Tiotropium Bromide Crystalline Forms and Solvent Control

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Solution Overview

Problem

Current methods for crystallizing Tiotropium bromide fail to consistently produce the same crystalline form, limiting the availability of pharmaceutical formulations with targeted release profiles and desired characteristics.

Innovation Solution

Development of multiple crystalline forms (Forms 1-12) and solvates of Tiotropium bromide, including micronized and amorphous forms, through specific solvent and temperature-controlled crystallization processes, such as using methanol and acetone, acetic acid, and n-propanol, to achieve distinct XRD patterns and physical properties.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional crystallization methods are used, then Tiotropium bromide can be produced, but the crystalline form is inconsistent and cannot be reliably controlled

Engineering Contradiction:

Improveconsistency of crystalline formVSAvoidcontrol over crystal structure

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The patent applies parameter changes by systematically varying crystallization conditions including solvent type (acetone, methanol, acetic acid, n-propanol), temperature ranges, and pH levels to produce different crystalline forms (Forms 1-12) with distinct XRD patterns, thereby achieving reliable control over crystal structure

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses solvents as intermediary substances to mediate the crystallization process. Different solvents (acetone, methanol, acetic acid, n-propanol) act as intermediaries that facilitate the formation of specific crystalline forms by interacting with Tiotropium bromide molecules during crystallization, enabling consistent production of desired polymorphs

Inventive Principle:

Principle #24Intermediary (Mediator)

2Adaptability or versatility

If multiple crystalline forms are developed, then pharmaceutical formulations with targeted release profiles can be designed, but the complexity of the crystallization process increases

Engineering Contradiction:

Improveavailability of forms with targeted release profilesVSAvoidcomplexity of crystallization process

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent segments the crystallization process into distinct pathways for producing different crystalline forms (Forms 1-12), each with specific solvent systems and temperature conditions. This segmentation allows formulation scientists to select appropriate forms for targeted release profiles without requiring a single complex process

Inventive Principle:

Principle #1Segmentation

3Stability of the object's composition

If solvent and temperature-controlled crystallization processes are used, then distinct crystalline forms with varying solubility and stability are obtained, but the number of process parameters to control increases

Engineering Contradiction:

Improvestability of crystalline formVSAvoidnumber of process parameters

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The patent systematically changes key parameters including solvent type (acetone, methanol, acetic acid, n-propanol), temperature ranges, and pH levels to produce crystalline forms with enhanced stability and controlled solubility, demonstrating that parameter optimization can achieve both stability and manufacturability

Inventive Principle:

Principle #35Parameter changes

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

Provides a range of Tiotropium bromide forms with varying solubility and stability, enabling the design of pharmaceutical dosage forms with tailored release profiles and improved bioavailability.

Implementation Method 1

crystallizing Tiotropium bromide from a mixture comprising methanol and acetone having a ratio of about 1/3 (vol/vol)

Methodology Applied

Scientific EffectCrystallization: Crystallisation

Data Source

PatentUS9108962B2Forms of tiotropium bromide and processes for preparation thereof

Publication Date: 2015.08.18 SICOR SOC ITAL CORTICOSTEROIDI SRL

AI summary

This invention relates to novel crystalline forms of tiotropium bromide, processes for preparing them, and their use in pharmaceutical formulations.