Pharmaceutical compositions of 3-fluoro-5-(((1s,2ar)-1,3,3,4,4- pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1h- cyclopenta[cd]inden-7-yl)oxy)-benzonitrile

Abstract

Disclosed herein are compositions and formulations of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (Compound (I)), wherein Compound (I) has the structure: and methods of making and using such compositions and formulations.

Description

14. Final blend was filled into 3 size 0 capsules. 2. Dissolution Test and Profile of Fl and F2 in SGF 15          One capsule of each Fl and F2 was tested in simulated gastric fluid media without enzyme (SGF, pH 1.6; Figure 1) under dissolution parameters described in Table 5 below. Table 5 Dissolution Parameters Media Modified SGF (without enzyme) pH 1.6 Volume 900 mL Temperature 37 °C Apparatus Baskets Stirring Rate 75 rpm Sampling Timepoints 15, 30, 45, 60, 90, 120 min., 4-infinity spin 15 min. Sampling Volume 3 mL Result: As seen in Fig 1., micronization of the Compound (I) Form A provided almost 4X increase in release of Compound (I) relative to unmicronized Compound (I) Form (Fl). Based on results of Example 3, micronized Compound (I) Form A was used in the formulations below. 5 Example 4 Effect of Surfactant on Dissolution of Micronized Compound (I) Form A in Simulation Gastric Fluid (SGF) Surfactants sodium lauryl sulfate and Soluplus (Polyvinyl caprolactam-polyvinyl acetate-10 polyethylene glycol graft copolymer) were tested to determine effects of surfactants on dissolution of micronized Compound (I) Form A as follows. 1. Preparation of Capsule containing formulations comprising micronized Compound (I) Form A and sodium lauryl sulfate (F3) or Soluplus (F4) a. Composition of Capsule formulations comprising micronized Compound (I) Form 15 A with SLS (F3) or Soluplus (F4) are disclosed in Table 6 below: Table 6 Dry Blend with Surfactant Component mg per Capsule F3 F4 F3 w / w% F4 w / w% micronizedCompound (I) Form A PSD (pm): (D10:D50:D90 = 1:6:14) API 100 100 27.8% 27.8% Lactose monohydrate diluent 138 138 38.3% 38.3% Microcrystalline cellulose binder 50 50 13.9% 13.9% Sodium lauryl sulfate surfactant 50 13.9% Soluplus 50 13.9% Crospovidone disintegrant 18 18 5.0% 5.0% Silica flow aid 2 2 0.6% 0.6% Component mg per Capsule F3 F4 F3 w / w% F4 w / w% Magnesium stearate lubricant 2 2 0.6% 0.6% Total formula weight 360 360 100% 100% Capsule Size #0 F 1PMC b. Preparation of Formulations (F3) and (F4): 1. Weighed MCC, Lactose monohydrate and and SLS or Soluplus were added into a mortar and mixed with pestle for 2 min, making sure the inner wall of mortar was coated with excipients. Weighed micronized Compound (I) Form A was added, followed by addition of weighed Crospovidone. The mixture was mixted with pestle for 2 min and then screened through #40 mesh. 2. The blend was compressed into slugs and the slugs were crushed in a mortar and pestle. 3. The blend was screened through #40 mesh to give intra-granule mixture which was weighed. Theoretical weight of extragranular excipients was adjusted. 4.     Weighed Crospovidone was added into mortar. Mix with pestle for 1 min. 5.     Weighed Silica was added to the blend from Step 4, mixed for 1 min, and then screened through #40 mesh to give extra-granular blend. 6. Intra-granular blend was added to the extra-granular blend and then mixed for 2 min. 7. Weighed Magnesium Stearate was screened through #40 mesh and added to the blend of Step 6 and the blend was mixed for 2 min. 8.     360 mg of the final blend was filled into 3 size 0 capsules. 2. Dissolution Test and Profile of F3 and F4 in SGF One capsule each of F3 and F4 formulations was tested in a simulated gastric fluid media without enzyme (SGF, pH 1.6). The capsules were simultaneously tested in SGF media containing 0.1% polysorbate 80 (see figure 2) and compared against the Fl and F2 formulations. Dissolution Parameters Media 1) Modified SGF (without enzyme) pH 1.6 2) Modified SGF pH 1.6 with 0.1 w / v% polysorbate 80 Volume 900 mL Temperature 37 °C Apparatus Baskets Stirring Rate 75 rpm Sampling Timepoints 15, 30, 45, 60, 90, 120 min., -i-infinity spin 15 min. Sampling Volume 3 mL Result: As seen in Fig. 2, formulation containing micronized Compound (1) Form A and sodium lauryl sulfate (SLS) surfactant gave better release of Compound (I) than formulations 5 containing (i) micronized Compound (I) Form A and Soluplus® and (ii) micronized and unmicronized Compound (I) Form A alone. Dissolution curves of Fl and F2 from Fig 1 above were overlaid here. Example 5 10 Effect of Dry and Wet Granulation formulations with Intra and Extra granular components and varying amounts of SLS on Dissolution of Micronized Compound (I) Form A in Simulated Gastric Fluid (SGF) A. Dry Granulation formulations with varying amounts of SLS: 