KRAS G12C Inhibitor Solid-State Forms for Regulatory Approval

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Solution Overview

Problem

Existing polymorphic forms of the KRAS G12C inhibitor Compound 1 do not meet the exacting purity and characterization standards required for regulatory approval, affecting solubility, stability, and bioavailability, which are crucial for effective cancer treatment.

Innovation Solution

Development of new crystalline, anhydrous, hydrate, and solvate forms of Compound 1, along with pharmaceutical compositions, to enhance solubility, stability, and bioavailability, thereby facilitating regulatory approval and therapeutic efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Manufacturing precision

If existing polymorphic forms of Compound 1 are used, then the compound can be manufactured and formulated, but they do not meet the exacting purity and characterization standards required for regulatory approval

Engineering Contradiction:

Improvepurity and characterization standardsVSAvoidregulatory approval

Core Design Contradiction:

Manufacturing precisionVSReliability

Solution Approach 1:

The patent applies parameter changes by discovering and characterizing new polymorphic forms (Forms I, II, III, and solvates) of Compound 1 with distinct crystal structures and physical properties. Each polymorphic form exhibits different X-ray diffraction patterns, melting points, and solubility characteristics, allowing selection of forms that meet stringent regulatory purity and characterization standards while ensuring reliable regulatory approval for cancer treatments

Inventive Principle:

Principle #35Parameter changes

2Ease of operation

If certain polymorphs are selected for drug formulation, then solubility and bioavailability can be improved, but stability under manufacturing and storage conditions may be compromised

Engineering Contradiction:

Improvesolubility and bioavailabilityVSAvoidstability under manufacturing and storage conditions

Core Design Contradiction:

Ease of operationVSStability of the object's composition

Solution Approach 1:

The patent applies local quality by providing multiple polymorphic forms of Compound 1, each with locally optimized properties for specific applications. For example, certain forms may exhibit enhanced solubility for improved bioavailability, while other forms demonstrate superior stability for manufacturing and storage. This allows formulation scientists to select or develop specific polymorphic forms tailored to particular dosage form requirements and storage conditions

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent applies composite materials by describing pharmaceutical compositions that incorporate selected polymorphic forms of Compound 1 with various excipients and formulation components. These composite formulations are designed to maintain the desired solubility and stability characteristics of the active compound while ensuring manufacturability and storage stability through careful selection of compatible formulation materials

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS12415806B1Solid state forms

Publication Date: 2025.09.16 AMGEN INC

AI summary

The present disclosure provides crystalline and amorphous forms of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2 (1H)-one, including several anhydrous, hydrate and solvate forms, and solid state forms thereof, pharmaceutical compositions, and methods of treating a disease mediated by KRAS G12C inhibition.