Benzodiazepinone Polymorph Crystallization for Bioavailability and Solubility
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Solution Overview
Problem
Existing benzodiazepinone compounds, such as (2R,3S)—N1-[(3S)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)-butanediamide, lack crystalline forms with desirable physiochemical properties like high bioavailability, solubility, and melting point, which are essential for effective pharmaceutical applications.
Innovation Solution
Development of crystalline forms of (2R,3S)—N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide, including N-2, IPA2-1, M3-1, P1, P2, P3, P4, P5, P6, and their combinations, characterized by specific XRPD patterns and crystallized from various solvents, with processes involving dissolution, anti-solvent addition, and isolation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If crystalline forms of benzodiazepinone compounds are developed, then bioavailability and solubility are improved, but manufacturing complexity increases
Solution Approach 1:
The patent applies parameter changes by developing multiple crystalline forms (polymorphs) of the benzodiazepinone compound, each with different crystal structures and physicochemical properties. By changing the crystalline state parameters, the patent achieves improved bioavailability and solubility while providing systematic methods for manufacturing each specific polymorph form.
Solution Approach 2:
The patent utilizes phase transitions by identifying and characterizing different crystalline phases (polymorphs) of the compound. Each polymorph represents a distinct solid phase with unique properties, and the patent provides methods for transitioning between these phases through controlled crystallization processes, thereby optimizing bioavailability while managing manufacturing complexity.
2Reliability
If crystalline forms with high solubility are developed, then pharmaceutical efficacy is enhanced, but crystallinity may be reduced
Solution Approach 1:
The patent resolves this contradiction by changing the crystalline parameters to create specific polymorph forms that balance solubility and crystallinity. Each polymorph is characterized by specific XRPD patterns and physicochemical properties, allowing optimization of pharmaceutical efficacy while maintaining adequate crystalline structure for stability.
Solution Approach 2:
The patent effectively creates composite crystalline structures through different polymorph forms, where each form combines specific molecular arrangements that provide both solubility enhancement and crystalline stability. The systematic characterization of these forms allows selection of the optimal balance between efficacy and stability for pharmaceutical applications.
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 crystalline forms exhibit improved bioavailability, solubility, and melting point, enhancing the pharmaceutical efficacy of benzodiazepinone compounds for treating various cancers.
Implementation Method 1
crystallized from various solvents, with processes involving dissolution, anti-solvent addition, and isolation
Data Source
AI summary
The present invention provides a crystalline form of (2R,3S)—N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide, represented by the structure of Compound (1), wherein the crystalline form comprises N-2 crystalline form, IPA2-1 crystalline form, M3-1 crystalline form, P4 crystalline form, P5 crystalline form, P6 crystalline form, or any combination thereof. The present invention also provides processes for the preparation of a the crystalline form, and pharmaceutical compositions comprising one or more of the crystalline forms.