Methods for making crystalline EDG-2 receptor antagonists

Abstract

Described herein is a method for making crystalline Form 1 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 315,898, filed March 2, 2022, which is incorporated by reference herein in its entirety.

[0002] Described herein is a method for making crystalline Form 1 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I). [Background technology]

[0003] Compound I is a potent, selective, orally available LPA1 receptor antagonist useful for treating various diseases or conditions, such as fibrotic diseases or conditions, as described herein. Compound I is a polymorphic substance, and four crystal forms have been identified. Reliably producing a single crystal form of a polymorphic substance can be a challenge. Described herein is a reliable and reproducible method for producing Form 1. Summary of the Invention [Problem to be solved by the invention]

[0004] Compound I is a polymorphic drug candidate in development for the treatment of diseases or conditions that would benefit from treatment with an LPA1 receptor antagonist, such as fibrotic diseases or conditions. Crystalline Form 1 of Compound I has been identified as the preferred crystalline form. At neutral / acidic pH, Compound I is highly insoluble in most solvents and prone to crystallize vigorously and uncontrollably as a mixture of polymorphs. A method for the preparation of Form 1 was previously developed that involves the addition of citric acid and Form 1 seeds to a solution of Compound I. The previously developed method utilized a narrow window of temperature and pH conditions as a means to prevent a supersaturated solution of Compound I from self-crystallizing into a mixture of polymorphs. The narrow window of reaction conditions for preparing Form 1 posed manufacturing challenges for the reliable production of Form 1. Thus, an improved manufacturing method for producing crystalline Form 1 of Compound I was needed. [Means for solving the problem]

[0005] Described herein are improved methods for the reliable production of crystalline Form 1 of Compound I. The methods described herein allow for the production of Form 1 without the need for seeding of Form 1.

[0006] In one aspect, described herein is 2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I): [ka] 2. A process for the preparation of crystalline form 1 of The method is (1) In a suitable solvent, a compound of formula 2: [ka] wherein M + Na + , K + , or Li + A compound of formula 2, to a slurry of citric acid; (2) isolating crystalline Form 1 of Compound I by filtration; The method of claim 1, wherein crystalline Form 1 of Compound I is characterized as having an X-ray powder diffraction (XRPD) pattern with peaks at 5.2±0.2° 2-theta, 9.0±0.2° 2-theta, 14.4±0.2° 2-theta, and 17.7±0.2° 2-theta, when measured using Cu(Kα) radiation.

[0007] In some embodiments, the suitable solvent for step (1) is tetrahydrofuran, methanol, ethanol, ethylene glycol, acetonitrile, water, or a combination thereof. In some embodiments, the suitable solvent for step (1) is a mixture of methanol and water.

[0008] In some embodiments, the mixture comprising the compound of Formula 2 is a solution.

[0009] In some embodiments, the citric acid slurry comprises citric acid in a suitable solvent. In some embodiments, the citric acid slurry comprises citric acid in a solvent selected from tetrahydrofuran, methanol, ethanol, ethylene glycol, acetonitrile, water, or combinations thereof. In some embodiments, the citric acid slurry comprises citric acid in methanol. In some embodiments, the slurry comprises at least 1.0 equivalent of citric acid relative to the amount of the compound of formula 2. In some embodiments, the slurry comprises about 1.2 equivalents to about 1.5 equivalents of citric acid relative to the amount of the compound of formula 2. In some embodiments, the concentration of citric acid in the slurry is about 0.5M to about 1.5M. In some embodiments, the concentration of citric acid in the slurry is about 1.0M. In some embodiments, the citric acid slurry comprises about 1.32 equivalents of citric acid relative to the amount of the compound of formula 2 in methanol at a concentration of about 1.0M.

[0010] In some embodiments, the citric acid slurry further comprises up to about 10% w / w seeds of crystalline Form 1 of Compound I. In some embodiments, the citric acid slurry further comprises 0% to about 5% w / w seeds of crystalline Form 1 of Compound I. In some embodiments, the citric acid slurry further comprises about 0.5% to about 5% w / w seeds of crystalline Form 1 of Compound I. In some embodiments, the citric acid slurry further comprises about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, or about 5% w / w seeds of crystalline Form 1 of Compound I.

[0011] In some embodiments, the citric acid slurry is heated to a temperature of about 40°C.

[0012] In some embodiments, the mixture comprising the compound of Formula 2 is added to the citric acid slurry over a period of about 10 minutes to about 120 minutes. In some embodiments, after the mixture comprising the compound of Formula 2 is added to the citric acid slurry, the resulting mixture is maintained at a temperature of about 40° C. for about 3 hours.

[0013] In some embodiments, the crystalline form 1 of compound I isolated after step (2) is further washed with a suitable solvent up to four times. In some embodiments, the suitable solvent used for washing is methanol, water, or a combination thereof. In some embodiments, the crystalline form 1 of compound I isolated after step (2) is further dried under vacuum. In some embodiments, the crystalline form 1 of compound I isolated after step (2) is dried under vacuum at a temperature of about 35° C. to about 45° C. for about 3 hours to about 36 hours. In some embodiments, the crystalline form 1 of compound I isolated after step (2) is further dried under vacuum at a temperature of about 40° C. for about 16 hours.

[0014] In some embodiments, the method further comprises a cooling step, in which the mixture obtained after step (1) is cooled prior to isolation of crystalline Form 1 of Compound I in step (2). In some embodiments, the mixture obtained after step (1) is cooled to about 10° C. In some embodiments, the mixture obtained after step (1) is cooled to about 10° C. over a period of about 3 hours.

[0015] In some embodiments, the mixture comprising the compound of Formula 2 is a compound of Formula 1: [ka] wherein R 1 is methyl or ethyl in a suitable solvent. It is obtained by saponification of the ester moiety of

[0016] In some embodiments, a suitable solvent for saponification comprises tetrahydrofuran, methanol, ethanol, ethylene glycol, acetonitrile, water, or a combination thereof, hi some embodiments, a suitable solvent for saponification comprises a mixture of methanol and water.

[0017] In some embodiments, the compound of formula 1 is dissolved in a suitable solvent to obtain a solution prior to saponification. In some embodiments, the suitable solvent is tetrahydrofuran, methanol, ethanol, ethylene glycol, acetonitrile, water, or a combination thereof. In some embodiments, the suitable solvent is methanol. In some embodiments, the method further comprises heating the resulting solution of the compound of formula 1 to a temperature of about 50° C. prior to saponification.

[0018] In some embodiments, the saponification is of the formula M-OH, where M-OH is NaOH, KOH, or LiOH, and M + are Na + , K + , or Li +In some embodiments, the metal hydroxide base is added as an aqueous solution. In some embodiments, the concentration of the metal hydroxide base in the water is about 0.5M to about 5.0M. In some embodiments, the concentration of the metal hydroxide base in the water is about 1.0M. In some embodiments, the saponification comprises at least 1.0 equivalent of metal hydroxide base relative to the amount of the compound of Formula 1. In some embodiments, the saponification comprises about 1.1 equivalents to about 1.25 equivalents of metal hydroxide base relative to the amount of the compound of Formula 1. In some embodiments, the metal hydroxide base is NaOH. In some embodiments, the temperature of the saponification step is about 60° C. In some embodiments, the saponification step is carried out for at least 2 hours. In some embodiments, the saponification step occurs for about 2 hours to about 4 hours.

[0019] In some embodiments, the compound of formula 2 is compound 2a: [ka] It has the structure:

[0020] In another aspect, described herein is 2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I): [ka] 2. A process for the preparation of crystalline form 1 of The method is (1) Compound of Formula 1: [ka] wherein R 1 is saponified in a suitable solvent to the ester moiety of the compound of formula 1, which is either methyl or ethyl, to give the compound of formula 2: [ka] wherein M +providing a reaction mixture comprising a compound of formula 2, (2) adding the reaction mixture of step (1) to a slurry of citric acid; (3) isolating crystalline Form 1 of Compound I by filtration; The method of claim 1, wherein crystalline Form 1 of Compound I is characterized as having an X-ray powder diffraction (XRPD) pattern with peaks at 5.2±0.2° 2-theta, 9.0±0.2° 2-theta, 14.4±0.2° 2-theta, and 17.7±0.2° 2-theta, when measured using Cu(Kα) radiation.

[0021] In some embodiments, the saponification is of the formula M-OH, where M-OH is NaOH, KOH, or LiOH, and M + are Na + , K + , or Li + The metal hydroxide base has the formula M-OH,

[0022] In some embodiments, the saponification in step (1) comprises (a) obtaining a solution of a compound of formula 1 in a suitable solvent; (b) optionally heating the solution of step (a); (c) adding a metal hydroxide base in an aqueous solution to the solution of step (a) and heating the reaction mixture to obtain a reaction mixture comprising the compound of formula 2.

[0023] In some embodiments, the suitable solvent in step (a) is methanol, and the solution in step (a) is heated to about 50°C.

[0024] In some embodiments, the concentration of the metal hydroxide base in water in step (c) is about 1.0 M, and about 1.1 equivalents to about 1.25 equivalents of the metal hydroxide base are used in step (c) relative to the amount of the compound of Formula 1. In some embodiments, the reaction mixture in step (c) is heated to about 60° C. for about 2 hours to about 4 hours.

[0025] In some embodiments, the metal hydroxide base in step (c) is NaOH and the compound of Formula 2 is Compound 2a: [ka] It has the structure:

[0026] In some embodiments, the citric acid slurry comprises about 1.2 equivalents to about 1.5 equivalents of citric acid relative to the amount of the compound of Formula 1 in methanol. In some embodiments, the concentration of citric acid in the slurry is about 0.5M to about 1.5M. In some embodiments, the concentration of citric acid in the slurry is about 1.0M. In some embodiments, the citric acid slurry comprises about 1.32 equivalents of citric acid at a concentration of about 1.0M relative to the amount of the compound of Formula 1 in methanol. In some embodiments, the citric acid slurry further comprises up to about 10% w / w seeds of crystalline Form 1 of Compound I. In some embodiments, the citric acid slurry further comprises about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, or about 5% w / w seeds of crystalline Form 1 of Compound I. In some embodiments, the mixture comprising the compound of Formula 2 is added onto the citric acid slurry over a period of about 10 minutes to about 120 minutes. In some embodiments, after the mixture comprising the compound of Formula 2 is added to the citric acid slurry, the resulting mixture is maintained at a temperature of about 40° C. for about 3 hours.

[0027] In another aspect, described herein is 2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I): [ka] 2. A process for the preparation of crystalline form 1 of The method is (1) The ester portion of the compound methyl 2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylate (compound 1a): [ka] is saponified with NaOH in a suitable solvent to give sodium 2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylate (compound 2a): [ka] providing a reaction mixture comprising: (2) adding the reaction mixture of step (1) to a slurry of citric acid; (3) isolating crystalline Form 1 of Compound I by filtration; The method of claim 1, wherein crystalline Form 1 of Compound I is characterized as having an X-ray powder diffraction (XRPD) pattern with peaks at 5.2±0.2° 2-theta, 9.0±0.2° 2-theta, 14.4±0.2° 2-theta, and 17.7±0.2° 2-theta, when measured using Cu(Kα) radiation.

[0028] In some embodiments, the saponification in step (1) comprises: a. obtaining a solution of compound 1a in methanol and heating it to a temperature of about 50° C.; b. adding about 1.1 equivalents to about 1.25 equivalents of NaOH relative to compound 1a as about 1.0 M aqueous solution to the solution of step (a) to obtain a reaction mixture; c. heating the reaction mixture of step (b) to about 60° C. for about 2 hours to about 4 hours.

[0029] In some embodiments, the citric acid slurry contains about 1.2 equivalents to about 1.5 equivalents of citric acid relative to the amount of the compound of Formula 1 in methanol. The concentration of citric acid in the slurry is about 1.0 M. The citric acid slurry contains 0% to about 5% w / w of crystalline Form 1 seeds of Compound I. In some embodiments, the citric acid slurry is heated to a temperature of about 40° C. The mixture containing the compound of Formula 2 is added to the citric acid slurry over a period of about 10 minutes to about 120 minutes. The resulting mixture is maintained at a temperature of about 40° C. for about 3 hours.

[0030] In some embodiments, the crystalline Form 1 of Compound I isolated after step (3) is further washed twice with a mixture of methanol and water, followed by two times with methanol, and further dried under vacuum at a temperature of about 35° C. to about 45° C. for about 3 hours to about 36 hours.

[0031] In another aspect, described herein is 2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I) prepared by the methods described herein. [ka] In some embodiments, crystalline Form 1 of Compound I is characterized as having an X-ray powder diffraction (XRPD) pattern with peaks at 5.2±0.2° 2-theta, 9.0±0.2° 2-theta, 14.4±0.2° 2-theta, and 17.7±0.2° 2-theta, as measured using Cu(Kα) radiation. In some embodiments, crystalline Form 1 of Compound I is substantially free of crystalline Form 2 of Compound I. In some embodiments, crystalline Form 1 of Compound I contains less than 1% w / w crystalline Form 2 of Compound I.

[0032] Also described herein, in some embodiments, is a pharmaceutical composition comprising crystalline Form 1 of Compound I prepared herein and at least one pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration in the form of a tablet, pill, capsule, suspension or solution. In some embodiments, the pharmaceutical composition is in the form of a solid form pharmaceutical composition. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill or capsule.

