Deuruxolitinib Phosphate Form 1 for Controlled Polymorph Stability

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Solution Overview

Problem

Existing forms of deuruxolitinib phosphate exhibit variability in properties such as solubility, dissolution rate, stability, and bioavailability, affecting clinical efficacy and safety, necessitating the development of a stable and well-defined polymorphic form.

Innovation Solution

The development of polymorph Form 1 of deuruxolitinib phosphate, characterized by specific XRPD peaks and DSC, FT-Raman, and TG-FTIR profiles, ensuring high deuterium incorporation and stability, with methods of preparation involving slurry formation in isopropanol or isopropanol/water mixtures.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing forms of deuruxolitinib phosphate are used, then manufacturing is simpler, but variability in solubility, dissolution rate, stability, and bioavailability affects clinical efficacy and safety

Engineering Contradiction:

Improveclinical efficacy and safety consistencyVSAvoidpolymorphic form stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent identifies and characterizes specific polymorphic forms (Form 1, Form 2, Form 3) of deuruxolitinib phosphate with distinct crystal lattice arrangements. Each polymorph exhibits different physical and chemical properties including solubility, dissolution rate, and stability. By selecting and controlling for specific polymorphic forms, the patent resolves the contradiction by providing a reliable, consistent composition that ensures clinical efficacy and safety while maintaining compositional stability through well-defined crystal structures.

Inventive Principle:

Principle #35Parameter changes

2Stability of the object's composition

If a specific polymorphic form is developed, then stability and solubility are enhanced, but the manufacturing process becomes more complex

Engineering Contradiction:

Improvepolymorphic form stabilityVSAvoidmanufacturing process complexity

Core Design Contradiction:

Stability of the object's compositionVSEase of manufacture

Solution Approach 1:

The patent employs slurry formation as a preliminary step in the manufacturing process. By preparing slurries of deuruxolitinib phosphate in specific solvents (isopropanol, isopropanol/water mixtures) and allowing controlled crystallization, the patent achieves consistent formation of desired polymorphic forms. This preliminary slurry preparation step simplifies subsequent processing while ensuring stable, well-defined polymorphic structures with enhanced solubility and dissolution characteristics.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent utilizes phase transition phenomena during crystallization from slurry to form specific polymorphic forms. By controlling conditions such as solvent composition, temperature, and evaporation rate, the patent directs the phase transition to produce consistent polymorphic forms (Form 1, Form 2, or Form 3) with desired stability and solubility properties, thereby achieving enhanced composition stability through controlled phase changes.

Inventive Principle:

Principle #36Phase transitions

3Reliability

If polymorphic forms are not controlled, then manufacturing is easier, but conversion between forms affects therapeutic effectiveness

Engineering Contradiction:

Improvetherapeutic effectiveness consistencyVSAvoidpolymorph characterization requirements

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent employs analytical techniques such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR) to characterize and identify polymorphic forms. These analytical methods replace complex mechanical control systems by providing non-invasive, precise identification of crystal structures. By using these substitutionary analytical approaches, the patent ensures consistent therapeutic effectiveness through accurate polymorph identification without requiring complex active control mechanisms during manufacturing.

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

Polymorph Form 1 provides enhanced stability, solubility, and bioavailability, ensuring consistent clinical efficacy and safety by minimizing conversion to other forms and maintaining therapeutic effectiveness.

Implementation Method 1

a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed in degrees 2-theta selected from 4.03±0.2, 14.54±0.2, 24.95±0.2, and 25.29±0.2 degrees

Methodology Applied

Scientific EffectX-ray diffraction: X-Ray

Implementation Method 2

a DSC spectrum (10° C./min) comprising an endotherm onset at 194.3±1.0° C. and peak at 197.4±1.0° C.

Methodology Applied

Scientific EffectEndothermic phase transition: Endothermic Reaction

Data Source

PatentUS20250326762A1Crystalline form of deuruxolitinib

Publication Date: 2025.10.23 SUN PHARMACEUTICAL IND INC

AI summary

The present disclosure is directed to polymorph Form 1 of 1H-pyrazole-1-propanenitrile, β-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-, (βR)-, phosphate (1:1) (deuruxolitinib phosphate). Also disclosed are methods of treatment using polymorph Form 1 of deuruxolitinib phosphate and methods of making polymorph Form 1 of deuruxolitinib phosphate.