Abstract:
Polymorphic forms of histone deacetylase inhibitors (HDAC) and methods of making and using such polymorphic forms are provided. Crystalline polymorphic forms can be characterized by their X-ray powder diffraction patterns, solubility, stability and other properties.

Description:
PRIORITY CLAIM 
       [0001]    This application claims priority to U.S. Provisional Patent Application Ser. No. 61/777,734, filed Mar. 12, 2013. The above referenced application is incorporated herein by reference as if restated in full. 
     
    
     BACKGROUND 
       [0002]    Acetylation of core histones plays an important role in the regulation of gene transcription by controlling nucleosomal packaging of DNA. Deacetylation of histones results in tight packing of nucleosomes and transcriptional repression due to limited access of transcription factors to DNA targets. Histone acetylation relaxes nucleosome structures, providing greater access for transcription factors. The balance between histone deacetylation and acetylation is modulated by the histone deacetyl-transferases (HDACs) and histone acetyl-transferases (HAT). An abnormal balance of these factors is correlated with abnormal cell growth and several forms of cancer as discussed in U.S. Pat. No. 8,318,808, incorporated by reference herein in its entirety. HDAC inhibitors, in particular, change the balance between acetylation and deacetylation resulting in growth arrest, differentiation, and apoptosis in many tumor cell types. U.S. Pat. No. 8,318,808. 
         [0003]    Of particular interest herein are HDAC inhibitors described in U.S. Pat. No. 8,318,808 and are based on, for example, fatty acids coupled with Zn 2+ -chelating motifs through aromatic Ω-amino acid linkers. In various aspects, the HDAC inhibitors may have the formula: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0004]    wherein X is chosen from H and CH3; Y is (CH2)n wherein n is 0-2; Z is chosen from (CH2)m wherein m is 0-3 and (CH)2; A is a hydrocarbyl group; B is o-aminophenyl or hydroxyl group; and Q is a halogen, hydrogen, or methyl. One HDAC inhibitor of particular (N-hydroxy-4-(3-methyl-2-phenyl-butyrylamino)-benzamide) is also known as AR-42. In one aspect, the structure of AR-42 is as follows: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0005]    AR-42 is a broad-spectrum deacetylase inhibitor of both histone and non-histone proteins with demonstrated greater potency and activity in solid tumors and hematological malignancies when compared to vorinostat (i.e., SAHA). See, e.g., Lu Y S, et al.,  Efficacy of a novel histone deacetylase inhibitor in murine models of hepatocellular carcinoma , Hepatology. 2007 October; 46(4):1119-30; Kulp S K, et al.,  Antitumor effects of a novel phenylbutyrate - based histone deacetylase inhibitor , ( S )- HDAC -42 , in prostate cancer , Clin Cancer Res. 2006 Sep. 1; 12(17):5199-206. 
         [0006]    AR-42 may also possess additional histone-independent mechanisms which contribute to its therapeutic profile. See, e.g., Chen M C, et al.,  Novel mechanism by which histone deacetylase inhibitors facilitate topoisomerase IIa degradation in hepatocellular carcinoma cells , Hepatology. 2011 January; 53(1):148-59; Chen C S, et al.,  Histone acetylation - independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase  1  complexes , J Biol. Chem. 2005 Nov. 18; 280(46):38879-87; Yoo C B, et al.,  Epigenetic therapy of cancer: past, present and future , Nat Rev Drug Discov. 2006 January; 5(1):37-50. 
         [0007]    AR-42 has a demonstrated inhibitory effect in tumors including, but not limited to, breast, prostate, ovarian, blood cell (e.g., lymphoma, myeloma, leukemia), liver, and brain. See, e.g., Mims A, et. al.,  Increased anti - leukemic activity of decitabine via AR -42- induced upregulation of miR -29 b: a novel epigenetic - targeting approach in acute myeloid leukemia , Leukemia. 2012 Nov. 26. doi: 10.1038/leu.2012.342. [Epub ahead of print]; Burns S S, et al.,  Histone deacetylase inhibitor AR -42  differentially affects cell - cycle transit in meningeal and meningioma cells, potently inhibiting NF 2- deficient meningioma growth , Cancer Res. 2013 Jan. 15; 73(2):792-803; Lu Y S, et. al.,  Radiosensitizing effect of a phenylbutyrate - derived histone deacetylase inhibitor in hepatocellular carcinoma , Int J Radiat Oncol Biol Phys. 2012 Jun. 1; 83(2); Zimmerman B, et. al.,  Efficacy of novel histone deacetylase inhibitor, AR 42 , in a mouse model of human T - lymphotropic virus type  1  adult T cell lymphoma , Leuk Res. 2011 November; 35(11):1491-7; Zhang S, et al.,  The novel histone deacetylase inhibitor, AR -42, inhibits gp130 /Stat 3  pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells , Int J. Cancer. 2011 Jul. 1; 129(1):204-13. 
         [0008]    The term “polymorph” or “polymorphic” refers to different crystalline forms of a chemical compound. Polymorphic forms of a compound may possess properties that affect the solubility, stability, bioavailability, and efficacy of a compound. Polymorphic forms of a compound can be compared, for example, to amorphous forms or other crystalline forms with respect to thermodynamic behaviors measured by a variety of techniques including, but not limited, to melting point, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), x-ray powder diffraction (XRPD), high performance liquid chromatography (HPLC), Raman microscopy, FT-IR spectroscopy, mass spectrometry (MS), and thermogravimetric analysis coupled with mass spectrometry (TG-MS). The physical stability of crystalline forms can be measured, for example, under conditions where the temperature and humidity in the environment are controlled for various time periods. 
       SUMMARY 
       [0009]    Aspects disclosed herein provide polymorphic or crystalline forms of AR-42, also known as (S)—N-hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide having the following chemical structure: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0010]    In one aspect, the polymorphic forms include salts, solvates, hydrates, anhydrous, co-crystalline and other crystalline forms and combinations. The polymorphic forms can be formulated into a variety of dosage forms having increased stability, increased bioavailability, sustained release, and other properties. Polymorphic forms of AR-42 described herein are characterized by methods including X-ray powder diffraction patterns (XRPD), differential scanning calorimetry (DSC), and thermogravimetry mass spectrometry (TG-MS). 
         [0011]    In another aspect, polymorphic forms of AR-42 can be made by combining AR-42 with any of the following exemplary solvents: methycyclohexane, isopentyl acetate, nethyl tetrahydrofuran-2, trimethylpentane 2,2,4-, diisopropyl ether, cumene, dichloroethane 1,2-, toluene, cyclohexanone, cyclohexane, anisole, diethyl carbonate (anyhydrous), octane, tert-butylmethyl ether (anhydrous), dimethoxyethane 1,2-, butyl acetate, absolute ethanol, dioxane, 1,4-, chloroform, methyl-1-propanol 2-, dimethyl-3-butanone 2,2-, hydroxy-4-methyl-2-pentanon 4-, tetrahydrofuran, fluorbenzene, chlorobenzene, acetonitrile, methanol, water, nitromethane, ethylbenzene, dimethyl-4-heptanone, 2,6-, trimethylbenzene 1,2,4-, dimethyl-3-butanone 2,2-, nitromethane, fluorobenzene, dioxane, 1,4, methyltetrahydrofuran, 2-, and pentyl acetate. 
         [0012]    In one aspect, the AR-42 polymorphic forms can be made by mixing AR-42 or a salt thereof with any of the above solvents, or other suitable solvents, with or without heating of the mixture and subsequent cooling and or evaporation of the solvents at various rates in order to form precipitated material which can be analyzed as described herein. 
     
    
     
       FIGURES 
         [0013]      FIG. 1  shows exemplary XRPD patterns for different lots of Form A of AR-42; 
           [0014]      FIG. 2  shows exemplary images of the AR-42 samples corresponding to the XRPD patterns of  FIG. 1 ; 
           [0015]      FIG. 3  shows exemplary XRPD patterns for the indicated polymorphic forms of AR-42; 
           [0016]      FIG. 4  shows exemplary images of the AR-42 samples corresponding to the XRPD patterns of  FIG. 3 ; 
           [0017]      FIG. 5  shows exemplary XRPD patterns for the indicated polymorphic forms of AR-42; 
           [0018]      FIG. 6  shows exemplary images of the AR-42 samples corresponding to the XRPD patterns of  FIG. 5 ; 
           [0019]      FIG. 7  shows exemplary XRPD patterns for the indicated polymorphic forms of AR-42; 
           [0020]      FIG. 8  shows exemplary images of the AR-42 samples corresponding to the XRPD patterns of  FIG. 7 ; 
           [0021]      FIG. 9  shows exemplary XRPD patterns for the indicated polymorphic forms of AR-42; 
           [0022]      FIG. 10  shows exemplary images of the AR-42 samples corresponding to the XRPD patterns of  FIG. 9 ; 
           [0023]      FIG. 11  shows exemplary XRPD patterns for the indicated polymorphic forms of AR-42; 
           [0024]      FIG. 12  shows exemplary images of the AR-42 samples corresponding to the XRPD patterns of  FIG. 11 ; 
           [0025]      FIG. 13  shows an exemplary TG-MS of Form D2; 
           [0026]      FIG. 14  shows an exemplary DSC of Form D2; 
           [0027]      FIG. 15  shows an exemplary TG-MS of Form A_minus; 
           [0028]      FIG. 16  shows an exemplary DSC of Form A_minus; 
           [0029]      FIG. 17  shows an exemplary TG-MS of Form Z; 
           [0030]      FIG. 18  shows an exemplary TG-MS of Form M1; 
           [0031]      FIG. 19  shows an exemplary DSC of Form M1; 
           [0032]      FIG. 20  shows an exemplary TG-MS of Form A_plus; 
           [0033]      FIG. 21  shows an exemplary DSC of Form A_plus; 
           [0034]      FIG. 22  shows an exemplary TG-MS of Form L2; 
           [0035]      FIG. 23  shows an exemplary TG-MS of Form M2; 
           [0036]      FIG. 24  shows an exemplary DSC of Form M2; 
           [0037]      FIG. 25  shows an exemplary TG-MS of Form B1; 
           [0038]      FIG. 26  shows an exemplary DSC of Form B1; 
           [0039]      FIG. 27  shows an exemplary TG-MS of Form A5a; 
           [0040]      FIG. 28  shows an exemplary DSC of Form A5a; 
           [0041]      FIG. 29  shows an exemplary TG-MS of Form R; 
           [0042]      FIG. 30  shows an exemplary DSC of Form R; 
           [0043]      FIG. 31  shows an exemplary TG-MS of Form H2; 
           [0044]      FIG. 32  shows an exemplary TG-MS of Form A5b; 
           [0045]      FIG. 33  shows an exemplary DSC of Form A5b; 
           [0046]      FIG. 34  shows an exemplary TG-MS of Form J1; 
           [0047]      FIG. 35  shows an exemplary DSC of Form J1; and 
           [0048]      FIG. 36  shows an exemplary DSC of Form L1. 
       