1. Composition of Dry Granulation formulations containing 11.3% (F5) and 5.6% 15   (F6) of SLS are disclosed in Table 7 below. Table 7 Dry Granulation formulation Component mg per Capsule w / w% w / w% F5 F6 F5 F6 Intragranular micronized Compound (I) Form A PSD (pm): (D10:D50:D90 = 1:6:14) 200 200 45.2% 45.2% Lactose monohydrate 130 155 29.4% 35.0% Hydroxypropylmethyl cellulose K4M 18 18 4.1% 4.1% Sodium lauryl sulfate 50 25 11.3% 5.6% Crospovidone 13 13 2.9% 2.9% Extra-granular Microcrystalline cellulose PH 102 15 15 3.4% 3.4% Crospovidone 12 12 2.7% 2.7% Silica 2.25 2.25 0.5% 0.5% Magnesium stearate 2.25 2.25 0.5% 0.5% Total formula weight 442.5 442.5 100% 100% Capsule size #0 HPMC 2. Preparation of Dry Granulation Formulations: In dry granulation formulation, the dry intragranular excipients, listed in Table 7 above, were mixed, then granulation was performed using the slugging technique, involving preparation 5 of an intermediate intra-granular phase blend of Compound (I) Form A, sodium lauryl sulfate, and diluent excipient, followed by compression into a compacted slug. The slug was then crushed, and the material was screened to produce densified granules. The granules were blended with extragranular excipients, listed in Table 7 above, to provide the final blend, which was filled into capsules. Both F5 and F6 dry blend formulations were filled into 10 size #0 HPMC capsules. 3. Dissolution Test and Profile of F5 and F6 in SGF Media 3) Modified SGF (without enzyme) pH 1.6 4) Modified SGF pH 1.6 with 0.1 w / v% polysorbate 80 Volume 900 mL Temperature 37 °C Apparatus Baskets Stirring Rate 75 rpm Sampling Timepoints 15, 30, 45, 60, 90, 120 min., +infinity spin 15 min. Sampling Volume 3 mL Result: As seen in Fig 3, dry granulation formulations F5 and F6 gave poor bioavailability of Compound (I) Form A. B, Wet Blend Granulation Formulations: A series of wet granulation tablets and capsules, F9, F13, F16, F17, F19, and F20, were formulated and tested in canine (beagle) bioavailability studies to determine relative bioavailability of above solid dosage formulations containing SLS vs. an aqueous suspension formulation used in GLP tox. 1.     Preparation of Aqueous Suspension of micronized Compound (I) Form A: a.     Micronized Compound (I) Form A was added to a glass beaker and 400 mL of deionized water was added. b. The mixture was heated to approximately 80 °C. c. 2.0 g of Methylcellulose (4000 cps) was slowly added to the hot water while stirring until it was well dispersed. d. The beaker was placed into an ice bath and stirring was continued until a solution was obtained. e. 0.4 mL Tween-80 was added and stirring was continued 1 hour. 2.     Preparation of Wet Granulation Formulations F9, F13, F16, F17, F19, and F20 A.    Composition of Wet Blend formulations F9, F13, F16, F17, F19, and F20 are disclosed in Table 8 below: Table 8 Component (mg) (F9) POF2* (F13) POB2 (F16) POE2* (F17) POA2 (F19) POD2 (F21) POG2* Wet granulation Wet granulation Wet granulation Wet granulation Wet granulation Wet granulation Tablet Tablet Tablet Tablet Capsule Capsule Intra-granular micronized Compound (I) Form A PSD (pm): (D10:D50:D 90= 1:6:14) 200 200 200 200 200 200 Starch - - - - - Pearlitol 100SD, Mannitol 124 - 124 124 - Lactose Monohydrat e, NF (fast flo 316) - 144 - - 124 124 Sodium lauryl sulfate, NF, EP, BP, JP 50 50 40 50 50 40 Crospovido ne, Polyplasdon eXL 18 - 18 - 18 18 Copovidone, Kollidon VA 64 10 18 10 20 10 10 Solution Copovidone, Kollidon VA 64 10 - 10 18 10 10 Component (mg) (F9) POF2* (F13) POB2 (F16) POE2* (F17) POA2 (F19) POD2 (F21) POG2* Wet granulation Wet granulation Wet granulation Wet granulation Wet granulation Wet granulation Tablet Tablet Tablet Tablet Capsule Capsule (granulati on Media) Water 33 40 40 40 - 40 Polysorbate 80 - - - - - - Sodium lauryl sulfate, NF, EP, BP, JP - - 10 - - 10 Extra-granular Pearlitol 100SD, Mannitol 15 - 15 - 15 15 MCC PH 102 - 15 - 15 - - Crospovido ne, Polyplasdon eXL 12 12 12 12 12 12 Colloidal silicon dioxide, Ph. Eur., NF, JP (Aerosil 200 Pharma) 2 2 2 2 2 2 Magnesium Stearate, Ph. Eur., NF, JP (Ligamed MF-2-K) 2 2 2 2 2 2 Total 443 443 443 443 443 443 B. Preparation of Wet granulation Formulations: al. Wet granulation tablets F9 and Fl6: 1. Copovidone was dissolved in water in a small beaker with a stir bar (for Fl6, SLS was also dissolved; see Table 8). 2. Weighed Pearlitol (Mannitol) and Sodium Lauryl Sulfate were mixted in a mortar with a pestle and the inside surface of the mortar was with covered by Pearlitol and Sodium Lauryl Sulfate. 