This study investigated the influence of croscarmellose sodium (CCS) and magnesium stearate (MgSt) on tablet hardness, hydration time, and disintegration time to understand their roles and interactions at different stages of the disintegration process using terahertz pulsed imaging technique. Six powder blends were formulated by combining three CCS concentrations (3%, 4%, and 5%w/w) and two MgSt concentrations (0.5% and 1%w/w) and were direct-compressed. A high-power terahertz time-domain spectrometer with an open-immersion cell was used to track the advancing liquid front in the tablet matrix during disintegration. The obtained liquid transport profiles were analysed alongside tensile strength and disintegration time to explore how CCS and MgSt affect the tablet matrix. The results highlighted (1) the critical role of the liquid penetration process in understanding the disintegration mechanisms, and (2) the contradictory effects of CCS and MgSt, as both excipients exhibited factors that accelerated and retarded disintegration at different stages. These findings lay the groundwork for optimising immediate-release tablet formulations and developing predictive disintegration models.

The disintegration behaviour of pharmaceutical tablets is a critical quality attribute influencing drug release, yet predicting it from formulation and processing parameters remains challenging due to complex underlying mechanisms. This work presents a novel, mechanistically grounded framework aimed at predicting immediate-release tablet disintegration. The framework uniquely integrates insights from advanced experimental techniques with two complementary computational models. Terahertz Pulsed Imaging (TPI) combined with an open immersion cell provides non-invasive, real-time monitoring of internal liquid transport kinetics, crucially accounting for simultaneous matrix erosion. This empirical data anchors the Representative Capillary Evolution Model (RCEM), a top-down model that interprets macroscopic disintegration behaviour through the evolution of a conceptual Representative Capillary (RC) structure, incorporating an Agitation Coefficient (Acoef) to bridge quiescent and agitated test conditions. Complementing this is the Dynamic Void Fraction Evolution Model (DVFEM), a bottom-up model that predicts the time-dependent evolution of the tablet's microstructure and the associated void fraction based on fundamental constituent properties (e.g., particle swelling, dissolution) and formulation details, using a unit cell concept. The RC serves as the unifying element linking DVFEM predictions to RCEM interpretations. An iterative strategy for integrating and calibrating these models is proposed, potentially enhanced by machine learning techniques. The framework offers a pathway to link Critical Material Attributes (CMAs) and Critical Processing Parameters (CPPs) to disintegration performance, aligning with Quality by Design (QbD) principles and holding potential to accelerate pharmaceutical formulation development.

We present a fast and reliable method for the simultaneous determination of pharmaceutical tablet thickness and porosity using terahertz time-domain spectroscopy (THz-TDS) in a transflection geometry. Leveraging high-power terahertz sources and detectors, the system achieves sufficient signal strength to extract both properties from a single THz measurement. This innovation removes the dependency on additional thickness measurements, previously required in traditional transmission setups using a laser gauge. Conventional methods are prone to a large error bar due to potential alignment errors and beam profile mismatches. By contrast, the proposed transflection approach simplifies the measurement process, offering a robust and calibration-free solution ideal for real-time process monitoring of tablet quality.

Conventional porosity measurements of pharmaceutical tablets using terahertz time-domain spectroscopy (THz-TDS) in transmission geometry require supplementary thickness measurements - typically using an optical laser gauge - to enable accurate porosity determination. However, discrepancies in beam profiles between the laser and THz systems, as well as the need for precise mechanical positioning of the tablet for the two measurements, introduce potential systematic errors and complicate the measurement setup. This study presents a robust and rapid alternative: a transflection-based THz-TDS method that simultaneously determines both tablet thickness and porosity from a single terahertz waveform. By utilising a state-of-the-art, high-power THz-TDS system, we obtained sufficiently strong reflection features to extract both parameters without additional instrumentation. This approach overcomes the limitations of conventional transmission setups, offering a non-destructive, calibration-free solution for in-line porosity monitoring in pharmaceutical tablet manufacturing.

Roller compaction is a crucial unit operation in pharmaceutical manufacturing, with its ribbon porosity widely recognised as a critical quality attribute. Terahertz spectroscopy has emerged as a fast and non-destructive technique to measure porosity in pharmaceutical products. From a sensing perspective, the irregular shape and uneven surface of fragmented ribbon pieces can affect the accuracy and precision of the measurements, particularly for techniques that probe only a small sampling volume. It is known that the porosity is not uniform within the ribbon structure, with variations expected across the width of the ribbon and in the microstructure corresponding to its surface texture. However, typical pharmaceutical analysis methods, such as envelope density, only report an average bulk porosity, are slow to operate and limited in accuracy. To address this challenge, we developed and trained convolutional neural network models using THz spectra as input to classify four types of topography typically encountered in ribbons: ridge, valley, flat plane and edge points. The classifiers achieved 91% validation accuracy in both identifying outliers and differentiating between ribbons of smooth and knurled surfaces. For the more challenging task of distinguishing between the ridges and valleys of knurled surfaces, an 81% testing accuracy was achieved. Once each measurement is paired with its topography, resolving the density distribution within the sample is possible. This data can be combined to arrive at an average bulk porosity value compatible with conventional pharmaceutical analysis.