    
    
     DETAILED DESCRIPTION 
       [0049]    Before describing several exemplary aspects described herein, it is to be understood that the invention is not limited to the details of construction or process steps set forth in the following description. The aspects described herein are capable of being practiced or being carried out in various ways. 
         [0050]    Aspects described herein provide polymorphic forms of AR-42 which have advantageous properties including but not limited to increased bioavailability, increased stability, and increased solubility. In one aspect, these properties relate to properties that will impart advantages with respect to formulating AR-42 into a suitable dosage form. 
         [0051]    Polymorphic forms of AR-42 have varying physical and chemical properties with respect, for example, solubility, melting temperature, hygroscopy, and vapor pressure which may affect the stability of a particular dosage form of AR-42. Drug formulation and dosage form selection have a significant impact on the cost of manufacturing. Stability of a particular dosage form may also significantly impact the shelf life of the drug, required frequency of refills, and the cost of the drug to the patient. Thus, selecting a polymorphic form with desired chemical properties may affect the cost of manufacture, the effectiveness of the drug, and the cost and convenience of using the drug for the patient. 
         [0052]    Physical properties such as flow, particle size, surface area, and hardness may significantly impact the pharmacokinetics of the drug. For example, the dissolution rate and half-life of the drug in the body will affect the maximum concentration in the blood, clearance of the drug, and whether the drug is resident in the body for the optimal period of time. 
         [0053]    Polymorphic forms of AR-42 were identified by conducting solubility assessments in a variety of solvents (e.g., methycyclohexane, isopentyl acetate, nethyl tetrahydrofuran-2, trimethylpentane 2,2,4-, diisopropyl ether, cumene, dichloroethane 1,2-, toluene, cyclohexanone, cyclohexane, anisole, diethyl carbonate (anyhydrous), octane, tert-butylmethyl ether (anhydrous), dimethoxyethane 1,2-, butyl acetate, absolute ethanol, dioxane, 1,4-, chloroform, methyl-1-propanol 2-, dimethyl-3-butanone 2,2-, hydroxy-4-methyl-2-pentanon 4-, tetrahydrofuran, fluorbenzene, chlorobenzene, acetonitrile, methanol, water, nitromethane, ethylbenzene, dimethyl-4-heptanone, 2,6-, trimethylbenzene 1,2,4-, dimethyl-3-butanone 2,2-, nitromethane, fluorobenzene, dioxane, 1,4, methyltetrahydrofuran, 2-, and pentyl acetate). The resulting polymorphic forms of AR-42 were characterized by methods including XRPD, TG-MS, and DSC. 
         [0054]    Methods for obtaining and characterizing polymorphic forms generally are known in the art as shown, for example, in H. G. Brittain, “Polymorphism in Pharmaceutical Solids”, 2nd edition [Informa Healthcare Press, New York, 2009], J. Bernstein, “Polymorphism in Molecular Crystals” [Clarendon Press, Oxford, 2002], and R. Hilfiker, “Polymorphism in the Pharmaceutical Industry [Wiley-VCH, Weinheim, 2006], incorporated by reference herein in their entirety. 
         [0055]      FIG. 1  shows exemplary XRPD patterns for four lots of crystalline AR-42 starting material, termed Form A. Solubility was assessed in a set of 20 organic solvents. As shown in  FIG. 1 , the XRPD patterns are consistent across the four samples. HPLC purity is in the range of 97.89 to 99.48%. 
         [0056]      FIG. 2  shows exemplary images of the AR-42 samples from 121 mL crystallization experiments using four different crystallization modes (cooling evaporative, anti-solvent addition, slurry, and solvent drop grinding. 
         [0057]    In one aspect, AR-42 polymorphic form A8 has the XRPD pattern as shown in  FIG. 3 . 
         [0058]    In one aspect, AR-42 polymorphic form A7 has the XRPD pattern as shown in  FIG. 3 . 
         [0059]    In one aspect, AR-42 polymorphic form A6 has the XRPD pattern as shown in  FIG. 3 . 
         [0060]    In one aspect, AR-42 polymorphic form A5b has the XRPD pattern as shown in  FIG. 3 . 
         [0061]    In one aspect, AR-42 polymorphic form A5a has the XRPD pattern as shown in  FIG. 3 . 
         [0062]    In one aspect, AR-42 polymorphic form A4 has the XRPD pattern as shown in  FIG. 3 . 
         [0063]    In one aspect, AR-42 polymorphic form A3 has the XRPD pattern as shown in  FIG. 3 . 
         [0064]    In one aspect, AR-42 polymorphic form A2 has the XRPD pattern as shown in  FIG. 3 . 
         [0065]    In one aspect, AR-42 polymorphic form SM has the XRPD pattern as shown in  FIG. 3 . 
         [0066]    In one aspect, AR-42 polymorphic form A_plus has the XRPD pattern as shown in  FIG. 3 . 
         [0067]    In one aspect, AR-42 polymorphic form A_minus has the XRPD pattern as shown in  FIG. 3 . 
         [0068]    In one aspect, AR-42 polymorphic form E has the XRPD pattern as shown in  FIG. 5 . 
         [0069]    In one aspect, AR-42 polymorphic form D3 has the XRPD pattern as shown in  FIG. 5 . 
         [0070]    In one aspect, AR-42 polymorphic form D2 has the XRPD pattern as shown in  FIG. 5 . 
         [0071]    In one aspect, AR-42 polymorphic form D1 has the XRPD pattern as shown in  FIG. 5 . 
         [0072]    In one aspect, AR-42 polymorphic form C has the XRPD pattern as shown in  FIG. 5 . 
         [0073]    In one aspect, AR-42 polymorphic form B1 has the XRPD pattern as shown in  FIG. 5 . 
         [0074]    In one aspect, AR-42 polymorphic form H2 has the XRPD pattern as shown in  FIG. 7 . 
         [0075]    In one aspect, AR-42 polymorphic form H1 has the XRPD pattern as shown in  FIG. 7 . 
         [0076]    In one aspect, AR-42 polymorphic form G_gel has the XRPD pattern as shown in  FIG. 7 . 
         [0077]    In one aspect, AR-42 polymorphic form F5_wet has the XRPD pattern as shown in  FIG. 7 . 
         [0078]    In one aspect, AR-42 polymorphic form F4_wet has the XRPD pattern as shown in  FIG. 7 . 
         [0079]    In one aspect, AR-42 polymorphic form F3 has the XRPD pattern as shown in  FIG. 7 . 
         [0080]    In one aspect, AR-42 polymorphic form F2 has the XRPD pattern as shown in  FIG. 7 . 
         [0081]    In one aspect, AR-42 polymorphic form F1 has the XRPD pattern as shown in  FIG. 7 . 
         [0082]    In one aspect, AR-42 polymorphic form J1 has the XRPD pattern as shown in  FIG. 9 . 
         [0083]    In one aspect, AR-42 polymorphic form J2 has the XRPD pattern as shown in  FIG. 9 . 
         [0084]    In one aspect, AR-42 polymorphic form K1 has the XRPD pattern as shown in  FIG. 9 . 
         [0085]    In one aspect, AR-42 polymorphic form L1 has the XRPD pattern as shown in  FIG. 9 . 
         [0086]    In one aspect, AR-42 polymorphic form L2 has the XRPD pattern as shown in  FIG. 9 . 
         [0087]    In one aspect, AR-42 polymorphic form M1 has the XRPD pattern as shown in  FIG. 9 . 
         [0088]    In one aspect, AR-42 polymorphic form M2 has the XRPD pattern as shown in  FIG. 9 . 
         [0089]    In one aspect, AR-42 polymorphic form R has the XRPD pattern as shown in  FIG. 11 . 
         [0090]    In one aspect, AR-42 polymorphic form S has the XRPD pattern as shown in  FIG. 11 . 
         [0091]    In one aspect, AR-42 polymorphic form T_wet has the XRPD pattern as shown in  FIG. 11 . 
         [0092]    In one aspect, AR-42 polymorphic form X_gel has the XRPD pattern as shown in  FIG. 11 . 
         [0093]    In one aspect, AR-42 polymorphic form Z has the XRPD pattern as shown in  FIG. 11 . 
         [0094]    Solubility assessment experiments were carried out in a variety of solvents followed by storage in a climate chamber for 48 to 72 hours at 40 degrees centigrade and 75% relative humidity. In another aspect, Form A_minus, Form A_plus, Form A5a, Form A5b, Form D2, Form B1, Form J1, Form J2, Form M1, Form M2, Form L1, Form L2, and Form Z exhibited a particular degree of stability and were examined using DSC and TG-MS as shown in  FIGS. 13 and 14  (Form D2),  FIGS. 15 and 16  (Form A_minus),  FIG. 17  (Form Z),  FIGS. 18 and 19  (Form M1),  FIGS. 20 and 21  (Form A_plus),  FIG. 22  (L2),  FIGS. 23 and 24  (Form M2);  FIGS. 25 and 26  (Form B1);  FIGS. 27 and 28  (Form A5a);  FIGS. 29 and 30  (Form R);  FIG. 31  (Form H2);  FIGS. 32 and 33  (Form A5b;  FIGS. 34 and 35  (Form J1); and  FIG. 36  (Form L1). 
         [0095]    In another aspect, the XRPD patterns for Form J1, Form A5a, Form M1 and Form M2, remained unchanged following storage exposure in the climate chamber in a climate chamber for 48 to 72 hours at 40 degrees centigrade and 75% relative humidity. In this aspect, these forms are considered particularly stable. 
         [0096]    In another aspect, using process solvents used to produce AR-42 Form A (i.e. water or ethanol) yielded Form D2, Form H1, and Form M2. In yet another aspect, the TG-MS analysis of Form D2 indicates it may be solvated (e.g.,  FIG. 13 ). In another aspect, the TG-MS and DSC analysis indicates that Form A_minus, Form A_plus, Form M1, Form M2, Form A5a, Form A5b and Form J1 are anhydrates. In yet another aspect, Form M2 is a potential anhydrate form, with somewhat lower melting point (i.e. T peak =187.4° C.) as compared to starting material Form A (i.e. T peak =204.2° C.). 
         [0097]    The AR-42 polymorphic or crystalline forms can be used to treat a patient in need of treatment as described herein. The terms “treat,” “prevent,” or similar terms, as used herein, do not necessarily mean 100% or complete treatment or prevention. Rather, these terms refer to various degrees of treatment or prevention of a particular disease (e.g., 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, or 1%) as recognized in the art as being beneficial. The terms “treatment” or “prevention” also refer to delaying onset of a disease for a period of time or delaying onset indefinitely. The term “treatment” or “treating” refers to administering a drug or treatment to a patient or prescribing a drug to a patient where the patient or a third party (e.g., caretaker, family member, or health care professional) administers the drug or treatment. 
         [0098]    The AR-42 polymorphic or crystalline forms also encompass derivatives. In one embodiment, the term “derivative” includes, but is not limited to, ether derivatives, acid derivatives, amide derivatives, ester derivatives and the like. Methods of preparing these derivatives are known to a person skilled in the art. For example, ether derivatives are prepared by the coupling of the corresponding alcohols. Amide and ester derivatives are prepared from the corresponding carboxylic acid by a reaction with amines and alcohols, respectively. 
         [0099]    The AR-42 polymorphic or crystalline forms also encompass hydrates of AR-42 polymorphic or crystalline forms (e.g., hemihydrate, monohydrate, dihydrate, trihydrate and the like). Hydrates of AR-42 may be prepared by contacting AR-42 with water under suitable conditions to produce the hydrate of choice. 
         [0100]    The AR-42 polymorphic or crystalline forms also encompass metabolites of AR-42 polymorphic or crystalline forms. “Metabolite” or “metabolites” refer to any substance produced from another substance by metabolism or a through a metabolic process of a living cell or organ. 
         [0101]    Any of the polymorphic AR-42 forms described herein can be administered orally, parenterally (IV, IM, depot-IM, SQ, and depot-SQ), sublingually, intranasally (inhalation), intrathecally, topically, or rectally. Dosage forms known to those of skill in the art are suitable for delivery of the AR-42 polymorphic forms described herein. 
         [0102]    The AR-42 polymorphic compounds can be formulated into suitable pharmaceutical preparations such as tablets, capsules, or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration. The AR-42 polymorphic compounds described herein can be formulated into pharmaceutical compositions using techniques and procedures well known in the art. 
         [0103]    In one aspect, about 0.1 to 1000 mg, about 5 to about 100 mg, or about 10 to about 50 mg of the AR-42 polymorphic compounds, or a physiologically acceptable salt or ester can be compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in compositions or preparations comprising the AR-42 polymorphic compounds is such that a suitable dosage in the range indicated is obtained. 
         [0104]    In another aspect, the compositions can be formulated in a unit dosage form, each dosage containing from about 1 to about 500 mg, or about 10 to about 100 mg of the active ingredient. The term “unit dosage from” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. 
