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Spurious loss features were observed in mixed-powder compressed pellets measured in transmission using terahertz time-domain spectroscopy. Loss features were identified in two types of pellets: PTFE-glass microspheres and PTFE-lactose. The features were found to be dependent on particle size and concentration. An explanation is proposed, based on varying optical thickness of the sample material.

Characterising powder flowability can be challenging when sample quantity is insufficient for a conventional shear cell test, especially in the pharmaceutical industry, where the cost of the active pharmaceutical ingredient (API) used is expensive at an early stage in the drug product development. A previous study demonstrated that powder flowability could be predicted based on powder physical properties and cohesiveness using a small quantity of powder samples (50 mg), but it remained an open question regarding the accuracy of the prediction compared to that measured using industry-standard shear cell testers and its potential to substitute the existing testers. In this study, 16 pharmaceutical powders were selected for a detailed comparative study of the predictive model. The flowability of the powders was predicted using a Bond number and given consolidation stresses, σ

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.

Investigating the liquid transport kinetics of solid catalysts is of great importance for gaining a better understanding of the manufacturing and performance of such catalysts during reaction upon contact with the liquid. Terahertz pulsed imaging (TPI) coupled with a newly designed flow cell was used to quantify the rate of water ingress into α-alumina pellets with a range of different porosities. A wide range of compaction forces (cold compaction, 7–58 kN) and sintering conditions (no firing and sintering at 1200 and 1300 °C) was investigated to explore the optimal pellet microstructure, i.e. mechanically strong but sufficiently porous for fast liquid transport kinetics. The results confirm that both the microstructure characteristics, particularly porosity, as well as the surface properties, i.e. wettability, influence the liquid transport kinetics. Fitting the TPI penetration rates with a power law shows that the type of observed mass transport characteristics is consistent with Darcy flow. The Lucas–Washburn equation was used to calculate the hydraulic radius based on the transport data. In summary, the results demonstrate that TPI has great potential to study the liquid transport kinetics of porous ceramic catalysts and catalyst supports and that can comfortably quantify transport processes at rates of 250 μm s−1 and beyond in such substrates for better quality control and optimised design and performance of such materials.

Porosity, one of the important quality attributes of pharmaceutical tablets, directly affects the mechanical properties, the mass transport and hence tablet disintegration, dissolution and ultimately the bioavailability of an orally administered drug. The ability to accurately and quickly monitor the porosity of tablets during manufacture or during the manufacturing process will enable a greater assurance of product quality. This tutorial systematically outlines the steps involved in the terahertz-based measurement method that can be used to quantify the porosity of a tablet within seconds in a non-destructive and non-invasive manner. The terahertz-based porosity measurement can be performed using one of the three main methods, which are (i) the zero-porosity approximation (ZPA); (ii) the traditional Bruggeman effective medium approximation (TB-EMA); and (iii) the anisotropic Bruggeman effective medium approximation (AB-EMA). By using a set of batches of flat-faced and biconvex tablets as a case study, the three main methods are compared and contrasted. Overall, frequency-domain signal processing coupled with the AB-EMA method was found to be most suitable approach in terms of accuracy and robustness when predicting the porosity of tablets over a range of complexities and geometries. This tutorial aims to concisely outline all the necessary steps, precautions and unique advantages associated with the terahertz-based porosity measurement method.

With advancements in the pharmaceutical industry pushing more towards tailored medicines, novel approaches to tablet manufacture are in high demand. One of the main drivers towards micro-scale batch production is the ability to fine-tune drug release. This study demonstrates the use of rapid tooling injection moulding (RTIM) for tablet manufacture. Tablets were manufactured with varying structural features to alter the surface area whilst maintaining the same volume, resulting in differing specific surface area (SSA). The precision of this technique is evaluated based on eleven polymer formulations, with the tablets displaying < 2% variability in mass. Further tablets were produced containing paracetamol in three different polymer-based formulations to investigate the impact of SSA on the drug release. Significant differences were observed between the formulations based on the polymers polyvinyl alcohol (PVA) and Klucel ELF. The polymer base of the formulation was found to be critical to the sensitivity of the drug release profile to SSA modification. The drug release profile within each formulation was modified by the addition of structural features to increase the SSA.

