Thermodynamically Stable Tosylate Salt Polymorph I

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Solution Overview

Problem

The existing forms of the tosylate salt of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide are metastable, leading to unwanted polymorph conversions that affect solubility and bioavailability, posing safety and quality risks in pharmaceutical formulations.

Innovation Solution

A thermodynamically stable polymorph I of the compound is developed, which is prepared through specific solvent conditions and seeding processes to prevent conversion to other polymorphs or solvates, ensuring high purity and stability in pharmaceutical compositions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If the existing metastable forms of the tosylate salt are used, then the compound can be prepared and formulated, but unwanted polymorph conversions occur that affect solubility and bioavailability

Engineering Contradiction:

Improvestability of polymorph formVSAvoidconsistency of solubility and bioavailability

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The patent applies parameter changes by identifying and establishing specific crystallization conditions (temperature, solvent composition, cooling rate) that produce polymorph I, the thermodynamically stable form. By controlling these parameters during preparation, the metastable polymorph II is converted to or prevented from forming, ensuring consistent solubility and bioavailability characteristics throughout the product lifecycle

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs preliminary action by pre-determining the optimal preparation method for obtaining polymorph I before formulation development. The stable polymorph form is established as the starting point for all subsequent formulation work, preventing polymorph conversion issues from arising in the first place rather than addressing them after they occur

Inventive Principle:

Principle #10Preliminary action

2Ease of manufacture

If metastable polymorphs are used in pharmaceutical formulations, then formulation development can proceed, but safety and quality risks arise from polymorph conversions

Engineering Contradiction:

Improveformulation developmentVSAvoidsafety and quality consistency

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The patent resolves this contradiction by establishing specific preparation parameters that directly yield polymorph I. The defined temperature range, solvent system, and crystallization conditions ensure that the stable form is obtained consistently, enabling formulation development to proceed with confidence in product safety and quality without risk of later polymorph conversions

Inventive Principle:

Principle #35Parameter changes

3Manufacturing precision

If polymorph conversions are prevented through stable form development, then solubility and bioavailability become reliable, but additional process steps are required for preparation

Engineering Contradiction:

Improveconsistency of solubility and bioavailabilityVSAvoidpreparation process complexity

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The patent applies preliminary action by incorporating all necessary control measures directly into the crystallization step itself. The stable polymorph I is formed during the initial preparation process through controlled cooling and solvent selection, eliminating the need for subsequent stabilization steps or additional process complexity while ensuring consistent solubility and bioavailability

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

The stable polymorph I maintains consistent properties, enhancing the safety and quality of pharmaceutical preparations by preventing unwanted conversions, thus ensuring reliable solubility and bioavailability, and is suitable for treating disorders related to abnormal angiogenesis and hyperpermeability processes.

Implementation Method 1

Methodology Applied

Scientific EffectPolymorphism:

Implementation Method 2

A thermodynamically stable polymorph I of the compound is developed, which is prepared through specific solvent conditions and seeding processes to prevent conversion to other polymorphs or solvates

Methodology Applied

Scientific EffectThermodynamic stability:

Implementation Method 3

A thermodynamically stable polymorph I of the compound is developed, which is prepared through specific solvent conditions and seeding processes

Methodology Applied

Scientific EffectCrystallization: Crystallisation

Data Source

PatentUS8877933B2Thermodynamically stable form of a tosylate salt

Publication Date: 2014.11.04 BAYER HEALTHCARE LLC

AI summary

The present invention relates to a novel form, thermodynamically stable at room temperature, of the tosylate salt of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide, to processes for its preparation, to medicaments comprising it and to its use in the control of disorders.