         [0105]    In one aspect, one or more of the AR-42 polymorphic compounds are mixed with a suitable pharmaceutically acceptable carrier to form compositions. Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion, or the like. Liposomal suspensions may also be used as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. In one aspect, the effective concentration is sufficient for lessening or ameliorating at least one symptom of the disease, disorder, or condition treated and may be empirically determined. 
         [0106]    Pharmaceutical carriers or vehicles suitable for administration of the AR-42 polymorphic compounds described herein include any such carriers suitable for the particular mode of administration. In addition, the active materials can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, or have another action. The compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients. 
         [0107]    In another aspect, if the AR-42 polymorphic compounds exhibit insufficient solubility, methods for solubilizing may be used. Such methods are known and include, but are not limited to, using co-solvents such as dimethylsulfoxide (DMSO), using surfactants such as TWEEN, and dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as salts or prodrugs, may also be used in formulating effective pharmaceutical compositions. 
         [0108]    The concentration of the compound is effective for delivery of an amount upon administration that lessens or ameliorates at least one symptom of the disorder for which the compound is administered. Typically, the compositions are formulated for single dosage administration. 
         [0109]    In another aspect, the AR-42 polymorphic compounds described herein may be prepared with carriers that protect them against rapid elimination from the body, such as time-release formulations or coatings. Such carriers include controlled release formulations, such as, but not limited to, microencapsulated delivery systems. The active compound can be included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated. The therapeutically effective concentration may be determined empirically by testing the compounds in known in vitro and in vivo model systems for the treated disorder. 
         [0110]    In another aspect, the AR-42 polymorphic compounds and compositions described herein can be enclosed in multiple or single dose containers. The enclosed compounds and compositions can be provided in kits, for example, including component parts that can be assembled for use. For example, an AR-42 polymorphic compound in lyophilized form and a suitable diluent may be provided as separated components for combination prior to use. A kit may include AR-42 polymorphic compound and a second therapeutic agent for co-administration. The AR-42 polymorphic compound and second therapeutic agent may be provided as separate component parts. A kit may include a plurality of containers, each container holding one or more unit dose of the AR-42 polymorphic compounds described herein. In one aspect, the containers can be adapted for the desired mode of administration, including, but not limited to tablets, gel capsules, sustained-release capsules, and the like for oral administration; depot products, pre-filled syringes, ampoules, vials, and the like for parenteral administration; and patches, medipads, creams, and the like for topical administration. 
         [0111]    The concentration of the AR-42 polymorphic compound in the pharmaceutical composition will depend on absorption, inactivation, and excretion rates of the active compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. 
         [0112]    In another aspect, the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions. 
         [0113]    If oral administration is desired, the compound can be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient. 
         [0114]    Oral compositions will generally include an inert diluent or an edible carrier and may be compressed into tablets or enclosed in gelatin capsules. For the purpose of oral therapeutic administration, the active compound or compounds can be incorporated with excipients and used in the form of tablets, capsules, or troches. Pharmaceutically compatible binding agents and adjuvant materials can be included as part of the composition. 
         [0115]    The tablets, pills, capsules, troches, and the like can contain any of the following ingredients or compounds of a similar nature: a binder such as, but not limited to, gum tragacanth, acacia, corn starch, or gelatin; an excipient such as microcrystalline cellulose, starch, or lactose; a disintegrating agent such as, but not limited to, alginic acid and corn starch; a lubricant such as, but not limited to, magnesium stearate; a glidant, such as, but not limited to, colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; and a flavoring agent such as peppermint, methyl salicylate, or fruit flavoring. 
         [0116]    When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials, which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings, and flavors. 
         [0117]    The active materials can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action. The AR-42 polymorphic compounds can be used, for example, in combination with an antitumor agent, a hormone, a steroid, or a retinoid. The antitumor agent may be one of numerous chemotherapy agents such as an alkylating agent, an antimetabolite, a hormonal agent, an antibiotic, colchicine, a vinca alkaloid, L-asparaginase, procarbazine, hydroxyurea, mitotane, nitrosoureas or an imidazole carboxamide. Suitable agents include those agents which promote depolarization of tubulin. Examples include colchicine and vinca alkaloids, including vinblastine and vincristine. 
         [0118]    In another aspect, the AR-42 polymorphic forms described herein can be co-administered or administered before or after immunization of a patient with a vaccine to enhance the immune response to the vaccine. In one aspect the vaccine is a DNA vaccine, for example, and HPV vaccine. 
         [0119]    In one aspect, solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent such as water for injection, saline solution, fixed oil, a naturally occurring vegetable oil such as sesame oil, coconut oil, peanut oil, cottonseed oil, and the like, or a synthetic fatty vehicle such as ethyl oleate, and the like, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvent; antimicrobial agents such as benzyl alcohol and methyl parabens; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates, and phosphates; and agents for the adjustment of tonicity such as sodium chloride and dextrose. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass, plastic, or other suitable material. Buffers, preservatives, antioxidants, and the like can be incorporated as required. 
         [0120]    Where administered intravenously, suitable carriers include, but are not limited to, physiological saline, phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents such as glucose, polyethylene glycol, polypropyleneglycol, and mixtures thereof. Liposomal suspensions including tissue-targeted liposomes may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known in the art. 
         [0121]    In another aspect, the AR-42 polymorphic compounds may be prepared with carriers that protect the compound against rapid elimination from the body, such as time-release formulations or coatings. Such carriers include controlled release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid, and the like. Methods for preparation of such formulations are known to those skilled in the art. 
         [0122]    In yet another aspect, compounds employed in the methods of the disclosure may be administered enterally or parenterally. When administered orally, compounds employed in the methods of the disclosure can be administered in usual dosage forms for oral administration as is well known to those skilled in the art. These dosage forms include the usual solid unit dosage forms of tablets and capsules as well as liquid dosage forms such as solutions, suspensions, and elixirs. When the solid dosage forms are used, they can be of the sustained release type so that the compounds employed in the methods described herein need to be administered only once or twice daily. 
         [0123]    The oral dosage forms can be administered to the patient 1, 2, 3, or 4 times daily. The AR-42 polymorphic compounds described herein can be administered either three or fewer times, or even once or twice daily. Hence, the HDAC inhibitor compounds employed in the methods of the disclosure be administered in oral dosage form. Whatever oral dosage form is used, they can be designed so as to protect the compounds employed in the methods described herein from the acidic environment of the stomach. Enteric coated tablets are well known to those skilled in the art. In addition, capsules filled with small spheres each coated to protect from the acidic stomach, are also well known to those skilled in the art. 
         [0124]    The terms “therapeutically effective amount” and “therapeutically effective period of time” are used to denote treatments at dosages and for periods of time effective to reduce neoplastic cell growth. As noted above, such administration can be parenteral, oral, sublingual, transdermal, topical, intranasal, or intrarectal. In one aspect, when administered systemically, the therapeutic composition can be administered at a sufficient dosage to attain a blood level of the compounds of from about 0.1 μM to about 100 mM. For localized administration, much lower concentrations than this can be effective, and much higher concentrations may be tolerated. One of skill in the art will appreciate that such therapeutic effect resulting in a lower effective concentration of the AR-42 polymorphic compound may vary considerably depending on the tissue, organ, or the particular animal or patient to be treated. It is also understood that while a patient may be started at one dose, that dose may be varied overtime as the patient&#39;s condition changes. 
         [0125]    It should be apparent to one skilled in the art that the exact dosage and frequency of administration will depend on the particular compounds employed in the methods of the disclosure administered, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, and other medication the individual may be taking as is well known to administering physicians who are skilled in this art. 
       EXAMPLES 
     Example 1 
     Solubility Assessment Experiments 
       [0126]    Tables 1-2 illustrate solubility experiments conducted on the indicated Form as classified by XRPD patterns. 
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 Concen- 
               
               
                   
                   
                 XRPD 
                   
                   
                 tration 
               
               
                 Index 
                 Well 
                 Form 
                 Exp. ID 
                 Solvent 
                 (mg/mL) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 995: B5 
                 n 
                 SAS33 
                 Trifluoroethanol, 2, 2, 
                 7 
               
               
                   
                   
                   
                   
                 2- 
               
               
                 2 
                 995: G5 
                 Form 
                 SAS38 
                 Hexafluorobenzene 
                 &lt;1 
               
               
                   
                   
                 A_wet** 
               
               
                 3 
                 995: F5 
                 Form 
                 SAS37 
                 Amyl Ether 
                 &lt;1 
               
               
                   
                   
                 A + Am* 
               
               
                 4 
                 995: A5 
                 Form B1 
                 SAS32 
                 Dimethyl-4- 
                 2 
               
               
                   
                   
                   
                   
                 heptanone 2,6- 
               
               
                 5 
                 955: E5 
                 n 
                 SAS36 
                 Toluene 
                 &lt;1 
               
               
                 6 
                 995: C5 
                 n 
                 SAS34 
                 Chloroform 
                 &lt;2 
               
               
                 7 
                 995: D5 
                 n 
                 SAS35 
                 Nitromethane 
                 1 
               
               
                 8 
                 996: B4 
                 Am_oily 
                 SAS1 
                 NMP 
                 482.5 
               
               
                   
               
               
                 n - low yield material therefore the form could not be assigned. 
               
