Processes for preparing solid state forms
The present disclosure is related to a polymorphic form of ritonavir prepared by novel methods that require less time to produce the polymorphic form, the methods of preparing the polymorphic form, pharmaceutical compositions comprising the polymorphic form produced by the provided methods, and corresponding methods of treatment with the polymorphic form produced by the provided methods.
1. A method for obtaining Form III ritonavir, wherein the method comprises the steps of:
melting a sample of ritonavir;
cooling the sample to a first temperature within a nucleation temperature range for a nucleation period, wherein the nucleation temperature range is from about 75° C. to about 100° C.;
wherein the nucleation period is between 1 and 23 hours;
crystallization of Form III ritonavir is substantially complete during the nucleation period; and
obtaining Form III ritonavir.
2. The method according to claim 1 , wherein the method further comprises:
holding the temperature at the first temperature for a nucleation period; and
ramping the sample from the first temperature to a second temperature;
wherein the first and second temperatures are within the nucleation temperature range.
3. The method according to claim 1 , wherein the X-ray powder diffraction pattern of Form III ritonavir comprises peaks at about 7.9° 2θ and about 9.1° 2θ.
4. The method according to claim 1 , wherein the form of the ritonavir sample to be melted is selected from amorphous ritonavir, Form I ritonavir, and Form II ritonavir.
5. The method according to claim 4 , wherein the form of the ritonavir sample to be melted is Form II ritonavir.
6. The method according to claim 1 , wherein the melting step comprises ramping the temperature of the sample to a melt temperature of 125° C. or greater.
7. The method according to claim 6 , wherein the melt temperature is between about 125° C. to about 128° C.
8. The method according to claim 6 , wherein the form of the ritonavir sample to be melted is Form II ritonavir; and
the melt temperature is above the melting point of Form II ritonavir and is held until no seed crystals of Form II ritonavir are present in the melt.
9. The method according to claim 6 , wherein the melt temperature is held for at least two minutes.
10. The method according to claim 6 , wherein the melt temperature is held for at least 15 minutes.
11. The method according to claim 6 , wherein the melt temperature is held between about 15 minutes and about 30 minutes.
12. The method according to claim 1 , wherein the nucleation temperature range is from about 75° C. to about 85° C.
13. The method according to claim 12 , wherein the first temperature is about 80° C.
14. The method according to claim 1 , wherein the obtained Form III ritonavir comprises a mixture of amorphous ritonavir and Form III ritonavir.
15. The method according to claim 1 , wherein the sample or ritonavir crystallizes and the crystallization is substantially complete during the nucleation period.
16. The method according to claim 1 , further comprising the step of cooling the obtained Form III ritonavir, and wherein the obtained Form III ritonavir is cooled to a temperature below the glass transition temperature of amorphous ritonavir.
17. The method according to claim 1 , wherein the obtained Form III ritonavir forms within the nucleation temperature range.
18. The method according to claim 1 , wherein the amount of ritonavir in the sample to be melted is between about 0.5 mg and about 5000 mg.
19. The method according to claim 1 , wherein the melting step is complete upon absence of any crystalline material as observed by hot stage optical microscopy.
20. The method according to claim 1 , wherein the nucleation period is performed under reduced gravity conditions.