Physical stability is a critical aspect of tablet formulation, with excipients significantly influencing long-term tablet performance, especially under humid conditions. This study investigated storage-induced changes in increasingly complex tablet formulations by sequentially incorporating croscarmellose sodium (CCS), magnesium stearate (MgSt), and lactose into microcrystalline cellulose (MCC)-based tablets prepared at different porosities and stored at 50°C/75% RH for up to 42 days. Storage induced changes occurred through two distinct stages. The first stage was governed by moisture uptake, with most sorption occurring within the first day of storage, resulting in tablet swelling and tensile strength reductions of 16-51% depending on formulation and porosity. The rate of these structural changes was strongly correlated with sorption kinetics. The second stage occurred after moisture uptake had largely stabilised and was characterised by continued changes in liquid penetration and swelling behaviour (quantified by sessile drop analysis), and disintegration performance. These later changes were highly formulation dependent, with MgSt containing formulations showing the greatest deterioration, where disintegration times increased from approximately 40 s to 500 s after storage. DVS measurements successfully predicted moisture uptake and tensile strength evolution across formulations and porosity levels. The results demonstrate that tablet stability is governed by a sequence of moisture driven structural changes followed by slower performance related changes, providing a practical framework for predicting stability assessment and formulation development from short-term measurements.

Disintegration and dissolution play a key role in drug release from oral immediate-release products. An improved understanding of these processes, the impact of process parameters and the critical material attributes are required to develop robust formulations and manufacturing processes. This study demonstrates an in-situ disintegration and dissolution monitoring system capable of capturing quantitative swelling and erosion data in a paddle dissolution apparatus. The system utilises optical coherence tomography integrated with a bathless direct heating vessel and overhead stirrer. A bespoke sample holder was developed to keep the tablets in place and allow swelling and erosion to be captured. Tablet swelling and erosion were captured and quantified for different paracetamol and ibuprofen formulations. For slowly disintegrating tablets (no disintegrant) consistent swelling that correlated with drug release was observed, with 10 % porosity tablets swelling up to 1000 µm in 2 min while 20 % porosity tablets swelled up to 1900 µm. For rapidly disintegrating tablets, phases of swelling and erosion dominated the disintegration process, the length and extent of which increased with increasing porosity. This new system has multiple academic and industrial applications, including identifying performance-controlling disintegration mechanisms in problem formulations and developing a deeper understanding of stability study results.

Liposomes are amongst the most promising and versatile nanomedicine products employed in recent years. In vitro release (IVR) tests are critical during development of new liposome-based products. The drug release characteristics of a formulation are affected by multiple factors related to the formulation itself and the IVR method used. While the effect of some of these parameters has been explored, their relative importance and contribution to the final drug release profile are not sufficiently understood to enable rational design choices. This prolongs the development and approval of new medicines. In this study, a machine learning workflow is developed which can be used to better understand patterns in liposome formulation properties, IVR methods, and the resulting drug release characteristics. A comprehensive database of liposome release profiles, including formulation properties, IVR method parameters, and drug release profiles is compiled from academic publications. A classification model is developed to predict the release profile type (kinetic class), with a significant increase in the balanced accuracy test score compared to a random baseline. The resulting machine learning approach enhances understanding of the complex liposome drug release dynamics and provides a predictive tool to accelerate the design of liposome IVR tests.

