Zero Headspace Filling for Aqueous Drug Stability

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Solution Overview

Problem

Aqueous pharmaceutical compositions face challenges due to mechanical and chemical stresses during manufacturing, packaging, storage, and handling, exacerbated by the presence of headspace in containers, which leads to degradation and aggregation of drug substances, necessitating the use of stabilizers like surfactants that are costly and regulated, and existing methods fail to eliminate headspace completely in syringes.

Innovation Solution

A method involving a container with zero headspace is achieved by filling it with an aqueous drug substance solution, purging with a soluble gas, and inserting a stopper under vacuum conditions, allowing the stopper to move while maintaining an airtight seal, thereby eliminating detectable headspace and reducing the need for stabilizers.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of operation

If headspace is present in the container, then the container can accommodate the stopper insertion space, but the drug substance is subjected to greater mechanical stress and chemical degradation

Engineering Contradiction:

Improvestopper insertion spaceVSAvoidmechanical stress and chemical degradation

Core Design Contradiction:

Ease of operationVSObject-affected harmful factors

Solution Approach 1:

The patent changes the physical state of the headspace by introducing a soluble gas that dissolves into the aqueous solution over time, transforming the gaseous headspace into liquid solution. This parameter change (from gas to liquid phase) eliminates the headspace volume while maintaining the necessary space for stopper insertion, thereby reducing mechanical stress and chemical degradation without compromising operability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent utilizes phase transition by introducing a soluble gas that transitions from gaseous state to dissolved state in the aqueous solution. This phase change allows the headspace to be eliminated as the gas dissolves, converting the gas-solution interface into a homogeneous liquid phase, thus eliminating the harmful effects of headspace while preserving container volume for stopper accommodation

Inventive Principle:

Principle #36Phase transitions

2Object-affected harmful factors

If surfactants are added to reduce degradation, then the gas-solution interface barrier is improved, but the cost and regulatory burden increase

Engineering Contradiction:

Improvedrug substance degradationVSAvoidformulation complexity and cost

Core Design Contradiction:

Object-affected harmful factorsVSEase of manufacture

Solution Approach 1:

The patent extracts or removes the harmful gas phase from the container by introducing a soluble gas that dissolves completely into the solution. By taking out the gaseous headspace and converting it to dissolved gas in the liquid phase, the gas-solution interface is eliminated, thereby removing the need for surfactants to provide protective barriers, thus reducing formulation complexity and cost

Inventive Principle:

Principle #2Taking out (Extraction)

3Object-affected harmful factors

If the container is filled to 100% capacity, then headspace is eliminated, but the stopper cannot be inserted

Engineering Contradiction:

Improveheadspace degradationVSAvoidstopper insertion

Core Design Contradiction:

Object-affected harmful factorsVSEase of operation

Solution Approach 1:

The patent applies parameter changes by introducing a soluble gas that undergoes dissolution over time, changing the volume occupied by the gas from a fixed headspace to a variable dissolved state. This allows the container to be filled to apparent 100% capacity with the stopper in place, while the soluble gas gradually dissolves to eliminate any remaining headspace, thus resolving the contradiction between full filling and stopper insertion

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 method results in a stable pharmaceutical composition with reduced subvisible particles and extended stability, comparable to or better than compositions with headspace, without the use of surfactants, and allows for long-term storage with minimal degradation.

Implementation Method 1

purging the container with at least one soluble gas... storing the container, wherein the stopper can move within the container while maintaining an airtight seal; and the storage step results in the container having no visibly detectable headspace

Methodology Applied

Scientific EffectGas dissolution: Absorption (physical)

Implementation Method 2

purging the container with at least one soluble gas... inserting a stopper into the open end of the container creating a headspace of soluble gas

Methodology Applied

Scientific EffectVacuum: Vacuum

Data Source

PatentUS11576971B2Method of filling a container with no headspace

Publication Date: 2023.02.14 HONG KONG KING FRIEND IND CO LTD

AI summary

The present invention is directed to methods for filling a container wherein the filled container has no headspace. The present invention is further directed to methods for stabilizing an aqueous drug substance solution by filling a container with the aqueous drug substance solution wherein the filled container has no headspace. The present invention is further directed to methods for detecting headspace in a container.