The compendial USP〈701〉 disintegration test method offers a crucial pass/fail assessment for immediate release tablet disintegration. However, its single end-point approach provides limited insight into underlying mechanisms. This study introduces a novel calorimetric approach, aimed at providing comprehensive process profiles beyond binary outcomes. We developed a novel disintegration reaction calorimeter to monitor the heat release throughout the disintegration process and successfully obtained enthalpy change profiles of placebo tablets with various porosities. The formulation comprised microcrystalline cellulose (MCC), anhydrous lactose, croscarmellose sodium (CCS), and magnesium stearate (MgSt). An abrupt temperature rise was observed after introducing the disintegration medium to tablets, and the relationship between the heat rise time and the tablet's porosity was investigated. The calorimeter's sensitivity was sufficient to discern distinct heat changes among individual tablets, and the analysis revealed a direct correlation between the two. Higher porosity corresponded to shorter heat rise time, indicating faster disintegration rates. Additionally, the analysis identified a concurrent endothermic process alongside the anticipated exothermic phenomenon, potentially associated with the dissolution of anhydrous lactose. Since lactose is the only soluble excipient within the blend composition, the endothermic process can be attributed to the absorption of heat as lactose molecules dissolve in water. The findings from this study underscore the potential of utilising calorimetric methods to quantify the wettability of complex compounds and, ultimately, optimise tablet formulations.

The disintegration process of pharmaceutical solid dosage forms commences on contact with the dissolution medium and continues with subsequent spontaneous imbibition of the medium in the tablet matrix. Identifying the location of the liquid front in situ during imbibition, therefore, plays a significant role in understanding and modelling the disintegration process. Terahertz pulsed imaging (TPI) technology can be used to investigate this process by its ability to penetrate and identify the liquid front in pharmaceutical tablets. However, previous studies were limited to samples suitable for a flow cell environment, i.e. flat cylindrical disk shapes; thus, most commercial tablets could only be measured with prior destructive sample preparation. This study presents a new experimental setup named open immersion to measure a wide range of pharmaceutical tablets in their intact form. Besides, a series of data processing techniques to extract subtle features of the advancing liquid front are designed and utilised, effectively increasing the maximum thickness of tablets that can be analysed. We used the new method and successfully measured the liquid ingress profiles for a set of oval convex tablets prepared from a complex eroding immediate-release formulation.

In industrial practice, the development of pharmaceutical dry granulation processes typically involves time- and resource-intensive multivariate experiments. These experiments are used to identify the set of operating conditions, their allowed ranges and chosen setpoints where the desired product quality and manufacturability criteria are met. The results are then used to define the control strategy for the manufacturing process to be included in the regulatory file.In this study, we show how systems modelling can be used to streamline the development of an industrial dry granulation process for an immediate release tablet. We integrate existing and enhanced unit operation and product performance models with a Bayesian hierarchical model to predict the probability to meet the USP < 711 > dissolution test specifications, which represent the current standard in the pharmaceutical industry to demonstrate compliance with regulatory expectations. We then use global sensitivity analysis to: (i) generate multivariate process understanding on the relative impact of material properties and process parameters on product quality attributes; (ii) predict the set of operating conditions (i.e., the process operating space) that allows us to meet the USP < 711 > test specifications with a given probability, as well as pre-defined manufacturability criteria. We finally use the results obtained at point (ii) to design targeted experiments to verify the predicted setpoints and operating space. We show how the proposed framework has the potential to remove >60% of the experimental burden (and hence the consumption of active pharmaceutical ingredient) required for process development compared to standard experimental protocols. (c) 2021 Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.

