Using density changes to monitor blending with magnesium stearate by terahertz time-domain spectroscopy
Abstract
Magnesium stearate (MgSt) is among the most common excipients and the most common lubricant in solid oral products. It is primarily added to tablet formulations to ease ejection during tablet compression. While commonly present in low concentrations, the addition of MgSt substantially affects the final tablet properties. Its impact is further not only concentration dependent but also varies with exposure of the formulation to shear, which worst-case results in over-lubrication. The presented study investigated the applicability of terahertz time-domain spectroscopy (THz-TDS) to monitor the shear-induced blend densification of microcrystalline cellulose blended with MgSt over a range of concentrations (0.3, 0.7, and 1.0 %). The effect of shear was investigated by variation of blending times (5 – 20 min) in a diffusion blender. THz-TDS measurements of the powder blends were acquired in transmission by measuring directly through the mixing container. The refractive index at terahertz frequencies was found to be sufficiently sensitive to resolve the densification of the blend with increased blending times. Thus, THz-TDS blend density measurements can be used as a surrogate parameter to evaluate the total shear exposure of a blend. Considerations regarding implementation are discussed. In the context the approach was integrated with the well-described THz-TDS-based tablet porosity analysis into a unified model to monitor and predict the tensile strength. Including the THz-TDS measurement on the blend allowed for a more accurate description of the tensile strength, reducing the root mean squared error by over 40 % (0.33 MPa). The possibility of monitoring the density changes of a blend non-invasively makes THz-TDS a promising process analytical technology approach for controlling the total shear impact on lubricated blends and tablet quality.
Introduction
The final steps of the tablet compression cycle are the ejection of the tablet from the die and the subsequent take-off from the lower punch. During these steps, the movement of the tablet relative to the tooling surfaces creates friction, which may damage the tablet and the tooling. During tablet manufacturing, high friction, often manifesting itself in high ejection forces, can be reduced by the addition of lubricants (Wang et al. 2010). Whilst the concept of external lubrication, where a lubricant is mechanically applied directly to the tooling before each compaction cycle, has been demonstrated in principle for different lubricants (De Backere et al., 2020, De Backere et al., 2023a), the realisation of external lubrication on a commercial scale remains challenging. Therefore, internal lubrication, the traditional approach where the lubricant is mixed into the formulation, prevails in the commercial manufacture of tablets (De Backere et al. 2020). Besides high ejection forces, the adhesion of formulation particles to the punches and die surfaces (sticking and picking) is a common challenge during tablet ejection and take-off. Addition of lubricants to the formulation may prevent this due to the anti-adhering properties of most lubricants (Shah et al. 1986).
Magnesium stearate (MgSt) is the most commonly used excipient to avoid complications during tablet ejection and take-off. Low concentrations (< 1 %) of MgSt typically suffice to improve the compression process (De Backere et al., 2023b, Li and Wu, 2014, Sun, 2015, Wang et al., 2010). Due to its friction-reducing properties (Wang et al. 2010) MgSt is generally classified as a lubricant (Raymond et al., 2009), but it also exhibits excellent anti-adherent (Shah et al. 1986) and glidant properties (Podczeck and Mia 1996). MgSt is a solid, organo-metallic salt of magnesium and a blend of fatty acids containing a high percentage of stearic and palmitic acid (European Pharmacopoeia, 2024). As with other solid lubricants, its effects on the formulation arise from boundary lubrication (Wang et al. 2010). Already at very low shear forces, the MgSt crystal lattice is cleaved, resulting in detached, plate-like particles (flakes) (Wada and Matsubara, 1994, Marwaha and Rubinstein, 1987). This detachment occurs during blending and other shear-inducing process steps, with the resulting MgSt-flakes subsequently adhering to other particles of the formulation and the tooling surface, i.e. boundary lubrication and often referred to as film formation. This layer reduces adhesive interactions as well as the particle–particle and particle-tooling contact area. Consequently, friction and powder adherence are reduced (Wang et al. 2010). While the structure of MgSt trihydrate has been solved (Herzberg et al. 2023), there is no solved crystal structure for the typical commercial grade of MgSt (hydrates with a varying molar ratio of water in the blend of fatty acids). Therefore, the exact nature of the lattice cleavage, flake formation, and adhesion to other particles, remains unresolved.
The adherence of MgSt to the other particles of the tablet formulation may have deteriorating effects on the drug product and MgSt has a substantial influence on tablet properties even at low concentrations. It has been found to decrease tablet mechanical strength and to slow down tablet disintegration and dissolution due to hydrophobicity of the fatty acid entities (Dansereau and Peck, 1987, Puckhaber et al., 2022, Puckhaber et al., 2023, Abe and Otsuka, 2012, Strickland et al., 1956 Uzunović and Vranić 2007). It is well known that the effects of MgSt on powder manufacturability and tablet properties highly depend on the total amount of shear the system is exposed to before tablet compression. Upon shear exposure flakes continuously detach from larger MgSt particles and adsorb on the other particles causing a higher surface coverage (Hafeez Hussain et al. 1988). Increased shear has been found to result in decreased ejection forces, decreased mechanical strength, and increased disintegration and dissolution times (Kushner IV and Moore, 2010, Mehrotra et al., 2007, Dansereau and Peck, 1987, Paul and Sun, 2018, Shah and Mlodozeniec, 1977, Puckhaber et al., 2023). Over-lubrication is a term used when the applied concentration or shear is too high and results in unacceptable tablet properties. In addition, an increased shear exposure or higher MgSt concentration has been found to affect blend flowability (Fahiq et al., 2007, Podczeck and Mia, 1996). Finally, a densification of the blend due to increased shear exposure or higher MgSt concentration was described in various studies (Shah and Mlodozeniec, 1977, Dansereau and Peck, 1987, Mehrotra et al., 2007, Kushner IV, 2012).
