Patent Publication Number: US-2021177829-A1

Title: Solid forms of ((s)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit of and priority to U.S. provisional patent application No. 62/672,461, filed on May 16, 2018, U.S. provisional patent application No. 62/672,462, filed on May 16, 2018, and U.S. provisional patent application No. 62/692,591, filed on Jun. 29, 2018, the entire contents of which are incorporated herein by reference. 
    
    
     TECHNICAL FIELD 
     The present disclosure relates to pharmaceutical compositions, including a solid form of a certain compound useful for inhibiting mutant isocitrate dehydrogenase 1 (mIDH1). 
     BACKGROUND 
     The solid form of a compound may be important when the compound is used for pharmaceutical purposes. For example, compared with an amorphous solid, the solid physical properties of a crystalline compound may change from one solid form to another, which may affect its suitability for pharmaceutical use. In addition, different solid forms of a crystalline compound can incorporate different types and/or different amounts of impurities. The solid form of a compound can also affect chemical stability upon exposure to heat and/or water over a period of time. 
     The compound ((S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (“Compound 1”) 
     
       
         
         
             
             
         
       
     
     is an selective inhibitor of R132X mIDH-1. The free base of Compound 1 can be formulated into a pharmaceutical composition for treating patients diagnosed with a mIDH-1 form of cancer. The pharmaceutical composition can be provided in a unit dosage form (e.g., a capsule or unit dosage form) for oral use. 
     A preparation of a lyophilized solid form of Compound 1 is described in the publication WO2016/044789. However, therapeutic compounds often exist in a variety of solid forms having different properties. There remains a need for identifying solid forms of Compound 1 useful for various therapeutic applications. 
     SUMMARY 
     Crystalline ((S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (Compound 1), and methods of making compositions comprising crystalline Compound 1, are disclosed herein. In some embodiments, a novel solid form of Compound 1 disclosed herein includes Compound 1 in a solid form designated as Type A, as well as compositions comprising a solid form of Compound 1. Novel compositions also include Compound 1 as a solid form designated as Type A, and/or crystalline and amorphous solid forms of Compound 1. The various solid forms of Compound 1 can be identified by certain characteristic properties. 
     A preferred solid form of ((S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (Compound 1) can be characterized by a reflection X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 6.3, 12.8, 13.8, 23.6, and 27.8 degrees±0.2° 2θ. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  depicts a dynamic vapor sorption (DVS) isotherm plot of Compound 1 Type A solid form. 
         FIG. 2  depicts a differential scanning calorimetry (DSC) thermogram for Compound 1 Type A solid form. 
         FIG. 3  depicts a thermogravimetric analysis (TGA) curve for Compound 1 Type A solid form. 
         FIG. 4  depicts X-ray powder diffraction (XRPD) pattern of Compound 1 Type A solid form. 
     
    
    
     DETAILED DESCRIPTION 
     The bioactive chemical ((S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile can be prepared as a solid form. The compound ((S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (“Compound 1”) is shown below: 
     
       
         
         
             
             
         
       
     
     Compound 1 can also be referred to as olutasidenib, CAS No. 1887014-12-1, (S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile, or 5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile. 
     Compound 1 can occur in an amorphous solid form or in a crystalline solid form or in mixtures of solid forms. Crystalline solid forms of Compound 1 can exist in one or more unique solid forms, which can additionally comprise one or more equivalents of water or solvent (i.e., hydrates or solvates, respectively). 
     As disclosed herein, crystalline form(s) of Compound 1 have distinct characteristic XRPD peaks (see Example 2) that are not characterized in previous disclosures of Compound 1. Accordingly, provided herein are crystalline Compound 1 solid forms, pharmaceutical compositions thereof, and methods of preparing those crystalline Compound 1 solid forms and methods of use thereof. 
     A novel Compound 1 solid form can be obtained by a method reported in Example 2. For example, Compound 1 Type A can be prepared by a solution comprising Compound 1 and a solvent, and concentrating the solution, then diluting the solution with a solvent, stirring the solution for a period of time and cooling the solution to precipitate a crystalline solid of Compound 1 Type A. In some embodiments, the solution is stirred at room temperature. In some embodiments, the solution is cooled to a temperature of about 0° C. In some embodiments, the solvent comprises ethyl acetate. 
     As used herein, the term “precipitate” refers to the formation of a solid substance from a solution containing the same substance. A substance which precipitates from solution may be amorphous or crystalline. Precipitation may occur under a variety of conditions known to those of skill in the art, including the treatment of a solution of a solute (e.g., solute A in solvent B) with an antisolvent (i.e., a solvent that is miscible with solvent B, but does not dissolve solute A). 
     Solid forms of Compound 1 can be identified by various analytical techniques, such as X-ray powder diffraction (XRPD). Solid forms of Compound 1 disclosed herein include Compound 1 Type A solid form, as well as compositions comprising a solid form of Compound 1 comprising Type A solid form. 
     A novel Compound 1 Type A solid form is characterized by an X-ray Powder Diffraction (XRPD) pattern, having diffraction peaks at angles (2 theta±0.2) of 6.3, 12.8, 13.8, 23.6, and 27.8. In some embodiments, a novel Compound 1 Type A is characterized by an X-ray Powder Diffraction (XRPD) pattern, having diffraction peaks at angles (2 theta±0.2) of 6.3, 12.8, 13.8, 23.6, and 27.8, corresponding to d-spacing (angstroms±0.2) of 14.0, 6.9, 6.4, 3.8, and 3.2, respectively. In some embodiments, Compound 1 Type A can be identified by X-ray Powder Diffraction (XRPD) pattern, having characteristic diffraction peaks at angles (2 theta±0.2) of 5.7, 6.3, 8.5, 10.6, 12.8, 13.8, 17.3, 22.0, 22.8, 23.6, and 27.8. In some embodiments, Compound 1 Type A can be identified by X-ray Powder Diffraction (XRPD) pattern, having characteristic diffraction peaks at angles (2 theta±0.2) of 5.7, 6.3, 8.5, 10.6, 12.8, 13.8, 17.3, 22.0, 22.8, 23.6, and 27.8, corresponding to d-spacing (angstroms±0.2) of 15.4, 14.0, 8.4, 6.9, 6.4, 5.1, 4.0, 3.9, 3.8, and 3.2, respectively. 
     In some embodiments, Compound 1 Type A solid form is characterized by an X-ray powder diffraction having peaks at the same or substantially the same angles (2θ±0.2) and corresponding d-spacing (Å±0.2) of: 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 2θ ± 
                 d-spacing 
               
