KRAS G12C Crystalline Forms for Dissolution and Bioavailability

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Solution Overview

Problem

Existing KRas inhibitors have not demonstrated sufficient safety and efficacy for cancer therapy, and there is a need for crystalline forms of the KRas G12C inhibitor that enhance dissolution rate, solubility, bioavailability, manufacturing, and storage shelf life.

Innovation Solution

Development of crystalline forms of the KRas G12C inhibitor 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-methoxy]-6,8-dihydro-5H-pyridopyrimidin-4-yl]-1-acetonitrile, characterized by specific X-ray powder diffraction patterns, differential scanning calorimetry, and thermogravimetric analysis profiles, to improve pharmaceutical properties.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Speed

If amorphous form of KRas G12C inhibitor is used, then compound can be obtained, but dissolution rate and bioavailability are insufficient

Engineering Contradiction:

Improvedissolution rateVSAvoidbioavailability

Core Design Contradiction:

SpeedVSReliability

Solution Approach 1:

The patent changes the physical state parameter of the compound from amorphous to crystalline form. Specifically, it provides crystalline forms with defined X-ray powder diffraction patterns and differential scanning calorimetry profiles, which fundamentally alters the dissolution kinetics and bioavailability compared to the amorphous form.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention utilizes phase transition from amorphous to crystalline state to improve pharmaceutical properties. The crystalline forms exhibit enhanced dissolution rates and bioavailability due to their ordered molecular structure and defined melting points, as demonstrated by the differential scanning calorimetry data showing sharp endothermic peaks characteristic of crystalline phases.

Inventive Principle:

Principle #36Phase transitions

2Quantity of substance

If crystalline forms are developed, then dissolution rate and solubility are enhanced, but manufacturing complexity increases

Engineering Contradiction:

ImprovesolubilityVSAvoidmanufacturing complexity

Core Design Contradiction:

Quantity of substanceVSEase of manufacture

Solution Approach 1:

The patent defines specific crystalline forms with characteristic X-ray powder diffraction patterns and differential scanning calorimetry profiles. By controlling crystallization parameters such as temperature, solvent composition, and cooling rates, the invention achieves desired crystalline forms with enhanced solubility while maintaining manufacturability through established crystallization techniques.

Inventive Principle:

Principle #35Parameter changes

3Duration of action of stationary object

If crystalline forms are produced, then storage shelf life is improved, but process development time increases

Engineering Contradiction:

Improvestorage shelf lifeVSAvoidprocess development time

Core Design Contradiction:

Duration of action of stationary objectVSLoss of time

Solution Approach 1:

The invention leverages the thermal stability of crystalline forms, evidenced by sharp endothermic peaks in differential scanning calorimetry at defined temperatures, to achieve improved storage shelf life. The crystalline structure resists degradation and polymorphic transformation under storage conditions, extending product stability.

Inventive Principle:

Principle #36Phase transitions

Solution Approach 2:

The patent employs analytical techniques such as X-ray powder diffraction and differential scanning calorimetry to characterize and verify crystalline forms, replacing the need for extensive trial-and-error testing. This systematic characterization approach accelerates process development by quickly identifying and validating suitable crystalline forms.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

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 provide enhanced dissolution rate, solubility, and bioavailability, along with improved manufacturing and storage stability, addressing the limitations of amorphous forms.

Implementation Method 1

crystalline forms of the KRas G12C inhibitor 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-methoxy]-6,8-dihydro-5H-pyridopyrimidin-4-yl]-1-acetonitrile, characterized by specific X-ray powder diffraction patterns

Methodology Applied

Scientific EffectX-ray diffraction: X-Ray

Implementation Method 2

characterized by specific X-ray powder diffraction patterns, differential scanning calorimetry, and thermogravimetric analysis profiles

Methodology Applied

Scientific EffectDifferential scanning calorimetry: Calorimetry

Implementation Method 3

characterized by specific X-ray powder diffraction patterns, differential scanning calorimetry, and thermogravimetric analysis profiles

Methodology Applied

Scientific EffectThermogravimetric analysis:

Data Source

PatentUS20250282778A1Crystalline forms of a KRAS g12c inhibitor

Publication Date: 2025.09.11 MIRATI THERAPEUTICS INC

AI summary

The present invention relates to crystalline forms of a KRas G12C inhibitor and salt thereof. In particular, the present invention relates to crystalline forms of the KRas G12C inhibitor 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile, pharmaceutical compositions comprising the crystalline forms, processes for preparing the crystalline forms and methods of use thereof.