Prediction of Critical Quality Attributes Based on the Numerical Simulation of Stress and Strain Distributions in Pharmaceutical Tablets.

Various stresses and strains are generated on the surface and inside of pharmaceutical tablets when an external force is applied. In addition, stresses in various directions can remain on the surface and inside the tablets because they are generally prepared by compaction of pharmaceutical powders using dies and punches. As it is difficult to measure the stress and strain generation in the tablets experimentally, a numerical simulation was applied by employing a finite element method (FEM). An elastic model is often used to represent stress and strain generation after loading an external force to tablets, and the Drucker-Prager cap (DPC) model has been widely recognized for representing the remaining stress distributions during the compaction of powder to tablet form. Firstly, this article describes an FEM simulation of the stress generation on the surface of the scored tablets after loading the bending force from the back side of the tablets. Next, the FEM simulation was introduced to determine the effect of diametrical compression on the stress and strain generation in the tablets by comparing the results measured experimentally. Furthermore, the residual stresses remaining inside the tablets were simulated using FEM, in which powder compaction was represented as the DPC model. A clear difference was observed in the residual stress distributions between the flat and convex tablets. This indicates that FEM simulation is useful for achieving a science-based understanding of critical quality attributes in various types of tablets.

Effects of tableting process parameters and powder lubrication levels on tablet surface temperature and moisture content.

Punch sticking is a recurrent problem during the pharmaceutical tableting process. Powder moisture content plays a key role in the buildup of sticking; it evaporates due to increased tablet temperature, accumulates at the punch-tablet interface, and causes sticking through capillary force. This study investigated the effects of compaction pressure (CP), compaction speed (CS), and lubrication level (magnesium stearate (MgSt) ratio) on tablet surface temperature (TST) and tablet surface moisture content (TSMC). TST and TSMC were measured with an infrared thermal camera and near-infrared sensor, respectively. Microcrystalline cellulose was used as the tableting powder and MgSt as the lubricant. The low range of CS values (16-32 mm/s) considered in this study did not have significant effects on TST and TSMC. MgSt ratio had a significant positive effect on TST; this may be explained by the increase in powder blend effusivity with the addition of MgSt. However, MgSt ratio did not have a significant effect on TSMC. CP had a significant positive effect on both TST and TSMC. Increased CP induced higher heat generation through particle deformation and friction during the compaction phase, leading to increased TST. Furthermore, the water vapor diffusion rate through the powder bed might have increased due to the rise in thermal energy and led to further moisture accumulation at the tablet-punch interface, causing the significant positive effect of CP on TSMC. This result may explain the occurrence of sticking regardless of the CP applied during the tableting process.

2D-Single-crystal hexagonal gold nanosheets for ultra-trace voltammetric determination of captopril.

Two dimensional single-crystal hexagonal gold nanosheets (SCHGNSs) were prepared by microwave heating of a solution of HAuCl4 in an ionic liquid. The SCHGNSs were characterized by field emission electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction, atomic force microscopy and electrochemical impedance spectroscopy. The SCHGNSs were then used to modify a graphite paste electrode for voltammetric determination of the hypertension drug captopril (CAP). The modified electrode showed a well-defined oxidation peak (at 0.41 V vs. Ag/AgCl) at pH 7.0 using differential pulse voltammetry. Under the optimum conditions, the response is linear in the 2-400 nM and 4.0-50 µM CAP concentration range, and the detection limit (at S/N = 3) is 0.3 nM. The sensor was successfully applied to the determination of CAP in pharmaceutical tablets and in spiked urine. Graphical abstract Schematic presentation of the preparation of single crystal hexagonal gold nanosheets and their use to modify a carbon paste electrode for ultra-trace voltammetric determination of the drug captopril.

Trace analysis of N-acetyl-L-cysteine using luminol-H2O2 chemiluminescence system catalyzed by silver nanoparticles.

N-Acetyl-L-cysteine (NAC) can inhibit the luminol-H2 O2 , reaction, which is catalyzed by silver nanoparticles. Based on this phenomenon a new method was developed for NAC determination. Under optimum conditions, a linear relationship between chemiluminescence intensity and NAC concentration was found in the range 0.034-0.98 µg/mL. The detection limit was 0.010 µg/mL (S/N =3), and the relative standard deviation (RSD) was <5% for 0.480 µg/mL NAC (n =5). This simple, sensitive and inexpensive method has been applied to measure the concentration of NAC in pharmaceutical tablets.

