Technical Field

The present invention relates to a novel crystalline polymorphic form of vismodegib designated as Form X and process for its preparation.

The invention further relates to pharmaceutical compositions comprising Form X and use of Form X in the treatment of cancer.

Background Art

Vismodegib is an oral Hedgehog signaling pathway inhibitor, which is approved for treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery and who are not candidates for radiation. Vismodegib is marketed by Genentech under the brand name ERIVEDGE ^® . Vismodegib is chemically designated as 2-chloro- V-(4-chloro-3-(pyridin-2- yl)phenyl)-4-(methylsulfonyl)benzamide and represented by the following chemical structure;

The preparation and therapeutic use of vismodegib have been described for the first time in European patent EP 1789390, according to which vismodegib is prepared by coupling 4- chloro-3-(pyridin-2-yl)aniline and 2-chloro-4-methylsulfonylbenzoic acid or by coupling 4- chloro-3-(pyridin-2-yl)aniline and 2-chloro-4-(methylsulfonyl)benzoyl chloride. Vismodegib may exist in different polymorphic forms.

European patent EP 1789390 discloses a crystalline free base of vismodegib, but polymorphic form of crystalline form is not defined or characterized. On the other hand, process for the preparation of said crystalline free base of vismodegib in European patent EP 1789390 was repeated in WO 2014195977. According to the teachings of European patent EP 1789390, prior art form of vismodegib was obtained by crystallizing vismodegib with acetone and ethyl acetate, then by recrystallizing from hot slurry of isopropyl acetate. The crystalline polymorphic form of vismodegib obtained by said process designated as Form I. The X-ray powder diffractogram (XRPD) of Form I was shown in Figure 1 of WO 2014195977.

WO2014195977 further discloses two polymorphic forms of vismodegib labeled as Form II, Form III and preparation thereof.

One another crystalline vismodegib polymorph Form SV has been disclosed in WO 2014147504.

The discovery of a new polymorph of an active ingredient provides an opportunity to improve its characteristics, increasing the possibilities available to a formulation specialist when developing a new pharmaceutical form, a drug with a particular release profile or a specific dissolution degree.

Based on these considerations, there still appears a need for new polymorphs of vismodegib having further improved physical and/or chemical properties. Hence it was thought worthwhile by the inventors of the present application to explore pharmaceutically novel polymorphs of vismodegib with good chemical purity and improved stability characteristics, which may further improve the characteristics of vismodegib in finished medicinal product.

Summary of the invention

The object of the present invention is to provide a new polymorphic form of vismodegib and process for the preparation of this novel polymorphic form of vismodegib.

Another object of the present invention is to provide pharmaceutical compositions comprising new polymorphic form of vismodegib.

Technical Problem

Active pharmaceutical ingredients (APIs) are individual components or mixture of components that are used as a part of a finished pharmaceutical drug or medicinal product, where they provide the pharmacological activity.

Research and development projects in the pharmaceutical industry mainly aim to investigate different possible synthetic routes, key intermediates, reaction steps, impurity profile, particle size, particle shape and polymorphism to produce these APIs with higher efficiency. Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties. The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid.

The relationship between polymorphic forms of pharmaceutically active substance and pharmaceutical product is well known in the pharmaceutical industry. Pharmaceutical formulation is affected by polymorphic form of the pharmaceutically active substance.

It is a well known fact that different polymorphic forms of the same drug may have substantial differences in certain pharmaceutically important properties such as dissolution characteristics, bioavailability patterns, handling properties, solubility, flow characteristics and stability. These different physical forms may also have different particle size, hardness and glass transition temperatures.

The discovery of new polymorphic forms and solvates of an active pharmaceutical ingredient provides a new opportunity to improve the performance characteristics of pharmaceutical finished product, the development of new polymorphic forms is always encouraged.

Therefore, there is a need to develop novel polymorphic forms of vismodegib having advantageous properties which are useful and well suitable for the preparation of various pharmaceutical compositions.

