Evaluation of Binders and Process Factors in Continuous Twinscrew Granulation

Zhuoyang “John” Lian, Divya Tewari, Thomas Dürig 

Ashland Specialty Ingredients, Wilmington, DE 19808 USA

INTRODUCTION 

This study explored a high dose formulation with model drug aceta-minophen and investigated the formulation (different binder types) and process factors (temperature, screw speed, feed rate, binder solution addition etc.) impact in an extrusion granulator process.

METHODOLOGY 

An experimental design approach was implemented to study the impact of screw speed, feed rate and barrel temperature on acetaminophen formulations comprising KlucelTM EXF hydroxypropylcellulose (HPC) or PlasdoneTM K-29/32 povidone (PVP) using a twin screw granulator for continuous granulation. Blends comprising acetaminophen, binder (KlucelTM EXF HPC or PlasdoneTM K-29/32 povidone), microcrystalline cellulose and fumed silica (formulation in Table 1) were granulated at various throughput (10 – 20 kg/hour), screw speeds (300 – 500 RPM) and temperatures (25 – 55°C) with addition of 14% water, before being dried with a fluid bed dryer to a moisture level less than 2%. The pro-cess variable details are listed in Table 2. The dried granules were sub-sequently milled using a Fitzmill and blended with 4% superdisintegrant and 0.25% lubricant. Milled granules were characterized by SEM for morphology, by Brookfield powder flow tester and by sieve analysis for particle size distribution. The tablets were made using a Manesty Beta Press, 7/16” SC tooling for a tablet weight of 600 mg.

Scanning Electron Microscopy (SEM): SEM was conduced on Hita-chi S-4000 Field Emission SEM. The sample was mounted on a stub and coated with Au/Pd to make the sample surface conductive and then examined in Secondary Electron Imaging (SEI) mode.

Particle Size Distribution (PSD): 50 gram sample was analyzed using a Retsch AS 200 sieve shaker, with screen sizes of mesh 20, 40, 60, 80, 100, 140, 200 and pan, with an amplitude of 5 and duration of 10 minutes.

Tablet Dissolution: Dissolution was conducted using pH 5.8 phos-phate buffer media with USP apparatus II (paddle) at 50 rpm.

Tablet Hardness: The tablets were compressed at 5kN, 10kN, 15kN, 20kN and 25kN main compression force, and hardness was evaluated using Key International hardness tester HT500S (n = 10).

Table 1: Formulation Components

T1

 

 

 

 

Table 2: Process Variables in the Experiment Design

T2

 

 

 

Experiments:

• 3 factors, 23 = 8 full factorial (red) + 3 center (blue) points

• Plasdone K-29/32 PVP was added as solution to evaluate impact of binder addition method

RESULTS AND DISCUSSION

Figure 2: Contour Plot for Particle Size, Impacted by Feed Rate, Screw Speed and Temperature (KlucelTM EXF HPC Formulation) 

Figure 3a (Left, KLucel HPC at 25C) Figure 3b (Right, KLucel HPC at 55C)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Top: Experiment at 25°C; Bottom: Experiment at 55°C

Higher feed rate and lower screw speed make coarser granules.

Lower temperature also makes coarser granules.

Figure 3: Compression Pro-files, Impacted by Feed Rate and Screw Speed (KlucelTM EXF HPC Formulation) 

Figure 4

 

 

 

 

 

 

 

 

Higher feed rate make stronger tablets. The granules particle size is an early indicator of better tablet hardness.

Figure 4: Compression Profiles, Impacted by Granulation Method and Binder Addition Method

Figure 5

 

 

 

 

 

 

 

 

Extrusion granulation tablets are stronger than those from high shear granulation. Add-ing binder in the form of a solution that is pumped into the barrel instead of in the initial dry blend, yields higher tablet strength.

Figure 5: Impact of Binder Type and Process on Granule Morphology 

Figure 6a (Plasdone PVP, ConsiGma-1) Figure 6b (Plasdone PVP, Glatt High Shear Granulator) Figure 6c (KLucel HPC, ConsiGma-1) Figure 6d (Klucel HPC, Glatt High Shear Granulator)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

In extrusion granulation, the excipients and the API are brought together by intense mixing from the screw ele-ments. In contrast to high shear granulation, we can still observe the individual mor-phology of the API. The ener-gy input is much higher for extrusion granulation.

Figure 7: Impact of Binder Type and Process on Tablet Hardness 

Figure 6 (New)

 

 

 

 

 

 

 

 

 

Compared with similar formula-tions prepared by traditional high shear wet granulation, the tab-lets produced from granules pre-pared by continuous extrusion granulation were markedly stronger without any negative impact on dissolution time

CONCLUSIONS 

Using a challenging high drug-load model formulation of a poorly compactible aceta-minophen we have illustrated that twin screw granulator and Klucel HPC are promising tools for continuous wet granulation. The continuous process can lead to cost reduction and better product/ process understanding. Tablets made via extrusion granulation had superior strength, low friability, and comparable dissolution to tablets made by tradition-al wet granulation.

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