Virtual screening of drug materials for pharmaceutical tablet manufacturability with reference to sticking.

The manufacturing of pharmaceutical solid dosage forms, such as tablets involves a large number of successive processing operations including crystallisation of the drug substance, granulation, drying, milling, mixing of the formulation, and compaction. Each step is fraught with manufacturing problems. Undesired adhesion of powders to the surface of the compaction tooling, known as sticking, is a frequent and highly disruptive problem that occurs at the very end of the process chain when the tablet is formed. As an alternative to the mechanistic approaches to address sticking, we introduce two different machine learning strategies to predict sticking directly from the chemical formula of the drug substance, represented by molecular descriptors. An empirical database for sticking behaviour was developed and used to train the machine learning (ML) algorithms to predict sticking properties from molecular descriptors. The ML model has successfully classified sticking/non-sticking behaviour of powders with 100% separation. Predictions were made for materials in the handbook of Pharmaceutical Excipients and a subset of molecules included in the ChemBL database, demonstrating the potential use of machine learning approaches to screen for sticking propensity early at drug discovery and development stages. This is the first-time molecular descriptors and machine learning were used to predict and screen for sticking behaviour. The method has potential to transform the development of medicines by providing manufacturability information at drug screening stage and is potentially applicable to other manufacturing problems controlled by the chemistry of the drug substance.

Impact testing as a new approach to determine mechanical strength of pharmaceutical tablets.

One of the most common standardised testing of tablet strength in the pharmaceutical industry is the tablet breaking force, which records data related to diametrical compression. This method does not account for a rapid transfer of energy such as free-falling tablets hitting a solid surface, which occurs throughout manufacture, packaging and shipping. Accordingly, the test shows poor correlation with tablet defect rate. Impact fracture force was identified as a test to measure the force absorbed by the material before fracturing when applying impact energy (dynamic stress). The testing methodology for impact fracture force was modified and developed to characterise pharmaceutical tablets. A wide range of tablet formulations with different compositions, sizes, shapes and strengths were evaluated. The results showed that the measured impact fracture force had superior correlation with tablet defect rate in comparison to the standard pharmaceutical tests for breaking and friability with good repeatability. This is the first instrumented impact fracture force tester for pharmaceutical tablets that enables quality by design robust products to withstand and survive mechanical stresses during the manufacturing process. This method has the potential to save extra resource and cost required to solve issues around tablet defects including manufacturing deviations, tablet waste, extra appearance testing, visual inspection and tablet sorting.

Calorimetric investigation on heat release during the disintegration process of pharmaceutical tablets.

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.

Understanding Excipient-Induced Crystallization of Spray-Dried Amorphous Solid Dispersion.

This study investigates the compatibility of excipients with the model system SDI-X and their role in the induced crystallization of the amorphous compound-X in tablet formulations. We aimed to establish a straightforward and practical screening approach for evaluating excipient-induced crystallization of SDI in tablet matrices. Three methodologies-binary powder mixture, binary compact, and bilayer tablets-were employed to qualitatively and quantitatively evaluate the recrystallization of SDI-X with various excipients under accelerated storage conditions. The results demonstrated that binary compacts, providing direct physical contact between SDI-X and excipients, are superior in reflecting realistic drug-excipient contact within pharmaceutical tablets, enabling a more accurate assessment of excipient-induced crystallization for SDI-X. In contrast, the broadly used conventional binary blends can significantly underestimate this risk due to insufficient proximity. In addition, the bilayer tablets further confirmed that crystallization initiates at the contact surface between SDI-X and the excipients. The study highlighted that not only hygroscopicity but also the type of excipient and its physical contact with SDI-X significantly influence the recrystallization extent and rate of SDI-X. Interestingly, less hygroscopic diluents such as mannitol and lactose induced much higher levels of crystallization of SDIs, contrary to expectations based on moisture content alone. This suggests that the excipient type and contact surface are more critical in inducing recrystallization than just the level of moisture. The findings emphasize the need for careful excipient selection, study design, and sample preparation to enable appropriate assessments of SDI-excipient compatibility.

