Stable Tiotropium Bromide Crystalline Form
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Solution Overview
Problem
Existing methods for producing tiotropium bromide result in unstable crystalline forms, leading to variations in batches and making it difficult to manufacture high-quality inhalable compositions, especially when scaling up production, which affects the drug's stability and effectiveness.
Innovation Solution
A method is developed to produce tiotropium bromide with monoclinic elementary cell parameters (a = 9.94 Å, b = 11.11 Å, c = 18.57 Å, β = 108.47°) that allows for the creation of a stable crystalline form which can be mixed with excipients, ground to precise particle sizes, and stored without degradation, even at elevated temperatures, ensuring consistent quality and processability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing methods are used to produce tiotropium bromide, then production can be carried out, but the crystalline form obtained is unstable leading to batch variations and quality inconsistency
Solution Approach 1:
The patent applies parameter changes by modifying the crystallization conditions, specifically using a solvent system comprising ethyl acetate and heptane with controlled temperature progression (from room temperature to refrigeration at 4-8°C). This systematic change in physical parameters produces a stable monoclinic crystalline form with reproducible unit cell dimensions, resolving the instability and batch variation problems of existing methods
Solution Approach 2:
The invention employs a composite solvent system combining ethyl acetate and heptane in specific proportions rather than using a single solvent. This composite approach creates optimal crystallization conditions that yield a stable crystalline form, addressing the reliability and consistency issues that single-solvent methods cannot resolve
2Productivity
If production is scaled up to increase output, then productivity improves, but maintaining consistent crystalline quality becomes more difficult
Solution Approach 1:
The patent establishes specific parameter ranges for scaling up production: solvent volume ratios (ethyl acetate:heptane), temperature ranges (room temperature to 4-8°C refrigeration), and crystallization timeframes. These defined parameters allow consistent quality to be maintained across different production volumes, enabling scalability without sacrificing crystalline form stability or batch consistency
3Manufacturing precision
If the crystalline form is ground to achieve precise particle size for inhalation, then aerodynamic properties improve, but the process becomes more complex and time-consuming
Solution Approach 1:
The patent performs preliminary action by producing the crystalline form with pre-optimized properties during the crystallization step itself. The controlled crystallization process yields particles with favorable size distribution and morphology that require minimal subsequent grinding or size reduction, thereby achieving precise particle size with simpler and faster 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 method produces a stable and reproducible crystalline form of tiotropium bromide that maintains effectiveness at high temperatures, enabling the production of high-quality inhalable compositions with consistent particle size and stability, suitable for use in respiratory treatments like COPD and asthma.
Implementation Method 1
a method for producing a crystalline compound comprising Tiotropium bromide
Data Source
AI summary
The present invention is related to crystalline compound comprising Tiotropium bromide and the process that shall be used in production of said compound.