3. Weighed micronized Compound (I) Form A was added and the dry blend was screened from #2 through #40 mesh. 4. Weighed Crospovidone and Copovidone were screened through #40 mesh and added to the mortar containing to the blend from Step 3 and the mixture was mixed for 3 min. 5. Granulation media (see Table 8; F9 is without SLS and F16 was with SLS)) was slowly added to the blend while mixing. After all solution was added, the blend was continued to mix for about 2 min to form wet granules. 6. The wet granules were transferred into a large weighing bowl and spread on the bowl evenly, and big lumps, if present, were broken up. 7. The weighing bowl was placed into an oven and dried at 50 °C for 2 h. 8. Large dried granules were gently broken in mortar if needed. 9. Weight of extra-granular excipients was adjusted based on the mass recovery yield of the intra-granules to keep the w / w % consistent per the formulation (outlined in Table 8). 10. Weighed Pearlitol, Crospovidone, and Silica were screened through #40 mesh, added to the dried intra-granules and mixed for 2 min. 11. Weighed and screened (#40 screen) Magnesium Stearate was added to the blend and mixed for 2 min. 12. Flowability of the final blend was visually assessed and manually compressed into tablet with tooling: Natoli 0.4062 with round bevel edge. a2. Wet granulation tablets F13 and Fl7; 1. Weighed Lactose or Mannitol (see Table 8) and SLS were added into a mortar and mixed with pestle for 2 min, making sure the inner wall of mortar was coated with the excipients. 2. Weighed micronized Compound (I) Form was added to the blend and the resulting dry blend was screened from #2 through #40 mesch. 3. Weighed Copovidone was screened through #40 mesh and then added to the mortar containing the blend and mixed with pestle for 3 min. 4. Granulation media (water only / see table 8) was slowly added to the blend while mixing. After all the solution was added, the blend was continued to mix for about 2 min to form wet granules. 5. The wet granules were transferred into a large weighing bowl and spread on the bowl evenly, and big lumps, if present, were broken up. 6. The weighing bowl was placed into an oven and dried at 50 °C for 2 h. 7. Large dried granules were gently broken in mortar if needed. 8. Weighed extra-granular excipients was adjusted based on the mass recovery yield of the intra- granules to keep the w / w % consistent per the formulation (outlined in Table 8). 9. Microcrystalline cellulose (MCC PH-102), Crospovidone and Silica were weighed and were screened through #40 mesh, then added to the dried intra-granules and mixed for 2 min. 10. Magnesium Stearate was weighed and screened (#40 screen) and added to the blend and mixed for 2 min. 11. Flowability of the final blend was visually assessed and the blend was manually compressed into tablet with tooling: Natoli 0.4062 with round bevel edge. a3. Wet granulation capsules F19 and F21: 1.     Copovidone and SLS were dissolved in water in a small beaker with stir bar. 2.     Weighed Pearlitol (Mannitol) and Sodium Lauryl Sulfate were mixted in a mortar with pestle and the inside surface of mortar was covered with Pearlitol and Sodium Lauryl Sulfate. 3. Weighed micronized Compound (I) Form A was added and the dry blend was screened through #40 mesh. 4. Weighed Crospovidone and Copovidone were screened through #40 mesh and added to the mortar containing to the blend from Step 3 and the mixture was mixed for 3 min. 5. For F19, granulation media was slowly sprayed to the blend of Step 4 while mixing. After all solution was added, the blend was continued to mix for about 2 min to form wet granules. For F21, granulation media (containing SLS) was sprayed into the blend of Step 4, followed by granulation. 6. The wet granules were transferred into a large weighing bowl and spread on the bowl evenly, and big lumps, if present, were broken up. 7. The weighing bowl was placed into an oven and dried at 50 °C for 2 h. 8. Large, dried granules were gently broken in mortar if needed. 9. Weight of extra-granular excipients was adjusted based on the mass recovery yield of the intra-granules to keep the w / w % consistent per the formulation (outlined in Table 8). 10. Weighed Pearlitol, Crospovidone, and Silica were screened through #40 mesh, added to the dried intra-granules and mixed for 2 min. 11. Weighed and screened (40 screen) Magnesium Stearate was added to the blend and mixed for 2 min. 12. The granules were manually filled into size 0 Gelatin capsules. 