Studying the dissolution of immediate release film coating using terahertz pulsed imaging.

Coated tablets introduce complexity to the dissolution process, even with readily soluble immediate release coating layers. Therefore, a more detailed understanding of the physical steps involved in the dissolution process can improve the efficiency of formulation and process design. The current study uses terahertz pulsed imaging to visualise the hydration process of microcrystalline cellulose (MCC) tablet cores that were film coated with an immediate release coating formulation upon exposure to the dissolution medium. Film coated tablets that were prepared from three levels of core porosity (10%, 20% and 30%) and with coating thickness in the range of 30µm to 250µm were investigated. It was possible to resolve and quantify the distinct stages of wetting of the coating layer, swelling of the MCC particles at the core surface, and dissolution of the coating layer followed by the ingress of dissolution media into the tablet core. The liquid transport process through the coating layer was highly consistent and scalable. The penetration rate through the coating layer and the tablet core both strongly depended on coating thickness and core porosity.

Enhanced in-situ liquid transport investigation setup for pharmaceutical tablet disintegration analysis using terahertz radiation.

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.

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.

Research progress on the application of spectral imaging technology in pharmaceutical tablet analysis.

Tablet as a traditional dosage form in pharmacy has the advantages of accurate dosage, ideal dissolution and bioavailability, convenient to carry and transport. The most concerned tablet quality attributes include active pharmaceutical ingredient (API) contents and polymorphic forms, components distribution, hardness, density, coating state, dissolution behavior, etc., which greatly affect the bioavailability and consistency of tablet final products. In the pharmaceutical industry, there are usually industry standard methods to analyze the tablet quality attributes. However, these methods are generally time-consuming and laborious, and lack a comprehensive understanding of the properties of tablets, such as spatial information. In recent years, spectral imaging technology makes up for the shortcomings of traditional tablet analysis methods because it provides non-contact and rich information in time and space. As a promising technology to replace the traditional tablet analysis methods, it has attracted more and more attention. The present paper briefly describes a series of spectral imaging techniques and their applications in tablet analysis. Finally, the possible application prospect of this technology and the deficiencies that need to be improved were also prospected.

Visualising liquid transport through coated pharmaceutical tablets using Terahertz pulsed imaging.

Dissolution of pharmaceutical tablets is a complex process, especially for coated tablets where layered structures form an additional barrier for liquid transport into the porous tablet matrix. A better understanding of the role of the coating structure in the mass transport processes that govern drug release, starting with the wetting of the coating layer by the dissolution medium, can benefit the formulation design and optimisation of the production. For this study, terahertz pulsed imaging was used to investigate how dissolution medium can penetrate coated tablets. In order to focus on the fundamental process, the model system for this proof-of-principle study consisted of tablet cores made from pure microcrystalline cellulose compacted to a defined porosity coated with Opadry II, a PVA-based immediate release coating blend. The coating was applied to a single side of flat-faced tablets using vacuum compression moulding. It was possible to resolve the hydration of the coating layer and the subsequent liquid ingress into the dry tablet core. The analysis revealed a discontinuity in density at the interface between coating and core, where coating polymer could enter the pore space at the immediate surface of the tablet cores during the coating process. This structure affected the liquid transport of the dissolution medium into the core. We found evidence for the formation of a gel layer upon hydration of the coating polymer. The porosity of the tablet core impacted the quality of coating and thus affected its dissolution performance (r =  0.6932 for the effective liquid penetration rate RPeff and the core porosity). This study established a methodology and can facilitate a more in-depth understanding of the role of coating on tablet dissolution.

Insights into the Control of Drug Release from Complex Immediate Release Formulations.

