Crystalline Hydrochloride Forms for Stable ABL1 Inhibitor Formulation
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Solution Overview
Problem
Existing pharmaceutical formulations of N-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide do not account for potential polymorphic forms, which can affect solubility, stability, and biological activity, posing risks such as contamination and toxicity.
Innovation Solution
Identification and characterization of distinct crystalline forms, including the hydrochloride salt forms A, B, and trihydrate H A, with specific XRPD patterns and thermal properties, enabling controlled drug development and formulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If multiple crystalline forms (polymorphs) of a drug compound are possible, then the drug can exhibit different physicochemical properties (solubility, stability, bioavailability), but this creates risks of contamination by unintended polymorphs during manufacture and storage
Solution Approach 1:
The patent applies preliminary action by conducting comprehensive polymorph screening and characterization during the early drug development phase. This includes systematic crystallization studies, X-ray diffraction analysis, and thermal analysis to identify all possible polymorphic forms before commercial manufacturing begins. By establishing a complete polymorph profile upfront, the patent prevents contamination risks during later manufacturing and storage operations.
2Productivity
If an amorphous dispersion formulation is used to improve solubility and bioavailability, then the drug's therapeutic efficacy is enhanced, but the formulation lacks the stability and manufacturing control provided by crystalline forms
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallization conditions (solvent type, temperature, pH, concentration) to produce different crystalline forms with distinct properties. By establishing structure-property relationships between polymorphs and their physicochemical characteristics, the patent enables selection of optimal crystalline forms for specific formulation requirements, balancing solubility enhancement with manufacturing stability and control.
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 provide improved stability, solubility, and safety profiles, reducing the risk of unintended polymorphs and enhancing the drug's efficacy in treating ABL1/BCR-ABL1-mediated disorders.
Implementation Method 1
XRPD patterns
Implementation Method 2
X-ray powder diffraction (XRPD) patterns
Implementation Method 3
thermal properties
Data Source
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AI summary
The present invention describes specific crystalline forms of N-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide. The present invention further relates to methods for preparing said crystalline forms, pharmaceutical compositions comprising said crystalline forms, and methods of using said crystalline forms and pharmaceutical compositions to treat disease.