[0033] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description, but it should be understood that the detailed description and specific examples, while indicating particular embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. [Brief description of the drawings]

[0034] [Figure 1] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of Form 1. [Diagram 2] FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of Form 1. [Diagram 3] FIG. 3 shows the thermogravimetric analysis (TGA) pattern of Form 1. [Figure 4] FIG. 4 shows the solid state 13C NMR spectrum of Form 1. [Diagram 5] FIG. 5 shows the X-ray powder diffraction (XRPD) pattern of Form 2. [Figure 6] FIG. 6 shows a differential scanning calorimetry (DSC) thermogram of Form 2. [Figure 7] FIG. 7 shows the solid state 13C NMR spectrum of Form 2. [Figure 8] FIG. 8 shows the X-ray powder diffraction (XRPD) pattern of Form 3. [Figure 9]FIG. 9 shows a differential scanning calorimetry (DSC) thermogram of Form 3. [Figure 10] FIG. 10 shows the solid state 13C NMR spectrum of Form 3. [Figure 11] FIG. 11 shows the X-ray powder diffraction (XRPD) pattern of Form 4. [Figure 12] FIG. 12 shows a differential scanning calorimetry (DSC) thermogram of Form 4. [Figure 13] FIG. 13 shows the Fourier transform IR spectroscopy (FTIR) pattern overlay of Forms 1, 2, 3, and 4. [Figure 14] FIG. 14 shows the solid-state 13C NMR spectrum of the amorphous form. [Figure 15] FIG. 15 shows the XRPD pattern of Form 1 obtained on a Malvern Panalytical Empyrean diffractometer. [Figure 16] FIG. 16 shows the XRPD pattern of Form 2 obtained on a Malvern Panalytical Empyrean diffractometer. [Figure 17] FIG. 17 shows the XRPD pattern of Form 1 obtained on a Stoe Stadi P,G.52.SYS.S072 diffractometer. [Figure 18] FIG. 18 shows the XRPD pattern of Form 2 obtained on a Stoe Stadi P,G.52.SYS.S072 diffractometer. [Figure 19] FIG. 19 shows an overlay of XRPD patterns of Form 1 (top XRPD) and Form 2 (bottom XRPD) obtained on a Stoe Stadi P,G.52.SYS.S072 diffractometer. [Figure 20] FIG. 20 shows the XRPD pattern of Form 1 obtained on a PANalytical X'Pert PRO MPD diffractometer. [Figure 21] FIG. 21 shows the XRPD pattern of Form 2 obtained on a PANalytical X'Pert PRO MPD diffractometer. [Figure 22]FIG. 22 shows a comparison of the XRPD patterns of Forms 1 (top XRPD) and 2 (bottom XRPD), highlighting the Form 2 peaks used to quantitate Form 1 over Form 2. [Diagram 23] FIG. 23 shows an XRPD overlay of the calibration standards used in the development of an XRPD limit test for the determination of Form 2 in Form 1 drug substance. [Figure 24] FIG. 24 shows the calibration curve used to develop an XRPD limit test for determining Form 2 in Form 1 drug substance. [Diagram 25] FIG. 25 shows the Raman spectrum of Form 1. [Figure 26] FIG. 26 shows the Raman spectrum of Form 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] 2-(4-Methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I) is a potent and selective LPA1 receptor antagonist. LPA1 receptor is activated by lysophosphatidic acid (LPA). LPA1 receptor antagonists are useful for treating diseases or conditions in which abnormal LPA signaling plays a role, such as atherosclerosis, myocardial infarction, and heart failure.

[0036] Compound I Compound I is a potent, selective, orally available LPA1 receptor antagonist useful for treating various diseases or conditions, such as fibrotic diseases or conditions, as described herein. In vivo, Compound I reversed skin thickening, significantly inhibited myofibroblast differentiation, and reduced collagen content in a mouse model of dermal fibrosis. Mechanistic investigations showed that the antifibrotic effect of LPA1 blockade may be mediated in part through inhibition of the Wnt signaling pathway. In clinical settings, Compound I was well tolerated in patients with diffuse cutaneous systemic sclerosis SSc (dcSSc), demonstrating target engagement and improved outcome measures (Y. Allanore et al. Arthritis & Rheumatology, Vol. 70, No. 10, October 2018, pp 1634-1643).

[0037] The preparation and use of Compound I have been previously described (see WO 2009 / 135590, U.S. Pat. No. 8,362,073, U.S. Pat. No. 8,445,530, U.S. Pat. No. 8,802,720, U.S. Pat. No. 9,328,071, each of which is incorporated by reference in its entirety). The preparation of crystalline Form 1 of Compound I has been previously described (see International Patent Application No. PCT / IB2021 / 000594 and U.S. Patent Application No. 17 / 463,369, each of which is incorporated by reference in its entirety).

[0038] Compound I has the chemical structure shown below: [ka] It refers to 2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid having the formula:

[0039] In some embodiments provided herein, Compound I is crystalline.

[0040] In some embodiments provided herein, compound I is in a single crystalline form. In some embodiments provided herein, compound I is in a single crystalline form that is substantially free of other crystalline forms. In some embodiments, the crystalline solid form is a single solid form, such as crystalline form 1. In some embodiments, "substantially free" refers to less than about 10% w / w, less than about 9% w / w, less than about 8% w / w, less than about 7% w / w, less than about 6% w / w, less than about 5% w / w, less than about 4% w / w, less than about 3% w / w, less than about 2.5% w / w, less than about 2% w / w, less than about 1.5% w / w, less than about 1% w / w, less than about 0.75% w / w, less than about 0.50% w / w, less than about 0.25% w / w, less than about 0.10% w / w, or less than about 0.05% w / w of any other crystalline form (e.g., form 2) in a sample of crystalline form 1. In some embodiments, "substantially free" means an undetectable amount (eg, by XRPD analysis).

[0041] In some embodiments, the crystallinity of the solid form is determined by X-ray powder diffraction (XRPD). In some embodiments, the crystallinity of the solid form is determined by solid state NMR. In some embodiments, the crystallinity of the solid form is determined by Fourier transform IR spectroscopy (FTIR).

[0042] Crystalline Form 1 of Compound I In one aspect, provided herein is crystalline Form 1 of Compound I. In some embodiments, provided is a composition comprising crystalline Form 1 of Compound I. In some embodiments, crystalline Form 1 of Compound I has the following structure: an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 1, when measured using Cu(Kα) radiation; an X-ray powder diffraction (XRPD) pattern obtained using Cu(Kα) radiation having peaks at 5.2±0.2° 2-theta, 9.0±0.2° 2-theta, 14.4±0.2° 2-theta, and 17.7±0.2° 2-theta, when measured using Cu(Kα) radiation; Approx. 1739.6cm-1 and a Fourier transform IR spectroscopy (FTIR) pattern having a peak at and at 293 K, unit cell parameters substantially equal to:

[0043] [Table 5]

[0044] A solid substantially the same as shown in FIG. 13 Carbon nuclear magnetic resonance (ssNMR) spectrum, A solid characterized by resonances (δc) at 23.35, 124.43, 126.78, 127.42, and 136.47 ppm 13 Carbon nuclear magnetic resonance (ssNMR) spectrum, or A combination of these

[0045] In some embodiments, crystalline Form 1 of Compound I has an X-ray powder diffraction (XRPD) pattern with peaks at 5.2±0.2° 2-theta, 9.0±0.2° 2-theta, 14.4±0.2° 2-theta, and 17.7±0.2° 2-theta, when measured using Cu(Kα) radiation.

[0046] In some embodiments, crystalline Form 1 of Compound I has an X-ray powder diffraction (XRPD) pattern with peaks at 5.2±0.2° 2-theta, 9.0±0.2° 2-theta, 14.4±0.2° 2-theta, and 17.7±0.2° 2-theta, as measured using Cu(Kα) radiation, and a peak at about 1739.6 cm -1 The compound has a Fourier transform IR spectroscopy (FTIR) pattern with a peak at

[0047] In some embodiments, crystalline Form 1 of Compound I has an X-ray powder diffraction (XRPD) pattern with peaks at 5.2±0.2° 2-theta, 9.0±0.2° 2-theta, 14.4±0.2° 2-theta, and 17.7±0.2° 2-theta, and a differential scanning calorimetry (DSC) thermogram with three endothermic events with an onset at about 198.5° C. and a peak at about 200.4° C., an onset at about 204.8° C. and a peak at about 205.8° C., and an onset at about 213.9° C. and a peak at about 216.3° C., as measured using Cu(Kα) radiation.

[0048] In some embodiments, crystalline Form 1 of Compound I is a solid state crystalline form characterized by an X-ray powder diffraction (XRPD) pattern with peaks at 5.2±0.2° 2-theta, 9.0±0.2° 2-theta, 14.4±0.2° 2-theta, and 17.7±0.2° 2-theta, as measured using Cu(Kα) radiation, and resonances (δc) at about 23.35 ppm, about 124.43 ppm, about 126.78 ppm, about 127.42 ppm, and about 136.47 ppm. 13 It has a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0049] In some embodiments, crystalline Form 1 of Compound I is a solid state crystalline form characterized by an X-ray powder diffraction (XRPD) pattern with peaks at 5.2±0.2° 2-theta, 9.0±0.2° 2-theta, 14.4±0.2° 2-theta, and 17.7±0.2° 2-theta, as measured using Cu(Kα) radiation, and resonances (δc) at about 23.35 ppm, about 124.43 ppm, about 126.78 ppm, about 127.42 ppm, and about 136.47 ppm. 13 It has a carbon nuclear magnetic resonance (ssNMR) spectrum and a differential scanning calorimetry (DSC) thermogram with three endothermic events having an onset at about 198.5°C and a peak at about 200.4°C, an onset at about 204.8°C and a peak at about 205.8°C, and an onset at about 213.9°C and a peak at about 216.3°C.

[0050] In some embodiments, crystalline Form 1 of Compound I has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. 1, when measured using Cu(Kα) radiation.

[0051] In some embodiments, crystalline Form 1 of Compound I has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. 1 and a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG. 2, when measured using Cu(Kα) radiation.

[0052] In some embodiments, the crystalline Form 1 of Compound I has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. 1 and a crystallite size distribution at about 1739.6 cm when measured using Cu(Kα) radiation. -1 In some embodiments, crystalline Form 1 of Compound I has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. 1 , and a peak at about 1739.6 cm, as measured using Cu(Kα) radiation. -1 3 and a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in FIG. 2.

[0053] In some embodiments, crystalline Form 1 of Compound I has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 1 and a solid state diffraction pattern substantially the same as that shown in FIG. 4, when measured using Cu(Kα) radiation. 13 In some embodiments, crystalline Form 1 of Compound I has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG 1 and a solid state diffraction (SNMR) spectrum substantially the same as that shown in FIG 4, when measured using Cu(Kα) radiation. 13 It has a carbon nuclear magnetic resonance (ssNMR) spectrum and a differential scanning calorimetry (DSC) thermogram substantially the same as those shown in FIG.

[0054] In some embodiments, crystalline Form 1 of Compound I has unit cell parameters at 293K substantially equal to:

[0055] [Table 6]

[0056] In some embodiments, crystalline Form 1 of Compound I is substantially the same solid form as shown in FIG. 13 In some embodiments, crystalline Form 1 of Compound I is characterized as having a carbon nuclear magnetic resonance (ssNMR) spectrum substantially similar to that shown in FIG. 13 Carbon nuclear magnetic resonance (ssNMR) spectrum and about 1739.6 cm -1 In some embodiments, crystalline Form 1 of Compound I is characterized as having a solid state image substantially similar to that shown in FIG. 13 It is characterized as having a carbon nuclear magnetic resonance (ssNMR) spectrum and a differential scanning calorimetry (DSC) thermogram substantially similar to those shown in FIG.

[0057] In some embodiments, crystalline Form 1 of Compound I is a solid state crystalline form characterized by resonances (δc) at about 23.35 ppm, about 124.43 ppm, about 126.78 ppm, about 127.42 ppm, and about 136.47 ppm. 13 It is characterized as having a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0058] In some embodiments, crystalline Form 1 of Compound I is a solid state crystalline form characterized by resonances (δc) at about 23.35 ppm, about 124.43 ppm, about 126.78 ppm, about 127.42 ppm, and about 136.47 ppm. 13 It is characterized as having a carbon nuclear magnetic resonance (ssNMR) spectrum, as well as a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG.

[0059] In some embodiments, crystalline Form 1 of Compound I is a solid state crystalline form characterized by resonances (δc) at about 23.35 ppm, about 124.43 ppm, about 126.78 ppm, about 127.42 ppm, and about 136.47 ppm. 13 Carbon nuclear magnetic resonance (ssNMR) spectrum and about 1739.6 cm -1 The compound is characterized as having a Fourier transform IR spectroscopy (FTIR) pattern with a peak at

[0060] In some embodiments, the crystalline Form 1 of Compound I has a molecular weight of about 1739.6 cm -1 In some embodiments, crystalline Form 1 of Compound I is characterized as having a Fourier transform IR spectroscopy (FTIR) pattern with a peak at about 1739.6 cm -1 and a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in FIG. 2.

