Prediction of in-vitro dissolution and tablet hardness from optical porosity measurements

The implementation of continuous technologies in pharmaceutical manufacturing not only offers new opportunities and benefits, but also requests novel approaches for process and quality control. Advanced control strategies in addition or instead of traditional end-product testing are required (Nasr et al., 2017). To satisfy this need, real-time information on the state of the process and the critical quality attributes (CQAs) must be acquired. Real-time data of the product CQAs also offers the option of real-time release testing (RTRT).

Process analytical technologies (PAT) for monitoring most CQAs during solid dosage manufacturing are available (Fonteyne et al., 2015, Laske et al., 2017). However, two major tablet CQAs, the hardness and the in-vitro dissolution are still commonly measured via destructive methods. The tablet hardness is either characterized by tensile strength or indentation hardness. For tensile strength manual or automated tablet testers in on-line or at-line mode are established. Indentation methods are rarely applied, although the technique has been further developed (Patel and Sun, 2016). In addition, more advanced methods have been developed. Tablet hardness was predicted via near infrared spectroscopy (NIRS) (Donoso et al., 2003, Blanco et al., 2006), NIR chemical imaging (Wahl et al., 2017) and Raman spectroscopy (Shah et al., 2007).

The established way of dissolution testing is the in-vitro off-line method. This route is labour and time intensive and represents only a small number of tablets. Attempts to introduce PAT were also undertaken. For coated tablets several technologies have been developed and implemented to predict the dissolution performance from coating thickness measurements. The drug dissolution rate was correlated with coating thickness predictions from NIRS (Wu et al., 2015, Ariyasu et al., 2017). The mean dissolution time (MDT) was predicted from Raman spectral data (Müller et al., 2012) and from terahertz waveforms (Ho et al., 2008). Recently, optical coherence tomography (OCT) was used to monitor coating thickness and predict dissolution profiles (Sacher et al., 2024).

Similar approaches have been investigated for uncoated tablets, such as prediction of dissolution profiles based on NIR spectra via multivariate models (Pawar et al., 2016, Zhao et al., 2019). Raman chemical imaging was used to predict the dissolution profile for various contents and particle size distributions (Galata et al., 2022). Dissolution profiles were also predicted from the features of OCT images by means of machine learning (Fink et al., 2023).

A quality attribute, which is directly linked to hardness and dissolution, is the tablet porosity. Several studies are available dealing with the relation between porosity and hardness (Kuentz and Leuenberger, 2000, Sun et al., 2018) and between porosity and dissolution (Riippi et al., 1998, Ansari and Stepanek, 2008, Singh et al., 2020). The tablet porosity is traditionally measured by means of mercury porosimetry or gas adsorption (Westermarck et al., 1998, Markl et al., 2018). An alternative is the calculation from dimensions and weight. While these methods are all tedious and partially destructive, ultrasound transmission, spectroscopy and terahertz pulsed imaging (TPI) have potential for fast data acquisition. It was shown that the ultrasound velocity was sensitive to the tablet porosity (Hakulinen et al., 2008). Variations in the tablet structure resulting from different particle size distributions of the raw materials could be clearly determined and visualized. The tensile strength of tablets was also predicted based on measurements of the ultrasound velocity (Simonaho et al., 2011). Another approach based on ultrasound transmission measurements was to correlate the acoustic wave propagation with the tablet porosity and the tensile strength (Xu et al., 2018).) The viscoelastic and scattering attenuation of an ultrasonic wave was used to predict the material properties and the grain size distribution of tablets (Vahdat et al., 2013, Sultan et al., 2023). The viscoelasticity of tablets itself could be characterized by measuring the dampening of resonance spectra, which were induced to tablets by a mechanical impact (Meynard et al., 2022). Therefore, the tablets were dropped on a hard surface and the free vibrations were recorded with a microphone.

NIRS and Raman spectroscopy were also proven suitable to predict tablet porosity (Shah et al., 2007). A more recent study concluded, that spectroscopic tools were not able to determine differences in physical tablet properties, if the variations in a stable robust process were limited (Peeters et al., 2016). Terahertz technologies have shown potential to measure the porosity and microstructure of tablets (Lu et al., 2020). The porosity measured via TPI was used to predict disintegration and dissolution time for immediate release tablets (Bawuah et al., 2021). Terahertz time-domain spectroscopy (THz-TDS) in reflection mode was used to determine the tablet porosity based on the reflected amplitude from the tablet surface as well as the tablet height from the time of flight (TOF) (Anuschek et al., 2023). An alternative approach to porosity measurement involves the integration of two laser techniques: gas in scattering media absorption spectroscopy (GASMAS) (Svanberg, 2010) and photon time of flight spectroscopy (pTOFS). GASMAS determines the concentration of a specific compound in a gas by tuning the laser wavelength its characteristic across absorption lines. pTOFS determines the amount of time it takes for light to travel through a solid object. The resulting signals from both GASMAS and pTOFS can be correlated with the porosity of tablets (Svensson et al., 2008). Utilizing a prototype instrument, the porosity has successfully been measured on roller-compacted ribbons (Johansson et al., 2021). This instrument quantifies optical porosity, defined as the ratio between the optical path length within voids of a sample measured with GASMAS and the total optical path length through the sample measured with pTOFS. Experimental and theoretical studies have established a relationship between optical and physical porosity (Svensson et al., 2010, Libois et al., 2019).

In this study, models for predicting the tablet hardness and its related dissolution profile based on the measurements of optical porosity were developed. Tablets were manufactured under different process conditions in a continuous wet granulation tableting line and measured at-line with an instrument, which combines GASMAS and pTOFS techniques. A data-driven approach was used to correlate the optical porosity with the parameters of a dissolution model and with tablet hardness. This novel concept allows for RTRT of dissolution and hardness based on non-destructive measurements of a physical tablet property.

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Formulation and Processing

Immediate release tablets consisting of 4 % methyl 4-hydroxybenzoate, also known as Methylparaben (Merck, Germany), as surrogate active pharmaceutical ingredient (API), 5 % Hydroxypropylmethylcellulose (HPMC) (JRS Pharma, Germany) as binder, 21.75 % microcrystalline cellulose (MCC) (DuPont, Ireland) and 68 % lactose monohydrate (Meggle, Germany) as filler, 0.25 % croscarmellose sodium as disintegrant (DFE, Netherlands) and 1 % magnesium stearate as lubricant (Merck, Germany).

Stephan Sacher, Andreas Kottlan, Jean-Baptiste Diop, Rikard Heimsten, Prediction of in-vitro dissolution and tablet hardness from optical porosity measurements, International Journal of Pharmaceutics, 2024, 124336, ISSN 0378-173,
https://doi.org/10.1016/j.ijpharm.2024.124336.

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