               
                   
                 0.2 
                 Å ± 0.2 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 5.7 
                 15.4 
               
               
                   
                 6.3 
                 14.0 
               
               
                   
                 8.5 
                 10.4 
               
               
                   
                 10.6 
                 8.4 
               
               
                   
                 11.4 
                 7.8 
               
               
                   
                 12.8 
                 6.9 
               
               
                   
                 13.8 
                 6.4 
               
               
                   
                 14.2 
                 6.2 
               
               
                   
                 15.2 
                 5.8 
               
               
                   
                 15.6 
                 5.7 
               
               
                   
                 17.3 
                 5.1 
               
               
                   
                 17.9 
                 5.0 
               
               
                   
                 18.2 
                 4.9 
               
               
                   
                 18.9 
                 4.7 
               
               
                   
                 19.6 
                 4.5 
               
               
                   
                 20.6 
                 4.3 
               
               
                   
                 21.5 
                 4.1 
               
               
                   
                 22.0 
                 4.0 
               
               
                   
                 22.8 
                 3.9 
               
               
                   
                 23.6 
                 3.8 
               
               
                   
                 24.5 
                 3.6 
               
               
                   
                 24.8 
                 3.6 
               
               
                   
                 25.3 
                 3.5 
               
               
                   
                 25.6 
                 3.5 
               
               
                   
                 26.0 
                 3.4 
               
               
                   
                 26.3 
                 3.4 
               
               
                   
                 27.0 
                 3.3 
               
               
                   
                 27.8 
                 3.2 
               
               
                   
                 28.9 
                 3.1 
               
               
                   
                 30.0 
                 3.0 
               
               
                   
                 31.2 
                 3.0 
               
               
                   
                 32.1 
                 2.8 
               
               
                   
                 33.6 
                 2.7 
               
               
                   
                 34.1 
                 2.6 
               
               
                   
                 36.3 
                 2.5 
               
               
                   
                 37.0 
                 2.4 
               
               
                   
                 38.1 
                 2.4 
               
               
                   
                   
               
            
           
         
       
     
     The presence of Compound 1 in the Type A solid form can be identified by one or more techniques, including DSC, TGA, DVS and XRPD. In some embodiments, Compound 1 Type A solid form is characterized by a differential scanning calorimetry (DSC) endotherm having a minima at about 256.64° C. The dynamic vapor sorption (DVS) isotherm plot of  FIG. 1 , the differential scanning calorimetry (DSC) thermogram of  FIG. 2 , the thermogravimetric analysis (TGA) plot in  FIG. 3  and the X-ray Powder Diffraction (XRPD) pattern in  FIG. 4  were each obtained by a composition comprising Compound 1, Type A solid form. The presence of Compound 1 Type A solid form can be identified by performing DSC, TGA, DVS and/or XRPD analysis of a composition and identifying sufficient similarity in comparison with the DVS isotherm plot in  FIG. 1 , the DSC thermogram in  FIG. 2 , the TGA plot in  FIG. 3  and/or the XRPD pattern of  FIG. 4 . 
     In some embodiments, a pharmaceutical composition can comprise, and/or be obtained from, Compound 1 Type A solid form characterized by a dynamic vapor sorption (DVS) isotherm plot substantially similar to  FIG. 1 . In some embodiments, a pharmaceutical composition can comprise, and/or be obtained from, Compound 1 Type A solid form characterized by a differential scanning calorimetry (DSC) thermogram substantially similar to  FIG. 2 . In some embodiments, a pharmaceutical composition can comprise, and/or be obtained from, Compound 1 Type A solid form characterized by a thermogravimetric analysis (TGA) plot substantially similar to  FIG. 3 . In some embodiments, a pharmaceutical composition can comprise, and/or be obtained from, Compound 1 Type A solid form characterized by an X-ray Powder Diffraction (XRPD) pattern substantially similar to  FIG. 4 . 
     In some embodiments, the present disclosure provides a composition comprising amorphous and crystalline solid forms of Compound 1. In some embodiments, the composition comprises crystalline Compound 1 and amorphous Compound 1, wherein the amorphous Compound 1 is present in an amount selected from the following ranges: 90-99%, 80-90%, 70-80%, 60-70%, 50-60%, 40-50%, 30-40%, 20-30%, 10-20%, 1-10% and 0-1%. 
     In some embodiments, the present disclosure provides a pharmaceutical composition such as a drug product or drug substance comprising a solid form of Compound 1 disclosed herein. In some embodiments, the present disclosure provides a pharmaceutical composition comprising crystalline solid Type A of Compound 1. For example, a pharmaceutical composition can comprise, and/or be obtained from, the solid form of Compound 1 designated as Type A solid form of Compound 1 and is characterized by an X-ray Powder Diffraction (XRPD) pattern, having characteristic diffraction peaks at angles (2 theta±0.2) of 6.3, 12.8, 13.8, 23.6, and 27.8. In some embodiments, a pharmaceutical composition can comprise, and/or be obtained from, the solid form of Compound 1 designated as Type A of Compound 1 and is characterized by an XRPD pattern having characteristic diffraction peaks at angles (2 theta±0.2) of 5.7, 6.3, 8.5, 10.6, 12.8, 13.8, 17.3, 22.0, 22.8, 23.6, and 27.8. In some embodiments, a pharmaceutical composition can comprise, and/or be obtained from, the solid form of Compound 1 Type A and is characterized by an X-ray Powder Diffraction (XRPD) pattern, having diffraction peaks at angles (2 theta±0.2) of 6.3, 12.8, 13.8, 23.6, and 27.8, corresponding to d-spacing (angstroms±0.2) of 14.0, 6.9, 6.4, 3.8, and 3.2, respectively. In some embodiments, a pharmaceutical composition can comprise, and/or be obtained from, the solid form of Compound 1 Type A and can be identified by X-ray Powder Diffraction (XRPD) pattern, having characteristic diffraction peaks at angles (2 theta±0.2) of 5.7, 6.3, 8.5, 10.6, 12.8, 13.8, 17.3, 22.0, 22.8, 23.6, and 27.8, corresponding to d-spacing (angstroms±0.2) of 15.4, 14.0, 8.4, 6.9, 6.4, 5.1, 4.0, 3.9, 3.8, and 3.2, respectively. 
     In some embodiments, a pharmaceutical composition can comprise, and/or be obtained from, the solid form of Compound 1 designated as Type A of Compound 1 and is characterized by an XRPD pattern having peaks at substantially the same angles (2θ±0.2) and corresponding d-spacing (Å±0.2) of: 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 2θ ± 
                 d-spacing 
               
