Crystalline Forms of BTK Inhibitor Compound 1 for Stable Formulation
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Solution Overview
Problem
The amorphous form of (S)-7-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, a potent BTK kinase inhibitor, poses challenges due to its low stability and handling difficulties in drug formulation.
Innovation Solution
Development of stable and easy-to-handle crystalline forms, specifically solvated and non-solvated forms (Form A and Form B), with Form B being anhydrous non-solvated, characterized by high melting point and non-hygroscopicity, suitable for drug formulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the amorphous form of Compound 1 is used, then the compound can be obtained through standard synthesis, but it exhibits low stability and handling difficulties in drug formulation
Solution Approach 1:
The patent applies parameter changes by transforming the physical state of Compound 1 from amorphous to crystalline form. This phase transition fundamentally alters the material's stability and handling properties, converting an unstable, difficult-to-handle amorphous compound into a stable, easy-to-manage crystalline form suitable for pharmaceutical formulation.
Solution Approach 2:
The invention directly utilizes phase transitions by inducing crystallization of Compound 1 from its amorphous state. The patent describes obtaining crystalline forms through controlled crystallization processes, where the compound transitions from a disordered amorphous phase to an ordered crystalline phase, thereby achieving improved stability and handling characteristics.
2Reliability
If crystalline forms are developed to improve stability and handling, then manufacturing and therapeutic efficacy are enhanced, but the complexity of the formulation process increases
Solution Approach 1:
The patent applies preliminary action by pre-establishing stable crystalline forms of Compound 1 before the actual drug formulation process. The crystallization steps are performed in advance to convert the unstable amorphous compound into stable crystalline forms, which then serve as ready-to-use materials for subsequent formulation processes, thereby simplifying the overall manufacturing workflow.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The crystalline forms, particularly Form B, offer improved stability and processing ease, enhancing the manufacturing and therapeutic efficacy of BTK inhibitors for treating autoimmune, inflammatory, and cancerous diseases with reduced side effects.
Implementation Method 1
Development of stable and easy-to-handle crystalline forms, specifically solvated and non-solvated forms (Form A and Form B), with Form B being anhydrous non-solvated, characterized by high melting point and non-hygroscopicity
Data Source
AI summary
The present invention relates to a crystalline form of (S)-7-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 1) for inhibiting Btk, methods of preparation thereof and pharmaceutical compositions, and use of the crystalline form above in the treatment of a disease, or in the manufacturing of a medicament for the treatment of a disease, such as an allergic disease, an autoimmune disease, an inflammatory disease, and a cancer.