Crystalline Salt Forms for Drug Stability
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Solution Overview
Problem
Current drug formulations of 1-(4-{1-[(E)-4-cyclohexyl-3-trifluoromethyl-benzyloxyimino]-ethyl}-2-ethyl-benzyl)-azetidine-3-carboxylic acid face challenges in achieving stable, crystalline forms that ensure reliable plasma concentrations, chemical stability, and long shelf life, as amorphous forms are unstable and difficult to handle.
Innovation Solution
Development of novel crystalline salt forms, specifically hydrochloride, malate, oxalate, and tartrate salts of the compound, which exhibit favorable stability and low hygroscopicity, characterized by specific X-ray powder diffraction patterns, and methods for their preparation involving reaction with corresponding acids in suitable solvents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If amorphous drug materials are used, then the drug can be obtained in a simple form, but the materials are difficult to handle, provide unreliable solubility, and are unstable and chemically impure
Solution Approach 1:
The patent transforms the drug from an amorphous state to a crystalline salt form, changing the physical and chemical parameters of the substance. This transformation resolves the contradiction by providing a form that is both manufacturable and reliably stable with predictable solubility characteristics
Solution Approach 2:
The patent creates composite crystalline structures by forming salts of the compound with various counterions. These composite crystalline materials combine the active pharmaceutical ingredient with counterion partners to achieve both ease of manufacture and reliable stability properties
2Reliability
If a stable crystalline form is provided, then handling and formulation become easier with reliable solubility, but it is not always achievable and crystallisation behaviour cannot be predicted from molecular structure alone
Solution Approach 1:
The patent uses salt formation as an intermediary approach to achieve crystalline forms. By introducing counterion partners, the compound can form stable crystalline salts with predictable crystallisation behavior, making the process more controllable and less dependent on unpredictable molecular structure alone
3Duration of action of stationary object
If the drug is stored over appreciable periods of time, then shelf life is extended, but the active component may exhibit significant change in physico-chemical characteristics
Solution Approach 1:
The patent changes the physical state from amorphous to crystalline and forms stable salt compounds, which fundamentally alters the stability parameters. These crystalline salt forms exhibit enhanced chemical stability and maintain their physico-chemical characteristics over extended storage periods, resolving the shelf life contradiction
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 crystalline salt forms provide enhanced stability, chemical purity, and prolonged shelf life, making them suitable for pharmaceutical applications, including oral and parenteral administration, with potential therapeutic benefits in treating lymphocyte-mediated disorders and cancer.
Implementation Method 1
The hydrochloride salt of Compound I may exist in a crystalline form. Suitably, the hydrochloride salt of Compound I is substantially crystalline. By 'substantially crystalline', we mean that the degree of crystallinity, as determined by X-ray powder diffraction data, is conveniently greater than about 20%
Data Source
AI summary
This invention relates to a hydrochloride, malate, oxalate and tartrate salt forms of 1-(4-{1-[(E)-4-cyclohexyl-3-trifluoromethyl-benzyloxyimino]-ethyl}-2-ethyl-benzyl)-azetidine-3-carboxylic acid (Compound I), to pharmaceutical compositions comprising this salt, to processes for forming this salt and to its use in medical treatment. In addition, the present invention also relates to new polymorphic forms of each of these salts, as well as to pharmaceutical compositions comprising these polymorphic forms, to processes for obtaining them, and their use in medical treatment.