AMG 397 Salt and Solvate Forms for Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing forms of AMG 397, a myeloid cell leukemia 1 protein (Mcl-1) inhibitor, lack improved properties suitable for clinical use.
Innovation Solution
Development of various salt and solvate forms of AMG 397, including crystalline forms with specific solvates such as trifluoroethanol, hexafluoroisopropanol, and 1-propanol, as well as amorphous and salt forms like hydrochloride, potassium, and sulfate salts.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If alternative forms of AMG 397 are developed, then stability and bioavailability are improved, but the complexity of the patent increases
Solution Approach 1:
The patent applies parameter changes by developing multiple salt forms (hydrochloride, sulfate, phosphate, acetate, fumarate, maleate, tartrate, citrate, lactate, succinate, trifluoroacetate) and solvate forms (acetone, acetonitrile, dichloromethane, dimethylformamide, ethanol, isopropanol, methanol, water) of AMG 397. Each salt and solvate form represents a different chemical parameter variation that improves stability and bioavailability while maintaining the core molecular structure. This systematic exploration of parameter space allows optimization of pharmaceutical properties without fundamentally changing the active molecule.
Solution Approach 2:
The patent creates composite material forms by combining AMG 397 with various counterions to form salts and with solvents to form solvates. These composite forms integrate the active pharmaceutical ingredient with auxiliary substances in defined stoichiometric ratios, creating new materials with enhanced stability and bioavailability profiles. The crystalline structures of these composite forms provide improved physical and chemical properties suitable for clinical use.
2Reliability
If alternative forms of AMG 397 are developed, then bioavailability is improved, but manufacturing complexity increases
Solution Approach 1:
The patent employs preliminary action by pre-forming AMG 397 into various salt and solvate forms during the synthesis process. The hydrochloride salt is formed by reaction with HCl, sulfate salts by reaction with sulfuric acid or sulfates, and solvates by crystallization from appropriate solvents. These preliminary formative actions during manufacturing simplify downstream processing and ensure consistent bioavailability without requiring additional complex formulation steps later.
Solution Approach 2:
The patent utilizes parameter changes by selecting specific salt formation conditions (pH, temperature, solvent system) and solvate crystallization parameters (solvent type, concentration, temperature) to optimize both bioavailability and manufacturing ease. Each salt and solvate form represents an optimized parameter set that balances pharmaceutical performance with manufacturability, allowing standard pharmaceutical manufacturing processes to produce the improved forms.
Data Source
AI summary
Disclosed herein are salt and solvate forms of (4S,7aR,9aR,10R,11E,14S,15R)-6′-chloro-10-methoxy-14,15-dimethyl-10-{[(9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-yl]methyl}-3′,4′,7a,8,9,9a,10,13,14,15-decahydro-2′H,3H,5H-spiro[1,19-etheno-16,16-cyclobuta[i][1,4]oxazepino[3,4-f][1,2,7]thiadlazacyclohexadecine-4,1 naphthalene]-16,16,18 (7H,17H)-trione (AMG 397): (AMG 397), 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.