Polymorph Selection for Compound I Storage Stability
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Solution Overview
Problem
There is a need for pharmaceutically useful forms of compounds like (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione that possess properties appropriate for processing, manufacturing, storage stability, and usefulness as a drug.
Innovation Solution
The development of crystalline forms, specifically polymorphs of Form A, B, C, D, E, and F, of the mentioned compound, which include Form B, C, D, E, and F, as well as mixtures thereof, along with pharmaceutical compositions comprising these forms and pharmaceutically acceptable excipients.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a crystalline form of Compound I is used, then storage stability and manufacturing consistency are improved, but the selection of appropriate polymorphs with optimal properties becomes more complex
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallization conditions (solvent type, temperature, pH, additives) to generate different polymorphic forms of Compound I. Each polymorph (Forms A-F) has distinct crystal packing arrangements and physical properties, allowing selection of optimal forms for specific pharmaceutical applications based on desired stability, solubility, and manufacturability characteristics.
Solution Approach 2:
The patent utilizes phase transitions by inducing controlled crystallization from solution phases to solid crystalline phases. Different polymorphic forms are obtained through controlled phase transitions using various solvents and crystallization methods, enabling the production of stable, well-defined crystalline forms suitable for pharmaceutical manufacturing while avoiding amorphous or metastable states.
2Ease of manufacture
If multiple polymorphs are developed, then options for processing and manufacturing are improved, but the complexity of characterizing and controlling crystal forms increases
Solution Approach 1:
The patent employs characteristic X-ray diffraction patterns as unique identifiers for each polymorph (Forms A-F). Each crystalline form exhibits distinct diffraction peak positions and intensities, serving as a fingerprint for identification and quality control. This allows rapid, non-destructive characterization and verification of the desired polymorphic form during manufacturing and storage.
Solution Approach 2:
The patent implements feedback control through systematic characterization of each polymorph's physical properties (XRPD patterns, DSC thermograms, solubility data, stability profiles). This feedback information guides the selection and production of appropriate polymorphs for specific pharmaceutical formulations, ensuring consistent quality and performance while simplifying manufacturing decisions.
3Stability of the object's composition
If crystalline forms with improved stability are selected, then storage and shelf life are enhanced, but solubility and bioavailability may be reduced
Solution Approach 1:
The patent applies local quality by optimizing the crystal packing arrangement in specific regions of the crystal structure to balance stability and solubility. Different polymorphs exhibit varying degrees of molecular exposure, hydrogen bonding networks, and crystal lattice energy, allowing selection of forms that provide adequate storage stability while maintaining sufficient solubility for pharmaceutical effectiveness.
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
These crystalline forms, particularly Form B, offer improved stability, manufacturability, and consistency, addressing issues of storage stability and drug product uniformity, thereby enhancing their utility in pharmaceutical applications.
Implementation Method 1
an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature comprising: at least three peaks, or at least four peaks, selected from the group consisting of 5.5, 7.1, 9.3, 16.5, and 19.0° 2θ±0.2° 2θ
Implementation Method 2
a differential scanning calorimetry thermogram comprising: an endotherm onset at about 307° C.
Implementation Method 3
a thermogravimetric analysis thermogram
Data Source
AI summary
The present invention provides crystalline forms of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (“Compound I”). Also provided are related pharmaceutical compositions, methods of preparation, and methods of treating hypertrophic cardiomyopathy (HCM), heart failure with preserved ejection fraction (HFpEF), diastolic dysfunction, left ventricular hypertrophy, and other cardiac diseases.