[0061] In some embodiments, the crystalline Form 1 of Compound I has a molecular weight of about 1739.6 cm -1 and a differential scanning calorimetry (DSC) thermogram having three endothermic events with an onset at about 198.5° C. and a peak at about 200.4° C., an onset at about 204.8° C. and a peak at about 205.8° C., and an onset at about 213.9° C. and a peak at about 216.3° C.

[0062] In some embodiments, crystalline Form 1 of Compound I has a DSC thermogram substantially the same as that shown in Figure 2. In some embodiments, crystalline Form 1 has a DSC thermogram with one or more endothermic events with an onset at about 198.5°C and a peak at about 200.4°C, an onset at about 204.8°C and a peak at about 205.8°C, and / or an onset at about 213.9°C and a peak at about 216.3°C. In some embodiments, crystalline Form 1 has a DSC thermogram with three endothermic events with an onset at about 198.5°C and a peak at about 200.4°C, an onset at about 204.8°C and a peak at about 205.8°C, and an onset at about 213.9°C and a peak at about 216.3°C.

[0063] In some embodiments, crystalline Form 1 of Compound I has a TGA pattern substantially the same as that shown in Figure 3. In some embodiments, crystalline Form 1 has a TGA pattern with 15.4% w / w loss from about 287.9°C to about 298.9°C. In some embodiments, crystalline Form 1 has a TGA pattern with less than 1% weight loss up to 200°C.

[0064] In some embodiments, crystalline Form 1 of Compound I has no reversible water uptake (about -0.1% w / w) at 0-95% relative humidity (RH). In some embodiments, crystalline Form 1 of Compound I has no reversible water uptake at 0-95% relative humidity (RH). In some embodiments, crystalline Form 1 of Compound I has reversible water uptake of less than 1% w / w at 0-95% relative humidity (RH). In some embodiments, crystalline Form 1 of Compound I has reversible water uptake of about -0.1% w / w at 0-95% relative humidity (RH).

[0065] In some embodiments, the crystalline Form 1 of Compound I has a molecular weight of about 1739.6 cm -1 The FTIR spectrum has a peak at

[0066] In some embodiments, crystalline Form 1 of Compound I has an unchanged FTIR after storage at 75% RH and 80° C. for 7 days.

[0067] In some embodiments, crystalline Form 1 of Compound I has a ssNMR spectrum substantially the same as that shown in Figure 4. In some embodiments, crystalline Form 1 has a ssNMR spectrum characterized by resonances (δc) at 23.35, 124.43, 126.78, 127.42, and 136.47 ppm. In some embodiments, crystalline Form 1 has a ssNMR spectrum further characterized by resonances (δc) at 54.41, 65.40, 138.94, 142.61, 148.68, 152.19, and 174.59 ppm. In some embodiments, crystalline Form 1 has a ssNMR spectrum characterized by resonances (δc) at 23.35, 36.40, 44.12, 45.70, 54.41, 65.40, 71.58, 110.97, 114.45, 121.00, 124.43, 126.78, 127.42, 131.27, 136.47, 138.94, 142.61, 148.68, 152.19, 172.07, and 174.59 ppm.

[0068] In some embodiments, crystalline Form 1 of Compound I converts to crystalline Form 2 when slurried in a solvent at or above 60° C. In some embodiments, crystalline Form 1 converts to crystalline Form 2 when slurried in MEK or 1-pentanol at a temperature of 60° C. or 70° C. In some embodiments, the form conversion is determined by FTIR.

[0069] In some embodiments, crystalline Form 1 of Compound I is anhydrous.

[0070] Preparation of Crystalline Form 1 of Compound I Disclosed herein is a method for synthesizing crystalline Form 1 of Compound I, as outlined in Scheme 1.

[0071] Scheme 1: Preparation of Crystalline Form 1 of Compound I [ka] In the formula, R 1 is methyl or ethyl, M + is a suitable cation.

[0072] Briefly, the compound of formula 1 undergoes a saponification reaction to yield the compound of formula 2. The compound of formula 2 is acidified by addition of citric acid to yield compound I, which is isolated directly from the reaction vessel as crystalline form 1 of compound 1.

[0073] Step (1): Synthesis of compound of formula 2 (saponification) In some embodiments, the ester moiety of a compound of formula 1 undergoes a saponification reaction to yield a compound of formula 2 in a suitable solvent.

[0074] In some embodiments, the compound of formula 2 is a compound of formula 1: [ka] wherein R 1 is methyl or ethyl in a suitable solvent. It is obtained by saponification of the ester moiety of

[0075] In some embodiments, a suitable solvent for the saponification reaction is tetrahydrofuran, methanol, ethanol, ethylene glycol, acetonitrile, water, or a combination thereof, hi some embodiments, a suitable solvent is a mixture of methanol and water.

[0076] In some embodiments, the compound of formula 1 is dissolved in a suitable solvent to obtain a solution prior to saponification. In some embodiments, the suitable solvent is tetrahydrofuran, methanol, ethanol, ethylene glycol, acetonitrile, water, or a combination thereof. In some embodiments, the suitable solvent is methanol, ethanol, water, or a combination thereof. In some embodiments, the suitable solvent is methanol. In some embodiments, the suitable solvent is ethanol. In some embodiments, the resulting solution of the compound of formula 1 is heated prior to saponification. In some embodiments, the resulting solution of the compound of formula 1 is heated to a temperature of about 50° C. prior to saponification. In some embodiments, “about 50° C.” means 45° C. to 55° C. In some embodiments, “about 50° C.” means 47° C. to 53° C. In some embodiments, the resulting solution of the compound of formula 1 is heated to a temperature of 47° C. to 53° C. prior to saponification.

[0077] In some embodiments, the saponification comprises a metal hydroxide base. In some embodiments, the saponification comprises a metal hydroxide base of the formula M-OH, where M-OH is NaOH, KOH, or LiOH, and M + are Na + , K + , or Li + In some embodiments, the saponification comprises a metal hydroxide base having the formula M-OH, where M-OH is NaOH, and M + is Na + In some embodiments, the saponification comprises a metal hydroxide base having the formula M-OH, where M-OH is KOH, and M + is K + In some embodiments, the saponification comprises a metal hydroxide base having the formula M-OH, where M-OH is LiOH, and M + Li + The metal hydroxide base has the formula M-OH,

[0078] In some embodiments, the saponification comprises at least 1.0 equivalent of metal hydroxide base relative to the amount of the compound of formula 1. In some embodiments, the saponification comprises about 1.1 equivalent to about 1.25 equivalent of metal hydroxide base relative to the amount of the compound of formula 1. In some embodiments, the saponification comprises about 1.0, about 1.05, about 1.1, about 1.15, about 1.2, about 1.25, or about 1.3 equivalent of metal hydroxide base relative to the amount of the compound of formula 1. In some embodiments, the saponification comprises about 1.15, about 1.16, about 1.17, about 1.18, about 1.19, about 1.20, about 1.21, about 1.22, about 1.23, about 1.24, or about 1.25 equivalent of metal hydroxide base relative to the amount of the compound of formula 1.

[0079] In some embodiments, the metal hydroxide base is added to the solution of Compound 1 as an aqueous solution. In some embodiments, the concentration of the aqueous solution of the metal hydroxide base is about 0.5M to about 5.0M. In some embodiments, the metal hydroxide base is added as an aqueous solution. In some embodiments, the concentration of the aqueous solution of the metal hydroxide base is about 0.5M to about 1.5M. In some embodiments, the concentration of the aqueous solution of the metal hydroxide base is about 0.1M, about 0.5M, about 1.0M, about 2.0M, or about 5.0M. In some embodiments, the concentration of the aqueous solution of the metal hydroxide base is about 1.0M. In some embodiments, the concentration of the aqueous solution of the metal hydroxide base is 1.0M.

[0080] In some embodiments, the temperature of the reaction is maintained throughout the addition of the metal hydroxide base. Base. In some embodiments, the temperature of the reaction is maintained at about 50° C. throughout the addition of the metal hydroxide base. In some embodiments, "about 50° C." means between 45° C. and 65° C. In some embodiments, "about 50° C." means between 47° C. and 63° C. In some embodiments, the temperature of the reaction is maintained at a temperature between 47° C. and 63° C. throughout the addition of the metal hydroxide base. In some embodiments, the temperature of the reaction is maintained throughout the addition of the metal hydroxide base by slow addition of the metal hydroxide base.

[0081] In some embodiments, the saponification step is carried out at an elevated temperature. In some embodiments, the saponification step is carried out at a temperature of about 50°C to about 70°C. In some embodiments, the saponification step is carried out at a temperature of about 60°C. In some embodiments, "about 60°C" means 55°C to 65°C. In some embodiments, "about 60°C" means 57°C to 63°C. In some embodiments, the saponification step is carried out at a temperature of 57°C to 63°C.

[0082] In some embodiments, the saponification step is carried out for at least 1 hour. In some embodiments, the saponification step is carried out for about 1 hour, about 2 hours, about 3 hours, or more. In some embodiments, the saponification step is carried out for at least 2 hours. In some embodiments, the saponification step is carried out for about 2 hours to about 4 hours. In some embodiments, the saponification step is carried out for about 2 hours. In some embodiments, "about 2 hours" means about 1 hour 30 minutes to about 2 hours 30 minutes. In some embodiments, "about 2 hours" means about 1 hour 45 minutes to about 2 hours 15 minutes. In some embodiments, "about 2 hours" means 1 hour 45 minutes to 2 hours 15 minutes. In some embodiments, the saponification step is carried out for 1 hour 45 minutes to 2 hours 15 minutes. In some embodiments, the saponification step is carried out for about 2 hours. In some embodiments, "about 3 hours" means about 2 hours 30 minutes to about 3 hours 30 minutes. In some embodiments, "about 3 hours" means about 2 hours 45 minutes to about 3 hours 15 minutes. In some embodiments, "about 3 hours" means between 2 hours 45 minutes and 3 hours 15 minutes. In some embodiments, the saponification step is carried out for between 2 hours 45 minutes and 3 hours 15 minutes.

[0083] In some embodiments, the saponification step is carried out for about 1 hour 45 minutes to 2 hours 15 minutes at a temperature between 57° C. and 63° C. In other embodiments, the saponification step is carried out for about 2 hours 45 minutes to 3 hours 15 minutes at a temperature between 57° C. and 63° C.

[0084] In other embodiments, the saponification involves an inorganic acid. In some embodiments, the inorganic acid is hydrochloric acid, sulfuric acid, trifluoroacetic acid, formic acid, or nitric acid. In some embodiments, the resulting acid is converted to a compound of formula 2 using a suitable base.

[0085] In some embodiments, the compound of formula 1 is compound 1a: [ka] It is.

[0086] In some embodiments, the compound of formula 1 is compound 1b: [ka] It is.

[0087] In some embodiments, the compound of formula 2 is compound 2a: [ka] It is.

[0088] In some embodiments, the compound of formula 2 is isolated prior to step (2): acidification. In some embodiments, the compound of formula 2 is purified prior to the acidification step.

[0089] In some embodiments, the compound of formula 2 is not isolated prior to step (2): acidification. In some embodiments, the reaction mixture of step (1) is added back to the reaction mixture used in step (2).

[0090] Step (2): Preparation of Crystalline Form 1 of Compound I (Acidification) In some embodiments, the compound of formula 2 undergoes an acidification reaction to provide the free acid Compound I. In some embodiments, the compound of formula 2 undergoes an acidification reaction to provide crystalline Form 1 of Compound I. In some embodiments, crystalline Form 1 of Compound I is isolated directly from the acidification reaction mixture.

[0091] Initial optimization for the preparation of crystalline form 1 of compound I Previous methods for preparing crystalline Form 1 of Compound I include a. adding citric acid to the reaction mixture of step (1) to quench excess metal hydroxide base and carefully control the pH to neutral; b. Immediately thereafter, adding seeds (e.g., 2%) of crystalline Form 1 of Compound I; c. Aging the mixture for exactly 15 minutes; d. adding additional citric acid immediately to crystallize Compound 1 into crystalline Form 1; It included:

[0092] Despite the ability of this method to produce crystalline form 1, it presents many manufacturing challenges and requires close monitoring due to the very narrow window of necessary conditions.

[0093] For example, in some instances, temperatures above 50°C result in the isolation of crystalline form 2 rather than crystalline form 1. In some cases, temperatures below 20°C result in rapid spontaneous crystallization, resulting in a mixture of polymorphs. Furthermore, in some cases, temperatures above 35°C provide crystalline particles with sizes below 500 μm and a monomodal partial size distribution. On the other hand, temperatures below 20°C result in a bimodal partial size distribution with partial sizes above 500 μm. As a result, to obtain crystalline form 1, the temperature of the previously reported acidification and crystallization method must be strictly controlled at 40°C throughout the process.

[0094] In some instances of the original method, crystalline form 2 is also isolated if the pH after base quenching is below 6.9. In some instances, Compound I may spontaneously crystallize if the pH of the reaction mixture is quickly lowered, resulting in a mixture of polymorphic forms or form 2. Furthermore, if the pH is too high when the seeds are added, the seeds will dissolve and not provide the benefit of seeding. As a result, slow and careful control of the pH is required throughout the process to obtain crystalline form 1.

[0095] Furthermore, in some cases, even with strict temperature and pH control, unseeded mixtures kept at 40° C. can result in spontaneous crystallization of crystalline form 2. In other instances, mixtures seeded with 2%-5% w / w seeds kept at 20° C. result in crystalline form 2. Slurrying the mixture at 20° C. for extended periods can result in very slow conversion of undesired form 2 to desired form 1, which is not a good manufacturing solution.

