Resmetirom Crystal Forms for Solubility and Stability
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Solution Overview
Problem
Existing crystalline forms of Resmetirom, such as the methyl isobutyl ketone solvate and dimethylacetamide solvate, are toxic and unsuitable for medicinal use, while the anhydrous form I has low solubility, poor stability, and poor compressibility, posing challenges for drug development.
Innovation Solution
Development of novel crystalline forms CSIV and CSV of Resmetirom with higher solubility, good physicochemical stability, and low hygroscopicity, achieved through specific preparation processes involving stirring in nitriles and alcohols, followed by drying.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Temperature
If crystalline form I is used, then melting point is high (about 321°C), but solubility is low and stability is poor
Solution Approach 1:
The patent changes the crystalline form parameters by disclosing specific polymorphic forms (Form A, Form B, Form C) with distinct X-ray diffraction patterns and physical properties. Each form represents a different crystalline arrangement that optimizes the balance between melting point and stability, resolving the contradiction through parameter variation in crystal structure.
Solution Approach 2:
The patent utilizes phase transition concepts by identifying different crystalline phases (Form A, Form B, Form C) that can transform under different conditions. The disclosure includes stability information indicating which forms are preferred under specific storage and processing conditions, enabling control over phase transitions to maintain desired properties.
2Ease of manufacture
If methyl isobutyl ketone solvate or dimethylacetamide solvate are used, then crystalline form can be obtained, but toxicity increases due to toxic organic solvents
Solution Approach 1:
The patent extracts and eliminates the toxic solvent components (methyl isobutyl ketone, dimethylacetamide) from the crystalline form structure. By disclosing anhydrous crystalline forms and forms with safe solvents like ethanol and isopropanol, the invention removes the harmful elements while maintaining crystalline structure and manufacturability.
Solution Approach 2:
The patent replaces toxic, persistent organic solvents with safer, more biodegradable solvents (ethanol, isopropanol) that are less harmful to the environment and human health. These alternative solvents serve the temporary function of facilitating crystallization but leave no toxic residue, effectively replacing harmful objects with safer alternatives.
3Measurement precision
If hydrate crystalline form is used, then HPLC purity reaches 96.4%, but impurity content affects appearance, stability, and increases toxicity
Solution Approach 1:
The patent extracts and removes water and toxic impurities from the crystalline structure by disclosing anhydrous forms and forms with safe solvents. The alternative crystalline forms presented (Form A, Form B, Form C with various solvents) eliminate the harmful impurities associated with hydrates while maintaining high purity through controlled crystallization processes.
Solution Approach 2:
The patent changes the compositional parameters of the crystalline form by disclosing forms with different solvent contents (anhydrous, ethanol solvate, isopropanol solvate). These parameter changes in composition allow achieving high purity without the toxic impurities present in hydrate forms, optimizing both purity and safety.
4Manufacturing precision
If crystalline form I is used, then specific starting materials are required, but preparation process becomes complicated
Solution Approach 1:
The patent creates universal crystallization processes that can produce different crystalline forms (A, B, C and their solvates) using similar procedural steps. The disclosure provides general preparation methods that can be applied to obtain various forms depending on desired properties, reducing the need for completely different preparation processes for each form.
Solution Approach 2:
The patent uses parameter changes in the crystallization process (temperature, solvent type, concentration) to obtain different crystalline forms from the same starting material. This allows maintaining a simple, universal preparation process while achieving form-specific properties by simply adjusting process parameters rather than changing the entire synthesis route.
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 forms exhibit enhanced solubility, stability, and compressibility, improving bioavailability, reducing drug side effects, and ensuring consistent drug quality under various conditions, thus enhancing drug efficacy and safety.
Implementation Method 1
The new forms exhibit enhanced solubility, stability, and compressibility, improving bioavailability
Implementation Method 2
a process comprising: stirring Compound I solid in a nitrile, separating the solid and drying to obtain Form CSIV
Implementation Method 3
stirring Compound I solid in a nitrile, separating the solid and drying to obtain Form CSIV
Data Source
AI summary
Novel crystalline forms of Resmetirom (Referred to as “Compound I”), and preparation methods thereof, pharmaceutical compositions containing the crystalline forms, and uses of the crystalline forms for preparing THR-β selective agonist drugs and drugs for treating NASH and HeFH. Compared with prior arts, the provided crystalline forms of Compound I have one or more improved properties, which is of great value to the optimization and development of the drugs containing Compound I.