Polymorph B MS-275 Crystallization Stability
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Solution Overview
Problem
The existing form of N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylamino-methyl]benzamide, known as polymorph A, is not thermodynamically stable, leading to conversion into other forms during storage, which complicates drug development and manufacturing, and poses challenges in achieving high chemical purity at larger scales.
Innovation Solution
The development of polymorph B, which is obtained through a process involving dissolution in water with hydrochloric acid, charcoal filtration, pH adjustment, washing, and drying, resulting in a thermodynamically stable form with enhanced chemical purity and absence of polymorph A.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If polymorph A is used as the known form of N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxycarbonylamino-methyl]benzamide, then the compound can be obtained through conventional purification methods, but the form is not thermodynamically stable and converts into other forms during storage
Solution Approach 1:
The patent changes the physical-chemical parameters of the compound by inducing formation of a new polymorph (polymorph B) with different crystal structure, melting point, and solubility characteristics compared to the known polymorph A. This parameter change results in a thermodynamically more stable form that maintains consistency during storage.
Solution Approach 2:
The patent utilizes phase transition processes including recrystallization from specific solvents (ethanol, methanol, acetonitrile) and temperature-controlled crystallization to transform the compound into polymorph B. The phase transition from amorphous or less stable crystalline forms to the thermodynamically stable polymorph B is achieved through controlled cooling and solvent selection.
2Manufacturing precision
If conventional purification methods are used, then the compound can be prepared, but high chemical purity cannot be achieved at larger scales
Solution Approach 1:
The patent optimizes purification parameters by selecting specific solvent systems (ethanol, methanol, acetonitrile) and temperature ranges (0-100°C) to achieve high chemical purity (>95%) at large scale. The recrystallization conditions are adjusted to favor formation of pure polymorph B while minimizing impurity carryover.
Solution Approach 2:
The patent employs recrystallization-based phase transition processes that enable separation of the compound from impurities. By controlling the phase transition during crystallization, high chemical purity is achieved at scale-up levels, with the thermodynamically stable polymorph B forming preferentially and excluding impurities from the crystal lattice.
3Ease of manufacture
If polymorph A is used for drug development, then existing literature and data are available, but the lack of thermodynamic stability complicates manufacturing and formulation
Solution Approach 1:
The patent changes the polymorphic state parameter of the compound from polymorph A to polymorph B, which has superior thermodynamic stability. This parameter change enables more reliable manufacturing and formulation, as polymorph B maintains its structure and properties under various storage and processing conditions.
Solution Approach 2:
The patent performs preliminary crystallization and purification steps under controlled conditions to ensure formation of polymorph B before final formulation. This preliminary action establishes the thermodynamically stable form early in the process, preventing subsequent polymorphic transformations that would complicate 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
Polymorph B is characterized by improved stability and purity, facilitating reliable large-scale manufacturing and maintaining consistent properties, making it suitable for medicinal applications, including the treatment of malignant tumors, autoimmune diseases, and dermatological conditions.
Implementation Method 1
The final step of the process comprises the recrystallization from ethanol
Implementation Method 2
The final step of the process comprises the purification of the compound via silica gel column chromatography
Implementation Method 3
The final step of the process comprises the purification of the compound via treatment with charcoal
Data Source
AI summary
The crystalline Polymorph B of N-(2-aminophenyl)-4-[N-(pyridine-3-yl)methoxy-carbonyaminomethyl]benzamide (MS-275) of formula Iis described, as well as the process for the production of said compound, and its use as a medicament for the treatment of selected diseases.