Colchicine Solid Complexes for Pharmaceutical Solubility

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

There is a need for new solid forms of colchicine with improved properties of solubility, stability, and processability to achieve consistency in pharmaceutical product batches, as different crystalline forms, non-crystalline forms, hydrates, and solvates of colchicine exhibit varying physical properties affecting therapeutic activity.

Innovation Solution

The development of solid complexes comprising colchicine with guests such as malic acid, oxalic acid, or para-toluenesulfonic acid, formed through methods like slurry formation, vapor diffusion, and crystallization, which interact with colchicine to create co-crystals with distinct physicochemical properties, including solubility and melting point modifications.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If different crystalline forms, non-crystalline forms, hydrates and solvates of colchicine are used, then variety in physical properties is achieved, but consistency in therapeutic activity and batch-to-batch reproducibility deteriorates

Engineering Contradiction:

Improvevariety in physical propertiesVSAvoidconsistency in therapeutic activity

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent applies parameter changes by systematically varying the guest molecule (malic acid, oxalic acid, para-toluenesulfonic acid) and stoichiometric ratios (1:1, 1:2, 1:3) to create multiple solid forms with distinct physical properties. Each form exhibits different melting points, solubility characteristics, and XRPD patterns, allowing optimization for specific therapeutic requirements while maintaining reproducibility through defined synthesis protocols.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite materials by forming co-crystals and complexes between colchicine and various guest molecules. These composite solid forms combine the pharmacological activity of colchicine with the structural and physical properties of the guest molecules, resulting in materials with enhanced solubility, stability, and reproducible therapeutic effects.

Inventive Principle:

Principle #40Composite materials

2Ease of manufacture

If conventional solid forms of colchicine are used, then manufacturing simplicity is maintained, but solubility and stability properties deteriorate

Engineering Contradiction:

Improvemanufacturing simplicityVSAvoidsolubility and stability properties

Core Design Contradiction:

Ease of manufactureVSStability of the object's composition

Solution Approach 1:

The patent uses guest molecules (malic acid, oxalic acid, para-toluenesulfonic acid) as intermediaries that mediate between colchicine and the desired physical properties. These guests form stable interactions with colchicine in the solid state, creating co-crystals that exhibit improved solubility and stability while maintaining relatively simple manufacturing processes through standard crystallization techniques.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent utilizes phase transition principles by controlling the crystallization process to form specific solid forms with distinct physical properties. By varying conditions such as solvent choice, temperature, and stoichiometry, the patent directs the phase transition to produce co-crystals with enhanced solubility and stability characteristics.

Inventive Principle:

Principle #36Phase transitions

3Device complexity

If existing solid forms of colchicine are used, then process simplicity is maintained, but dissolution and therapeutic activity consistency deteriorate

Engineering Contradiction:

Improveprocess simplicityVSAvoiddissolution and therapeutic activity consistency

Core Design Contradiction:

Device complexityVSManufacturing precision

Solution Approach 1:

The patent applies segmentation by dividing the colchicine solid form into distinct molecular components (colchicine and guest molecules) arranged in specific stoichiometric ratios (1:1, 1:2, 1:3). This segmentation allows each component to contribute specific properties to the final solid form, enabling precise control over dissolution characteristics and therapeutic activity consistency.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent replaces mechanical mixing and conventional crystallization with more controlled methods such as vapor diffusion and controlled evaporation. These methods provide finer control over the formation of solid forms, ensuring consistent dissolution profiles and therapeutic activity while maintaining reasonable process complexity.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

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

These solid complexes exhibit enhanced solubility, stability, and processability, allowing for consistent pharmaceutical formulations and improved therapeutic efficacy, as demonstrated by specific XRPD, FT-Raman, and DSC analyses, with potential applications in treating various diseases including gout and inflammatory disorders.

Implementation Method 1

preparing colchicine malic acid co-crystal by vapor diffusion of hexanes into an ethyl acetate solution containing equimolar amounts of colchicine and L-malic acid

Methodology Applied

Scientific EffectVapor diffusion: Diffusion