Hydrobromide Salt Solid Forms for Stable Oral Gamma-Secretase Inhibitors
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing gamma-secretase inhibitors, such as (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide, face challenges in achieving optimal therapeutic characteristics like high affinity, gamma-secretase deactivation duration, oral bioavailability, tissue distribution, stability, and solid state properties for pharmaceutical formulations, including chemical and thermal stability, solubility, hygroscopicity, and manufacturability.
Innovation Solution
Development of various crystalline and amorphous solid forms of the hydrobromide salt of the compound, characterized by specific XRPD patterns, melting points, and particle sizes, which enhance stability, solubility, and manufacturability, facilitating the production of pharmaceutically acceptable solid dosage forms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If gamma-secretase inhibitors are developed to achieve high affinity and prolonged deactivation duration, then therapeutic efficacy is improved, but solid state stability and manufacturability deteriorate
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallization conditions (temperature, pH, solvent composition, cooling rates) to obtain different polymorphic forms of the gamma-secretase inhibitor. Each polymorph exhibits different solid state properties while maintaining the same chemical structure and therapeutic activity, allowing optimization of both efficacy and stability through parameter control during formulation development
2Stability of the object's composition
If crystalline forms are developed to improve solid state stability, then manufacturability is improved, but solubility and bioavailability may deteriorate
Solution Approach 1:
The patent utilizes parameter changes by controlling crystallization parameters (temperature profiles, pH levels, solvent ratios) to access different polymorphic forms with varying solubility characteristics. This allows the selection of crystalline forms that provide adequate solid state stability while maintaining sufficient solubility for effective oral bioavailability, resolving the contradiction between stability and solubility
Solution Approach 2:
The patent employs composite materials by forming hydrobromide salt complexes of the gamma-secretase inhibitor, where the salt formation creates a new crystalline structure that combines the stability benefits of crystalline forms with improved solubility characteristics. The salt complex acts as a composite system that simultaneously satisfies both stability and solubility requirements
3Adaptability or versatility
If multiple polymorphic forms are obtained to optimize properties, then formulation flexibility is improved, but manufacturing complexity increases
Solution Approach 1:
The patent applies parameter changes by establishing controlled crystallization protocols that can be scaled from laboratory to manufacturing scale. By optimizing parameters such as temperature ramps, holding times, and pH adjustment rates, the process achieves consistent production of desired polymorphic forms with reproducible properties, reducing manufacturing complexity while maintaining formulation flexibility
Solution Approach 2:
The patent uses copying by creating standardized crystallization procedures and characterization methods that can be replicated across different batches and manufacturing sites. The established protocols serve as templates for producing consistent polymorphic forms, simplifying manufacturing while preserving the ability to optimize formulation properties through controlled parameter variation
Data Source
AI summary
The present disclosure relates to: a) solid state forms of hydrobromide salts of Compound 1; b) pharmaceutical compositions comprising one or more solid state forms of hydrobromide salts of Compound 1, and, optionally, a pharmaceutically acceptable carrier; c) methods of treating tumors or cancers by administering one or more solid state forms of hydrobromide salts of Compound 1 to a subject in need thereof; and d) methods for the preparation of solid state forms of Compound 1.