Amorphous Perindopril Sodium Salt Stabilization via Carbonate Buffering

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Solution Overview

Problem

Current formulations of perindopril sodium salt are unstable due to rapid degradation upon contact with the atmosphere and lack effective additives for enhancing stability, particularly in industrial-scale preparation processes.

Innovation Solution

A stable amorphous formulation of perindopril sodium salt is achieved by dissolving perindopril erbumine in a water or alcohol-water mixture, adding an aqueous solution of sodium hydrogen carbonate, and blending with inert ingredients, followed by drying at temperatures over 40°C to inhibit decomposition and facilitate tabletting.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If perindopril sodium salt is used in pharmaceutical formulations, then effective vasodilatation and antihypertensive action is achieved, but rapid degradation occurs upon contact with atmosphere

Engineering Contradiction:

Improvestability of perindopril sodium saltVSAvoidshelf life of formulation

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

Sodium hydrogen carbonate is introduced as an intermediary substance that mediates between perindopril sodium salt and atmospheric moisture/CO2. The carbonate buffer system absorbs harmful atmospheric components and prevents direct degradation of the active ingredient, thereby extending shelf life while maintaining reliability

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent creates an inert microenvironment within the formulation by incorporating sodium hydrogen carbonate, which buffers against pH changes and atmospheric moisture. This inert environment protects the sensitive perindopril sodium salt from degradation without requiring external inert gas packaging

Inventive Principle:

Principle #39Inert atmosphere (Inert environment)

2Reliability

If crystallized α-form of perindopril erbumine is used with sodium hydrogen carbonate, then some stabilization is achieved, but stabilization effect is limited to contact surfaces only

Engineering Contradiction:

Improvestabilization effectVSAvoidformulation homogeneity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent changes the physical state parameter of perindopril erbumine from crystalline α-form to amorphous form. This parameter change allows the substance to mix homogeneously with sodium hydrogen carbonate at the molecular level, transforming the stabilization mechanism from surface-contact only to throughout-the-formulation, thereby achieving uniform stabilization without increasing complexity

Inventive Principle:

Principle #35Parameter changes

3Ease of operation

If perindopril erbumine is dissolved and converted to sodium salt, then pharmaceutical usability is improved, but the sodium salt converts to oil and degrades rapidly upon contact with atmosphere

Engineering Contradiction:

Improvepharmaceutical usabilityVSAvoidstability of sodium salt formulation

Core Design Contradiction:

Ease of operationVSStability of the object's composition

Solution Approach 1:

The patent creates a composite material system combining perindopril sodium salt with sodium hydrogen carbonate in specific proportions. This composite formulation maintains the pharmaceutical advantages of the sodium salt form while the embedded carbonate component provides continuous protection against atmospheric degradation, achieving both ease of operation and compositional stability

Inventive Principle:

Principle #40Composite materials

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 resulting amorphous perindopril sodium salt exhibits enhanced stability and suitability for pharmaceutical preparations, preventing decomposition products like diketopiperazine and hydrolysis products, maintaining stability even at higher temperatures and humidity.

Implementation Method 1

The decomposition of ACE inhibitors may take place in several ways: by hydrolysis of the ester group, especially in a side chain

Methodology Applied

Scientific EffectHydrolysis prevention: Hydrolysis

Implementation Method 2

dried in a stream of warm air with a temperature over 40 °C

Methodology Applied

Scientific EffectEvaporation: Evaporation

Data Source

PatentEP1948224B1Stable formulation of amorphous perindopril salts, a process for their preparation, especially industrial preparation, and their use in the therapy of hypertension

Publication Date: 2014.03.12 SILVERSTONE PHARMA EST

AI summary

There is disclosed a stable formulation of amorphous perindopril erbumine of the formula which is obtained in such a way that perindopril erbumine, which may also be prepared in situ from perindopril and tert-butylamine, or perindopril erbumine hydrate is dissolved in demineralized water or in a mixture of demineralized water and alcohol, to this solution a solution of sodium hydrogen carbonate is added for stabilization, inert ingredients for tabletting are wetted therewith, dried in vacuo by lyophilization or at normal pressure with a stream of warm air at not more than 40°C, hydrophobic additives to facilitate tabletting are added, it is homogenized and the granulate is tabletted. Disclosed is also a stable formulation of amorphous perindopril sodium salt obtained by modification of the drying procedure in the process of preparing the granulate. X-ray powder diffraction investigations show that perindopril erbumine is present in amorphous form and does not contain crystal a, ß and ? forms.