How a Continuous Process is Revolutionizing Pharmaceutical Manufacturing
The tiny granules that power your pills
Have you ever wondered how the medicine tablet you take maintains the exact right dosage of active ingredient in every single dose? Or how pharmaceutical companies can produce millions of pills with consistent quality and effectiveness? The answer often lies in a crucial but overlooked manufacturing process called granulation—and a technological innovation known as twin-screw granulation (TSG) that is transforming how medicines are made 1 8 .
Imagine trying to compress fine powder—like flour—into a perfect, sturdy tablet. You'd encounter dust that flies away, ingredients that separate, and powder that stubbornly refuses to flow evenly into a tablet press.
For decades, this process was done in large batches, but a shift toward continuous manufacturing is now underway. At the heart of this revolution is twin-screw granulation, a process that not only enhances efficiency but offers unprecedented control over product quality. Through a powerful combination of experimental investigation and advanced computer modeling, scientists are unlocking the secrets of this complex process, paving the way for more effective and reliable medicines 5 .
A twin-screw granulator consists of two intermeshing screws rotating inside a barrel. Powdered ingredients (active pharmaceutical ingredients and excipients) are fed into one end, while a liquid binder is added along the barrel. As the materials are conveyed along the screws' length, they undergo mixing, wetting, and aggregation, emerging as uniform granules at the outlet 8 .
What makes this system remarkably flexible is its modular screw design. Engineers can customize the screw configuration using different types of elements:
Compared to traditional batch granulation techniques, TSG offers significant benefits:
The continuous nature of TSG allows for real-time monitoring and adjustments, leading to more consistent product quality 4 .
TSG requires significantly less liquid to form granules than traditional high-shear batch granulation, reduces processing times, and minimizes material waste 1 .
Granules produced via TSG are typically more porous and less spherical than those from high-shear granulation, resulting in tablets with higher tensile strength 1 .
While the effect of process parameters like screw speed and liquid content had been studied, a fundamental understanding of what actually happens inside the granulator was still lacking. A groundbreaking doctoral dissertation from Purdue University set out to change this by investigating one of the most critical yet overlooked processes: granule breakage 9 .
The researcher designed novel experiments to isolate and study breakage in a systematic way:
Instead of using conventional powders, the team prepared pre-formed model granules with a carefully controlled range of mechanical strengths (dynamic yield strength).
Experiments were conducted using two different screw configurations: one containing only conveying elements and another using distributive mixing elements.
After processing, the resulting granules were analyzed for their size distribution and shape. The team also performed geometric analysis of open volume within screw elements 9 .
The experiment yielded crucial insights into the mechanics of twin-screw granulation:
Breakage Mechanisms Differ by Screw Element: In conveying elements, breakage occurs primarily through "edge chipping"—where small pieces break off from larger granules. In distributive mixing elements, breakage is more intensive, combining both chipping and "crushing" of the entire granule 9 .
Maximum Granule Size is Geometrically Constrained: The research identified that there is a maximum granule size that can survive passage through each type of screw element—approximately 3.5 mm for conveying elements and 3.2 mm for distributive mixing elements—directly determined by the largest open space within the screw geometry 9 .
Strength Matters, But Only to a Point: Breakage probability decreases as granule strength increases, but only up to a point (about 9 kPa of dynamic yield strength). For stronger granules, breakage characteristics become independent of formulation and depend solely on screw geometry 9 .
Implications for Formulation Robustness: This finding explains why TSG is more robust to formulation changes than high-shear wet granulation. The process is governed more by mechanical geometry than by subtle variations in powder properties 9 .
| Screw Element Type | Primary Breakage Mechanism | Maximum Unbroken Granule Size | Dependence on Material Strength |
|---|---|---|---|
| Conveying Elements | Edge chipping | 3.49 mm | Inverse relationship up to 9 kPa |
| Distributive Mixing Elements | Chipping and crushing | 3.18 mm | Inverse relationship up to 9 kPa |
| Formulation Property | Effect in Conveying Elements | Effect in Distributive Mixing Elements |
|---|---|---|
| API Type | Significant effect on granule size distribution | Minimal effect on granule size distribution |
| Liquid-to-Solid Ratio | Strongly affects granule size | Strongly affects granule size |
| Blend Wettability | Reflects differences in granule properties | No significant difference in granule properties |
| Dynamic Yield Strength | Affects granule porosity | Affects granule porosity |
| Material Category | Specific Examples | Function in Research |
|---|---|---|
| Pharmaceutical Fillers | Microcrystalline Cellulose (MCC), Lactose Monohydrate, Mannitol | Form the bulk of the granule; different types have different compaction and absorption properties 1 5 |
| Active Pharmaceutical Ingredients (APIs) | Acetaminophen, Ibuprofen, various model APIs | The active therapeutic component; researchers study how API properties affect granulation 2 5 |
| Binder Solutions | Hypromellose (HPMC), Povidone (PVP), Hydroxypropyl Cellulose (HPC) | Liquid binders that facilitate particle aggregation; concentration and viscosity significantly impact granule growth 2 3 |
| Granulating Liquids | Water, Ethanol, Isopropanol | The solvent for binder solutions; choice affects drying rate and compatibility with moisture-sensitive APIs 8 |
As the field advances, researchers are increasingly turning to computational tools to complement experimental work:
Tracks the movement and collisions of individual particles, providing insights into powder flow and mixing dynamics within the screws 3 .
Mathematical frameworks that describe how populations of granules change in size and properties over time during the granulation process 3 .
Models the behavior of the liquid binder as it interacts with the powder, helping to understand liquid distribution—a critical factor in granule formation 3 .
Combining multiple simulation techniques (e.g., DEM-CFD coupling) to capture the complex interplay between particle dynamics and fluid behavior 3 .
The investigation into twin-screw granulation represents more than just technical optimization—it embodies a fundamental shift in pharmaceutical manufacturing philosophy. Through detailed experimental studies of fundamental mechanisms like granule breakage and the application of advanced simulation techniques, researchers are developing a profound understanding of this complex process.
As research continues to bridge the gap between experimental observation and predictive modeling, twin-screw granulation stands as a shining example of how deeper process knowledge translates directly to better medicines—ensuring that every tablet you take contains exactly what it should, dose after dose, batch after batch.