BTK Inhibitor Polymorphs for Stable and Soluble Formulation

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Solution Overview

Problem

Current treatments for diseases associated with Bruton's tyrosine kinase (Btk) activity lack effective and stable crystalline forms of the Btk inhibitor ibrutinib, which are crucial for therapeutic efficacy.

Innovation Solution

Development of crystalline forms of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, including polymorphs, solvates, and amorphous phases, along with pharmaceutically acceptable salts, to enhance therapeutic efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments for Btk activity are used, then therapeutic options are available, but effective and stable crystalline forms of the Btk inhibitor are lacking

Engineering Contradiction:

Improvestability of crystalline formVSAvoidavailability of crystalline forms

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies parameter changes by discovering and characterizing multiple crystalline forms (polymorphs) of ibrutinib with different structural parameters. Each polymorph (Forms I, II, III, IV, V, VI, VII) has distinct crystal packing arrangements, hydrogen bonding patterns, and molecular conformations that result in different stability and solubility characteristics, thereby providing reliable stable crystalline forms while maintaining therapeutic effectiveness

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite crystalline structures by forming solvates and hydrates of ibrutinib with various solvents and water molecules. These composite crystalline forms incorporate solvent molecules within the crystal lattice, creating stable structures with improved handling properties while maintaining the pharmacologically active ibrutinib component

Inventive Principle:

Principle #40Composite materials

2Stability of the object's composition

If crystalline forms of the Btk inhibitor are developed, then stability is improved, but manufacturing complexity increases

Engineering Contradiction:

Improvestability of crystalline formVSAvoidcomplexity of crystalline structure

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The patent segments the complex problem of ibrutinib crystallization by identifying and characterizing distinct polymorphic forms and solvate types separately. Each crystalline form is independently characterized with its own stability profile, allowing selection of the most appropriate form for specific manufacturing and formulation needs without requiring mastery of all possible crystalline structures

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent uses parameter changes to control crystallization outcomes by optimizing variables such as solvent selection, temperature, pH, and concentration. These controlled parameter changes enable reproducible formation of specific crystalline forms with desired stability characteristics while simplifying the manufacturing process through standardized crystallization protocols

Inventive Principle:

Principle #35Parameter changes

3Reliability

If multiple crystalline forms are created, then therapeutic effectiveness is enhanced, but solubility challenges arise

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoidsolubility of inhibitor

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent exploits parameter changes in crystal lattice structure to modulate solubility properties. Different polymorphs and solvates exhibit varying degrees of lattice energy, molecular exposure, and intermolecular interactions, resulting in different solubility profiles. This allows selection or development of crystalline forms with optimized solubility for specific therapeutic applications while maintaining effectiveness

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses solvent molecules as intermediaries in forming solvate crystalline structures. These solvent molecules act as mediators between the ibrutinib molecules, creating crystal lattices with controlled solubility characteristics. The solvent intermediaries can be selected to optimize both stability and solubility properties for downstream formulation and delivery

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20260062417A1Crystalline forms of a brutons tyrosine kinase inhibitor

Publication Date: 2026.03.05 PHARMACYCLICS LLC

AI summary

Described herein is the Bruton's tyrosine kinase (Btk) inhibitor 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, including crystalline forms, solvates and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical compositions that include the Btk inhibitor, as well as methods of using the Btk inhibitor, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.