               
                 *(Form A + Am) - crystalline Form A is present as well as an amorphous phase: the amorphous could be from a solid amorphous material as well as from a slightly wet material. 
               
               
                 **wet solid material. 
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 Index 
                 Well 
                 XRPD Form 
                 Exp. ID 
                 Concentration (mg/mL) 
                 Solvent 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 997: C3 
                 Form A 
                 SAS5 
                 20.3 
                 Dimethyl-4-heptanone 2,6- 
               
               
                 2 
                 997: D3 
                 Form A 
                 SAS6 
                 20.6 
                 Trifluoroethanol, 2,2,2- 
               
               
                 3 
                 997: I3 
                 Form A 
                 SAS11 
                 21.2 
                 Nitromethane 
               
               
                 4 
                 997: L3 
                 Form A 
                 SAS14 
                 21.4 
                 Hexafluorobenzene 
               
               
                 5 
                 997: K3 
                 Form A 
                 SAS13 
                 18.4 
                 Amyl Ether 
               
               
                 6 
                 997: J3 
                 Form A 
                 SAS12 
                 18.8 
                 Toluene 
               
               
                 7 
                 997: G3 
                 Form A + Form B1 
                 SAS9 
                 108.9 
                 Acetone 
               
               
                 8 
                 997: E3 
                 Form B1 
                 SAS7 
                 20.8 
                 Chloroform 
               
               
                 9 
                 997: F3 
                 Form B1_wet** 
                 SAS8 
                 243.7 
                 Isophorone 
               
               
                 10 
                 997: A4 
                 Form B1 + Form D1 
                 SAS15 
                 32.3 
                 Dioxane, 1,4- 
               
               
                 11 
                 997: A3 
                 Form C 
                 SAS2 
                 472.5 
                 Dimethyl Sulfoxide 
               
               
                 12 
                 997: B3 
                 Form D1 
                 SAS4 
                 19.7 
                 Nitrobenzene 
               
               
                 13 
                 997: H3 
                 Form E 
                 SAS10 
                 313.3 
                 Tetrahydrofuran 
               
               
                   
               
               
                 **wet solid material. 
               
             
          
         
       
     
       Example 2 
     Anti-Solvent Addition Crystallization Experiments 
       [0127]    Tables 3-5 illustrate anti-solvent addition crystallization experiments conducted on the indicated Form. In this example, saturated solutions of AR42 were prepared in the following solvents: Acetone, 2-Butanone, Methanol, Ethanol, Isopropanol, Acetonitrile, 1,4-Dioxane and Dimethylformamide. Excess AR42 was added to the solvent and the suspension equilibrated for 24 hours. After equilibration, the suspension was filtered through a 0.2 μM filter to remove particulate solids. 
         [0128]    An equal volume of anti-solvent selected from the following list was added to 300 μL of the saturated solutions of AR42: Toluene, Nitrobenzene, Nitromethane, Water, n-Heptane, Cyclohexane. An additional 300 μL of anti-solvent was added if no precipitation occurred. Aliquots of 300 μL of anti-solvent were added until precipitation occurred or the total volume was 1,200 μL of anti-solvent. The solution was allowed to incubate for 60 minutes at room temperature in between the addition of anti-solvent. If no precipitation occurred after the last addition of anti-solvents, samples were incubated for 24 hours at 4° C. Samples in which precipitation occurred were centrifuged for 10 minutes at 3000 rpm to separate the liquid from the solid. The liquid phase was removed and the solid phase dried and analyzed by XRPD. The solutions in which no precipitation occurred were placed under deep vacuum and dried to completion. Solids were collected and analysed by XRPD. 
         [0129]    The following combinations of solvent and anti-solvent were used: 
         [0130]    Acetone with Toluene or Nitrobenzene or Nitromethane or water; 
         [0131]    2-Butanone with Toluene or n-Heptane or Cyclohexane or Nitrobenzene or Nitromethane; 
         [0132]    Methanol with Toluene or Nitrobenzene or Nitromethane or water; 
         [0133]    Ethanol with Toluene or Nitrobenzene or Nitromethane or water; 
         [0134]    Isopropanol with Toluene or n-Heptane or Cyclohexane or Nitrobenzene or Nitromethane or water; 
         [0135]    Acetonitrile with Toluene or Nitrobenzene or Nitromethane or water; 
         [0136]    1,4-Dioxane with Toluene or Cyclohexane or Nitrobenzene or Nitromethane or water; and 
         [0137]    Dimethylformamide with Toluene or Nitrobenzene or Nitromethane or water. 
         [0000]    
       
         
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 Anti solvent - 
                   
                   
                   
               
               
                   
                 Well before 
                   
                   
                   
                 Solvent 
                 Exp. 
                 Concentration 
               
               
                 Index 
                 stability 
                 XRPD Form a   
                 XRPD Form b   
                 Anti solvent 
                 Ratio (x:1) 
                 ID 
                 (mg/mL) 
                 Stock Solvent 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 AS01:E2 
                 Am_oily 
                 n 
                 Water 
                 2 
                 AS36 
                 335 
                 Dimethylformamide 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 N,N- 
               
               
                 2 
                 AS01: C1 
                 Form A 
                 Form A 
                 Nitromethane 
                 1 
                 AS3 
                 175.9 
                 Acetone 
               
               
                 3 
                 AS01:J1 
                 Form A 
                 Form A 
                 Water 
                 1 
                 AS13 
                 390.5 
                 methanol 
               
               
                 4 
                 AS01:D1 
                 Form A 
                 Form A 
                 Water 
                 2 
                 AS4 
                 175.9 
                 Acetone 
               
               
                 5 
                 AS01:F1 
                 Form A_minus 
                 Form A_minus 
                 Heptane, N- 
                 1 
                 AS6 
                 130.7 
                 Butanone 2- 
               
               
                 6 
                 AS01:B2 
                 Form A_wet** 
                 Form A + Am* 
                 Water 
                 2 
                 AS23 
                 227.8 
                 Propanol 2- 
               
               
                 7 
                 AS01:K1 
                 Form A + 
                 Form A 
                 Water 
                 1 
                 AS17 
                 134.1 
                 Ethanol 
               
               
                   
                   
                 Form H1 
               
               
                 8 
                 AS01:L1 
                 Form A2 
                 Form A 
                 Heptane, N- 
                 4 
                 AS19 
                 227.8 
                 Propanol 2- 
               
               
                 9 
                 AS01:I1 
                 Form B1 + 
                 Form A 
                 Nitromethane 
                 1 
                 AS9 
                 130.7 
                 Butanone 2- 
               
               
                   
                   
                 Form F5 
               
               
                 10 
                 AS01:B1 
                 Form D1_wet** 
                 Form D2 
                 Nitrobenzene 
                 1 
                 AS2 
                 175.9 
                 Acetone 
               
               
                 11 
                 AS01:A1 
                 Form F1 
                 Form A 
                 Toluene 
                 1 
                 AS1 
                 175.9 
                 Acetone 
               
               
                 12 
                 AS01:E1 
                 Form F1 
                 Form A + Am* 
                 Toluene 
                 1 
                 AS5 
                 130.7 
                 Butanone 2- 
               
               
                 13 
                 AS01:D2 
                 Form G_gel 
                 Form A + Am* 
                 Cyclohexane 
                 2 
                 AS29 
                 46.8 
                 Dioxane, 1,4- 
               
               
                 14 
                 AS01:G1 
                 Form W + Am* 
                 Form A + Form 
                 Cyclohexane 
                 1 
                 AS7 
                 130.7 
                 Butanone 2- 
               
               
                 15 
                 AS01:C2 
                 Wet sample 
                 Form A + Am* 
                 Toluene 
                 3 
                 AS28 
                 46.8 
                 Dioxane, 1,4- 
               
               
                 16 
                 AS01:H1 
                 Wet sample 
                 Form W + Am* 
                 Nitrobenzene 
                 1 
                 AS3 
                 130.7 
                 Butanone 2- 
               
               
                 17 
                 AS01:A2 
                 n 
                 n 
                 Cyclohexane 
                 3 
                 AS20 
                 227.8 
                 Propanol 2- 
               
               
                   
               
               
                   a XRPD form assigned after Recrystallization (as wet or dry solid) thus before the stability studies; 
               
               
                   b XRPD form assigned after the stability studies (48-72 H, at 40° C./75% RH). 
               
               
                 *the assigned crystalline form is present as well as an amorphous phase; the amorphous could be from a solid amorphous material as well as from a slightly wet material. 
               