               
                   
                 0.2 
                 Å ± 0.2 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 5.7 
                 15.4 
               
               
                   
                 6.3 
                 14.0 
               
               
                   
                 8.5 
                 10.4 
               
               
                   
                 10.6 
                 8.4 
               
               
                   
                 11.4 
                 7.8 
               
               
                   
                 12.8 
                 6.9 
               
               
                   
                 13.8 
                 6.4 
               
               
                   
                 14.2 
                 6.2 
               
               
                   
                 15.2 
                 5.8 
               
               
                   
                 15.6 
                 5.7 
               
               
                   
                 17.3 
                 5.1 
               
               
                   
                 17.9 
                 5.0 
               
               
                   
                 18.2 
                 4.9 
               
               
                   
                 18.9 
                 4.7 
               
               
                   
                 19.6 
                 4.5 
               
               
                   
                 20.6 
                 4.3 
               
               
                   
                 21.5 
                 4.1 
               
               
                   
                 22.0 
                 4.0 
               
               
                   
                 22.8 
                 3.9 
               
               
                   
                 23.6 
                 3.8 
               
               
                   
                 24.5 
                 3.6 
               
               
                   
                 24.8 
                 3.6 
               
               
                   
                 25.3 
                 3.5 
               
               
                   
                 25.6 
                 3.5 
               
               
                   
                 26.0 
                 3.4 
               
               
                   
                 26.3 
                 3.4 
               
               
                   
                 27.0 
                 3.3 
               
               
                   
                 27.8 
                 3.2 
               
               
                   
                 28.9 
                 3.1 
               
               
                   
                 30.0 
                 3.0 
               
               
                   
                 31.2 
                 3.0 
               
               
                   
                 32.1 
                 2.8 
               
               
                   
                 33.6 
                 2.7 
               
               
                   
                 34.1 
                 2.6 
               
               
                   
                 36.3 
                 2.5 
               
               
                   
                 37.0 
                 2.4 
               
               
                   
                 38.1 
                 2.4 
               
               
                   
                   
               
            
           
         
       
     
     Pharmaceutical compositions reported herein can be combined with a pharmaceutically acceptable carrier or excipient. In some embodiments, pharmaceutical compositions reported herein can be provided in a unit dosage form container (e.g., in a vial or bag or the like). In some embodiments, pharmaceutical compositions reported herein can be provided in an oral dosage form. 
     In some embodiments, the pharmaceutical composition comprises an active pharmaceutical ingredient (API) comprising, consisting essentially of, or consisting of Compound 1 prepared under applicable Good Manufacturing Practice (GMP). For example, the pharmaceutical composition can be a batch composition comprising Compound 1 (preferably including Solid Form Type A of Compound 1), wherein the batch composition adheres to Good Manufacturing Practices (e.g., ICH Harmonised Tripartite Guideline, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients Q7, Current Step 4 version dated 10 Nov. 2010). More preferably, the GMP batch composition can be a homogenous blended batch comprising Type A Solid Form of Compound 1. The FDA (Food and Drug Administration) provides applicable guidance on Good Manufacturing Practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. As used with respect to manufacture of API under GMP, “manufacturing” is defined to include all operations of receipt of materials, production, packaging, repackaging, labelling, relabelling, quality control, release, storage and distribution of APIs and the related controls. An “API Starting Material” is a raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API Starting Materials normally have defined chemical properties and structure. 
     In some embodiments, an oral dosage form of Compound 1 Type A can be a capsule. In some embodiments, an oral dosage form of Compound 1 Type A is a tablet. In some embodiments, an oral dosage form comprises a filler. In some embodiments, an oral dosage form comprises two fillers. In some embodiments, an oral dosage form comprises one or more fillers. In some embodiments, the filler is selected from the group consisting of Avicel PH101 (50 μm) and Avicel PH102 (100 μm). In some embodiments, an oral dosage form comprises one or more disintegrants. In some embodiments a disintegrant is Ac-Di-Sol. In some embodiments, the oral dosage form comprises one or more lubricants. In some embodiments, the lubricant is magnesium stearate. In some embodiments, an oral dosage form comprises one or more glidants, anti-adherents and/or anti-statics. In some embodiments, the glidant, anti-adherent and/or anti-static is colloidal silicon dioxide. In some embodiments, an oral dosage form is prepared via dry blending. In some embodiments, an oral dosage form is a tablet and is prepared via dry granulation. 
     In some embodiments, the present disclosure provides methods of inhibiting mutant isocitrate dehydrogenase 1 (mIDH1), comprising administering a solid form of Compound 1 to a subject. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition responsive to inhibition of mutant isocitrate dehydrogenase 1 (mIDH1), comprising administering a solid form of Compound 1 (e.g., Compound 1 as a Type A solid form) to a subject in need thereof. In some embodiments, the disease, disorder, or condition is associated with mutant isocitrate dehydrogenase. 
     In some embodiments, the present disclosure provides methods of treating cancer comprising administering a solid form of Compound 1 (e.g., Compound 1 as a Type A solid form) to a subject in need thereof. In some embodiments, the present disclosure provides methods of reducing 2-hydroxyglutarate comprising administering a solid form of Compound 1 (e.g., Compound 1 as a Type A solid form) to a subject in need thereof. In some embodiments, treatment is administered after one or more symptoms have developed. In other embodiments, treatment is administered in the absence of symptoms. For example, treatment is administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment is also continued after symptoms have resolved, for example to prevent, delay or lessen the severity of their recurrence. 
     EXAMPLES 
     Instrumentation and Methods 
     Unless otherwise indicated, the following instrumentation and methods were used in the working examples described herein. 
     Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker or Varian spectrometers at 300 MHz. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Mass spectra were collected using a Waters ZQ Single Quad Mass Spectrometer (ion trap electrospray ionization (ESI)). High performance liquid chromatograph (HPLC) analyses were obtained using a XBridge Phenyl or C18 column (5 μm, 50×4.6 mm, 150×4.6 mm or 250×4.6 mm) with UV detection (Waters 996 PDA) at 254 nm or 223 nm using a standard solvent gradient program (Methods 1-2). 
     LCMS Method 1 (ESI, 4 Min Method): 
     Instruments and Conditions: 
     
