Tipiracil Polymorphs and Purification Process
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current processes for preparing 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione hydrochloride face challenges in achieving high purity and specific polymorphic forms, leading to impurities and reduced efficacy in pharmaceutical applications.
Innovation Solution
Development of novel crystalline and amorphous polymorphs, including a dimethyl sulfoxide solvate, and improved processes for purification and solid dispersion with pharmaceutically acceptable excipients to enhance purity and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional processes are used to prepare 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione hydrochloride, then the basic compound can be obtained, but the purity is insufficient and impurities remain
Solution Approach 1:
The patent applies parameter changes by optimizing reaction conditions including temperature ranges (0-5°C, 25-30°C, 65-70°C), pH values (adjusted to 2-3 with HCl), solvent ratios (methanol:water in specific proportions), and reaction times to maximize product purity and minimize impurity formation during synthesis and purification steps
Solution Approach 2:
The patent employs extraction techniques where the crude product is dissolved in methanol and purified by selective precipitation using water as an anti-solvent, followed by filtration to separate and remove impurities from the final product, achieving high purity levels
2Manufacturing precision
If conventional processes are used to prepare the compound, then the compound can be obtained, but specific polymorphic forms cannot be achieved
Solution Approach 1:
The patent utilizes phase transitions by controlling crystallization conditions including temperature changes (cooling from 65-70°C to 0-5°C), solvent evaporation, and anti-solvent addition to induce formation of specific crystalline polymorphic forms (Form-I, Form-II, Form-III) with defined X-ray diffraction patterns and stable physical properties
Solution Approach 2:
The patent achieves polymorphic form control by adjusting critical parameters such as solvent composition (methanol, water, isopropanol ratios), temperature profiles during crystallization, pH levels, and cooling rates to selectively produce desired crystal forms with specific efficacy and stability characteristics
3Manufacturing precision
If purification processes are applied to improve purity, then impurities are reduced, but the process complexity increases
Solution Approach 1:
The patent divides the purification process into distinct sequential stages: (1) initial filtration of reaction mixture, (2) selective precipitation using anti-solvent, (3) vacuum filtration, and (4) washing with specific solvents, allowing each step to target specific impurity types and achieve cumulative purification without requiring complex equipment
Solution Approach 2:
The patent uses methanol as an intermediary solvent to dissolve the crude product and facilitate selective precipitation, and employs water or isopropanol as anti-solvents to induce crystallization, simplifying the purification process through chemical mediation rather than complex mechanical separation systems
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 polymorphs and purification processes result in high-purity 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione hydrochloride with enhanced stability and reduced impurities, suitable for pharmaceutical formulations.
Implementation Method 1
The present invention provides novel crystalline and amorphous polymorphs of 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione hydrochloride
Implementation Method 2
U.S. Pat. No. 9,527,833B2 of Taiho pharmaceuticals has described three crystalline polymorphic forms of 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione hydrochloride namely crystalline form-I, II and III
Implementation Method 3
The present inventors also provides an improved process for the preparation of 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione hydrochloride and its polymorphs and process for the purification of Tipiracil and its intermediate compound
Data Source
AI summary
The present invention relates to solid state forms of 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione hydrochloride compound of formula-1a and their processes for the preparation thereof and an improved process for the preparation of 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione hydrochloride.The present inventors also provides an amorphous polymorph of the combination drug consisting of 2′-deoxy-5-(trifluoromethyl) uridine and 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione monohydrochloride and its process for the preparation.