Processes for preparing solid state forms
Inventors
Radocea, Adrian • Croom, Jordan Michael • CHAN, Larry Robin • BHAVSAR, Ami Sanat • Smith, Pamela A. • Byrn, Stephen R. • PARENT, Stephan D. • PURCELL, Dale K.
Assignees
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Publication Number
US-12318370-B2
Publication Date
2025-06-03
Expiration Date
Abstract
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.
Core Innovation
The disclosure addresses the need for rapid and consistent preparation of anhydrous ritonavir Form III. It provides background on prior ritonavir polymorphs, including Forms I, II, and IV, and notes prior mislabeling of “Form IV” as a mixture containing Form III. The disclosure frames Form III as an identifiable anhydrous polymorph that is obtained by a controlled thermal polymorph-conversion approach.
The disclosure provides a method in which a sample of ritonavir is melted and then cooled to a first temperature within a nucleation temperature range for a nucleation period. During that nucleation period, crystallization of Form III ritonavir is substantially complete, and Form III ritonavir is obtained. The disclosure also discusses optional thermal profile features, including holding or ramping and recovery cooling below the glass transition temperature of amorphous ritonavir.
Form III ritonavir is characterized by defined analytical signatures, including XRPD peaks at about 7.9° and about 9.1° 2θ, with optional additional peaks. DSC characterization includes an endotherm onset at about 114°C, and the disclosure discusses analytical/characterization variability considerations. The disclosure further reports that Form III can be obtainable in less time than previously reported, can be performed under reduced gravity, and is characterized by non-hygroscopic behavior and superior aqueous solubility versus Forms I and II.
Claims Coverage
The patent claims are centered on one independent method claim for obtaining Form III ritonavir, with dependent claims that refine the process conditions, starting material forms, optional thermal variations, handling conditions, and characterization-based definitions. Across the independent claim and refinements, the inventive features comprise thermal melting followed by controlled nucleation cooling within a defined temperature range for a defined period to achieve substantially complete crystallization of Form III, and characterizing Form III by XRPD and/or DSC signatures plus optional post-obtaining cooling below the glass transition temperature of amorphous ritonavir.
Thermal melting followed by nucleation cooling to obtain Form III
Melting a sample of ritonavir, cooling the sample to a first temperature within a nucleation temperature range for a nucleation period, wherein crystallization of Form III ritonavir is substantially complete during the nucleation period, and obtaining Form III ritonavir.
Nucleation temperature range for substantially complete crystallization of Form III
Cooling the sample to a first temperature within a nucleation temperature range from about 75°C to about 100°C for the nucleation period such that crystallization of Form III ritonavir is substantially complete during the nucleation period.
Nucleation period duration enabling substantially complete crystallization
Using a nucleation period between 1 and 23 hours such that crystallization of Form III ritonavir is substantially complete during the nucleation period.
Post-obtaining cooling below the amorphous glass transition temperature
Cooling the obtained Form III ritonavir to a temperature below the glass transition temperature of amorphous ritonavir.
X-ray powder diffraction pattern characteristic of Form III
Defining Form III ritonavir by an X-ray powder diffraction pattern having peaks at about 7.9° 2θ and about 9.1° 2θ.
Overall, the claimed coverage ties Form III ritonavir acquisition to melting followed by nucleation cooling within a defined nucleation temperature range and nucleation period to achieve substantially complete crystallization, optionally includes post-obtaining cooling below the glass transition temperature of amorphous ritonavir, and includes XRPD-defined signatures for Form III.
Stated Advantages
Can be obtainable in less time than previously reported.
Non-hygroscopic behavior.
Superior aqueous solubility versus Forms I and II.
Documented Applications
Pharmaceutical compositions comprising the Form III ritonavir product and pharmaceutically acceptable excipients.
Therapeutic use involving HIV protease inhibition.
Therapeutic use involving COVID-19 treatment associated with CYP3A4 inhibition.
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