Rivaroxaban Crystalline Dihydrate Polymorph Production
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Solution Overview
Problem
Current oral dosage forms of Rivaroxaban utilize the less soluble modification I, despite the availability of more soluble modification II, due to difficulties in large-scale production and stability issues, leading to suboptimal bioavailability and solubility.
Innovation Solution
A novel crystalline dihydrate of Rivaroxaban with improved solubility and stability, characterized by specific X-ray powder diffraction and infrared spectra, is developed, along with a commercially viable production process using a crystalline formic acid solvate as an intermediate, enabling enhanced bioavailability and commercial production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If modification II of Rivaroxaban is used to improve solubility, then solubility is improved, but manufacturing complexity and cost increase due to difficult large-scale production
Solution Approach 1:
The patent changes the physical-chemical parameters of Rivaroxaban by discovering and utilizing a new polymorphic form (modification III) with different crystal structure characteristics. This polymorph exhibits improved solubility compared to modification I while being manufacturable through conventional processes, thus resolving the contradiction between solubility improvement and manufacturing ease.
Solution Approach 2:
The patent employs a simple, cost-effective crystallization process using common solvents to produce modification III, avoiding the need for expensive or complex manufacturing procedures. The process uses readily available materials and standard equipment, making it economically viable for large-scale production while achieving the desired solubility improvement.
2Ease of manufacture
If modification I of Rivaroxaban is used for commercial production, then ease of manufacture is improved, but solubility and bioavailability deteriorate
Solution Approach 1:
The patent modifies the crystal structure parameters of Rivaroxaban by introducing modification III, which has different lattice energy and molecular packing characteristics compared to modification I. These structural parameter changes result in improved solubility while maintaining compatibility with existing manufacturing processes, thus improving solubility without sacrificing ease of manufacture.
3Quantity of substance
If polymorphically pure modification II is produced, then solubility is improved, but production time and cost increase due to complex purification requirements
Solution Approach 1:
The patent employs a self-purifying crystallization process where modification III crystallizes in high purity form directly from the solution without requiring extensive purification steps. The crystallization conditions are optimized so that the desired polymorph forms preferentially, eliminating the need for time-consuming purification operations and enabling rapid production.
Solution Approach 2:
The patent accelerates the production process by using a direct crystallization method that skips intermediate purification steps. The process moves quickly from dissolution to crystallization to isolation, reducing overall production time while maintaining high purity and solubility characteristics of modification III.
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 crystalline dihydrate exhibits 2.5 to 3-fold improved solubility and stability, facilitating commercial production of pharmaceutical compositions with improved bioavailability and maintaining polymorphic stability under proper conditions, suitable for oral administration.
Implementation Method 1
Rivaroxaban exists in several polymorphic forms, which have been called 'modification I', 'modification II' and 'modification III'
Implementation Method 2
A novel crystalline dihydrate of Rivaroxaban with improved solubility and stability, characterized by specific X-ray powder diffraction and infrared spectra
Implementation Method 3
characterized by an X-ray powder diffraction pattern comprising peaks at 2-theta angles of 7.1°, 9.8°, 10.6°, 19.7°, 24.2°, and 27.3°+/−0.2°
Implementation Method 4
X-ray powder diffraction pattern comprising peaks at 2-theta angles
Implementation Method 5
The invention also relates to a crystalline formic acid solvate of Rivaroxaban, processes for the preparation of crystalline Rivaroxaban formic acid solvate and to the use of said Rivaroxaban formic acid solvate in the manufacture of the crystalline dihydrate of Rivaroxaban
Data Source
AI summary
Provided are a crystalline dihydrate of Rivaroxaban, processes for the preparation thereof, pharmaceutical compositions containing the crystalline dihydrate and processes for preparing and storing the pharmaceutical compositions. Also provided are a crystalline formic acid solvate of Rivaroxaban, processes for the preparation of crystalline Rivaroxaban formic acid solvate and the use of the Rivaroxaban formic acid solvate in the manufacture of the crystalline dihydrate of Rivaroxaban.