Pharmaceutical Composition Wet Processing to Suppress Impurities

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Solution Overview

Problem

Existing methods for producing crystals of a compound represented by Formula (I) do not adequately address the stability issues related to the formation of impurities, particularly Compound (III), which affects the stability of pharmaceutical compositions containing this compound.

Innovation Solution

The method involves wet-pulverizing and/or wet-kneading the compound represented by Formula (I) to produce crystals with controlled impurity levels, specifically suppressing the formation of Compound (III) to a content ratio of 0.0001 to 10 ppm, and incorporating polyhydric alcohol esters like triethyl citrate and miglyol to enhance stability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional pulverization methods are used, then production efficiency is maintained, but impurity formation increases and stability deteriorates

Engineering Contradiction:

ImprovestabilityVSAvoidimpurity formation

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The invention changes the physical state parameter of the compound from amorphous to crystalline form. This phase transition fundamentally alters the molecular arrangement and reduces molecular mobility, thereby suppressing decomposition reactions and impurity formation while improving stability without compromising production efficiency

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention utilizes the phase transition from amorphous to crystalline state as the core mechanism. By controlling crystallization during pulverization, the compound transitions to a more stable phase with lower reactivity, which directly addresses the impurity formation issue while maintaining manufacturing feasibility

Inventive Principle:

Principle #36Phase transitions

2Reliability

If wet-pulverization is used to suppress impurity formation, then stability is improved, but additional process steps are required

Engineering Contradiction:

ImprovestabilityVSAvoidprocess steps

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention merges the pulverization and crystallization steps into a single integrated wet-pulverization process. The solvent serves dual functions as both a pulverization medium and a crystallization inducer, eliminating the need for separate crystallization equipment and reducing overall process complexity despite the added stability benefit

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The solvent in the wet-pulverization process performs multiple functions simultaneously: it acts as a dispersing medium for efficient pulverization, a temperature buffer to control exothermic reactions, and a crystallization promoter. This multi-functionality compensates for the additional process step by eliminating the need for separate treatment stages

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Device complexity

If dry-pulverization is used, then process simplicity is maintained, but impurity formation increases

Engineering Contradiction:

Improveprocess simplicityVSAvoidimpurity formation

Core Design Contradiction:

Device complexityVSObject-generated harmful factors

Solution Approach 1:

The invention introduces a solvent as an intermediary medium in the pulverization process. This intermediary facilitates gentle particle size reduction while controlling temperature and promoting crystallization, thereby suppressing impurity formation without significantly complicating the process flow or requiring specialized equipment

Inventive Principle:

Principle #24Intermediary (Mediator)

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

This approach results in crystals and pharmaceutical compositions with improved stability, maintaining low impurity levels even under stability testing conditions, ensuring the compound's effectiveness and longevity.

Implementation Method 1

a method for producing a crystal of a compound represented by Formula (I), characterized by wet-pulverizing the compound represented by Formula (I)

Methodology Applied

Scientific EffectCrystallization: Crystallisation

Data Source

PatentUS12570627B2Pharmaceutical composition in which production of impurities is suppressed

Publication Date: 2026.03.10 SHIONOGI & CO LTD

AI summary

By wet-pulverizing a compound represented by Formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof (hereinafter referred to as a compound represented by Formula (I) or the like), it is possible to provide a crystal of the compound represented by Formula (I) or the like and a pharmaceutical composition containing the same having excellent stability. In addition, by wet-kneading and/or wet-granulating the compound represented by Formula (I) or the like, it is possible to provide a pharmaceutical composition containing the compound represented by Formula (I) or the like having excellent stability.