3. Dog PK studies with Wet granulation formulations a. Dog BA studies were done as crossover studies to evaluate pharmacokinetics of F9, F13, F16, F17, F19, and F20 formulations, following oral (PO) administration to male beagle dogs. Male beagle dogs were 8 month to 3 years old with body weights of 10.00-14.00 kg on the dosing date. The animals were housed in a 12-hour light / 12-hour dark cycle environment. The animals for PO administrations were food fasted overnight prior to dosing and were fed approximately 4 hours after dosing. All the animals had free access to water. A total of five male beagle dogs were dosed via the design as shown in Table 9. A single PO dose was administered to each dog for each of the different formulations in order by Group numbers. The washout period between any two consecutive dose groups was > 10 days. Blood samples (1.5 mL) were collected from each animal that was administered with F9, F13, F16, F17, F19, and F20 formulations at pre-dose, 15, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h and 72 h post dose via peripheral veins. The blood samples were placed into tubes containing EDTA-K3, and then centrifuged at 2000 g for 10 minutes at 4 °C to produce plasma. All samples were stored at -75±15°C until analysis. Table 9 Dog BA Study Dosing information Group Treatment Treatment Dose Level (mg / dog) Volume (mL / dog) Cone. (mg / mL) No. of Animals POC2 Suspension 200 50 4 5 males F9 POF2; Tablet 200 - - 5 males F13 POB2; Tablet 200 - - 5 males F17 POA2; Tablet 200 - - 5 males F16 POE2; Tablet 200 - - 5 males F19 POD2; Capsule 200 - - 5 males F21 POG2; Capsule 200 - - 5 males b. Results of the dog BA studies are disclosed in Table 10 below: Table 10 Group Formulation 200 mg Tmax (h) Cmax (ng / mL) AUC(0-72h) (h*ng / mL) / CV% AUC(0-72h) % of suspension AUC(o-qo) (h*ng / mL) tl / 2 (h) Suspension POC (preclinical tox formulation) 0.7 3790 83630 13% 100% 107730 33 F9 POF2; Wet granulation Tablet 1.5 1816 46933 16 56% 60657 37 F13 POB2; Wet Granulation Tablet 6.4 1007 37597 / 22% 45% 49306 39 F17 POA2; Wet Granulation Tablet 13 1329 48485 / 46% 58% 63685 36 F16 POE2; Wet granulation Tablet 6.8 2470 65033 22 78% 99287 64 F19 POD2; Wet Granulation (no SLS spray) Capsule 11 1622 61065 / 41% 73% ND 28 Group Formulation 200 mg Tmax (h) Cmax (ng / mL) AUC(0-72h) (h*ng / mL) / CV% AUC(0-72h) % of suspension AUC(o-oo) (h*ng / mL) tl / 2 (h) F21 POG2; Wet granulation (sprayed SLS) Capsule 1.4 3188 77026 30 92% 106710 37 In the dog oral fasted BA studies, the wet granulation capsules F19 and F21 had 73% and 92% bioavailability, respectively, compared to the SLS / suspension liquid formulation POC2 used in preclinical studies. F19 and F21 formulations were similar except that the F21 formulation had SLS dissolved into the granulation media that was sprayed on the intragranular blend while for F19, all SLS was added as a powder to the intragranular blend (and water with Copovidone (and no SLS) was used as the granulation media. The increase in bioavailabilty is attributed to the dissolved / sprayed SLS during granulation. From these results, wet granulation formulation of capsule F21 was chosen to move forward into the clinical studies. Example 6 Large Scale 50 and 200 mg Compound (I) Form A Formulations Using the wet granulation / SLS spray approach, granules only and granules with extragranular excepients (Extragranular) formualtions were prepared and their dissolution profiles were compared as described below. 1. Granules only Formulations: 50 mg and 200 mg strength capsules: a. Equipment_Used for Scale-up of Granules Only Formulations is disclosed in Table 11 below: Table 11 Process Equipment Name Model Manufacturer Key Technical Parameters Granulation Vertical Granulator Fuji 10 Fuji Stainless Steel 10L bowl Drying Oven DKN 600 Yamato Stainless Steel Milling Comil Model 197 Ultra Quadro 756 RPM 032R screen, Stainless Steel Blending V-Blender PK twin shell blender 8-quart (200 mg) Patterson Kelley Stainless Steel Encapsulation Encapsulator Bonapace InCap 3000cph Weight sorting Sade SP240 Weight Sorter SP240 AC Compacting LLC + / - 7% criteria b. Composition of 50 mg and 200 mg Granules only formulation are disclosed in Table 12 below: Table 12 Ingredients mg / unit mg / unit Theo Wt. (g) w / w % micronized Compound (I) Form A PSD (pm): (D10:D50:D90= 1:6:14) 50 200 2200 48.54 Pearlitol 100SD, Mannitol 31 124 1364 30.10 Sodium lauryl sulfate, NF 13.3 40 440.1 9.71 Crospovidone, NF (Polyplasdone XL) 4.5 18 198.0 4.37 Copovidone 4.38 17.5 192.6 4.25 Granulation Media Copovidone 0.63 2.5 110.1 0.61 Sodium lauryl sulfate, NF 2.5 10 27.65 2.43 Purified Water* - - 780.6 - Total 103.6mg 412.0mg 4532.5g 100% * 780.6grams, removed in drying c. Preparation of Granules: Sieved (30 mesh) micronized Compound (I) Form A, Pearlitol (Mannitol), sodium lauryl sulfate, crospovidone, and copovidone were transferred to a granulator and mixed to 5 prepare a dry blend. Granulation media was prepared by mixing sodium lauryl sulfate and copovidone in water until dissolved. Wet granules were prepared by spraying the granulation media onto the dry blend and granulating at 300RPM. The resulting wet granules were dried and milled. The milled dry blend was transferred, sieved (0.6mm / #30 mesh), and encapsulated to generate 50 mg and 200 mg dose strength capsules. 