Solution to Problem

In an embodiment invention relates to a novel solid form of vismodegib.

In another embodiment, this new form of vismodegib, besides being stable, meet the pharmaceutical requirements such as storage, shelf life, solubility and high purity.

Description of embodiments

A first aspect of the present invention relates to a novel polymorphic form of vismodegib. This new anhydrous form hereinafter is referred as crystalline Form X of vismodegib. Form X is characterized by an XRPD pattern having characteristic peaks at 9.37 ± 0.2, 11.49 ± 0.2, 15.70 ± 0.2, 16.56 ± 0.2, 18.84 ± 0.2, 18.95 ± 0.2 and 23.85 ± 0.2 degree 2-theta. Furthermore, Form X of vismodegib can be characterized by an XRPD pattern with characteristic peaks at 10.61 ± 0.2, 12.10 ± 0.2, 15.94 ± 0.2, 17.27 ± 0.2, 21.36 ± 0.2, 23.56 ± 0.2, 25.85 ± 0.2 and 28.42 ± 0.2 degree 2-theta.

Form X is characterized by a powder X-ray diffraction pattern, as shown in figure 1.

Form X is also characterized by an IR spectrum, as shown in figure 3 and characterized by a DSC thermogram, as shown in figure 4. A second aspect of the present invention relates to a process for preparing novel polymorphic Form X of vismodegib.

The Form X according to the present invention may be obtained by: a) providing a solution of dissolving vismodegib in a suitable organic solvent, b) heating and stirring the solution at a suitable temperature, c) cooling the solution to room temperature, d) filtering and isolating the obtained solid, e) washing the obtained solid as pure crystalline vismodegib designated as Form X with C1-C5 alcohol.

Wherein suitable solvent in step (a) is selected from, 2-propanol, 1 -propanol, 1 -butanol, 2- butanol, tert-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert- butyl acetate, toluene, xylene, chloroform, dichloromethane, carbon tetrachloride, ethylene dichloride, chlorobenzene, acetonitrile, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran (THF), 1,4-dioxane, 2-methoxyethanol, A,A-di methyl forma midc (DMF), N, N- d i m c t h y 1 ac c t a m i dc (DMAc), N- m c t h y 1 p y ro 1 i do n c (NMP), pyridine, dimethylsulfoxide (DMSO), sulfolane, formamide, acetamide, propanamide, pyridine, formic acid, acetic acid, propionic acid, hexane, heptane, cyclohexane, cycloheptane and cyclooctane or mixtures thereof.

The suitable temperature used in step (b) is selected from room temperature to reflux temperature of the solvent used.

The degree of purity of the active ingredient and the resulting possible changes of the efficacy, further important properties for the pharmaceutical processing can be affected in an adverse manner.

The process of the present invention affords Form X of vismodegib in high purity and high yield. The Form X of vismodegib is obtained having purity greater than 99% by area percentage in HPLC.

Stability plays an important role in the drug development process. Stability of a pharmaceutical product may be defined as the capability of that particular formulation, in a specific container or closure system, to remain within its chemical, physical, microbiological, therapeutic and toxicological specifications to assure its attributed quality, e.g., identity, purity, strength etc. until drug expiry.

Stability of a pharmaceutical product is strongly influenced by changes in solid-state form of the API. The changes in solid state form of the API may be resulted from the conditions of product manufacturing process. Examples of processing that may cause polymorphic changes including grinding, milling, heating, and applying compression. Manufacturing conditions that include a solvent (e.g., wet granulation, polymorphs in solution, and polymorphs in suspension) may facilitate changes in the solid-state form of API. These variations comprising polymorphic transformations, hydrate/solvate formations and dehydration/desolvation reactions in the solid-state form of API, may cause stability problems in finished pharmaceutical products. Therefore, crystalline stability of API has a critical role on satisfying the essentialities of qualified pharmaceutical product and stable polymorphs of API should be used in pharmaceutical formulations.

