Anhydrous Sodium Hyodeoxycholate Form II Crystallization
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Solution Overview
Problem
Current methods for extracting hyodeoxycholic acid from porcine bile lack information on crystalline forms and polymorphism of its sodium salt, leading to instability and difficulty in conservation due to high hygroscopicity, which affects the chemical and polymorphic purity and bioavailability of the final product.
Innovation Solution
A new anhydrous polymorphic crystalline form of sodium hyodeoxycholate (form II) is developed, along with a process to prepare it, which provides high chemical and polymorphic purity, stability, and optimal chemical-physical characteristics, including defined particle size and morphology, enhancing bioavailability and reducing the need for additional processing steps like grinding or micronization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If conventional extraction methods are used to obtain sodium hyodeoxycholate, then the extraction process is simple, but the product exhibits high hygroscopicity leading to instability and difficulty in conservation
Solution Approach 1:
The patent applies parameter changes by controlling crystallization conditions (temperature, solvent composition, pH, evaporation rate) to obtain a specific polymorphic form (Form I) of sodium hyodeoxycholate that exhibits reduced hygroscopicity compared to conventional methods, thereby improving product stability while maintaining manufacturing feasibility
Solution Approach 2:
The patent utilizes phase transitions during the crystallization process, where sodium hyodeoxycholate transitions from an amorphous or unstable crystalline state to a stable polymorphic Form I through controlled evaporation and temperature variation, resulting in a product with lower hygroscopicity and improved conservation properties
2Device complexity
If conventional extraction methods are used, then the process requires fewer specialized steps, but the chemical and polymorphic purity of the final product is compromised
Solution Approach 1:
The patent applies preliminary action by performing multiple purification steps including precipitation with hydrochloric acid, filtration, washing with water and ethanol, and controlled crystallization before final drying, ensuring high chemical and polymorphic purity is achieved upfront to prevent contamination and maintain Form I stability
Solution Approach 2:
The patent utilizes parameter changes during sequential purification steps, adjusting pH, temperature, and solvent composition at each stage to selectively precipitate and isolate sodium hyodeoxycholate in its pure polymorphic Form I, achieving high manufacturing precision through controlled physical-chemical transformations
3Productivity
If conventional methods are used to obtain sodium hyodeoxycholate, then the production is faster, but additional processing steps like grinding or micronization are required
Solution Approach 1:
The patent applies parameter changes by controlling crystallization kinetics (cooling rate, evaporation speed, agitation) to directly produce sodium hyodeoxycholate in polymorphic Form I with optimal particle size and morphology, eliminating the need for subsequent grinding or micronization steps and maintaining ease of manufacture
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 form II exhibits high stability in humidity sorption cycles, is non-hygroscopic, and maintains stability over time, improving the pharmaceutical properties and ease of storage, while achieving high yield and purity, thus addressing the limitations of existing processes.
Implementation Method 1
a) at least one purification step of HDCA of formula II, carried out through preparation of a salt of an alkaline-earth metal of hyodeoxycholic acid and its subsequent acidification to obtain purified HDCA; b) preparation of NaHDC through treatment of purified HDCA with NaOH up to pH comprised between 8.5 and 9.5; c) obtaining the polymorphic form FII of NaHDC through reprecipitation by an organic solvent
Implementation Method 2
c) obtaining the polymorphic form FII of NaHDC through reprecipitation by an organic solvent selected from a ketonic solvent, a solvent belonging to the category of esters, an alcohol, a solvent belonging to the category of nitriles or they mixture
Data Source
AI summary
The object of the present invention is a new anhydrous polymorphic crystalline form of sodium hyodeoxycholate (NaHDC) named as form II (FII) and the process for preparing it. Such a process makes it possible to obtain sodium hyodeoxycholate in the anhydrous polymorphic form II (FII), with high chemical and polymorphic purity. The invention also describes the anhydrous polymorphic crystalline forms of NaHDC named as form I (FI) and form III (Fill), the hydrated forms of NaHDC named as SI and SII, crystalline forms of NaHDC, respectively hydrated with four and eight water molecules and the amorphous form.