Crystalline forms of a ryanodine receptor modulator and uses thereof

1. A method of treating congenital RYR1-related myopathy, comprising administering to a subject in need thereof a therapeutically-effective amount of a pharmaceutical composition, the 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.

2. The method of claim 1 , wherein if an X-ray diffraction pattern of the crystalline form is obtained using measurement conditions, the measurement conditions comprising:

Start Position [°2θ]

3.00

End Position [°2θ]

54.99

Step Size [°2θ]

0.018

Scan Step Time [s]

34.92

Measurement Temperature [° C.]

25.00

K-Alpha1 [Å]

1.54

K-Alpha2 [Å]

1.54

K-Beta [Å]

1.39

Spinning

Yes

then at least four X-ray diffraction peaks selected from 7.3±0.1, 13.2±0.1, 14.6±0.1, 17.1±0.1, 18.0±0.1, 18.3±0.1, 23.2±0.1, 23.9±0.1, 24.4±0.1, and 28.6±0.1 degrees two theta (°θ) are observed.

3. The method of claim 2 , wherein X-ray diffraction peaks at 7.3±0.1, 14.6±0.1, 18.0±0.1, 22.4±0.1, and 24.4±0.1 degrees two theta (°θ) are observed.

4. The method of claim 2 , wherein X-ray diffraction peaks at 7.3±0.1, 11.1±0.1, 14.6±0.1, 18.0±0.1, 19.2±0.1, 22.4±0.1, 23.2±0.1, and 24.4±0.1 degrees two theta (°θ) are observed.

5. The method of claim 2 , wherein X-ray diffraction peaks at 7.3±0.1, 11.0±0.1, 11.1±0.1, 11.5±0.1, 13.2±0.1, 14.6±0.1, 15.2±0.1, 17.1±0.1, 18.0±0.1, 18.3±0.1, 19.2±0.1, 20.2±0.1, 21.4±0.1, 22.4±0.1, 23.2±0.1, 23.9±0.1, 24.4±0.1 and 28.6±0.1 degrees two theta (°θ) are observed.

6. The method of claim 2 , wherein X-ray diffraction peaks substantially as shown in FIG. 6 are observed.

7. The method of claim 1 , 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.

8. The method 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 .

9. The method 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.

10. The method 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.

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

12. The method 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.

13. The method 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.

14. The method 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.

15. The method of claim 1 , wherein the unit dosage form is a tablet.

16. The method of claim 1 , wherein the unit dosage form is a gastro-resistant tablet.

17. The method of claim 1 , wherein the unit dosage form is suitable for oral administration.

18. The method of claim 1 , wherein the pharmaceutical composition further comprises a pharmaceutically-acceptable excipient.

19. The method of claim 1 , wherein the pharmaceutical composition comprises about 20 mg to about 200 mg of the crystalline form.

20. The method of claim 1 , wherein the therapeutically-effective amount is about 200 mg per day.

21. The method of claim 1 , wherein the therapeutically-effective amount is about 300 mg per day.

22. The method of claim 1 , wherein the therapeutically-effective amount is about 400 mg per day.

23. A method of treating congenital RYR1-related myopathy, comprising administering to a subject in need thereof a therapeutically-effective amount of a pharmaceutical composition, the 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.