Calcium Oxybate Monohydrate Crystallization for Stable Solid Form
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Solution Overview
Problem
Existing methods for preparing calcium oxybate lack comprehensive characterization and fail to produce a stable, pharmaceutically acceptable form, such as the monohydrate form, which is crucial for effective pharmaceutical applications.
Innovation Solution
A method involving the reaction of calcium hydroxide with gamma-butyrolactone, followed by ethanol and isopropanol treatment, is used to produce Form A monohydrate of calcium oxybate, characterized by XRPD, DSC, and TGA to ensure purity and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If calcium oxybate is prepared by conventional methods (evaporation or simple crystallization), then the preparation process is simple, but the product lacks stable pharmaceutical form and comprehensive characterization
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallization temperature, solvent composition (water:ethanol ratios), and pH conditions to obtain different solid forms of calcium oxybate. This allows selection of the stable monohydrate form (Form A) with defined XRPD patterns while maintaining a manageable preparation process
Solution Approach 2:
The patent performs preliminary characterization actions by conducting XRPD, TGA, and DSC analyses before finalizing the preparation method. This ensures the product meets pharmaceutical stability requirements and provides comprehensive documentation of the solid form properties
2Manufacturing precision
If calcium oxybate is prepared without comprehensive characterization (no XRPD, TGA, or DSC analyses), then the preparation process is simpler and faster, but the pharmaceutical suitability and purity cannot be ensured
Solution Approach 1:
The patent implements a streamlined characterization protocol by performing XRPD, TGA, and DSC analyses on representative samples during the development phase. This allows rapid confirmation of the monohydrate form identity and stability without requiring exhaustive testing of every batch, thus maintaining productivity while ensuring pharmaceutical quality
3Stability of the object's composition
If calcium oxybate is prepared as non-hydrated form, then the product is non-hygroscopic, but the stable pharmaceutical form (monohydrate) cannot be obtained
Solution Approach 1:
The patent applies local quality by controlling the crystallization environment to specifically produce the monohydrate form with defined water content (approximately 6-8% w/w). The controlled water activity during crystallization ensures the formation of the stable monohydrate polymorph rather than the anhydrous form, achieving both stability and controlled hygroscopicity
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 method yields a stable Form A monohydrate of calcium oxybate, ensuring pharmaceutical suitability with precise control over impurities and hydration levels, enhancing its therapeutic efficacy.
Implementation Method 1
reacting an aqueous slurry of calcium hydroxide with gamma-butyrolactone to form an aqueous solution of calcium oxybate
Implementation Method 2
adding ethanol and isopropanol treatment, is used to produce Form A monohydrate of calcium oxybate
Implementation Method 3
adding ethanol and isopropanol treatment, is used to produce Form A monohydrate of calcium oxybate
Data Source
AI summary
The present invention is directed to Form A of monohydrate of calcium oxybate, a pharmaceutically acceptable composition thereof, its method of making, and use thereof.