During drug product development, stability studies are used to ensure that the safety and efficacy of a product are not affected during storage. Any change in the dissolution performance of a product must be investigated, as this may indicate a change in the bioavailability. In this study, three different griseofulvin formulations were prepared containing microcrystalline cellulose (MCC) with either mannitol, lactose monohydrate, or dibasic calcium phosphate anhydrous (DCPA). The tensile strength, porosity, contact angle, disintegration time, and dissolution rate were measured after storage under five different accelerated temperature and humidity conditions for 1, 2, and 4 weeks. The dissolution rate was found to decrease after storage for all three batches, with the change in dissolution rate strongly correlating with the storage humidity. The changes in physical properties of each formulation were found to relate to either the premature swelling (MCC/DCPA, MCC/lactose) or dissolution (MCC/mannitol) of particles during storage. These results are also discussed with consideration of the performance- and stability-controlling mechanisms of placebo tablets of the same formulations (Maclean et al., 2021; Maclean et al., 2022).

The use of additive manufacturing techniques in conjunction with injection moulding is becoming increasingly popular, with financial and time benefits to coupling the techniques. This study demonstrates a systematic development process of 3D printed rapid tooled moulds using stereolithography. A high flexural modulus and elongation were found to increase the likelihood of success of a mould material in the injection moulding process. Success is defined as the mould surviving the process and being capable of producing the desired object successfully. Stereolithography was found to produce high quality moulds when a diagonal print orientation and a scaling factor of 109.3% is employed. The presented technique and systematic workflow is highly suitable for the production of moulds with detailed micro-features. This is of particular interest for rapid tooling for micro-injection moulding for the manufacture of pharmaceuticals and medical devices, where the microstructure directly impacts the performance of the products.

Oral solid dosage forms, the most widely used pharmaceutical products, are typically manufactured through a series of processes that transform a blend of drug and excipient particles into a densified product with consistent quality attributes. While the densification of powder during processing is crucial and directly impacts the quality of the drug product, there is still scarcity of non-destructive and fast sensor systems that provide access to the powder density at critical process stages. This review discusses methods for monitoring density variations of particulate matter by describing their principles and presenting application examples. The techniques discussed range from common in-line methods such as near-infrared spectroscopy, acoustic emission and ultrasonic methods as well as techniques with potential to be more frequently applied in a pharmaceutical manufacturing line, i.e., terahertz spectroscopy and imaging, microwave technique, electrical tomography and X-ray based methods. This review also compares these techniques in terms of measurement and data processing time, resolution and its ability to be integrated in a process.

We investigate fabrication of compacts using polytetrafluoroethylene (PTFE) and polyethylene (PE), and the effect of compaction conditions on their terahertz transmission properties. The conditions used to fabricate compressed powder samples for terahertz time-domain spectroscopy (THz-TDS) can impact the accuracy of the measurements and hence the interpretation of results. This study investigated the effect of compaction conditions on the accuracy of the THz-TDS analysis. Two polymers that are commonly used as matrix materials in terahertz spectroscopy studies were explored using a compaction simulator and a hydraulic press for sample preparation. THz-TDS was used to determine the refractive index and loss coefficient to compare the powder compacts (pellets) to the values of solid material. Sample porosity, axial relaxation and tensile strength were measured to assess the material’s suitability for terahertz spectroscopy. It was found that PTFE is the preferable material for creating THz-TDS samples due to its low porosity and high tensile strength. PE was found to show significant porosity at all compaction pressures, making it an unsuitable material for the accurate determination of optical parameters from THz-TDS spectroscopy measurements. The larger particle sizes of PE resulted in compacts that exhibited significantly lower tensile strength than those made from PTFE making handling and storage difficult.

Particle swelling is a crucial component in the disintegration of a pharmaceutical tablet. The swelling of particles in a tablet creates stress inside the tablet and thereby pushes apart adjoining particles, eventually causing the tablet to break-up. This work focused on quantifying the swelling of single particles to identify the swelling-limited mechanisms in a particle, i.e. diffusion- or absorption capacity-limited. This was studied for three different disintegrants (sodium starch glycolate/SSG, croscarmellose sodium/CCS, and low-substituted hydroxypropyl cellulose/L-HPC) and five grades of microcrystalline cellulose (MCC) using an optical microscope coupled with a bespoke flow cell and utilising a single particle swelling model. Fundamental swelling characteristics, such as diffusion coefficient, maximum liquid absorption ratio and swelling capacity (maximum swelling of a particle) were determined for each material. The results clearly highlighted the different swelling behaviour for the various materials, where CCS has the highest diffusion coefficient with 739.70 μm2/s and SSG has the highest maximum absorption ratio of 10.04 g/g. For the disintegrants, the swelling performance of SSG is diffusion-limited, whereas it is absorption capacity-limited for CCS. L-HPC is both diffusion- and absorption capacity-limited. This work also reveals an anisotropic, particle facet dependant, swelling behaviour, which is particularly strong for the liquid uptake ability of two MCC grades (PH101 and PH102) and for the absorption capacity of CCS. Having a better understanding of swelling characteristics of single particles will contribute to improving the rational design of a formulation for oral solid dosage forms.