For this aspect, crystalline stability of Form X of vismodegib was investigated under the following conditions: a sample was kept in an open flask at 105 °C for 30 days, packed samples were kept at 40 °C under 75% relative humidity (RH) and at 25 °C under 60% relative humidity (RH) for 6 months. The crystalline stability referred here, is the stability of a polymorphic form of API with respect to polymorph transformations, hydration, or amorphization through time under these conditions.

The crystalline stability of vismodegib Form X was investigated and determined by X-ray powder diffraction method. Results showed that any polymorphic transformation to another crystal form or any degradation in crystalline Form X did not occur. Crystalline Form X showed crystalline stability under dry heating at 105 °C for 30 days, at 40 °C / 75% RH and at 25 °C / 60% RH for 6 months.

The chemical stability of crystalline Form X of vismodegib is also important and its stability in finished product at room-temperature storage can be predicted from shorter-term storage under accelerated conditions of high temperature and humidity. In the present invention, samples of obtained crystalline Form X of vismodegib were kept under dry heating in open flask at 105 °C for 30 days in an oven, and in FDPE pack at 40 °C & 75% RH and at 25 °C & 60% RH for 6 months in stability chambers to test chemical stability. The chemical stability of the samples was determined by HPFC method. Table 1 shows the stability results of vismodegib Form X prepared according to the present invention. Form X samples stayed stable under all conditions without any change in the impurity profile and without increase in the impurity amounts.

Table 1. Vismodegib Form X stability test results

A third aspect of the present invention relates to pharmaceutical compositions comprising crystalline Form X of vismodegib along with a pharmaceutically acceptable carrier.

Brief description of the drawings: Fig. 1 shows the X-Ray Powder Diffraction (XRPD) pattern of crystalline Form X of vismodegib as obtained in example 1

Fig. 2 shows the X-Ray Powder Diffraction (XRPD) pattern of crystalline Form X of vismodegib as obtained in example 4

Fig. 3 shows the Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectra of crystalline Form X of vismodegib

Fig. 4 shows the Differential Scanning Calorimetry (DSC) thermogram of crystalline Form X of vismodegib

Instrumental parameters: DSC parameters:

Differential scanning calorimetry (DSC) thermograms were obtained using a differential scanning calorimeter (TA instrument, Waters, USA) by using the following instrument parameters; start temperature: 25 °C, final temperature: 350 °C and heating rate: 10 °C/min.

FTIR parameters:

Samples were measured as neat by ATR (Attenuated Total Reflectance) on Shimadzu FTIR Spectrometer IR Prestige-21 (Shimadzu Corporation, Kyoto, Japan) in the range of 600 - 4000 cm ^-1 with 20 scans and 4 cm ^-1 resolution.

PXRD Method of Analysis:

X-Ray powder diffractograms were measured using a Shimadzu LabX XRD-6100 X-ray diffractometer (Shimadzu Corporation, Japan) by using the following instrument parameters;

The measurement conditions were as follows:

Radiation: Cu (1.5406 A) Filter for Kb: Nickel Voltage: 40.0 kV Current: 30.0 mA

Scan range: 3.00 - 40.00° Scan mode: Continuous scan Scan speed: 2.07min Sampling pitch: 0.020°

Following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.

EXAMPLES

Preparation of new crystalline Form X of vismodegib Example 1

HBTU (2.78 g, 7.3 mmol, 1.5 equiv.) and triethylamine (2.05 mL, 14.7 mmol, 3.0 equiv.) were added into a mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (1.26 g, 5.3 mmol, 1.1 equiv.) and dichloromethane (20 mL), stirred at 20 - 25 °C for 20 min. Then, 4-chloro-3- (pyridin-2-yl)aniline (1.0 g, 4.8 mmol, 1.0 equiv.) was added. The reaction mixture was stirred at 20 - 25 °C for 24 h. After completion of the reaction, water (10 mL) was added, the solvent was evaporated in vacuo. Methanol (5 mL) was added onto the residue and the mixture was heated, stirred at 70 °C for 2 h. After cooling and stirring for 1 h at 20 - 25 °C, the mixture was filtered. The product crystals were washed with 2-propanol. Crude product in methanol (15 mL) was heated to 70 °C and stirred at this temperature for 3 h. After cooling and stirring for 1 day at 20 - 25 °C, the mixture was filtered, the product crystals were washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (1.5 g, 72.8%, 99.65% HPLC purity). XRD, DSC, FTIR.

