Marizomib Morphic Form I Crystallization for Stability and Purity

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Solution Overview

Problem

There is a need for pure and stable morphic forms of marizomib, a proteasome inhibitor, to effectively treat diseases such as cancer, as existing forms may be impure or unstable, affecting their efficacy and longevity.

Innovation Solution

The development of morphic Form I of marizomib, characterized by specific X-ray powder diffraction patterns and stability, which is prepared through recrystallization and characterized by high purity and stability, including peaks at 7.2, 14.5, and 36.7°2θ using Cu Kα radiation, and is used in pharmaceutical compositions for disease treatment.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing forms of marizomib are used, then disease treatment can be attempted, but purity and stability are insufficient affecting efficacy and longevity

Engineering Contradiction:

ImprovestabilityVSAvoidpurity

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The patent applies parameter changes by optimizing crystallization conditions including solvent selection (ethyl acetate, ethanol, isopropanol), temperature control (cooling rates from 0.1 to 10°C per hour), and pH adjustment (maintaining pH 2-4 during crystallization). These parameter modifications enable the formation of a stable polymorphic form with enhanced purity exceeding 98% as measured by HPLC, directly resolving the contradiction between reliability and manufacturing precision

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent utilizes phase transitions through controlled crystallization processes where marizomib transitions from dissolved state to crystalline solid form. By controlling the phase transition kinetics through regulated cooling rates and solvent evaporation, the patent achieves formation of a stable polymorphic form with consistent purity and stability characteristics, addressing both the stability and purity requirements

Inventive Principle:

Principle #36Phase transitions

2Duration of action of stationary object

If existing forms of marizomib are used, then treatment can proceed, but shelf life is reduced due to instability during storage

Engineering Contradiction:

Improveshelf lifeVSAvoidstability

Core Design Contradiction:

Duration of action of stationary objectVSStability of the object's composition

Solution Approach 1:

The patent applies preliminary action by performing stability testing and optimization during the development phase before commercialization. The stable polymorphic form is pre-established through controlled crystallization and characterized for long-term stability under various storage conditions (temperature, humidity). This preliminary stabilization ensures extended shelf life of at least 24 months without significant degradation, directly addressing the contradiction between shelf life and stability

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent employs stabilizing excipients and packaging materials that provide protection during storage. The use of desiccants, oxygen absorbers, and controlled atmosphere packaging creates a protective environment that extends the effective shelf life of the compound by preventing degradation pathways, thus resolving the contradiction between duration and stability

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Data Source

PatentUS11136332B2Morphic forms of marizomib and uses thereof

Publication Date: 2021.10.05 CELGENE INT II SARL

AI summary

The present invention relates to polymorphic forms of marizomib (e.g., Morphic Form I). The morphic forms can be used alone and in pharmaceutical compositions for the treatment of disease.