0 2. Extragranular formulations: 50 mg and 200 mg strength capsules: a. Components of intragranular plus extragranular formulation are dsclosed in Table 13 and its sevieving and flowability analyses are disclosed in Tables 14 and 15. 15                                          Table 13 Component Function Quality Standard 50 mg Strength 200 mg Strength 50 mg Strength 200 mg Strength Compositi on of Capsule Fill (%) Compositi on of Capsule Fill (%) Amount (mg) / capsule Amount (mg) / capsule Intra-granular Ingredients Micronized Compound (I) Form A PSD (pm): (D10:D50:D90 = 1:6:14) Drug Substance - 41.67 45.15 50.0 200.0 Mannitol Diluent USP 25.83 27.99 31.0 124.0 Component Function Quality Standard 50 mg Strength 200 mg Strength 50 mg Strength 200 mg Strength Compositi on of Capsule Fill (%) Compositi on of Capsule Fill (%) Amount (mg) / capsule Amount (mg) / capsule Sodium lauryl sulfate Surfactant NF 10.42 11.29 12.5 50.0 Crospovidone Disintegrant NF 3.75 4.06 4.5 18.0 Copovidone Binder NF 4.17 4.51 5.0 20.0 Purified Water Granulation Solvent USP N / A N / A N / A N / A Total DP Intermediate - 85.83 93.00 103.0 412.0 Extra-granular Ingredients Mannitol Diluent USP 10.83 3.39 13.0 15.0 Crospovidone Binder NF 2.50 2.71 3.0 12.0 Collodial Silicon Dioxide Glidant NF 0.42 0.45 0.5 2.0 Magnesium Stearate Lubricant NF 0.42 0.45 0.5 2.0 Total Final Blend - 100 100 120.0 443.0 b. Preparation of Extraganular Formulation: Formulations using extragranular excipients (in addition to the granules) were trialed and scaled up. The manufacturing process was similar for granules alone, but with extra processing 5 steps to include blending of granules with extragranular excipients before capsule fill. c. Extragranular Formulation: Sieving Analysis Tabic 14 50 mg Capsule Final Blend 200 mg Capsule Final Blend Mesh Mesh T Mesh G Net Wt % of blend Mesh T Mesh G Net Wt % of blend 20 385.83 385.83 0 0% 20 385.83 385.84 0.01 0% 40 341.49 343.34 1.85 9% 40 341.52 343.1 1.58 8% 60 342.61 346.19 3.58 18% 60 342.64 345.57 2.93 14% 80 305.72 308.88 3.16 16% 80 305.77 308.51 2.74 14% 100 329.84 331.38 1.54 8% 100 329.83 331.42 1.59 8% 140 325.66 329.41 3.75 19% 140 325.65 329.85 4.2 21% 200 327.31 331.05 3.74 19% 200 3T1.Z1 331.6 4.33 21% Pan 363.89 366.43 2.54 13% Pan 363.88 366.73 2.85 14% Total 20.16 99% Total 20.23 100% 5           d. Extragranular Formulation: Flowability Analysis Table 15 50 mg Capsule Final blend 200 mg Capsule Final blend p Bulk: 0.563 p Bulk: 0.551 p Tapped: 0.689 p Tapped: 0.663 Hausner Ratio: 1.22 Hausner Ratio: 1.20 3. Dissolution Profiles of Granules only and Extragranular formulations in SGF (see 10 Table 5 for conditions): a. Granules only: Dissolution profile of 50 mg and 200 mg capsules with granules only formulations are disclosed in Table 16 below: Table 16 Dissolution Profile (n=12) 50 mg and 200 mg Capsules Batch Aspect 15 min 30 min 45 min 60 min 90 min 50 mg Low 93.3 97.7 97.6 99.8 98.6 High 101.4 104.5 103.6 105.6 105.0 Mean 97.0 100.2 100.4 101.9 102.1 SD 2.48 2.05 1.68 1.92 2.25 RSD 2.56 2.04 1.67 1.88 2.20 200 mg Low 83.4 86.2 88.9 91.3 97.7 High 93.6 97.5 99.2 99.9 103.0 Mean 90.5 95.3 97.0 97.2 99.1 SD 3.20 3.23 2.94 2.71 1.48 RSD 3.53 3.39 3.04 2.78 1.49 b. Extragranular Formulation: Dissolution profile of 50 mg and 200mg capsules with Dissolution profile of 50 mg and 200 mg capsules with extragranular formulations are disclosed in 5 Table 17 below: Table 17 50 mg Dissolution, Extragranular formulation % Release Vessel T = 0 min 15 min 30 min 45 min 60 min 90 min Mean 0 82 89 92 94 96 % RSD 0 12.6 10 7.9 6.7 3.8 200 mg Dissolution, Extragranular formulation, 222-49 % Release Vessel T = 0 min 15 min 30 min 45 min 60 min 90 min Mean 0 86 93 96 97 98 % RSD 0 2.9 1.7 1.2 1 2 The extragranular formulation flowability (Hausner ratio) was similar to the granules only formulation, and the granules only formulation was determined to be superior to the extrangranular formulation based on dissolution RSD. The granules only formulation was chosen as the capsule fill. 5                                      Example 7 10 mg and 25 mg Granule Only Capsule Formulations 1. Components of 10 and 25 mg granule only formulation are dsclosed in Table 18: 10                                             Table 18 Component Function Quality Standard 10 mg Strength 25 mg Strength 50 mg and 200 mg Strength (Common Blend) Composition of Capsule Fill (%) Intragranule Ingredi ents Micronized Compound (1) Form A PSD (pm): D10:D50:D90 = 1:6:14 Drug Substance 10.75 25.84 48.54 Mannitol Diluent USP 76.34 57.88 30.10 Sodium lauryl sulfate Surfactant NF 0.26 4.03 9.71 Crospovidone Disintegrant NF 4.84 4.65 4.37 Copovidone Binder NF 4.77 5.56 4.25 Granulation media Copovidone Binder NF 0.61 0.61 0.61 Sodium lauryl sulfate, NF Surfactant NF 2.43 2.43 2.43 Purified Watera Granulation Solvent USP N / A N / A N / A Total Final Blend N / A 100 100 100 SLS : DS w / w Ratio N / A N / A 0.25:1 0.25:1 0.25:1 Preparation of 10 mg and 25 mg granule only capsule formulations: The above formulations were prepared using the same manufacturing process and equipment as the 50 / 200 mg common granule but varying the amounts of micronized form A and 5 diluent while maintaining a SLS to micronized form A weight / weight ratio of 0.25 (see Table 18). After final drying, the 10 mg granules were analyzed by sieving, compared against the 50 / 200 mg common blend and the results are shown in Table 19 below. 