PDE9 Inhibitor Monohydrate Crystal Forms for Solubility and Stability
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Solution Overview
Problem
Existing forms of the PDE9 inhibitor 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one lack enhanced solubility, oral bioavailability, and physical stability, which are crucial for effective drug development and treatment of diseases like sickle cell disease.
Innovation Solution
Development of two monohydrate crystalline forms (MH1 and MH2) of the PDE9 inhibitor, characterized by specific XRPD patterns, dehydration and melting endothermic peaks, and IR absorptions, which enhance solubility and stability, and their use in pharmaceutical compositions for oral administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If existing forms of the PDE9 inhibitor are used, then the drug can be administered, but solubility and oral bioavailability are insufficient
Solution Approach 1:
The patent applies parameter changes by developing multiple crystalline forms (polymorphs) of the PDE9 inhibitor with different physical and chemical properties. Specifically, Form I, Form II, and Form III represent different crystal structures with varying solubility characteristics, allowing optimization of both solubility and bioavailability through selection of the appropriate polymorphic form for administration
2Reliability
If existing forms of the PDE9 inhibitor are used, then the drug can be administered, but physical stability is insufficient
Solution Approach 1:
The patent addresses physical stability by characterizing and controlling phase transitions between different crystalline forms. The detailed XRPD patterns, DSC thermograms, and TGA data for each polymorphic form provide criteria for identifying stable forms under specific conditions, enabling selection of the most physically stable form for long-term storage and administration
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 monohydrate crystalline forms MH1 and MH2 improve solubility and stability, enabling effective treatment of sickle cell disease by increasing cGMP levels and fetal hemoglobin production, thereby reducing disease symptoms.
Implementation Method 1
having an XRPD pattern comprising peaks of 2θ angles at about 9.1, 11.5, 16.2, 16.7, 18.2, 18.9, 19.8, 22.6, and 26.4 degrees 2θ
Implementation Method 2
having an XRPD pattern comprising peaks of 2θ angles at about 9.1, 11.5, 16.2, 16.7, 18.2, 18.9, 19.8, 22.6, and 26.4 degrees 2θ
Implementation Method 3
having a dehydration endothermic peak at about 40-100° C. and a melting endothermic peak at about 184.4° C. in a differential scanning calorimetry (DSC) thermogram
Implementation Method 4
exhibiting dehydration between ambient and about 90° C. with a weight loss of about 4.4% in a thermogravimetric analysis (TGA)
Implementation Method 5
having characteristic absorptions at about 782 cm−1, 1123 cm−1, 1562 cm−1 and 1655 cm−1 in an infrared (IR) spectrum
Data Source
AI summary
The present disclosure relates to crystalline polymorph forms of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one.