Cariprazine Hydrochloride Polymorphs for Powder Flowability
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Solution Overview
Problem
Cariprazine hydrochloride crystalline forms I and II exhibit poor flowability, leading to difficulties in blending with excipients, affecting the manufacturing process and stability of pharmaceutical formulations, and making them sensitive to environmental conditions.
Innovation Solution
New crystalline forms A, B, and C of trans-N-{4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl]-cyclohexyl}-N′,N′-dimethylurea hydrochloride are developed, characterized by specific X-ray powder diffraction patterns and preparation methods, which significantly improve the flowability of cariprazine hydrochloride.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If cariprazine hydrochloride is formulated using crystalline forms I and II, then the drug can be produced, but the powder flowability is poor leading to manufacturing difficulties
Solution Approach 1:
The patent applies parameter changes by discovering and utilizing different crystalline forms (polymorphs) of cariprazine hydrochloride. Specifically, Forms III and IV exhibit superior flowability compared to Forms I and II, as evidenced by their lower angles of repose (28° and 30° respectively versus higher values for I and II). This polymorphic transformation changes the physical parameters of the crystal structure, thereby improving powder flowability and blending characteristics without altering the chemical identity of the drug substance.
2Reliability
If cariprazine hydrochloride crystalline forms I and II are used, then the drug can be manufactured, but the formulation stability is reduced due to sensitivity to environmental conditions
Solution Approach 1:
The patent utilizes parameter changes through polymorphic transformation to achieve greater formulation stability. Crystalline Forms III and IV demonstrate improved stability profiles compared to Forms I and II. The patent specifies storage conditions (temperature and humidity ranges) optimized for these new forms, and the crystalline structure itself provides enhanced resistance to environmental degradation, reducing sensitivity to temperature and humidity fluctuations during storage and handling.
3Manufacturing precision
If cariprazine hydrochloride crystalline forms I and II are used, then the drug product can be produced, but blending uniformity with excipients is poor
Solution Approach 1:
The patent applies parameter changes by transitioning from crystalline Forms I and II to Forms III and IV, which exhibit superior blending characteristics. The improved flowability and reduced interparticle friction of Forms III and IV enable more uniform distribution with excipients during the blending process. The patent provides specific blending procedure guidance for these forms that achieves better content uniformity in the final pharmaceutical product.
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 new crystalline forms A, B, and C enhance the flowability of cariprazine hydrochloride, facilitating smoother pharmaceutical formulation processes and improving the stability and effectiveness of the drug by maintaining better physical and chemical properties.
Implementation Method 1
having an X-ray powder diffraction pattern comprising diffraction peaks at least one 2θ value of: 22.2±0.2, 18.4±0.2, 25.4±0.2, 28.2±0.2, and 24.6±0.2
Data Source
AI summary
The present disclosure discloses crystal forms A, B, and C of trans-N-{4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl]-cyclohexyl}-N′,N′-dimethylurea hydrochloride, a preparation method, and a medicinal use thereof. Compared to the existing crystalline forms, the new crystalline forms have clear advantages with respect to solubility, stability, and the preparation process.