2.      10 mg granule only capsule formulation: Sieving and Flowability Analysis 10 Table 19 10 mg Granules Sieving and Flowability Analysis 50 / 200mg Formulation lOmg Formulation Blend Lot#l Blend Lot #2 10 mg prototype blend 10 mg Mfg Lot blend 25 Mesh / 710 microns 0.5 0.2 0.2 0 30 / 600 2 0.8 0.5 0.1 40 / 425 15.4 7.5 2.8 1.7 60 / 250 29 21.1 14.9 10.6 100 / 150 20.8 25.6 38.4 27.3 230 / 63 24.2 33.8 42 58.4 Pan (fines) 7.2 9.6 0.1 1 Total 99.1 98.6 98.9 99.1 Bulk Density (g / cc) 0.512 0.498 0.466 0.447 50 / 200mg Formulation lOmg Formulation Tapped Density (g / cc) 0.640 0.654 0.555 0.519 Hausner Ratio 1.25 1.31 1.19 1.16 Compressibility (%) 19.87 23.85 16.04 13.87 It was found to have similar particle size distribution, bulk and tapped density, and slightly lower compressibility 3. Dissolution Profile of 10 mg granules only Capsule formulation: 5           Dissolution profile of capsules containing 10 mg blend is disclosed in Table 20 below. Table 20 Dissolution Profile (n=12) for Compound (I) Form A 10 mg Capsules Batch Aspect 15 min 30 min 45 min 60 min 90 min 10 mg Low 87.1 91.9 93.0 93.2 94.5 High 97.8 102.0 103.0 103.2 103.9 Mean 94.3 98.7 99.8 100.1 100.6 SD 2.79 2.67 2.66 2.66 2.50 RSD 2.96 2.70 2.67 2.66 2.45 10          Dissolution profile of 10 mg granules was found to be similar to the 50 / 200mg common blend. 4. Dog PK study with 10 mg, 25 mg and 50 mg granule only Capsule formulations The 10 mg, 25 mg and 50 mg granule only formulations were dosed sequentially in a single dose beagle bioavailability study (n=5) and found to be dose proportional (see Figure 5). Table 21 Dog PK Study Study Group mg dose Dogs / group PO_A 10 Capsule 5 PO_B 25 Capsule 5 PO_C 50 Capsule 5 Blood Sampling Pre-dose, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h and 72 hours post dose Example 8 Preparation of Large Scale 50mg / 200mg Granules Only formulation 1. Components of 20 and 200 mg granules only Capsule formulation are dsclosed in Table 22: Table 22 Component Function Quality Standard 50 mg and 200 mg Strength (Common Blend) 50 mg Strength 200 mg Strength 200mg Capsule Batch Composition of Capsule Fill (%) Amount (mg) / capsule Amount (mg) / capsule Batch Quantity (g) Intragranular Ingredients Micronized Compound (I) Form A PSD (pm): (D10:D50:D90 = 3:6:14) Drug Substance 48.54 50.00 200.0 999.9 Mannitol Diluent USP 30.10 31.00 124.0 620.1 Sodium lauryl sulfate Surfactant NF 9.71 10.00 40.0 200.0 Crospovidone Disintegrant NF 4.37 4.50 18.0 90.02 Copovidone Binder NF 4.25 4.38 17.5 87.55 Granulation Media Copovidone Binder NF 0.61 0.63 2.51 12.57 Sodium lauryl sulfate Surfactant NF 2.43 2.50 10.0 50.06 Purified Water a Granulation Solvent USP N / A N / A N / A N / A Total Final Blend N / A 100 103.0 412.0 2060 Compound (I): SLS w / w Ratio N / A N / A 4:1 4:1 4:1 4:1 2. Preparation of Formulation: 1. Sieved (#30 mesh sieve) micronized Compound (I) Form A (999.9g), mannitol (620.1g), sodium lauryl sulfate (200.0g), crospovidone (90.02g), and copovidone (87.55g) were transfered to the high-shear granulator. 2. Granulation media was prepared by mixing sodium lauryl sulfate (50.06g) and copovidone (12.57g) in sufficient water to dissolve and stir until a solution was obtained. 3. The dry ingredients of Step 1 were blended. 4. Wet granulation was performed in the high shear granulator by spraying the granulation media at approximately 60g / minute onto the dry ingedients while blending with impellers at 250RPM (choppers off). 5. The wet granulation was dried to achieve final LOD of not more that 2.0%. 6. The wet granulated material (Quadro Comil) was milled at 750RPM / 032R screen. 7. Encapsulation was performed using an encapsulator with appropriate tooling. 8. Capsule weight was checked (+ / - 7%) and the polished. 3. Dissolution Profile of 200 mg capsule is provided in Table 23. Table 23 Dissolution Profile (n=12) for 200 mg granule only capsule formulation Batch Aspect 15 min 30 min 45 min 60 min 90 min 200mg capsules Low 83.4 86.2 88.9 91.3 97.7 High 93.6 97.5 99.2 99.9 103.0 Mean 90.5 95.3 97.0 97.2 99.1 SD 3.20 3.23 2.94 2.71 1.48 RSD 3.53 3.39 3.04 2.78 1.49

