Crystalline Piperazine Carboxylate Forms for Stable Bioavailable Dosage
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Solution Overview
Problem
The discovery and selection of solid forms of pharmaceutical compounds are complex and unpredictable, affecting properties such as solubility, stability, and bioavailability, which can lead to formulation issues and market withdrawal, as seen in the case of Ritonavir ™.
Innovation Solution
Development of novel crystalline forms of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate for oral, mucosal, parenteral, sublingual, transdermal, buccal, or topical administration, characterized by specific X-ray powder diffraction patterns and thermal analysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If polymorphic forms of a compound are used, then solubility and bioavailability can be improved, but stability and predictability worsen due to the complex and unpredictable nature of solid form selection
Solution Approach 1:
The patent performs preliminary identification and characterization of multiple polymorphic forms (Forms I, II, III, IV, V, and VI) with specific XRPD patterns, DSC profiles, and solubility data before product development. This advance knowledge allows selection of the most suitable crystalline form for the intended application, avoiding later formulation failures.
Solution Approach 2:
The patent systematically varies crystallization parameters including solvent type (acetone, ethanol, isopropanol, toluene, dichloromethane), temperature conditions, and pH levels to generate and characterize multiple polymorphic forms. This methodical parameter exploration enables identification of stable forms with optimized bioavailability characteristics.
2Adaptability or versatility
If different crystal forms are discovered, then formulation flexibility and therapeutic benefits are enhanced, but manufacturing and storage stability may deteriorate
Solution Approach 1:
The patent assigns different polymorphic forms to different formulation needs and routes of administration. For example, certain crystalline forms may be selected for oral dosage forms requiring high solubility, while other stable forms are chosen for parenteral preparations requiring storage stability. Each form's properties are optimized for its specific application context.
Solution Approach 2:
The patent conducts comprehensive stability testing and characterization of each polymorphic form under various manufacturing and storage conditions before product development. This includes assessing moisture sensitivity, thermal stability, and chemical stability to anticipate and prevent potential stability issues during later production and storage phases.
3Reliability
If amorphous solids are selected for enhanced dissolution profile, then bioavailability improves, but physical and chemical stability deteriorates
Solution Approach 1:
The patent employs solvatomorph formation by incorporating solvent molecules (acetone, ethanol, isopropanol, toluene, dichloromethane) into the crystal lattice. This approach modifies the dissolution profile through solvent-solute interactions while maintaining the physical stability provided by the crystalline structure, achieving a balance between the benefits of amorphous forms and the stability of crystalline forms.
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 crystalline forms provide stable and bioavailable dosage forms for treating disorders like pain, neurological disorders, and cancer, enhancing formulation and therapeutic benefits.
Implementation Method 1
crystalline form A having an X-ray powder diffraction pattern comprising peaks at 18.1, 20.1, and 22.3 degrees 2θ ± 0.2 degrees 2θ using Cu Ka radiation at 1.54 Å
Implementation Method 2
characterized by specific X-ray powder diffraction patterns
Implementation Method 3
characterized by specific X-ray powder diffraction patterns and thermal analysis
Data Source
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AI summary
Provided herein are dosage forms comprising the crystalline forms of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate and their use in methods of treating diseases and disorders, including inflammatory bowel disease, neurological disorder, or cancer, wherein the method comprises administering the dosage forms to a patient in need thereof.