               
                 **wet solid material: n- low yield material therefore the form could not be assigned. 
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
               
                   
                   
                   
                   
                 AS - Solvent 
                 Exp. 
                 Concentration 
                   
               
               
                 Index 
                 Well 
                 XRPD Form a   
                 Anti solvent 
                 Ratio (x:1) 
                 ID 
                 (mg/mL) 
                 Stock Solvent 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 AS02:E1 
                 Form E + Form I 
                 Nitromethane 
                 3 
                 AS26 
                 13.5 
                 Acetonitrile 
               
               
                 2 
                 AS02:A1 
                 Form F5_wet** 
                 Nitromethane 
                 4 
                 AS12 
                 390.5 
                 methanol 
               
               
                 3 
                 AS02:C1 
                 Form H1 
                 Nitromethane 
                 3 
                 AS16 
                 134.1 
                 Ethanol 
               
               
                 4 
                 AS02:B1 
                 Form H1_wet** 
                 Toluene 
                 3 
                 AS14 
                 134.1 
                 Ethanol 
               
               
                 5 
                 AS02:D1 
                 Wet sample 
                 Toluene 
                 3 
                 AS18 
                 227.8 
                 Propanol 2- 
               
               
                   
               
               
                   a XRPD form assigned after Recrystallization (as wet or dry solid) thus before the stability studies; 
               
               
                 **wet solid material. 
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 5 
               
               
                   
               
               
                   
                 Well before 
                   
                   
                   
                 AS- Solvent 
                 Exp. 
                 Concentration 
                   
               
               
                 Index 
                 stability 
                 XRPD Form a   
                 XRPD Form b   
                 Anti solvent 
                 Ratio (x:1) 
                 ID 
                 (mg/mL) 
                 Stock Solvent 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 AS04:B4 
                 Am_oily 
                 Form A 
                 Nitromethane 
                 4 
                 AS35 
                 335 
                 Dimethylformamide 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 N,N- 
               
               
                 2 
                 AS04:H3 
                 Form B1 + 
                 Form A_low 
                 Water 
                 4 
                 AS27 
                 13.5 
                 Acetonitrile 
               
               
                   
                   
                 Form F1 
                 yield 
               
               
                 3 
                 AS04:D3 
                 Form D1 
                 Form D2 + Am* 
                 Nitrobenzene 
                 4 
                 AS21 
                 227.8 
                 Propanol 2- 
               
               
                 4 
                 AS04:I3 
                 Form D1 
                 Form D2 
                 Nitrobenzene 
                 4 
                 AS30 
                 46.8 
                 Dioxane, 1,4- 
               
               
                 5 
                 AS04:G3 
                 Form D1 
                 Form D2 + Am* 
                 Nitrobenzene 
                 4 
                 AS25 
                 13.5 
                 Acetonitrile 
               
               
                 6 
                 AS04:B3 
                 Form D1 
                 Form D2 
                 Nitrobenzene 
                 4 
                 AS11 
                 390.5 
                 methanol 
               
               
                 7 
                 AS04:A4 
                 Form D1 
                 Form D2 
                 Nitrobenzene 
                 4 
                 AS34 
                 335 
                 Dimethylformamide 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 N,N- 
               
               
                 8 
                 AS04:C3 
                 Form D1 
                 Form D2 
                 Nitrobenzene 
                 4 
                 AS15 
                 134.1 
                 Ethanol 
               
               
                 9 
                 AS04:K3 
                 Form D1 + 
                 Form A + 
                 Water 
                 4 
                 AS32 
                 46.8 
                 Dioxane, 1,4- 
               
               
                   
                   
                 Form F1 
                 Form B1 
               
               
                 10 
                 AS04:J3 
                 Form D1 + 
                 Form A + 
                 Nitromethane 
                 4 
                 AS31 
                 46.8 
                 Dioxane, 1,4- 
               
               
                   
                   
                 Form F1 
                 Form D3_min*** 
               
               
                 11 
                 AS04:A3 
                 Form D3 
                 Form A + 
                 Toluene 
                 4 
                 AS10 
                 390.5 
                 methanol 
               
               
                   
                   
                   
                 Form D3 
               
               
                 12 
                 AS04:E3 
                 Form F1 
                 Form A 
                 Nitromethane 
                 4 
                 AS22 
                 227.8 
                 Propanol 2- 
               
               
                 13 
                 AS04:F3 
                 Form F1 
                 Form A 
                 Toluene 
                 4 
                 AS24 
                 13.5 
                 Acetonitrile 
               
               
                 14 
                 AS04:L3 
                 Form T_wet** 
                 Form A 
                 Toluene 
                 4 
                 AS33 
                 335 
                 Dimethylformamide 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 N,N- 
               
               
                   
               
               
                 *the assigned crystalline form is present as well as an amorphous phase; the amorphous could be from a solid amorphous material as well as from a slightly wet material. 
               
               
                 **wet solid material. 
               
               
                 ***a minimum amount of crystalline form is present in mixture with a predominant crystalline form. 
               
             
          
         
       
     
       Example 3 
     Cooling-Evaporative Crystallization Experiments 
       [0138]    Tables 6-7 illustrate cooling evaporative crystallization experiments conducted on the indicated Form. Slurries of AR42 were prepared by adding an excess of AR42 to standard HPLC vials containing the following solvents and solvent mixtures: Methanol, Tetrahydrofuran, Ethyl acetate, 2-Methyltetrahydrofuran, Ethanol, Acetonitrile, 1,2-Dichloroethane, Fluorbenzene, 1,2-Dimethoxyethane, Propionitrile, Isobutanol, Isopropyl acetate, Butyl Acetate, Chlorobenzene, 2-Ethoxyethanol, 1-Pentanol, Cyclohexanone, 4-Hydroxy-4-Methyl-2-Pentanone, Methanol/Acetonitrile (50:50), Acetonitrile/Chloroform (50:50), Methanol/p-Xylene (50:50), 1,2-Dimethoxyethane/Methanol (50:50), 1,2-Dimethoxyethane/Isopropylether (50:50), Formamide/Methanol (50:50), Cyclohexanone/Tetrahydrofuran (50:50), Cyclohexane/N-methyl-2-pyrrolidone (50:50), Cyclohexane/Cyclohexanone (50:50), Methylcyclohexane/1,2-Dichloroethane (50:50), Cyclohexanone/1,4-Dioxane (50:50), Octane/1-Octanol (50:50), Xylene-p/Nitrobenzene (50:50), n-Heptane/1-Octanol (50:50), Cyclohexanone//Methylcyclohexane (50:50), Methylcyclohexane/4-Hydroxy-4-methyl-2-pentanone (50:50), Anisole/Nitrobenzene (50:50) and Cyclohexanone/N-methyl-2-pyrrolidone (50:50). 
         [0139]    The vials were placed in the Crystal16, heated to 50° C. and held at that temperature for 1 hour. Subsequently the vials were cooled to 5° C. with a cooling rate of 10° C./h. The samples were aged at 5° C. for 72 hours. 
         [0140]    Samples in which solids were present were centrifuged for 10 minutes at 3000 rpm to separate the liquid from the solid. The liquid phase was removed and the solid phase dried and analysed by XRPD. The samples in which no solids were present were placed under deep vacuum and dried to completion. Solids were collected and analysed by XRPD. 
         [0000]    
       
         
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 6 
               
               
                   
               
               
                   
                 Well after 
                   
                   
                   
                   
                   
                   
                   
                   
                 Stock 
               
               
                   
                 recrystal- 
                   
                   
                   
                 Exp. 
                 Solvent 
                 Solvent 
                 Solvent 
                 Solvent 
                 Conc. 
               
               
                 Index 
                 lization 
                 XRPD Form a   
                 XRPD Form b   
                 XRPD Form c   
                 ID 
                 1 (%) 
                 2 (%) 
                 1 
                 2 
                 (mg/mL) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 C01:E2 
                 Form A 
                 Form A 
                 Form A_wet** 
                 ML26 
                 50 
                 50 
                 Cyclohexane 
                 N-methyl-2- 
                 37 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 pyrrolidone 
               
               
                 2 
                 C01:B2 
                 Form A 
                 Form A 
                 Form A 
                 ML23 
                 50 
                 50 
                 Dimethoxyethane 
                 Isopropyl 
                 31 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 1,2- 
                 ether 
               
               
                 3 
                 C01:G1 
                 Form A 
                 Form A + 
                 Form A_wet** 
                 ML10 
                 100 
                 — 
                 Propionitrile 
                 — 
                 31 
               
               
                   
                   
                   
                 Form B1 
               
               
                 4 
                 C01:E1 
                 Form A_wet** 
                 Form A 
                 Form A_wet** 
                 ML7 
                 100 
                 — 
                 Dichloroethane 
                 — 
                 76 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 1,2- 
               
               
                 5 
                 C01:H2 
                 Form A_wet 
                 Form U1 + Am* 
                 Form Z 
                 ML32 
                 50 
                 50 
                 Heptane, N- 
                 Octanol-1 
                 34 
               
               
                 6 
                 C01:F1 
                 Form A_wet** 
                 Form A_wet** 
                 Form A_wet** 
                 ML8 
                 100 
                 — 
                 Fluorbenzene 
                 — 
                 28 
               
               
                 7 
                 C01:A1 
                 Form A_wet** 
                 Form A 
                 Form A + Am* 
                 ML3 
                 100 
                 — 
                 Ethyl acetate 
                 — 
                 34 
               
               
                 8 
                 C01:J1 
                 Form A + Am* 
                 Form U1 + Am* 
                 Form A + Am* 
                 ML13 
                 100 
                 — 
                 Butyl Acetate 
                 — 
                 37 
               
               
                 9 
                 C01:K1 
                 Form A + Am 
                 Form A_wet** 
                 Form A + Am* 
                 ML14 
                 100 
                 — 
                 Chlorobenzene 
                 — 
                 42 
               
               
                 10 
                 C01:H1 
                 Form A + 
                 Form B1_wet** 
                 Form A_wet** 
                 ML11 
                 100 
                 — 
                 Isobutanol 
                 — 
                 132 
               
               
                   
                   
                 Form B1 
               
               
                 11 
                 C01:D1 
                 Form A + 
                 Form A + 
                 Form A + 
                 ML6 
                 100 
                 — 
                 Acetonitrile 
                 — 
                 32 
               
               
                   
                   
                 Form J1 
                 Form J1 
                 Form J1 
               
               
                 12 
                 C01:F2 
                 Form A2 + Am 
                 Form U1 + Am 
                 Form Z_wet** 
                 ML30 
                 50 
                 50 
                 Octane 
                 Octanol-1 
                 34 
               
               
                 13 
                 C01:A2 
                 Form B1_wet** 
                 Form A7 + Am* 
                 Form A 
                 ML20 
                 50 
                 50 
                 Acetonitrile 
                 Chloroform 
                 37 
               
               
                 14 
                 C01:I1 
                 Form B1_wet** 
                 Form B1_wet** 
                 Form A_wet** 
                 ML12 
                 100 
                 — 
                 Isopropyl 
                 — 
                 36 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 acetate 
               
               
                 15 
                 C01:G2 
                 Form D1_wet** 
                 Form D1_wet** 
                 Form A_wet** 
                 ML31 
                 50 
                 50 
                 Xylene-p 
                 Nitrobenzene 
                 36 
               
               
                 16 
                 C01:C1 
                 Form H1 
                 Form A 
                 Form A 
                 ML5 
                 100 
                 — 
                 Ethanol 
                 — 
                 133 
               
               
                 17 
                 C01:B1 
                 Form K_wet 
                 Form A 
                 Form A 
                 ML4 
                 100 
                 — 
                 Methyltetra- 
                 — 
                 79 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 hydrofuran, 2- 
               
               
                 18 
                 C01:C2 
                 Form L1 
                 Form L1 
                 Form L1 
                 ML24 
                 50 
                 50 
                 Formamide 
                 methanol 
                 103 
               
               
                 19 
                 C01:D2 
                 Form X_gel 
                 Form U2 + Am* 
                 Form A_wet** 
                 ML27 
                 50 
                 50 
                 Cyclohexane 
                 Cyclohexanone 
                 36 
               
               
                 20 
                 C01:L1 
                 Form Z_wet 
                 Form U1 + Am* 
                 Form Z_wet** 
                 ML16 
                 100 
                 — 
                 Pentanol 1- 
                 — 
                 132 
               
               
                 21 
                 C01:I2 
                 Wet sample 
                 Form D1_wet** 
                 Form A 
                 ML36 
                 50 
                 50 
                 Cyclohexanone 
                 N-methyl-2- 
                 111 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 pyrrolidone 
               
               
                   
               
               
                 *the assigned crystalline form is present as well as an amorphous phase; the amorphous could be from a solid amorphous material as well as from a slightly wet material. 
               
