Continuous Hot Melt Granulation of Low Soluble Pharmaceuticals
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Solution Overview
Problem
Current melt granulation techniques require low-melting binders that can be unstable during handling and storage, and they limit the options for suitable polymers, making it difficult to achieve amorphous solid dispersions of active pharmaceutical ingredients without physical instability or degradation.
Innovation Solution
A melt granulation process using polyvinyl alcohol (PVA) as a polymer to stabilize active pharmaceutical ingredients in their amorphous form, where the API is heated above its melting point and solidified within or on the PVA during the cooling step, eliminating the need for additional binders and enhancing dissolution properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If low-melting binders are used in melt granulation, then agglomeration of solid particles is achieved, but the binders become unstable during handling and storage
Solution Approach 1:
The patent changes the temperature parameter from low (50-90°C) to high (above polymer melting point but below decomposition point), which fundamentally alters the binder's physical state and stability characteristics. This temperature parameter change transforms the binder from a low-melting unstable substance to a high-temperature stable polymer system.
Solution Approach 2:
The patent replaces the short-living unstable low-melting binder with a thermally stable polymer that can be processed at high temperatures. The polymer serves as a durable, stable binder that maintains its properties throughout handling and storage, eliminating the stability issues of traditional binders.
2Ease of manufacture
If low-melting binders are used in melt granulation, then particle agglomeration is achieved, but the options for suitable polymers are limited
Solution Approach 1:
By changing the operating temperature parameter to high temperatures, the patent expands the range of suitable polymers from only low-melting materials to include any thermoplastic polymer with appropriate thermal stability. This parameter change opens up a vast library of polymer options including polyvinyl alcohol, cellulose derivatives, and other pharmaceutical-grade polymers.
Solution Approach 2:
The patent makes the polymer serve multiple functions: as a binder for agglomeration, as a stabilizing matrix for the active pharmaceutical ingredient, and as a processable material at high temperatures. This multi-functionality is achieved by selecting polymers that can withstand the elevated processing temperatures while maintaining their binding and stabilizing properties.
3Productivity
If conventional hot melt extrusion is used, then continuous processing is achieved, but physical instability and degradation of active pharmaceutical ingredients occur
Solution Approach 1:
The patent optimizes the temperature parameter to be above the polymer melting point but below the decomposition point of the active pharmaceutical ingredient. This precise temperature control maintains the API in its desired crystalline or amorphous state while enabling continuous processing, thus resolving the contradiction between productivity and stability.
Solution Approach 2:
The polymer acts as an intermediary matrix that protects the active pharmaceutical ingredient during processing and storage. It stabilizes the API in the desired state (crystalline or amorphous) and prevents degradation, while still allowing continuous processing through the extrusion mechanism.
4Reliability
If the active pharmaceutical ingredient is heated above its melting point, then amorphous solid dispersion is formed, but energy consumption increases
Solution Approach 1:
The patent utilizes the phase transition of the active pharmaceutical ingredient from crystalline to amorphous state by heating above its melting point. This phase transition creates an amorphous solid dispersion with enhanced dissolution properties. The energy input is justified by the significant improvement in bioavailability and dissolution rate.
Solution Approach 2:
By changing the temperature parameter above the API melting point, the patent transforms the physical state of the API from crystalline to amorphous. This parameter change fundamentally alters the dissolution characteristics, providing a therapeutic benefit that outweighs the additional energy consumption required for heating.
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
This method effectively stabilizes active pharmaceutical ingredients in an amorphous form, improving their dissolution profile and providing beneficial properties compared to traditional hot melt extrusion methods, with twin-screw melt granulation being particularly suitable for achieving these results.
Implementation Method 1
the active pharmaceutical ingredient is heated above its melting point and solidified within or on the polyvinyl alcohol during the cooling step
Implementation Method 2
the active pharmaceutical ingredient is heated above its melting point and solidified within or on the polyvinyl alcohol during the cooling step
Implementation Method 3
Polymeric carriers with high glass transition temperatures seem to be well suited to stabilize these systems by limiting molecular mobility
Data Source
AI summary
The present invention relates to a process for loading a polymer with an active pharmaceutical ingredient in a melt granulation process and to the prepared product. More specifically the invention relates to a process of preparing granules which contain at least one active pharmaceutical ingredient and polyvinyl alcohol.