[0096] Thus, this original method relies on using a narrow window of pH and temperature conditions throughout the method to prevent supersaturated solutions of Compound I from self-crystallizing into a mixture of polymorphs. At the neutral / acidic pH required to form the free acid Compound I, the compound is highly insoluble, and the final highly saturated solution is thermodynamically unstable and prone to vigorous, spontaneous crystallization into a mixture of polymorphs.

[0097] Improved Preparation of Crystalline Form 1 of Compound I In some embodiments, crystalline Form 1 of Compound I is a compound of Formula 2: [ka] wherein M + Na + , K + , or Li + A compound of formula 2, onto a slurry of citric acid in a suitable solvent.

[0098] In some embodiments, crystalline Form 1 of Compound I is characterized as having an X-ray powder diffraction (XRPD) pattern with peaks at 5.2±0.2° 2-theta, 9.0±0.2° 2-theta, 14.4±0.2° 2-theta, and 17.7±0.2° 2-theta, as measured using Cu(Kα) radiation.

[0099] In some embodiments, the suitable solvent is tetrahydrofuran, methanol, ethanol, ethylene glycol, acetonitrile, water, or a combination thereof, hi some embodiments, the suitable solvent is a mixture of methanol and water.

[0100] In some embodiments, the mixture comprising the compound of formula 2 is a solution. In some embodiments, the mixture comprising the compound of formula 2 is a solution. [ka] wherein R 1 is methyl or ethyl in a suitable solvent. In some embodiments, the mixture comprising the compound of formula 2 is a reaction mixture obtained from the saponification reaction described above.

[0101] In some embodiments, the citric acid slurry comprises citric acid in a suitable solvent. In some embodiments, the citric acid slurry comprises citric acid in a solvent selected from tetrahydrofuran, methanol, ethanol, ethylene glycol, acetonitrile, water, or combinations thereof. In some embodiments, the citric acid slurry comprises citric acid in methanol.

[0102] In some embodiments, the slurry comprises at least 1.0 equivalent of citric acid relative to the amount of the compound of formula 2. In some embodiments, the slurry comprises at least 1.0 equivalent of citric acid relative to the amount of the compound of formula 1 used in the saponification reaction. In some embodiments, the slurry comprises about 1.2 equivalents to about 1.5 equivalents of citric acid relative to the amount of the compound of formula 2. In some embodiments, the slurry comprises about 1.2 equivalents to about 1.5 equivalents of citric acid relative to the amount of the compound of formula 1 used in the saponification reaction. In some embodiments, the concentration of citric acid in the slurry is about 0.5M to about 1.5M. In some embodiments, the concentration of citric acid in the slurry is about 0.5M, about 0.6M, about 0.7M, about 0.8M, about 0.9M, about 1.0M, about 1.1M, about 1.2M, about 1.3M, about 1.4M, or about 1.5M. In some embodiments, the concentration of citric acid in the slurry is about 1.0M. In some embodiments, the citric acid slurry has a concentration of about 1.0 M and contains about 1.32 equivalents of citric acid relative to the amount of compound of Formula 2 in methanol. In some embodiments, the citric acid slurry has a concentration of about 1.0 M and contains about 1.32 equivalents of citric acid relative to the amount of compound of Formula 1 used in the saponification reaction above in methanol.

[0103] In some embodiments, the citric acid slurry further comprises seed crystals of crystalline Form 1 of Compound I. In some instances, the seed crystals are small crystals used as a base to grow large single crystals. In some instances, the crystals form slowly from random intermolecular interactions in the absence of the seed crystals. In some instances, when the seeds are placed in a saturated or supersaturated solution, the seeds act as nucleation sites for the desired crystallization from (e.g., crystalline Form 1 of Compound I).

[0104] In some embodiments, the citric acid slurry further comprises up to about 10% w / w of seeds of crystalline form 1 of compound I. In some embodiments, the citric acid slurry further comprises 0% to about 5% w / w of seeds of crystalline form 1 of compound I. In some embodiments, the citric acid slurry further comprises about 0.5% to about 5% w / w of seeds of crystalline form 1 of compound I. In some embodiments, the citric acid slurry further comprises about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, or about 5% w / w of seeds of crystalline form 1 of compound I. In some embodiments, the % w / w is based on the expected amount of compound I. In some embodiments, the % w / w is based on the amount of compound of formula 2. In some embodiments, the % w / w is based on the amount of compound of formula 1 used in the saponification reaction above.

[0105] In some embodiments, the citric acid slurry does not contain seed crystals of crystalline Form 1 of Compound I.

[0106] In some embodiments, the citric acid slurry is heated prior to the addition of the mixture comprising the compound of formula 2. In some embodiments, the citric acid slurry is heated to about 40° C. In some embodiments, the temperature of the slurry is maintained at about 40° C. throughout the addition of the mixture comprising the compound of formula 2. In some embodiments, “about 40° C” means 35° C. to 45° C. In some embodiments, “about 40° C” means 37° C. to 43° C. In some embodiments, the temperature of the slurry is maintained at a temperature of 37° C. to 43° C. throughout the addition of the mixture comprising the compound of formula 2. In some embodiments, the temperature of the slurry is constant throughout the addition of the mixture comprising the compound of formula 2 by slow addition of the mixture comprising the compound of formula 2. In some embodiments, the mixture comprising the compound of formula 2 is added to the citric acid slurry for about 1 hour, about 2 hours, about 3 hours, or more. In some embodiments, the mixture comprising the compound of formula 2 is added to the citric acid slurry over about 2 hours. In some embodiments, “about 2 hours” means about 1 hour 30 minutes to about 2 hours 30 minutes. In some embodiments, "about 2 hours" means from about 1 hour 45 minutes to about 2 hours 15 minutes. In some embodiments, "about 2 hours" means from 1 hour 30 minutes to 2 hours 30 minutes. In some embodiments, "about 2 hours" means from 1 hour 45 minutes to 2 hours 15 minutes. In some embodiments, the mixture containing the compound of Formula 2 is added to the citric acid slurry over a period of 1 hour 30 minutes to 2 hours 30 minutes. In other embodiments, the mixture containing the compound of Formula 2 is added to the citric acid slurry over a period of about 10 minutes to about 120 minutes.

[0107] In some embodiments, after the addition of the mixture containing the compound of formula 2 is added to the citric acid slurry, the resulting mixture is maintained or aged at a temperature of about 40° C. In some embodiments, “about 40° C” means 35° C. to 45° C. In some embodiments, “about 40° C” means 37° C. to 43° C. In some embodiments, the resulting mixture is maintained or aged for about 1 hour, about 2 hours, about 3 hours, or more. In some embodiments, the resulting mixture is aged for about 2 hours. In some embodiments, “about 2 hours” means about 1 hour 30 minutes to about 2 hours 30 minutes. In some embodiments, “about 2 hours” means about 1 hour 45 minutes to about 2 hours 15 minutes. In some embodiments, “about 2 hours” means 1 hour 45 minutes to about 2 hours 15 minutes. In some embodiments, the resulting mixture is aged for about 3 hours. In some embodiments, “about 3 hours” means about 2 hours 30 minutes to about 3 hours 30 minutes. In some embodiments, “about 3 hours” means about 2 hours 45 minutes to about 3 hours 15 minutes. In some embodiments, "about 3 hours" means between 2 hours 45 minutes and 3 hours 15 minutes. In some embodiments, after the addition of the mixture containing the compound of Formula 2 is added to the citric acid slurry, the resulting mixture is maintained at a temperature of about 40° C. for about 3 hours.

[0108] In some embodiments, the mixture is cooled prior to isolation. In some embodiments, the mixture is cooled to about 0° C. to about 10° C. In some embodiments, the mixture is cooled to about 10° C. In some embodiments, "about 10° C." means 5° C. to 15° C. In some embodiments, "about 50° C." means 7° C. to 13° C. In some embodiments, the mixture is cooled to 7° C. to 13° C. prior to isolation.

[0109] In some embodiments, the mixture is cooled immediately. In other embodiments, the mixture is cooled slowly. In some embodiments, the mixture is cooled for about 1 hour, 2 hours, 3 hours, 4 hours, or more. In some embodiments, the cooled mixture is maintained at a lower temperature for about 1 hour, 2 hours, 3 hours, 4 hours, or more. In some embodiments, the mixture is cooled to about 10° C. over a period of about 3 hours.

[0110] In some embodiments, crystalline Form 1 of Compound I is isolated by filtration.

[0111] In some embodiments, the isolated crystalline form 1 of compound I is washed with a suitable solvent. In some embodiments, the isolated crystalline form 1 of compound I is washed with a suitable solvent once, twice, three times, four times or more. In some embodiments, the isolated crystalline form 1 of compound I is washed with a suitable solvent up to four times. In some embodiments, the suitable solvent used for washing is tetrahydrofuran, methanol, ethanol, ethylene glycol, acetonitrile, water or a combination thereof. In some embodiments, the suitable solvent used for washing is methanol, water or a combination thereof. In some embodiments, each of the washings is performed with the same solvent. In other embodiments, some washings are performed with one suitable solvent, such as methanol, and other washings are performed with another suitable solvent, such as a 1:1 methanol / water mixture.

[0112] In some embodiments, the isolated crystalline form 1 of compound I is dried. In some embodiments, the isolated crystalline form 1 of compound I is dried under vacuum. In some embodiments, the isolated crystalline form 1 of compound I is dried at elevated temperature. In some embodiments, the isolated crystalline form 1 of compound I is dried at a temperature of about 40° C. In some embodiments, the isolated crystalline form 1 of compound I is dried at a temperature of about 35° C. to about 45° C. In some embodiments, the isolated crystalline form 1 of compound I is dried under vacuum at a temperature of about 35° C. to about 45° C. In some embodiments, the isolated crystalline form 1 of compound I is dried under vacuum at a temperature of about 35° C. to about 45° C. for about 3 hours to about 36 hours. In some embodiments, the isolated crystalline form 1 of compound I is dried under vacuum at a temperature of about 40° C. for about 16 hours.

[0113] In some embodiments, the isolated Compound I is isolated as crystalline Form 1 and shows no evidence of other forms. In some embodiments, the isolated Compound I is isolated as crystalline Form 1 and shows no evidence of crystalline Form 2.

[0114] In some embodiments, the inverse addition of a mixture comprising a compound of Formula 2 to a slurry comprising citric acid is more robust, scalable, predictable, and less expensive than previous methods of adding acid to a compound of Formula 2. The improved methods function to provide crystalline Form 1 without the stringent parameter requirements that remain unpredictable in earlier methods.

[0115] In some embodiments, crystalline Form 1 of Compound I is synthesized as outlined in the Examples.

[0116] Described herein are pharmaceutical compositions of compound Compound I that are substantially free of impurities. In some embodiments, the pharmaceutical compositions are substantially free of Compound I impurities. In some embodiments, the pharmaceutical compositions contain less than about 1% w / w of Compound I impurities. In some embodiments, the pharmaceutical compositions contain less than about 1% w / w, less than about 0.75% w / w, less than about 0.50% w / w, less than about 0.25% w / w, less than about 0.20% w / w, less than about 0.15% w / w, less than about 0.10% w / w, or less than about 0.05% w / w of Compound I impurities. In some embodiments, the amount of Compound I impurities is undetectable. In some embodiments, the amount of Compound I impurities is undetectable by NMR, HPLC, etc.

[0117] In some embodiments, the impurities of compound I include one or more degradants of compound I. In some embodiments, the impurities of compound I include one or more intermediates used in the synthesis of compound I. In some embodiments, the impurities of compound I include one or more intermediates used in the synthesis of compound I. [ka] or a combination thereof.

[0118] As used herein, "pharmacologically acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., does not cause undesirable biological effects or interact in a deleterious manner with any of the components of the composition in which it is contained, and that may be administered to an individual.

[0119] The term "pharmaceutical acceptable salt" refers to the cationic form of the therapeutically active agent combined with a suitable anion, or in an alternative embodiment, the form of the therapeutically active agent that consists of the anionic form of the therapeutically active agent combined with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M.Berge, L.D.Bighley, D.C.Monkhouse, J.Pharm.Sci.1977,66,1-19. P.H.Stahl and C.G.Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zuerich: Wiley-VCH / VHCA,2002. Pharmaceutical salts are useful in solid dosage forms because they are typically more soluble and more rapidly soluble in gastric and intestinal fluids than non-ionic species. Furthermore, their solubility is often a function of pH, allowing selective dissolution in one or another part of the gastrointestinal tract, an ability that can be manipulated as an aspect of delayed- and sustained-release behavior. Also, salt-forming molecules can be in equilibrium with neutral forms, allowing for tailored passage across biological membranes.

[0120] In some embodiments, the pharma- ceutically acceptable salt of compound I is obtained by reacting compound I with a base. In some embodiments, the base is an inorganic base. In such a situation, the acidic proton of compound I is replaced by a metal ion, such as lithium, sodium, potassium, magnesium, or calcium. Acceptable inorganic bases used to form salts with compound I include, but are not limited to, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as sodium salts, calcium salts, potassium salts, or magnesium salts. In some embodiments, the compounds provided herein are sodium salts of compound I.

