Ibrutinib Crystalline Forms for Stable BTK Inhibitor Formulation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing treatments for diseases associated with Bruton's tyrosine kinase (Btk) activity lack effective crystalline forms of the Btk inhibitor ibrutinib, which can provide stable and efficient therapeutic benefits.
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, with specific X-ray powder diffraction patterns and thermal properties, to enhance the stability and efficacy of Btk inhibition.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If amorphous or non-crystalline forms of ibrutinib are used, then the compound can be synthesized and formulated, but the stability and therapeutic efficacy are insufficient
Solution Approach 1:
The patent applies parameter changes by identifying and characterizing specific crystalline forms (polymorphs) of ibrutinib with distinct X-ray powder diffraction patterns. Different crystalline forms exhibit different stability profiles, and the patent selects specific polymorphic forms that optimize both stability and therapeutic efficacy. This involves changing the physical state parameters of the compound from amorphous to specific crystalline arrangements.
Solution Approach 2:
The patent utilizes phase transitions by establishing methods to convert ibrutinib from amorphous or non-crystalline states to specific crystalline forms. The characterization of melting points, thermal properties, and diffraction patterns enables control over phase transitions during formulation and storage, ensuring the compound maintains its optimal crystalline state for stability and efficacy.
2Manufacturing precision
If a single crystalline form is selected for pharmaceutical formulation, then manufacturing consistency can be achieved, but adaptability to different therapeutic needs is reduced
Solution Approach 1:
The patent applies universality by demonstrating that multiple crystalline forms of ibrutinib can serve different therapeutic purposes. Each polymorphic form is characterized with its unique properties (solubility, stability, bioavailability), allowing selection of appropriate forms for different indications, patient populations, or formulation types while maintaining manufacturing precision through controlled crystallization methods.
Solution Approach 2:
The patent enables adaptability through parameter changes by showing how varying crystallization conditions (solvent type, temperature, pH, concentration) produce different polymorphic forms with tailored properties. This allows optimization of the compound's physical and chemical parameters to match specific therapeutic requirements while maintaining consistent manufacturing processes for each form.
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
The crystalline forms of ibrutinib provide improved stability and therapeutic efficacy by maintaining the inhibitor's activity, allowing for effective treatment of diseases mediated by Btk activity.
Implementation Method 1
an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.7±0.1° 2-Theta, 13.6±0.1° 2-Theta, 16.1±0.1° 2-Theta, 18.9±0.1° 2-Theta, 21.3±0.1° 2-Theta, and 21.6±0.1° 2-Theta
Data Source
Figure 1
Figure 2
Figure 3
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.