The pharmaceutical industry is currently undergoing two transitions – from Quality by Testing (QbT) to Quality by Design (QbD) (Yu, 2008) and from batch to continuous manufacturing (Fonteyne et al., 2015, Plumb, 2005, Lee et al., 2015) – both developments heavily encouraged by regulatory authorities (FDA 2004a) and the ICH (ICH, 2009, ICH, 2011, ICH, 2023, ICH, 2024). Implementing a continuous process is considered beneficial from an industrial and regulatory perspective by reducing monetary and time investment, and by increasing agility, flexibility, quality, understanding, and robustness of pharmaceutical manufacturing (Lee et al., 2015, Fonteyne et al., 2015). Continuous manufacturing is inherently linked to the transition from QbT to QbD as it necessitates understanding of critical process parameters and raw material or intermediate product quality attributes to ensure high product quality (Lee et al., 2015, Su et al., 2019; Yu 2008). The pharmaceutical industry and regulatory agencies acknowledge that these transitions require novel process analytical technology (PAT) tools that allow a detailed analysis of raw materials, intermediates, the process, and the product (Hinz, 2006, FDA., 2004b). Implementing PAT tools is believed to facilitate process and product understanding, ultimately, allowing the establishment of real-time monitoring of critical quality and material attributes, as well as critical process parameters. Incorporating PAT strategies and continuous manufacturing can further enable real-time release (RTR) testing. In RTR testing, PAT-based monitoring strategies ensure that the process continuously produces a drug product within quality specifications (ICH Q8 2009; Markl et al. 2020). This requires the development of “fit-for-purpose” PAT procedures, based on prior knowledge of the product, process, and analytical procedure as outlined in ICH Q14.
During powder blending, the API content and blend uniformity are considered relevant quality attributes to monitor due to their direct link to the content and content uniformity of the drug product (Kim et al. 2021). Although the excipient concentration and their blend homogeneity can significantly influence the finished product, they are commonly not monitored through in-process controls. Since the extent of powder lubrication can directly influence the quality of produced tablets it would be beneficial to monitor lubrication during the manufacturing process independent of the production setup being batch-wise or continuous. In common process conrol strategies, variations in lubricant concentration or shear exposure may only be found by testing the finished tablet product. Incorporating a PAT strategy for blend lubrication would allow direct monitoring and potential control of blend lubrication and lubrication-dependent quality parameters effectively preventing over-lubrication phenomena. Monitoring strategies of the lubricant concentration have only been suggested in few studies (Aguirre-Mendez and Romañach, 2007, Cameron and Briens, 2019a, Cameron and Briens, 2019b, Crouter and Briens, 2016, Duong et al., 2003, Ebube et al., 1998). Process analytical tools to assess varying shear exposure are even less commonly investigated. Thermal effusivity (Nakagawa et al., 2013, Uchiyama et al., 2014, Yoshihashi et al., 2013) and NIR reflectance spectroscopy (Abe and Otsuka, 2012, Nakagawa et al., 2013, Otsuka and Yamane, 2009) have been proposed to monitor shear dependent lubrication of blends. NIR reflectance spectroscopy has also been suggested as a PAT tool to measure the shear-dependent changes in tablet the breaking force (Otsuka and Yamane, 2006, Otsuka and Yamane, 2009).
The non-destructive, non-ionising nature of the electromagnetic radiation used (60 GHz – 4 THz = 2 – 130 cm−1) and the fast acquisition rates (sub-second) make THz-TDS ideal for PAT applications. The technique can be used in transmission and reflection mode (Zeitler et al. 2010). As many pharmaceutical materials show a high transmittance at terahertz frequencies, even rather thick or dense samples can be probed in transmission. Further, most polymeric materials are at least semi-transparent, enabling measurement through container walls (Zeitler et al. 2010). These features enabled transmission measurements of blends through a blending container in a previous study (Anuschek et al. 2024a). As THz-TDS records the signal in the time-domain, extraction of the absorption coefficient and the refractive index is possible without using complex physical models, such as the Kramers-Kronig relations (Markl et al. 2017). Numerous studies have demonstrated the correlation of the refractive index with material density, including materials such as pharmaceutical tablets and powders, in both transmission (Bawuah et al., 2021, Anuschek et al., 2024a) and reflection (Anuschek et al., 2023, Stranzinger et al., 2019).
The presented study evaluates the suitability of THz-TDS in determining blend density for monitoring the shear-dependent lubrication with MgSt by variation of the blending time. This ultimately aims to establish a monitoring strategy based on THz-TDS primarily for shear-dependent lubrication and its effect on tablet quality.
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Materials
In this study microcrystalline cellulose (MCC) (Avicel pH 200, FMC, Philadelphia, PA, USA) and magnesium stearate (MgSt) (Peter Greven, Bad Münstereifel, Germany) were used.
Moritz Anuschek, Thea Nilsson, Anne Linnet Skelbæk-Lorenzen, Thomas Kvistgaard Vilhelmsen, J.Axel Zeitler, Jukka Rantanen, Using density changes to monitor blending with magnesium stearate by terahertz time-domain spectroscopy, International Journal of Pharmaceutics, Volume 672, 2025, 125303, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.125303.
Read also our introduction article on Magnesium Stearate here:
