A novel approach to support formulation design on twin screw wet granulation technology: Understanding the impact of overarching excipient properties on drug product quality attributes

Abstract

The overall objective of this work is to understand how excipient characteristics influence the drug product quality attributes and process performance of a continuous twin screw wet granulation process. The knowledge gained in this study is intended to be used for Quality by Design (QbD)-based formulation design and formulation optimization. Three principal components which represent the overarching properties of 8 selected pharmaceutical fillers were used as factors, whereas factors 4 and 5 represented binder type and binder concentration in a design of experiments (DoE). The majority of process parameters were kept constant to minimize their influence on the granule and drug product quality. 27 DoE batches consisting of binary filler/binder mixtures were processed via continuous twin screw wet granulation followed by tablet compression. Multiple linear regression models were built providing understanding of the impact of filler and binder properties on granule and tablet quality attributes (i.e. 16 DoE responses). The impact of fillers on the granule and tablet responses was more dominant compared to the impact of binder type and concentration. The filler properties had a relevant effect on granule characteristics, such as particle size, friability and specific surface area. Binder type and concentration revealed a relevant influence on granule flowability and friability as well as on the compactability (required compression force during tableting to obtain target hardness). In order to evaluate the DoE models' validity, a verification of the DoE models was performed with new formulations (i.e. a new combination of filler, binder type and binder concentration) which were initially not included in the dataset used to build the DoE models. The combined PCA (principle component analysis)/DoE approach allowed to link the excipient properties with the drug product quality attributes.

The Influence of Equipment Design and Process Parameters on Granule Breakage in a Semi-Continuous Fluid Bed Dryer after Continuous Twin-Screw Wet Granulation

“…Many investigations have already been performed on continuous twin-screw wet granulation as unit operation. Some studies have been focusing on the influence of process parameters [6,[8][9][10] and formulation properties [11][12][13][14][15][16][17][18] upon granule quality attributes. Other studies targeted a more fundamental understanding of the twin-screw granulation mechanism [7,8,[19][20][21][22][23].…”

Advances in Twin-Screw Granulation Processing

“…In another study, the same group applied a QbD methodology using the continuous ConsiGma ® extrusion line to investigate the formulation optimization of twin-screw granulated composition of various binary filler/binder grades and ratios [ 91 ]. By using multiple linear regression models, the authors were able to understand the impact of the filler/binder properties on the granule and tablet CQAs.…”

Design and Use of a Thermogelling Methylcellulose Nanoemulsion to Formulate Nanocrystalline Oral Dosage Forms

“…[ 5–7 ] However, incorporation of the methods into conventional formulation processes is susceptible to many problems. For example, suitable excipients have to be investigated through tedious trial‐and‐error experiments, [ 8–10 ] and API inhomogeneity raises a potential risk that causes overdosed or ineffective treatment. [ 11 ]…”

“…[5][6][7] However, incorporation of the methods into conventional formulation processes is susceptible to many problems. For example, suitable excipients have to be investigated through tedious trial-anderror experiments, [8][9][10] and API inhomogeneity raises a potential risk that causes overdosed or ineffective treatment. [11] Methylcellulose (MC) and hydroxypropyl methylcellulose (HPMC) are two types of natural-based cellulose ester excipients that have been widely formulated into oral solid dosage forms in food and pharmaceutical applications.…”