Prince Bawuah

Detection of porosity of pharmaceutical compacts by terahertz radiation transmission and light reflection measurement techniques

We report on the non-destructive quantification of the porosity of pharmaceutical compacts (microcrystalline cellulose tablets) by using both optical and terahertz techniques. For the full analysis of the porosity of pharmaceutical tablets, the results obtained in both cases have shown that optical and terahertz techniques are complementary. The intrinsic refractive index of microcrystalline cellulose was estimated using the effective refractive index obtained from the time delay of the THz pulse together with the Bruggeman model for effective media. Once this intrinsic refractive index is known, the unknown porosity of the tablet can be estimated with the aid of the measured effective refractive index as well as the thickness of the pharmaceutical tablet. The method was tested using a set of thirteen tablets having different porosities. It is shown that the error in the estimation of the unknown tablets porosity is less than 1%. In addition, surface roughness was measured by using an optical interferometer and gloss by using a diffractive-optical-element based glossmeter. The measurement was achieved by scanning the tablets with a probe beam and detecting the reflected light. The surface roughness and gloss data show relatively good correlation with the porosities of the tablets.

Non-contact weight measurement of flat-faced pharmaceutical tablets using terahertz transmission pulse delay measurements.

By measuring the time delay of a terahertz pulse traversing a tablet, and hence its effective refractive index, it is possible to non-invasively and non-destructively detect the weight of tablets made of microcrystalline cellulose (MCC). Two sets of MCC tablets were used in the study: Set A (training set) consisted of 13 tablets with nominally constant height but varying porosities, whereas Set B (test set) comprised of 21 tablets with nominally constant porosity but different heights. A linear correlation between the estimated absolute weight based on the terahertz measurement and the measured weight of both sets of MCC tablets was found. In addition, it was possible to estimate the height of the tablets by utilizing the estimated absolute weight and calculating the relative change of height of each tablet with respect to an ideal tablet. A good agreement between the experimental and the calculated results was found highlighting the potential of this technique for in-line sensing of the weight, porosity and the relative change in height of the tablets compared to a reference/ideal tablet. In this context, we propose a quantitative quality control method to assess the deviations in porosity of tablets immediately after compaction.

Terahertz study on porosity and mass fraction of active pharmaceutical ingredient of pharmaceutical tablets

In this study, terahertz time-domain spectroscopic (THz-TDS) technique has been used to ascertain the change in the optical properties, as a function of changing porosity and mass fraction of active pharmaceutical ingredient (API), of training sets of pharmaceutical tablets. Four training sets of pharmaceutical tablets were compressed with microcrystalline cellulose (MCC) excipient and indomethacin API by varying either the porosity, height, and API mass fraction or all three tablet parameters. It was observed, as far as we know, for the first time, that the THz time-domain and frequency-domain effective refractive index, as well as, the frequency-domain effective absorption coefficient both show linear correlations with the porosity and API mass fraction for training sets of real pharmaceutical tablets. We suggest that, the observed linear correlations can be useful in basic research and quality inspection of pharmaceutical tablets. Additionally, we propose a novel optical strain parameter, based on THz measurement, which yields information on the conventional strain parameter of a tablet as well as on the change of fill fraction of solid material during compression of porous pharmaceutical tablets. We suggest that the THz measurement and proposed method of data analysis, in addition to providing an efficient tool for basic research of porous media, can serve as one of the novel quality by design (QbD) implementation techniques to predict critical quality attributes (CQA) such as porosity, API mass fraction and strain of flat-faced pharmaceutical tablets before production.

Estimation of Young's modulus of pharmaceutical tablet obtained by terahertz time-delay measurement.

In this paper, it is suggested that Youngs modulus of pharmaceutical tablets with different porosity can be estimated from terahertz (THz) pulse time delay. We demonstrate such a possibility using a training set of tablets compressed from starch acetate. Once the mechanical properties are taught to the THz measurement system, using an ideal tablet as a reference, it is possible to get information about the Youngs modulus of the tablet. Here, we show that there are optical counterparts of classical mechanical laws that couple the Youngs modulus and porosity of the tablet.

A structure parameter for porous pharmaceutical tablets obtained with the aid of Wiener bounds for effective permittivity and terahertz time-delay measurement

A structure parameter that can be used to predict the pattern of arrangement of porous inclusions in pharmaceutical tablets is introduced. By utilizing the effective refractive index of a pharmaceutical tablet obtained from terahertz time-domain measurements, we have shown that there exists a promising correlation between the calculated structural parameter and the porosity of training sets of pharmaceutical tablets, having well-defined characterization. Knowing of the structural arrangement, i.e. combined constituent skeletal-pore elements in series, parallel or mixed within porous media, could serve as a basis for understanding the ingress and permeation of liquids in such media. In the realm of pharmaceutical applications, such knowledge of the structural arrangement of air voids within a medicinal tablet could enable correlation with mechanical strength and dissolution behaviour in aqueous systems.

