Crystalline forms of a Bruton's tyrosine kinase inhibitor

Inventors

Purro, Norbert • Smyth, Mark S. • Goldman, Erick • Wirth, David D.

Assignees

Pharmacyclics LLC • Nanoscale Combinatorial Synthesis Inc

Abstract

Described herein is the Bruton's tyrosine kinase (Btk) inhibitor 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, including crystalline forms, solvates and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical compositions that include the Btk inhibitor, as well as methods of using the Btk inhibitor, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.

Core Innovation

The disclosure relates to crystalline, solvated, and amorphous forms of the irreversible Btk inhibitor ibrutinib (Compound 1). The crystalline forms are defined by XRPD peak sets (Forms A–F) using 2-theta peak positions and are characterized by IR, DSC, and TGA.

The disclosure further provides stability and humidity performance and solubility information, together with conditions of form preparation from specific solvents. The crystalline forms include definitions of salt and solvate, including pharmaceutically acceptable salts and acid addition salts, and are described in terms of aqueous solubility and non-hygroscopicity.

In addition, the disclosure provides pharmaceutical compositions incorporating Compound 1 in specific crystalline forms, including oral solid dosage formulations and formulations with pharmaceutically acceptable excipients. The documented disclosure includes example unit-dose capsule/tablet compositions, crystalline forms A–F of ibrutinib with XRPD diagnostic 2-theta peak sets, and characterization including stability under humidity and temperature, DSC and TGA behavior for anhydrous versus desolvate forms, GVS moisture sorption, pH-dependent aqueous solubility, HPLC purity ranges, and low (S)-isomer.

Claims Coverage

The independent claim covers a pharmaceutical composition comprising a crystalline form of ibrutinib and a pharmaceutically acceptable excipient, with the crystalline form produced by an alcohol-containing solvent process and characterized by specified XRPD 2-theta peaks. The related inventive features are defined through independent-claim key constraints, while dependent claims refine solvent choice, optional water content, alternative peak sets, and recovery from the solvent solution.

Overall, the claim coverage centers on a pharmaceutical composition containing a crystalline form of ibrutinib characterized by specific XRPD 2-theta peaks and produced via an alcohol-containing solvent process; dependent features refine the alcohol choice, optionally include water, and require recovery from the solvent solution.

Stated Advantages

Documented Applications