               
                 **wet solid material. 
               
               
                 ***a minimum amount of crystalline form is present in mixture with a predominant crystalline form. 
               
               
                   a XRPD form assigned after Recrystallization (as wet or dry solid) thus before the stability studies; 
               
               
                   b XRPD form assigned after storage of the samples under ambient conditions for 1-1.5 weeks. 
               
               
                   c XRPD form assigned after the stability studies (48-72 H, at 40° C./75% RH). 
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 7 
               
               
                   
               
               
                   
                 Well after 
                   
                   
                   
                   
                   
                   
                   
                   
                 Stock 
               
               
                   
                 recrystal- 
                   
                   
                   
                 Exp. 
                 Solvent 
                 Solvent 
                 Solvent 
                 Solvent 
                 Conc. 
               
               
                 Index 
                 lization 
                 XRPD Form a   
                 XRPD Form b   
                 XRPD Form c   
                 ID 
                 1 (%) 
                 2 (%) 
                 1 
                 2 
                 (mg/mL) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 C02:J1 
                 Form A 
                 Form A 
                 Form A 
                 ML10 
                 — 
                 — 
                 Propionitrile 
                 — 
                 31 
               
               
                 2 
                 C02:C1 
                 Form A 
                 Form A 
                 Form A 
                 ML3 
                 — 
                 — 
                 Ethyl acetate 
                 — 
                 34 
               
               
                 3 
                 C02:D3 
                 Form A 
                 Form A 
                 Form A 
                 ML28 
                 50 
                 50 
                 Methyl- 
                 Dichloro- 
                 40 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 cyclohexane 
                 ethane 1,2- 
               
               
                 4 
                 C02:F1 
                 Form A + 
                 Form A + 
                 Form J1 
                 ML6 
                 — 
                 — 
                 Aceto- 
                 — 
                 32 
               
               
                   
                   
                 Form J1 
                 Form J1 
                   
                   
                   
                   
                 nitrile 
               
               
                 5 
                 C02:K1 
                 Form A + 
                 Form A + 
                 Form A_low 
                 ML11 
                 — 
                 — 
                 Isobutanol 
                 — 
                 132 
               
               
                   
                   
                 Form J1 
                 Form J1 
                 yield 
               
               
                 5 
                 C02:K2 
                 Form A3 
                 Form L2 
                 Form L2 
                 ML23 
                 50 
                 50 
                 Dimethoxy- 
                 Isopropyl 
                 31 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 ethane 1,2- 
                 ether 
               
               
                 7 
                 C02:A2 
                 Form A3 
                 Form A + 
                 Form A 
                 ML13 
                 — 
                 — 
                 Butyl 
                 — 
                 37 
               
               
                   
                   
                   
                 Form A3 
                   
                   
                   
                   
                 Acetate 
               
               
                 8 
                 C02:E1 
                 Form A4 
                 Form A + 
                 Form A 
                 ML5 
                 — 
                 — 
                 Ethanol 
                 — 
                 133 
               
               
                   
                   
                   
                 Form A3 
               
               
                 9 
                 C02:A3 
                 Form A4 
                 Form R 
                 Form A 
                 ML25 
                 50 
                 50 
                 Cyclo- 
                 Tetra- 
                 107 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 hexanone 
                 hydrofuran 
               
               
                 10 
                 C02:C3 
                 Form A4 
                 Form B1_wet** 
                 Form A + 
                 ML27 
                 50 
                 50 
                 Cyclohexane 
                 Cyclo- 
                 36 
               
               
                   
                   
                   
                   
                 Form B1 
                   
                   
                   
                   
                 hexanone 
               
               
                 11 
                 C02:H2 
                 Form A7 
                 Form A7 
                 Form A_plus 
                 ML20 
                 50 
                 50 
                 Acetonitrile 
                 Chloroform 
                 37 
               
               
                 12 
                 C02:D1 
                 Form A8 
                 Form A8 
                 Form A 
                 ML4 
                 — 
                 — 
                 Methyltetra- 
                 — 
                 79 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 hydrofuran, 2- 
               
               
                 13 
                 C02:G3 
                 Form B1 
                 Form B1 
                 Form B1 
                 ML33 
                 50 
                 50 
                 Cyclo- 
                 Methyl- 
                 37 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 hexanone 
                 cyclohexane 
               
               
                 14 
                 C02:F2 
                 Form B1 
                 Form B1 
                 A + 
                 ML18 
                 — 
                 — 
                 
                           
                 
                 — 
                 144 
               
               
                   
                   
                   
                   
                 Form B1 
                   
                   
                   
                 pentanon 4- 
               
               
                 15 
                 C02:D2 
                 Form B1 
                 Form B1 
                 Form A + 
                 ML16 
                 — 
                 — 
                 Pentanol 1- 
                 — 
                 132 
               
               
                   
                   
                   
                   
                 Form B1 
               
               
                 16 
                 C02:E3 
                 Form B1 
                 Form B1 
                 Form A + 
                 ML29 
                 50 
                 50 
                 Cyclo- 
                 Dioxane, 1,4- 
                 81 
               
               
                   
                   
                   
                   
                 Form B1 
                   
                   
                   
                 hexanone 
               
               
                 17 
                 C02:H3 
                 Form B1_wet** 
                 Form B1_wet** 
                 Form A + 
                 ML34 
                 50 
                 50 
                 Methyl- 
                 Hydroxy-4- 
                 28 
               
               
                   
                   
                   
                   
                 Form B1 
                   
                   
                   
                 cyclohexane 
                 methyl-2- 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 pentanon 4- 
               
               
                 18 
                 C02:I3 
                 Form D1 
                 Form D1 
                 Form A 
                 ML35 
                 50 
                 50 
                 Anisole 
                 Nitrobenzene 
                 36 
               
               
                 19 
                 C02:F3 
                 Form D1_wet 
                 Form D1_wet 
                 Form A + Am* 
                 ML31 
                 50 
                 50 
                 Xylene-p 
                 Nitrobenzene 
                 36 
               
               
                 20 
                 C02:H1 
                 Form F1 
                 Form A + 
                 Form A 
                 ML8 
                 — 
                 — 
                 Fluorbenzene 
                 — 
                 28 
               
               
                   
                   
                   
                 Form F1 
               
               
                 21 
                 C02:G1 
                 Form F2 
                 Form A3 
                 Form A 
                 ML7 
                 — 
                 — 
                 Dichloro- 
                 — 
                 76 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 ethane 1,2- 
               
               
                 22 
                 C02:B2 
                 Form F3 
                 Form A + 
                 Form A 
                 ML14 
                 — 
                 — 
                 Chlorobenzene 
                 — 
                 42 
               
               
                   
                   
                   
                 Form F1 
               
               
                 23 
                 C02:B1 
                 Form J1 
                 Form J1 
                 Form J1 
                 ML2 
                 — 
                 — 
                 Tetra- 
                 — 
                 383 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 hydrofuran 
               
               
                 24 
                 C02:J2 
                 Form J1 
                 Form J2 
                 Form J2 
                 ML22 
                 50 
                 50 
                 Dimethoxy- 
                 methanol 
                 94 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 ethane 1,2- 
               
               
                 25 
                 C02:I1 
                 Form J1 
                 Form J2 
                 Form J1 
                 ML9 
                 — 
                 — 
                 Dimethoxy- 
                 — 
                 315 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 ethane 1,2- 
               
               
                 26 
                 C02:G2 
                 Form J1 
                 Form B1 + 
                 Form A + 
                 ML19 
                 50 
                 50 
                 methanol 
                 Aceto- 
                 97 
               
               
                   
                   
                   
                 Form J1 
                 Form J1 
                   
                   
                   
                   
                 nitrile 
               
               
                 27 
                 C02:L1 
                 Form L1 
                 Form L1 
                 Form L1 
                 ML12 
                 — 
                 — 
                 Isopropyl 
                 — 
                 36 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 acetate 
               
               
                 28 
                 C02:L2 
                 Form L1 
                 Form L1 
                 Form L1 
                 ML24 
                 50 
                 50 
                 Formamide 
                 methanol 
                 103 
               
               
                 29 
                 C02:A1 
                 Form M1 
                 Form M1 
                 Form M1 
                 ML1 
                 — 
                 — 
                 methanol 
                 — 
                 539 
               
               
                 30 
                 C02:C2 
                 Form M2 
                 Form M2 
                 Form M2 
                 ML15 
                 — 
                 — 
                 Ethoxy- 
                 — 
                 468 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 ethanol 2- 
               
               
                 31 
                 C02:E2 
                 Form R 
                 Form R 
                 Form A 
                 ML17 
                 — 
                 — 
                 Cyclo- 
                 — 
                 421 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 hexanone 
               
               
                 32 
                 C02:I2 
                 Form S + Am 
                 Form B1 + 
                 Form A_plus 
                 ML21 
                 50 
                 50 
                 methanol 
                 Xylene-p 
                 88 
               
               
                   
                   
                   
                 Form F1 
               
               
                   
               
               
                 *the assigned crystalline form is present as well as an amorphous phase; the amorphous could be from a solid amorphous material as well as from a slightly wet material. 
               
               
                 **wet solid material. 
               
               
                 ***a minimum amount of crystalline form is present in mixture with a predominant crystalline form. 
               
               
                   a XRPD form assigned after Recrystallization (as wet or dry solid) thus before the stability studies; 
               
               
                   b XRPD form assigned after storage of the samples under ambient conditions for 1-1.5 weeks. 
               
