Treprostinil Monohydrate Stability and Static Charge Reduction

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Solution Overview

Problem

The anhydrous form of treprostinil is unstable at room temperature, leading to dimer formation and requiring refrigeration for storage and transport, making it difficult to handle and increasing safety risks due to static electrical charges.

Innovation Solution

The development of a stable treprostinil monohydrate form, which is prepared through recrystallization and air-drying at controlled temperatures, eliminating the need for refrigeration and reducing static charges, thereby enhancing stability and safety.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of operation

If the anhydrous form of treprostinil is stored at room temperature, then handling and shipping are simplified, but the compound becomes unstable and forms dimers

Engineering Contradiction:
Improvehandling and shipping convenienceVSAvoidchemical stability
Core Design Contradiction:
Ease of operationVSStability of the object's composition

Solution Approach 1:

The patent applies parameter changes by modifying the molecular structure of treprostinil to create the monohydrate form (treprostinil monohydrate). This structural parameter change introduces a water molecule into the crystal lattice, which fundamentally alters the stability characteristics of the compound, allowing it to remain stable at room temperature without forming dimers.

Inventive Principle:
Principle #35Parameter changes

Solution Approach 2:

The invention creates a composite material by forming a hydrate complex where treprostinil molecules are associated with water molecules in a specific crystalline structure. This composite approach combines the active pharmaceutical ingredient with water in a stoichiometric ratio, resulting in a new material form that exhibits improved stability while maintaining therapeutic activity.

Inventive Principle:
Principle #40Composite materials

2Stability of the object's composition

If the anhydrous form of treprostinil is refrigerated for storage, then chemical stability is maintained, but storage and shipping complexity increases

Engineering Contradiction:
Improvechemical stabilityVSAvoidstorage and shipping requirements
Core Design Contradiction:
Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The patent applies parameter changes by modifying the molecular structure of treprostinil to create the monohydrate form (treprostinil monohydrate). This structural parameter change introduces a water molecule into the crystal lattice, which fundamentally alters the stability characteristics of the compound, allowing it to remain stable at room temperature without forming dimers.

Inventive Principle:
Principle #35Parameter changes

3Object-affected harmful factors

If the anhydrous form of treprostinil is handled, then static electrical charges accumulate creating safety risks, but the monohydrate form reduces these charges improving safety

Engineering Contradiction:
Improvesafety risks from static chargesVSAvoidcrystalline structure stability
Core Design Contradiction:
Object-affected harmful factorsVSStability of the object's composition

Solution Approach 1:

The patent applies parameter changes by modifying the molecular structure of treprostinil to create the monohydrate form (treprostinil monohydrate). This structural parameter change introduces a water molecule into the crystal lattice, which fundamentally alters the stability characteristics of the compound, allowing it to remain stable at room temperature without forming dimers.

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 monohydrate form of treprostinil is significantly more stable at room temperature, easier to handle, and safer to work with, allowing for improved storage, shipment, and formulation without the need for cold conditions, while maintaining high purity and therapeutic effectiveness.

Implementation Method 1

The monohydrate is stable at room temperature over a longer period of time than other forms of treprostinil

Methodology Applied
Scientific EffectHydrogen bonding:

Implementation Method 2

air-drying at controlled temperatures

Methodology Applied
Scientific EffectEvaporation: Evaporation

Data Source

PatentEP2300408B1Process for the preparation of treprostinil monohydrate and its use for storage and shipping
Publication Date: 2016.04.13 UNITED THERAPEUTICS CORP
  • EP2300408B1 patent drawingFigure 1a
  • EP2300408B1 patent drawingFigure 1b
  • EP2300408B1 patent drawing

AI summary

There is provided a stable monohydrate form of treprostinil and pharmaceutical formulation comprising the same, method of making and using the same.