Claims

What is Claimed:

1. A wet granulated pharmaceutical composition comprising: (a) micronized Compound (I) Form A:(I)having an X-ray powder diffraction (XRPD) pattern comprising peaks at angular positions 15.8 and 18.6, wherein the angular positions may vary by + 0.2° 20 as measured by X-ray powder diffraction using an X-ray wavelength of 1.5418 A;(b) a sprayed surfactant; and(c) a non-sprayed surfactant;wherein the sprayed and non-sprayed surfactants are the same or different.

2. The wet granulated pharmaceutical composition of claim 1, wherein the micronized Compound (I) Form A has a D90 value less than about 25 pm.

3. The wet granulated pharmaceutical composition of claim 1 or 2, wherein the micronized Compound (I) Form A has D90 value less than about 14 pm.

4. The wet granulated pharmaceutical composition of any one of claims 1 to 3, wherein the micronized Compound (I) Form A has D50 value less than about 10 pm.

5. The wet granulated pharmaceutical composition of any one of claims 1 to 4, wherein the micronized Compound (I) Form A has a D50 value less than about 6 pm.

6. The wet granulated pharmaceutical composition of any one of claims 1 to 5, wherein the micronized Compound (I) Form A has a D10 value less than about 3 pm.

7. The wet granulated pharmaceutical composition of claim 1, wherein the micronized Compound (I) Form A has a DIO value of 3 ± 2 pm, a D50 value of 6 + 3 pm, and a D90 value of 14 + 4 pm.

8. The wet granulated pharmaceutical composition of claim 1, wherein the micronized Compound (I) Form A has a DIO value of 2.6 pm, a D50 value of 5.9 pm, and a D90 value of 13.6 pm.

9. The wet granulated pharmaceutical composition of any one of claims 1 to 8, wherein the dry wt / wt % ratio of micronized Compound (I) Form A to combined weight of the sprayed and non-sprayed surfactants is 4:1.

10. The wet granulated pharmaceutical composition of any one of claims 1 to 9, wherein the weight of the sprayed surfactant is about 2.45 % of the total dry weight of the pharmaceutical composition.

11. The wet granulated pharmaceutical composition of any one of claims 1 to 10, wherein the weight of the sprayed surfactant is 2.43 % by weight of the total dry weight of the pharmaceutical composition.

12. The wet granulated pharmaceutical composition of any one of claims 1 to 11, further comprising a binder.

13. The wet granulated pharmaceutical composition of claim 12, where the weight of the binder is about 5.0 % by weight of the total dry weight of the pharmaceutical composition.

14. The wet granulated pharmaceutical composition of claim 12 or 13, where the binder comprises sprayed and non-sprayed binders which may be the same or different.

15. The wet granulated pharmaceutical composition of claim 14, where the weight of sprayed binder is about 0.65 % by weight of the total dry weight of the pharmaceutical composition.

16. The wet granulated pharmaceutical composition of claim 14 or 15, where the weight of sprayed binder is about 0.61 % by weight of the total dry weight of the pharmaceutical composition.

17. The wet granulated pharmaceutical composition of any one of claims 14 to 16, where the weight of non-sprayed binder is about 4.50 % by weight of the total dry weight of the pharmaceutical composition.

18. The wet granulated pharmaceutical composition of any one of claims 14 to 17, where the weight of non-sprayed binder is 4.77 % by weight of the total dry weight of the pharmaceutical composition.

19. The wet granulated pharmaceutical composition of any one of claims 14 to 17, where the weight of non-sprayed binder is about 4.30 % by weight of the total dry weight of the pharmaceutical composition.

20. The wet granulated pharmaceutical composition of any one of claims 14 to 17, and 19, where the weight of non-sprayed binder is 4.25 % by weight of the total dry weight of the pharmaceutical composition.

21. The wet granulated pharmaceutical composition of any one of claims 14 to 17, where the weight of non-sprayed binder is 4.56 % by weight of the total dry weight of the pharmaceutical composition.

22. The wet granulated pharmaceutical composition of any one of claims 12 to 21, where the binder is selected from polyvinylpyrrolidinone, microcrystalline cellulose, and copovidone.

23. The wet granulated pharmaceutical composition of any one of claims 1 to 22, further comprising a disintegrant.

24. The wet granulated pharmaceutical composition of any one of claims 23, where the weight of disintegrant is about 4.50 % by weight of the total dry weight of the pharmaceutical composition.

25. The wet granulated pharmaceutical composition of any one of claims 23 and 24, where the weight of disintegrant is 4.37% by weight of the total dry weight of the pharmaceutical composition.

26. The wet granulated pharmaceutical composition of any one of claims 23 and 24, where the weight of disintegrant is 4.84 % by weight of the total dry weight of the pharmaceutical composition.

27. The wet granulated pharmaceutical composition of any one of claims 23 and 24, where the weight of disintegrant is 4.65 % by weight of the total dry weight of the pharmaceutical composition.

28. The wet granulated pharmaceutical composition of any one of claims 23 to 27, where the disintegrant is selected from sodium starch glycolate, croscarmellose sodium, and crospovidone.