         
         HPLC: Waters HT2790 Alliance MS: Waters ZQ Single Quad Mass Spectrometer 
         UV: Waters 996 PDA 
       
    
     Conditions: 
     
         
         Mobile phase A 95% water/5% methanol with 0.1% Formic Acid 
         Mobile phase B (B) 95% methanol/5% water with 0.1% Formic Acid 
         Column XBridge Phenyl or C18, 5 μm 4.6×50 mm 
         Column temperature Ambient 
         LC gradient Linear 5-95% B in 2.5 min, hold 95% B to 3.5 min 
         LC Flow rate 3 mL/min 
         UV wavelength 220 nm and 254 nm 
         Ionization Mode Electrospray Ionization; positive/negative 
       
    
     LCMS Method 2: (APCI, 20 Min) 
     Instruments and Conditions: 
     
         
         HPLC-Agilent 1100 series. 
         Column: Agela Technologies Durashell C18, 3 μm, 4.6×50 mm,). 
         Mobile Phase A: ACN+0.1% TFA. 
         Mobile Phase B: Water+0.1% TFA. 
       
    
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Gradient:  
                 %  
               
               
                   
                 Time (min) 
                 B 
               
               
                   
                   
               
             
            
               
                   
                 00 
                 95 
               
               
                   
                 15 
                 05 
               
               
                   
                 18 
                 05 
               
               
                   
                 20 
                 95 
               
               
                   
                   
               
            
           
         
       
         
         Flow Rate: 1 mL/min. 
         ColumnTemperature: Ambient. 
         Detector: 254 nm. 
       
    
     X-ray Powder Diffraction (XRPD) 
     High resolution X-ray Powder Diffraction experiments were performed with a Panalytical X&#39;Pert 3  Powder X-ray diffractometer on a Si zero-background holder. The 2θ position was calibrated against Panalytical 640 Si powder standard. Details of the XRPD method are listed below: 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                   
                 Parameters for Reflection Mode 
               
               
                   
                   
               
             
            
               
                   
                 X-Ray wavelength 
                 Cu, kα, Kαl (Å): 1.540598, 
               
               
                   
                   
                 Kα2 (Å): 1.544426 
               
               
                   
                   
                 Kα2/Kα1 intensity ratio: 0.50 
               
               
                   
                 X-Ray tube setting 
                 45 kV, 40 mA 
               
               
                   
                 Divergence slit 
                 Automatic 
               
               
                   
                 Scan mode 
                 Continuous 
               
               
                   
                 Scan range (°2TH) 
                 3°-40° 
               
               
                   
                 Step size (°2TH) 
                 0.0131 
               
               
                   
                 Scan speed (°/s) 
                 0.033 
               
               
                   
                   
               
            
           
         
       
     
     Peaks are reported as diffraction angles at 2 theta, with d-spacing measured in angstroms. 
     Thermal Analysis 
     Thermo gravimetric analysis (TGA) experiments were performed on TA Q500 TGA from TA Instruments. Samples were heated at 10° C./min from about 20° C. to about 300° C. using dry nitrogen to purge the system. The details of the method are provided below: 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Parameters 
                 TGA 
               
               
                   
                   
               
             
            
               
                   
                 Pan Type 
                 Platinum plate, open 
               
               
                   
                 Temperature 
                 RT-250° C. 
               
               
                   
                 Ramp rate 
                 10° C./min 
               
               
                   
                 Purge gas 
                 N 2   
               
               
                   
                   
               
            
           
         
       
     
     Differential scanning calorimetry (DSC) experiments were performed on a TA Q2000 DSC from TA Instruments. Samples were heated at 10° C./min from about 20° C. to about 300° C. using dry nitrogen to purge the system. The details of the method are provided below: 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Parameters 
                 DSC 
               
               
                   
                   
               
             
            
               
                   
                 Pan Type 
                 Aluminum pan, closed 
               
               
                   
                 Temperature 
                 RT-250° C. 
               
               
                   
                 Ramp rate 
                 10° C./min 
               
               
                   
                 Purge gas 
                 N 2   
               
               
                   
                   
               
            
           
         
       
     
     Dynamic Vapor Sorption 
     Dynamic vapor sorption (DVS) was obtained using a Surface Measurement Systems (SMS) DVS Intrinsic. The details of the method are provided below: 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Parameters 
                 Values 
               
               
                   
                   
               
             
            
               
                   
                 Temperature 
                 25° C. 
               
               
                   
                 Sample size 
                 10-20 mg 
               
               
                   
                 Gas and flow rate 
                 N2, 200 mL/min 
               
               
                   
                 dm/dt 
                 0.002%/min 
               
               
                   
                 Min. dm/dt stability duration 
                 10 min 
               
               
                   
                 Max. equilibrium time 
                 360 min 
               
               
                   
                 RH range 
                 20% RH-95% RH-0% RH-95% RH 
               
               
                   
                 RH step size 
                 10% (90% RH-0% RH-90% RH) 
               
               
                   
                   
                 5% (95% RH-90% RH and 
               
               
                   
                   
                 90% RH-95% RH) 
               
               
                   
                   
               
            
           
         
       
     
     Example 1—Synthesis of (S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (Compound 1) 
     Intermediate 1: (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride 
     
       
         
         
             
             
         
       
     
     Step-1: (R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide 
     
       
         
         
             
             
         
       
     
     To a mixture of 2,6-dichloroquinoline-3-carbaldehyde (15.0 g, 66.37 mmol) and (R)-2-methylpropane-2-sulfinamide (8.85 g, 73.14 mmol) in 1,2-dichloroethane (150 mL) was added CuSO 4  (16.0 g, 100.25 mmol). The resulting mixture was heated to 55° C. and stirred at 55° C. overnight. After TLC and MS showed complete disappearance of starting materials, the mixture was cooled to room temperature and filtered through a pad of Cellite®. The pad of Celite® was then rinsed with CH 2 Cl 2 . The filtrate was evaporated to dryness in vacuo and purified by SiO 2  column chromatography (0 to 25% hexanes/EtOAc) to afford the title compound, (R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide, as a yellow solid (17.7 g, 81% yield). 
     Step-2: (R)-N-((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide. 
     