               
                   c XRPD form assigned after the stability studies (48-72 H, at 40° C./75% RH). 
               
               
                             indicates data missing or illegible when filed 
               
             
          
         
       
     
       Example 4 
     Solvent-Drop Grinding Experiments 
       [0141]    Table 8 illustrates solvent-drop grinding experiments conducted on the indicated Form. AR42 was subjected to grinding for 30 minutes with a frequency of 30 Hz and with one single drop of the following solvents: Acetonitrile, Isopropanol, 1,2-Dichloroethane, Fluorbenzene, 1,2-Dimethoxyethane, Nitromethane, Propyl acetate, Butyl Acetate, Cyclohexanone, 1,2-Propanediol, Benzonitrile, 1-Octanol. Subsequently, the solids were collected and analysed by XRPD. 
         [0000]    
       
         
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 8 
               
               
                   
               
               
                   
                 Well after 
                   
                   
                   
                 Exp. 
                   
               
               
                 Index 
                 grinding 
                 XRPD Form a   
                 XRPD Form b   
                 XRPD Form c   
                 ID 
                 Screen Solvent 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 GR2:H1 
                 Form A 
                 Form A5a 
                 Form A 
                 ML8 
                 Propyl acetate 
               
               
                 2 
                 GR2:G1 
                 Form A_min + 
                 Form A5b + 
                 Form A5a 
                 ML7 
                 Nitromethane 
               
               
                   
                   
                 Form T 
                 Am* 
               
               
                 3 
                 GR2:K1 
                 Form A_wet** 
                 Form A_wet** 
                 Form A 
                 ML11 
                 Propanediol 1,2- 
               
               
                 4 
                 GR2:A2 
                 Form A 
                 Form A 
                 Form A 
                 ML13 
                 Octanol-1 
               
               
                 5 
                 GR2:A1 
                 Form A + 
                 Form A_wet** 
                 Form A 
                 ML1 
                 — (dry grinding) 
               
               
                   
                   
                 Form B1 
               
               
                 6 
                 GR2:E1 
                 Form A + 
                 Form A 
                 Form A 
                 ML5 
                 Fluorbenzene 
               
               
                   
                   
                 Form F1 
               
               
                 7 
                 GR2:D1 
                 Form A + 
                 Form A 
                 Form A 
                 ML4 
                 Dichloroethane 1,2- 
               
               
                   
                   
                 Form F1 
               
               
                 8 
                 GR2:J1 
                 Form A + 
                 Form A 
                 Form A 
                 ML10 
                 Cyclohexanone 
               
               
                   
                   
                 Form V 
               
               
                 9 
                 GR2:I1 
                 Form A3 
                 Form A 
                 Form A 
                 ML9 
                 Butyl Acetate 
               
               
                 10 
                 GR2:F1 
                 Form A5a 
                 Form A5a 
                 Form A5a 
                 ML6 
                 Dimethoxy ethane, 1,2- 
               
               
                 11 
                 GR2:L1 
                 Form D1 
                 Form D1 
                 Form A 
                 ML12 
                 Benzonitrile 
               
               
                 12 
                 GR2:C1 
                 Form H2 
                 Form A2 
                 Form A 
                 ML3 
                 Propanol 2- 
               
               
                 13 
                 GR2:B1 
                 Form J1 
                 Form J1 
                 Form J1 
                 ML2 
                 Acetonitrile 
               
               
                 14 
                 GR1:A1 
                 Form J1 
                 Form J1 
                 Am 
                 ML14 
                 Acetonitrile 
               
               
                   
               
               
                 *the assigned crystalline form is present as well as an amorphous phase; the amorphous could be from a solid amorphous material as well as from a slightly wet material. 
               
               
                 **wet solid material. 
               
               
                 ***a minimum amount of crystalline form is present in mixture with a predominant crystalline form. 
               
               
                   a XRPD form assigned after Recrystallization (as wet or dry solid) thus before the stability studies; 
               
               
                   b XRPD form assigned after storage of the samples under ambient conditions for 1.5-2 weeks. 
               
               
                   c XRPD form assigned after the stability studies (46-72 H, at 40° C./75% RH). 
               
             
          
         
       
     
       Example 5 
     Slurry Conversion Experiments 
       [0142]    Tables 9-10 illustrate slurry conversion experiments conducted on the indicated Form. Suspensions of AR42 were prepared by adding and excess of AR42 to the following solvents and solvent mixtures: tert-Butyl methyl ether, Chloroform, Methanol, Tetrahydrofuran, Diisopropyl ether, 2-Methyltetrahydrofuran, Ethanol, Cyclohexane, Acetonitrile, 1,2-Dichloroethane, Fluorbenzene, 1,2-Dimethoxyethane, Diethoxymethane, Hexafluorobenzene, 2,2,4-Trimethylpentane, Water, Methylcyclohexane, Nitromethane, 1,4-Dioxane, 2,2-Dimethyl-3-butanone, 2-Methyl-1-Propanol, Toluene, Octane, Diethyl carbonate, Butyl Acetate, Chlorobenzene, Ethylbenzene, Isopentyl Acetate, Pentyl acetate, Cumene, Anisole, Cyclohexanone, Diethylene glycol dimethyl ether, 1,2,4-Trimethylbenzene, 4-Hydroxy-4-methyl-2-pentanon, 2,6-Dimethyl-4-heptanone. The slurries were stirred at ambient temperature for one week. Subsequently, the samples were centrifuged for 10 minutes at 3000 rpm to separate the liquid from the solid. The solid phase was analysed by XRPD. The solids and liquids were dried under vacuum and analysed by XRPD. 
         [0000]    
       
         
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 9 
               
               
                   
               
               
                   
                 Well after 
                   
                   
                   
                 Exp. 
                   
                 Conc. 
               
               
                 Index 
                 slurry 
                 XRPD Form a   
                 XRPD Form b   
                 XRPD Form c   
                 ID 
                 Solvent 
                 (mg/mL) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 SL01:G3 
                 Form A 
                 Form A 
                 Form A 
                 ML32 
                 Cyclohexanone 
                 207 
               
               
                 2 
                 SL01:H1 
                 Form A 
                 Form A 
                 Form A 
                 ML8 
                 Cyclohexane 
                 41 
               
               
                 3 
                 SL01:C2 
                 Form A 
                 Form A 
                 Form A 
                 ML15 
                 Trimethylpentane 
                 42 
               
               
                   
                   
                   
                   
                   
                   
                 2,2,4- 
               
               
                 4 
                 SL01:E2 
                 Form A 
                 Form A + Am* 
                 Form A 
                 ML17 
                 Methylcyclohexane 
                 44 
               
               
                 5 
                 SL01:E1 
                 Form A 
                 Form A 
                 Form A 
                 ML5 
                 Diisopropyl ether 
                 42 
               
               
                 6 
                 SL01:K2 
                 Form A 
                 Form A_wet** 
                 Form A_wet** 
                 ML23 
                 Octane 
                 41 
               
               
                 7 
                 SL01:A2 
                 Form A 
                 Form A_wet** 
                 Form A + Am* 
                 ML13 
                 Diethoxymethane 
                 44 
               
               
                 8 
                 SL01:B2 
                 Form A 
                 Form A 
                 Form A 
                 ML14 
                 Hexafluorobenzene 
                 43 
               
               
                 9 
                 SL01:J2 
                 Form A 
                 Form A_wet** 
                 Form A_wet* 
                 ML22 
                 Toluene 
                 41 
               
               
                 10 
                 SL01:F3 
                 Form A_wet** 
                 Form A_wet** 
                 Form A + Am* 
                 ML31 
                 Anisole 
                 41 
               
               
                 11 
                 SL01:H2 
                 Form A_wet** 
                 Form A + Am* 
                 Form A + Am* 
                 ML20 
                 Dimethyl-3-butanone 
                 43 
               
               
                   
                   
                   
                   
                   
                   
                 2,2- 
               
               
                 12 
                 SL01:I2 
                 Form A_wet** 
                 Form A5a + 
                 Form A5a 
                 ML21 
                 Methyl-1-Propanol 2- 
                 206 
               
               
                   
                   
                   
                 Am_min* 
               
               
                 13 
                 SL01:I3 
                 Form A_wet** 
                 Form A6_wet** 
                 Form A5a 
                 ML34 
                 Trimethylbenzene 
                 41 
               
               
                   
                   
                   
                   
                   
                   
                 1,2,4- 
               
               
                 14 
                 SL01:E3 
                 Form A_wet** 
                 Form A_wet** 
                 Form A + Am* 
                 ML30 
                 Cumene 
                 42 
               
               
                 15 
                 SL01:L2 
                 Form A_wet** 
                 Form A_wet** 
                 Form A_wet** 
                 ML24 
                 Diethyl carbonate, 
                 43 
               
               
                   
                   
                   
                   
                   
                   
                 anhydrous 
               
               
                 16 
                 SL01:K3 
                 Form A_wet** 
                 Form A + Am* 
                 Form A + Am* 
                 ML36 
                 Dimethyl-4- 
                 43 
               
               
                   
                   
                   
                   
                   
                   
                 heptanone, 2,6- 
               
               
                 17 
                 SL01:A1 
                 Form A_wet** 
                 Form A_low 
                 n 
                 ML1 
                 tert-Butylmethyl 
                 43 
               
               
                   
                   
                   
                 yield 
                   
                   
                 ether, anhydrous 
               
               
                 18 
                 SL01:A3 
                 Form A_wet** 
                 Form A_wet** 
                 Form A + Am* 
                 ML25 
                 Butyl Acetate 
                 41 
               
               
                 19 
                 SL01:D3 
                 Form A_wet** 
                 Form A_wet** 
                 Form A + Am* 
                 ML28 
                 Isopentyl Acetate 
                 42 
               
               
                 20 
                 SL01:J1 
                 Form A3 + Am* 
                 Form A + 
                 Form A 
                 ML10 
                 Dichloroethane 1,2- 
                 44 
               
               
                   
                   
                   
                 Form B1 
               
               
                 21 
                 SL01:B1 
                 Form A7 + Am* 
                 Form A3 + Am* 
                 Form A + Am* 
                 ML2 
                 Chloroform 
                 41 
               
               
                 22 
                 SL01:J3 
                 Form B1_wet** 
                 Form B1 
                 Form A5a 
                 ML35 
                 Hydroxy-4-methyl- 
                 251 
               
               
                   
                   
                   
                   
                   
                   
                 2-pentanon 4- 
               
               
                 23 
                 SL01:D1 
                 Form E 
                 Form E 
                 Form A_wet 
                 ML4 
                 Tetrahydrofuran 
                 452 
               
