Successful compaction of tablet is based on the development of a suitable formulation which contains different materials i.e. drug substance, fillers, binders and lubricants (Rowe et al., 2003). Lubrication, especially with magnesium stearate, is one of the most critical stages in tableting (Li and Wu, 2014) and thus it has been widely studied (Bossert and Stains, 1980; Johansson, 1985; Paul and Sun, 2017; Wang et al., 2010). Magnesium stearate (MgSt) is the most commonly used lubricant in tablet formulation with concentrations ranging from 0.25% to 5.0% (Rowe et al., 2006), although it is preferred to use the lowest concentration due to its hydrophobic nature which can retard the dissolution of tablets. MgSt forms a layer on a surface of the particle and reduces the friction and cohesive forces between particles and the die wall, thus improving compressibility. The mechanism used in tablet formulation, is called mechanofusion (dry coating) or boundary lubrication, where MgSt has a structured contact on the host particle (Koskela et al., 2018). This phenomenon has been studied and it has been concluded that it is difficult to measure the distribution of MgSt (Lakio et al., 2013) from the surface of
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the material. It is evident that MgSt will influence powder flowability, compactability and dissolution (Llusa et al., 2010; Pingali et al., 2011). The disadvantage of MgSt is its decompactabality and increasing dissolution time mainly due to an over-lubrication phenomenon (Ketterhagen, 2015; Mosig and Kleinebudde, 2014, 2015; Narang et al., 2010;
Sun and Kleinebudde, 2016). This has been shown to be formulation (Koskela et al., 2018) and process dependent. The effect of lubrication on different integrated process units in a continuous manufacturing line has been studied to some extent in blenders (Oka et al., 2016), and in roller compaction (Akseli et al., 2011; Miguélez-Morán et al., 2008; Yu et al., 2013).
The lubrication process could be determined by measuring the coefficient of friction occurring in the ejection phenomenon during tableting. The equation of coefficient of friction is (1)
F
II= μF
┴(1)
where FII, μ, and F┴ are the force of friction proportional to the external load (F┴), the coefficient of friction, and the normal force applied, respectively (Li and Wu, 2014). The ejection force is needed to push the tablet out from the die in the tablet press (Wang et al, 2010). A low friction force is a desired feature, since it is desirable to keep any fragmentation and capping as low as possible (Nordström and Alderborn, 2015).
The mixing time of MgSt has been widely studied. It has been shown that the mixing parameters have a critical influence on productivity (Bolhuis et al., 1975; Ragnarsson et al., 1979; Shah and Mlodozenie, 1977). The mixing time of MgSt is a critical parameter exerting an effect on the tablets’ crushing strengths especially in scaling-up processes (Virtanen et al, 2008). A longer mixing time also increases the brittleness of the tablet and reduces tablet hardness (Bolhuis et al., 1987) which can be a quality problem in the final product. The mode of adding lubricant has a significant role e.g. in dry granulation processes (Mosig and Kleinebudde, 2014). The most typical way to add MgSt is by mixing it before tableting, but it has been shown that an external addition method could lower the amount of MgSt needed in the formulation (Yamamura et al., 2009). It has been postulated that a careful choice of the formulation ingredients e.g. the type disintegrant, could reduce the hydrophobic effect of MgSt (Bolhuis et al, 1981). The schematic illustration of MgSt’s function in flowability and compactability is shown in Figure 14 (Koskela et al., 2018).
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Figure 14. The function of MgSt in flowability and compactability (Adapted from Koskela et al., 2018).
In the continuous manufacturing field, the effect of lubrication on the whole CM line has not been evaluated to any major extent. In a separate unit operation, Oka et al., 2016 highlighted that the risk of potential over-lubrication in continuous mixing is very low as compared to the situation in the batch mode and there is no need for a two-stage addition of MgSt. This is because the material spends a shorter time in the blender, and the amount of material in the system is lower. Furthermore, the mixing order strategy of MgSt has been shown to influence the powder flow properties, weight variability, tablet weight and dissolution in the CM line (Pingali et al., 2011).
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3 AIMS OF THE STUDY
The general aims of this study were to comprehensively demonstrate the effect of formulation and process parameters on product quality, using both short and long run continuous manufacturing process lines with different configurations (top-down and horizontal set-up). The more specific aims of the study were as follows:
I To devise a robust and stable continuous manufacturing process settings, by exploring the design space after an investigation of the lubrication-based parameters influencing the continuous direct compression tableting of high dose tablets.
II To examine how both intentional and unintentional disturbances could affect the critical quality attributes (CQA's) of the final product and to create a deviation document, which would reveal the changes during the runs.
III To demonstrate the conversion of high-shear wet granulation (HSWG) batch process to a continuous roller compaction (RC) process without any significant formulation changes.
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4 LUBRICANT BASED DETERMINATION OF DESIGN SPACE FOR CONTINUOUSLY MANUFACTURED HIGH DOSE
PARACETAMOL TABLETS
1ABSTRACT
The objective of this study was to devise robust and stable continuous manufacturing process settings, by exploring the design space after an investigation of the lubrication-based parameters influencing the continuous direct compression tableting of high dose paracetamol tablets. Experimental design was used to generate a structured study plan which involved 19 runs. The formulation variables studied were the type of lubricant (magnesium stearate or stearic acid) and its concentration (0.5, 1.0 and 1.5%). Process variables were total production feed rate (5, 10.5 and 16 kg/h), mixer speed rpm (500, 850 and 1200 rpm), and mixer inlet port for lubricant (A or B). The continuous direct compression tableting line consisted of loss-in-weight feeders, a continuous mixer and a tablet press. The Quality Target Product Profile (QTPP) was defined for the final product, as the flowability of powder blends (2.5 s), tablet strength (147 N), dissolution in 2.5 min (90%) and ejection force (425 N). A design space was identified which fulfilled all the requirements of QTPP. The type and concentration of lubricant exerted the greatest influence on the design space. For example, stearic acid increased the tablet strength.
Interestingly, the studied process parameters had only a very minor effect on the quality of the final product and the design space. It is concluded that the continuous direct compression tableting process itself is insensitive and can cope with changes in lubrication, whereas formulation parameters exert a major influence on the end product quality.
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1 Adapted with permission of Elsevier from: Taipale-Kovalainen K, Karttunen A-P, Ketolainen J, Korhonen O. Lubricant based determination of design space for continuously manufactured high dose paracetamol tablets. European Journal of Pharmaceutical Sciences 115: 1-10,2018
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