Evaluation of the Impact of the Concentration and Mixing Time of Magnesium Stearate in Tablet Formulations – A Design of Experiment (DOE) Approach

Introduction

Magnesium stearate (MgSt) is a common lubricant that is added to tablet formulations to reduce the friction between granules or powders and the die wall during compression and ejection. Its popularity may be attributed to its relatively low friction coefficient and large “covering potential,” which are desirable lubricant properties.¹ An effective amount of lubrication is usually needed during high speed tableting at the production level to avoid issues during tablet ejection. The typical range of MgSt used as a lubricant is between 0.25 to 5 %, w/w. The effective concentration of MgSt in the final formulation should take into consideration its impact on various critical tablet quality attributes. While increasing the MgSt amounts would reduce the ejection forces, it has been reported that higher MgSt concentrations adversely impacted tablet hardness, disintegration and dissolution times.² Hence, the MgSt concentration is an important parameter to be managed in any given tablet formulation.

It is ideal to achieve a uniform distribution of MgSt particles on the surfaces of the active pharmaceutical ingredient (API) and excipient particles. Lubrication is achieved through the surface coverage arising from adsorption of the MgSt onto the particles in the formulation during the initial phase of mixing.³ As mixing continues, MgSt particles will become sheared off from the aggregates. The overmixing of MgSt is unfavorable, and the lubrication efficiency may be diminished. In this regard, it is also industrially recognized that sieving of MgSt before mixing it into the tablet formulation is important to break up the MgSt agglomerates as the agglomerates may hinder the lubrication efficiency or result in bonding issues within the tablet formulation.

The purpose of this study was to evaluate the impact of MgSt concentration (Roquette Magnesium Stearate) and MgSt mixing time on the tablet ejection forces and resultant tablet properties (tablet hardness and disintegration time) based on a model formulation of microcrystalline cellulose (MICROCEL® 102 SD; MCC) and mannitol (PEARLITOL® 200 SD). The MCC-mannitol formulation was selected as a representative tablet formulation comprising a blend of materials that deform plastically or undergo brittle fragmentation respectively. A Design of Experiment (DOE) approach was employed to understand the relative impact of the two variables on the responses within the design space. The results of this study would serve as a useful reference for similar formulations that require the optimization of MgSt concentration and mixing time.

Materials and Methods

Roquette Magnesium Stearate (specific surface area of 5-10 m²/g) was used as the lubricant while MCC (MICROCEL® 102 SD) and mannitol (PEARLITOL® 200 SD) were used as the fillers in a 1:1 blend ratio for this study. The formulations varied in terms of the MgSt concentration (0.2-1.5 %, w/w) and mixing time for the incorporation of MgSt (1-12 min). Based on a central composite study design, 13 runs were generated for evaluation (table 1). Runs were randomized and runs 5-9 were the center points included in DOE design to check for linearity, process stability and detect variability in data.

The fillers (MCC and mannitol) were first blended using the Turbula blender (T2F, WAB) at 40 rpm for 5 minutes. Roquette magnesium stearate was sieved and added to the MCC-mannitol blend and blended as a second step at 40 rpm. The mixing time of MgSt was varied according to the conditions listed in table 1. Tablets were prepared using the compaction simulator (StylOne, Medelpharm), simulating a Fette P2090 rotary tablet press at 28 rpm, which corresponded to a speed of 60480 tablets/h. Tablets of 350 mg target weight were prepared using a 11.28 mm flat face round punch, under various compression forces between 10-20 kN. The tablet ejection force (determined from the compaction runs), tablet hardness (PTB420, PharmaTest) and disintegration time (PTZ Auto, PharmaTest) were determined for each tablet formulation. The data was statistically analyzed and modeled using the Minitab 21 software based on the input variables. Model testing was subsequently carried out to verify the model generated from the study.