Huntington's disease is caused by the expansion of a CAG repeat within exon 1 of the HTT gene, which is unstable, leading to further expansion, the extent of which is brain region and peripheral tissue specific. The identification of DNA repair genes as genetic modifiers of Huntington's disease, that were known to abrogate somatic instability in Huntington's disease mouse models, demonstrated that somatic CAG expansion is central to disease pathogenesis, and that the CAG repeat threshold for pathogenesis in specific brain cells might not be known. We have previously shown that the HTT gene is incompletely spliced generating a small transcript that encodes the highly pathogenic exon 1 HTT protein. The longer the CAG repeat, the more of this toxic fragment is generated, providing a pathogenic consequence for somatic expansion. Here, we have used the R6/2 mouse model to investigate the molecular and behavioural consequences of expressing exon 1 HTT with 90 CAGs, a mutation that causes juvenile Huntington's disease, compared to R6/2 mice carrying ∼200 CAGs, a repeat expansion of a size rarely found in Huntington's disease patient's blood, but which has been detected in post-mortem brains as a consequence of somatic CAG repeat expansion. We show that nuclear aggregation occurred earlier in R6/2(CAG)90 mice and that this correlated with the onset of transcriptional dysregulation. Whereas in R6/2(CAG)200 mice, cytoplasmic aggregates accumulated rapidly and closely tracked with the progression of behavioural phenotypes and with end-stage disease. We find that aggregate species formed in the R6/2(CAG)90 brains have different properties to those in the R6/2(CAG)200 mice. Within the nucleus, they retain a diffuse punctate appearance throughout the course of the disease, can be partially solubilized by detergents and have a greater seeding potential in young mice. In contrast, aggregates from R6/2(CAG)200 brains polymerize into larger structures that appear as inclusion bodies. These data emphasize that a subcellular analysis, using multiple complementary approaches, must be undertaken in order to draw any conclusions about the relationship between HTT aggregation and the onset and progression of disease phenotypes.

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.

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.

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.

The aim of the present work was to develop a pilot scale process to produce drug-loaded filaments for 3D printing of oral solid dose forms by fused filament fabrication (FFF). Using hot melt extrusion, a viable operating space and understanding of processing limits were established using a hydrophilic polymer (hydroxypropyl methylcellulose (HPMC) - Affinisol (TM) LV15). This was then extended to formulate paracetamol (PCM) loaded Affinisol (TM) 15LV filaments across a wide range of compositions (5-50 wt% drug). From the process development work, challenges in achieving a pilot scale process for filament production for pharmaceutical applications have been highlighted. 3D printing trials across the range of compositions demonstrated limitations concerning the ability to print successfully across all compositions. Results from characterisation techniques including thermal and mechanical testing when applied to the formulated filaments indicated that these techniques are a useful predictive measure for assessing the ability to print a given formulation via filament methods. Oral solid dosage forms of variable surface area to mass ratios printed from suitable filament compositions demonstrated the ability to modify the release rates of drug for fixed formulations across substantial timescales.

A comprehensive commercial control strategy for tablet content and content uniformity focussed on the unit operation of compression is presented and is proposed to enable real time release for these critical quality attributes. The control strategy is based on process understanding, process control through compaction force weight control on the tablet press, periodic checks of mean and individual tablet weight combined with at-line testing of tablet content by near infrared (NIR). The application of the at-line NIR tablet content method is discussed and an acceptance criteria based on a parametric tolerance interval test (PTIT) is proposed. Sample handling limitations and spectral acquisition time for the NIR content method limit the sample size, however the chosen PTIT assures an appropriate level of batch coverage. Data are presented for ten commercial-scale batches that demonstrates the control strategy delivered the quality standard for content and content uniformity.

Background Over the past 10 years, we have consistently found that a wide range of molecular, immunohistochemical and physiological phenotypes are highly comparable between R6/2 transgenic and knock-in (HdhQ150 and zQ175) mouse lines that carry similar CAG repeat expansions. This observation led us to identify the presence of the exon 1 HTT protein in all knock-in models. Given that exon 1 HTT contributes to Huntington’s disease pathogenesis, we set out to establish an R6/2 colony with a CAG repeat expansion of a size that more closely resembles those found in HD patients, and succeeded in generating a colony with 90 CAGs. Aims To assess and compare the molecular, immunohistochemical and physiological phenotypes of the R6/2 (CAG)90 and (CAG)200 mouse lines. Methodologies Behavioural and physiological assessments, Real-time qPCR, Seprion-ligand ELISA, Agarose Gel Electrophoresis for Resolving Aggregates (AGERA), Time-resolved Förster resonance energy transfer (TR-FRET), Western blotting, Cytoplasmic and Nuclear Fractionation, Immunohistochemistry. Results End stage disease occurred at ˜26 weeks of age for R6/2 mice with (CAG)90 as compared to ˜14 weeks in (CAG)200 mice, and the onset of weight loss, grip strength and rotarod performance were correspondingly delayed and progressed more slowly. Interestingly, transcriptional dysregulation occurred earlier in the (CAG)90 mice, at 4 weeks of age. By 8 weeks of age, the level of transcriptional dysregulation was equivalent in both R6/2 lines. TR-FRET and Seprion-ligand ELISA showed that HTT aggregation occurred earlier in the nucleus in (CAG)90 R6/2 mice, than those with a (CAG)200 repeat. By 8 weeks of age, immunohistochemistry with MW8 showed the nuclear aggregation in the (CAG)90 line to be diffuse, whereas that in the (CAG)200 line was more likely to appear as nuclear inclusions. Equivalent levels of transcriptional dysregulation were associated with these apparently very different forms of nuclear HTT aggregation. The rate of disease progression was associated with the accumulation of cytoplasmic inclusions. Conclusions Despite end stage disease occurring later in (CAG)90 R6/2 mice, than those with a (CAG)200 repeat, both the onset of transcriptional dysregulation and appearance of HTT aggregation in the nucleus occurred earlier in R6/2 (CAG)90 mice than in R6/2 (CAG)200 mice. Funding This work was supported by the CHDI Foundation.

