At-line porosity sensing for non-destructive disintegration testing in immediate release tablets.

Fully automated at-line terahertz time-domain spectroscopy in transmission mode is used to measure tablet porosity for thousands of immediate release tablets. The measurements are rapid and non-destructive. Both laboratory prepared tablets and commercial samples are studied. Multiple measurements on individual tablets quantify the random errors in the terahertz results. These show that the measurements of refractive index are precise, with the standard deviation on a single tablet being about 0.002, with variation between measurements being due to small errors in thickness measurement and from the resolution of the instrument. Six batches of 1000 tablets each were directly compressed using a rotary press. The tabletting turret speed (10 and 30 rpm) and compaction pressure (50, 100 and 200 MPa) were varied between the batches. As expected, the tablets compacted at the highest pressure have far lower porosity than those compacted at the lowest pressure. The turret rotation speed also has a significant effect on porosity. This variation in process parameters resulted in batches of tablets with an average porosity between 5.5 and 26.5%. Within each batch, there is a distribution of porosity values, the standard deviation of which is in the range 1.1 to 1.9%. Destructive measurements of disintegration time were performed in order to develop a predictive model correlating disintegration time and tablet porosity. Testing of the model suggested it was reasonable though there may be some small systematic errors in disintegration time measurement. The terahertz measurements further showed that there are changes in tablet properties after storage for nine months in ambient conditions.

Modelling the Evolution of Pore Structure during the Disintegration of Pharmaceutical Tablets.

Pharmaceutical tablet disintegration is a critical process for dissolving and enabling the absorption of the drug substance into the blood stream. The tablet disintegration process consists of multiple connected and interdependent mechanisms: liquid penetration, swelling, dissolution, and break-up. One key dependence is the dynamic change of the pore space in a tablet caused by the swelling of particles while the tablet takes up liquid. This study analysed the changes in the pore structure during disintegration by coupling the discrete element method (DEM) with a single-particle swelling model and experimental liquid penetration data from terahertz-pulsed imaging (TPI). The coupled model is demonstrated and validated for pure microcrystalline cellulose (MCC) tablets across three porosities (10, 15, and 22%) and MCC with three different concentrations of croscarmellose sodium (CCS) (2, 5, and 8% w/w). The model was validated using experimental tablet swelling from TPI. The model captured the difference in the swelling behaviour of tablets with different porosities and formulations well. Both the experimental and modelling results showed that the swelling was lowest (i.e., time to reach the maximum normalised swelling capacity) for tablets with the highest CCS concentration, cCCS = 8%. The simulations revealed that this was caused by the closure of the pores in both the wetted volume and dry volume of the tablet. The closure of the pores hinders the liquid from accessing other particles and slows down the overall swelling process. This study provides new insights into the changes in the pore space during disintegration, which is crucial to better understand the impact of porosity and formulations on the performance of tablets.

Polarization-dependent wideband metamaterial absorber for ultraviolet to near-infrared spectral range applications.

The need for wideband metamaterial absorbers (WBMA) for applications other than sensing and filtering has demanded modifications to the conventional three-layer metal-insulator-metal (MIM) absorber configuration. This modification often results in complex geometries and an increased number of layers requiring complex lithographic processes for fabrication. Here, we show that a metamaterial absorber with rectangular geometry in the simple MIM configuration can provide wideband absorption covering the ultraviolet and near-infrared spectral range. Due to its asymmetric nature, the WBMA is sensitive to the polarization of the incident light and independent of the angle of incidence up to about 45° depending on the polarization of the incident light. The characteristics of the WBMA presented here may be useful for applications such as detectors for wide spectral band applications.

Terahertz time-domain spectroscopy for powder compact porosity and pore shape measurements: An error analysis of the anisotropic bruggeman model.

