AMG 176 Crystalline Salt and Solvate Forms for Solubility and Stability
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Solution Overview
Problem
Existing forms of the Mcl-1 inhibitor AMG 176 do not possess optimal properties for clinical use, particularly in terms of solubility and stability, necessitating the development of alternative crystalline salt and solvate forms with improved characteristics.
Innovation Solution
The development of various crystalline salt and solvate forms of AMG 176, including ammonium, diethylamine, diethanolamine, imidazole, and potassium salts, as well as solvates with solvents like toluene and acetone, which exhibit unique XRPD patterns and thermal properties, enhancing solubility and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing forms of AMG 176 are used, then the compound is available for Mcl-1 inhibition, but solubility and stability properties are suboptimal for clinical use
Solution Approach 1:
The patent applies parameter changes by converting AMG 176 into different salt forms (ammonium, diethylamine, diethanolamine, imidazole, potassium salts) and solvate forms (toluene, acetone solvates). These chemical modifications alter the physical and chemical parameters of the compound, specifically improving solubility and stability characteristics while maintaining the core Mcl-1 inhibitory activity. Each salt and solvate form represents a distinct parameter variation that addresses the suboptimal properties of the original compound.
2Adaptability or versatility
If existing forms of AMG 176 are used, then the compound structure is maintained, but clinical utility is limited due to inadequate solubility and stability
Solution Approach 1:
The patent enhances clinical utility by systematically varying the chemical parameters of AMG 176 through salt formation with different bases (ammonium, diethylamine, diethanolamine, imidazole, potassium) and solvate formation with various solvents (toluene, acetone). These parameter changes produce a library of derivatives with differentiated solubility and stability profiles, enabling selection of the most suitable form for specific clinical applications and patient needs.
Data Source
AI summary
Disclosed herein are salt and solvate forms of. (1S,3′R,6′R,7′S,8′E,11′S,12′R)-6-chloro-7′-methoxy-11′,12′-dimethyl-3,4-dihydro-2H,15′H-spiro[naphthalene-1,22′-[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.03,6.019,24]pentacosa[8,16,18,24]tetraen]-15′-one 13′,13′-dioxide (AMG 176):such as crystalline salt and solvate forms thereof. Also disclosed are methods of making the salt and solvate forms, and methods of treating diseases and disorders with the salt and solvate forms.