The aim of this study was to establish the suitability of terahertz (THz) transmission measurements to accurately measure and predict the critical quality attributes of disintegration time and the amount of active pharmaceutical ingredient (API) dissolved after 15, 20 and 25 min for commercial tablets processed at production scale.

Oral dosage forms are an integral part of modern health care and account for the majority of drug delivery systems. Traditionally the analysis of the dissolution behaviour of a dosage form is used as the key parameter to assess the performance of a drug product. However, understanding the mechanisms of disintegration is of critical importance to improve the quality of drug delivery systems. The disintegration performance is primarily impacted by the hydration and subsequent swelling of the powder compact. Here we compare liquid ingress and swelling data obtained using terahertz pulsed imaging (TPI) to a set of mathematical models. The interlink between hydration kinetics and swelling is described by a model based on Darcy's law and a modified swelling model based on that of Schott. Our new model includes the evolution of porosity, pore size and permeability as a function of hydration time. Results obtained from two sets of samples prepared from pure micro-crystalline cellulose (MCC) indicate a clear difference in hydration and swelling for samples of different porosities and particle sizes, which are captured by the model. Coupling a novel imaging technique, such as TPI, and mathematical models allows better understanding of hydration and swelling and eventually tablet disintegration.

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.

Huntington's disease (HD) is an inherited neurodegenerative disorder of which skeletal muscle atrophy is a common feature, and multiple lines of evidence support a muscle-based pathophysiology in HD mouse models. Inhibition of myostatin signaling increases muscle mass, and therapeutic approaches based on this are in clinical development. We have used a soluble ActRIIB decoy receptor (ACVR2B/Fc) to test the effects of myostatin/activin A inhibition in the R6/2 mouse model of HD. Weekly administration from 5 to 11 weeks of age prevented body weight loss, skeletal muscle atrophy, muscle weakness, contractile abnormalities, the loss of functional motor units in EDL muscles and delayed end-stage disease. Inhibition of myostatin/activin A signaling activated transcriptional profiles to increase muscle mass in wild type and R6/2 mice but did little to modulate the extensive Huntington's disease-associated transcriptional dysregulation, consistent with treatment having little impact on HTT aggregation levels. Modalities that inhibit myostatin signaling are currently in clinical trials for a variety of indications, the outcomes of which will present the opportunity to assess the potential benefits of targeting this pathway in HD patients.

Purpose The impact of granule densification in high-shear wet granulation on tabletting and product performance was investigated, at pharmaceutical production scale. Product performance criteria need to be balanced with the need to deliver manufacturability criteria to assure robust industrial scale tablet manufacturing processes. A Quality by Design approach was used to determine in-process control specifications for tabletting, propose a design space for disintegration and dissolution, and to understand the permitted operating limits and required controls for an industrial tabletting process.Methods Granules of varying density (filling density) were made by varying water amount added, spray rate, and wet massing time in a design of experiment (DoE) approach. Granules were compressed into tablets to a range of thicknesses to obtain tablets of varying breaking force. Disintegration and dissolution performance was evaluated for the tablets made. The impact of granule filling density on tabletting was rationalised with compressibility, tabletability and compactibility.Results Tabletting and product performance criteria provided competing requirements for porosity. An increase in granule filling density impacted tabletability and compactability and limited the ability to achieve tablets of adequate mechanical strength. An increase in tablet solid fraction (decreased porosity) impacted disintegration and dissolution. An attribute-based design space for disintegration and dissolution was specified to achieve both product performance and manufacturability.Conclusion The method of granulation and resulting granule filling density is a key design consideration to achieve both product performance and manufacturability required for modern industrial scale pharmaceutical product manufacture and distribution.