Azilsartan Crystalline Forms Solubility and Bioavailability
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Solution Overview
Problem
Current crystalline forms of azilsartan have relatively low solubilities and bioavailabilities, which affect their efficacy in treating hypertension, and there is a need for novel forms with improved physicochemical properties and a cost-effective preparation process.
Innovation Solution
Development of novel crystalline forms of azilsartan (forms A-K) with specific X-ray powder diffraction patterns and a preparation process involving dissolution in a good solvent followed by cooling to form crystals, which enhances solubility, bioavailability, and stability, suitable for pharmaceutical compositions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If conventional crystalline forms of azilsartan are used, then the preparation process is simple, but the solubility and bioavailability are relatively low
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallization parameters including solvent selection (ethyl acetate, ethanol, methanol, acetone, DMSO, DMF, THF, toluene, hexane), temperature conditions, and cooling rates to generate multiple crystalline forms (Forms A-K) with different solubility profiles. This allows optimization of solubility while maintaining manufacturability through controlled crystallization processes.
Solution Approach 2:
The patent utilizes phase transitions during crystallization, where azilsartan transitions from dissolved state in solvent to crystalline solid form. By controlling the phase change process through temperature variation and solvent selection, the patent achieves different crystalline forms with optimized solubility and bioavailability properties while maintaining a relatively simple preparation process.
2Ease of manufacture
If conventional crystalline forms of azilsartan are used, then the preparation process is simple, but the bioavailability is relatively low
Solution Approach 1:
The patent employs parameter changes by exploring different crystallization conditions including various solvents, temperatures, and cooling rates to produce multiple crystalline forms (A-K) with different bioavailability characteristics. This systematic parameter optimization enables selection of forms with improved bioavailability while maintaining process simplicity.
Solution Approach 2:
The patent creates multiple crystalline forms that are structural copies or variants of the base azilsartan molecule, each with different physical properties. By producing these crystalline copies through controlled crystallization, the patent achieves improved bioavailability while maintaining a relatively simple preparation process compared to complex formulation methods.
3Quantity of substance
If novel crystalline forms with high solubility are developed, then the bioavailability improves, but the preparation process complexity increases
Solution Approach 1:
The patent applies parameter changes by optimizing crystallization parameters such as solvent selection, temperature profiles, and cooling rates to achieve high solubility in novel crystalline forms (A-K). By systematically varying these parameters, the patent improves solubility and bioavailability while keeping the preparation process relatively simple and scalable for industrial production.
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 novel crystalline forms exhibit increased solubility, thermal stability, and better bioavailability, effectively reducing clinical systolic blood pressure, making them suitable for the prevention and treatment of hypertension while being industrially friendly to produce.
Implementation Method 1
dissolving azilsartan in a good solvent to form a solution
Implementation Method 2
forming crystals by cooling the solution
Data Source
AI summary
The present invention relates to the field of pharmaceutical chemistry. Disclosed herein is a crystalline form of azilsartan, which is substantially pure. The crystalline form is crystalline form A, form B, form C, form D, form E, form F, form G, form H, form I, form J or form K. The substantially pure crystalline forms of azilsartan of the invention generally have good properties such as high solubility, high bioavailability, good stability, long shelf life and good antistatic property. The crystalline forms of azilsartan generally exhibit an excellent performance in reducing clinical systolic blood pressure (SBP) and average 24-hour SBP. Disclosed herein are methods of preparing the substantially pure crystalline forms of azilsartan, pharmaceutical compositions comprising the crystalline forms, and preparation methods and uses thereof.