(708h) Experimental Analysis of Pharmaceutical Twin-Screw Wet Granulation Using Hydrophilic and Hydrophobic Formulations | AIChE

(708h) Experimental Analysis of Pharmaceutical Twin-Screw Wet Granulation Using Hydrophilic and Hydrophobic Formulations


Verstraeten, M. - Presenter, Ghent University
De Beer, T., Ghent University
Ghijs, M., Ghent University
Van Hauwermeiren, D., Ghent University
Nopens, I., Ghent University
Lee, K., Pfizer Inc.
Turnbull, N., Pfizer Inc.
am Ende, M. T., Worldwide Research and Development, Pfizer Inc.
Doshi, P., Worldwide Research and Development, Pfizer Inc.

Traditional pharmaceutical solid-dosage manufacturing exists of batch-wise processes which are rather inefficient and expensive. Today, efforts are made to shift from batch to continuous processing. Twin-screw granulation is a promising continuous wet granulation technique for solid dosage manufacturing. Nevertheless, little is known about how process and equipment settings affect granule formation mechanisms and kinetics.


The aim of this study was to evaluate the twin-screw granulation process for both hydrophilic and hydrophobic formulations to understand the role of the individual screw modules and process settings, as well as their interaction upon granule formation. This involved investigating the influence of process settings on granule properties at different locations in the screw barrel.

Results from this experimental study will be used for the development, calibration and validation of a two-dimensional Population Balance Model (PBM) involving particle properties (granule size and liquid content or density/porosity) relevant for twin screw granulation. The 2D PBM will incorporate the rate processes which are considered dominant in the wetting and mixing zones of the granulator, such as aggregation and breakage, based on an inflow and outflow granule size distribution in each zone. The experimental data from different locations inside the granulator will be used to obtain the unknown model parameters for individual screw modules.

Material and methods


Two hydrophobic model drug formulations were used. Therefore, two poorly water soluble APIâ??s (60% w/w) were separately blended with 16% (w/w) lactose monohydrate (Lactochem® Regular, DFE Pharma, Goch, Germany), 16% (w/w) microcrystalline cellulose (Avicel® PH 101, FMC, Philadelphia, USA), 3% (w/w) hydroxypropylcellulose (Klucel® EXF, Ashland, Covington, Kentucky, USA) and 5% (w/w) crosscarmellose sodium (Ac-Di-Sol®, FMC, Philadelphia, USA).

Because a poor flowability was observed for one model formulation, 0.5 % (w/w) colloidal silicon dioxide (CAB-O-SIL® M-5, Cabot Corporation, Alpharetta Georgia, USA) was added to that formulation in order to ensure adequate dosing of the dry ingredients into the granulation module. Additionally, a hydrophilic formulation existing of 97.5% (w/w) lactose monohydrate (Lactochem® Regular, DFE Pharma, Goch, Germany) and 2.5% (w/w) Polyvinylpyrrolidone (Kollidon®30, BASF, Ludwigshafen, Germany) was studied. All formulations were processed using demineralized water as granulation liquid.


Granules were produced using the high shear wet granulation module of the ConsiGmaTM-25 system (GEA Pharma systems, Collette, Wommelgem, Belgium).

To develop and calibrate the 2D PBM model, a 3-level full factorial Design of Experiments (DoE) (MODDE 11, MKS Umetrics, Umeå, Sweden) was performed for three formulations by varying the following parameters: screw speed (450-900 rpm), material throughput (5-25 kg/h) and liquid-to-solid ratio (formulation dependent). The temperature of the cooling water around the granulator barrel was kept constant at 25°C. This DoE was executed for one screw arrangement existing of 2 kneading zones of each six kneading elements ordered at a stagger angle of 60°. Several responses were assessed and are described below.

In order to gain insight in the granulation progress along the length of the granulation barrel, samples were collected in well-defined zones of the granulator unit:

  • Location 1: Before the first kneading zone, where the granulation liquid is added (wetting)
  • Location 3: After the first kneading zone
  • Location 5: After the second kneading zone
  • Location 6: After the chopper section being a kneading block at the end of the screw (i.e. granulator outlet).

Granules collected at these locations were oven dried (24h, 40°C, 25% RH) and granule size distribution (QICPIC®, Sympatec GmbH, Clausthal-Zellerfeld, Germany) was measured. Furthermore, all samples were sieved in different fractions (i.e. >2000, 1000-2000, 850-500, 150-500, 75-150 and <150 µm) using a Retsch VE 1000 sieve shaker (Haan, Germany). True density (Helium-pycnometry, Accupyc 1330 Pycnometer, Micrometrics, Norcross, USA) and specific surface area (Brunauerâ??Emmettâ??Teller (BET)-theory) was measured for every fraction.

Moreover, distribution of moisture among the different sieve fractions was assessed using a colored tracer (0.5% w/w cochenillered) dissolved in the granulation liquid. UV spectroscopy was used to measure tracer content in every sieve fraction, allowing to visualize the moisture content per sieve fraction at the different locations of the granulator. This experimental data about granule properties collected at intermediate locations inside the screw barrel will help to describe the dynamics during twin-screw granulation to be included in the aimed 2D PBM.

The granules collected at the end of the barrel (location 6) were oven dried (24h, 40°C, 25% RH) and analyzed for several responses: torque, granule size distribution (QICPIC®, Sympatec GmbH, Clausthal-Zellerfeld, Germany), friability (Friabilator, PTFE Pharma Test, Hainburg, Germany), flowability (Ring Shear Tester RST-XS, Dietmar Schulze, Wolfenbüttel, Germany), mean residence time and Peclet number (determined with residence time distribution â?? SentroPAT FO system, Sentronic, Dresden, Germany).


This experimental study proved the ability to capture the stepwise formation and transition of granules at the different locations inside the granulator in terms of granule properties (e.g. granule size, moisture, density/porosity).

It was affirmed that process parameters like liquid-to-solid ratio can dictate the formation of granules and their corresponding quality attributes. Furthermore it should be emphasized that differences are observed between hydrophilic and hydrophobic formulations. This could be derived from the measured moisture content in the different sieve fractions along the length of the granulator barrel. Results showed a more heterogeneous moisture distribution among the different size fractions in the hydrophobic formulations where moisture is less likely to be found in the smaller size regions. This could be explained by a significant fraction of un-wetted particles.