[0121] Reference to pharmaceutically acceptable salts should be understood to include solvent addition forms. In some embodiments, solvates contain stoichiometric or non-stoichiometric amounts of solvent and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the methods described herein. Furthermore, the compounds provided herein may exist in unsolvated and solvated forms.

[0122] Therapeutic agents that can be administered to mammals, such as humans, must be prepared according to regulatory guidelines. Such government regulatory guidelines are called Good Manufacturing Practices (GMP). GMP guidelines outline acceptable levels of contamination of active therapeutic agents, such as, for example, the amount of residual solvent in the final product. Preferred solvents are those that are suitable for use in GMP facilities and consistent with industrial safety concerns. Solvent categories are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), “Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005).

[0123] Solvents are divided into three classes: Class 1 solvents are toxic and should be avoided; Class 2 solvents are solvents that have restricted use during the manufacture of therapeutic agents; Class 3 solvents are solvents that have low toxicity potential and low risk to human health. Data for Class 3 solvents show low toxicity in acute or short-term studies and negative genotoxicity studies.

[0124] Class 1 solvents to be avoided include benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethene; and 1,1,1-trichloroethane.

[0125] Examples of Class 2 solvents are acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, N-methylpyrrolidine, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene, and xylene.

[0126] Class 3 solvents, which have low toxicity, include acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.

[0127] Residual solvents in active pharmaceutical ingredients (APIs) originate from the manufacture of the APIs. In some cases, the solvents are not completely removed by the actual manufacturing techniques. The appropriate selection of solvents for the synthesis of APIs can enhance the yield or determine properties such as crystal morphology, purity and solubility. Therefore, the solvent is an important parameter in the synthesis process.

[0128] In some embodiments, the composition comprising Compound I comprises an organic solvent. In some embodiments, the composition comprising Compound I comprises a residual amount of an organic solvent. In some embodiments, the composition comprising Compound I comprises a residual amount of a Class 3 solvent. In some embodiments, the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran. In some embodiments, the Class 3 solvent is selected from ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropanol, and ethanol.

[0129] In some embodiments, the composition comprising Compound I comprises a detectable amount of an organic solvent. In some embodiments, the organic solvent is a Class 3 solvent.

[0130] In another embodiment is a composition comprising Compound I comprising a detectable amount of solvent that is less than about 1%, wherein the solvent is selected from acetone, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, ethanol, heptane, and 2-propanol. In a further embodiment is a composition comprising Compound I comprising a detectable amount of solvent that is less than about 5000 ppm. In yet a further embodiment is a composition comprising Compound I comprising a detectable amount of solvent that is less than about 5000 ppm, less than about 4000 ppm, less than about 3000 ppm, less than about 2000 ppm, less than about 1000 ppm, less than about 500 ppm, or less than about 100 ppm.

[0131] Unless otherwise stated, the following terms used in this application have the definitions set forth below. Use of the term "including" and other forms such as "include," "includes," and "included" is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0132] As used herein, the term "acceptable" with respect to a formulation, composition or ingredient means having no lasting deleterious effects on the general health of the subject being treated.

[0133] The term "modulate" as used herein means to interact with a target directly or indirectly to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

[0134] The term "modulator" as used herein refers to a molecule that interacts with a target directly or indirectly. Interactions include, but are not limited to, interactions of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an agonist.

[0135] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, the oral route.

[0136] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of an agent or compound administered to relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case is optionally determined using techniques such as dose escalation studies.

[0137] The terms "enhance" or "enhancing," as used herein, mean to increase or prolong either in potency or duration of a desired effect. Thus, in terms of enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0138] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates, such as chimpanzees, and other ape and monkey species; domestic animals, such as cows, horses, sheep, goats, pigs, and the like; domestic animals, such as rabbits, dogs, cats, and laboratory animals, including rodents, such as rats, mice, and guinea pigs. In one aspect, the mammal is a human.

[0139] The terms "treat", "treating" or "treatment" as used herein include alleviating, attenuating or ameliorating at least one symptom of a disease or condition, preventing further symptoms, inhibiting a disease or condition, e.g., halting the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating conditions caused by a disease or condition, or prophylactically and / or therapeutically arresting the symptoms of a disease or condition.

[0140] Pharmaceutical Compositions In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharma- ceutical acceptable inactive ingredients that facilitate the processing of active compounds into medicament-use preparations. Appropriate formulations depend on the route of administration selected. A summary of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), and such disclosures are incorporated herein by reference.

[0141] In some embodiments, the compounds described herein are administered in a pharmaceutical composition, either alone or in combination with a pharma- ceutically acceptable carrier, excipient, or diluent. Administration of the compounds and compositions described herein can be by any method that allows delivery of the compound to the site of action.

[0142] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is provided as a bolus, electuary, or paste.

[0143] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surface active agent or dispersant. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and formulated to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. Push-fit capsules can contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures, may be used. Dyes or pigments may be added to tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0144] It will be understood that in addition to the ingredients specifically mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, e.g., those suitable for oral administration may include flavoring agents.

[0145] Methods of Administration and Treatment Regimen In one embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are used in the preparation of medicaments for treating diseases or conditions in mammals that would benefit from the modulation of LPA1 receptor activity.The method for treating any of the diseases or conditions described herein in a mammal in need of such treatment comprises administering to said mammal a pharmaceutical composition comprising at least one compound disclosed herein or its pharmaceutically acceptable salt, active metabolite, prodrug or pharmaceutically acceptable solvate in a therapeutically effective amount.

[0146] In certain embodiments, the compositions containing the compounds described herein are administered for preventive and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to patients already suffering from a disease or condition in an amount sufficient to cure or at least partially halt at least one of the symptoms of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drug, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose-finding clinical trials.

[0147] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0148] In any of the foregoing aspects, there are further embodiments in which an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is (a) administered systemically to the mammal, and / or (b) administered orally to the mammal.

[0149] In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered at a dose selected from about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, and about 400 mg. In some embodiments, the dose is administered once a day. In some embodiments, the dose is administered twice a day. EXAMPLES

[0150] Abbreviation: Aq or aq: aqueous ACN or MeCN: Acetonitrile DCM: dichloromethane DSC: Differential scanning calorimetry DVS: Dynamic Vapor Sorption Et: Ethyl EtOAc: Ethyl acetate EtOH: Ethanol Equivalent or equivalent: equivalent FTIR: Fourier transform infrared h or hr: hours hrs: hours HPLC: High performance liquid chromatography LC-MS or LCMS or LC / MS: Liquid Chromatography-Mass Spectrometry M: mole MEK: Methyl ethyl ketone Me: Methyl MeOH: Methanol Me-THF or Methyl THF: 2-Methyltetrahydrofuran mins or min: minutes NaOH: Sodium hydroxide NMR: nuclear magnetic resonance RH: Relative humidity rt or RT: room temperature SCXRD: Single crystal X-ray diffraction ssNMR: solid state nuclear magnetic resonance TGA: Thermogravimetric analysis THF: Tetrahydrofuran vol: volume, typically used for reaction volumes or ratios of solvents w / w: weight ratio XRPD: X-ray powder diffraction

[0151] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0152] Example 1: Preparation of 2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I) The preparation of Compound I has been previously described (see WO 2009 / 135590, U.S. Pat. Nos. 8,362,073, 8,445,530, 8,802,720, and 9,328,071, each of which is incorporated by reference in its entirety).

[0153] Example 2: Preparation of Crystalline Form 1 of Compound I - Initial Optimized Method The preparation of crystalline Form 1 of Compound I has been previously described (see International Patent Application No. PCT / IB2021 / 000594 and U.S. Patent Application No. 17 / 463,369, each of which is incorporated by reference in its entirety). The preparation of crystalline Form 1 of Compound I includes the following steps: [ka]

[0154] a) Saponification: Methyl 2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylate (1a, 10 g, 22 mmol, 1 equiv) was dissolved in methanol (164 mL, 1.64 vol) and heated to 50° C. with stirring. Aqueous NaOH (1 M, 26 mL, 1.21 equiv) was added to the stirred solution over 30 min, followed by water (3 mL, 0.3 vol). The reaction was stirred at 60° C. for 3 h, at which point LCMS indicated complete reaction of 1a. The reaction mixture was cooled to 20° C. and filtered to remove insoluble material. The pH of the resulting solution was 13.2.

[0155] b) Acidification / Crystallization: The solution was acidified to pH 7.5 with 1 M citric acid (aq). The solution was seeded with Form 1 crystals (2% by weight), cooled to 10° C. over 3 hours, and maintained at 10° C. for 1 hour. The resulting suspension was filtered and the solid was washed with 1:1 water:methanol (2×5 volumes), followed by methanol (2×5 volumes). The solid was dried in a vacuum oven at 40° C. to give Compound I (9.2 g, 95%, Form 1 by XRPD).

[0156] Example 3: Large-Scale Preparation of Crystalline Form 1 of Compound I The process of Example 2 was repeated on a kilogram scale to identify manufacturing challenges for reliable production of Form 1. Control of the polymorphism of Compound I is difficult and requires a tightly controlled window of conditions to obtain Form 1. At neutral / acidic pH, Compound I is highly insoluble in most solvents, so the supersaturated solution (the final stage of production) is thermodynamically unstable and tends to crystallize vigorously and spontaneously (i.e., uncontrollably) as a mixture of polymorphs.

[0157] Precise control of the pH by sequential addition of citric acid is required. Citric acid is added carefully first to bring the pH to exactly neutral (i.e., to quench excess NaOH). The reaction is then seeded with Form 1. Citric acid is then added a second time to bring the pH to acid and release the free carboxylic acid compound I. Too high a pH during this process will result in dissolution of the seeds, while too low a pH will cause uncontrolled crystallization.

[0158] During this process, precise control of temperature is also required. If the temperature is too low (e.g., about 20°C), rapid crystallization is triggered, resulting in a mixture of Form 2 and Form 1. Temperatures above about 40°C favor Form 2. A "sweet spot" (still unstable) at 40°C with properly optimized seeding was found. The fine balance between temperature / seeding revealed the criticality of the conditions: (if left unseeded, the solution of Compound I will spontaneously crystallize). Moreover, spontaneous crystallization at 40°C can again result in Form 2.

[0159] The method of Example 2 relies on preventing a supersaturated solution of Compound I from self-crystallizing into a mixture of polymorphs using a narrow window of temperature and pH conditions.

[0160] a) Saponification: Compound 1a (1.00 equiv.) and methanol (16.40 V) are charged to reactor A at a target temperature of 20 °C (tolerance limit: 17-23 °C). The mixture is heated to a target temperature of 50 °C (47-53 °C) and 1 M sodium hydroxide solution (1.21 equiv.) is added while maintaining the temperature at approximately 50 °C (47-60 °C). The sodium hydroxide transfer line is rinsed with purified water (0.22 V) and the resulting reaction mixture is heated to 60 °C (57-63 °C) and stirred at 60 °C (57-63 °C) for 3 h (2 h 45-3 h 15). The progress of the reaction is monitored and if the remaining starting material is greater than 1.0%, the reaction time is extended by 1 h and resampled. Once the reaction is complete, the reaction mixture containing compound 2a is cooled to 20 °C (17-23 °C). The resulting solution is passed through a polished filter (0.3 μm) into reactor B. Rinse reactor A, filter, and transfer line with methanol (0.50 C) and heat the solution to 40 °C (37-43 °C).

[0161] b) Acidification / Crystallization: Add citric acid solution (1 M, about 0.127 equivalents) to the solution in reactor B (from step a). Adjust the pH of the solution to pH 8.0 (7.5-8.5). If the pH stabilizes above 8.5, add additional 1 M citric acid solution in 0.05 equivalent increments. Add a separate suspension of seed crystals of crystalline form 1 of compound I (about 2% w / w, 60 g / L) in methanol to the mixture in reactor B and stir the resulting mixture at 40 °C (37-43 °C) for 15 minutes (15-25 minutes). After ensuring that the seed crystals have not dissolved, add the remaining 1 M citric acid solution (about 1.189 equivalents) while maintaining the temperature at 40 °C (37-43 °C). The reaction mixture is stirred at 40°C (37-43°C) for 3 hours (2h45-3h15) and then cooled to 10°C (7-13°C) within 3 hours (2h45-3h15).

[0162] Isolation: The mother liquor is filtered and the cake is washed with a methanol:purified water mixture (1:1) (2 x 5.00 V). The cake is further washed with methanol (2 x 5.00 V). The wet solid is dried under full vacuum at 40 °C (37-43 °C) for 3 h (3-36 h) to constant weight. The isolated solid is the undesired crystalline form 2 of compound I as confirmed by XRPD, DSC and IR.

[0163] As demonstrated in this example, even with careful control of temperature, pH and time, the process is highly unstable.

[0164] Example 4: Improved Preparation of Crystalline Form 1 of Compound I - Inverse Addition to Citric Acid [ka] Step (1) - Compound 2a: Compound 1a (1.00 equiv.) and methanol (16.91 V) are charged to reactor A at a target temperature of 20 °C (tolerance limit: 15-25 °C). The mixture is heated to a target temperature of 50 °C (47-53 °C) and 1 M sodium hydroxide solution (1.21 equiv.) is added while maintaining the temperature at approximately 50 °C (47-60 °C). The sodium hydroxide transfer line is rinsed with purified water (0.12 V) and the resulting reaction mixture is heated to 60 °C (57-63 °C) and stirred at 60 °C (57-63 °C) for 2 h (1 h 45 - 2 h 15). Monitor the progress of the reaction and if the remaining starting material is greater than 1.0%, extend the reaction time by 1 h and resample. Once the reaction is complete, the reaction mixture containing compound 2a is cooled to 40 °C (37-43 °C) to prepare it for the next step.