Example 2

HBTU (27.8 g, 73 mmol, 1.5 equiv.) and triethylamine (20.5 mL, 147 mmol, 3.0 equiv.) were added into a dichloromethane (100 mL) mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (12.6 g, 53.7 mmol, 1.1 equiv.) and stirred at 20 - 25 °C for 20 min. Then, 4-chloro-3- (pyridin-2-yl)aniline (10.0 g, 48.8 mmol, 1.0 equiv.) was added and the reaction mixture was stirred at 20 - 25 °C for 24 h. After completion of the reaction, water (40 mL) was added and the solvent was evaporated in vacuo. Methanol (20 mL) was added onto the residue and the mixture was heated and stirred at 70 °C for 2 h. After cooling and stirring for 1 h at 20 - 25 °C, the mixture was filtered and product crystals were washed with 2-propanol. Methanol (35 mL) mixture of crude product was heated to 70 °C and stirred at this temperature for 2 h. After cooling and stirring for 1 h at 20 - 25 °C, the mixture was filtered, the product crystals were washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (15.7 g, 76.3%, 99.71% HPLC purity). XRD, DSC, FTIR

Example 3

HBTU (138.9 g, 366 mmol, 1.5 equiv.) and triethylamine (100.0 mL, 717 mmol, 3.0 equiv.) were added into a dichloromethane (300 mL) mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (74.5 g, 317 mmol, 1.3 equiv.) and stirred at 20 - 25 °C for 1 h. Then, 4-chloro-3- (pyridin-2-yl)aniline (50.0 g, 244 mmol, 1.0 equiv.) was added and the reaction mixture was stirred at 22 - 25 °C overnight. After completion of the reaction, water (160 mL) was added and the solvent was evaporated in vacuo. Methanol (80 mL) was added onto the residue and the mixture was heated and stirred at 70 °C for 1 h. After cooling and stirring at 20 - 25 °C overnight, the mixture was filtered, the product crystals were washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (93.8 g, 91.2%, 99.64% HPLC purity). Example 4

HBTU (13.89 g, 36.6 mmol, 1.5 equiv.) and triethylamine (10.2 mL, 73.2 mmol, 3.0 equiv.) were added into a dichloromethane (50 mL) mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (7.45 g, 31.7 mmol, 1.3 equiv.), then, 4-chloro-3-(pyridin-2-yl)aniline (5.0 g, 24.4 mmol, 1.0 equiv.) was added to the reaction mixture and stirred at 20 - 25 °C for 24 h. After completion of the reaction, water (20 mL) was added and the solvent was evaporated in vacuo. Methanol (10 mL) was added onto the residue and the mixture was heated and stirred at 70 °C for 1 h. After cooling and stirring for 1 h at 20 - 25 °C, the mixture was filtered and product crystals were washed with 2-propanol. Ethanol (15 mL) mixture of crude product was heated to 70 °C and stirred at this temperature for 1 h. After cooling and stirring overnight at 20 - 25 °C, the mixture was filtered, the product crystals were washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (7.32 g, 71.1%, 96.91% HPLC purity).

