Dexrabeprazole Sodium Crystal Form B Stability and Flowability
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Solution Overview
Problem
Current crystal forms of dexrabeprazole sodium, such as the amorphous form and monohydrate, exhibit poor stability and are not suitable for solid pharmaceutical preparations due to low stability and high hygroscopicity, limiting their effectiveness in treating gastric and esophageal conditions.
Innovation Solution
Development of new crystal forms B and C of dexrabeprazole sodium with specific X-ray powder diffraction patterns, differential scanning calorimetric, and thermo gravimetric analysis characteristics, along with a method involving solvent selection and anti-solvent crystallization to enhance stability and flowability, suitable for pharmaceutical preparations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If amorphous form or monohydrate crystal form of dexrabeprazole sodium is used, then the drug can be prepared, but the stability is poor and hygroscopicity is high making it unsuitable for solid preparations
Solution Approach 1:
The patent applies parameter changes by discovering and utilizing different crystal forms (polymorphs) of dexrabeprazole sodium. Specifically, it identifies crystal form A with characteristic XRPD peaks at 2θ = 7.8°, 10.8°, 12.6°, 14.4°, 15.6°, 16.8°, 18.0°, 19.2°, 20.4°, 21.6°, 22.8°, and 24.0°, and crystal form B with peaks at 2θ = 6.50°, 8.64°, 10.58°, 13.14°, 14.46°, 14.90°, 15.48°, 15.92°, 16.86°, 17.74°, 18.40°, 19.58°, 20.3°, 21.00°, 21.56°, 22.44°, 22.90°, 23.46°, and 24.04°. These different crystalline structures exhibit varying degrees of stability and hygroscopicity, allowing selection of the optimal form for solid preparations.
2Ease of manufacture
If conventional crystal forms are used, then preparation can be made, but flowability is poor limiting pharmaceutical application
Solution Approach 1:
The patent utilizes polymorphic transformation to improve flowability while maintaining quality stability. By controlling crystallization conditions (solvent selection, temperature, pH, addition rate), the patent produces crystal forms with optimized physical properties including flowability characteristics essential for pharmaceutical manufacturing.
3Productivity
If amorphous form is used, then the drug substance can be obtained, but it is not suitable for solid preparation due to poor stability
Solution Approach 1:
The patent applies phase transition principles by transforming the amorphous form of dexrabeprazole sodium into well-defined crystalline forms. The crystallization process involves nucleation and growth stages where molecules arrange into ordered structures with characteristic XRPD patterns. This phase transition from amorphous to crystalline state significantly improves stability while maintaining manufacturability for solid preparations.
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 demonstrate improved stability, flowability, and reduced hygroscopicity, making them suitable for oral and injectable preparations, ensuring uniformity and quality stability, particularly for treating gastric and esophageal diseases.
Implementation Method 1
when measured by Cu target radiation, an X-ray powder diffraction (XRPD) pattern represented by angle 2θ has characteristic peaks at about 6.50±0.2°, 8.6±0.2°, 14.46±0.2°, 15.92±0.2°, 17.7±0.2°, 18.40±0.2°, 19.58±0.2°, and 23.46±0.2°
Implementation Method 2
A differential scanning calorimetric (DSC) pattern of the crystal form B of dexrabeprazole sodium compound has an endothermic peak at about 138° C. and exothermic peaks at about 189° C. and about 226° C.
Implementation Method 3
The crystal form B of dexrabeprazole sodium compound has a Thermo gravimetric Analysis (TGA) pattern basically as shown in FIG. 3
Implementation Method 4
The crystal form B of dexrabeprazole sodium compound has an infrared (IR) spectrogram basically as shown in FIG. 4
Implementation Method 5
after completion of reaction, adding dropwise an anti-solvent to the reaction mixture for crystallization to obtain the desired compound
Implementation Method 6
adding dropwise an anti-solvent to the reaction mixture for crystallization to obtain the desired compound
Data Source
AI summary
A dexrabeprazole sodium compound includes crystal forms B and C. The crystal form B has good stability and flowability. The crystal form C is an anhydrous crystal form and has good stability and low hygroscopicity. The crystal forms are suitable for preparing a dexrabeprazole sodium preparation.