Lumacaftor Crystalline Form A Solubility and Stability
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Solution Overview
Problem
The existing crystalline forms of Lumacaftor, such as Form I, lack stability and solubility, which are crucial for effective drug application and storage, and the unpredictability of polymorphic forms complicates their development and characterization.
Innovation Solution
A novel crystalline form, designated as Form A, is developed with improved stability and solubility, characterized by specific X-ray powder diffraction patterns and obtained through dissolving the free form of the compound in ketones or a mixture of ketones and ethers, followed by evaporation, resulting in a white solid with enhanced properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing crystalline forms (Form I) are used, then the compound can be obtained through conventional methods, but the stability and solubility are insufficient for effective drug application
Solution Approach 1:
The patent applies parameter changes by modifying the crystallization conditions, specifically using ketone solvents (acetone, methyl ethyl ketone, or methyl isobutyl ketone) at controlled temperatures (20-80°C) to obtain a new crystalline form with superior stability and solubility characteristics compared to Form I
Solution Approach 2:
The patent utilizes phase transitions by controlling the crystallization process from solution to solid state, where the compound transitions from dissolved state in ketone solvents to a stable crystalline form through controlled evaporation and temperature management, resulting in improved physical properties
2Quantity of substance
If existing crystalline forms (Form I) are used, then the compound can be obtained through conventional methods, but the solubility is insufficient for effective drug application
Solution Approach 1:
The patent applies parameter changes by modifying the crystallization conditions, specifically using ketone solvents (acetone, methyl ethyl ketone, or methyl isobutyl ketone) at controlled temperatures (20-80°C) to obtain a new crystalline form with superior stability and solubility characteristics compared to Form I
Solution Approach 2:
The patent uses ketone solvents as intermediary substances to facilitate the formation of the new crystalline form, where the solvent acts as a medium that enables the compound to crystallize in a more soluble and stable form during the preparation process
3Reliability
If all solid forms are studied to provide drugs with improved stability or solubility, then better drug performance can be achieved, but the development time and complexity increase
Solution Approach 1:
The patent applies preliminary action by proactively developing and characterizing a new crystalline form with known superior properties before actual drug formulation, thereby avoiding time-consuming trial-and-error studies of multiple polymorphic forms during later development stages
Solution Approach 2:
The patent applies parameter changes by modifying the crystallization conditions, specifically using ketone solvents (acetone, methyl ethyl ketone, or methyl isobutyl ketone) at controlled temperatures (20-80°C) to obtain a new crystalline form with superior stability and solubility characteristics compared to Form I
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 A exhibits higher solubility and stability, facilitating improved drug efficacy and easier preparation, making it suitable for further drug development and treatment of cystic fibrosis, particularly when combined with Ivacaftor.
Implementation Method 1
dissolving the free form of the compound in ketones or a mixture of ketones and ethers
Implementation Method 2
followed by evaporation, resulting in a white solid
Implementation Method 3
X-ray powder diffraction pattern (CuKα radiation) at 25°C shows characteristic peaks at 2theta values
Implementation Method 4
X-ray powder diffraction pattern shows one or more characteristic peaks at 2theta values
Data Source
Figure 1~2
Figure 3
Figure 4~5
AI summary
The present disclosure provides crystalline form A of 3-(6-(1-(2, 2-difluorobenzo [d] [1, 3] dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid and process of preparation thereof. The crystalline form A has low hygroscopicity, good stability, is convenient to store. It has higher solubility than that of prior art and therefore plays an important role in further optimization and development of the drug.