               
                 24 
                 SL01:F1 
                 Form E 
                 Form A3 
                 Form A 
                 ML6 
                 Methyltetrahydro- 
                 203 
               
               
                   
                   
                   
                   
                   
                   
                 furan, 2- 
               
               
                 25 
                 SL01:K1 
                 Form F1 
                 Form A_wet** 
                 Form A 
                 ML11 
                 Fluorbenzene 
                 42 
               
               
                 26 
                 SL01:G2 
                 Form F4_wet** 
                 Form A + Am* 
                 Form A + Am* 
                 ML19 
                 Dioxane, 1,4- 
                 74 
               
               
                 27 
                 SL01:G1 
                 Form H1 
                 Form A 
                 Form A 
                 ML7 
                 Ethanol absolute 
                 195 
               
               
                 28 
                 SL01:I1 
                 Form J1 
                 Form J1 
                 Form J1 
                 ML9 
                 Acetonitrite 
                 44 
               
               
                 29 
                 SL01:F2 
                 Form Y + Am* 
                 Form M2 + Am* 
                 Form M2 
                 ML18 
                 Nitromethane 
                 44 
               
               
                 30 
                 SL01:B3 
                 Wet sample 
                 Form F3_wet** 
                 Form A + Am* 
                 ML26 
                 Chlorobenzene 
                 43 
               
               
                 31 
                 SL01:C3 
                 Wet sample 
                 Form F1_wet** 
                 Form A + Am* 
                 ML27 
                 Ethylbenzene 
                 42 
               
               
                 32 
                 SL01:D2 
                 Wet sample 
                 Form M2_wet** 
                 Form M2 
                 ML16 
                 Water 
                 42 
               
               
                   
               
               
                 *the assigned crystalline form is present as well as an amorphous phase; the amorphous could be from a solid amorphous material as well as from a slightly wet material. 
               
               
                 **wet solid material. 
               
               
                 ***a minimum amount of crystalline form is present in mixture with a predominant crystalline form. 
               
               
                   a XRPD from assigned after crystallization experiment (as wet or dry solid) thus before the stability studies; 
               
               
                   b XRPD form assigned after storage of the samples under ambient conditions to 1-1.5 weeks. 
               
               
                   c XRPD form assigned after the stability studies (48-72 H, at 40° C./75% RH). 
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 10 
               
               
                   
               
               
                   
                 Well after 
                   
                   
                   
                 Experiment 
                   
                 Stock Conc. 
               
               
                 Index 
                 slurry 
                 XRPD Form a   
                 XRPD Form b   
                 XRPD Form c   
                 ID 
                 Solvent 
                 (mg/mL) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 SL02:F2 
                 Form A 
                 Form A 
                 Form A 
                 ML17 
                 Methylcyclohexane 
                 44 
               
               
                 2 
                 SL02:F3 
                 Form A 
                 Form A 
                 Form A 
                 ML28 
                 Isopentyl Acetate 
                 42 
               
               
                 3 
                 SL02:F1 
                 Form A 
                 Form A 
                 Form A 
                 ML6 
                 Methyltetrahydrofuran, 
                 203 
               
               
                   
                   
                   
                   
                   
                   
                 2- 
               
               
                 4 
                 SL02:D2 
                 Form A 
                 Form A_low 
                 Form A_low 
                 ML15 
                 Trimethylpentane 
                 42 
               
               
                   
                   
                   
                 yield 
                 yield 
                   
                 2,2,4- 
               
               
                 5 
                 SL02:E1 
                 Form A 
                 Form A 
                 Form A 
                 ML5 
                 Diisopropyl ether 
                 42 
               
               
                 6 
                 SL02:G3 
                 Form A 
                 Form A 
                 Form A 
                 ML30 
                 Cumene 
                 42 
               
               
                 7 
                 SL02:J1 
                 Form A 
                 Form A 
                 Form A 
                 ML10 
                 Dichloroethane 1,2- 
                 44 
               
               
                 8 
                 SL02:K2 
                 Form A 
                 Form A 
                 Form A 
                 ML22 
                 Toluene 
                 41 
               
               
                 9 
                 SL02:I3 
                 Form A 
                 Form A 
                 Form A 
                 ML32 
                 Cyclohexanone 
                 207 
               
               
                 10 
                 SL02:H1 
                 Form A 
                 Form A 
                 Form A 
                 ML8 
                 Cyclohexane 
                 41 
               
               
                 11 
                 SL02:H3 
                 Form A 
                 Form A 
                 Form A 
                 ML31 
                 Anisole 
                 41 
               
               
                 12 
                 SL02:B2 
                 Form A 
                 Form A 
                 Form A 
                 ML13 
                 Diethoxymethane 
                 44 
               
               
                 13 
                 SL02:C2 
                 Form A 
                 Form A 
                 Form A 
                 ML14 
                 Hexafluorobenzene 
                 43 
               
               
                 14 
                 SL02:B3 
                 Form A 
                 Form A 
                 Form A 
                 ML24 
                 Diethyl carbonate, 
                 43 
               
               
                   
                   
                   
                   
                   
                   
                 anhydrous 
               
               
                 15 
                 SL02:A3 
                 Form A 
                 Form A 
                 Form A 
                 ML23 
                 Octane 
                 41 
               
               
                 16 
                 SL02:A1 
                 Form A 
                 Form A 
                 Form A 
                 ML1 
                 tert-Butylmethyl 
                 43 
               
               
                   
                   
                   
                   
                   
                   
                 ether, anhydrous 
               
               
                 17 
                 SL02:A2 
                 Form A 
                 Form A 
                 Form A 
                 ML12 
                 Dimethoxyethane, 
                 242 
               
               
                   
                   
                   
                   
                   
                   
                 1,2- 
               
               
                 18 
                 SL02:C3 
                 Form A + 
                 Form A + 
                 Form A 
                 ML25 
                 Butyl Acetate 
                 41 
               
               
                   
                   
                 Form A3 
                 Form A3 
               
               
                 19 
                 SL02:G1 
                 Form A + 
                 Form A + 
                 Form A 
                 ML7 
                 Ethanol absolute 
                 195 
               
               
                   
                   
                 Form H3 
                 Form H3 
               
               
                 20 
                 SL02:H2 
                 Form A3 
                 Form A4 
                 Form A 
                 ML19 
                 Dioxane, 1,4- 
                 74 
               
               
                 21 
                 SL02:B1 
                 Form A4 
                 Form A4 
                 Form A5a 
                 ML2 
                 Chloroform 
                 41 
               
               
                 22 
                 SL02:J2 
                 Form A5a 
                 Form A5a 
                 Form A5a 
                 ML21 
                 Methyl-1-Propanol 2- 
                 206 
               
               
                 23 
                 SL02:I2 
                 Form A6 
                 Form A6 
                 — d   
                 ML20 
                 Dimethyl-3-butanone 
                 43 
               
               
                   
                   
                   
                   
                   
                   
                 2,2- 
               
               
                 24 
                 SL02:L3 
                 Form B1 
                 Form B1 
                 Form A 
                 ML35 
                 Hydroxy-4-methyl-2- 
                 251 
               
               
                   
                   
                   
                   
                   
                   
                 pentanon 4- 
               
               
                 25 
                 SL02:D1 
                 Form E 
                 Form E 
                 Form A 
                 ML4 
                 Tetrahydrofuran 
                 452 
               
               
                 26 
                 SL02:L1 
                 Form F1 
                 Form A + 
                 Form A 
                 ML11 
                 Fluorbenzene 
                 42 
               
               
                   
                   
                   
                 Form F1 
               
               
                 27 
                 SL02:D3 
                 Form F3 
                 Form F3 
                 Form A 
                 ML26 
                 Chlorobenzene 
                 43 
               
               
                 28 
                 SL02:I1 
                 Form J1 
                 Form J1 
                 Form J1 
                 ML9 
                 Acetonitrile 
                 44 
               
               
                 29 
                 SL02:C1 
                 Form M1 
                 Form M1 
                 Form M1 
                 ML3 
                 methanol 
                 510 
               
               
                 30 
                 SL02:E2 
                 Form M2 
                 Form M2 
                 Form M2 
                 ML16 
                 Water 
                 42 
               
               
                 31 
                 SL02:G2 
                 Form M2 + Am 
                 Form M2 + Am 
                 Form M2 
                 ML18 
                 Nitromethane 
                 44 
               
               
                 32 
                 SL02:E3 
                 Form S 
                 Form A + 
                 Form A 
                 ML27 
                 Ethylbenzene 
                 42 
               
               
                   
                   
                   
                 Form F1 
               
               
                 33 
                 SL02:A4 
                 Form U1 + Am 
                 Form U1 + Am 
                 Form A + Am 
                 ML36 
                 Dimethyl-4- 
                 43 
               
               
                   
                   
                   
                   
                   
                   
                 heptanone, 2,6- 
               
               
                 34 
                 SL02:K3 
                 Form U1 + Am 
                 n 
                 Form A + Am 
                 ML34 
                 Trimethylbenzene 
                 41 
               
               
                   
                   
                   
                   
                   
                   
                 1,2,4- 
               
               
                 35 
                 SL03:A5 
                 — 
                 Form A6 
                 Form A5b 
                 
                           
                 
                 Dimethyl-3-butanone 
                 
                           
                 
               
               
                   
                   
                   
                   
                   
                 ML20 
                 2,2- 
                 43 
               
               
                 36 
                 SL07:A8/ 
                 Form A_wet 
                 Form A 
                 — e   
                 ML29 
                 Pentyl acetate 
                 139 
               
               
                   
                 SL03:C8 
               
               
                   
               
               
                 *the assigned crystalline form is present as well as an amorphous phase; the amorphous could be from a solid amorphous material as well as from a slightly wet material. 
               
               
                 **wet solid material. 
               
               
                 ***a minimum amount of crystalline form is present in mixture with a predominant crystalline form. 
               
               
                   a XRPD form assigned after crystallization experiment (as wet or dry solid) thus before the stability studies; 
               
               
                   b XRPD form assigned after storage of the samples under ambient conditions for 1-1.5 weeks. 
               
               
                   c XRPD form assigned after the stability studies (48-72 H, at 40° C./75% RH). 
               
               
                   d see entry#35 in Table 10 for the XRPD form after stability studies. 
               
               
                   e — no stability studies were carried out. 
               
               
                             indicates data missing or illegible when filed 
               
             
          
         
       
     
         [0143]    Although the above description refers to particular aspects, it is to be understood that these aspects are merely illustrative. It will be apparent to those skilled in the art that various modifications and variations can be made to the polymorphic forms and methods described herein. Thus, it is intended that the present description include modifications and variations that are within the scope of the appended claims and their equivalents.