LSD1 Inhibitor Salt Forms Reduce Hygroscopicity
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Solution Overview
Problem
Hygroscopicity issues with biologically active compounds like LSD1 inhibitors affect their stability and handling in pharmaceutical formulations, leading to variations in biological efficacy and uniformity of compositions, making it difficult to develop effective and stable antitumor agents.
Innovation Solution
Development of polymorphic and amorphous forms, salts, co-crystals, solvates, and hydrates of the LSD1 inhibitor Compound I, along with processes for their synthesis and pharmaceutical compositions, to reduce hygroscopicity and improve handling characteristics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If hygroscopic compounds are used in pharmaceutical formulations, then the compound can be easily obtained and synthesized, but the compound absorbs moisture leading to variations in compound mass and difficulty in accurately evaluating biological efficacy
Solution Approach 1:
The patent applies parameter changes by modifying the physical and chemical parameters of the compound through salt formation. By converting the hygroscopic free base form into non-hygroscopic salt forms (such as hydrochloride, sulfate, trifluoroacetate salts), the compound's moisture absorption characteristics are fundamentally altered, enabling accurate mass measurement and biological efficacy evaluation while maintaining ease of manufacture through established salt formation protocols
2Ease of manufacture
If hygroscopic compounds are used in pharmaceutical formulations, then the compound can be synthesized, but the compound absorbs moisture leading to variations in compound mass depending on water present in surrounding environment
Solution Approach 1:
The patent changes the chemical parameter of the compound by forming stable salt forms with various acids (hydrochloric acid, sulfuric acid, trifluoroacetic acid, etc.). This transformation fundamentally alters the compound's hygroscopic properties, converting moisture-absorbing free bases into non-hygroscopic salts that maintain uniform mass composition regardless of environmental humidity, thereby ensuring formulation stability
Solution Approach 2:
The patent creates composite material structures by combining the active pharmaceutical ingredient (LSD1 inhibitor) with counterions from various acids to form salt complexes. These composite salt forms (e.g., Compound I hydrochloride, Compound I sulfate) exhibit improved physical and chemical stability compared to the parent compound, eliminating moisture absorption issues while preserving biological activity
3Ease of manufacture
If hygroscopic compounds are used in pharmaceutical formulations, then the compound can be processed, but the compound becomes sticky causing problems during processing
Solution Approach 1:
The patent changes the physical parameter of the compound's surface properties and bulk characteristics through salt formation. The resulting salt forms (hydrochloride, sulfate, trifluoroacetate, etc.) exhibit fundamentally different rheological properties compared to the hygroscopic free base, eliminating stickiness and enabling smooth processing through standard pharmaceutical manufacturing operations such as tablet compression, capsule filling, and granulation
Data Source
AI summary
Forms of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile, designated herein as Compound I, were prepared and characterized in the solid state. Also provided are processes of manufacture and methods of using the forms of Compound I.