Results And Discussions

Tablets were prepared between 10-20 kN to determine the corresponding hardness values with respect to the two variables – MgSt concentration and mixing time. Regardless of compression force, higher concentrations of MgSt resulted in lower tablet hardness (figure 1-A). This is not unexpected, as the greater formation of the MgSt film around the particles in the formulation with higher MgSt concentrations may have interfered with the particle bonding and densification of the formulation, resulting in lower overall mechanical strength. This is also in congruent with the results obtained with longer MgSt mixing time, as shown for formulations with 0.85 %, w/w MgSt (figure 1-B), where the increase in mixing time was not beneficial for the tablet hardness. Although these observations have been reported in the literature,^2-4 there is a gap in the understanding of the relative effects of MgSt concentration and mixing time in a formulation with both materials that deform plastically or undergo brittle fragmentation. This further supported the need to evaluate both variables on the resultant tablet properties simultaneously through a DOE approach.

Figure 1. Tablet hardness values determined for (a) different MgSt concentrations with a 6.5 min MgSt mixing time and (b) different mixing times based on a formulation with 0.85 % MgSt.

The responses obtained in accordance with the study design are shown in table 2. For the tablet hardness response, tablets prepared at 15 kN were selected for statistical analysis. It is generally understood that tablet porosity is an important consideration for tablet disintegration time. To minimize the effects of porosity differences on tablet disintegration time, the final thickness of the tablets prepared for disintegration evaluation were maintained at 2.12 mm across all formulations.

Reproducibility of results was observed with the five center point runs (Runs 5-9). The ejection force response was not considered in the modeling due to the small variation observed in the dataset. The modeled equation for tablet hardness, as a function of MgSt concentration (variable A; expressed in %) and mixing time (variable B; expressed in min) is as follows:

Equation 1: Tablet hardness (N) = 108.31 − 2.38A − 0.251B − 1.35AB

Both the MgSt concentration and mixing time were significant factors. The main effects plot for tablet hardness is shown in figure 3. As the MgSt concentration increased, the tablet hardness decreased. The longer the mixing time, the lower the resultant tablet hardness. To better understand the relationship between tablet hardness and the two variables (MgSt concentration and mixing time) within the operating conditions, the contour plots were used (figure 4). To obtain tablet hardness above 100 N for the given formulation, for a high MgSt concentration (above 1 %), it would be important to manage the mixing time by employing a mixing time as short as possible. This can be related to the understanding of the MgSt mixing theory as described in the literature,^3,5 where the adsorbed MgSt particles may deagglomerate from the particles as mixing progresses due to the shear effects. This would negatively affect the tablet hardness as the deagglomerated MgSt, especially at higher concentrations, would interfere with the bonding within the tablet formulation.

For tablet disintegration time, the modeled equation as a function of MgSt concentration (variable A; expressed in %) and mixing time (variable B; expressed in min) is as follows:

Equation 2: Tablet disintegration time (s) = 32.61 + 32.01A − 3.93B + 0.247B²

Both variables were significant in the model, with p values of < 0.05. An increase in MgSt concentration resulted in longer disintegration times, as can be seen from the main effects plot (figure 4). A quadratic relationship between mixing time and tablet disintegration time was observed. For the formulations investigated, an optimal mixing time between 6-9 min resulted in shorter disintegration time.

Based on the contour and surface plots (figure 5), it was evident that the tablet disintegration time was greatly impacted by the MgSt concentration. The contour regions at higher concentration corresponded with higher disintegration times regardless of the mixing time. With higher amounts of MgSt, the hydrophobic film that is formed by MgSt would have affected the penetration of water into the tablet to a greater extent. Collectively, the findings were in good agreement with the results reported by Yüksel et al. ²

Conclusion

An understanding of how the MgSt concentration and MgSt mixing time would impact the tablet formulation is imperative to manage the desired tablet properties. In this study, a representative formulation comprising MCC and mannitol as plastically deforming and brittle fragmenting fillers respectively was selected for evaluation. While the ejection forces registered were well below 250 N, the results of the DOE demonstrated the significant impact of both MgSt concentration and mixing time on the hardness and tablet disintegration time. Furthermore, the quantitative effects described by the modeled equations for both responses could serve as a useful reference for similar tablet formulations.

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Source: Roquette, website Evaluation of the Impact of the Concentration and Mixing Time of Magnesium Stearate in Tablet Formulations – A Design of Experiment (DOE) Approach