Crystalline forms of a ryanodine receptor modulator and uses thereof

1. A crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, wherein if a melting point of the crystalline form is obtained by:

(a) equilibrating a sample of said crystalline form at a temperature of about 20° C. in a temperature-controlled chamber; and

(b) increasing the temperature of the temperature-controlled chamber at about 10° C./minute to 250° C. using a differential scanning calorimetry instrument,

then a melting point of 208-210° C.(T onset ) is obtained.

2. The crystalline form of claim 1 , wherein the crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate is characterized by a differential scanning calorimetry profile substantially as shown in FIG. 7 .

3. The crystalline form of claim 1 , wherein if a thermogravimetric analysis of the crystalline form is obtained by:

(a) equilibrating a sample of said crystalline form at 25° C. in a temperature-controlled chamber; and

(b) increasing the temperature at a scan rate of about 10° C./minute to 250° C. using a thermogravimetric analysis instrument,

then a thermogravimetric analysis profile substantially as shown in FIG. 8 is obtained.

4. The crystalline form of claim 1 , wherein if a dynamic vapor sorption profile of the crystalline form is obtained by:

(a) equilibrating a sample of said crystalline form at 25° C. and 50% relative humidity in a temperature-controlled and humidity-controlled chamber until mass variation is less than 0.002% per minute for 6 hours;

(b) increasing the relative humidity from 50% to 90% at a rate of 10% per hour;

(c) equilibrating the sample at 90% relative humidity until mass variation of less than 0.002% per minute for 6 hours is observed;

(d) decreasing the relative humidity from 90% to 0% at a rate of 10% per hour;

(e) equilibrating the sample at 0% relative humidity until mass variation of less than 0.002% per minute for 6 hours is observed; and

(f) increasing the relative humidity from 0% to 50% at a rate of 10% per hour,

then a dynamic vapor sorption profile substantially as shown in FIG. 9 is obtained.

5. The crystalline form of claim 1 , wherein the crystalline form is substantially anhydrous.

6. The crystalline form of claim 1 , wherein the crystalline form comprises a population of particles, wherein at least about 90% by mass of the particles comprise a diameter of no greater than about 90 microns.

7. The crystalline form of claim 1 , wherein the crystalline form comprises a population of particles, wherein at least about 50% by mass of the particles comprise a diameter of no greater than 30 microns.

8. The crystalline form of claim 1 , wherein the crystalline form comprises a population of particles, wherein at least about 50% by mass of the particles comprise a diameter of between about 10 microns and about 30 microns.

9. A pharmaceutical composition comprising in solid unit dosage form a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, wherein if a melting point of the crystalline form is obtained by:

(a) equilibrating a sample of said crystalline form at 20° C. in a temperature-controlled chamber; and

(b) increasing the temperature of the temperature-controlled chamber at 10° C. /minute to 250° C. using a differential scanning calorimetry instrument,

then a melting point of 208-210° C. (T onset ) is obtained.

10. The pharmaceutical composition of claim 9 , wherein the unit dosage form is a tablet.

11. The pharmaceutical composition of claim 9 , wherein the unit dosage form is a gastro-resistant tablet.

12. The pharmaceutical composition of claim 9 , wherein the unit dosage form is suitable for oral administration.

13. The pharmaceutical composition of claim 9 , further comprising a pharmaceutically-acceptable excipient.

14. A method of treating a condition, comprising administering to a subject in need thereof a therapeutically-effective amount of a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, wherein if a melting point of the crystalline form is obtained by:

(a) equilibrating a sample of said crystalline form at a temperature of about 20° C. in a temperature-controlled chamber; and

(b) increasing the temperature of the temperature-controlled chamber at a scan rate of about 10° C./minute to 250° C. using a differential scanning calorimetry instrument,

then a melting point of 208-210° C. (T onset ) is obtained,

wherein the condition is catecholaminergic polymorphic ventricular tachycardia, heart failure, muscular dystrophy, or malignant hyperthermia.

15. The method of claim 14 , wherein the condition is catecholaminergic polymorphic ventricular tachycardia.

16. The method of claim 14 , wherein the condition is heart failure.

17. The method of claim 14 , wherein the condition is a muscular dystrophy.

18. The method of claim 17 , wherein the muscular dystrophy is Duchenne Muscular Dystrophy.

19. The method of claim 14 , wherein the condition is malignant hyperthermia.

20. The method of claim 14 , wherein the therapeutically-effective amount is about 100 mg to about 200 mg per day.

21. The method of claim 14 , wherein the therapeutically-effective amount is about 200 mg per day.

22. The method of claim 14 , wherein the therapeutically-effective amount is about 300 mg per day.

23. The method of claim 14 , wherein the therapeutically-effective amount is about 400 mg per day.

24. A pharmaceutical composition comprising a gastro-resistant tablet, the gastro-resistant tablet comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate as an active ingredient, and a pharmaceutically-acceptable carrier, wherein if a melting point of the crystalline form is obtained by:

(a) equilibrating a sample of said crystalline form at 20° C. in a temperature-controlled chamber; and

(b) increasing the temperature of the temperature-controlled chamber at 10° C./minute to 250° C. using a differential scanning calorimetry instrument,

then a melting point of 208-210° C. (T onset ) is obtained.

25. A method of treating catecholaminergic polymorphic ventricular tachycardia comprising administering to a subject in need thereof a pharmaceutical composition according to claim 24 .