Application of continuous twin screw granulation for the metformin hydrochloride extended release formulation

Abstract

This study focuses on evaluating the potential of transferring from a batch process to continuous process for manufacturing of the extended release formulation. Metformin hydrochloride (HCl) was used in the model formulation which was intended to contain the high amount of hydrophilic drug. The effects of barrel temperature, binder type, powder feed rate, and screw speed on granule properties (size and strength) and torque value in twin screw granulation were investigated. Due to the high content of hydrophilic model drug, the granules prepared at a higher temperature with HPMC binding solution had the narrower size distribution and greater strength than the granules prepared with distilled water as a binding solution. After continuous drying and milling steps, the granules (continuous process) satisfied the fundamental purpose of granulation with size and flowability, despite different shape compared with the granules (batch process). Furthermore, there were no significant differences between two granulation processes in tablet properties, such as tablet hardness and in vitro release. The considerations and strategies used in this study to transfer from a batch to continuous process can be applied to other existing formulations based on high shear granulation to enable rapid process transfer in the pharmaceutical industry.

Introduction

In the pharmaceutical industry, applications of continuous manufacturing process have recently gained considerable interest. Continuous process offers many advantages over the batch process, including the ability to prepare the same final product at the desired scale regardless of equipment scale, no requirement for scale-up study, and enabling a 24-h automatic production line (‘light-out’ operation) (Chatterjee, 2012, Leuenberger, 2001, Plumb, 2005, Schaber et al., 2011). Moreover, continuous process minimizes the risk of operator exposure. Product quality can be continuously monitored and controlled using advanced process analytical technologies (Beer et al., 2014). Therefore, many pharmaceutical companies are now exchanging batch processes for continuous processes (Desai et al., 2015). Recently, the U.S. Food and Drug Administration (FDA) has approved Orkambi™ (lumacaftor/ivacaftor), the first new drug application approved using a continuous manufacturing technology and Prezista™ (darunavir), the first new drug application supplement approved for switching from an existing batch process to a continuous one (Yu and Kopcha, 2017).

Pharmaceutical companies will be able to easily introduce continuous process for solid dosage lines if transfer from the batch process to continuous process is possible. There are three major manufacturing methods for solid dosage forms: wet granulation, dry granulation, and direct compression (Byrn et al., 2015). Dry granulation and direct compression are relatively simple to apply to continuous process. However, twin screw granulation, a representative continuous process in wet granulation, is difficult to transfer from a batch process to continuous process because a different mechanism is required to form the granules in a very short time, unlike in conventional batch process such as high shear granulation (Beer et al., 2014). For this reason, there have been many studies investigating various factors that affect twin screw granulation (Cartwright et al., 2013, Dhenge et al., 2011, Dhenge et al., 2010, Dhenge et al., 2013, El Hagrasy et al., 2013, Kumar et al., 2014, Saleh et al., 2015, Vercruysse et al., 2015a, Vercruysse et al., 2012, Vercruysse et al., 2015b). Twin screw granulation produces granules with a broader size distribution compared to other wet granulation processes. Also, formulation properties and process parameters have a complex influence on granule properties in twin screw granulation. It is important to select major parameters and ranges in the screening step based on experiences and background knowledge about twin screw granulation. However, these studies have mainly investigated in immediate release or placebo formulation. In various studies of twin screw granulation, there have been only three concerning controlled release formulation (Thompson and O’Donnell, 2015, Vanhoorne et al., 2016a, Vanhoorne et al., 2016b). In addition, there is a lack of information concerning batch to continuous process transfer, with only one study describing the technology for transferring from high shear batch to twin screw continuous granulation using immediate release formulation (Beer et al., 2014). When studying new formulations for some drugs with a focus on continuous twin screw granulation, it is possible to change the formulation for applying twin screw granulation. However, it is impossible to change the original formulation when transferring the wet granulation process from high shear granulation to twin screw granulation to improve production efficiency in pharmaceuticals. Therefore, transfer of the controlled release formulation from a batch process to continuous process should be studied.

When the formulation cannot be changed, there are limited parameters to apply twin screw granulation. In formulation properties, intra-modification or binder addition type is available. There are two types of binder addition method (Saleh et al., 2015, Seem et al., 2015). One is dry binder (in the solid phase) and another is wet binder (in the liquid phase). They showed different results in investigation with same other factors (Saleh et al., 2015). The difference in the wettability of each binder addition type on applied powder mixture accounts for these different results. Therefore, it is necessary to study the effect of binder addition type on the formulation. On the other hand, process parameters such as powder feed rate, screw speed, barrel temperature, and liquid to solid ratio can be applied more easily. However, those ranges are narrowed when the controlled release polymer with high viscosity in wetted state is used.

In this study, the metformin HCl 1000 mg extended release tablet was used as a model formulation. This formulation is based on high shear granulation, batch process. This study considers the transfer from a batch process to continuous process and strategies for transference without the addition or removal of any excipient from the original metformin HCl extended release tablet formulation. By applying twin screw granulation on the controlled release formulation, this study investigates how formulation properties and process parameters affect granule properties in twin screw granulation.