Nilotinib Hydrochloride Form L Crystallization
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Solution Overview
Problem
There is a need for novel polymorphic forms of nilotinib hydrochloride with improved characteristics such as chemical purity, flowability, solubility, morphology, stability, storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents to enhance the performance and market acceptance of pharmaceutical products for treating chronic myelogenous leukemia.
Innovation Solution
A novel crystalline form of nilotinib hydrochloride, designated as Form L, is developed, characterized by specific X-Ray diffraction patterns, differential scanning calorimetry, and thermogravimetric analysis, which is prepared by dissolving nilotinib in a mixture of formic acid and ethylformate, adding hydrochloric acid, and isolating the product through conventional techniques, resulting in improved physiochemical properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing polymorphic forms of nilotinib hydrochloride are used, then the basic therapeutic function is achieved, but the chemical purity, solubility, and stability are insufficient
Solution Approach 1:
The patent applies parameter changes by discovering and characterizing multiple polymorphic forms (Form A through Form O) of nilotinib hydrochloride, each with distinct crystal structures and physical properties. By changing the polymorphic form parameter, the invention achieves improved chemical purity, solubility, and stability compared to existing forms. The specific crystal packing arrangements and molecular conformations in each polymorph directly influence these critical pharmaceutical properties.
Solution Approach 2:
The invention utilizes phase transitions between different polymorphic forms to optimize drug properties. The patent describes methods for converting between polymorphic forms through controlled crystallization conditions, solvent selection, and temperature management. These phase transition processes enable the production of polymorphs with superior chemical purity and enhanced solubility characteristics.
2Stability of the object's composition
If existing polymorphic forms are used, then manufacturing is straightforward, but stability to dehydration and polymorphic conversion is poor
Solution Approach 1:
The patent employs parameter changes by identifying polymorphic forms with specific hydration states and thermal stability characteristics. Forms such as the anhydrous polymorphs are selected for their enhanced stability to dehydration. The invention provides detailed characterization of these forms through thermogravimetric analysis, differential scanning calorimetry, and X-ray diffraction, enabling selection of the most stable form for manufacturing while maintaining ease of production through established crystallization techniques.
3Ease of operation
If existing polymorphic forms are used, then basic drug delivery is achieved, but flowability and morphology are inadequate
Solution Approach 1:
The invention applies parameter changes by optimizing crystal morphology through controlled crystallization processes. Different polymorphic forms exhibit distinct habit patterns, particle sizes, and surface characteristics that directly impact flowability and manufacturability. The patent describes how adjusting crystallization parameters such as solvent composition, temperature profiles, and addition rates produces polymorphs with improved flow properties and controlled morphology suitable for pharmaceutical manufacturing.
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 novel crystalline form L of nilotinib hydrochloride exhibits enhanced chemical purity, solubility, and stability, with distinct analytical profiles compared to existing forms, offering improved performance characteristics and stability, thus addressing the limitations of existing polymorphic forms.
Implementation Method 1
dissolving nilotinib in a mixture of formic acid and ethylformate
Implementation Method 2
adding hydrochloric acid, and isolating the product
Implementation Method 3
isolating nilotinib hydrochloride Form L... characterized by specific X-Ray diffraction patterns
Data Source
AI summary
The present invention relates to novel crystalline form of nilotinib hydrochloride, process for its preparation and pharmaceutical composition comprising the same.