL at 24 hrs). Trifluoroacetate Type B converted to Type A in SGF after an hour. However, no form change was observed of trifluoroacetate Type A and HCl Type I in SGF. The XRPD patterns of residual solid are shown in  FIG. 101 ,  FIG. 102 , and  FIG. 103 . 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 40 
               
             
             
               
                   
               
               
                   
                 1 hr 
                 4 hrs 
                 24 hrs 
               
             
          
           
               
                 Starting 
                   
                   
                 Form 
                   
                   
                 Form 
                   
                   
                 Form 
               
               
                 Material 
                 S 
                 pH 
                 change 
                 S 
                 pH 
                 change 
                 S 
                 pH 
                 change 
               
               
                   
               
               
                 TFA 
                 15.9 
                 2.2 
                 No 
                 19.8 
                 2.2 
                 No 
                 23.2 
                 2.1 
                 No 
               
               
                 Type A 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 TFA 
                 14.3 
                 2.0 
                 Yes 
                 18.4 
                 2.0 
                 Yes 
                 21.4 
                 1.8 
                 Yes 
               
               
                 Type B 
                   
                   
                 (Type A) 
                   
                   
                 (Type A) 
                   
                   
                 (Type A) 
               
               
                 HCl 
                 11.7 
                 1.7 
                 No 
                 17.7 
                 1.9 
                 No 
                 25.1 
                 1.8 
                 No 
               
               
                 Type I 
               
               
                   
               
               
                 S: solubility, mg/mL. 
               
             
          
         
       
     
       Example 59 
       [0323]    The solubility of trifluoroacetate Type A, Type B and hydrochloride Type I was measured in the FaSSIF alternative media at ambient temperature. Approximately 15 mg of solid sample was weighted into a 4-mL plastic tube, and 3 mL of the media was added before leaving the suspension on a rolling incubator (25 r/min). 1.0 mL aliquot of the suspension was sampled for centrifugation with the supernatant submitted for HPLC and pH measurement and solid for XRPD characterization at 1 hr, 4 hr and 24 hrs, respectively. The results are summarized in Table 41 and the solubility curves are displayed in  FIG. 104 . All three salts exhibit poor solubility in the FaSSIF alternative media (&lt;0.01 mg/mL at 24the kinetic hrs). Trifluoroacetate Type B converted to Type A after an hour. However, no form change was observed of trifluoroacetate Type A and HCl Type I. The XRPD patterns of residual solid are shown in  FIG. 105 ,  FIG. 106 , and  FIG. 107 . 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 41 
               
             
             
               
                   
               
               
                   
                 1 hr 
                 4 hrs 
                 24 hrs 
               
             
          
           
               
                 Starting 
                   
                   
                 Form 
                   
                   
                 Form 
                   
                   
                 Form 
               
               
                 Material 
                 S 
                 pH 
                 change 
                 S 
                 pH 
                 change 
                 S 
                 pH 
                 change 
               
               
                   
               
               
                 TFA 
                 &lt;LOD 
                 6.5 
                 No 
                 &lt;LOD 
                 6.4 
                 No 
                 &lt;LOD 
                 6.4 
                 No 
               
               
                 Type A 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 TFA 
                 &lt;LOD 
                 6.4 
                 Yes 
                 &lt;LOD 
                 6.4 
                 Yes 
                 &lt;LOD 
                 6.3 
                 Yes 
               
               
                 Type B 
                   
                   
                 (Type A) 
                   
                   
                 (Type A) 
                   
                   
                 (Type A) 
               
               
                 HCl 
                 0.0033 
                 5.0 
                 No 
                 0.0017 
                 5.3 
                 No 
                 0.0046 
                 5.1 
                 No 
               
               
                 Type I 
               
               
                   
               
               
                 S: solubility, mg/mL; 
               
               
                 LOD: 0.00064 mg/mL. 
               
             
          
         
       
     
       Example 60 
       [0324]    The solubility of trifluoroacetate Type A, Type B and HCl Type I was measured in the FeSSIF alternative media at ambient temperature. Approximately 36 mg of solid sample was weighted into a 4-mL plastic tube, and 3 mL of the media was added before leaving the suspension on a rolling incubator (25 r/min). 1.0 mL aliquot of the suspension was sampled for centrifugation with the supernatant submitted for HPLC and pH measurement and solid for XRPD characterization at 1 hr, 4 hr and 24 hrs, respectively. The results are summarized in Table 42 and the solubility curves are displayed in  FIG. 108 . All three salts exhibit a solubility of ˜3 mg/mL at first one hour. HCl Type I exhibits an equilibrium solubility of 3.5 mg/mL at 24 hrs, while trifluoroacetate (both Type A and Type B) exhibit a decreasing solubility after an hour. Trifluoroacetate Type A converted to Type B after an hour. However, no form change was observed of trifluoroacetate Type B and hydrochloride Type I. The XRPD patterns of residual solid were included in  FIG. 109 ,  FIG. 110 , and  FIG. 111 . 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 42 
               
