Crystalline Form C Stability for NPY5 Antagonist
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
The existing process for producing N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide yields unstable crystalline Form A, complicating the development of solid dosage formulations, and lacks stable crystalline forms suitable for pharmaceutical use.
Innovation Solution
A process is developed to produce four crystalline forms, including pure Form A, Form C, the mesylate salt, and the fumarate salt, with Form C being the most thermodynamically stable at room temperature, suitable for pharmaceutical compositions and stable above 81°C, and Form A stable above 81°C, ensuring stability and ease of processing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If the original process using EDC-HCl is employed, then Compound I is produced, but the product is obtained as a mixture of unstable crystalline Form A and amorphous compound
Solution Approach 1:
The patent changes the chemical parameters of the reaction process by replacing EDC-HCl with thionyl chloride and dimethylacetamide, which fundamentally alters the product's crystalline form and stability characteristics, transforming unstable Form A into stable Form C
Solution Approach 2:
The patent utilizes phase transition concepts by controlling the crystallization process to obtain specific polymorphic forms (anhydrous forms A and C, and solvate form D) with different stability characteristics, where Form C represents the most stable phase at room temperature
2Ease of operation
If crystalline Form A is used for pharmaceutical formulation, then the compound can be processed, but it transforms to another crystal form on storage
Solution Approach 1:
The patent performs preliminary action by pre-converting the compound into its most stable crystalline form (Form C) before pharmaceutical formulation, preventing subsequent polymorphic transformations during storage and ensuring long-term compositional stability
Solution Approach 2:
The patent converts the harmful polymorphic transformation issue into a benefit by identifying and utilizing the stable Form C, which not only prevents transformation problems but also provides superior processing characteristics and thermodynamic stability
3Productivity
If a streamlined process using thionyl chloride is employed, then the free base step is performed in-situ and yield is improved, but stable crystalline forms must be identified
Solution Approach 1:
The patent applies self-service by allowing the reaction process itself to generate the stable crystalline form C directly, where the thionyl chloride-mediated coupling reaction inherently produces the thermodynamically stable polymorph without requiring additional purification or form conversion steps
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 C provides improved stability and ease of processing, making it suitable for pharmaceutical dosage forms, while Form A maintains stability at higher temperatures, addressing the instability issues of the original process.
Implementation Method 1
The disclosed coupling process employed EDC-HCl and required the separate free base formation step of the pyrazole salt prior to use. Safety and cost concerns associated with the EDC-HCl route led to the development of the present route, which uses thionyl chloride as an improved reagent for the transformation
Implementation Method 2
The original process for the preparation of Compound I, as disclosed in WO 01/14376, yielded Compound I as a mixture of crystalline Form A and amorphous compound. However, the instability of Form A at room temperature complicated the development of solid dosage formulations for compound I
Implementation Method 3
The novel crystal Form C is the most thermodynamically stable crystalline form of Compound I below 81 °C., while the most thermodynamically stable crystalline form of compound (I) above 81 °C is Form A
Data Source
Figure 1
Figure 2
Figure 3
AI summary
The present invention relates to a process for producing crystalline trans-N-[l-(2-fluorophenyl)- S-pyrazoly]-3-oxospiro[6-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide and novel salts, hydrates and polymorphs thereof.