Example 5

HBTU (13.89 g, 36.6 mmol, 1.5 equiv.) and triethylamine (10.2 mL, 73.2 mmol, 3.0 equiv.) were added into a dichloromethane (100 mL) mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (7.45 g, 31.7 mmol, 1.3 equiv.) and stirred at 20 - 25 °C for 1 h. Then, 4-chloro-3- (pyridin-2-yl)aniline (5.0 g, 24.4 mmol, 1.0 equiv.) was added and the reaction mixture was stirred at 20 - 25 °C for overnight. After completion of the reaction, water (20 mL) was added and the solvent was evaporated in vacuo. Methanol (10 mL) was added onto the residue and the mixture was heated and stirred at 70 °C for 1 h. After cooling and stirring for 30 min at 20 - 25 °C, and then stirring for 2 h at 0 °C, the mixture was filtered and product crystals were washed with 2-propanol. 1-Propanol (15 mL) mixture of crude product was heated to 70 °C and stirred at this temperature for 1 h. After cooling and stirring at 20 - 25 °C overnight, the mixture was filtered, the product crystals were washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (7.05 g, 68.5%, 96.25% HPFC purity).

Example 6

HBTU (13.89 g, 36.6 mmol, 1.5 equiv.) and triethylamine (10.2 mF, 73.2 mmol, 3.0 equiv.) were added into a dichloromethane (100 mF) mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (7.45 g, 31.7 mmol, 1.3 equiv.) and stirred at 0 °C for 1 h. Then, 4-chloro-3-(pyridin-2- yl)aniline (5.0 g, 24.4 mmol, 1.0 equiv.) was added and the reaction mixture was stirred at 0 °C for 1 h then at 20 - 25 °C overnight. After completion of the reaction, water (20 mL) was added and the solvent was evaporated in vacuo. Methanol (10 mL) was added onto the residue and the mixture was heated and stirred at 70 °C for 1 h. After cooling and stirring at 20 - 25 °C for 33 min, and then stirring at 0 °C for 2 h, the mixture was filtered and product crystals were washed with 2-propanol. 2-Propanol (15 mL) mixture of crude product was heated to 70 °C and stirred at this temperature for 1 h. After cooling and stirring for 30 min at 20 - 25 °C and then for 2 h at 0 °C, the mixture was filtered, the product crystals were washed with 2- propanol and dried to afford white to off-white crystalline Form X of vismodegib (7.30 g, 70.9%, 97.48% HPLC purity).

Example 7

HBTU (13.89 g, 36.6 mmol, 1.5 equiv.) and triethylamine (10.2 mL, 73.2 mmol, 3.0 equiv.) were added into a dichloromethane (100 mL) mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (7.45 g, 31.7 mmol, 1.3 equiv.) and stirred at 0 °C for 30 min. Then, 4-chloro-3-(pyridin- 2-yl)aniline (5.0 g, 24.4 mmol, 1.0 equiv.) was added and the reaction mixture was stirred at 0 °C overnight. After completion of the reaction, water (20 mL) was added and the solvent was evaporated in vacuo. Methanol (10 mL) was added onto the residue and the mixture was heated and stirred at 70 °C for 1 h. After cooling and stirring for 33 min at 20 - 25 °C, and then stirring for 2 h at 0 °C, the mixture was filtered and product crystals were washed with 2- propanol. 1-Butanol (15 mL) mixture of crude product was heated to 70 °C and stirred at this temperature for 1 h. After cooling and stirring at 20 - 25 °C overnight, the mixture was filtered, the product crystals were washed with 2-propanol and dried to afford white to off- white crystalline Form X of vismodegib (4.23 g, 41.1%, 99.09% HPLC purity).

Example 8

HBTU (13.89 g, 36.6 mmol, 1.5 equiv.) and triethylamine (10.2 mL, 73.2 mmol, 3.0 equiv.) were added into a dichloromethane (100 mL) mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (7.45 g, 31.7 mmol, 1.3 equiv.) and stirred at 0 °C for 30 min. Then, 4-chloro-3-(pyridin- 2-yl)aniline (5.0 g, 24.4 mmol, 1.0 equiv.) was added and the reaction mixture was stirred at 0 °C for 1 h. After completion of the reaction, water (20 mL) was added and the solvent was evaporated in vacuo. Methanol (10 mL) was added onto the residue and the mixture was heated and stirred at 70 °C for 1 h. After cooling and stirring at 20 - 25 °C overnight, the mixture was filtered and product crystals were washed with 2-propanol. 1-Hexanol (15 mL) mixture of crude product was heated to 70 °C and stirred at this temperature for 1 h. After cooling and stirring for 1 h at 20 - 25 °C, the mixture was filtered, the product crystals were washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (6.48 g, 66.5%, 99.86% HPLC purity).

