Rivastigmine Hydrogentartrate Polymorphs for Dissolution and Stability
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Solution Overview
Problem
Current pharmaceutical formulations of rivastigmine hydrogentartrate lack a uniform morphology, favorable dissolution rate, bioavailability, and chemical stability, which affects its pharmacological properties and processability in pharmaceutical dosage forms.
Innovation Solution
Development of rivastigmine hydrogentartrate in amorphous and polymorphic forms, specifically Forms I and II, characterized by distinct X-ray powder diffraction patterns and thermal behavior, which are stable, reproducible, and suitable for pharmaceutical tablet formulation, involving crystallization, aging, and drying processes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If rivastigmine hydrogentartrate is prepared in conventional crystalline form, then it has defined melting point and stability, but it lacks uniform morphology and favorable dissolution rate
Solution Approach 1:
The patent applies parameter changes by controlling crystallization conditions (solvent type, temperature, pH, concentration) to produce polymorphic forms I and II with distinct X-ray diffraction patterns and thermal behaviors. These controlled parameter changes result in materials with uniform morphology and improved dissolution rates while maintaining chemical stability.
Solution Approach 2:
The patent utilizes phase transitions by preparing rivastigmine hydrogentartrate in specific polymorphic forms through controlled crystallization from different solvents (ethanol, ethyl acetate, acetone, isopropanol). The phase transition from solution to solid crystal form determines the polymorphic structure, which in turn affects dissolution rate and morphology uniformity.
2Reliability
If rivastigmine hydrogentartrate is prepared in conventional crystalline form, then it has reproducible crystal structure, but it exhibits inter-individual variability in dissolution and bioavailability
Solution Approach 1:
The patent systematically varies crystallization parameters (solvent selection, temperature profiles, pH conditions) to obtain polymorphic forms with consistent and reproducible dissolution characteristics. Polymorphic form I from ethanol and form II from ethyl acetate both provide reliable, consistent dissolution rates that reduce inter-individual variability.
Solution Approach 2:
The patent achieves local quality by creating uniform crystal morphology at the micro-level through controlled polymorphic formation. This uniformity in crystal habit and particle morphology ensures consistent dissolution behavior across different batches and reduces variability in bioavailability.
3Ease of manufacture
If rivastigmine hydrogentartrate is prepared using standard crystallization methods, then the process is simple, but the product lacks favorable dissolution rate and bioavailability
Solution Approach 1:
The patent maintains ease of manufacture by using straightforward crystallization processes from common solvents while improving dissolution rate through parameter optimization. The simple process of dissolving the salt in a suitable solvent, adjusting pH if needed, and crystallizing by cooling or evaporation yields polymorphic forms with superior dissolution characteristics.
Solution Approach 2:
The patent exploits phase transitions during crystallization from simple solvent systems to produce polymorphic forms with enhanced dissolution rates. The controlled transition from liquid solution to solid crystal phase, achieved through temperature change or solvent removal, creates the desired polymorphic structure without complex processing.
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 polymorphic forms of rivastigmine hydrogentartrate exhibit improved dissolution rates, bioavailability, reduced inter-individual variability, and chemical stability, enabling enhanced pharmacological properties and easier processing into tablets, while allowing for targeted release profiles and improved formulation design.
Implementation Method 1
The hydrogentartrate of the (S)-enantiomer (from ethanol) is said to melt at 123-125 °C... the free base and L-(+)-tartaric acid are dissolved in methanol, the clear solution is cooled to room temperature, gradually precipitated with acetone and left to crystallize at 5°C
Implementation Method 2
The hydrochloride of rivastigmine is reported to have a melting point of 135-136 °C... The hydrogen tartrate of the (S)-enantiomer (from ethanol) is said to melt at 123-125 °C... the product is said to have a melting point of 125 to 126°C... The product precipitates upon cooling to 0°C; the melting point is 124°C
Data Source
Figure 1
Figure 2
Figure 3~4
AI summary
Rivastigmine hydrogentartrate in amorphous form or in a crystalline form characterized by an X-ray powder diffraction pattern exhibiting peaks at 2Θ values of 5.1, 14.7, 16.5, 17.6, 18.6, 20.4, 21.1° ± 0.2° (Form I), or 2Θ values of 9.5, 11.3, 13.2, 14.1, 15.5, 19.1 20.0° ± 0.2° (Form II), methods for its preparation and pharmaceutical compositions comprising the same.