Fluid co-administered with oral medication directly affects its behaviour. Often, people use fluids other than water when taking their medications. Capsules (mainly gelatine- and HPMC-based) are widely used solid oral dosage forms. The presented study aimed to investigate the behaviour of gelatine and HPMC capsules in several fluids in vitro and in vivo. The second aim was to assess the influence of administered fluids on the gastric emptying. The third aim was to assess the usability and predictive power of different in vitro methods for drug analysis and compare them with in vivo data. For in vitro studies, two systems with different complexities were used: the compendial USP 2 apparatus and the GastroDuo biorelevant model. In both systems, 25 mL of SGF and 240 mL of tested fluid were used. To obtain the in vivo data, a clinical study with 12 young and healthy volunteers was performed. In this study, the salivary tracer technique, which utilises caffeine kinetics as a marker of a dosage form behaviour in the GIT, was used. In vitro, the temperature strongly affected the opening times of gelatine capsules (rapid opening in warm media and slower in cold). In vivo, the opening time of gelatine capsules in warm black tea was slightly delayed in comparison to warm water. The differences in opening times between warm and cold water and warm black tea and cold water were significant. In USP 2 Apparatus, HPMC capsules were more sensitive to the tested media than in the biorelevant GastroDuo model. There were no significant differences in the opening times of HPMC capsules in vivo. Gastric emptying of warm water, cold water or warm black tea was not affected, suggesting that the altered in vivo absorption kinetics was caused by the in vivo behaviour of the capsules, depending on their properties and not by changes in the gastric emptying of the co-administered fluids. The presented study allows a better understanding of gelatine and HPMC capsules behaviour in vitro and in vivo administered with different fluids. Moreover, it demonstrated the relevance of in vivo data as well as the limitations of in vitro tools.

Accelerated development of oral solid dosage forms necessitates effective strategies to link clinical data across development stages. Emerging predictive tools present a viable alternative, ensuring targeted clinical performance with a significantly reduced dependence on traditional clinical bridging studies. This paper introduces a biopharmaceutics bridging risk assessment (BBRA) tool that extends opportunities to avoid clinical bridging studies beyond the biopharmaceutics classification system (BCS) classes 1 and 3, utilizing physiologically based biopharmaceutics modeling (PBBM) and advanced in vitro tools (such as the TNO (Netherlands Organisation for Applied Scientific Research) transit intestinal model, TIM). PBBM uses experimental solubility, dissolution, and permeability input, validated by clinical data, to enhance risk assessment granularity and understanding, while TIM uniquely simulates physiological gastrointestinal conditions, complementary to traditional dissolution tests. The decision-tree framework, aligned with ICH M9 principles, supports iterative decision-making across the drug development life cycle, from preclinical to postapproval phases. An analysis of 32 AstraZeneca bridging cases showed that application of BBRA could reduce the number of clinical studies by 70%. By leveraging in vivo predictions and comprehensive clinical insights, our strategic approach mitigates late-stage BE failure risks, expedites market introduction, and ensures effective patient treatments.

Physical stability testing is crucial in pharmaceutical development, requiring a thorough understanding of how moisture interacts with materials to ensure tablet integrity and performance. This study explores how tablet porosity and the inclusion of swelling excipients influence moisture uptake and stability across different length and time scales, from particle-level interactions to tablet behaviour and from short-term moisture sorption using dynamic vapour sorption (DVS) to long-term storage effects. Two tablet formulations were tested: pure MCC and MCC-CCS (8%), each with four different porosities. A predictive framework was developed to estimate porosity changes in stored tablets by accounting for particle swelling. The study highlights rapid structural changes, including reductions in tensile strength, bulk density, and porosity, which occur mostly within the first day of storage. By linking powder and tablet DVS data and establishing correlations between DVS and real-storage data, this study provides a framework for predicting moisture sorption behaviour in tablets over time. This approach enhances the predictability of tablet stability, reducing the need for extensive long-term storage studies and enabling faster, more reliable stability assessments. Ultimately, these findings provide a stronger foundation for optimising stability testing and formulation performance.

Continuous manufacturing offers advantages over traditional batch methods, including agility, efficiency, and sustainability. However, transitioning to continuous manufacturing in process development is challenging due to the need for early adoption of industrial-scale equipment. Conversely, batch processes require extensive scale-up studies before commercialization, which continuous processes can avoid. A more efficient approach is to use batch trials in early development to design formulations and processes for continuous manufacturing, requiring assessment of their transferability. This study compares the dissolution behavior of immediate-release tablets manufactured via batch and Continuous Direct Compression (CDC), using ibuprofen, a BCS Class II drug. A Design of Experiments (DoE) approach varied formulation properties and tensile strength, with three methods: i) similarity factor ([f2]), ii) Weibull model fitting and Partial Least Squares (PLS) regression, and iii) Gaussian Process Regression (GPR) to assess the transferability of batch trial data and dissolution models for CDC formulation and process design. Dissolution profiles were identical between batch and CDC trials when formulations and tensile strength matched, with differences observed only due to deviations in actual tensile strength. The PLS model indicated minimal impact of operational modes on dissolution behavior. The GPR model based only on batch trial data predicted CDC dissolution profiles with a mean R2 of 0.910 and RMSE of 4.88%. Overall, the transferability analysis confirmed the predictive capacity of the developed model using batch trial data on the dissolution behavior of tablets manufactured via a CDC line.