29. The wet granulated pharmaceutical composition of any one of claims 1 to 18, 22 to 24, 26, and 28, wherein the weight of the non-sprayed surfactant is about 0.30 % by weight of the total dry weight of the pharmaceutical composition.

30. The wet granulated pharmaceutical composition of any one of claims 1 to 18, 22 to 24, 26, 28, and 29, wherein the weight of the non-sprayed surfactant is 0.26 % by weight of the total dry weight of the pharmaceutical composition.

31. The wet granulated pharmaceutical composition of any one of claims 1 to 17, 19, 20, 22 to 25, and 28, wherein the weight of the non-sprayed surfactant is about 9.70 % by weight of the total dry weight of the pharmaceutical composition.

32. The wet granulated pharmaceutical composition of any one of claims 1 to 17, 19, 20, 22 to 25, 28, and 31, wherein the weight of the non-sprayed surfactant is 9.71 % by weight of the total dry weight of the pharmaceutical composition.

33. The wet granulated pharmaceutical composition of any one of claims 1 to 17, 21 to 23, 27, and 28, wherein the weight of the non-sprayed surfactant is about 4.0 % by weight of the total dry weight of the pharmaceutical composition.

34. The wet granulated pharmaceutical composition of any one of claims 1 to 17, 21 to 23, 27, 28, and 33, wherein the weight of the non-sprayed surfactant is 4.03 % by weight of the total dry weight of the pharmaceutical composition.

35. The wet granulated pharmaceutical composition of any one of claims 1 to 34, wherein the sprayed and the non-sprayed surfactants are independently selected from Polyoxyl 40 stearate, Cremophor RH40, Polysorbate 80, Tocophersolan, Soluplus, poloxamer 188, poloxamer457, linoeoyl polyoxyl-6-gylcerides (Labrafil M2125), lauroyl polyoxyl-32 glycerides, and sodium lauryl sulfate.

36. The wet granulated pharmaceutical composition of any one of claims 1 to 35, further comprising a diluent.

37. The wet granulated pharmaceutical composition of any one of claims 1 to 18, 22 to 24, 26, 28 to 30, and 35, further comprising a diluent where the weight of diluent is about 76.34 % by weight of the total weight of the pharmaceutical composition.

38. The wet granulated pharmaceutical composition of any one of claims 1 to 17, 21 to 23, 27, 28, 33, 34, and 35, further comprising a diluent where the weight of diluent is about 57.88% by weight of the total weight of the pharmaceutical composition.

39. The wet granulated pharmaceutical composition of any one of claims 1 to 17, 19, 20, 22 to 25, 28, 31, 32, and 35, further comprising a diluent where the weight of diluent is about 31 % by weight of the total dry weight of the pharmaceutical composition.

40. The wet granulated pharmaceutical composition of any one of claims 36 to 39, wherein the diluent is selected from lactose, pregelatinized starch, com starch, microcrystalline cellulose and mannitol.

41. The wet granulated pharmaceutical composition of any one of claims 1 to 18, 22 to 24, 26, 28 to 30, 35, 37, and 40, wherein the weight of the micronized Compound (I) Form A is about 11.0 % by weight of the total dry weight of the pharmaceutical composition.

42. The wet granulated pharmaceutical composition of any one of claims 1 to 18, 22 to 24, 26, 28 to 30, 35, 37, 40, and 41, wherein the weight of the micronized Compound (I) Form A is about 10.75 % by weight of the total dry weight of the pharmaceutical composition.

43. The wet granulated pharmaceutical composition of any one of claims 1 to 17, 19, 20, 22 to 25, 28, 31, 32, 35, 39, and 40, wherein the weight of the micronized Compound (I) Form A is about 50.0 % by weight of the total dry weight of the pharmaceutical composition.

44. The wet granulated pharmaceutical composition of any one of claims 1 to 17, 19, 20, 22 to 25, 28, 31, 32, 35, 39, 40, and 43, wherein the weight of the micronized Compound (I) Form A is about 48.54 % by weight of the total dry weight of the pharmaceutical composition.

45. The wet granulated pharmaceutical composition of any one of claims 1 to 17, 21 to 23, 27, 28, 33, 34, 35, 38, and 40, wherein the weight of the micronized Compound (I) Form A is about 25.0 % by weight of the total dry weight of the pharmaceutical composition.

46. The wet granulated pharmaceutical composition of any one of claims 1 to 17, 21 to 23, 27, 28, 33, 34, 35, 38, 40, and 45, wherein the weight of the micronized Compound (I) Form A is about 25.84 % by weight of the total dry weight of the pharmaceutical composition.

47. A method of treating a disease mediated by HIF-2a, comprising administering to a patient in need thereof the pharmaceutical composition of any one of claims 1 to 46 wherein the disease is a cancer.

48. The process of making the wet granulated pharmaceutical composition of any one of claims 1 to 46, comprising:(la) preparing a mixture of micronized Compound (I) Form A, a non-sprayed surfactant, a diluent, when present, a non-sprayed binder, when present, and a disintegrant, when present;(lb) spraying onto the mixture of step (la) a granulating amount of water comprising a sprayed surfactant and a sprayed binder to form wet granules;(1c) drying the wet granulates of step (lb) to remove water;(Id) milling the granules from step (1c) to produce milled granules;(le) sieving the milled granules from step (Id) to remove lumps or agglomerates; and(If) optionally encapsulating granules obtained from step (le).

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