Wet granulation redefined: case study on continuous wet granulation of high dose drug metformin without subsequent drying procedure

Introduction

Wet granulation is a common pharmaceutical process involving a granulation liquid to agglomerate powder, followed by a drying phase. This method increases processing time, energy consumption, and manufacturing costs due to the need for a drying process. This paper introduces a novel wet granulation method using potassium sodium tartrate tetrahydrate (PST) as an excipient, which serves as both a granulation liquid donor and acceptor, eliminating the need for additional granulation liquid and drying steps. Metformin HCl, a high-dose API used for type 2 diabetes, was chosen to demonstrate the efficacy of this method. This study aimed to identify the key process parameters for optimal granulation and tableting outcomes. The investigation focused on the compressibility of the granules, analyzing factors such as screw speed, feed rate, and barrel temperature for their impact on the processes.

Materials and methods

Active and excipients

Metformin HCl granules were formulated via PST-granulation (Table 1), and subsequently tableted (Table 2).

Table 1. Formulation of the granulation step (internal phase)

Ingredient	Supplier	Content
Metformin HCl powder	Exemed	79.6%
Fumed silica (Aerosil® 200)	Evonik	0.40%
Potassium sodium tartrate	BASF	15.0%
Poly(vinyl pyrrolidon) K 30 (Kollidon® 30)	BASF	5.0%

Table 2. Tableting formulation (Metformin HCl 500 mg)

Ingredient	Supplier	Content
Granules (Table 1)	-	98.00%
Sodium stearyl fumarate (PRUV®)	JRS	2.00%

Equipment

Granulation experiments were conducted using a twin-screw extruder (Pharma 11, ThermoFisher), featuring an 11 mm screw diameter and a length-to-diameter ratio of 40:1 The processes were conducted according to the DoE scheme listed in Table 3.

Table 3. Process parameters Kollitab® PST-granulation

Trial	Screw speed [rpm]	Feed rate [g/h]	Temperature [°C]
C1/4/8	100	800	100
V2	125	600	90
V3	75	1000	110
V5	75	1000	90
V7	75	600	90
V9	125	600	110
V10	125	1000	90
V11	75	600	110
	125	1000	110

Granule’s particle size was analyzed using a particle size analyzer (Mastersizer 3000, Malvern) applying a dispersion air pressure of 1.0 bar for a duration of 30 seconds. Tableting trials were conducted on a compaction simulator (STYL’One Evolution, KORSCH) with roundshaped, flat-faced punches (diameter 12 mm) targeting a 500 mg API load. Equipment compliant with compendial methods (USP, Ph. Eur.) was used for powder and tablet characterization.

Results and discussion

Granulation experiments

As demonstrated in a previous case study [1], the processing window for a powder blend containing Kollitab® PST in twin-screw granulation can be defined using a Design of Experiments (DoE) approach, varying screw speed, feed rate, and barrel temperature. The granulation experiments showed distinct particle growth due to Kollitab® PST’s unique behavior. At temperatures above 90°C, water of crystallization is released, facilitating wet granulation [2]. Upon cooling, the water is reabsorbed, resulting in dry granules suitable for further processing. Our analysis of the experimental data identified three distinct groups based on particle growth and physical properties. The first group exhibited lower particle growth, along with low bulk densities (DBU), tapped densities (DTA), and flowability, as indicated by the Hausner ratio (HAR) and angle of repose (AOR) (trials V2 and V7).

The second group consisted of trials with larger particle sizes, higher DBU and DTA, and superior particle flow properties (trials V3, V5, V10 and V11). The third group was framed by the others, featuring moderate particle sizes, average DBU and DTA, and medium flow characteristics (trials V6, C1, C4, C8 and V9).

The variations in granulation properties observed across different trials can be attributed to the specific process parameters employed. For instance, higher screw speed and feed rate generally resulted in a larger particle size and a better flow property. The heat energy applied during the residence time of the particles, particularly PST, was the primary factor influencing the granulation efficiency. This detailed analysis underpins the importance of optimizing process parameters to achieve desired granulation and tableting characteristics.