Solid Forms of Kinase Modulating Compound I
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Solution Overview
Problem
Current treatments for c-Kit and/or c-Fms and/or Flt3 mediated diseases lack effective solid forms and crystalline forms of Compound I and Compound II, which are essential for therapeutic applications.
Innovation Solution
The development of solid forms, polymorphic forms, and crystalline forms of Compound I and Compound II, including specific forms like Compound I Form A, B, C, and D, and Compound II, characterized by unique X-ray powder diffractograms, differential scanning calorimetry, and thermogravimetric analysis, are provided, along with processes for their preparation and use in pharmaceutical compositions for treating c-Kit and/or c-Fms and/or Flt3 mediated diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Compound I and Compound II are developed for therapeutic applications, then therapeutic efficacy is improved, but lack of effective solid forms and crystalline forms limits their practical use
Solution Approach 1:
The patent applies parameter changes by developing multiple polymorphic forms (Forms A, B, C, D) of Compound I and crystalline forms of Compound II, each with distinct crystal structures characterized by unique X-ray powder diffractograms. These different solid forms exhibit varying physical properties such as solubility, stability, and bioavailability, allowing optimization of therapeutic efficacy while providing manufacturing flexibility through multiple viable solid forms
Solution Approach 2:
The patent creates composite pharmaceutical compositions that incorporate specific crystalline forms of Compound I and Compound II with excipients and carriers. These composite materials combine the active compounds in optimized crystal forms with formulation components to enhance stability, solubility, and delivery, thereby resolving the contradiction between therapeutic efficacy and ease of manufacture
2Ease of operation
If multiple crystalline forms (Forms A-D) are developed, then solubility and bioavailability are improved, but characterization and quality control become more complex
Solution Approach 1:
The patent employs characteristic X-ray powder diffractogram patterns as unique identifiers for each polymorphic form (Forms A, B, C, D). Each form displays distinct diffraction peaks at specific 2θ angles, serving as a fingerprint for identification and quality control. This approach simplifies differentiation and characterization of the various crystalline forms through a reliable, standardized analytical method
Solution Approach 2:
The patent replaces complex physical characterization methods with X-ray powder diffraction analysis for identifying and differentiating polymorphic forms. This substitution provides a non-destructive, rapid, and highly specific method for characterizing crystal structures, reducing the complexity of quality control while enabling precise identification of each form based on its unique diffraction pattern
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
These forms demonstrate therapeutic efficacy in treating conditions such as tenosynovial giant cell tumor, pigmented villonodular synovitis, malignant peripheral nerve sheath tumors, breast cancer, acute myeloid leukemia, and other diseases by effectively inhibiting c-Kit and c-Fms protein kinases, offering improved treatment options.
Implementation Method 1
Compound I Form A is characterized by an X-ray powder diffractogram comprising the following peaks (± 0.2°): at 7.1, 22.9 and 27.6 °2θ, as determined on a diffractometer using Cu-Kα radiation
Implementation Method 2
as determined on a diffractometer using Cu-Kα radiation
Implementation Method 3
characterized by an X-ray powder diffractogram comprising the following peaks (± 0.2°): at 7.1, 22.9 and 27.6 °2θ, as determined on a diffractometer using Cu-Kα radiation
Implementation Method 4
characterized by an X-ray powder diffractogram comprising the following peaks (± 0.2°): at 7.1, 22.9 and 27.6 °2θ, as determined on a diffractometer using Cu-Kα radiation
Data Source
Figure 1
Figure 2
Figure 3~4
AI summary
Solid forms of the compound, [5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- (6-trifluoromethyl-pyridin-3-ylmethyl)-amine HC1 salt (Compound I) and its free base, active on the receptor protein kinases c-Kit and/or c-Fms and/or Flt3, were prepared and characterized. Also provided are methods of using the solid forms.