Aficamten-Tartaric Acid Co-Crystal for Solubility and Stability
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Solution Overview
Problem
Current sarcomere-targeting drugs for cardiac diseases like hypertrophic cardiomyopathy lack sufficient selectivity for cardiac tissue, leading to side effects and limited efficacy, and existing crystalline forms of Aficamten exhibit low solubility, affecting drug performance.
Innovation Solution
Development of a co-crystal form of Aficamten with tartaric acid (Form CSI), characterized by specific X-ray powder diffraction peaks, which enhances solubility, flowability, stability, and reduces hygroscopicity, improving bioavailability and manufacturing efficiency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If existing crystalline forms of Aficamten are used, then the drug can be manufactured, but solubility is low which affects bioavailability
Solution Approach 1:
The patent creates a co-crystal composite material by combining Aficamten with tartaric acid in a defined stoichiometric ratio (1:0.5 to 1:1.5). This composite crystalline structure exhibits enhanced solubility and bioavailability compared to the parent compound alone, as the co-crystal form allows for improved dissolution characteristics while maintaining the therapeutic activity of Aficamten.
Solution Approach 2:
The patent changes the physical-chemical parameters of Aficamten by forming a co-crystal with tartaric acid. This transformation modifies the crystalline lattice structure, resulting in altered solubility, hygroscopicity, and dissolution rates. The co-crystal form achieves higher solubility and reduced hygroscopicity, directly improving bioavailability and drug performance.
2Stability of the object's composition
If conventional crystalline forms are used, then manufacturing is possible, but hygroscopicity is high which affects storage stability
Solution Approach 1:
The co-crystal composite structure formed with tartaric acid reduces the hygroscopicity of Aficamten. The tartaric acid molecules integrate into the crystal lattice in a way that reduces the compound's affinity for water, thereby improving storage stability and reducing the harmful effect of hygroscopicity during manufacturing and storage.
3Reliability
If prior art crystalline forms are used, then the drug can be produced, but crystal transformation occurs which increases production risks
Solution Approach 1:
The patent establishes a new crystalline form with specific physical-chemical parameters that are more stable during manufacturing and storage. By defining the co-crystal structure with precise stoichiometric ratios and characterizing it through X-ray diffraction and other analytical methods, the patent eliminates or reduces crystal transformation issues, thereby improving production reliability and reducing the complexity of controlling crystal form changes.
4Reliability
If existing drug forms are used, then treatment can be administered, but selectivity for cardiac tissue is insufficient leading to side effects
Solution Approach 1:
The patent changes the physical form of Aficamten to a co-crystal structure that may influence the drug's pharmacokinetic properties. While the molecular structure remains the same, the co-crystal form can alter absorption, distribution, and metabolism characteristics, potentially enhancing cardiac selectivity and reducing off-target effects, though this requires further pharmacological validation.
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
Form CSI demonstrates higher solubility, better flowability, low hygroscopicity, and enhanced stability, ensuring consistent drug quality and bioavailability, reducing production costs and risks associated with crystal transformation.
Implementation Method 1
pharmaceutical co-crystals are crystalline materials composed of two or more different molecules (one of which is the API) in a defined stoichiometric ratio within the same crystal lattice that are associated by nonionic and noncovalent bonds
Implementation Method 2
the X-ray powder diffraction pattern of Form CSI comprises characteristic peaks at 2theta values of 12.2°±0.2°, 14.7°±0.2° and 19.1°±0.2° using CuKα radiation
Data Source
AI summary
The present disclosure relates to co-crystal of Aficamten and tartaric acid, and preparation methods thereof, pharmaceutical compositions containing the crystalline forms, and uses of the co-crystal for preparing cardiac myosin inhibitor and drugs for treating hypertrophic cardiomyopathy.