Solid TYK2 Inhibitor Forms for Solubility and Stability
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Solution Overview
Problem
Existing TYK2 inhibitors lack effective solid forms that provide improved aqueous solubility, stability, and ease of formulation, which are crucial for treating TYK2-mediated disorders.
Innovation Solution
Development of crystalline polymorphs of TYK2 inhibitors, such as Compound 1, in various solid forms (e.g., Form A, Form C) with specific XRPD patterns, characterized by improved solubility, stability, and reduced impurities, formulated with pharmaceutically acceptable carriers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing TYK2 inhibitors are used in conventional forms, then the basic inhibitory activity is maintained, but aqueous solubility and stability are insufficient
Solution Approach 1:
The patent applies parameter changes by transforming the TYK2 inhibitor from conventional forms to specific crystalline polymorphs ( Forms A, B, C, D, E, F, G, H, I, or J) with defined crystal structures. This changes the physical state parameters to achieve both improved aqueous solubility and enhanced stability, resolving the contradiction between these two properties.
Solution Approach 2:
The patent utilizes phase transitions by establishing specific crystalline phases (polymorphs) of the TYK2 inhibitor. By controlling the phase transition to specific crystal forms with defined unit cell parameters and space groups, the invention achieves both high stability and adequate solubility, overcoming the limitations of conventional forms.
2Ease of manufacture
If conventional TYK2 inhibitor forms are used, then synthesis is straightforward, but formulation ease and bioavailability are limited
Solution Approach 1:
The patent changes the physical parameters of the TYK2 inhibitor by providing specific crystalline polymorphs with defined XRPD patterns and thermal properties. These parameter changes enable easier formulation and improved bioavailability while maintaining manufacturing feasibility through established crystallization methods.
3Manufacturing precision
If amorphous forms or impure samples are used, then preparation is simpler, but therapeutic efficacy and purity are reduced
Solution Approach 1:
The patent employs phase transition control to transform amorphous or impure samples into specific crystalline polymorphs. By controlling the crystallization process to obtain pure crystalline forms with characteristic XRPD patterns, the invention achieves high purity while the systematic approach to crystallization keeps the process manageable.
Solution Approach 2:
The patent replaces complex purification mechanisms with crystallization-based separation. By utilizing the self-organizing nature of crystallization, impure samples are transformed into pure crystalline polymorphs through controlled phase transitions, simplifying the overall purification process while achieving high manufacturing precision.
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 enhance the therapeutic efficacy of TYK2 inhibitors by providing improved bioavailability and stability, enabling effective treatment of autoimmune, inflammatory, and other TYK2-mediated disorders.
Implementation Method 1
a crystalline Form C of Compound 1 is provided: comprising an XRPD pattern substantially as shown in FIG. 10 (top trace)
Implementation Method 2
the solid form exhibits characterized by a TGA analysis of mass loss between 165° C. and 175° C.
Implementation Method 3
the solid form exhibits characterized by a DSC comprising a peak onset at about 247° C.
Data Source
AI summary
Solid forms of TYK2 inhibitors, pharmaceutical compositions thereof and methods of treatment are described herein.