[0165] Step (2) - Crystalline Form 1 of Compound I: Charge reactor B with 1M citric acid solution in methanol (1.36 equivalents of citric acid) and seed crystals of crystalline Form 1 of Compound I (1% w / w). Heat the resulting mixture to a target temperature of 40°C (tolerance limit: 37-43°C). Charge the reaction mixture (step (1)) containing Compound 2a from reactor A through a 0.3 μm polished filter into the citric acid mixture in reactor B within 2 hours (1 h 30 min - 2 h 30 min) while maintaining the temperature at 40°C (37-43°C). Rinse the transfer line with methanol (0.50 V). Stir the resulting mixture at 40°C (37-43°C) for 3 hours (2 h 30 - 3 h 30) and then cool to 10°C (7-13°C) within 3 hours (2 h 30 - 3 h 30).

[0166] Isolation: Filter the mixture and wash the wet cake twice with a mixture of methanol / purified water (1:1, 2 x 5.16 V) and then twice with methanol (2 x 5.16 V). Dry the wet solid at 40 °C (35-45 °C) for 16 h (3-36 h) under full vacuum to constant weight.

[0167] The isolated solid is crystalline form 1 of compound I. Crystalline form 2 is not detectable.

[0168] Example 5: Process Parameter Study The aim of this study was to test its robustness to consistently obtain polymorphic form 1. For this purpose, seed concentration, carboxylate addition rate and stirring speed were tested at low and high levels / speeds. The effect of temperature cycling was also tested to generate larger crystals and facilitate filtration. Only minor modifications were made to optimize the hydrolysis step by shortening the saponification time, also limiting the time during which potential hydrolysis of the product could occur. The stability of the compound I suspension before isolation was then tested, and finally a simulation of drying in a rotary dryer was performed, similar to the previous two steps.

[0169] A total of eight tests were carried out on this process at laboratory scale, and the results are detailed in the following paragraphs.

[0170] Example 6: Robustness of reverse addition crystallization The promotion of different polymorphic forms is usually promoted by solvent composition, temperature, impurities, supersaturation or crystallization time. The reverse addition of carboxylate to citric acid solution causes the product to collapse, so crystallization time and supersaturation are no longer parameters that need to be carefully controlled. The solvent composition is defined and well controlled by the amount of methanol and water that enter the process. Therefore, the amount of seeds (Example 6a), the input time (Example 6b) and the stirring pattern (Example 6c) were tested. Finally, the test with the most favorable and most unfavorable conditions for the target polymorph was repeated (Example 6d) to confirm the results.

[0171] The results of these tests are shown in Table 1.

[0172] [Table 1-1]

[0173] Example 6a: Seed amount Reverse addition crystallization was successfully tested using 5% w / w seed. Since dosing the carboxylate salt into the citric acid solution causes the carboxylic acid to precipitate with a large excess of seeds, reduction of the initial seed bed was tested up to 1.0% w / w. Even under "worst case conditions" regarding addition time and stirring (see Table 1), crystalline form 1 was consistently obtained. Further reduction to 0.5% w / w, without any seeds, consistently yielded crystalline form 1.

[0174] Example 6b: Carboxylate Solution Addition Time Carboxylate dosing is intended to be carried out regularly over a period of approximately 2 hours in production. In case of transfer issues, a very fast dosing, i.e. 10 min with the addition funnel fully open, was tested in Test 2. The seed loading was kept at 1% w / w. Test 2 resulted in crystalline form 1 (based on IR) and a typical impurity profile for the isolated product. The duration of addition of the carboxylate solution to the seeded citric acid solution did not affect the polymorphic form for the extremes tested (10 min and 120 min) (see Table 1).

[0175] Example 6c: Effect of Stirring Localized hot spots may affect the polymorphism due to rapid dosing, insufficient stirring, or a combination of these two factors. For this reason, the effect of stirring was tested. Axial stirrers (pitched blade turbine) and radial stirrers (half-moon impeller) were investigated. Seed amount was kept at 1% w / w and carboxylate solution was dosed over 2 hours. Again, isolated product polymorph form 1 (based on IR) and typical impurity profile were obtained in all studies (see Table 1). Stirring with lower mixing efficiency did not affect the polymorphic form of Compound I crystals.

[0176] Example 6d: Replication Two replicates were performed using standard and "worst case" conditions (Table 2). In both cases, crystalline form 1 was obtained.

[0177] [Table 2-1]

[0178] These results confirm the robustness of the inverse crystallization process. The robustness of the process was experienced with respect to stirring efficiency and carboxylate dosing time. Two repetitions of the test at the best and less favorable conditions confirmed the results already obtained. In both cases, the Form 1 polymorph was obtained with an on-spec impurity profile.

[0179] Example 7: X-ray Powder Diffraction (XRPD) The following diffractometer was used, but other types of diffractometers can be used. Additionally, other wavelengths can be used and converted to Cu Kα. In some embodiments, synchrotron radiation X-ray powder diffraction (SR-XRPD) can be used to characterize the crystalline form.

[0180] "Diagram peaks", to the extent that they exist, are a subset of observed peaks that are used to distinguish one crystalline polymorph from another (polymorphs are crystalline forms having the same chemical composition). Characteristic peaks are determined by assessing, to within ±0.2° 2-theta, which observed peaks, if any, are present in one crystalline polymorph of a compound relative to all other known crystalline polymorphs of that compound.

[0181] STOE Stadi-P Transmission Diffractometer X-ray powder diffraction was performed on a STOE Stadi-P transmission diffractometer using Cu-Kα1 radiation. A linear position-sensitive detector was used for capillary measurements and flat-prepared samples, and an image plate position-sensitive detector (IP-PSD) was used for temperature-resolved XRPD, humidity-resolved XRPD, and robotic samples in 96-well plates. Measurement data were visualized and evaluated with the software WinXPOW V2.12.

[0182] 2-theta peak values ​​provided for XRPD are within ±0.2° 2-theta.

[0183] Characterization of the solid-state forms of compound I The X-ray powder diffraction pattern of crystalline form 1 of compound I is shown in Figure 1. The X-ray powder diffraction pattern of crystalline form 2 of compound I is shown in Figure 5. The X-ray powder diffraction pattern of crystalline form 3 of compound I is shown in Figure 8. The X-ray powder diffraction pattern of crystalline form 4 of compound I is shown in Figure 11.

[0184] Characterization of Crystalline Form 1 of Compound I The X-ray powder diffraction pattern of crystalline Form 1 of Compound I is shown in Figure 1. Characteristic XRPD peaks include 5.2±0.2° 2-theta, 9.0±0.2° 2-theta, 14.4±0.2° 2-theta, and 17.7±0.2° 2-theta.

[0185] Characterization of Crystalline Form 2 of Compound I The X-ray powder diffraction pattern of crystalline Form 2 of Compound I is shown in Figure 6. Characteristic XRPD peaks include 5.6±0.2° 2-theta, 7.6±0.2° 2-theta, 8.1±0.2° 2-theta, 9.4±0.2° 2-theta, 14.9±0.2° 2-theta, and 16.3±0.2° 2-theta.

[0186] Characterization of Crystalline Form 3 of Compound I The X-ray powder diffraction pattern of crystalline Form 3 of Compound I is shown in Figure 8. Characteristic XRPD peaks include 4.2±0.2° 2-theta, 6.8±0.2° 2-theta, 15.1±0.2° 2-theta, 25.0±0.2° 2-theta, 25.5±0.2° 2-theta, and 26.4±0.2° 2-theta.

[0187] In some embodiments, measurements of independently prepared samples on different instruments may result in variability of greater than ±0.2° 2-theta. Independently prepared samples of crystalline forms 1 and 2 were characterized on three additional diffractometers.

[0188] Malvern Panalytical Empyrean Diffractometer Equipment:Malvern Panalytical Type: Empyrean equipped with a Pixcel 1D detector, copper XRD tube, theta-theta goniometer and sample changer.

[0189] Characterization of Crystalline Form 1 of Compound I The X-ray powder diffraction pattern of crystalline Form 1 of Compound I is shown in Figure 15. Characteristic XRPD peaks include 5.2±0.2° 2-theta, 9.0±0.2° 2-theta, 14.4±0.2° 2-theta, and 17.7±0.2° 2-theta.

[0190] Characterization of Crystalline Form 2 of Compound I The X-ray powder diffraction pattern of crystalline Form 2 of Compound I is shown in Figure 16. Characteristic XRPD peaks include 5.6±0.2° 2-theta, 7.6±0.2° 2-theta, 8.1±0.2° 2-theta, 9.4±0.2° 2-theta, 14.8±0.2° 2-theta, and 16.2±0.2° 2-theta.

[0191] Stoe Stadi P,G.52.SYS.S072 Instrumentation and Measurement Parameters

[0192] [Table 7]

[0193] Sample preparation: A cylindrical volume determined by the washer and two pieces of foil was slightly overfilled with a small amount of sample and then smoothed with two glass slides to obtain a powder disk, which was then fixed in a Ni-coated metal sample holder.

[0194] Characterization of Crystalline Form 1 of Compound I The X-ray powder diffraction pattern of crystalline Form 1 of Compound I is shown in Figure 17. Characteristic XRPD peaks include 5.2±0.2° 2-theta, 9.0±0.2° 2-theta, 14.4±0.2° 2-theta, and 17.7±0.2° 2-theta.

[0195] Characterization of Crystalline Form 2 of Compound I The X-ray powder diffraction pattern of crystalline Form 2 of Compound I is shown in Figure 18. Characteristic XRPD peaks include 5.5±0.2° 2-theta, 7.5±0.2° 2-theta, 8.0±0.2° 2-theta, 9.4±0.2° 2-theta, 14.8±0.2° 2-theta, and 16.2±0.2° 2-theta.

[0196] An overlay of the XRPD of Form 1 (top spectrum) and Form 2 (bottom spectrum) is shown in FIG.

[0197] PANalytical X'Pert PRO MPD Diffractometer X-ray powder diffraction (XRPD, transmission mode): XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation generated using an Optix long fine focus source. An elliptical tilted multilayer mirror was used to focus the Cu Kα X-rays through the specimen onto the detector. Sample specimens were sandwiched between 3 μm thick films and analyzed in transmission geometry. Prior to analysis, silicon specimens (NIST SRM 640f) were analyzed to confirm that the observed position of the Si 111 peak matched the NIST certified position. A beam stop, short anti-scatter extension, and an anti-scatter knife edge were used to minimize background generated by air. Soller slits for the incident and diffracted beams were used to minimize divergence from axial spread. Diffraction patterns were collected using a scanning position sensitive detector (X'Celerator) positioned 240 mm from the specimen and Data Collector software v.5.5.

[0198] X-ray powder diffraction peak identification process: A rounding algorithm was used to round each peak to the nearest 0.1° or 0.01° 2θ depending on the instrument used to collect the data and / or the inherent peak resolution. Peak locations along the x-axis (° 2-theta) for both figures and tables were determined using TRIADS® v2.1.1 software and rounded to 1 or 2 significant decimal places based on the criteria listed above. Variability in peak locations was determined according to the USP discussion of variability in X-ray powder diffraction (USP-NF 2021, Issue 2, <941> , Characterization of Crystalline and Partially Crystalline Solids by X-Ray Powder Diffraction (XRPD), 1_GUID-14EBB55E-0D24-45A1-A84F-FE4DCAAEE3E8_1_en-US, formula before 2013) are given within ±0.2° 2-theta. In some embodiments, measurements of samples prepared independently on different instruments may result in variability greater than ±0.2° 2-theta. For the d-space listing, the wavelength used to calculate the d-spacings was 1.5405929 Å, Cu-Kα1 wavelength (Phys.Rev.A56(6)4554-4568(1997)).

[0199] Characterization of Crystalline Form 1 of Compound I The X-ray powder diffraction pattern of crystalline Form 1 of Compound I is shown in Figure 20. Characteristic XRPD peaks include 5.2±0.2° 2-theta, 9.0±0.2° 2-theta, 14.4±0.2° 2-theta, and 17.7±0.2° 2-theta.

[0200] Characterization of Crystalline Form 2 of Compound I The X-ray powder diffraction pattern of crystalline Form 2 of Compound I is shown in Figure 21. Characteristic XRPD peaks include 5.5±0.2° 2-theta, 7.5±0.2° 2-theta, 8.0±0.2° 2-theta, 9.4±0.2° 2-theta, 14.8±0.2° 2-theta, and 16.2±0.2° 2-theta.

[0201] XRPD Limit Testing Method Using the PANalytical X'Pert PRO MPD Diffractometer A non-limiting method development of an XRPD limit test for determining Form 2 in Form 1 drug substance is described. Specificity, the ability to unambiguously evaluate an analyte in the presence of components that might be expected to be present, was assessed by comparing the XRPD patterns of Forms 1 and 2. The specificity of Form 2 is good in Form 1 drug substance, as several peaks highlighted in Figure 22 can be used to quantitate Form 2 (lower spectrum) of Form 1 (top spectrum).

