Impact of pharmaceutical tablet properties on optical porosimetry performance

Abstract

The porosity of a pharmaceutical tablet influences liquid transport, disintegration and dissolution, rendering its monitoring and control crucial for quality by design. Optical porosimetry, a non-destructive process analytical technology (PAT), combines gas in scattering media absorption spectroscopy (GASMAS), photon time-of-flight spectroscopy (PToFS), tablet thickness measurement and tablet solid refractive index. This article presents a short tutorial on optical porosimetry theory and a performance study of optical porosimetry on pharmaceutical tablets via design of experiments. The investigated tablets share the same formulation, solid refractive index and diameter but differ in porosity (∼0.05 and 0.25) and thickness (1, 3 and 5 mm). Critical user-controllable factors impacting the measurement accuracy and precision of the investigated tablets were identified. These are the manufactured tablet thickness, porosity, the user-estimated solid refractive index, and the number of optical porosimetry measurements in decreasing order of significance. A comparison between tablet porosity measured by optical porosimetry and by nominal measurements revealed that optical porosimetry tends to overestimate the porosity of the investigated tablets, particularly at low porosities, and has greater variability. While optical porosimetry poses advantages as a non-destructive and rapid PAT for real-time release testing, users need to be aware of the appropriate range of tablet thickness, porosity and the solid refractive index estimate.

Introduction

The porosity of a pharmaceutical tablet, defined as the volumetric fraction of air relative to the tablet sample, is determined by the critical process parameters (CPPs) during manufacturing, such as compaction pressure, and informs the critical quality attributes (CQAs) on tablet performance, such as disintegration time. Therefore, it is imperative to control and monitor tablet porosity to achieve quality by design (QbD).

From the beginning of the pharmaceutical tablet manufacturing process, raw material properties, such as particle size and shape, determine the flowability, compactability, and inter-particle porosity. The optimal so-called critical material attributes are highly dependent on the specific formulation. For example, for a powder blend of microcrystalline cellulose (MCC) and paracetamol, it was shown that both the paracetamol concentration and MCC particle size change the flowability (Soppela et al., 2010). Another study showed specifically for a mass ratio of MCC and paracetamol, small, spherical drug particles could improve flowability and decrease porosity between particles in the overall bulk powder (Kaerger et al., 2004). The next step of agglomeration via wet or dry granulation can adjust the flowability, compactability and inter-particle porosity of the powder mixture (Kleinebudde, 2004, van den Ban and Goodwin, 2017). However, it was demonstrated that under excessive wet granulation, a lower limit of the inter-particle porosity may be reached. The lower limit inhibits the rearrangement and fragmentation of particles in the next manufacturing step of tablet compaction (van den Ban and Goodwin, 2017). Other processing methods, such as dry coating, increase bulk density and decrease inter-particle porosity for particle flow enhancement (Kunnath et al., 2021).

Upon compacting the particles to form a tablet, the choice of punch shape, compaction pressure and compaction speed play a determining role on the tablet’s microstructure, including pore size, shape, distribution, orientation and connectivity (Sinka et al., 2009, Kadiri and Michrafy, 2013, Bawuah and Zeitler, 2021, Bawuah et al., 2023). All these CPPs and CQAs ultimately contribute to the porosity of the pharmaceutical tablet. The punch shape determines the extent of porosity heterogeneity within the tablet (Sinka et al., 2009, Kadiri and Michrafy, 2013). Numerous models, such as those by Heckel, 1961, Kawakita and Tsutsumi, 1965, Cooper and Eaton, 1962 and Wünsch et al. (2019), were developed to better understand the effect of compaction pressure on the change in porosity during compaction. The Ryshkewitch equation relates tablet porosity with tensile strength, which is a CQA for assessing tablets’ suitability for transport and distribution (Ryshkewitch, 1953, Tye et al., 2005).

When the patient obtains and consumes the tablet, liquid first penetrates through the tablet pores. The process of liquid penetration and absorption is governed by the interplay of multiple factors, including wettability, permeability, capillary rise, pore size distribution, pore structure, and pore connectivity (Gane, 2005, Markl et al., 2017, Markl and Zeitler, 2017, Yang et al., 2018, Vaitukaitis et al., 2020, Ferdoush et al., 2023). Among these factors, pore size distribution, pore structure and pore connectivity all relate to the tablet porosity.

Given the significance of porosity, numerous studies have investigated the overall effect of porosity on the rate of liquid transport into the tablet core (Quodbach and Kleinebudde, 2015, Yassin et al., 2015, Markl et al., 2018c, Skelbæk-Pedersen et al., 2020, Al-Sharabi et al., 2020, Dong et al., 2021). As the liquid contacts the particles, swelling and strain recovery occurs, disrupting the interparticle bonds, leading to tablet disintegration and dissolution, which are important CQAs for assessing tablet performance (Markl and Zeitler, 2017). Extensive studies with different pharmaceutical formulations and particle properties showed the determinative role of porosity in pharmaceutical tablet disintegration and dissolution (Riippi et al., 1998, Delalonde and Ruiz, 2008, Hattori and Otsuka, 2011, Quodbach and Kleinebudde, 2015, van den Ban and Goodwin, 2017, Skelbæk-Pedersen et al., 2020, Bawuah et al., 2021), which contribute to the final significant CQAs of drug release profile and bioavailability (Markl and Zeitler, 2017). The critical role of porosity in the respective stages of the pharmaceutical tablet life cycle is thus demonstrated.