Example 9

The mixture of vismodegib (5 g) in dichloromethane (10 mL) was stirred at reflux temperature for 1 - 2 h and then stirred at 20 - 25 °C for 1 - 2 h. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.4 g, 88.0%, 99.90% HPLC purity).

Example 10

The mixture of vismodegib (5 g) in ethyl acetate (10 mL) was stirred at 70 °C for 1 h and then stirred at 20 - 25 °C for 1 h. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.6 g, 92.0%, 99.90% HPLC purity).

Example 11

The mixture of vismodegib (5 g) in acetonitrile (10 mL) was stirred at 70 °C for 1 h and then stirred at 20 - 25 °C for 1 h. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.6 g, 98.0%, 99.92% HPLC purity).

Example 12

The mixture of vismodegib (5 g) in acetone (10 mL) was stirred at 55 °C for 1 h and then stirred at 20 - 25 °C for 1 h. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.0 g, 80.0%, 99.94% HPLC purity).

Example 13

The mixture of vismodegib (5 g) in n-hexane (15 mL) was stirred at 70 °C for 1 h and then stirred at 20 - 25 °C for 1 h. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.6 g, 92.0%, 99.69% HPLC purity).

Example 14

The mixture of vismodegib (5 g) in n-hexane (20 mL) was stirred at 75 °C for 2 h and then stirred at 20 - 25 °C for 2 h. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.8 g, 96.0%, 99.76% HPLC purity).

Example 15

The mixture of vismodegib (5 g) in toluene (15 mL) was stirred at 110 °C for 1 h and then stirred at 20 - 25 °C for 1 h. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.6 g, 92.0%, 99.83% HPLC purity).

Example 16

The mixture of vismodegib (5 g) in chloroform (15 mL) was stirred at 70 °C for 1 h and then stirred at 20 - 25 °C for 1 h. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.0 g, 80.0%, 99.89% HPLC purity).

Example 17

The mixture of vismodegib (5 g) in tetrahydrofuran (15 mL) was stirred at 70 °C for 1 h and then stirred overnight at 20 - 25 °C. Product was isolated by filtration, washed with 2- propanol and dried to afford white to off-white crystalline Form X of vismodegib (2.6 g, 52.0%, 99.96% HPLC purity).

Example 18

The mixture of vismodegib (5 g) in isobutanol (15 mL) was stirred at 110 °C for 1 h and then stirred overnight at 20 - 25 °C. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.6 g, 92.0%, 96.76% HPLC purity).

Example 19

The mixture of vismodegib (5 g) in 1,2-propanediol (15 mL) was stirred at 100 °C for 1 h and then stirred overnight at 20 - 25 °C. Product was isolated by filtration, washed with 2- propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.5 g, 90.0%, 98.42% HPLC purity).

Example 20

The mixture of vismodegib (5 g) in methanol / N,N-dimethylformamide (15 mL / 3 mL) was stirred at 80 °C for 2 h and then stirred at 20 - 25 °C for 2 h. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.2 g, 84.0%, 99.62% HPLC purity).

Example 21

The mixture of vismodegib (5 g) in methanol / dimethyl sulfoxide (15 mL / 3 mL) was stirred at 80 °C for 2 h and then stirred at 20 - 25 °C for 2 h. Product was isolated by filtration, washed with 2-propanol and dried to afford white to off-white crystalline Form X of vismodegib (4.1 g, 82.0%, 99.58% HPLC purity).