Dasatinib Anhydrous Polymorph Crystallization
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Solution Overview
Problem
There is a need for additional solid state forms of dasatinib to improve its performance characteristics, particularly its solubility and stability, which is essential for effective treatment of chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia.
Innovation Solution
The development of an anhydrous form of dasatinib, characterized by a specific powder XRD pattern, is achieved through crystallization from mixtures containing compounds like N-(2-hydroxyethyl)piperazine, N-ethyldiisopropylamine, DMSO, methanol, and water, or ethanol, allowing for the creation of pharmaceutical compositions with enhanced properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If dasatinib is crystallized from conventional solvents and conditions, then existing polymorphic forms (H1-7, BU-2, E2-1, N-6, T1H1-7, T1E2-1) are obtained, but their solubility and stability are insufficient for optimal therapeutic performance
Solution Approach 1:
The patent applies parameter changes by modifying crystallization conditions including solvent composition (DMSO, methanol, water, ethanol), temperature gradients, and pH levels to generate a novel anhydrous polymorphic form of dasatinib with improved solubility and stability characteristics compared to existing forms
Solution Approach 2:
The invention utilizes phase transitions during crystallization from liquid solution to solid crystal form, controlling the transition conditions to stabilize a new anhydrous polymorphic form that exhibits superior solubility and stability properties for enhanced therapeutic performance
2Reliability
If additional solid state forms of dasatinib are developed, then solubility and stability are improved, but the complexity of characterizing and controlling polymorphic forms increases
Solution Approach 1:
The patent employs X-ray diffraction (XRD) and differential scanning calorimetry (DSC) techniques to characterize and identify the new polymorphic form, replacing complex manual characterization methods with sophisticated analytical instrumentation that provides precise and reliable data for polymorph identification and control
3Reliability
If dasatinib is formulated with targeted release profiles, then therapeutic efficacy is enhanced, but the manufacturing process becomes more complex
Solution Approach 1:
The patent prepares dasatinib in advance as a specifically characterized anhydrous polymorphic form with known and optimized solubility and stability properties, allowing formulation scientists to more easily design targeted release profiles without dealing with the uncertainties of less characterized polymorphic forms
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 anhydrous form of dasatinib exhibits improved solubility and stability, facilitating targeted release profiles and easier processing, thereby enhancing its therapeutic efficacy and usability in leukemia treatments.
Implementation Method 1
crystallizing dasatinib from a mixture comprising the compound 1, N-(2-hydroxyethyl) piperazine N-ethyldiisopropylamine, and a mixture of DMSO, methanol and water
Data Source
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AI summary
The present invention relates to polymorphs of dasatinib, process for preparing said polymorphs, and pharmaceutical compositions thereof.