             
             
               
                   
               
               
                   
                 1 hr 
                 4 hrs 
                 24 hrs 
               
             
          
           
               
                 Starting 
                   
                   
                 Form 
                   
                   
                 Form 
                   
                   
                 Form 
               
               
                 Material 
                 S 
                 pH 
                 change 
                 S 
                 pH 
                 change 
                 S 
                 pH 
                 change 
               
               
                   
               
               
                 TFA 
                 3.0 
                 5.0 
                 Yes 
                 2.1 
                 5.0 
                 Yes 
                 0.5 
                 5.0 
                 Yes 
               
               
                 Type A 
                   
                   
                 (Type B) 
                   
                   
                 (Type B) 
                   
                   
                 (Type B) 
               
               
                 TFA 
                 3.3 
                 5.0 
                 No 
                 3.0 
                 5.0 
                 No 
                 1.1 
                 4.9 
                 No 
               
               
                 Type B 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 HCl 
                 2.9 
                 4.8 
                 No 
                 3.5 
                 4.8 
                 No 
                 3.5 
                 4.9 
                 No 
               
               
                 Type I 
               
               
                   
               
               
                 S: solubility, mg/mL. 
               
             
          
         
       
     
       Example 61 
       [0325]    The solubility of trifluoroacetate Type A, Type B and HCl Type I was measured in acetate buffer (pH 5.5) at ambient temperature. Approximately 15 mg of solid sample was weighted into a 4-mL plastic tube, and 3 mL of acetate pH 5.5 buffer was added before leaving the suspension on a rolling incubator (25 r/min). 1.0 mL aliquot of the suspension was sampled for centrifugation with the supernatant submitted for HPLC and pH measurement and solid for XRPD characterization at 4 hr and 24 hrs, respectively. The results are summarized in Table 43 and the solubility curves are displayed in  FIG. 112 . Trifluoroacetate Type A exhibits higher solubility in acetate pH 5.5 buffer, and no form change was observed. However, Type B converted to Type A in acetate pH 5.5 buffer. While HCl Type I exhibits lower solubility in acetate pH 5.5 buffer comparing with trifluoroacetate, and HCl Type I converted to Type II in acetate pH 5.5 buffer. The XRPD patterns of residual solid were included in  FIG. 113 ,  FIG. 114 , and  FIG. 115 . 
         [0000]    
       
         
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 43 
               
             
             
               
                   
               
               
                   
                 4 hrs 
                 24 hrs 
               
             
          
           
               
                 Starting 
                   
                   
                 Form 
                   
                   
                 Form 
               
               
                 Material 
                 S 
                 pH 
                 change 
                 S 
                 pH 
                 change 
               
               
                   
               
             
          
           
               
                 TFA 
                 1.9 
                 5.5 
                 No 
                 3.5 
                 5.4 
                 No 
               
               
                 Type A 
                   
                   
                   
                   
                   
                   
               
               
                 TFA 
                 0.89 
                 5.4 
                 Yes 
                 2.2 
                 5.2 
                 Yes 
               
               
                 Type B 
                   
                   
                 (Type A + B) 
                   
                   
                 (Type A) 
               
               
                 HCl 
                 0.59 
                 4.8 
                 Yes 
                 1.1 
                 4.9 
                 Yes 
               
               
                 Type I 
                   
                   
                 (Type II) 
                   
                   
                 (Type II) 
               
               
                   
               
               
                 S: solubility, mg/mL. 
               
             
          
         
       
     
       Example 62 
       [0326]    The solubility of trifluoroacetate Type A, Type B and HCl Type I was measured in the phosphate (pH 6.0) alternative media at ambient temperature. Approximately 15 mg of solid sample was weighted into a 4-mL plastic tube, and 3 mL of media was added before leaving the suspension on a rolling incubator (25 r/min). 1.0 mL aliquot of the suspension was sampled for centrifugation with the supernatant for HPLC and pH measurement and solid for XRPD characterization at 4 hr and 24 hrs, respectively. The results are summarized in Table 44, and the solubility curves are displayed in  FIG. 116 . HCl Type I exhibits higher solubility, while trifluoroacetate Type A exhibits lower solubility. Trifluoroacetate Type A firstly converted to Type B at 4 hrs and back to Type A at 24 hrs, while Type B converted to Type A at 24 hrs. No form change was observed of HCl Type I. The XRPD patterns of residual solid were included in  FIG. 117 ,  FIG. 118 , and  FIG. 119 . 
         [0000]    
       
         
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 44 
               
             
             
               
                   
               
               
                   
                 4 hrs 
                 24 hrs 
               
             
          
           
               
                 Starting 
                   
                   
                 Form 
                   
                   
                 Form 
               
               
                 Material 
                 S 
                 pH 
                 change 
                 S 
                 pH 
                 change 
               