The kinetics of water transport into tablets, and how it can be controlled by the formulation as well as the tablet microstructure, are of central importance in order to design and control the dissolution and drug release process, especially for immediate release tablets. This research employed terahertz pulsed imaging to measure the process of water penetrating through tablets using a flow cell. Tablets were prepared over a range of porosity between 10% to 20%. The formulations consist of two drugs (MK-8408: ruzasvir as a spray dried intermediate, and MK-3682: uprifosbuvir as a crystalline drug substance) and NaCl (0% to 20%) at varying levels of concentrations as well as other excipients. A power-law model is found to fit the liquid penetration exceptionally well (average R2>0.995). For each formulation, the rate of water penetration, extent of swelling and the USP dissolution rate were compared. A factorial analysis then revealed that the tablet porosity was the dominating factor for both liquid penetration and dissolution. NaCl more significantly influenced liquid penetration due to osmotic driving force as well as gelling suppression, but there appears to be little difference when NaCl loading in the formulation increases from 5% to 10%. The level of spray dried intermediate was observed to further limit the release of API in dissolution.

Calibration transfer between modelled and commercial pharmaceutical tablet for API quantification using backscattering NIR, Raman and transmission Raman spectroscopy (TRS).

Backscattering NIR, Raman (BSR) and transmission Raman spectroscopy (TRS) coupled with chemometrics have shown to be rapid and non-invasive tools for the quantification of active pharmaceutical ingredient (API) content in tablets. However, the developed models are generally specifically related to the measurement conditions and sample characteristics. In this study, a number of calibration transfer methods, including DS, PDS, DWPDS, GLSW and SST, were evaluated for the spectra correction between modelled tablets produced in the laboratory and commercial samples. Results showed that the NIR and BSR spectra of commercial tablet corrected by DWPDS and PDS, respectively, enabled accurate API predictions with the high ratio of prediction error to deviation (RPDP) values of 2.33 and 3.03. The most successfully approach was achieved with DS corrected TRS data and SiPLS modelling (161 variables) and yielded RMSEP of 0.72 %, R2P of 0.946 and RPDP of 4.35. The proposed calibration transfer strategy offers the opportunities to analyse samples produced in different conditions; in the future, its implication will find extensively process control and quality assurance applications and benefit all possible users in the entire pharmaceutical industry.

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.

Electrically Tunable Lens (ETL)-Based Variable Focus Imaging System for Parametric Surface Texture Analysis of Materials.

Electrically tunable lenses (ETLs) are those with the ability to alter their optical power in response to an electric signal. This feature allows such systems to not only image the areas of interest but also obtain spatial depth perception (depth of field, DOF). The aim of the present study was to develop an ETL-based imaging system for quantitative surface analysis. Firstly, the system was calibrated to achieve high depth resolution, warranting the accurate measurement of the depth and to account for and correct any influences from external factors on the ETL. This was completed using the Tenengrad operator which effectively identified the plane of best focus as demonstrated by the linear relationship between the control current applied to the ETL and the height at which the optical system focuses. The system was then employed to measure amplitude, spatial, hybrid, and volume surface texture parameters of a model material (pharmaceutical dosage form) which were validated against the parameters obtained using a previously validated surface texture analysis technique, optical profilometry. There were no statistically significant differences between the surface texture parameters measured by the techniques, highlighting the potential application of ETL-based imaging systems as an easily adaptable and low-cost alternative surface texture analysis technique to conventional microscopy techniques.

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.

Assembly of a UV-LED induced fluorescence system for rapid determination of amiloride in pharmaceutical tablet and human serum.

A simple and sensitive fluorescence method has been developed for the determination of amiloride (AMI) in pharmaceutical tablet and human serum with a portable, cost-effective, and easy-to-operate fluorescence system. The fluorescence system was assembled with some optical and electronic devices mainly including a 370 nm light-emitting-diode (LED) as light source, a fiber spectrometer and a Raspberry Pi computer. With the system, AMI produced a strong fluorescence emission at 413 nm, and the emitted intensity can maintain good stability with in a wide pH range from 2 to 8. The proposed method was successfully applied to the determinations of AMI in pharmaceutical tablet and human serum. Their detection limits were 1.67 ng mL-1 and 1.43 ng mL-1 respectively, and the recovery was in the range of 94.06-114.0%. Those obtained results proved that the proposed methods combined with the developed fluorescence system could be employed for the routine analysis of amiloride in pharmaceutical tablet and human serum, especially for the fast analysis of them under field conditions.

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.