Clevidipine Composition With Controlled Water Content to Limit Impurities

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Solution Overview

Problem

Clevidipine pharmaceutical compositions suffer from stability issues due to impurities arising from hydrolysis, decarboxylation, and condensation reactions, which compromise the purity and potency of the drug.

Innovation Solution

The development of pharmaceutical compositions with reduced levels of impurities such as Substance 23, 24, 25, and H168/79, achieved by controlling temperature and water content during manufacturing and storage, and using specific HPLC methods for detection and quantification.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of operation

If clevidipine is formulated as a liquid emulsion for intravenous administration, then the drug can be delivered effectively and prevented from adhering to plastic administration sets, but impurities arise from hydrolysis, decarboxylation, and condensation reactions that compromise stability and purity

Engineering Contradiction:

Improvedeliverability of insoluble drugVSAvoidstability of clevidipine composition

Core Design Contradiction:

Ease of operationVSStability of the object's composition

Solution Approach 1:

The patent applies parameter changes by controlling temperature (maintaining at 2-8°C) and water content (limiting to specific levels) during manufacturing and storage to prevent hydrolysis, decarboxylation, and condensation reactions. This resolves the contradiction by modifying environmental parameters to maintain composition stability while preserving the emulsion's deliverability function.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates an inert environment by controlling the formulation to minimize water content and using nitrogen or other inert gases during manufacturing and storage. This prevents hydrolytic breakdown and degradation reactions, maintaining stability while allowing the emulsion to function as an effective drug delivery vehicle.

Inventive Principle:

Principle #39Inert atmosphere (Inert environment)

2Ease of operation

If clevidipine is stored at room temperature for extended periods, then accessibility and ease of use improve, but degradation increases leading to higher impurity levels and reduced potency

Engineering Contradiction:

Improveaccessibility of drugVSAvoidpotency of drug

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

The patent applies preliminary action by pre-formulating the emulsion with stabilizers and controlling manufacturing conditions to prevent degradation before storage. The formulation is designed in advance to resist hydrolysis and oxidation, allowing the drug to maintain potency even when stored at room temperature for extended periods, thus improving accessibility without sacrificing reliability.

Inventive Principle:

Principle #10Preliminary action

3Productivity

If standard manufacturing processes are used for clevidipine emulsion, then production efficiency and productivity are maintained, but impurity levels exceed acceptable thresholds

Engineering Contradiction:

Improvemanufacturing efficiencyVSAvoidimpurity level control

Core Design Contradiction:

ProductivityVSManufacturing precision

Solution Approach 1:

The patent modifies manufacturing parameters including temperature control during emulsion preparation, water content limitations, and pH control to prevent formation of degradation impurities. These parameter changes are integrated into the manufacturing process without significantly impacting productivity, achieving both efficient production and precise impurity control below acceptable thresholds.

Inventive Principle:

Principle #35Parameter changes

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 compositions maintain stability and potency of clevidipine for at least 36 months at 2-8°C, with reduced impurity levels, ensuring effective treatment of conditions like hypertension and angina.

Implementation Method 1

a number of impurities which may be derived from clevidipine through a hydrolysis, decarboxylation and condensation reaction

Methodology Applied

Scientific EffectHydrolysis: Hydrolysis

Implementation Method 2

a number of impurities which may be derived from clevidipine through a hydrolysis, decarboxylation and condensation reaction

Methodology Applied

Scientific EffectDecarboxylation:

Implementation Method 3

using specific HPLC methods for detection and quantification

Methodology Applied

Scientific EffectChromatography: Chromatography

Data Source

PatentUS20250213540A1Pharmaceutical compositions and methods for producing low impurity concentrations of the same

Publication Date: 2025.07.03 CHIESI FARMACEUTICI SPA

AI summary

A composition having clevidipine as an active ingredient is described. The composition includes clevidipine as an active ingredient and an amount of the impurity H168/79 that is no greater than about 1.5%, or where the ratio between clevidipine and H168/79 is equal or above 60 to 1.