[0202] Generation of Calibration Model: Calibration standards containing 0-10% Form 2 in Form 1 were prepared by geometric mixing of the components without extraneous sample handling.

[0203] [Table 8]

[0204] An XRPD overlay of the calibration standards is shown in Figure 23. Peaks unique to Form 2 are highlighted (dotted line) and showed good linearity based on visual evaluation.

[0205] A spreadsheet was developed to calculate the peak areas at approximately 5.6°, 7.6°, and 8.1° normalized to the total peak area in the range of 4.0 to 25.5°.

[0206] The calibration curve is shown in Figure 24. The regression statistics along with the limits of detection (LOD) and quantitation (LOQ) are summarized below.

[0207] [Table 9]

[0208] [Table 10]

[0209] [Table 11]

[0210] The LOD and LOQ were calculated using the following formula: LOD = (3.3 × σ) / S LOQ = (10 × σ) / S where σ is the standard error of the linear regression and S is the slope of the calibration curve. The LOD and LOQ were calculated to be 1.0% and 2.8% (w / total), respectively.

[0211] Example 8: Differential Scanning Calorimetry (DSC) 9.1 Mettler DSC822e DSC measurements are carried out using a Mettler DSC822e (module DSC822e / 700 / 109 / 414935 / 0025). 40 μl Al crucibles with sealed lids and pinholes are used. All measurements are carried out with a nitrogen gas flow rate of 50 mL / min and a typical heating rate of 10 °C / min. The measurement data are evaluated via the software STARe V8.10.

[0212] 9.2 Perkin Elmer Diamond DSC DSC scans were obtained using a Perkin Elmer Diamond DSC. Samples were sealed in aluminum pans which were punctured to allow residual solvent to escape. Scans were obtained from 25-240°C at 10°C / min. The system was calibrated with indium (MP 156.6°C) and tin (MP 231.9°C) prior to use.

[0213] Characterization of the solid forms of compound I The DSC thermogram of crystalline Form 1 of Compound I is shown in FIG.

[0214] The DSC thermogram of crystalline Form 2 of Compound I is shown in FIG.

[0215] The DSC thermogram of crystalline Form 3 of Compound I is shown in FIG.

[0216] The DSC thermogram of crystalline Form 4 of Compound I is shown in FIG.

[0217] Differential Scanning Calorimetry (DSC) thermogram thermal events for the solid forms are as set forth in the table below.

[0218] [Table 12]

[0219] Example 9: Thermogravimetric Analysis (TGA) Method 10.1:Mettler TGA851e Thermogravimetric analysis is carried out using a Mettler TGA851e (module TGA / SDTA851e / SF1100 / 042). Measurements are carried out using 100 μl Al crucibles with sealed lids and holes and with a nitrogen gas flow of 50 mL / min. The measurement data are evaluated via the software STARe V8.10.

[0220] Method 10.2: Perkin Elmer Pyris Systems TGA was obtained on either a Perkin Elmer Pyris system. Samples were run from 25 to 200 °C at 10 °C / min. Barium chloride dihydrate was used to verify the accuracy of the system.

[0221] Characterization of the solid forms of compound I The TGA pattern of crystalline Form 1 of Compound I is shown in FIG.

[0222] The thermogravimetric analysis (TGA) patterns of the solid forms are as set forth in the table below.

[0223] [Table 13]

[0224] Example 10: Dynamic Vapor Sorption (DVS) Moisture sorption / desorption isotherms are recorded on a DVS-1 from SURFACE MEASUREMENT SYSTEMS. Two cycles are carried out at 25° C., increasing the relative humidity (RH) from 0 to 95% and back to 0%. The data are evaluated with the software DVSWin V.2.15.

[0225] The reversible water absorption in Form 1 of Compound I as determined by DVS is less than 1% (approximately −0.1% w / w between 0 RH and 95% RH).

[0226] Example 11: Fourier Transform Infrared (FTIR) Spectroscopy A Nicolet Magna 750 system was used to collect FTIR of the different solid forms of Compound I. Samples were prepared in 1% KBr and compressed at 10,000 lbs.

[0227] A partial Fourier transform infrared (FTIR) pattern overlay of crystalline forms 1, 2, 3 and 4 of Compound I is shown in Figure 13. The FTIR spectrum of crystalline form 1 has a peak at approximately 1739.6 cm -1 The FTIR spectrum of crystalline form 2 has a peak at about 1731.7 cm -1 The FTIR spectrum of crystalline form 3 has a peak at about 1722.0 cm -1 The FTIR spectrum of crystalline form 4 has a peak at about 1743.9 cm -1 It has a peak at

[0228] Example 12: Fourier transform Raman spectroscopy Raman spectra were acquired with a Raman module connected to a Nicolet 6700 IR spectrophotometer (Thermo Nicolet) equipped with an indium gallium arsenide (InGaAs) detector. Wavelength verification was performed using sulfur and cyclohexane. Each sample was prepared for analysis by placing it in a 13 mm diameter stainless steel cup and flattening the material. A Thermo Nicolet Step-and-Repeat accessory was used to rotate the cup during data acquisition. Three spectra were collected for each sample from the outer ring to the inner ring of the sample cup. Approximately 0.5 W of Nd:YVO4 laser power (1064 nm excitation wavelength) was used to irradiate the sample. Each spectrum was captured using a 2 cm -1 The data consisted of 512 simultaneous additive scans with a spectral resolution of 100 kHz. Three spectra of each sample were averaged using Omnic v7.2 (ThermoElectron).

[0229] The variation in Raman peak positions is based on the observed sharpness and 1 cm -1 Data point interval (2cm -1 Based on data acquisition using a resolution of ±2cm -1 Peak picking was performed using OMNIC software, version 7.2, Thermo Electron Corporation. The observed peaks include all Raman peaks of a given morphology, excluding very weak intensity peaks and broad peaks with poorly defined maxima.

[0230] The Raman spectrum of Form 1 is shown in FIG.

[0231] The Raman spectrum of Form 2 is shown in FIG.

[0232] Example 13: Solid-state nuclear magnetic resonance (ssNMR) spectroscopy All spectra were acquired using a Bruker DRX500 spectrometer equipped with an 11.7 Tesla magnet and a 4 mm diameter solid probe, using the following parameters:

[0233] [Table 14]

[0234] All spectra are indirectly referenced to tetramethylsilane using the radio frequency signal of adamantane. All samples were packed in a 4 mm OD rotor constructed of zirconia fitted with a Kel-F driving cap. A Gaussian convolution was applied to the free induction decays before Fourier transformation. GB=0.035 and LB=-10.0 Hz.

[0235] Characterization of Crystalline Form 1 of Compound I The ssNMR spectrum of crystalline Form 1 of Compound I is shown in Figure 4. Resonances characteristic of Form 1 are listed below. δc / ppm:23.35,36.40,44.12,45.70,54.41,65.40,71.58,110.97,114.45,121.00,124 .43,126.78,127.42,131.27,136.47,138.94,142.61,148.68,152.19,172.07,174.59

[0236] Characterization of Crystalline Form 2 of Compound I The ssNMR spectrum of crystalline Form 2 of Compound I is shown in Figure 7. Resonances characteristic of Form 2 are listed below. δc / ppm:20.59,37.04,44.03,46.84,55.25,66.34,71.74,111.25,116.90,122.48,123 .63,126.39,128.34,131.33,136.78,137.69,141.73,149.44,153.68,172.82,175.49

[0237] Characterization of Crystalline Form 3 of Compound I The ssNMR spectrum of crystalline Form 3 of Compound I is shown in Figure 10. Resonances characteristic of Form 3 are listed below. δc / ppm:21.72 # ,22.23# ,43.81,46.00,54.01,64.56,67.67,109.22,110.33,119.58,122.99,126.71,130.28 # ,138.46 # ,139.68,140.34,143.63,144.25,146.87,150.90,168.32,176.47 # A broadened or split signal whose shape or chemical shift may change.

[0238] Characterization of the amorphous form of compound I The ssNMR spectrum of the amorphous form of Compound I is shown in FIG.

[0239] Example 14: Stability of solid forms The physical stability of Forms 1, 2, and 3 was investigated at 80° C. / 75% RH to determine if interconversion was observed. After being stressed in open glass vials for 1 week, samples were examined by FTIR.

[0240] No changes in the FTIR spectra were observed for either form, suggesting that these forms are relatively stable in the solid state.

[0241] Example 15: Solubility Studies The solubility of the different polymorphs was measured in phosphate buffer at pH 7.4 at 25° C. Samples were analyzed for each form as a function of time to determine the equilibrium value. The residual solids from each sample were analyzed to ensure that the form did not change during the experiment. The concentration (mg / mL) versus time data is listed below for each form.

[0242] [Table 15]

[0243] The equilibrium solubility values ​​at 24 hours show that Forms 3 and 4 are more than twice as soluble as Form 1. The 24 hour result for Form 2 was more than 30% greater than Form 1.

[0244] It should be noted that the analysis of the residual solid did not show polymorphic transformation during the experiment. The data of Forms 3 and 4 are equivalent within experimental error.

[0245] Example 16: Single Crystal X-ray Diffraction (SCXRD) of Crystal Form 1 of Compound I Crystallization of Compound I from propyl acetate gave crystals - 0.5×0.04×0.02 mm 3 in size - which were sealed in a Lindemann glass capillary. The X-ray diffraction data were collected on a Bruker / AXS three-circle diffractometer equipped with a SMART APEX area detector, a low-temperature device (model LT 2) and a molybdenum-K α rotating anode generator, operating at 50 kV / 120 mA and adjusted to a fine focus of 0.5 x 5 mm 2 . ω-scans were applied with a step width of 0.3° and an exposure time of 60 seconds using the program package SMART V 5.628 (Bruker AXS, 2001) to collect data frames. Data processing with the program SAINT+ Release 6.45 (Bruker AXS, 2003) gave 6452 reflections (θ min = 2.04, θ max = 28.06; -8 < h < 8, -7 < k < 13, -22 < l < 22), of which 4753 reflections were unique (R int = 0.0829, R σ = 0.2353). The cell parameters were refined using 720 reflections. The phase problem was solved by the direct method using the XS module of SHELXTL 6.14 (Bruker AXS, 2000).

[0246] The structure was refined by the least-squares method ((F o 2 - F c 2 ) 2 minimization) using the XL module of SHELXTL 6.14 (Bruker AXS, 2000). The positions of all H atoms were determined from a difference Fourier synthesis map, S goodness of fit=0.780,R all data =0.2189(R obs.data =0.0536 for 1479 reflections with |F obs |>4σ,wR2 all data =0.1080,wR2 obs.data = 0.0759). The largest unassigned peak in the difference map is 3 This corresponds to -0.193 electrons versus +0.162 electrons per unit area. The average estimated standard deviation (esd) for CC bonds is 0.005 Å, for OC bonds is 0.004 Å, for NC bonds is 0.004 Å, and for CH bonds is 0.03 Å. The average esd for CCC bond angles is 0.4, and for CCCC torsion angles is 0.5°.

[0247] The crystal structure of crystalline Form 1 of Compound I was determined at 293 K and a summary of the structural data can be found in Tables 1 and 2.

[0248] [Table 1-2]

[0249] [Table 2-2]

[0250] [Table 2-3]

[0251] Example 17: Single Crystal X-ray Diffraction (SCXRD) of Crystalline Form 2 of Compound I Crystallization of compound I from N-methyl-2-pyrrolidone / methanol yielded size- 0.6 × 0.2 × 0.2 mm 3 Crystals of 1,2-dichloro-1,2,3,4-tetrafluoroethylene (1,2,4-tetrafluoroethylene) were obtained and sealed in Lindemann glass capillaries. X-ray diffraction data were obtained using a SMART APEX area detector, a cryogenic device (model LT 2), and a copper-K ion exchanger operated at 45 kV / 650 μA. αCollected on a Bruker / AXS three-circle diffractometer equipped with a microfocus generator and a focused beam Montel multilayer optic with an image focus spot diameter of about 250 μm (Wiesmann et al., 2007). ω-scans were applied with a step width of 0.3° and an exposure time of 5 s using the program package SMART V 5.628 (Bruker AXS, 2001) to collect data frames. Data processing with the program SAINT+ Release 6.45 (Bruker AXS, 2003) yielded 23571 reflections (θ min =2.80, θ max =69.16; -7 < h < 6, -28 < k < 26, -34 < l < 38), of which 4163 reflections were unique (R int =0.0242, R σ =0.0190). Refinement of the cell parameters was carried out using 99 local cell parameter determinations observed during data integration. Empirical absorption correction was applied using the program SADABS, a module of SAINT 6.45 (Bruker AXS, 2003). The phase problem was solved by the direct method with the XS module of SHELXTL 6.14 (Bruker AXS, 2000).

[0252] The structure was refined by least-squares minimization ((F o 2 - F c 2 ) 2 ) using the XL module of SHELXTL 6.14 (Bruker AXS, 2000). The positions of all H atoms were determined experimentally from a difference Fourier synthesis map, S goodness of fit =1.039, R all data =0.0490 (R obs.data =0.0379 for 3283 reflections with |F obs | > 4σ, wR2 all data =0.1041, wR2 obs.data =0.0971). The largest unassigned peak in the difference map was Å 3This corresponds to -0.179 electrons versus +0.185 electrons per unit. The average estimated standard deviation (esd) for CC bonds is 0.002 Å, for OC bonds is 0.002 Å, for NC bonds is 0.002 Å, and for CH bonds is 0.02 Å. The average esd for CCC bond angles is 0.2, and the average esd for CCCC torsion angles is 0.2°.

