Linaclotide Alpha-Crystalline Form Stability

Solution Overview

Problem

There is a need for improved forms of linaclotide with enhanced stability, including greater storage stability and resistance to chemical degradation compared to amorphous linaclotide.

Innovation Solution

A novel α-crystalline form of linaclotide is developed, characterized by specific X-ray powder diffraction patterns and prepared through crystallization in aqueous acid solutions, which can be isolated and distinguished from amorphous linaclotide using diffraction, thermal, and spectroscopic properties.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of manufacture

If amorphous linaclotide is used, then ease of manufacture is improved, but stability and resistance to chemical degradation deteriorate

Engineering Contradiction:

Improveease of manufactureVSAvoidstability

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The patent applies parameter changes by transforming linaclotide from an amorphous state to a crystalline state (α-crystalline form). This phase transition fundamentally alters the physical and chemical parameters of the substance, resulting in enhanced stability, reduced chemical degradation, and improved storage characteristics while maintaining manufacturability through controlled crystallization processes.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention directly utilizes phase transitions by converting linaclotide from an amorphous phase to a crystalline phase. The patent describes methods for inducing crystallization that transform the molecular arrangement and packing, thereby achieving superior stability and resistance to degradation compared to the amorphous form, while the crystallization process itself provides a manufacturable pathway.

Inventive Principle:

Principle #36Phase transitions

2Ease of manufacture

If amorphous linaclotide is used, then ease of manufacture is improved, but storage stability deteriorates

Engineering Contradiction:

Improveease of manufactureVSAvoidstorage stability

Core Design Contradiction:

Ease of manufactureVSDuration of action of stationary object

Solution Approach 1:

The patent applies parameter changes by transforming linaclotide from an amorphous state to a crystalline state (α-crystalline form). This phase transition fundamentally alters the physical and chemical parameters of the substance, resulting in enhanced stability, reduced chemical degradation, and improved storage characteristics while maintaining manufacturability through controlled crystallization processes.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention directly utilizes phase transitions by converting linaclotide from an amorphous phase to a crystalline phase. The patent describes methods for inducing crystallization that transform the molecular arrangement and packing, thereby achieving superior stability and resistance to degradation compared to the amorphous form, while the crystallization process itself provides a manufacturable pathway.

Inventive Principle:

Principle #36Phase transitions

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 α-crystalline form of linaclotide exhibits improved stability and reduced degradation, maintaining effectiveness and purity over time, making it suitable for treating gastrointestinal disorders.

Implementation Method 1

prepared through crystallization in aqueous acid solutions

Methodology Applied

Scientific EffectCrystallization: Crystallisation

Implementation Method 2

characterized by specific X-ray powder diffraction patterns

Methodology Applied

Scientific EffectX-ray diffraction: X-Ray

Data Source

PatentUS8293704B2Crystalline form of linaclotide

Publication Date: 2012.10.23 ALLERGAN PHARMACEUTICALS INTERNATIONAL LTD

AI summary

The present invention relates to crystalline forms of linaclotide, as well as to various methods and processes for the preparation and use of the crystalline forms.