       
         
         
             
             
         
       
     
     To a solution of (R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide (8.85 g, 26.88 mmol) in anhydrous CH 2 Cl 2  (200 mL) at −60° C. was added dropwise MeMgBr (3M solution in diethyl ether, 13.5 mL, 40.54 mmol). The resulting reaction mixture was stirred at about −60 to −50° C. for 3 hours and then stirred at −20° C. overnight under an atmosphere of N 2 . After TLC and MS showed complete disappearance of starting materials, saturated NH 4 Cl (163 mL) was added at −20° C. and the resulting mixture was stirred for 10 minutes. The aqueous phase was extracted with CH 2 Cl 2  (100 mL×3), dried over anhydrous Na 2 SO 4 , filtered, and evaporated. The residue was purified by column chromatography on an ISCO® chromatography system (SiO 2 : Gold column; gradient; hexanes to 100% EtOAc) to provide the title compound, (R)-N-((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide, as a yellow solid (5.8 g, 63% yield). 
     Step-3: (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride (A). 
     
       
         
         
             
             
         
       
     
     A mixture of (R)-N-((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (6.6 g, 19.13 mmol) in 1,4-dioxane (41 mL) and 1N HCl (41 mL) was heated at reflux overnight. The solvents were evaporated in vacuo and the resulting residue was dissolved in hot water and lyophilized. The crude product was triturated with diethyl ether to afford the title compound A as a yellow solid (9.0 g, ee: 98.4%).  1 H NMR (300 MHz, DMSO-d 6 ): δ ppm 12.4 (br s, 1 H), 8.32 (br s, 2 H), 8.07 (s, 1 H), 7.85 (d, J=2.2 Hz, 1 H), 7.63 (dd, J1=8.8 Hz, J2=2.5 Hz, 1 H), 7.40 (d, J=8.8 Hz, 1 H), 4.40-4.45 (m, 1 H), 1.53(d, J=8.5 Hz, 3 H). LCMS (Method 2): Rt 3.42 min, m/z 223.1 [M+H] + . 
     Intermediate 2: 5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile 
     
       
         
         
             
             
         
       
     
     Step-1: 2-cyano-5-fluoropyridine 1-oxide 
     
       
         
         
             
             
         
       
     
     A solution of 5-fluoropicolinonitrile (7.27 g, 59.5 mmol) in CHCl 3  (60 mL) was added dropwise by addition funnel to a solution of m-CPBA (&lt;77%, 22.00 g, 98 mmol) in CHCl3 160 mL). The solution was stirred at reflux for 4 days, at which time LCMS showed ˜85% conversion. The sample was allowed to cool, then sodium sulfite (12.4 g, 98 mmol) was added and the sample was stirred at room temperature for three hours, during which time the solution became thick with a white precipitate. The sample was diluted with DCM (300 mL) and filtered on a Buchner funnel, and the filter cake was washed with DCM (˜400 mL). A white material precipitated in the filtrate. The filtrate mixture was washed with saturated aqueous NaHCO 3  (400 mL), during which the solids went into solution. The organic layer was washed with water (300 mL), then dried (MgSO 4 ) and filtered. Silica gel was added and the mixture was evaporated under reduced pressure. The material was chromatographed by Biotage MPLC (340 g silica gel column) with 0 to 100% EtOAc in hexanes, with isocratic elution when peaks came off to provide 2-cyano-5-fluoropyridine 1-oxide (4.28 g, 31.0 mmol, 52% yield) as a white solid. 
       1 H NMR (300 MHz, DMSO-d 6 ): δ ppm 8.85-8.93 (m, 1 H), 8.23 (dd, J=9.09, 6.74 Hz, 1 H), 7.53-7.64 (m, 1 H). LCMS (Method 1): Rt 0.57 min., m/z 138.9 [M+H] + . 
     Step 2: 6-cyano-3-fluoropyridin-2-yl acetate 
     
       
         
         
             
             
         
       
     
     A solution of 2-cyano-5-fluoropyridine 1-oxide (4.28 g, 31.0 mmol) in acetic anhydride (40 ml, 424 mmol) was heated at reflux (150° C. bath) for three days, during which the clear solution turned dark. The sample was concentrated under reduced pressure. The residue was dissolved in MeOH (30 mL) and stirred for 1 hour. Silica gel was added and the solvent was evaporated under reduced pressure. The material was chromatographed by Biotage MPLC (100 g silica gel column) with 0 to 23% EtOAc in hexanes to provide 6-cyano-3-fluoropyridin-2-yl acetate (3.32 g, 18.43 mmol, 60% yield) as a clear liquid that solidified on cooling.  1 H NMR (300 MHz, CHLOROFORM-d): δ ppm 7.65-7.75 (m, 2 H), 2.42 (s, 3 H). LCMS (Method 1): Rt 1.54 min., m/z 138.8 (loss of acetate). 
     Step 3: 5-fluoro-6-oxo-1,6-dihydropyridine-2-carbonitrile 
     
       
         
         
             
             
         
       
     
     A solution of 6-cyano-3-fluoropyridin-2-yl acetate (3.32 g, 18.43 mmol) in MeOH (40 ml) was treated with potassium carbonate (5.10 g, 36.9 mmol) and stirred at room temperature for four hours. LCMS at 2 hours showed the reaction had gone to completion. The solvent was evaporated under reduced pressure. The residue was dissolved in water (100 mL) and acidified to pH≤1 with 1M HCl. The solution was extracted with EtOAc (3×100 mL). The combined organic extracts were dried (Na 2 SO 4 ), filtered, and evaporated under reduced pressure to provide 5-fluoro-6-oxo-1,6-dihydropyridine-2-carbonitrile (2.34 g, 16.94 mmol, 92% yield) as a white solid.  1 H NMR (300 MHz, DMSO-d 6 ): δ ppm 12.92 (br s, 1 H), 7.73 (br s, 1 H), 7.43 (br s, 1 H). LCMS (Method 1): Rt 0.70 min., m/z 138.9 [M+H] + . 
     Step 4: 5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (B) 
     
       
         
         
             
             
         
       
     
