Continuous Metformin Spray Granulation for Flowable, Stable Dosage Forms
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Solution Overview
Problem
Existing processes for producing metformin-containing dosage forms face challenges such as poor tabletability, low flowability, and stability issues, particularly with metformin hydrochloride, requiring extensive processing and resulting in unsatisfactory granule properties.
Innovation Solution
A continuous process for producing metformin or its acid addition salts as granules by introducing droplets of a solution or suspension into a process chamber, where droplets are guided by a process gas to form larger particles through repeated deposition and evaporation, allowing control over particle size and stability, and enabling further processing into tablets.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If active ingredient is processed by crushing, grinding, and sieving to obtain fine powders, then the active ingredient can be further processed into dosage forms, but the fine powders exhibit poor flowability and low stability with aggregation and clumping
Solution Approach 1:
The invention changes the particle size parameter from fine powders to granules with specific size ranges (d10: 50-150 μm, d50: 150-300 μm, d90: 300-500 μm). This parameter change fundamentally alters the physical properties, improving flowability and stability while maintaining processability into dosage forms.
Solution Approach 2:
The invention creates composite granules that combine the active ingredient with excipients in a controlled matrix. This composite structure prevents aggregation and clumping of the pure active ingredient, thereby improving stability and flowability while maintaining manufacturability.
2Ease of manufacture
If batch processes are used for granule production with preprocessed ground and sieved active ingredient, then dosage forms can be produced, but the granule properties are not satisfactory especially with regard to flowability and stability
Solution Approach 1:
The invention transitions from batch processes to a continuous granulation process. This continuous action ensures consistent particle growth and uniform granule properties, thereby improving flowability and stability compared to discontinuous batch processes that produce variable granule characteristics.
Solution Approach 2:
The continuous process enables precise control of granulation parameters (liquid distribution, residence time, temperature) to produce granules with optimized size distribution and physical properties, directly improving flowability and stability.
3Strength
If wet granulation with binder is used for metformin, then tabletability improves, but production costs increase
Solution Approach 1:
The invention extracts or eliminates the need for additional binder materials by using the active ingredient itself or minimal excipients in the granulation process. This removes the cost associated with wet granulation binders while maintaining adequate tabletability through optimized granule structure and properties.
Solution Approach 2:
The invention uses minimal or no expensive binder materials, relying instead on the granulation process itself to create sufficient cohesion. This substitutes costly binders with a more economical process-based approach that achieves similar or better tabletability.
4Productivity
If spray drying is used to produce active ingredient powders, then particles can be produced, but they require further processing and exhibit processing disadvantages such as lack of flowability
Solution Approach 1:
The invention changes the critical particle size parameter from the sub-50 μm range (spray dried powders) to a controlled granule size range with d50 of 150-300 μm. This parameter change fundamentally improves flowability and eliminates the need for further size enlargement processing, while maintaining high production efficiency.
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 process achieves high throughput and yield with granules exhibiting improved flowability and stability, suitable for further processing into tablets and controlled-release dosage forms that release the active ingredient in deep intestinal sections.
Implementation Method 1
introducing droplets from a spray composition into an injection zone of the process chamber, in which the liquid evaporates
Implementation Method 2
repeatedly passing the solid particles past sprayed droplets in the process chamber with the aid of a process gas jet
Implementation Method 3
droplets, which have already lost some of the liquid they contain, comes into contact with solid particles and larger solid particles are formed by deposition
Data Source
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AI summary
A process for continuous production of an active ingredient granulate is provided and comprises the following steps: (a) providing a spraying composition by dissolving or dispersing an active ingredient and optionally one or more auxiliaries in a liquid; (b) providing solid particles in a process space; (c) introducing droplets of the spraying composition into an injection zone of the process space in which the liquid is evaporated; (d) repeatedly running the solid particles past spray-introduced droplets in the process space using a process gas jet, so that at least a proportion of the droplets, which may already have lost a portion of the obtained liquid, comes into contact with solid particles, thus forming larger solid particles by agglomeration; (e) withdrawal of the active ingredient granulate from the process space in the form of solid particles, wherein the active ingredient comprises metformin or an acid addition salt of metformin, in particular metformin hydrochloride.