In the last decade significant advances have been made in process analytical technologies and digital manufacturing of pharmaceutical oral solid dosage forms leading to enhanced product knowledge and process understanding. These developments provide an excellent platform for realising real-time release testing (RTRT) to eliminate all, or certain, off-line end product tests assuring that the drug product is of intended quality. This review article presents the state of the art, an RTRT development workflow as well as challenges and opportunities of RTRT in batch and continuous manufacturing of pharmaceutical tablets. Critical quality attributes, regulatory aspects and the scientific basis of enabling technologies and models for RTRT are discussed and a systematic development workflow for the robust design of an RTRT environment is presented. This includes the discussion of key considerations for the identification of the critical quality attributes and points of testing as well as the development of the sampling strategy, a hard and/or soft sensor approach and operational procedures. The final sections present two RTRT use cases in an industrial setting as well as critically discuss challenges and provide a future perspective of RTRT.

Optical Coherence Tomography (OCT) is a promising technology for monitoring of pharmaceutical coating processes. However, the pharmaceutical development and manufacturing require a periodic validation of the sensor's accuracy. For this purpose, we propose polyethylene terephthalate (PET) films as a model system, to periodically validate the measurements during manufacturing. This study proposes a new approach addressing the method validation requirement in the pharmaceutical industry and presents results for complementary methods. The methods investigated include direct measurement of the layer thickness using a micrometer gauge as reference, X-ray micro computed tomography, transmission and reflectance terahertz pulsed imaging, as well as 1D- and 3D-OCT. To quantify the significance of OCT for pharmaceutical coatings, we compared the OCT results for commercial Thrombo ASS and Pantoloc tablets with direct measurements of coating thickness via light microscopy of microtome cuts. The results of both methods correlate very well, indicating high intra- and inter-tablet variations in the coating thickness for the commercial tablets. The light microscopy average measured coating thickness of Thrombo ASS (Pantoloc) was 71.0 µm (83.7 µm), with an inter-coating variability of 8.7 µm (6.5 µm) and an intra-coating variability of 2.3 µm to 9.4 µm (2.1 µm to 6.7 µm).

Current study evaluated the processability and characteristics of prills made of an active pharmaceutical ingredient/fatty acid (API/FA) suspension instead of previously studied API/FA solutions to enlarge the application field of prilling. Metformin hydrochloride (MET) and paracetamol (PAR) were used as model APIs while both the effect of drug load (10–40%) and FA chain length (C14–C22) were evaluated. API/FA suspensions were processable on lab-scale prilling equipment without thermal degradation, nozzle obstruction or sedimentation in function of processing time. The collected prills were spherical (AR ≥ 0.898) with a smooth surface (sphericity ≥ 0.914) and a particle size of ±2.3 mm and 2.4 mm for MET and PAR prills, respectively, independent of drug load and/or FA chain length. In vitro drug release evaluation revealed a faster drug release at higher drug load, higher API water solubility and shorter FA chain length. Solid state characterisation via XRD and Raman spectroscopy showed that API and FA crystallinity was maintained after thermal processing via prilling and during storage. Evaluation of the similarity factor indicated a stable drug release (f2 > 50) from MET and PAR prills after 6 months storage at 25 °C or 40 °C.