Terahertz time-domain spectroscopy (THz-TDS) is a novel technique which has been applied for pore structure analysis and porosity measurements. For this, mainly the anisotropic Bruggeman (AB-EMA) model is applied to correlate the effective refractive index (n eff) of a tablet and the porosity as well as to evaluate the pore shape based on the depolarisation factor L. This paper investigates possible error sources of the AB-EMA for THz-TDS based tablet analysis. The effect of absorption and tablet anisotropy - changes of pore shape with porosity and density distribution - have been investigated. The results suggest that high tablet absorption has a negligible effect on the accuracy of the AB-EMA. In regards of tablet anisotropy the accuracy of the porosity determination is not impaired significantly. However, density distribution and variations in the pore shape with porosity resulted in an unreliable extraction of the tablet pore shape. As an extension of the AB-EMA a new concept was introduced to convert the model into bounds for L. This new approach was found useful to investigate tablet pore shape but also the applicability of the AB-EMA for an unknown set of data.

Sensing Water Absorption in Hygrothermally Aged Epoxies with Terahertz Time-Domain Spectroscopy.

In the field of non-destructive testing, terahertz sensing has been used to analyze a wide range of materials where the most successful applications have involved materials that are semi-transparent to terahertz radiation. In this work, we demonstrate the sensitivity of terahertz time-domain spectroscopy to quantify water absorption in hygrothermally aged simple and commercial epoxy systems supported by conventional gravimetric analysis.

A Fast and Non-destructive Terahertz Dissolution Assay for Immediate Release Tablets.

There is a clear need for a robust process analytical technology tool that can be used for on-line/in-line prediction of dissolution and disintegration characteristics of pharmaceutical tablets during manufacture. Tablet porosity is a reliable and fundamental critical quality attribute which controls key mass transport mechanisms that govern disintegration and dissolution behavior. A measurement protocol was developed to measure the total porosity of a large number of tablets in transmission without the need for any sample preparation. By using this fast and non-destructive terahertz spectroscopy method it is possible to predict the disintegration and dissolution of drug from a tablet in less than a second per sample without the need of a chemometric model. The validity of the terahertz porosity method was established across a range of immediate release (IR) formulations of ibuprofen and indomethacin tablets of varying geometries as well as with and without debossing. Excellent correlation was observed between the measured terahertz porosity, dissolution characteristics (time to release 50% drug content) and disintegration time for all samples. These promising results and considering the robustness of the terahertz method pave the way for a fully automated at-line/on-line porosity sensor for real time release testing of IR tablets dissolution.

Simultaneous investigation of the liquid transport and swelling performance during tablet disintegration.

Fast disintegrating tablets have commonly been used for fast oral drug delivery to patients with swallowing difficulties. The different characteristics of the pore structure of such formulations influence the liquid transport through the tablet and hence affect the disintegration time and the release of the drug in the body. In this work, terahertz time-domain spectroscopy and terahertz pulsed imaging were used as promising analytical techniques to quantitatively analyse the impact of the structural properties on the liquid uptake and swelling rates upon contact with the dissolution medium. Both the impact of porosity and formulation were investigated for theophylline and paracetamol based tablets. The drug substances were either formulated with functionalised calcium carbonate (FCC) with porosities of 45% and 60% or with microcrystalline cellulose (MCC) with porosities of 10% and 25%. The terahertz results reveal that the rate of liquid uptake is clearly influenced by the porosity of the tablets with a faster liquid transport observed for tablets with higher porosity, indicating that the samples exhibit structural similarity in respect to pore connectivity and pore size distribution characteristics in respect to permeability. The swelling of the FCC based tablets is fully controlled by the amount of disintegrant, whereas the liquid uptake is driven by the FCC material and the interparticle pores created during compaction. The MCC based formulations are more complex as the MCC significantly contributes to the overall tablet swelling. An increase in swelling with increasing porosity is observed in these tablets, which indicates that such formulations are performance-limited by their ability to take up liquid. Investigating the effect of the microstructure characteristics on the liquid transport and swelling kinetics is of great importance for reaching the next level of understanding of the drug delivery, and, depending on the surface nature of the pore carrier function, in turn controlling the performance of the drug mainly in respect to dissolution in the body.

Plasmonic Implanted Nanogrooves for Optical Beaming.