Porosity is therefore listed as one of the key parameters to be considered as CQA by the United States Food and Drug Administration (Jiang and Lawrence, 2009), and its measurement is imperative to QbD. Conventional measurement techniques include mercury porosimetry, gas pycnometry, thermoporometry and oil immersion. These techniques use fluids to penetrate the open, connected pores (Markl et al., 2018b). In addition to being invasive, a long measurement time is required, and hence, these methods are only suitable for off-line assessments on a small number of tablet samples from a batch. X-ray micro-computed tomography is a non-destructive technique that requires a long measurement and processing time (Markl et al., 2018b). It provides detailed information on the tablet’s pore structure, but it is unsuitable for porosity analysis at an industrial production scale. More straightforward techniques that take a relatively shorter time to quantify porosity include mass and dimensional measurements and envelope density and volume measurements (Sun, 2017). The true density of the formulation is needed to determine the porosity from these raw measurements. These two techniques can be deployed at-line but are unsuitable for on-line or in-line measurements. Despite the two techniques being non-destructive, the sampled tablets cannot be returned to the manufacturing line since the measurement probes directly interact with the tablets.

Non-destructive spectroscopic techniques such as ultrasound (Hakulinen et al., 2008, Xu et al., 2018), near-infrared (NIR) (Shah et al., 2007, Luukkonen et al., 2008), Raman (Shah et al., 2007) and terahertz (THz) (Markl et al., 2018a, Bawuah et al., 2020, Bawuah et al., 2021, Bawuah et al., 2023, Anuschek et al., 2023, Anuschek et al., 2024) are promising porosity process analytical technologies (PATs) for fast on-line and in-line measurements. Depending on whether transmission or reflection measurement mode is adopted, the recorded spectra contain information on either the sample volume or the surface. Ultrasound is a contact measurement, and good material-dependent correlations between the extracted ultrasonic wave velocity and tablet porosity were shown (Hakulinen et al., 2008, Xu et al., 2018). NIR, Raman and terahertz spectroscopy are non-contact techniques. NIR and Raman spectroscopy use a material-dependent correlation model to relate the spectral data, often representing a change in surface scattering response, to the pharmaceutical tablet porosity.

The spectral data were also used to predict tablet disintegration and dissolution via fitting correlations with regression models and via artificial neural networks (Reich, 2005, Freitas et al., 2005, Otsuka et al., 2007, Müller et al., 2012, Hernandez et al., 2016, Pawar et al., 2016, Zeng et al., 2022, Galata et al., 2022). However, it was shown that Raman spectroscopy is insensitive to changes in particle properties caused by wet granulation. Prediction models using Raman spectroscopy thus could not be established between particle properties and the tablet’s quality attributes such as porosity and disintegration time (Peeters et al., 2016). Terahertz spectroscopy deterministically measures the sample refractive index of a pharmaceutical tablet. A set of tablets with different porosities is required to calibrate the solid refractive index of the tablet material, and this allows the pharmaceutical tablet porosity to be calculated (Bawuah et al., 2020). The automated at-line terahertz spectroscopy application for fast porosity measurements was demonstrated on a commercial batch of 5000 tablets (Bawuah et al., 2023). The measured porosities were also shown to correlate well with tablet disintegration and dissolution times (Bawuah et al., 2021). These technological developments establish the huge potential of spectroscopic PATs as real-time release testing (RTRT) tools.

Optical porosimetry is another non-destructive and non-contact spectroscopic porosity PAT. It uses electromagnetic waves in the visible and near-infrared regions. It operates by a sequence of tablet thickness measurement, user-estimation of tablet solid refractive index, gas in scattering media absorption spectroscopy (GASMAS) and photon time-of-flight spectroscopy (PToFS) (Svensson et al., 2010, Johansson et al., 2021). Optical porosimetry is unique to the PATs mentioned above for pharmaceutical tablets in that it is a stochastic method and does not require calibration.

Previous efforts focused on utilising the technique in quantifying the optical porosity of different porous media, such as ceramics and pharmaceutical tablets (Svensson et al., 2010, Mei et al., 2014). The optical porosity of a sample is quantified by the path lengths traversed by scattered photons; hence, it is different from physical porosity. Correlations between optical and physical porosity were established (Svensson et al., 2010, Mei et al., 2014). Recently, a mechanistic theory has been developed to directly relate the stochastically measured optical porosity to physical porosity (Libois et al., 2019). Optical porosimetry has since then been applied to determine the physical porosity of pharmaceutical ribbons (Johansson et al., 2021). Given the unique, stochastic and calibration-free approach, this paper provides a short explanation of the analytical measurement theory and evaluates the capability of optical porosimetry in determining the physical porosity of pharmaceutical tablets. Specifically, the critical user-controllable factors that impact the accuracy and precision of the determined physical porosity were investigated. These enable the assessment of the technique’s performance as a porosity PAT for RTRT applications in the future.

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Pharmaceutical tablet production

Microcrystalline cellulose (Avicel PH-102, FMC Europe NV, Belgium) (43.2 w%), lactose anhydrous (Supertab 21AN, DFE Pharma, Germany) (51.8 w%), croscarmellose sodium (AcDiSol, IFF, United States) (3.0 w%), magnesium stearate (Ligamed MF-2-V-MB, Peter Greven GmbH & Co. KG, Germany) (1.0 w%) and indomethacin (Sigma-Aldrich, Merck KGaA, Germany) (1.0 w%) were first placed in a plastic container. The powders were manually mixed in the plastic container by repeated inversion, rotation and shaking of the container. The quantity of material was too large for mixing with a pestle and mortar, but too small for effective mixing in an automated blender. The mixed powder were compacted into flat cylindrical tablets of 10 mm diameter using a compaction simulator (HB50, Huxley Bertram Engineering Ltd, UK).

Chi Ki Leung, Andreas Kottlan, Rikard Heimsten, Märta Lewander Xu, J. Axel Zeitler, Impact of pharmaceutical tablet properties on optical porosimetry performance, International Journal of Pharmaceutics, Volume 676, 2025, 125567, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.125567.

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