A key principle of developing a new medicine is that quality should be built in, with a thorough understanding of the product and the manufacturing process supported by appropriate process controls. Quality by design principles that have been established for the development of drug products/substances can equally be applied to the development of analytical procedures. This paper presents the development and validation of a quantitative method to predict the concentration of piroxicam in Kollidon&reg, VA 64 during hot melt extrusion using analytical quality by design principles. An analytical target profile was established for the piroxicam content and a novel in-line analytical procedure was developed using predictive models based on UV-Vis absorbance spectra collected during hot melt extrusion. Risks that impact the ability of the analytical procedure to measure piroxicam consistently were assessed using failure mode and effect analysis. The critical analytical attributes measured were colour (L* lightness, b* yellow to blue colour parameters&mdash, in-process critical quality attributes) that are linked to the ability to measure the API content and transmittance. The method validation was based on the accuracy profile strategy and ICH Q2(R1) validation criteria. The accuracy profile obtained with two validation sets showed that the 95% &beta, expectation tolerance limits for all piroxicam concentration levels analysed were within the combined trueness and precision acceptance limits set at &plusmn, 5%. The method robustness was tested by evaluating the effects of screw speed (150&ndash, 250 rpm) and feed rate (5&ndash, 9 g/min) on piroxicam content around 15% w/w. In-line UV-Vis spectroscopy was shown to be a robust and practical PAT tool for monitoring the piroxicam content, a critical quality attribute in a pharmaceutical HME process.

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.

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.

Terahertz pulsed imaging (TPI) was applied to analyse the inner structure of multiple unit pellet system (MUPS) tablets. MUPS tablets containing different amounts of theophylline pellets coated with Eudragit® NE 30 D and with microcrystalline cellulose (MCC) as cushioning agent were analysed. The tablets were imaged by TPI and the results were compared to X-ray microtomography. The terahertz pulse beam propagates through the tablets and is back-reflected at the interface between the MCC matrix and the coated pellets within the tablet causing a peak in the terahertz waveform. Cross-section images of the tablets were extracted at different depths and parallel to the tablet faces from 3D terahertz data to visualise the surface-near structure of the MUPS tablets. The images of the surface-near structure of the MUPS tablets were compared to X-ray microtomography images at the same depths. The surface-near structure could be clearly resolved by TPI at depths between 24 and 152 μm below the tablet surface. An increasing amount of pellets within the MUPS tablets appears to slightly decrease the detectability of the pellets within the tablets by TPI. TPI was shown to be a non-destructive method for the detection of pellets within the tablets and could resolve structures thicker than 30 μm. In conclusion, a proof-of-concept was provided for TPI as a method of quality control for MUPS tablets.

The additive manufacturing industry achieved a corporate annual growth rate of 25.9% according to the Forbes analysis of the Wohlers Report 2016. This high growth rate is placed in perspective when looking at the past 27 years where the corporate annual growth rate has averaged 26.2% each year indicating that additive manufacturing is clearly a growing industry. Such growth needs to be supported by suitable quality testing methods: with the economic success achieved in this market and the associated transition from mass production toward mass customization comes the need for new and innovative methods to assess the quality of the 3D printed geometries. This will be especially important for pharmaceutical products where a sub-standard quality of the final product can have detrimental consequences for patient health and safety. [Formula: see text]

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., final draft, peerReviewed

The pharmaceutical industry requires a rapid nondestructive technique for monitoring porosity of tablets. Here effective porosity of compressed lactose pellets was investigated using THz time-domain spectroscopy (THz TDS).

This study presents a modelling framework to predict the flowability of various commonly used pharmaceutical powders and their blends. The flowability models were trained and validated on 86 samples including single components and binary mixtures. Two modelling paradigms based on artificial intelligence (AI) namely, a radial basis function (RBF) and an integrated network were employed to model the flowability represented by the flow function coefficient (FFC) and the bulk density (RHOB). Both approaches were utilized to map the input parameters (i.e. particle size, shape descriptors and material type) to the flow properties. The input parameters of the blends were determined from the particle size, shape and material type properties of the single components. The results clearly indicated that the integrated network outperformed the single RBF network in terms of the predictive performance and the generalization capabilities. For the integrated network, the coefficient of determination of the testing data set (not used for training the model) for FFC was R2=0.93, reflecting an acceptable predictive power of this model. Since the flowability of the blends can be predicted from single component size and shape descriptors, the integrated network can assist formulators in selecting excipients and their blend concentrations to improve flowability with minimal experimental effort and material resulting in the (i) minimization of the time required, (ii) exploration and examination of the design space, and (iii) minimization of material waste.

In this study, terahertz time domain spectroscopy (THz-TDS) is used to analyze how the geometry of a compact affects its pore structure (pore shape and orientation). By using flat-faced and biconvex compacts, it was evident from our analysis that pores tend to assume specific shapes and orientations based on the compact's geometry and this was found to significantly affect the extracted optical properties of samples prepared by mixing a material with polyethylene (PE) as diluent and subsequent compaction. However, such sensitivity to the pore properties opens a number of industrial applications such as for quality testing of pharmaceutical tablets. A comparison made between the PE based compacts and a set of pharmaceutical tablets prepared from the same formulation has revealed that flatfaced and biconvex compacts possess different pore geometries and hence different optical properties.