               
                   
               
             
          
           
               
                 TFA 
                 0.28 
                 5.8 
                 Yes 
                 0.99 
                 5.5 
                 Back to Form A 
               
               
                 Type A 
                   
                   
                 (Type B) 
                   
                   
                   
               
               
                 TFA 
                 0.39 
                 5.3 
                 No 
                 2.7 
                 4.9 
                 Yes 
               
               
                 Type B 
                   
                   
                   
                   
                   
                 (Type A) 
               
               
                 HCl 
                 1.2 
                 3.9 
                 No 
                 4.1 
                 4.4 
                 No 
               
               
                 Type I 
               
               
                   
               
               
                 S: solubility, mg/mL. 
               
             
          
         
       
     
       Example 63 
       [0327]    Physical and chemical stability evaluation of trifluoroacetate Type A, trifluoroacetate Type B, and HCl Type I was performed at 25° C./60%RH, 40° C./75%RH and 60° C. for 1, 2, 4 and 8 weeks. In the experiments, approximately 20 mg of solid was placed into a 1.5-mL glass vial. The vials were stored under 25° C./60%RH (uncapped), 40° C./75%RH (uncapped) and 60° C. (capped) conditions for 8 weeks. XRPD analysis was then employed to check the crystalline form of the solid, and HPLC was utilized to determine the purity profile at 1, 2, 4 and 8 weeks. From the stability results summarized in Table 45, both trifluoroacetate Type A and HCl Type I are physically and chemically stable under 25° C./60%RH, 40° C./75%RH and 60° C. conditions for 8 weeks. The solid form change of trifluoroacetate Type A at 2 and 4 weeks was postulated to the air-exposure when the sample was taken out for XRPD characterization. Trifluoroacetate Type B is chemically stable, however, physically unstable evidenced by conversion to Type A under these conditions. XRPD patterns overlay of trifluoroacetate Types A and B and HCl Type I at stressed conditions are displayed from  FIG. 120  to  FIG. 128 . 
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                 TABLE 45 
               
             
             
               
                   
               
               
                   
                 Initial 
                 Time 
                 25° C./60% RH 
                 40° C./75% RH 
                 60° C. (capped) 
               
             
          
           
               
                   
                 HPLC 
                 point 
                 HPLC 
                 Solid 
                 HPLC 
                 Solid 
                 HPLC 
                 Solid 
               
               
                 Salt 
                 purity 
                 (weeks) 
                 purity 
                 form 
                 purity 
                 form 
                 purity 
                 form 
               
               
                   
               
               
                 TFA 
                 99.9% 
                 1 
                 99.9% 
                 Type A 
                 99.9% 
                 Type A 
                 99.9% 
                 Type A 
               
               
                 Type A 
                   
                 2 
                 99.9% 
                 Type B 
                 99.9% 
                 Type B 
                 99.9% 
                 Type B 
               
               
                   
                   
                 4 
                 99.9% 
                 Type 
                 99.9% 
                 Type 
                 99.9% 
                 Type 
               
               
                   
                   
                   
                   
                 A + B 
                   
                 A + B 
                   
                 A + B 
               
               
                   
                   
                 6 
                 — 
                 Type A 
                 — 
                 Type A 
                 — 
                 Type A 
               
               
                   
                   
                 8 
                 99.9% 
                 Type A 
                 99.9% 
                 Type A 
                 99.9% 
                 Type A 
               
               
                 TFA 
                 99.9% 
                 1 
                 99.9% 
                 Type A 
                 99.9% 
                 Type A 
                 99.9% 
                 Type A 
               
               
                 Type B 
                   
                 2 
                 99.9% 
                 Type A 
                 99.9% 
                 Type A 
                 99.9% 
                 Type A 
               
               
                   
                   
                 4 
                 99.9% 
                 Type A 
                 99.9% 
                 Type A 
                 99.9% 
                 Type A 
               
               
                   
                   
                 8 
                 99.9% 
                 Type A 
                 99.9% 
                 Type A 
                 99.9% 
                 Type A 
               
               
                 HCl 
                 99.9% 
                 1 
                 99.9% 
                 Type I 
                 99.9% 
                 Type I 
                 99.9% 
                 Type I 
               
               
                 Type I 
                   
                 2 
                 99.9% 
                 Type I 
                 99.9% 
                 Type I 
                 99.9% 
                 Type I 
               
               
                   
                   
                 4 
                 99.9% 
                 Type I 
                 99.9% 
                 Type I 
                 99.9% 
                 Type I 
               
               
                   
                   
                 8 
                 99.9% 
                 Type I 
                 99.9% 
                 Type I 
                 99.9% 
                 Type I 
               
               
                   
               
               
                 The solid form change of TFA Type A at 2 and 4 weeks was postulated to the air-exposure taken out for XRPD characterization.

Technology Category: c