VCP/p97 Inhibitor Crystalline Forms for Stable Formulation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for targeting Valosin containing protein VCP/p97 lack effective inhibitors that can selectively inhibit its function, which is essential for cellular viability.
Innovation Solution
Development of crystalline forms of 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, including pharmaceutically acceptable salts such as hydrochloric acid, sulfuric acid, and p-toluenesulfonic acid salts, which exhibit specific X-ray powder diffraction patterns, thermo-gravimetric analysis, and differential scanning calorimetry profiles, providing a stable form of the inhibitor.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If crystalline forms of VCP/p97 inhibitor are developed, then therapeutic effectiveness and selectivity are improved, but manufacturing complexity and characterization requirements increase
Solution Approach 1:
The patent explores multiple crystalline forms and polymorphs of the VCP/p97 inhibitor by changing physical parameters such as temperature, pressure, and solvent conditions during crystallization. Different crystalline forms (Form I, Form II, Form III) are obtained through controlled variation of these parameters, each with distinct XRPD patterns and thermal properties, allowing optimization of therapeutic effectiveness while managing manufacturing complexity through systematic parameter exploration
Solution Approach 2:
The patent utilizes phase transition processes including crystallization, melting, and polymorphic transformation to develop stable crystalline forms of the inhibitor. Characterization techniques such as DSC (differential scanning calorimetry) and XRPD (X-ray powder diffraction) are employed to identify and verify the phase structures. The study examines phase transitions at specific temperatures (e.g., melting points, polymorphic transitions) to establish stable crystalline forms suitable for therapeutic use
2Reliability
If multiple pharmaceutically acceptable salts are synthesized, then bioavailability and stability are improved, but synthesis time and resource consumption increase
Solution Approach 1:
The patent synthesizes multiple pharmaceutically acceptable salts (hydrochloride, hydrobromide, sulfate, methanesulfate, benzenesulfate, p-toluenesulfate, phosphosphate, citrate, tartarate, gentisate, acetate, adipate, benzoate, glutamate, glycolate, lactate, malate, malonate, succinate) of the VCP/p97 inhibitor to enhance bioavailability and stability. Each salt form is characterized by specific XRPD patterns and thermal properties, allowing selection of optimal salts for different therapeutic applications while managing synthesis time through systematic exploration of salt formation methods
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 the inhibitor effectively target VCP/p97, offering potential therapeutic benefits in treating various cancers by inhibiting its function, thereby addressing the lack of effective inhibitors in current treatments.
Implementation Method 1
an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 1
Implementation Method 2
characteristic peaks at 7.5° 2-Theta, 10.8° 2-Theta, 12.5° 2-Theta, 17.4° 2-Theta, 18.8° 2-Theta, 20.3° 2-Theta, 20.5° 2-Theta, 22.4° 2-Theta, 22.5° 2-Theta, and 22.6° 2-Theta
Implementation Method 3
a thermo-gravimetric analysis (TGA) substantially similar to the one set forth in FIG. 2
Implementation Method 4
a DSC thermogram substantially similar to the one set forth in FIG. 3
Implementation Method 5
a DSC thermogram with an endotherm at about 233° C.
Data Source
AI summary
Described herein are crystalline forms of 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, and pharmaceutically acceptable salts and solvates thereof. Also described herein are pharmaceutical formulations of 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide, and pharmaceutically acceptable salts and solvates thereof.