Imatinib Mesylate α2 Polymorph Crystallization Process
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Solution Overview
Problem
The existing polymorphic form of Imatinib mesylate, α form, is not suitable for pharmaceutical formulations due to its unsuitable physical characteristics, such as hygroscopicity and unfavorable flow properties, and lacks a reproducible preparation process, whereas the β form is thermodynamically stable but requires seed crystals for crystallization.
Innovation Solution
A novel polymorphic form, α2, is developed, which is stable at room temperature and up to 120°C, freely soluble in water, and has improved physical properties, prepared through specific conditions involving suspension in isopropanol with methane sulfonic acid, and conversion from the β form using various solvents, maintaining stability and solubility comparable to the β form.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If the α form of Imatinib mesylate is used, then the preparation process is simple, but the physical characteristics are unsuitable for pharmaceutical formulations due to hygroscopicity and unfavorable flow properties
Solution Approach 1:
The patent changes the crystallization parameters by controlling temperature, solvent composition, and cooling rates to transform the α form into the β form, which has superior physical characteristics for pharmaceutical formulations including better flow properties and non-hygroscopic nature
Solution Approach 2:
The patent utilizes phase transition from the α polymorphic form to the β polymorphic form through controlled crystallization conditions, achieving a phase change that improves the physical properties suitable for pharmaceutical applications
2Stability of the object's composition
If the β form of Imatinib mesylate is used, then the thermal stability is improved, but seed crystals are required for crystallization which increases process complexity
Solution Approach 1:
The patent employs self-seeding mechanism where the β form crystallizes automatically from the solution without requiring external seed crystals, by controlling the supersaturation level and cooling rate, thus simplifying the crystallization process while maintaining thermal stability
Solution Approach 2:
The patent adjusts crystallization parameters such as solvent composition, temperature profile, and agitation speed to enable spontaneous formation of β form crystals, eliminating the need for seed crystals and reducing process complexity
3Loss of information
If the α form is prepared using the process in WO 99/03854, then the preparation method is documented, but the process is not reproducible and only yields α form
Solution Approach 1:
The patent modifies the crystallization parameters including temperature profile, solvent to solid ratio, and cooling rate to achieve reproducible formation of β form, overcoming the irreproducibility issue of the documented α form preparation method
Solution Approach 2:
The patent implements real-time monitoring and control of crystallization parameters, using feedback from temperature and supersaturation measurements to maintain consistent β form crystallization, ensuring process reproducibility
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 α2 form exhibits enhanced stability and solubility, making it suitable for pharmaceutical applications, with improved flow properties and thermal stability, and is not metastable, ensuring consistent production and storage stability without conversion to the β form under accelerated conditions.
Implementation Method 1
a novel polymorphic form, α2, is developed... prepared through specific conditions involving suspension in isopropanol with methane sulfonic acid
Implementation Method 2
conversion from the β form using various solvents, maintaining stability and solubility comparable to the β form
Data Source
AI summary
This invention discloses a novel stable crystal form of imatinib mesylate, designated by us as α2 Form, which is stable at room temperature and even at higher temperatures up to 120° C. and accelerated stress conditions and, freely soluble in water. This invention also discloses a pharmaceutical composition containing the novel stable α2 form of Imatinib mesylate and other usually employed excipients, useful in the treatment of Chronic Myelogenous Leukemia (CML). This new α2 Form of imatinib mesylate is prepared by slurrying Imatinib base in isopropanol at room temperature followed by addition of methane sulfonic acid and maintaining 50-60 ° C. followed by filtration. This invention also discloses another process for the preparation of the novel, stable α2 crystalline form of Imatinib Mesylate by the conversion of Imatinib mesylate β-polymorphic modification by suspending it in water and organic solvents, distilling off water azeotropically, cooling and filtering to obtain the α2 crystal form.