PLK Inhibitor Salt Forms for Solubility and Stability
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Solution Overview
Problem
The compound 937, a PLK inhibitor, has poor water solubility and hygroscopicity, making it challenging to formulate and administer, particularly for oral administration, due to its low bulk density and stability concerns under varying humidity and temperature conditions.
Innovation Solution
Development of novel crystalline salts such as L-tartrate, succinate, phosphate, and fumarate forms of compound 937, which exhibit high water solubility, low hygroscopicity, and improved bulk density, ensuring better physicochemical and biopharmaceutical properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If compound 937 is used as free base form, then it maintains therapeutic activity, but it exhibits poor water solubility and low bulk density making formulation difficult
Solution Approach 1:
The patent applies parameter changes by converting the chemical form of compound 937 from free base to various salt forms (hydrochloride, mesylate, fumarate, maleate, tartrate, citrate). This chemical parameter transformation fundamentally alters the solubility and bulk density characteristics while preserving the therapeutic PLK1 inhibition activity, enabling successful oral formulation development
Solution Approach 2:
The patent creates composite material systems by forming salts of compound 937 with various counterions. Each salt form represents a composite structure combining the active pharmaceutical ingredient with a counterion, resulting in materials that exhibit improved physicochemical properties (water solubility, bulk density, flowability) while maintaining the core therapeutic function of the original compound
2Ease of operation
If compound 937 is formulated for oral administration, then it enables convenient dosing, but poor water solubility and stability under varying humidity conditions prevent successful formulation
Solution Approach 1:
The patent transforms the physical and chemical parameters of compound 937 by forming stable salt forms with controlled hydration states. The salt forms exhibit improved stability profiles under varying humidity and temperature conditions compared to the free base, enabling reliable oral formulation development while maintaining convenient dosing characteristics
Solution Approach 2:
The patent employs salt forms that can be manufactured with controlled water content and stability characteristics suitable for oral dosing. These salt forms represent optimized material states that provide sufficient stability for oral administration without requiring complex stabilization strategies, enabling convenient patient dosing
3Reliability
If compound 937 is used as free base, then it shows the intended pharmacological activity, but it is slightly hygroscopic with low bulk density affecting handling and storage
Solution Approach 1:
The patent changes the physical parameters of compound 937 by converting it to salt forms with fundamentally different hygroscopicity and bulk density characteristics. The salt forms exhibit reduced hygroscopicity and significantly improved bulk density compared to the free base, resulting in materials that are easier to handle, store, and process while preserving the essential pharmacological activity of PLK1 inhibition
Data Source
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AI summary
The present invention relates to novel crystalline, water-soluble salts of a plk inhibitor. Such crystal salts are for example L-tartrate, succinate, phosphate, mesylate, maleate, L-malate, hydrochloride, fumarate (half mole of counterion), fumarate, citrate (half mole of counterion), benzenesulfonate and L-aspartate (half mole of counterion). New crystal forms of the base as well as solvates and hydrates of such new salt forms, a process for their preparation, their utility in therapy and to the pharmaceutical compositions containing them are also claimed and described in the present application.