Stable Amorphous Ticagrelor via Solvent Precipitation

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Solution Overview

Problem

Current methods for preparing amorphous ticagrelor lack a commercially viable and stable process, as they often result in unstable forms that degrade over time under varying temperature and humidity conditions.

Innovation Solution

A process involving dissolving ticagrelor in chlorinated hydrocarbons or cyclic ethers and then adding it to a hydrocarbon solvent, followed by stirring and isolation through cooling, precipitation, and drying, to produce a stable amorphous form that maintains its X-ray powder diffraction pattern over several months at different temperatures and humidity levels.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of manufacture

If freeze drying technique is used in aqueous ethanolic solution, then amorphous ticagrelor can be prepared, but the product lacks stability and degrades over time

Engineering Contradiction:

Improvepreparation methodVSAvoidstability of amorphous ticagrelor

Core Design Contradiction:

Ease of manufactureVSStability of the object's composition

Solution Approach 1:

The invention changes the solvent system parameters from aqueous ethanolic solutions to organic solvent systems (acetonitrile/water or methanol/water mixtures with specific ratios). This parameter change in solvent composition enables the formation of a stable amorphous structure that resists degradation, directly resolving the contradiction between ease of manufacture and product stability.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention uses composite solvent systems combining organic solvents (acetonitrile or methanol) with water in specific ratios. This composite approach creates a unique solvation environment that stabilizes the amorphous form of ticagrelor, preventing the degradation issues seen with simple aqueous ethanolic solutions.

Inventive Principle:

Principle #40Composite materials

2Productivity

If spray drying or evaporation techniques are used, then amorphous ticagrelor can be obtained, but the product shows instability under varying temperature and humidity conditions

Engineering Contradiction:

Improvepreparation efficiencyVSAvoidstability under storage conditions

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The invention modifies the solvent composition parameters to organic/water mixtures with controlled ratios, which fundamentally changes the drying and stabilization process. This parameter change ensures that the amorphous form remains stable under varying temperature and humidity conditions, resolving the reliability issue while maintaining productivity through efficient evaporation or spray drying.

Inventive Principle:

Principle #35Parameter changes

3Ease of operation

If ultrasonic irradiation is applied to dissolve ticagrelor in aqueous ethanol, then amorphous ticagrelor can be prepared, but the product lacks commercial viability due to instability

Engineering Contradiction:

Improvedissolution processVSAvoidstability of amorphous ticagrelor

Core Design Contradiction:

Ease of operationVSStability of the object's composition

Solution Approach 1:

The invention changes the solvent system from aqueous ethanol to organic solvent/water mixtures (acetonitrile or methanol with water). This parameter change maintains the ease of dissolution (with or without ultrasonic irradiation) while fundamentally improving the stability of the resulting amorphous ticagrelor, making it commercially viable.

Inventive Principle:

Principle #35Parameter changes

4Manufacturing precision

If distillation under reduced pressure is used to isolate amorphous ticagrelor from acetonitrile-water mixture, then amorphous product can be obtained, but the process lacks commercial viability

Engineering Contradiction:

Improveisolation purityVSAvoidcommercial viability

Core Design Contradiction:

Manufacturing precisionVSEase of manufacture

Solution Approach 1:

The invention optimizes the solvent ratio parameters in the acetonitrile-water or methanol-water systems to enable effective isolation through simple evaporation or spray drying. This parameter optimization maintains high manufacturing precision for purity while simplifying the overall process to achieve commercial viability.

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

The method consistently produces a stable amorphous ticagrelor with no changes in XRPD pattern, ensuring high purity and stability at various storage conditions, as demonstrated by HPLC purity and XRPD pattern consistency across multiple examples.

Implementation Method 1

dissolving ticagrelor in a solvent selected from the group consisting of chlorinated hydrocarbons, esters, cyclic ethers, and mixtures thereof to form a solution

Methodology Applied

Scientific EffectSolvation: Solvation

Implementation Method 2

adding the solution of step a) to a hydrocarbon solvent to obtain the stable amorphous ticagrelor

Methodology Applied

Scientific EffectPrecipitation: Precipitation

Implementation Method 3

stirring at a temperature of from about -10°C to about 15°C

Methodology Applied

Scientific EffectCooling: Cooling

Data Source

PatentUS10017515B2Stable amorphous ticagrelor and a process for its preparation

Publication Date: 2018.07.10 SUN PHARMACEUTICAL INDUSTRIES LTD

AI summary

The present invention relates to a stable amorphous ticagrelor and a process for its preparation.