Machine learning and artificial intelligence (AI) is transforming the way pharmaceutical products are developed across drug discovery, process engineering, and pharmaceutics functions. AI for nanomedicine development is enabling faster and more accurate prediction of critical quality attributes (CQAs). However, the full potential of AI is limited by the quality and accessibility of data. Unlike adjacent fields such as the chemical sciences, the pharmaceutics domain lacks curated, open-access databases, particularly for nanomedicines. To address this, here we curate an open-access local database focused on liposomal formulations. The database includes formulation parameters, in vitro release (IVR) testing conditions, and digitised drug release data. By evaluating the entries in the database qualitatively and quantitatively, we identified challenges in current data reporting practices. This includes incomplete reporting of formulation and IVR testing conditions, as well as inconsistent quality of drug release plots and their data format. Based on our analysis, we propose a set of data standards and a database structure to support harmonisation for nanomedicine formulation and IVR data. Our open-access database aims to improve data accessibility and transparency to enable the development of robust AI models for IVR and CQA prediction, ultimately streamlining nanomedicine development.

Moisture sensitivity poses a challenge in formulating oral dosage forms, particularly when considering disintegrants' swelling due to prior moisture exposure, impacting performance and physical stability. This study utilises dynamic vapour sorption to simulate real-world storage scenarios, investigating the equilibrium moisture content and dynamics of eight commonly used excipients in oral solid dosage forms. A model was developed to determine the kinetic rate constant of moisture sorption and desorption for different storage conditions. Dynamic vapour sorption tests revealed that excipients with higher moisture-binding capacities showed slower equilibration to the target relative humidity (RH). Elevated temperatures accelerated the moisture sorption/desorption process for all excipients, reducing the equilibrated moisture content for most, except mannitol and lactose. Particle imaging over a 14-day accelerated storage period quantified swelling, indicating approximately 6% increase in particle diameter for croscarmellose sodium (CCS) and sodium starch glycolate (SSG), and a lesser 2.7% for microcrystalline cellulose (MCC), predominantly caused by the humidity. All excipients reached their swelling peak within the first day of storage, with permanent particle size enlargement for CCS and SSG, whereas MCC displayed a partial reversibility post-storage. Enhancing our understanding of excipients' stability and interaction with moisture and the resulting particle swelling contributes to the rational design of oral solid dosage formulations and promotes a better understanding of their long-term physical stability.

In this study, a compartmental disintegration and dissolution model is proposed for the prediction and evaluation of the dissolution performance of directly compressed tablets. This dissolution model uses three compartments (Bound, Disintegrated, and Dissolved) to describe the state of each particle of active pharmaceutical ingredient. The disintegration of the tablet is captured by three fitting parameters. Two disintegration parameters, β0 and βt,0, describe the initial disintegration rate and the change in disintegration rate, respectively. A third parameter, α, describes the effect of the volume of dissolved drug on the disintegration process. As the tablet disintegrates, particles become available for dissolution. The dissolution rate is determined by the Nernst-Brunner equation, whilst taking into account the hydrodynamic effects within the vessel of a USP II (paddle) apparatus. This model uses the raw material properties of the active pharmaceutical ingredient (solubility, particle size distribution, true density), lending it towards early development activities during which time the amount of drug substance available may be limited. Additionally, the strong correlations between the fitting parameters and the tablet porosity indicate the potential to isolate the manufacturing effects and thus implement the model as part of a real-time release testing strategy for a continuous direct compression line.

