Lipoprotein Crystal Forms for Stability and Powder Flow
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Solution Overview
Problem
Existing crystal forms of the lipoprotein compound (2S)-3-(3-{[(2-{3-[(2S)-2-carboxyl-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy}ethyl)({3-[(2S)-2-carboxyl-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl}methyl)amino]methyl}phenyl)-2-[(3R)-pyrrolidin-3-yl]propionic acid exhibit poor stability, agglomeration, and poor fluidity, making them unsuitable for industrial production and clinical applications.
Innovation Solution
Development of distinct crystal forms A, B, C, D, and E, characterized by specific X-ray powder diffraction patterns, and preparation methods involving solvent mixing, stirring, crystallization, filtration, and drying, along with the creation of pharmaceutically acceptable salts like hydrochloride, succinate, meglumine salt, maleate, and others, to enhance stability and suitability for pharmaceutical use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If amorphous drug products are used, then they can be produced, but they exhibit poor product stability, difficulty in filtration, easy agglomeration, and poor fluidity
Solution Approach 1:
The patent applies phase transition by transforming the amorphous drug substance into crystalline forms through controlled crystallization processes. Different crystal forms (Forms I-VI) are obtained by varying crystallization conditions such as solvent selection, temperature, and pH, thereby achieving stable solid-state structures with improved filtration, fluidity, and storage stability while maintaining manufacturability
Solution Approach 2:
The patent employs parameter changes by systematically varying crystallization parameters including solvent type (water, ethanol, isopropanol, acetonitrile, etc.), temperature ranges, pH levels, and drying conditions to obtain distinct crystal forms with different properties. This allows optimization of both manufacturing ease and product stability by selecting appropriate crystal forms for specific applications
2Adaptability or versatility
If different crystallization and storage conditions are used, then various crystal structures can be obtained, but this leads to changes in crystal structure and production of other forms
Solution Approach 1:
The patent applies preliminary action by pre-establishing specific crystallization protocols and storage conditions for each crystal form. By defining precise preparation methods including solvent selection, temperature control, pH adjustment, and drying parameters beforehand, the patent ensures that the intended crystal form is obtained consistently and remains stable during storage, preventing unwanted polymorphic transitions
3Reliability
If salt formation is performed to improve properties, then physicochemical properties can be enhanced, but it requires development of new salt forms with superior properties
Solution Approach 1:
The patent applies parameter changes by systematically varying salt formation parameters including selection of different counterions (sodium, potassium, calcium, magnesium salts), solvent systems, pH conditions, and crystallization temperatures. This systematic approach enables identification of salt forms with superior solubility, stability, and manufacturability while managing development complexity through structured experimentation
Solution Approach 2:
The patent employs phase transitions in salt formation by controlling the crystallization process to obtain stable solid-state salt forms from solution or melt. By adjusting parameters such as solvent composition, temperature, and evaporation rate, the patent transforms the drug substance into stable salt crystal forms with improved physicochemical properties suitable for pharmaceutical applications
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 crystal forms and salts provide improved chemical and physical stability, enabling better industrial production and clinical efficacy by addressing issues of agglomeration and fluidity, thus enhancing the drug's suitability for pharmaceutical applications.
Implementation Method 1
having an X-ray powder diffraction pattern represented by a diffraction angle 2θ having characteristic peaks at 8.343, 18.020, and 21.028
Implementation Method 2
X-ray powder diffraction pattern represented by a diffraction angle 2θ
Implementation Method 3
Different crystallization and storage conditions may lead to changes in the crystal structure of the compound
Data Source
Figure 1~2
Figure 3~4
Figure 5~6
AI summary
The present disclosure relates to a crystal form of a lipoprotein compound and a preparation method therefor. Specifically, the present disclosure provides a crystal form of (2S)-3-(3-{[(2-{3-[(2S)-2-carboxyl-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy}ethyl)({3-[(2S)-2-carboxyl-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl}methyl)amino]methyl}phenyl)-2-[(3R)-pyrrolidin-3-yl]propionic acid and a preparation method therefor.