Crystalline Form B HCl Salt Stability and Solubility

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

There is a need for a solid form of the compound 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide that is physically and chemically stable across various storage conditions, has sufficient solubility for further processing, and can mitigate pH effects better than other salts.

Innovation Solution

The development of crystalline Form B of the compound, which is a HCl salt, characterized by specific unit cell parameters, powder x-ray diffraction patterns, and solubility properties, providing stability and solubility suitable for pharmaceutical applications.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If a solid form of the compound is provided for pharmaceutical use, then the compound can be isolated and purified, but the solid form may lack physical and chemical stability across various storage conditions

Engineering Contradiction:

Improvephysical and chemical stabilityVSAvoidstability across storage conditions

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies parameter changes by converting the compound into a hydrochloride salt form, which fundamentally alters the physical and chemical parameters of the substance. This salt formation transforms an unstable free base into a stable crystalline solid that maintains integrity across varying storage conditions including temperature and humidity fluctuations.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates a composite structure by forming a salt between the compound and hydrochloric acid. This composite material approach combines the active pharmaceutical ingredient with a stabilizing counterion, resulting in a new material entity that exhibits enhanced stability properties while retaining the therapeutic activity of the original compound.

Inventive Principle:

Principle #40Composite materials

2Manufacturing precision

If the compound is isolated and purified through synthesis steps, then the compound can be obtained as a purified solid, but the yield may be lost during isolation and purification

Engineering Contradiction:

Improvepurification qualityVSAvoidyield loss

Core Design Contradiction:

Manufacturing precisionVSLoss of substance

Solution Approach 1:

The patent utilizes phase transitions by inducing crystallization of the compound as a hydrochloride salt from solution. This phase change from dissolved state to crystalline solid enables efficient separation and purification while minimizing material loss, as the crystallization process selectively precipitates the desired compound in high purity form.

Inventive Principle:

Principle #36Phase transitions

3Ease of manufacture

If the compound is provided in a solid form suitable for pharmaceutical formulation, then the compound can be processed further, but the solubility may be insufficient for preparation of other solid forms

Engineering Contradiction:

ImproveprocessabilityVSAvoidsolubility

Core Design Contradiction:

Ease of manufactureVSQuantity of substance

Solution Approach 1:

The invention applies parameter changes by altering the solubility characteristics of the compound through salt formation. The hydrochloride salt exhibits improved solubility properties compared to the free base, enabling the compound to dissolve sufficiently in appropriate solvents for further processing, formulation, and conversion into other solid dosage forms while maintaining manufacturability.

Inventive Principle:

Principle #35Parameter changes

4Reliability

If other salt forms of the compound are used, then the compound can be provided in solid form, but the pH effects are not adequately mitigated

Engineering Contradiction:

ImprovepH stabilityVSAvoidpH effects

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent converts the potentially harmful pH effects into a benefit by selecting hydrochloric acid as the counterion. The resulting hydrochloride salt not only mitigates adverse pH effects but also provides enhanced stability and desirable physicochemical properties. The hydrochloride form transforms the problematic acidity into a stabilizing feature that improves overall drug performance and storage characteristics.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

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

Crystalline Form B of the compound achieves physical and chemical stability across a range of storage conditions, maintains sufficient solubility for further processing, and effectively mitigates pH effects, making it suitable for pharmaceutical use.

Implementation Method 1

The present invention provides crystalline Form B of Compound (I)

Methodology Applied

Scientific EffectCrystallisation: Crystallisation

Implementation Method 2

characterized by specific unit cell parameters, powder x-ray diffraction patterns

Methodology Applied

Scientific EffectX-ray diffraction: X-Ray

Data Source

PatentUS12291517B2Crystalline form of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-D3) pyridazine-3-carboxamide

Publication Date: 2025.05.06 BRISTOL MYERS SQUIBB CO

AI summary

Disclosed is crystalline Form B of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl) amino)-N-(methyl-d3)pyridazine-3-carboxamide. Form B is the HCl salt of a neat crystalline form. Characterization data for Form B are disclosed.