Predicting the critical quality attributes of ibuprofen tablets via modelling of process parameters for roller compaction and tabletting

https://doi.org/10.1016/j.ijpharm.2019.05.011Get rights and content

Abstract

Roller compaction is a low cost granulation process which application is sometimes limited by the granular loss of compactability and reduced drug dissolution rate. Hence, the design of a robust manufacturing process is key in order to ensure quality of tablets. In this study, for ibuprofen tablets with high drug loading (<7% excipients), the correlations between two critical process parameters (CPPs), namely roller force during granulation and compaction pressure during tabletting, and several critical quality attributes (CQAs) were investigated using a design of experiment (DoE) approach. Multivariate analysis (MVA) was utilized to identify the best regression model to predict CQAs such as disintegration, dissolution, weight uniformity, hardness, porosity and tensile strength for 200 and 600 mg ibuprofen tablets. The tabletting compaction pressure had a greater impact on the aforementioned CQAs than compactor roller force. The Principal Component Analysis (PCA) correlation loading plot showed that compaction pressure was directly related to disintegration time, tensile strength and hardness, and inversely related to both the percentage of drug dissolved and porosity. The inverse correlations were observed for the roller force applied during dry granulation. Amongst all the regression models constructed, multiple linear regression (MLR) showed the best correlation between CPPs and CQAs.

Introduction

Ibuprofen is an analgesic drug that is widely used by the oral route, although its hydrophobic behaviour makes the development of fast dissolving formulations challenging (Moore et al., 2015). Moreover, poor powder flowability, inadequate compaction behaviour and tendency to stick to tablet punches are also important technical limitations to be solved during the development of ibuprofen tablets (Gandhi et al., 2016). Different novel strategies have been applied to improve some of these tabletting limitations, such as crystal engineering (Gandhi et al., 2016, Qu et al., 2017, Rasenack and Muller, 2002), hot melt extrusion (Dhumal, 2010, Gryczke et al., 2011) and spray drying (Shen et al., 2011, Walsh et al., 2018). Other studies using more conventional pharma-technical approaches, such as particle size control (Liu et al., 2008), moisture content control (Elkhider et al., 2007), suitable selection of tablet punches (Roberts et al., 2003) and roller compaction (Kleinebudde, 2004) have also been proposed.

Roller compaction has become the method of choice for dry granulation in the pharmaceutical industry due to its lower economic cost compared to wet granulation (Peter et al., 2010, Shlieout et al., 2000). Dry granulation improves content uniformity and material flow behaviour, but also possesses other advantages over wet granulation, as there is no need to use water or other solvent, which is beneficial in the context of avoiding degradation of certain compounds. The fundamental mechanisms underpinning roller compaction are complex, as many variables are involved such as roll pressure, roll speed, roll gap, roll dimension, friction, feed method and pressure, amongst others. Generally, only three parameters can be controlled during the process: roll pressure, roll gap and roll speed (Li and Chern, 2006).

In the case of ibuprofen, roller compaction has been shown to be a suitable technique to manufacture tablets (Cespi et al., 2014, Murray et al., 1998). However, the two most important disadvantages associated with the use of this technique are a loss of compactability of the constituents to be tabletted and a reduced drug dissolution rate from tablets (Sun and Kleinebudde, 2016, Teng et al., 2009). In practice, roller compaction and tabletting still largely rely on experience and trial-and-error. There is an apparent need to further investigate roller compaction and tabletting process development and scale-up using a methodology that is based on fundamental understanding, but is also applicable to actual practice in pharmaceutical companies (Li and Chern, 2006).

A robust manufacturing process is key in order to ensure tablets comply with pharmacopeial requirements. The implementation of a Quality by Design (QbD), Design of Experiment (DoE) approach is necessary to fully understand the relationship between Critical Process Parameters (CPPs) for roller compaction and tabletting and Critical Quality Attributes (CQAs) of ibuprofen tablets, such as disintegration, dissolution, weight uniformity, hardness, porosity and tensile strength (Mohammed et al., 2015).

In this study, the correlations between two controllable process parameters during roller compaction and tabletting (roller force and compaction pressure, respectively) and CQAs of ibuprofen tablets with high drug loading (<7% excipients) were investigated using a DoE. Multivariate analysis (MVA) was utilised to identify the best multivariate regression model to predict CQAs. Based on previous results (Matji et al., 2017), the dry granulation process was performed at roller forces between 50 and 70 kN. The granules were mixed with <7% of excipients and compacted in an industrial rotary tablet press with pressures between 50 and 200 MPa. DoE and MVA were applied to two different dose strength tablets containing 200 or 600 mg of ibuprofen.

Section snippets

Materials

Ibuprofen grade 70 (90% below 70 µm) was provided by Shasun Chemicals and Drug Ltd (India). Croscarmellose sodium (Ac-Di-Sol®) was purchased from FMC (USA). Silicon dioxide (Aerosil® 200 from Evonik, Germany) and magnesium stearate (Kirsch Pharma, Germany) were of pharmacopoeial excipient grade. All other reagents were analytical grade. Nurofen® (Reckitt Benckiser Healthcare Ltd, UK) and Neobrufen® FG (Abbott, Spain) ibuprofen marketed formulations were used as comparators in the dissolution

Results and discussion

CQAs of high ibuprofen loaded tablets manufactured at different roller forces in the roller compactor and compaction pressures in a rotary tablet press, with a dose strength of 200 and 600 mg, are illustrated in Table 1, Table 2 respectively (Visual appearance of final manufactured tablets is shown in Fig. S1, Supplementary material). No sticking issues were detected at any of the working conditions tested. In the DoE, no significant differences were observed in weight variation for either 200

Conclusions

Ibuprofen tablets with high drug loading (<7% excipients) that complied with pharmacopoeial specifications for weight uniformity, disintegration and dissolution, were successfully prepared by roller compaction follow by tabletting of granules in a rotary tablet press. From a QbD perspective, the DoE is a powerful tool to investigate and understand the effect of key CPPs on the CQAs of ibuprofen tablets and to establish a design of space with low risk. MLR models showed a good correlation of

Declaration of Competing Interest

None.

Acknowledgements

We would like to thank Industrial Farmaceutica Cantabria (Torrejón, Spain) for their support and assistance to perform this work. This study was partially supported by the Complutense University of Madrid and a Science Foundation Ireland grant co-funded under the European Regional Development Fund (SFI/12/RC/2275) provided to Prof. A. M. Healy.

References (40)

Cited by (0)

View full text