Polymorphic Solid Forms Enhance Drug Solubility
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Solution Overview
Problem
The unpredictability of polymorphic forms of pharmaceutical compounds affects their physical properties, stability, and bioavailability, making it challenging to develop effective pharmaceutical formulations for conditions like cancer and hyperplasias.
Innovation Solution
Development of new solid state forms of 17-Ethynyl-10R,13S-dimethyl-2,3,4,5S,6,7,8R,9S,10,11,12,13,14S,15,16,17-hexadecahydro-1H-cyclopenta[a]phenanthrene-3S,17S-diol, including crystalline and amorphous forms, characterized using methods like XRPD, DSC, and TGA, to enhance solubility and bioavailability for treating hormone-sensitive cancers and hyperplasias.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If a compound exists in multiple polymorphic forms, then different physical properties (solubility, stability, bioavailability) can be achieved, but the unpredictability of which form will form makes formulation development difficult
Solution Approach 1:
The patent applies preliminary action by pre-defining specific crystalline forms ( Forms I-VIII) with predetermined solubility and stability characteristics before formulation development. By establishing which polymorphic forms possess desirable properties in advance, the unpredictable polymorphic transformation problem is resolved, allowing formulators to select from known stable forms rather than dealing with unpredictable transformations during development
Solution Approach 2:
The patent employs parameter changes by modifying crystallization conditions (temperature, solvent type, pH, additives) to control which specific polymorphic form precipitates. By systematically varying these parameters, the invention enables selective formation of desired crystalline forms with predictable solubility and stability profiles, eliminating the randomness of polymorphic outcomes
2Reliability
If metastable polymorphic forms are used to enhance solubility and bioavailability, then therapeutic efficacy improves, but these forms may transform to more stable forms with lower solubility over time
Solution Approach 1:
The patent applies beforehand cushioning by incorporating stabilizing excipients and optimizing formulation conditions prior to administration. These pre-established protective measures prevent or delay the transformation of metastable high-solubility forms to stable low-solubility forms during storage and in vivo, cushioning against the harmful effect of polymorphic transformation on solubility and efficacy
Solution Approach 2:
The patent utilizes phase transitions by carefully controlling the crystallization process to trap molecules in metastable high-energy configurations that correspond to soluble polymorphic forms. By manipulating temperature, solvent, and crystallization kinetics, the invention stabilizes these metastable phases and prevents their transition to more stable but less soluble forms, maintaining enhanced bioavailability
3Reliability
If extensive characterization methods (XRPD, DSC, TGA) are used to identify and stabilize polymorphic forms, then formulation reliability improves, but the complexity and time required for development increases
Solution Approach 1:
The patent applies preliminary action by pre-characterizing each polymorphic form (Forms I-VIII) extensively using XRPD, DSC, and TGA before formulation development begins. By establishing complete characterization data for each form in advance, including stability profiles and transformation conditions, the invention eliminates the need for ongoing complex characterization during formulation development, reducing overall complexity while maintaining reliability
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 characterized solid state forms of the compound improve solubility and bioavailability, leading to effective treatment of hormone-sensitive cancers and hyperplasias, such as prostate and breast cancer, by stabilizing the polymorphic forms and optimizing their physical properties.
Implementation Method 1
characterized using methods like XRPD, DSC, and TGA
Implementation Method 2
characterized using methods like XRPD, DSC, and TGA
Implementation Method 3
characterized using methods like XRPD, DSC, and TGA
Data Source
AI summary
The invention provides and describes solid state 17α-ethynyl-5α-androstane-3α,17β-diol including amorphous and crystalline forms and specific polymorphic forms thereof. Anhydrates and solvates of 17α-ethynyl-5α-androstane-3α,17β-diol include Form III anhydrate and Form I solvate. The invention further relates to solid and suspension formulations containing 17α-ethynyl-5α-androstane-3α,17β-diol in a described solid state form and use of the formulations to treat cancers or precancers such as prostate cancer or breast cancer in subjects or human patients. The invention also relates to methods to make liquid formulations from solid state forms of 17α-ethynyl-5α-androstane-3α,17β-diol and uses of such formulations in treating the described conditions.