Oxime Ether Solid Forms for MS Drug Stability

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Solution Overview

Problem

There is a need for novel drug products to treat multiple sclerosis and other autoimmune diseases affecting the central nervous system, as existing technologies face challenges in predicting and preparing stable crystalline forms of pharmaceutical compounds, which are crucial for effective treatment.

Innovation Solution

Development of solid forms comprising salts of (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carboxylic acid, including specific salts like HCl, oxalate, L-tartrate, and hemifumarate, characterized by unique X-ray powder diffraction patterns and DSC thermograms, to enhance solubility, stability, and bioavailability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Difficulty of detecting and measuring

If alternative solid forms of pharmaceutical compounds are developed to modulate physical and chemical properties, then solubility and bioavailability are enhanced, but the complexity of identifying and selecting the appropriate solid form increases

Engineering Contradiction:

Improvesolubility and bioavailabilityVSAvoidcomplexity of identifying and selecting solid form

Core Design Contradiction:

Difficulty of detecting and measuringVSDevice complexity

Solution Approach 1:

The patent applies parameter changes by developing multiple solid forms (crystalline, amorphous, salt forms) of the pharmaceutical compound with different physical and chemical parameters. Each solid form has distinct properties such as solubility, stability, and bioavailability characteristics, allowing optimization of drug delivery by selecting the appropriate solid form based on therapeutic needs

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs composite materials by creating salt forms of the compound with different counterions (e.g., hydrochloride, sulfate, nitrate). These composite salt forms exhibit modified physical and chemical properties compared to the parent compound, enabling enhanced solubility and bioavailability while providing a systematic approach to property modulation

Inventive Principle:

Principle #40Composite materials

2Stability of the object's composition

If crystalline forms of pharmaceutical compounds are prepared, then physical and chemical stability is improved, but it is not possible to predict apriori if crystalline forms exist or how to successfully prepare them

Engineering Contradiction:

Improvephysical and chemical stabilityVSAvoidpredictability and preparation of crystalline forms

Core Design Contradiction:

Stability of the object's compositionVSEase of manufacture

Solution Approach 1:

The patent applies preliminary action by systematically exploring and characterizing multiple solid forms before clinical development. The inventors prepared and characterized various crystalline forms, amorphous forms, and salt forms in advance, determining their stability profiles, solubility characteristics, and manufacturing properties. This preliminary characterization provides a foundation for selecting the most suitable solid form for development, reducing later surprises

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent utilizes parameter changes by modifying crystallization conditions (solvents, temperatures, pH, additives) to generate different polymorphic forms and salt forms. By systematically varying these parameters, the inventors were able to prepare multiple crystalline forms with different stability profiles, enabling selection of the most manufacturable and stable form for each specific application

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS11958805B2Solid forms comprising an oxime ether compound, compositions and methods of use thereof

Publication Date: 2024.04.16 NOVARTIS AG

AI summary

Provided herein are formulations, processes, solid forms and methods of use relating to (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carboxylic acid.