Aspacytarabine Crystalline Polymorph Form B Stability

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Solution Overview

Problem

The challenge lies in identifying and stabilizing a reproducible and therapeutically effective polymorphic form of Aspacytarabine, a drug used for treating neoplastic diseases, as existing forms exhibit variability in stability and bioavailability due to differences in crystalline and amorphous forms, leading to inconsistent manufacturing and efficacy.

Innovation Solution

A new thermodynamically stable crystalline polymorph (Form B) of Aspacytarabine is developed, characterized by specific X-Ray Powder diffraction patterns and high chemical purity, along with a process involving catalytic hydrogenation and pH adjustment to ensure reproducible production and enhanced stability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If amorphous form of Aspacytarabine is used, then solubility is improved, but stability deteriorates

Engineering Contradiction:

ImprovesolubilityVSAvoidstability

Core Design Contradiction:

Quantity of substanceVSStability of the object's composition

Solution Approach 1:

The patent applies phase transition by converting the amorphous form of Aspacytarabine into a crystalline polymorph form. This phase transition resolves the contradiction by providing a stable crystalline structure that maintains adequate solubility while significantly improving storage stability and reducing conversion to degradation products.

Inventive Principle:

Principle #36Phase transitions

2Quantity of substance

If different polymorphic forms are used, then solubility and dissolution rate vary, but manufacturing consistency deteriorates

Engineering Contradiction:

ImprovesolubilityVSAvoidmanufacturing consistency

Core Design Contradiction:

Quantity of substanceVSManufacturing precision

Solution Approach 1:

The patent applies parameter changes by establishing specific crystallization conditions including pH range (2-9), temperature ranges, and solvent selection criteria. These controlled parameter changes ensure that the desired crystalline polymorph Form B is consistently produced during manufacturing, resolving the issue of manufacturing inconsistency while maintaining optimal solubility characteristics.

Inventive Principle:

Principle #35Parameter changes

3Stability of the object's composition

If crystalline form is used, then stability is improved, but solubility deteriorates

Engineering Contradiction:

ImprovestabilityVSAvoidsolubility

Core Design Contradiction:

Stability of the object's compositionVSQuantity of substance

Solution Approach 1:

The patent applies local quality by creating a specific crystalline polymorph structure with particular molecular arrangements and intermolecular interactions. This localized structural optimization allows the crystal lattice to maintain stability while incorporating features that preserve solubility, such as specific hydrogen bonding patterns and molecular conformations, thus resolving the contradiction between stability and solubility.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS20230331762A1Crystalline form of aspacytarabine

Publication Date: 2023.10.19 BIOSIGHT

AI summary

The present invention relates to a novel crystalline polymorph of (¾)-2-amino-4-(0-42R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyptetrahydrofuran-2-yl)-2-oxo-1,2- dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (also known as BST-236, Astarabine® or aspacytarabine), processes of preparation thereof, and uses thereof for the treatment of neoplastic diseases.