Morphic forms of G1T38 and methods of manufacture thereof
Inventors
Smith, Alexander • White, Hannah S. • Andres, Patricia • Sun, Xufeng • Zhu, Lei • Vlahova, Petinka I.
Assignees
Pharmacosmos Holding AS • Pharmacosmos AS • Gi Therapeutics Inc • Curia Global Inc
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Publication Number
US-11261193-B2
Publication Date
2022-03-01
Expiration Date
Abstract
This invention provides an unexpectedly stable, highly crystalline form of the di-HCl salt of for advantageous therapeutic pharmaceutical efficacy and dosage form stability.
Core Innovation
The invention relates to an isolated crystalline Form B of the di-HCl salt of G1T38 (Compound 2). The isolated crystalline Form B is characterized as a specific solid form with a defined X-ray powder diffraction (XRPD) pattern comprising at least three 2θ values selected from a specified set, and additional solid-state characterization attributes.
The disclosure also addresses the need for solid forms of Compound 2 (di-HCl salt) that have desirable stability and remain the same solid form under conditions relevant to formulation and storage. Multiple solid forms are found, and only Form A/B/D are suitable, with Form B remaining Form B after exposure to high humidity in dynamic vapor sorption (DVS).
The disclosure further provides a process for producing crystalline Form B of the specified di-HCl salt from the free base using aqueous HCl, followed by sequential solution handling to afford the crystalline Form B. The resulting solid form is characterized by the same XRPD-based identity, and is used in the context of pharmaceutical compositions and cancer-related combination therapies.
Claims Coverage
The provided claim coverage defines isolated crystalline Form B of the di-HCl salt by a required XRPD peak set, and also includes a process claim for producing crystalline Form B from the free base in aqueous HCl. Across the dependent claims, coverage adds tighter XRPD peak inclusion constraints, optional DSC onset endotherm constraints, optional hydrate status, and a pharmaceutical composition context with pharmaceutically acceptable excipients.
Isolated crystalline form B defined by an XRPD peak set
An isolated crystalline Form B of the di-HCl salt is characterized by an XRPD pattern comprising at least three 2θ values selected from 6.5±0.2°, 9.5±0.4°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.3±0.2°, 19.9±0.2°, and 22.4±0.2°.
Process for producing crystalline form B of the di-HCl salt
A process for producing crystalline Form B of the specified di-HCl salt comprises heating the free base in aqueous HCl, sequential stirring and filtering steps with temperature changes, and filtering to afford crystalline Form B characterized by the specified XRPD pattern.
XRPD peak set requiring at least four specified 2θ values
The isolated crystalline Form B has an XRPD pattern comprising at least four selected 2θ values from the listed set.
Mandatory inclusion of the 9.5±0.4° XRPD peak
The isolated crystalline Form B has an XRPD pattern comprising at least the 2θ value of 9.5±0.4°.
Dsc onset endotherms as additional thermal characterization
The isolated crystalline Form B is characterized by DSC onset endotherms of about 105±20°C, about 220±20°C, and about 350±20°C.
Form b as a hydrate
The isolated crystalline Form B is a hydrate.
Pharmaceutical composition with pharmaceutically acceptable excipient for solid dosage delivery
A pharmaceutical composition comprises the isolated crystalline Form B and a pharmaceutically acceptable excipient for solid dosage delivery.
Overall, the claim coverage centers on defining isolated crystalline Form B of the di-HCl salt by an XRPD pattern with at least three specified 2θ peaks, and on producing that crystalline Form B by converting the free base in aqueous HCl and obtaining the same XRPD-defined solid form. Additional coverage further specifies peak-count requirements, thermal characterization, hydrate status, and pharmaceutical composition context.
Stated Advantages
Unexpected stability under thermal stress at 60°C for 7 days.
Long-term stability at 25°C/60% RH for ≥1 year.
Only Form A/B/D are suitable among multiple solid forms, with Form B remaining Form B after high humidity exposure in DVS.
Suitability for therapeutic efficacy and pharmaceutical formulation.
Documented Applications
Use in pharmaceutical formulation for therapeutic efficacy, including formulation as a solid dosage delivery with pharmaceutically acceptable excipients.
Therapeutic context involving CDK4/6 inhibition in pRb-positive cancers such as estrogen receptor positive (ER+) breast cancer.
Combination therapies for cancer indications, including combinations with BTK inhibitors, Syk inhibitors, PD-1 inhibitors, BCL-2 inhibitors, other targeted agents, chemotherapeutic agents, and immunotherapeutic agents.
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