Resmetirom Crystal Form CSVI for Solubility and Stability

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Solution Overview

Problem

Existing crystalline forms of Resmetirom exhibit low solubility, poor grinding stability, poor compressibility, and high hygroscopicity, which affect drug performance and safety.

Innovation Solution

Development of a novel crystalline form, Form CSVI, with characteristic X-ray powder diffraction peaks at specific 2θ values, prepared using nitrile and water or nitrile and alcohol solvent mixtures, demonstrating high solubility, low hygroscopicity, good compressibility, and stability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If crystalline form I is prepared from methyl isobutyl ketone solvate and dimethylacetamide solvate, then the crystalline form has better properties, but it requires toxic Class II solvents which are not suitable for medicinal use

Engineering Contradiction:

Improvecrystalline form propertiesVSAvoidtoxicity from Class II solvents

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent uses water as an intermediary solvent to replace toxic Class II solvents (methyl isobutyl ketone and dimethylacetamide) in the preparation process. Water acts as a safe mediator that enables the formation of crystalline form I without introducing harmful substances, thus resolving the contradiction between obtaining reliable crystalline properties and avoiding toxic harmful factors

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the solvent parameters from toxic organic solvents to water, fundamentally altering the preparation conditions. This parameter change maintains the ability to produce crystalline form I with its desirable properties while eliminating the toxicity issue associated with Class II solvents

Inventive Principle:

Principle #35Parameter changes

2Reliability

If crystalline form I is used, then it has better properties, but it has low solubility which affects drug performance

Engineering Contradiction:

Improvecrystalline form propertiesVSAvoidsolubility

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent changes the crystalline form parameters by discovering and utilizing form CSVI, which has different crystal lattice parameters and molecular arrangement compared to form I. This parameter change in crystalline structure results in improved solubility while maintaining the stability and other desirable properties of the crystalline form

Inventive Principle:

Principle #35Parameter changes

3Reliability

If crystalline form I is used, then it has better properties, but it has poor grinding stability as most transform to amorphous after grinding

Engineering Contradiction:

Improvecrystalline form propertiesVSAvoidgrinding stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent changes the crystalline form from form I to form CSVI, altering the crystal structure parameters such as lattice energy, molecular packing, and intermolecular interactions. These parameter changes result in a crystalline form that maintains its structure during grinding, thereby improving grinding stability while preserving other desirable properties

Inventive Principle:

Principle #35Parameter changes

4Reliability

If crystalline form I is used, then it has better properties, but it has poor compressibility and very poor flowability which affect manufacturing

Engineering Contradiction:

Improvecrystalline form propertiesVSAvoidcompressibility and flowability

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent changes the crystalline form parameters by transitioning from form I to form CSVI, which has different mechanical properties due to variations in crystal lattice structure, molecular orientation, and intermolecular forces. These parameter changes improve compressibility and flowability, making the material easier to manufacture while maintaining its therapeutic efficacy and stability

Inventive Principle:

Principle #35Parameter changes

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 CSVI offers improved solubility, stability, and reduced hygroscopicity, enhancing drug absorption, bioavailability, and product quality, while maintaining chemical and physical stability under various conditions.

Implementation Method 1

prepared using nitrile and water or nitrile and alcohol solvent mixtures

Methodology Applied

Scientific EffectCrystallisation: Crystallisation

Implementation Method 2

characteristic X-ray powder diffraction peaks at specific 2θ values

Methodology Applied

Scientific EffectX-ray diffraction: X-Ray

Data Source

PatentUS12595254B2Crystal form of Resmetirom, preparation method therefor, and use thereof

Publication Date: 2026.04.07 CRYSTAL PHARMA CO LTD

AI summary

The present invention relates to a new crystal form of Resmetirom (referred to as “Compound I”) and a preparation method therefor, a pharmaceutical composition comprising the crystal form, and a use of the crystal form in preparing a THR-β selective agonist drug and a drug for treating NASH and HeFH. Compared with the prior art, the provided crystal form of the compound I has one or more improved properties, solves problems existing in the prior art, and has a great value for the optimization and development of drugs containing the compound I.