Crystalline Salt Forms for Stable Pharmaceutical Dosage
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Solution Overview
Problem
Current pharmaceutical formulations of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one lack stable crystalline forms suitable for solid dosage forms, leading to challenges in bioavailability, stability, and manufacturability.
Innovation Solution
Development of novel crystalline salt forms, such as maleate and camsylate salts, which are physically stable and less susceptible to hydration, allowing for controlled crystallization and improved properties in solid dosage forms, including specific polymorphic forms like maleate polymorph Form A and camsylate polymorph Form A.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If amorphous or non-crystalline forms of Compound 1 are used, then flexibility in formulation is maintained, but stability and bioavailability are compromised
Solution Approach 1:
The patent applies parameter changes by transforming the physical state of Compound 1 from amorphous to crystalline forms through controlled crystallization processes. Specific parameters such as temperature, solvent composition, and crystallization rate are modified to produce stable crystalline polymorphs (Forms I-IV) and solvates that exhibit improved stability and bioavailability while maintaining formulation feasibility
Solution Approach 2:
The patent creates composite materials by forming crystalline complexes of Compound 1 with co-formers such as cyclic carbonates (ethylene carbonate, propylene carbonate) and other solvents. These composite crystalline structures combine the properties of both compounds, resulting in enhanced stability and controlled release characteristics while providing well-defined crystal lattices suitable for solid dosage forms
2Productivity
If conventional non-crystalline formulations are used, then manufacturing simplicity is maintained, but bioavailability and stability are reduced
Solution Approach 1:
The patent applies preliminary action by pre-establishing well-defined crystalline structures and polymorphic forms of Compound 1 before final formulation. The controlled crystallization process creates stable, reproducible crystal forms with predictable dissolution and bioavailability characteristics, eliminating the need for complex post-processing or stabilization steps during manufacturing
Solution Approach 2:
The patent utilizes phase transitions by controlling the transition from liquid/solution phase to solid crystalline phase through controlled crystallization. This phase transition allows Compound 1 to form stable crystalline polymorphs and solvates with specific melting points, densities, and dissolution rates that enhance bioavailability while providing robust solid-state properties for easy manufacturing
3Reliability
If stable crystalline forms are developed, then stability and bioavailability improve, but crystal structure control becomes more challenging
Solution Approach 1:
The patent uses co-formers such as cyclic carbonates (ethylene carbonate, propylene carbonate) and other solvents as intermediaries to mediate the crystallization of Compound 1. These intermediary substances facilitate the formation of specific polymorphic forms and solvates by acting as template molecules during crystallization, thereby controlling crystal structure while enhancing stability. The co-formers become integral parts of the crystal lattice, providing structural stability and reproducible physical properties
Solution Approach 2:
The patent applies parameter changes by systematically varying crystallization conditions including temperature profiles, solvent composition ratios, cooling rates, and supersaturation levels to control which polymorphic form crystallizes. By adjusting these parameters, the process selectively produces desired crystal forms (Forms I-IV) with specific stabilities and dissolution rates, achieving both stability and manufacturability
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 salt forms enhance bioavailability, stability, and manufacturability, making them suitable for bulk preparation and handling, particularly in solid dosage forms, while maintaining non-hygroscopic properties.
Implementation Method 1
controlled crystallization and improved properties in solid dosage forms
Data Source
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AI summary
The present invention relates to novel polymorphic forms of 8-fluoro-2-{4- [(methylamino)methyl]phenyf}-1,3,4,5-tetrahydro-6H-azepino(5,4,3-cd]indol-6-one;(I), and to processes for their preparation. Such polymorphic forms may be a component of a pharmaceutical composition and may be used to treat a mammalian disease condition mediated by poly(ADP-ribose) polymerase activity including the disease condition such as cancer.