[0253] The crystal structure of crystalline Form 2 of Compound I was determined at 293 K and a summary of the structural data can be found in Tables 3 and 4.

[0254] [Table 3]

[0255] [Table 4-1]

[0256] [Table 4-2]

[0257] The experimentally determined powder diffraction pattern is in agreement with that calculated from the crystal structure.

[0258] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are to be included within the spirit and scope of this application and the appended claims.

Claims

1. 2-(4-Methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I): 【Chemistry 24】 1. A process for the preparation of crystalline form 1 of The method comprises: (1) In a suitable solvent, a compound of formula 2: 【Chemistry 25】 wherein M ＋ is Na ＋ , K. ＋ , or Li ＋ a compound of formula 2, to a slurry of citric acid; (2) isolating the crystalline Form 1 of Compound I by filtration; 1. A method wherein crystalline Form 1 of Compound I is characterized as having an X-ray powder diffraction (XRPD) pattern with peaks at 5.2±0.2° 2-theta, 9.0±0.2° 2-theta, 14.4±0.2° 2-theta, and 17.7±0.2° 2-theta, when measured using Cu(Kα) radiation.

2. 2. The method of claim 1, wherein the suitable solvent in step (1) is tetrahydrofuran, methanol, ethanol, ethylene glycol, acetonitrile, water, or a combination thereof.

3. 10. The method of claim 1, wherein the suitable solvent in step (1) is a mixture of methanol and water.

4. 10. The method of claim 1, wherein the mixture containing the compound of formula 2 is a solution.

5. 10. The method of claim 1, wherein the citric acid slurry comprises citric acid in a suitable solvent.

6. 10. The method of claim 1, wherein the citric acid slurry comprises citric acid in a solvent selected from tetrahydrofuran, methanol, ethanol, ethylene glycol, acetonitrile, water, or combinations thereof.

7. 10. The method of claim 1, wherein the citric acid slurry comprises citric acid in methanol.

8. 10. The method of claim 1, wherein the slurry comprises at least 1.0 equivalent of citric acid relative to the amount of the compound of Formula 2.

9. 10. The method of claim 1, comprising about 1.2 equivalents to about 1.5 equivalents of citric acid relative to the amount of the compound of formula 2.

10. 10. The method of claim 1, wherein the concentration of the citric acid in the slurry is from about 0.5M to about 1.5M.

11. 11. The method of claim 10, wherein the concentration of the citric acid in the slurry is about 1.0 M.

12. 10. The method of claim 1, wherein the citric acid slurry comprises about 1.32 equivalents of citric acid relative to the amount of the compound of Formula 2 in methanol at a concentration of about 1.0 M.

13. 10. The method of claim 1, wherein the citric acid slurry further comprises up to about 10% w / w of Compound I crystalline Form 1 seeds.

14. 14. The method of claim 13, wherein the citric acid slurry further comprises 0% to about 5% w / w of Compound I crystalline Form 1 seeds.

15. 14. The method of claim 13, wherein the citric acid slurry further comprises about 0.5% to about 5% w / w of Compound I crystalline Form 1 seeds.

16. 14. The method of claim 13, wherein the citric acid slurry further comprises about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, or about 5% w / w of crystalline Form 1 of Compound I seeds.

17. 10. The method of claim 1, wherein the citric acid slurry is heated to a temperature of about 40°C.

18. 10. The method of claim 1, wherein the mixture containing the compound of Formula 2 is added to the citric acid slurry over a period of about 10 minutes to about 120 minutes.

19. 10. The method of claim 1, wherein after the addition of the mixture containing the compound of Formula 2 is added to the citric acid slurry, the resulting mixture is maintained at a temperature of about 40° C. for about 3 hours.

20. 10. The method of claim 1, wherein the crystalline Form 1 of Compound I isolated after step (2) is further washed with a suitable solvent up to four times.

21. 21. The method of claim 20, wherein the suitable solvent used for washing is methanol, water, or a combination thereof.

22. 10. The method of claim 1, wherein the crystalline Form 1 of Compound I isolated after step (2) is further dried under vacuum.

23. 23. The method of claim 22, wherein the crystalline Form 1 of Compound I isolated after step (2) is further dried under vacuum at a temperature of about 35° C. to about 45° C. for about 3 hours to about 36 hours.

24. 23. The method of claim 22, wherein the crystalline Form 1 of Compound I isolated after step (2) is further dried under vacuum at a temperature of about 40° C. for about 16 hours.

25. 10. The method of claim 1, further comprising a cooling step, wherein the mixture obtained after step (1) is cooled prior to the isolation of crystalline Form 1 of Compound I in step (2).

26. 26. The method of claim 25, wherein the mixture obtained after step (1) is cooled to about 10°C.

27. 26. The method of claim 25, wherein the mixture obtained after step (1) is cooled to about 10°C over a period of about 3 hours.

28. The mixture containing the compound of formula 2 is a mixture containing the compound of formula 1: 【Chemistry 26】 wherein R １ is methyl or ethyl in a suitable solvent The method according to claim 1, wherein the compound is obtained by saponification of the ester moiety of

29. 29. The method of claim 28, wherein the suitable solvent for the saponification comprises tetrahydrofuran, methanol, ethanol, ethylene glycol, acetonitrile, water, or a combination thereof.

30. 29. The method of claim 28, wherein the suitable solvent for the saponification comprises a mixture of methanol and water.

31. 29. The method of claim 28, wherein the compound of formula 1 is dissolved in a suitable solvent to obtain a solution before saponification.

32. 32. The method of claim 31 , wherein the suitable solvent is tetrahydrofuran, methanol, ethanol, ethylene glycol, acetonitrile, water, or a combination thereof.

33. 32. The method of claim 31 , wherein the suitable solvent is methanol.

34. 32. The method of claim 31, further comprising heating the resulting solution of the compound of Formula 1 to a temperature of about 50°C prior to saponification.

35. The saponification is of the formula M-OH, where M-OH is NaOH, KOH, or LiOH, and M ＋ are respectively Na ＋ , K. ＋ , or Li ＋ 29. The method of claim 28, comprising a metal hydroxide base having the formula M-OH,

36. 36. The method of claim 35, wherein the metal hydroxide base is added as an aqueous solution.

37. 37. The method of claim 36, wherein the concentration of the metal hydroxide base in water is from about 0.5 M to about 5.0 M.

38. 37. The method of claim 36, wherein the concentration of the metal hydroxide base in water is about 1.0 M.

39. 36. The method of claim 35, wherein the saponification comprises at least 1.0 equivalent of the metal hydroxide base relative to the amount of the compound of Formula 1.

40. 36. The method of claim 35, wherein the saponification comprises about 1.1 equivalents to about 1.25 equivalents of the metal hydroxide base relative to the amount of the compound of Formula 1.

41. 36. The method of claim 35, wherein the metal hydroxide base is NaOH.

42. 36. The method of claim 35, wherein the temperature of the saponification step is about 60°C.

43. 36. The method of claim 35, wherein the saponification step is carried out for at least 2 hours.

44. 36. The method of claim 35, wherein the saponification step is carried out for about 2 hours to about 4 hours.

45. The compound of formula 2 has the structure of compound 2a: 【Chemistry 27】 2. The method of claim 1, comprising:

46. 2-(4-Methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I): 【Chemistry 28】 1. A process for the preparation of crystalline form 1 of The method comprises: (1) Compound of Formula 1: 【Chemistry 29】 wherein R １ is saponified to the ester moiety of the compound of formula 1, which is methyl or ethyl in a suitable solvent, to give a compound of formula 2: 【Transformation 30】 wherein M ＋ is a suitable cation; and (2) adding the reaction mixture of step (1) to a slurry of citric acid; (3) isolating the crystalline Form 1 of Compound I by filtration; 1. A method wherein crystalline Form 1 of Compound I is characterized as having an X-ray powder diffraction (XRPD) pattern with peaks at 5.2±0.2° 2-theta, 9.0±0.2° 2-theta, 14.4±0.2° 2-theta, and 17.7±0.2° 2-theta, when measured using Cu(Kα) radiation.

47. The saponification is of the formula M-OH, where M-OH is NaOH, KOH, or LiOH, and M ＋ are respectively Na ＋ , K. ＋ , or Li ＋ 47. The method of claim 46, comprising a metal hydroxide base having the formula M-OH,

48. The saponification in step (1) a. obtaining a solution of the compound of formula 1 in a suitable solvent; b. optionally heating the solution of step (a); c) adding the metal hydroxide base as an aqueous solution to the solution of step (a) and heating the reaction mixture to obtain the reaction mixture containing the compound of Formula 2.

49. the suitable solvent in step (a) is methanol, and heating the solution of step (a) to about 50°C; 49. The method of claim 48.

50. the concentration of the metal hydroxide base in water in step (c) is about 1.0 M; and about 1.1 equivalents to about 1.25 equivalents of the metal hydroxide base are used in step (c) relative to the amount of the compound of formula 1; 49. The method of claim 48.

51. heating the reaction mixture of step (c) to about 60° C. for about 2 hours to about 4 hours; 49. The method of claim 48.

52. the metal hydroxide base in step (c) is NaOH; and The compound of formula 2 is compound 2a: 【Chemistry 31】 49. The method of claim 48 having the structure:

53. 47. The method of claim 46, wherein the citric acid slurry comprises about 1.2 equivalents to about 1.5 equivalents of citric acid relative to the amount of the compound of Formula 1 in methanol.

54. 47. The method of claim 46, wherein the concentration of the citric acid in the slurry is from about 0.5 M to about 1.5 M.

55. 55. The method of claim 54, wherein the concentration of the citric acid in the slurry is about 1.0 M.

56. 47. The method of claim 46, wherein the citric acid slurry comprises about 1.32 equivalents of citric acid relative to the amount of the compound of Formula 1 in methanol at a concentration of about 1.0 M.

57. 47. The method of claim 46, wherein the citric acid slurry further comprises up to about 10% w / w of Compound I crystalline Form 1 seeds.

58. 58. The method of claim 57, wherein the citric acid slurry further comprises about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, or about 5% w / w of crystalline Form 1 of Compound I seeds.

59. 47. The method of claim 46, wherein the mixture containing the compound of Formula 2 is added to the citric acid slurry over a period of about 10 minutes to about 120 minutes.

60. 47. The method of claim 46, wherein after the addition of the mixture containing the compound of Formula 2 is added to the citric acid slurry, the resulting mixture is maintained at a temperature of about 40° C. for about 3 hours.

61. 2-(4-Methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I): 【Chemistry 32】 1. A process for the preparation of crystalline form 1 of The method comprises: (1) Ester portion of compound methyl 2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylate (compound 1a): 【Transformation 33】 is saponified with NaOH in a suitable solvent to give sodium 2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylate (compound 2a): 【Transformation 34】 providing a reaction mixture comprising: (2) adding the reaction mixture of step (1) to a slurry of citric acid; (3) isolating the crystalline Form 1 of Compound I by filtration; 1. A method wherein crystalline Form 1 of Compound I is characterized as having an X-ray powder diffraction (XRPD) pattern with peaks at 5.2±0.2° 2-theta, 9.0±0.2° 2-theta, 14.4±0.2° 2-theta, and 17.7±0.2° 2-theta, when measured using Cu(Kα) radiation.

62. The saponification in step (1) a. obtaining a solution of compound 1a in methanol and heating it to a temperature of about 50° C.; b. adding about 1.1 equivalents to about 1.25 equivalents of NaOH relative to compound 1a as an about 1.0 M aqueous solution to the solution of step (a) to obtain a reaction mixture; c) heating the reaction mixture of step (b) to about 60° C. for about 2 hours to about 4 hours.

63. the citric acid slurry comprises about 1.2 equivalents to about 1.5 equivalents of citric acid relative to the amount of the compound of Formula 1 in methanol; the concentration of the citric acid in the slurry is about 1.0 M; and the citric acid slurry containing 0% to about 5% w / w seeds of crystalline Form 1 of Compound I; 62. The method of claim 61.

64. The citric acid slurry is heated to a temperature of about 40°C; adding a mixture containing a compound of Formula 2 to the citric acid slurry over a period of about 10 minutes to about 120 minutes; and maintaining the resulting mixture at a temperature of about 40° C. for about 3 hours; 62. The method of claim 61.

65. the crystalline Form 1 of Compound I isolated after step (3) is further washed twice with a mixture of methanol and water, followed by twice with methanol, and further dried under vacuum at a temperature of about 35° C. to about 45° C. for about 3 hours to about 36 hours; 62. The method of claim 61.

66. 10. The method of claim 1, further comprising preparing a pharmaceutical composition by mixing the crystalline Form 1 of Compound I with at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in the form of a solid form pharmaceutical composition.

67. The method of claim 66, wherein the pharmaceutical composition is in the form of a tablet, pill, or capsule.

68. The method described in claim 66, wherein the pharmaceutical composition is in the form of a tablet and contains about 50 mg to about 300 mg of crystalline form 1 of compound I.

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