     A mixture of 5-fluoro-6-oxo-1,6-dihydropyridine-2-carbonitrile (2.31 g, 16.73 mmol) and potassium carbonate (4.86 g, 35.2 mmol) in a 200 mL round bottom flask was treated with DMF (46 mL) and stirred for 15 minutes. MeI (1.2 mL, 19.19 mmol) was added and the mixture was stirred at room temperature for 45 minutes. The solvent was evaporated under reduced pressure. The residue was mixed with water (150 mL) and extracted with DCM (2×150 mL). The combined organic extracts were dried (MgSO 4 ), filtered, treated with silica gel, and evaporated under reduced pressure, then evaporated further at 60° C. under high vacuum. The material was chromatographed by Biotage MPLC with 0 to 35% EtOAc in hexanes, with isocratic elution at 16% EtOAc and 35% EtOAc while peaks were eluted. The peak that was eluted with 16% EtOAc was O-methylated material and was discarded. The peak that was eluted with 35% EtOAc provided the title compound B (1.70 g, 11.17 mmol, 67% yield) as a solid.  1 H NMR (300 MHz, DMSO-d 6 ): δ ppm 7.53 (dd, J=9.38, 7.62 Hz, 1 H), 7.18 (dd, J=7.77, 4.84 Hz, 1 H), 3.60 (s, 3 H). LCMS (Method 1): Rt 0.94 min., m/z 152.9 [M+H] + . 
     Step 5: (S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (Compound 1) 
     
       
         
         
             
             
         
       
     
     A mixture of 5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile B (1.23 g, 8.09 mmol), (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride A (1.91 g, 7.37 mmol) and N,N-diisopropylethylamine (3.8 mL, 21.8 mmol) in anhydrous dimethyl sulfoxide (57 mL) under N 2  was heated to 110° C. and stirred for 6 hours. After cooling to room temperature, the mixture was partitioned between EtOAc/H 2 O (750 mL/750 mL). The organic layer was separated, dried (Na 2 SO 4 ), and concentrated in vacuum. The residue was purified on an ISCO® chromatography system twice (40 g silica gel column, EtOAc/hexanes 0˜100%; 80 g silica gel column, MeOH/dichloromethane 0˜5%). The colorless fractions were combined and dichloromethane was removed under reduced pressure on rotavap until a lot of white solid precipitated out. The white solid was collected by filtration and washed with cold MeOH. It was then mixed with MeCN/H 2 O (10 mL/25 mL) and lyophilized to afford the title compound 1 as a white solid (790 mg). m.p. 262-264° C.  1 H NMR (300 MHz, DMSO-d 6 ) δ: 12.07 (s, 1H), 7.75 (s, 1H), 7.73 (d, J=2.2 Hz, 1H), 7.51 (dd, J=8.6, 2.3 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 6.93 (d, J=7.7 Hz, 1H), 5.95 (d, J=8.0 Hz, 1H), 4.68 (m, 1H), 3.58 (s, 3H), 1.50 (d, J=6.6 Hz, 3H). LCMS (Method 2): 100% pure@254 nm, Rt 10.78 min, m/z 355, 357 [M+H]+. The filtrate and the colored fractions (TLC pure) from the second ISCO were combined and treated with activated charcoal and filtered (until the filtrate is colorless). The filtrate was then concentrated under reduced pressure on rotavap to remove dichloromethane until a lot of white solid precipitated out. The white solid was collected by filtration and washed with cold MeOH. It was then mixed with MeCN/H 2 O (10 mL/25 mL) and lyophilized to afford the title compound 1 as a white solid (970 mg). m.p. 262-264° C.  1 H NMR (300 MHz, DMSO-d 6 ) δ: 12.06 (s, 1H), 7.75 (s, 1H), 7.73 (d, J=2.5 Hz, 1H), 7.51 (dd, J=8.6, 2.3 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 5.95 (d, J=8.0 Hz, 1H), 4.68 (m, 1H), 3.58 (s, 3H), 1.50 (d, J=6.9 Hz, 3H). LCMS (Method 2): 100% pure@254 nm, m/z 355, 357 [M+H]+. 
     Example 2—Solid form of (S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile 
     Compound 1 can be prepared via the method described in Example 1. Compound 1 was dissolved in 18 volumes of dichloromethane (all volumes are with respect to the quantity of compound 1 (v/w)). The resulting solution was then concentrated under reduced pressure to approximately 5 volumes. To the mixture was added 5 volumes of ethyl acetate. The mixture was concentrated under reduced pressure to 5 volumes. To the mixture was added an additional 5 volumes of ethyl acetate, and the mixture again concentrated under reduced pressure to 5 volumes. The mixture was diluted to 10 volumes with ethyl acetate, and the mixture stirred at room temperature for 18 hours and then cooled to 0° C. The mixture was stirred at 0° C. for 3 hours and then filtered. The solids were rinsed with ethyl acetate and dried under vacuum (counterbalanced by nitrogen) at ambient temperature. 
     The crystalline solid was determined to be the solid form of Compound 1 Type A. The DVS Isotherm of Compound 1 Type A is shown in  FIG. 1 . DVS shows maximum water uptake of 0.25% w/w at 25° C./90% RH, indicating that Compound 1 Type A is not hygroscopic. 
     The thermal behavior Compound 1 Type A was evaluated using DSC. An endothermic event was observed at 256.6° C. (peak max). The onset temperature and heat of fusion were 255.0° C. and 108.7 J/g respectively ( FIG. 2 ). 
     TGA data ( FIG. 3 ) do not show significant release of moisture or nonaqueous residual volatiles from Compound 1 Type A. 
     The X-ray powder diffraction pattern of the crystalline Compound 1 Type A is depicted in  FIG. 4 , and the corresponding data is summarized in Table 2-1: 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 2-1 
               
               
                   
                   
               
               
                   
                 2 theta ± 
                 d-spacing 
               
               
                   
                 0.2 
                 Å ± 0.2 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 5.7 
                 15.4 
               
               
                   
                 6.3 
                 14.0 
               
               
                   
                 8.5 
                 10.4 
               
               
                   
                 10.6 
                 8.4 
               
               
                   
                 11.4 
                 7.8 
               
               
                   
                 12.8 
                 6.9 
               
               
                   
                 13.8 
                 6.4 
               
               
                   
                 14.2 
                 6.2 
               
               
                   
                 15.2 
                 5.8 
               
               
                   
                 15.6 
                 5.7 
               
               
                   
                 17.3 
                 5.1 
               
               
                   
                 17.9 
                 5.0 
               
               
                   
                 18.2 
                 4.9 
               
               
                   
                 18.9 
                 4.7 
               
               
                   
                 19.6 
                 4.5 
               
               
                   