Mohammed Al-Sharabi's affiliation was incorrect at the time of publishing. The updated affiliation appears below.

The use of inkjet printing for pharmaceutical manufacturing is gaining interest for production of personalized dosage forms tailored to specific patients. As part of the manufacturing, it is imperative to ensure that the correct dose is printed. The aim of this study was to use inkjet printing for manufacturing of personalized dosage forms combined with the use of near-infrared (NIR) and Raman spectroscopy as complementary analytical techniques for active pharmaceutical ingredient (API) quantification of the inkjet-printed dosage forms. Three APIs, propranolol (0.5–4.1 mg), montelukast (2.1–12.1 mg), and haloperidol (0.6–4.1 mg) were inkjet printed in 1 cm2 areas on a porous substrate. The printed doses were non-destructively analyzed by transmission NIR and Raman spectroscopy (both transmission and backscatter). X-ray computed microtomography (μ-CT) analysis was undertaken for porosity measurements of the substrate. The API content was confirmed using high-performance liquid chromatography (HPLC), and the content in the dosage forms was modeled from the NIR and Raman spectra using partial least squares regression (PLS). HPLC analysis revealed a linear correlation of the number of layers printed to the API content. The resulting PLS models for both NIR and Raman had R2 values between 0.95 and 0.99. The best predictive model was obtained using NIR, followed by Raman spectroscopy. μ-CT revealed the substrate to be highly porous and optimal for inkjet printing. In conclusion, NIR and Raman spectroscopic techniques could be used complementary as fast API quantification tools for inkjet-printed medicines.

The aim of this study was to evaluate the choice of polymer and polymer level on the performance of the microstructure and wettability of hot-melt extruded solid dispersion of Glyburide (Gly) as a model drug. The produced solid dispersion were characterised using scanning electron microscopy (SEM), image analysis using a focus variation instrument (FVI), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), X-ray microtomography (XµT), dynamic contact angle measurement and dissolution analysis using biorelevant dissolution media (FASSIF). SEM and focus variation analysis showed that the microstructure and surface morphology was significantly different between samples produced. This was confirmed by further analysis using XµT which showed that an increase in polymer content brought about a decrease in the porosity of the hot-melt extruded dispersions. DSC suggested complete amorphorisation of Gly whereas XRPD suggested incomplete amorphorisation. The static and dynamic contact angle measurement correlated with the dissolution studies using FASSIF media indicating that the initial liquid imbibition process as captured by the dynamic contact angle directly affects the dissolution performance.

Terahertz pulsed imaging (TPI) coupled with a customised flow cell has previously been used successfully to study liquid transport in porous media, such as powder compacts. In some samples, the tracking of the liquid front remains challenging when the refractive indices of liquid and sample are similar and hence little contrast is observed. In this work, we found that even when the relative difference between the refractive indices of liquid and sample is high, it can still be challenging to track the reflection peak of water in some samples while it works fine in others. It is hypothesised that this is due to the formation of a water gradient in these samples due to their specific microstructure and we explore methods to overcome this limitation.

The disintegration process of pharmaceutical tablets is a crucial step in the oral delivery of a drug. Tablet disintegration does not only refer to the break up of the interparticle bonds, but also relates to the liquid absorption and swelling behaviour of the tablet. This study demonstrates the use of the sessile drop method coupled with image processing and models to analyse the surface liquid absorption and swelling kinetics of four filler combinations (microcrystalline cellulose (MCC)/mannitol, MCC/lactose, MCC/dibasic calcium phosphate anhydrous (DCPA) and DCPA/lactose) with croscarmellose sodium as a disintegrant. Changes in the disintegration performance of these formulations were analysed by quantifying the effect of compression pressure and storage condition on characteristic liquid absorption and swelling parameters. The results indicate that the disintegration performance of the MCC/mannitol and MCC/lactose formulations are driven by the liquid absorption behaviour. For the MCC/DCPA formulation, both liquid absorption and swelling characteristics affect the disintegration time, whereas DCPA/lactose tablets is primarily controlled by swelling characteristics of the various excipients. The approach discussed in this study enables a rapid (< 1 min) assessment of characteristic properties that are related to tablet disintegration to inform the design of the formulation, process settings and storage conditions.

