Crystal Form I of Hex-4-Inoic Acid Derivative for Stable Formulation
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Solution Overview
Problem
Existing crystal forms of 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivatives exhibit varying physicochemical properties, affecting their suitability as active pharmaceutical substances, particularly in terms of dissolution rate and bioavailability, and require additional additives like glidants for handling and formulation.
Innovation Solution
Development of a novel crystal form I with specific X-ray diffraction peaks at 2[θ] values, prepared by dissolving the compound in methanol and adding isopropyl acetate, which demonstrates improved thermal stability, compressibility, and reduced static electricity, facilitating easier handling and formulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If crystal form II or amorphous form is used, then the compound can be obtained, but the physicochemical properties are inferior and additional glidants are required for handling
Solution Approach 1:
The patent applies parameter changes by modifying the crystallization conditions (solvent system, temperature, addition rate) to transform the compound from inferior crystal forms or amorphous state into crystal form I, which possesses superior physicochemical properties including better flowability and reduced static electricity, thereby eliminating the need for additional glidants
Solution Approach 2:
The patent uses isopropyl acetate as an intermediary substance added to the methanolic solution during crystallization. This intermediary agent mediates the crystallization process to specifically induce crystal form I, which has improved handling characteristics and does not require additional glidants for formulation
2Reliability
If conventional crystal forms are used, then the compound is available, but dissolution rate and bioavailability are limited
Solution Approach 1:
The patent changes the crystallization parameters (solvent composition, temperature profile, addition rate) to produce crystal form I, which exhibits superior dissolution rate and bioavailability compared to conventional crystal forms, thereby improving therapeutic effectiveness without complicating the manufacturing process
3Reliability
If crystal form I is prepared with specific diffraction peaks, then thermal stability and compressibility are improved, but the preparation process requires controlled conditions
Solution Approach 1:
The patent establishes specific preparation parameters (methanol as solvent, controlled addition of isopropyl acetate, temperature control) that reliably produce crystal form I with the desired diffraction peaks and superior thermal stability and compressibility, balancing process control requirements with product quality
Solution Approach 2:
The crystallization process is designed to be self-regulating where the controlled addition of isopropyl acetate to the methanolic solution automatically induces crystallization of crystal form I with the characteristic diffraction pattern, reducing the need for complex external control mechanisms
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
Crystal form I exhibits enhanced physicochemical properties, including thermal stability, compressibility, and reduced static electricity, making it suitable for pharmaceutical formulations and long-term storage without the need for additional glidants.
Implementation Method 1
a method of preparing the crystal form I of the compound of Chemical Formula 1, which comprises dissolving (3S)-3-(4-(3-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)benzyloxy)phenyl)hex-4-inoic acid and an L-lysine salt in methanol, adding isopropyl acetate, and obtaining a crystal form I of a compound of Chemical Formula 1 from the reaction product
Implementation Method 2
According to powder X-ray diffraction (PXRD) analysis, the crystal form I and the crystal form II have different crystal structures. the crystal form I of the compound of Chemical Formula 1 exhibits an X-ray powder diffraction pattern having 4 or more diffraction peaks, for example, 4, 5, 6, 7, 8, 9, 10 or more diffraction peaks, at 2[θ] values selected from 4.61±0.2, 5.49±0.2, 6.84±0.2, 11.74±0.2, 12.05±0.2, 13.74±0.2, 16.50±0.2, 16.94±0.2, 18.45±0.2, 19.11±0.2, 20.13±0.2, 20.42±0.2, 20.87±0.2, 21.57±0.2, 23.04±0.2, and 25.02±0.2
Data Source
AI summary
The present invention relates to a novel crystal form of a 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative, a preparation method therefore and a pharmaceutical composition comprising same. A crystal form I of a compound of chemical formula 1, according to the present invention, exhibits more excellent physicochemical properties such as thermal stability, static electricity-inducing capability, compressibility, etc. compared to an amorphous form or a crystal form II, and thus is especially useful for preparation and long-term storage.