                 20.6 
                 4.3 
               
               
                   
                 21.5 
                 4.1 
               
               
                   
                 22.0 
                 4.0 
               
               
                   
                 22.8 
                 3.9 
               
               
                   
                 23.6 
                 3.8 
               
               
                   
                 24.5 
                 3.6 
               
               
                   
                 24.8 
                 3.6 
               
               
                   
                 25.3 
                 3.5 
               
               
                   
                 25.6 
                 3.5 
               
               
                   
                 26.0 
                 3.4 
               
               
                   
                 26.3 
                 3.4 
               
               
                   
                 27.0 
                 3.3 
               
               
                   
                 27.8 
                 3.2 
               
               
                   
                 28.9 
                 3.1 
               
               
                   
                 30.0 
                 3.0 
               
               
                   
                 31.2 
                 3.0 
               
               
                   
                 32.1 
                 2.8 
               
               
                   
                 33.6 
                 2.7 
               
               
                   
                 34.1 
                 2.6 
               
               
                   
                 36.3 
                 2.5 
               
               
                   
                 37.0 
                 2.4 
               
               
                   
                 38.1 
                 2.4 
               
               
                   
                   
               
            
           
         
       
     
     Example 3—Polymorph Screening 
     Polymorph screening for Compound 1 was conducted under different conditions, including anti-solvent addition, evaporation, slurry, solid/liquid vapor diffusion, crash cooling and grinding. 
     Slurry experiments were conducted at 4° C., RT and 50° C. in different solvent systems. For each experiment about 20 mg of Compound 1 Type A was suspended in 0.25-0.5 mL of solvent in a 1.5-mL glass vial. After the suspension was stirred for about one week at the desired temperature, the remaining solids were isolated for XRPD analysis. Results are summarized in Table 3-1. 
     
       
         
           
               
               
               
               
             
               
                   
                 TABLE 3-1 
               
               
                   
                   
               
               
                   
                 Solvent, v/v 
                 Temperature, ° C. 
                 Solid Form 
               
               
                   
                   
               
             
            
               
                   
                 EtOH 
                 RT 
                 Type A 
               
               
                   
                 Acetone 
                 RT 
                 Type A 
               
               
                   
                 ACN 
                 RT 
                 Type A 
               
               
                   
                 2-Me-THF/Heptane, 3:1 
                 RT 
                 Type A 
               
               
                   
                 IPAc 
                 RT 
                 Type A 
               
               
                   
                 MTBE 
                 RT/50 
                 Type A* 
               
               
                   
                 MIBK 
                 RT/50 
                 Type A* 
               
               
                   
                 1,4-Dioxane 
                 RT 
                 Type A 
               
               
                   
                 Toluene 
                 RT 
                 Type A 
               
               
                   
                 IPA 
                 RT 
                 Type A 
               
               
                   
                 Heptane 
                 RT/50 
                 Type A* 
               
               
                   
                 H 2 O 
                 RT/50 
                 Type A* 
               
               
                   
                 EtOH/H 2 O, 3:7 aw = 0.8 
                 RT 
                 Type A 
               
               
                   
                 EtOH/H 2 O, 9:1 aw = 0.5 
                 RT 
                 Type A 
               
               
                   
                 EtOH/H 2 O, 95:5 aw = 0.3 
                 RT 
                 Type A 
               
               
                   
                 EtOH/H 2 O, 985:15 aw = 0.1  
                 RT 
                 Type A 
               
               
                   
                 Cyclopentylmethylether 
                 4 
                 Type A 
               
               
                   
                 DMF 
                 4 
                 Type A** 
               
               
                   
                 ACN/H 2 O, 3:1 
                 4 
                 Type A 
               
               
                   
                 DCM 
                 4 
                 Type A 
               
               
                   
                 MeOH 
                 RT 
                 Type A 
               
               
                   
                 EtOAc 
                 RT 
                 Type A 
               
               
                   
                   
               
               
                   
                 *Type A observed at both RT (one week) and 50° C. (four days) 
               
               
                   
                 **Clear solution obtained at 4° C. stirring and solids obtained from evaporation at RT 
               
            
           
         
       
     
     Evaporation experiments were conducted under 12 conditions. For each experiment about 15 mg of Compound 1 Type A was dissolved in ˜1.0 mL of solvent in a 1.5-mL glass vial. The resulting clear solutions were subjected to slow evaporation at RT to induce precipitation. The solids, if observed, were isolated for XRPD analysis. The results are summarized in Table 3-2. 
     
       
         
           
               
             
               
                 TABLE 3-2 
               
             
            
               
                   
               
               
                 Summary of evaporation experiments 
               
            
           
           
               
               
               
            
               
                   
                 Solvent, v/v 
                 Solid Form 
               
               
                   
                   
               
               
                   
                 ACN 
                 Type A 
               
               
                   
                 MeOH 
                 Type A 
               
               
                   
                 EtOAc 
                 Amorphous 
               
               
                   
                 MEK 
                 Type A 
               
               
                   
                 Acetone 
                 Oil 
               
               
                   
                 DCM 
                 Amorphous 
               
               
                   
                 THF 
                 Amorphous 
               
               
                   
                 1,4-Dioxane 
                 Oil 
               
               
                   
                 Acetic acid 
                 N/A 
               
               
                   
                 CHCl 3   
                 Amorphous 
               
               
                   
                 2-Me-THF 
                 Type A 
               
               
                   
                 MeOH/H 2 O, 1:1 
                 Type A 
               
               
                   
                   
               
               
                   
                 N/A: No solids obtained 
               
            
           
         
       
     
     A total of 8 anti-solvent addition experiments were carried out. About 5 mg of Compound 1 Type A was dissolved in 0.5-3.0 mL solvent to obtain a clear near saturated solution. 0.25-8.0 mL anti-solvent was then added to induce precipitation. The precipitate was isolated for XRPD analysis after stirring the resulting suspension overnight. Results are summarized in Table 3-3. 
     
