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 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.

2. The crystalline form of claim 1 , 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.

3. The crystalline form of claim 1 , 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.

4. The crystalline form of claim 1 , 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.

5. The crystalline form of claim 1 , wherein X-ray diffraction peaks substantially as shown in FIG. 6 are observed.

6. 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.

7. 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.

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

9. 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.

10. 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 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.

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

12. The pharmaceutical composition of claim 10 , wherein the unit dosage form is a gastro-resistant tablet.

13. The pharmaceutical composition of claim 10 , wherein the unit dosage form is suitable for oral administration.

14. The pharmaceutical composition of claim 10 , comprising about 20 mg to about 200 mg of the crystalline form.

15. The pharmaceutical composition of claim 10 , comprising about 23.5 mg to about 235 mg of the crystalline form.

16. A method of treating catecholaminergic polymorphic ventricular tachycardia, comprising administering to a subject in need thereof a solid composition, wherein the solid composition comprises 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 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.

17. The method of claim 16 , wherein the therapeutically-effective amount is about 100 mg to about 200 mg per day.

18. The method of claim 16 , wherein the therapeutically-effective amount is about 200 mg per day.

19. A method of treating catecholaminergic polymorphic ventricular tachycardia, comprising administering to a subject in need thereof a pharmaceutical composition in solid unit dosage form, the pharmaceutical composition comprising a gastro-resistant tablet, the gastro-resistant tablet comprising 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 the crystalline form is characterized by an X-ray diffraction pattern having 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).

20. The pharmaceutical composition of claim 10 , further comprising a pharmaceutically-acceptable excipient.

21. A method of treating malignant hyperthermia, comprising administering to a subject in need thereof a solid composition, wherein the solid composition comprises 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 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.

22. The method of claim 21 , wherein the therapeutically-effective amount is about 100 mg to about 200 mg per day.

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

24. A method of treating malignant hyperthermia, comprising administering to a subject in need thereof a pharmaceutical composition in solid unit dosage form, the pharmaceutical composition comprising a gastro-resistant tablet, the gastro-resistant tablet comprising 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 the crystalline form is characterized by an X-ray diffraction pattern having 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).