The objective of this study was to analyze differences in the subtle microstructure of three different grades of HMPC hard capsule shells using mechanical, spectroscopic, microscopic and tomographic approaches. Dynamic mechanical analysis (DMA), thermogravimetric analysis (TGA), vibrational spectroscopic, X-Ray scattering techniques as well as environmental scanning electron microscopy (ESEM) and optical coherence tomography (OCT) were used. Two HPMC capsules manufactured via chemical gelling, one capsule shell manufactured via thermal gelling and one thermally gelled transparent capsule were included. Characteristic micro-structural alterations (associated manufacturing processes) such as mechanical and physical properties relevant to capsule performance and processability were thoroughly elucidated with the integration of data obtained from multi-methodological investigations. The physico-chemical and physico-mechanical data obtained from a gamut of techniques implied that thermally gelled HPMC hard capsule shells could offer an advantage in terms of machinability during capsule filling, owing to their superior micro- and macroscopic structure as well as specifically the mechanical stability under dry or humid conditions.

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.

We have developed an approach to investigate density variations in a moving powder bed by means of terahertz pulsed imaging. Terahertz measurements were acquired continuously during the rotation of a container filled with different grades of lactose and microcrystalline cellulose powder. Relative density distributions were resolved for different compaction stages of the powder, which indicated high variations of the powder density.

In recent years, terahertz in-line sensing has been used to monitor the film coating thickness of individual pharmaceutical tablets during the coating process. In the previous work, the in-line measurements were verified against off-line measurements of samples from the same population. Here, we report on our recent progress to further verify the validity of the terahertz in-line measurement modality using discrete element modelling for an artificial lab-scale tablet mixing process inside a tablet pan coater. By coupling discrete modelling with a ray-tracing method, it is then possible to estimate the cumulative measurements taken, which in turn can guide towards the fine-tuning of the selection criteria as part of measurement analysis. © The Institution of Engineering and Technology 2018.

In contact-less printing, such as piezo-electric drop on demand printing used in the study, the drop formation process is independent of the substrate. This means that having developed a printable formulation, printed pharmaceutical dosage forms can be obtained on any pharmaceutical grade substrate, such as polymer-based films. In this work we evaluated eight different oral films based on their suitability as printing substrates for sodium picosulfate. The different polymer films were compared regarding printed spot morphology, chemical stability and dissolution profile. The morphology of printed sodium picosulfate was investigated with scanning electron microscopy and optical coherence tomography. The spreading of the deposited drops was found to be governed by the contact angle of the ink with the substrate. The form of the sodium picosulfate drops changed on microcrystalline cellulose films at ambient conditions over 8 weeks and stayed unchanged on other tested substrates. Sodium picosulfate remained amorphous on all substrates according to small and wide angle X-ray scattering, differential scanning calorimetry and polarized light microscopy measurements. The absence of chemical interactions between the drug and substrates, as indicated by infrared spectroscopy, makes all tested substrates suitable for printing sodium picosulfate onto them.

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.

A Therapeutic Nipple Shield (TNS) was previously developed to respond to the global need for new infant therapeutic delivery technologies. However, the release efficiency for the same Active Pharmaceutical Ingredient (API) from different therapeutic matrices within the TNS formulation has not yet been investigated. To address this, in-vitro release of elemental zinc into human milk from two types of Texel non-woven fibre mats of varying thickness and different gram per square meter values, placed inside the TNS was explored and compared to the release from zinc-containing rapidly disintegrating tablets. In-vitro delivery was performed by means of a breastfeeding simulation apparatus, with human milk flow rates and suction pressure adjusted to physiologically relevant values, and release was quantified using Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES). It was found that a total recovery of 62–64 % elemental zinc was obtained after the human milk had passed through the fibre insert, amounting to a 20–48% increase compared to previous zinc delivery studies using rapidly disintegrating tablets within the TNS. This indicates that non-woven Texel fibre mats were identified as the superior dosage form for oral zinc delivery into human milk using a TNS.

