Fluorine-Substituted Indazole Form II for Solubility–Stability Balance

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Solution Overview

Problem

Drug polymorphism affects the quality and efficacy of fluorine-substituted indazole compounds, necessitating the development of stable and pharmacokinetically superior crystal forms for effective pharmaceutical use.

Innovation Solution

Identification and characterization of Crystal Form II of methyl (4,6-diamino-2-(7-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl)pyrimidin-5-yl)carbamate, exhibiting excellent pharmacokinetic properties, high stability, and low hygroscopicity, suitable for pharmaceutical applications.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If different crystal forms of the same drug are used, then solubility and bioavailability may be improved, but stability and hygroscopicity may deteriorate

Engineering Contradiction:

ImprovesolubilityVSAvoidstability

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent applies parameter changes by systematically varying crystallization conditions (solvent type, temperature, pH, additives) to obtain different crystal forms with optimized properties. Crystal Form II was obtained by crystallizing from acetonitrile at controlled temperatures, achieving a balance of solubility, stability, and low hygroscopicity through precise control of physical and chemical parameters during the crystallization process.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If crystal form development is conducted to improve pharmacokinetic properties, then drugability is enhanced, but the complexity of the development process increases

Engineering Contradiction:

Improvepharmacokinetic propertiesVSAvoiddevelopment process complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies preliminary action by conducting comprehensive crystal form screening and characterization before preclinical studies. Multiple crystal forms were identified and characterized in advance using XRPD, DSC, and solubility measurements, allowing the selection of Crystal Form II with optimal pharmacokinetic properties before proceeding to animal studies and clinical development, thereby reducing later development risks.

Inventive Principle:

Principle #10Preliminary action

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

Crystal Form II demonstrates good stability, solubility, and pharmacokinetic properties, making it suitable for pharmaceutical uses as a soluble guanylate cyclase stimulator, particularly in treating cardiovascular and lipid-related conditions.

Implementation Method 1

X-ray powder diffraction (XRPD) pattern

Methodology Applied

Scientific EffectX-ray diffraction: X-Ray

Implementation Method 2

X-ray powder diffraction (XRPD) pattern

Methodology Applied

Scientific EffectDiffraction: Diffraction

Implementation Method 3

differential scanning calorimetry (DSC) thermogram

Methodology Applied

Scientific EffectDifferential scanning calorimetry: Calorimetry

Data Source

PatentEP4640676A1Crystal form of fluorine-substituted indazole compound and use thereof

Publication Date: 2025.10.29 SUNSHINE LAKE PHARMA CO LTD

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AI summary

The present invention relates to a crystal form of a fluorine-substituted indazole compound and a use thereof. The present invention also relates to a pharmaceutical composition comprising the crystal form. Specifically, the crystal form or the pharmaceutical composition can be used for treating and preventing cardiovascular diseases or conditions.