Fast and non-destructive pore structure analysis using terahertz time-domain spectroscopy

Pharmaceutical tablets are typically manufactured by the uni-axial compaction of powder that is confined radially by a rigid die. The directional nature of the compaction process yields not only anisotropic mechanical properties (e.g. tensile strength) but also directional properties of the pore structure in the porous compact. This study derives a new quantitative parameter, Sa, to describe the anisotropy in pore structure of pharmaceutical tablets based on terahertz time-domain spectroscopy measurements. The Sa parameter analysis was applied to three different data sets including tablets with only one excipient (functionalised calcium carbonate), samples with one excipient (microcrystalline cellulose) and one drug (indomethacin), and a complex formulation (granulated product comprising several excipients and one drug). The overall porosity, tablet thickness, initial particle size distribution as well as the granule density were all found to affect the significant structural anisotropies that were observed in all investigated tablets. The Sa parameter provides new insights into the microstructure of a tablet and its potential was particularly demonstrated for the analysis of formulations comprising several components. The results clearly indicate that material attributes, such as particle size and granule density, cause a change of the pore structure, which, therefore, directly impacts the liquid imbibition that is part of the disintegration process. We show, for the first time, how the granule density impacts the pore structure, which will also affect the performance of the tablet. It is thus of great importance to gain a better understanding of the relationship of the physical properties of material attributes (e.g. intragranular porosity, particle shape), the compaction process and the microstructure of the finished product.

Noninvasive porosity measurement of biconvex tablets using terahertz pulses

Biconvex pharmaceutical microcrystalline cellulose (MCC) compacts were investigated by the detection of terahertz (THz) pulse delay in the transmission measurement mode. The dimensions of the tablets were kept as constants but the porosity was a priori known variable. It is shown that the porosity of the biconvex compact has a linear correlation with the THz pulse delay. By constructing a calibration line between these two parameters (i.e. porosity and THz pulse delay), it is possible to non-invasively detect porosity of biconvex tablets. We suggest that this preliminary study could be the starting point of in-depth future studies on the screening of porosity and related properties of real biconvex pharmaceutical tablets using terahertz sensing techniques.

Characterisation of pore structures of pharmaceutical tablets: a review

Traditionally, the development of a new solid dosage form is formulation-driven and less focus is put on the design of a specific microstructure for the drug delivery system. However, the compaction process particularly impacts the microstructure, or more precisely, the pore architecture in a pharmaceutical tablet. Besides the formulation, the pore structure is a major contributor to the overall performance of oral solid dosage forms as it directly affects the liquid uptake rate, which is the very first step of the dissolution process. In future, additive manufacturing is a potential game changer to design the inner structures and realise a tailor-made pore structure. In pharmaceutical development the pore structure is most commonly only described by the total porosity of the tablet matrix. Yet it is of great importance to consider other parameters to fully resolve the interplay between microstructure and dosage form performance. Specifically, tortuosity, connectivity, as well as pore shape, size and orientation all impact the flow paths and play an important role in describing the fluid flow in a pharmaceutical tablet. This review presents the key properties of the pore structures in solid dosage forms and it discusses how to measure these properties. In particular, the principles, advantages and limitations of helium pycnometry, mercury porosimetry, terahertz time-domain spectroscopy, nuclear magnetic resonance and X-ray computed microtomography are discussed.

On the role of API in determining porosity, pore structure and bulk modulus of the skeletal material in pharmaceutical tablets formed with MCC as sole excipient

The physical properties and mechanical integrity of pharmaceutical tablets are of major importance when loading with active pharmaceutical ingredient(s) (API) in order to ensure ease of processing, control of dosage and stability during transportation and handling prior to patient consumption. The interaction between API and excipient, acting as functional extender and binder, however, is little understood in this context. The API indomethacin is combined in this study with microcrystalline cellulose (MCC) at increasing loading levels. Tablets from the defined API/MCC ratios are made under conditions of controlled porosity and tablet thickness, resulting from different compression conditions, and thus compaction levels. Mercury intrusion porosimetry is used to establish the accessible pore volume, pore size distribution and, adopting the observed region of elastic intrusion-extrusion at high pressure, an elastic bulk modulus of the skeletal material is recorded. Porosity values are compared to previously published values derived from terahertz (THz) refractive index data obtained from exactly the same tablet sample sets. It is shown that the elastic bulk modulus is dependent on API wt% loading under constant tablet preparation conditions delivering equal dimensions and porosity. The findings are considered of novel value in respect to establishing consistency of tablet production and optimisation of physical properties.

Optics-based compressibility parameter for pharmaceutical tablets obtained with the aid of the terahertz refractive index

The objective of this study is to propose a novel optical compressibility parameter for porous pharmaceutical tablets. This parameter is defined with the aid of the effective refractive index of a tablet that is obtained from non-destructive and contactless terahertz (THz) time-delay transmission measurement. The optical compressibility parameter of two training sets of pharmaceutical tablets with a priori known porosity and mass fraction of a drug was investigated. Both pharmaceutical sets were compressed with one of the most commonly used excipients, namely microcrystalline cellulose (MCC) and drug Indomethacin. The optical compressibility clearly correlates with the skeletal bulk modulus determined by mercury porosimetry and the recently proposed terahertz lumped structural parameter calculated from terahertz measurements. This lumped structural parameter can be used to analyse the pattern of arrangement of excipient and drug particles in porous pharmaceutical tablets. Therefore, we propose that the optical compressibility can serve as a quality parameter of a pharmaceutical tablet corresponding with the skeletal bulk modulus of the porous tablet, which is related to structural arrangement of the powder particles in the tablet.