The application of terahertz pulsed imaging (TPI) in an in-line configuration to monitor the coating thickness distribution of pharmaceutical tablets has the potential to improve the performance and quality of the spray coating process. In this study, an in-line TPI method is used to measure coating thickness distributions on pre-coated tablets during mixing in a rotating pan, and compared with results obtained numerically using the discrete element method (DEM) combined with a ray-tracing technique. The hit rates (i.e. the number of successful coating thickness measurements per minute) obtained from both terahertz in-line experiments and the DEM/ray-tracing simulations are in good agreement, and both increase with the number of baffles in the mixing pan. We demonstrate that the coating thickness variability as determined from the ray-traced data and the terahertz in-line measurements represents mainly the intra-tablet variability due to relatively uniform mean coating thickness across tablets. The mean coating thickness of the ray-traced data from the numerical simulations agrees well with the mean coating thickness as determined by the off-line TPI measurements. The mean coating thickness of in-line TPI measurements is slightly higher than that of the off-line measurements. This discrepancy can be corrected based on the cap-to-band surface area ratio of the tablet and the cap-to-band sampling ratio obtained from ray-tracing simulations: the corrected mean coating thickness of the in-line TPI measurements shows a better agreement with that of the off-line measurements.

This work demonstrates a new in-line measurement technique for monitoring the coating growth of randomly moving tablets in a pan coating process. In-line quality control is performed by an optical coherence tomography (OCT) sensor allowing nondestructive and contact-free acquisition of cross-section images of film coatings in real time. The coating thickness can be determined directly from these OCT images and no chemometric calibration models are required for quantification. Coating thickness measurements are extracted from the images by a fully automated algorithm. Results of the in-line measurements are validated using off-line OCT images, thickness calculations from tablet dimension measurements, and weight gain measurements. Validation measurements are performed on sample tablets periodically removed from the process during production. Reproducibility of the results is demonstrated by three batches produced under the same process conditions. OCT enables a multiple direct measurement of the coating thickness on individual tablets rather than providing the average coating thickness of a large number of tablets. This gives substantially more information about the coating quality, that is, intra- and intertablet coating variability, than standard quality control methods.

The paper presents a new in-line measurement technique for determining the coating thickness and uniformity of pharmaceutical pellets during film-coating in a fluid-bed apparatus. Non-destructive and contact-free process monitoring was performed via an optical coherence tomography (OCT) sensor providing cross-section images. Through the OCT measurements, the coating thickness could be determined directly, without a chemometric calibration model required for the quantification. The direct integration of the OCT sensor head into the fluid-bed systems allowed continuous monitoring of the coating growth. Moreover, the in-line investigation of the intra- and inter-pellet coating uniformity was possible due to OCT׳s high acquisition rate. Results of the in-line OCT measurements were validated using both off-line OCT images and particle size analysis by performing an image analysis of samples that were periodically removed from the process during the production. Three batches were produced under the same process conditions demonstrating the reproducibility of the results. Rather than providing the temporal and spatial average of a large number of pellets, the OCT sensor characterized local pellet properties of up to 130 individual pellets per minute. Therefore, the OCT technology allows the operator to directly monitor the coating thickness and uniformity in sub-micron resolution, which makes it a promising in-line PAT method.

This study demonstrates the use of optical coherence tomography (OCT) to simultaneously characterize the roughness of the tablet core and coating of pharmaceutical tablets. OCT is a high resolution non-destructive and contactless imaging methodology to characterize structural properties of solid dosage forms. Besides measuring the coating thickness, it also facilitates the analysis of the tablet core and coating roughness. An automated data evaluation algorithm extracts information about coating thickness, as well as tablet core and coating roughness. Samples removed periodically from a pan coating process were investigated, on the basis of thickness and profile maps of the tablet core and coating computed from about 480,000 depth measurements (i.e., 3D data) per sample. This data enables the calculation of the root mean square deviation, the skewness and the kurtosis of the assessed profiles. Analyzing these roughness parameters revealed that, for the given coating formulation, small valleys in the tablet core are filled with coating, whereas coarse features of the tablet core are still visible on the final film-coated tablet. Moreover, the impact of the tablet core roughness on the coating thickness is analyzed by correlating the tablet core profile and the coating thickness map. The presented measurement method and processing could be in the future transferred to in-line OCT measurements, to investigate core and coating roughness during the production of film-coated tablets.

Terahertz in-line sensing was successfully demonstrated for measuring the film coating thickness of individual pharmaceutical tablets during the film coating process. This paper reports our recent progress to further validate the terahertz in-line measurement technique with discrete element modelling for a lab-scale tablet mixing process inside a tablet pan coater.