       
         
           
               
               
               
               
             
               
                   
                 TABLE 3-3 
               
               
                   
                   
               
               
                   
                 Solvent, v/v 
                 Anti-solvent 
                 Solid Form 
               
               
                   
                   
               
             
            
               
                   
                 MeOH 
                 H 2 O 
                 Type A 
               
               
                   
                 DMSO 
                 H 2 O 
                 Type A 
               
               
                   
                 ACN 
                 Heptane 
                 N/A 
               
               
                   
                 THF 
                 Heptane 
                 Type A 
               
               
                   
                 EtOAc 
                 Heptane 
                 Type A 
               
               
                   
                 MEK 
                 Heptane 
                 Type A 
               
               
                   
                 Acetone 
                 Heptane 
                 Type A 
               
               
                   
                 DCM 
                 Heptane 
                 Type A 
               
               
                   
                   
               
               
                   
                 N/A: no solid obtained 
               
            
           
         
       
     
     Both solid vapor diffusion and solution vapor diffusion methods were used. Two solid vapor diffusion experiments were conducted. For each one, approximately 30 mg of Compound 1 Type A sample was weighted into a 3-mL vial, which was then placed into a 20-mL vial containing 4 mL of volatile solvent. The 20-mL vial was sealed and kept at RT for about two weeks allowing sufficient time for organic vapor of the solvents to interact with the solid sample. The solids thus obtained were isolated for XRPD test. Five solution vapor diffusion experiments were conducted. Approximate 15-30 mg of Compound 1 Type A sample was dissolved in 2-4 mL of an appropriate solvent to obtain a saturated solution in a 5-mL vial. The solution was then placed into a 20-mL vial containing 4 mL of volatile solvents. The 20-mL vial was sealed and kept at RT for about two weeks allowing sufficient time for organic vapor of the anti-solvent to interact with the solution sample. The precipitates thus obtained were isolated for XRPD analysis. The results are summarized in Table 0-1 indicating no new form was observed. 
     
       
         
           
               
             
               
                 TABLE 0-1 
               
             
            
               
                   
               
               
                 Summary of vapor diffusion experiments 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Method 
                 Solvent, v/v 
                 Anti-solvent 
                 Solid Form 
               
               
                   
                   
               
               
                   
                 Solid vapor 
                 H 2 O 
                 N/A 
                 Type A 
               
               
                   
                 diffusion 
                 DCM 
                 N/A 
                 Type A 
               
               
                   
                 Solution vapor 
                 ACN 
                 IPA 
                 Amorphous 
               
               
                   
                 diffusion 
                 MeOH 
                 Toluene 
                 Type A 
               
               
                   
                   
                 EtOAc 
                 Heptane 
                 Amorphous 
               
               
                   
                   
                 Acetone 
                 Toluene 
                 Type A 
               
               
                   
                   
                 THF 
                 Heptane 
                 Amorphous 
               
               
                   
                   
               
            
           
         
       
     
     Example 4—Formulations of Compound 1 Type A 
     Compound 1 Type A can be formulated into a form (e.g., a capsule or unit dosage form) for oral use. 
     Compound 1 Type A was formulated into capsules as summarized in Table 4-1. Each encapsulated drug product excipient meets the requirements of the respective current United States Pharmacopeia (USP) or National Formulary (NF) monograph. As permitted under EMA/CHMP/QWP/834816/2015, reference is made to the current compendial monographs in lieu of inclusion of the current compendial specifications. The capsule shells, which consist of gelatin and about 2.9% w/w of titanium dioxide (E171), are specified according to the current compendial requirements for each ingredient. Each excipient may be obtained from qualified suppliers that meet the cited specifications, and may be accepted upon a supplier certificate of analysis with minimal confirmatory identification testing upon receipt and periodic confirmation of supplier results. 
     
       
         
           
               
               
               
               
             
               
                 TABLE 4-1 
               
               
                   
               
               
                 Dose 
                   
                   
                 Relative 
               
               
                 Strength 
                 Function 
                 Component 
                 weight 2   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 50 mg or 
                 Active 
                 Compound 1 Type A, Micronized 1   
                 33.00 
               
               
                 150 mg 
                 Filler 
                 Microcrystalline Cellulose NF/EP 
                 61.12 
               
               
                   
                   
                 (Avicel PH101) 
                   
               
               
                   
                 Disintegrant 
                 Croscarmellose Sodium NF/EP 
                 4.95 
               
               
                   
                 Lubricant 
                 Magnesium Stearate NF/EP 
                 1.00 
               
               
                   
                   
                 Hard gelatin capsule shell, size 2  
                 wt x 
               
               
                   
                   
                 or size 00, white opaque 
                   
               
               
                   
               
               
                   1 20% excess Compound 1 Type A was micronized to obtain sufficient material needed for the batch. 
               
               
                   2 As used herein, relative weights (or % w/w) are given as a percentage relative to the total weight of the formulation. 
               
            
           
         
       
     
     Compound 1 Type A was formulated into tablets or capsules as summarized in Table 4-2. 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE 4-2 
               
               
                   
               
               
                   
                   
                 Formulation 
                 Formulation 
                 Formulation 
                 Formulation 
               
               
                 Component 
                 Function 
                 1 (% w/w) 
                 2 (% w/w) 
                 3 (% w/w) 
                 4 (% w/w) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Compound 1 
                 Active 
                 33.0 
                 33.0 
                 33.0 
                 33.0 
               
               
                 Type A 
                   
                   
                   
                   
                   
               
               
                 Avicel PH101 
                 Filler 
                 61.0 
                 0 
                 49.0 
                 49.0 
               
               
                 (50 μm ) 
                   
                   
                   
                   
                   
               
               
                 Avicel PH102 
                 Filler 
                 0.0 
                 60.0 
                 10.0 
                 10.0 
               
               
                 (100 μm) 
                   
                   
                   
                   
                   
               
               
                 Ac-Di-Sol 
                 Disintegrant 
                 5.0 
                 5.0 
                 6.0 
                 6.0 
               
               
                 Magnesium 
                 Lubricant 
                 1.0 
                 1.0 
                 1.0 
                 1.0 
               
               
                 Stearate 
                   
                   
                   
                   
                   
               
               
                 Colloidal 
                 Glidant/anti- 
                 0.0 
                 1.0 
                 1.0 
                 1.0 
               
               
                 Silicon 
                 adherent/ 
                   
                   
                   
                   
               
               
                 Dioxide 
                 anti-static 
                   
                   
                   
                   
               
               
                 Manufacturing 
                 — 
                 Dry  
                 Dry  
                 Dry 
                 Dry 
               
               
                 Process 
                   
                 blending 
                 blending 
                 granulation 
                 granulation 
               
               
                 Final Dosage 
                 — 
                 Capsule 
                 Capsule 
                 Capsule 
                 Tablet 
               
               
                 Form