Claims for Patent: 11,020,376

Summary for Patent: 11,020,376

Title:	Crystalline form of lorlatinib free base
Abstract:	This invention relates to acrystalline form of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-5-oxo-10,15,16,17-tetrahydro-2H- -8,4-(metheno)pyrazolo[4,3-h] [2,5,11]benzoxadiazacyclo-tetradecine-3-carbonitrile (lorlatinib) free base (Form 7). This invention also relates to pharmaceutical compositions comprising Form 7, and to methods of using Form 7 and such compositions in the treatment of abnormal cell growth, such as cancer, in a mammal.
Inventor(s):	Pencheva; Klimentina Dimitrova (Sandwich, GB), Birch; Melissa Jane (Sandwich, GB), McAllister; Stephen Mark (Sandwich, GB), Rowland; Martin Gregory (Sandwich, GB), Smales; Ian Leonard (Sandwich, GB)
Assignee:	Pfizer Inc. (New York, NY)
Application Number:	16/535,747
Patent Claims:	1. A solid dosage form of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2- H-8,4-(m etheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carb- onitrile (lorlatinib) free base (Form 7), wherein the dosage form has a powder X-ray diffraction (PXRD) pattern comprising peaks at 2.theta. values of: 9.6, 10.1 and 16.2 .degree.2.theta..+-.0.2 .degree.2.theta.. 2. The dosage form of claim 1, wherein the dosage form is a tablet, wherein the tablet comprises a tablet core. 3. The tablet of claim 2, wherein the tablet core is 1-30% of lorlatinib free base (Form 7) on a w/w basis. 4. The tablet of claim 3, wherein the tablet core is about 10% of lorlatinib free base (Form 7) on a w/w basis. 5. The tablet of claim 3, wherein the tablet core is about 15% of lorlatinib free base (Form 7) on a w/w basis. 6. The tablet of claim 2, wherein the tablet core further comprises a filler. 7. The tablet of claim 6, wherein the filler is microcrystalline cellulose, dibasic calcium phosphate anhydrous, lactose monohydrate, or a combination thereof. 8. The tablet of claim 7, wherein the filler is microcrystalline cellulose. 9. The tablet of claim 8, wherein the tablet core is 35-60% microcrystalline cellulose on a w/w basis. 10. The tablet of claim 9, wherein the tablet core is about 53% microcrystalline cellulose on a w/w basis. 11. The tablet of claim 9, wherein the tablet core is about 58% microcrystalline cellulose on a w/w basis. 12. The tablet of claim 7, wherein the filler is dibasic calcium phosphate anhydrous. 13. The tablet of claim 12, wherein the tablet core is 10-35% dibasic calcium phosphate anhydrous on a w/w basis. 14. The tablet of claim 13, wherein the tablet core is about 29% dibasic calcium phosphate anhydrous on a w/w basis. 15. The tablet of claim 13, wherein the tablet core is about 27% dibasic calcium phosphate anhydrous on a w/w basis. 16. The tablet of claim 7, wherein the filler is lactose monohydrate. 17. The tablet of claim 16, wherein the tablet core is 35% lactose monohydrate on a w/w basis. 18. The tablet of claim 2, wherein the tablet core further comprises a disintegrant. 19. The tablet of claim 18, wherein the disintegrant is starch, alginic acid, silicates, or a combination thereof. 20. The tablet of claim 19, wherein the starch is sodium starch glycolate. 21. The tablet of claim 20, wherein the tablet core is 2-5% sodium starch glycolate on a w/w basis. 22. The tablet of claim 21, wherein the tablet core is about 3% sodium starch glycolate on a w/w basis. 23. The tablet of claim 2, wherein the tablet core further comprises a lubricant. 24. The tablet of claim 23, wherein the lubricant is magnesium stearate, sodium lauryl sulfate, talc, or a combination thereof. 25. The tablet of claim 24, wherein the lubricant is magnesium stearate. 26. The tablet of claim 25, wherein the tablet core is 0.5-2.5% magnesium stearate on a w/w basis. 27. The tablet of claim 26, wherein the tablet core is about 1% magnesium stearate on a w/w basis. 28. The tablet of claim 26, wherein the tablet core is about 2% magnesium stearate on a w/w basis. 29. The tablet of claim 2, wherein the tablet further comprises a film coating having a film coating weight. 30. The tablet of claim 29, wherein the film coating is Opadry II Tan or Opadry II Lavender. 31. The tablet of claim 29, wherein the film coating weight is about 3% on a w/w basis of the tablet core weight. 32. The tablet of claim 2, wherein the tablet comprises about 25 mg or about 50 mg or about 100 mg (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2- H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbo- nitrile (lorlatinib) free base (Form 7). 33. The tablet of claim 2, wherein the tablet consists of: 25 mg (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2- H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbo- nitrile (lorlatinib) free base; 143.325 mg microcrystalline cellulose; 71.675 mg dibasic calcium phosphate anhydrous; 7.500 mg sodium starch glycolate; 2.500 mg magnesium stearate; and 7.500 mg Opadry II Tan. 34. The tablet of claim 2, wherein the tablet consists of: 50 mg (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2- H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbo- nitrile (lorlatinib) free base; 286.650 mg microcrystalline cellulose; 143.350 mg dibasic calcium phosphate anhydrous; 15.000 mg sodium starch glycolate; 5.000 mg magnesium stearate; and 15.000 mg Opadry II Lavender. 35. The tablet of claim 2, wherein the tablet consists of: 100 mg (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2- H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbo- nitrile (lorlatinib) free base; 355.540 mg microcrystalline cellulose; 177.800 mg dibasic calcium phosphate anhydrous; 20.000 mg sodium starch glycolate; 13.330 mg magnesium stearate; and 20.000 mg Opadry II Lavender. 36. A tablet comprising 1-30% of lorlatinib free base (Form 7), 35-60% microcrystalline cellulose; 10-35% dibasic calcium phosphate anhydrous; 2-5% sodium starch glycolate; and 0.5-2.5% magnesium stearate; on a w/w basis, wherein the tablet has a powder X-ray diffraction (PXRD) pattern comprising peaks at 2.theta. values of: 9.6, 10.1 and 16.2 .degree.2.theta..+-.0.2 .degree.2.theta.. 37. A tablet comprising 1-30% of lorlatinib free base (Form 7), 35-60% microcrystalline cellulose; 10-35% lactose monohydrate; 2-5% sodium starch glycolate; and 0.5-1.5% magnesium stearate; on a w/w basis, wherein the tablet has a powder X-ray diffraction (PXRD) pattern comprising peaks at 2.theta. values of: 9.6, 10.1 and 16.2 .degree.2.theta..+-.0.2 .degree.2.theta..