Variable Hydrate Crystalline Form F for PDE10 Inhibitor Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current drug formulations of Compound (I), a PDE10 inhibitor, face challenges in achieving stable crystalline forms that are easily manufacturable, cost-effective, and maintain bioavailability and release characteristics during storage and shipment.
Innovation Solution
Development of novel crystalline forms, specifically a variable hydrate form (Form F) with a primitive monoclinic lattice and specific X-ray powder diffraction patterns, which can accommodate varying amounts of water, ensuring stability and consistent manufacturing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a stable crystalline form is selected for drug formulation, then manufacturing consistency and shelf-stability are improved, but the complexity of identifying and producing the correct polymorph increases
Solution Approach 1:
The patent applies parameter changes by identifying specific crystalline forms (polymorphs) of Compound (I) with distinct structural parameters and stability characteristics. Different polymorphic forms are characterized by specific X-ray diffraction patterns, melting points, and solubility parameters, allowing selection of the most stable form for formulation while maintaining manufacturing consistency.
Solution Approach 2:
The patent uses X-ray powder diffraction (XRPD) patterns as a fingerprinting method to copy and identify specific polymorphic forms. By establishing reference XRPD patterns for each polymorph, the invention enables rapid identification and quality control without requiring complex structural analysis, thus reducing the complexity of polymorph identification while ensuring reliability.
2Productivity
If a crystalline form is optimized for large-scale manufacturing, then production efficiency and cost-effectiveness are improved, but the risk of polymorphic transformation during storage increases
Solution Approach 1:
The patent applies preliminary action by pre-characterizing multiple polymorphic forms of Compound (I) and selecting the most stable crystalline form for manufacturing. The chosen polymorph is optimized for large-scale production while its stability profile is established in advance through thermal analysis, solubility studies, and storage testing, preventing polymorphic transformation during subsequent storage and shipment.
Solution Approach 2:
The patent implements feedback mechanisms through rigorous characterization and quality control of the selected crystalline form. XRPD analysis, differential scanning calorimetry (DSC), and other analytical methods are used to monitor the polymorphic form throughout manufacturing and storage, providing feedback to ensure the form remains stable and does not transform under various conditions.
3Ease of operation
If a crystalline form with good handling characteristics is selected, then ease of formulation and processing are improved, but the bioavailability and release characteristics may be compromised
Solution Approach 1:
The patent applies local quality by optimizing specific properties of the selected polymorph for different aspects of drug development. The crystalline form is chosen to have good flowability, compressibility, and solubility characteristics locally optimized for both manufacturing handling and in vivo performance. This may involve selecting a polymorph with specific crystal packing arrangements that balance mechanical properties with dissolution rate.
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 forms, particularly Form F, provide a stable and cost-effective solution for large-scale production, maintaining bioavailability and release characteristics, and are suitable for pharmaceutical compositions to inhibit PDE10 activity.
Implementation Method 1
The various polymorphic forms of Compound (I) are characterized by unique XRPD spectra
Implementation Method 2
Polymorphic forms A, B, and D are characterized as anhydrous polymorphs of Compound (I). Polymorphic forms C and E are characterized as solvates of Compound (I). Polymorphic form F and shifted form F represent the same polymorph and is characterized as a variable hydrate of Compound (I).
Data Source
AI summary
The invention relates to a novel variable hydrate crystalline form of 1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone, methods for the preparation thereof, pharmaceutical compositions thereof and their use in the inhibition of PDE10.