CDK Inhibitor Salts for Solubility and Stability
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Solution Overview
Problem
The compound 125, a potent cdk inhibitor, is poorly water-soluble and hygroscopic, making it unsuitable for oral administration and prone to chemical degradation, which affects its stability and efficacy in pharmaceutical formulations.
Innovation Solution
Development of novel crystalline salts such as maleate, malonate, and glycolate salts with improved solubility and reduced hygroscopicity, which are suitable for pharmaceutical development and offer enhanced biopharmaceutical properties, including high water solubility and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the compound 125 is used in its free base form, then it shows potent cdk inhibitor activity, but it is poorly water-soluble and hygroscopic, making it unsuitable for oral administration
Solution Approach 1:
The patent applies parameter changes by converting the compound from its free base form to various salt forms (hydrochloride, mesylate, fumarate, maleate, etc.). This chemical modification changes the physical and chemical parameters of the compound, specifically improving water solubility and reducing hygroscopicity while maintaining the core therapeutic activity. The salt formation allows the compound to achieve suitable biopharmaceutical properties for oral administration.
Solution Approach 2:
The patent uses salt-forming agents (acids such as hydrochloric acid, methanesulfonic acid, fumaric acid, maleic acid) as intermediaries to transform the free base compound into pharmaceutically acceptable salt forms. These intermediaries facilitate the conversion process and enable the compound to achieve the desired solubility and stability characteristics without altering its fundamental pharmacological activity.
2Ease of operation
If the compound is formulated as a tri-hydrochloride salt to improve solubility, then aqueous solubility increases to about 10 mg/ml, but the salt becomes amorphous and hygroscopic, thus not suitable for oral formulation
Solution Approach 1:
The patent applies parameter changes by selecting specific acid counterions (such as mesylate, fumarate, maleate) and controlling crystallization conditions to produce crystalline salt forms. This changes the physical state from amorphous to crystalline, thereby reducing hygroscopicity while maintaining improved solubility characteristics compared to the free base form.
Solution Approach 2:
The patent applies local quality by creating distinct crystalline forms with specific properties. Different salt forms (mesylate, fumarate, maleate) exhibit different degrees of crystallinity and hygroscopicity, allowing selection of the optimal form for specific formulation requirements. Each salt form has localized properties optimized for different aspects of drug delivery.
3Ease of operation
If the compound absorbs water from the atmosphere, then it shows increased water content up to 2% at 90% RH, but this leads to chemical degradation and affects stability
Solution Approach 1:
The patent applies parameter changes by converting the hygroscopic free base into crystalline salt forms with reduced water affinity. The salt forms exhibit significantly lower water uptake compared to the free base, thereby reducing the driving force for chemical degradation pathways that are moisture-dependent. This parameter change directly addresses the stability issue while maintaining handling properties.
Solution Approach 2:
The patent applies preliminary anti-action by pre-converting the compound into stable crystalline salt forms that are resistant to moisture uptake before formulation and storage. This preventive measure counteracts the potential harmful effect of hygroscopicity and subsequent chemical degradation, ensuring long-term stability during handling and storage conditions.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The new salt forms provide a crystalline, rapidly dissolving, and stable form of the compound 125, suitable for oral administration, improving its therapeutic efficacy and handling properties, and allowing for safer and more effective treatment of cell proliferative disorders like cancer.
Implementation Method 1
The initially obtained free base was converted into the tri-hydrochloride salt in order to improve solubility of the compound
Implementation Method 2
The new salts are crystalline, less hygroscopic, rapidly-dissolving solids with high water solubility
Data Source
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AI summary
The present invention relates to novel crystalline form(s) of water-soluble salts and of free base of a cdk inhibitor. Such crystal salts are for example fumarate, L-malate, maleate, succinate, adipate, malonate, glycolate, phosphate, mesylate, L-lactate, hydrochloride, di-hydrochloride, tri-hydrochloride. Hydrates and polymorphs 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.