Surface plasmon polaritons are electromagnetic surface waves, which, due to their nanoscale nature, are efficiently used for modifying an output of optical field through a metallic nanoslit, e.g., extraordinary optical transmission and beaming of light. Herein, the phenomenon of optical beaming by employing a regular array of semicylinder-shaped grooves around a nanoslit has been investigated based on numerical simulations. By analyzing the behavior of Poynting vectors in near surroundings of the slit, we have successfully demonstrated that grooves which are embedded on the layer at the exit side of the slit produce enhanced directionality of the output light than the unembedded ones. In case of semicylinder-shaped grooves, the calculated intensity of the output beam was 1.5-times, at near and far distances, higher than that of the grating grooves. Our analysis shows that positioning of the groove right at the exit of the slit is crucial for the enhancement of the beaming effect. This is due to the conversion of surface plasmon polaritons into a freely propagating field and the possible excitation of localized surface plasmons because of the presence of nanogroove. Furthermore, the proposed geometries are made of Aluminum, which is a plasmonic material and commonly applied for the fabrication of optical nanostructures. Manipulating of light (beaming, focusing/guiding, and splitting) by nanoslit can be beneficial to several applications such as nano-resolution optical imaging, sensors, and plasmonic circuits.

Investigating elastic relaxation effects on the optical properties of functionalised calcium carbonate compacts using optics-based Heckel analysis.

Heckel analysis is a widely used method for the characterisation of the compression behaviour of pharmaceutical samples during the preparation of solid dosage formulations. The present study introduces an optical version of the Heckel equation that is based on a combination of the conventional Heckel equation together with the linear relationship defined between the effective terahertz (THz) refractive index and the porosity of pharmaceutical tablets. The proposed optical Heckel equation allows us to, firstly, calculate the zero-porosity refractive index, and, secondly, predict the in-die development of the effective refractive index as a function of the compressive pressure during tablet compression. This was demonstrated for five batches of highly porous functionalised calcium carbonate (FCC) excipient compacts. The close match observed between the estimated in-die effective refractive index and the measured/out-of-die effective THz refractive index supports the validity of the proposed form of the equation. By comparing the measured and estimated in-die tablet properties, a clear change in the porosity and hence, the effective refractive index, due to post-compression elastic relaxation of the FCC compacts, has been observed. We have, therefore, proposed a THz-based compaction setup that will permit in-line monitoring of processes during tablet compression. We envisage that this new approach in tracking powder properties introduced in this preliminary study will lead to the onset of further extensive and detailed future studies.

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.

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.

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.

Characterization of the Pore Structure of Functionalized Calcium Carbonate Tablets by Terahertz Time-Domain Spectroscopy and X-Ray Computed Microtomography.

Novel excipients are entering the market to enhance the bioavailability of drug particles by having a high porosity and, thus, providing a rapid liquid uptake and disintegration to accelerate subsequent drug dissolution. One example of such a novel excipient is functionalized calcium carbonate, which enables the manufacture of compacts with a bimodal pore size distribution consisting of larger interparticle and fine intraparticle pores. Five sets of functionalized calcium carbonate tablets with a target porosity of 45%-65% were prepared in 5% steps and characterized using terahertz time-domain spectroscopy and X-ray computed microtomography. Terahertz time-domain spectroscopy was used to derive the porosity using effective medium approximations, that is, the traditional and an anisotropic Bruggeman model. The anisotropic Bruggeman model yields the better correlation with the nominal porosity (R2 = 0.995) and it provided additional information about the shape and orientation of the pores within the powder compact. The spheroidal (ellipsoids of revolution) shaped pores have a preferred orientation perpendicular to the compaction direction causing an anisotropic behavior of the dielectric porous medium. The results from X-ray computed microtomography confirmed the nonspherical shape and the orientation of the pores, and it further revealed that the anisotropic behavior is mainly caused by the interparticle pores. The information from both techniques provides a detailed insight into the pore structure of pharmaceutical tablets. This is of great interest to study the impact of tablet microstructure on the disintegration and dissolution performance.

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.

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.

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.

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

In this paper, it is suggested that Young's 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 Young's modulus of the tablet. Here, we show that there are optical counterparts of classical mechanical laws that couple the Young's modulus and porosity of the tablet.

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.

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 tablet's 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.