Amorphous Atorvastatin Stability via Sodium Hydroxide

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Solution Overview

Problem

Existing pharmaceutical compositions of atorvastatin suffer from instability due to susceptibility to heat, humidity, low pH, and light, and require large amounts of insoluble stabilizers or complex packaging processes to maintain stability and bioavailability.

Innovation Solution

A packaged pharmaceutical composition of amorphous atorvastatin with sodium hydroxide as an alkali metal additive, exposed to an atmosphere with 1-16% oxygen, preferably 2-12% oxygen, combined with disintegrants like croscarmelose sodium and crospovidone, and suitable coatings for enhanced stability and bioavailability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If large amounts of insoluble stabilizers (calcium carbonate, magnesium oxide) are used to stabilize atorvastatin, then stability is improved, but ease of manufacture deteriorates due to difficulty in achieving even distribution and processing

Engineering Contradiction:

ImprovestabilityVSAvoidease of manufacture

Core Design Contradiction:

Stability of the object's compositionVSEase of manufacture

Solution Approach 1:

The patent changes the chemical state of the stabilizer from insoluble (calcium carbonate, magnesium oxide) to soluble (sodium hydroxide). This parameter change enables even distribution throughout the formulation and simplifies processing, while maintaining stabilization effectiveness through controlled solubility and pH modulation

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces an intermediary substance (sodium hydroxide) that mediates between the atorvastatin and the stabilizing function. Sodium hydroxide acts as a soluble stabilizer that can be evenly distributed and processed, serving as an intermediary that provides stability without the manufacturing difficulties of insoluble salts

Inventive Principle:

Principle #24Intermediary (Mediator)

2Stability of the object's composition

If complex packaging processes with inert gas or oxygen absorbers are used to reduce oxygen content, then stability is improved, but device complexity increases

Engineering Contradiction:

ImprovestabilityVSAvoiddevice complexity

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The patent enables the formulation to stabilize itself through the inherent properties of sodium hydroxide and the controlled oxygen atmosphere (1-16%). The system self-regulates stability without requiring external inert gas packaging or oxygen absorbers, eliminating complex packaging processes while maintaining protection against degradation

Inventive Principle:

Principle #25Self-service

3Reliability

If amorphous atorvastatin is used to improve bioavailability, then bioavailability is improved, but stability deteriorates due to susceptibility to heat, humidity, low pH and light

Engineering Contradiction:

ImprovebioavailabilityVSAvoidstability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent creates a composite formulation combining amorphous atorvastatin with sodium hydroxide and other excipients in a specific ratio range. This composite structure provides both the bioavailability benefits of amorphous form and the stability benefits through the stabilizing action of sodium hydroxide and controlled formulation composition

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

The patent changes the chemical environment parameters by using sodium hydroxide to control pH and create a stable microenvironment around the amorphous atorvastatin. This parameter change protects the amorphous form from degradation by heat, humidity, low pH and light while maintaining its bioavailability advantages

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 composition achieves high stability and bioavailability with reduced oxygen content and minimal alkali metal additive, along with improved dissolution rates and even distribution of stabilizers, avoiding the need for large amounts of insoluble stabilizers and complex packaging.

Implementation Method 1

the composition comprises amorphous atorvastatin, a salt or ester thereof as active ingredient and sodium hydroxide as alkali metal additive

Methodology Applied

Scientific EffectChemical stabilization:

Implementation Method 2

exposed to an atmosphere comprising 1 to 16 % by volume of oxygen

Methodology Applied

Scientific EffectOxygen exposure control:

Implementation Method 3

combined with disintegrants like croscarmelose sodium and crospovidone, and suitable coatings for enhanced stability and bioavailability

Methodology Applied

Scientific EffectDisintegration:

Data Source

PatentEP1986608B1Pharmaceutical composition comprising amorphous atorvastatin

Publication Date: 2012.11.21 KRKA TOVARNA ZDRAVIL D D

AI summary

The invention relates to a packaged pharmaceutical composition of atorvastatin of improved stability and bioavailability wherein the composition comprises small amounts of an alkali metal additive and is exposed to an atmosphere comprising 1 to 16 % by volume of oxygen.