Nanoparticles can be used in pharmaceuticals to provide a targeted and prolonged release of active pharmaceutical ingredient (API). Nanoparticles are growing in application in the field of oncology due to developments in the field, but still there are issues faced with studying the in vitro release of long-acting injectables. A method using the sample and separate approach via ultracentrifugation was used for a polymeric nanoparticle product with an in vitro release over 10 days. This method is laborious, with many areas of manual intervention, which reduces robustness and provides limited temporal resolution of the in vitro release profile due to sampling timepoints. NanoDis is a recently developed automated sampling system that uses tangential flow filtration (TFF) to separate released and encapsulated API over the in vitro release profile, with minimal analyst input and enhanced temporal resolution compared to other methods. This article highlights the success of implementing NanoDis for automated sampling of polymeric nanoparticles, with release profiles comparable to the ultracentrifugation method, showing potential for a more robust and quality control friendly method.

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).

Dissolution of ionizable drugs and their salts is a function of drug surface solubility driven by the surface pH, i.e., the microenvironmental pH at the solid/liquid interface, which will deviate from bulk pH when there is an acid-base reaction occurring at the solid/liquid interface. In this work, we first present a brief overview of the modeling approaches available in the literature, classified according to the rate-determining step assumed in the dissolution process. In the second part, we present and evaluate the prediction performance of two different modeling approaches for surface pH. The first method relies only on thermodynamic equilibria, while the second method accounts for transport phenomena of charged compounds through the diffusional boundary layer using the Nernst - Planck equation. Model outcomes are compared with experimental data taken from the literature and obtained during this work. In terms of surface pH predictions, the models provide identical values for weak acids or weak bases. The models' outcomes for bases are in good agreement with experimental data in acidic conditions (bulk pH 1-4), while overpredictions are observed in the 5-7 bulk pH range in a system-dependent manner. Deviations can be related to the effect of surface dissolution (also referred to as surface reaction), which may become a controlling mechanism and slow the replenishment of the unionized drug at the surface of the crystal. Surface pH predictions for acids are generally in good agreement with experiments, with a slight underestimation for some drug examples, which could be related to errors in intrinsic solubility determination or to the assumption of thermodynamic equilibrium at the surface of the drug. A good agreement is also observed for salts with the thermodynamic model except for mesylate salts, suggesting that other phenomena, not currently included in the thermodynamic equilibrium model, may determine the surface pH.

Acalabrutinib maleate tablets correspond to an improved formulation compared to acalabrutinib capsules as they can be dosed with and without acid reducing agents and therefore benefit more cancer patients. The dissolution specification for the drug product was determined using all the information available on the drug safety, efficacy, and in vitro performance. In addition, a physiologically based biopharmaceutics model was developed for acalabrutinib maleate tablets on the back of a previously published model for acalabrutinib capsules to establish that the proposed drug product dissolution specification would ensure safe and effective products for all patients including those under acid reducing agent treatment. The model was built, validated, and used to predict the exposure of virtual batches where the dissolution was slower than that of the clinical target. A combination of exposure prediction and the use of a PK-PD model allowed it to be demonstrated that the proposed drug product dissolution specification was acceptable. This combination of models enabled a larger safe space than would have been granted by consideration of bioequivalence only.

www.dissolutiontech.com 100 INTRODUCTION The virtual workshop, “A Quest for Biowaiver, Including Next Generation Dissolution Characterization and Modelling,” was held on November 16–17th, 2022, via the MS Teams platform. The conference was co-sponsored by Jagiellonian University Medical College (JUMC) in Cracow, Poland and the American Association of Pharmaceutical Scientists (AAPS). The workshop was chaired by Vivian Gray (AAPS) and Prof Aleksander Mendyk (JUMC), with the support of the co-chairs Prof Nikoletta Fotaki (AAPS), Prof Jie Shen (AAPS), and Dr Jakub Szlęk (JUMC).

Stability studies are an integral part of the drug development process for any drug product. In addition to monitoring chemical degradation, the physical stability of a drug product must also be evaluated to ensure that the drug release and performance is not affected by storage. In this study, directly compressed tablets of 16 different formulations were exposed to an accelerated stability program to quantify changes in tablet breaking force, porosity, contact angle and disintegration time. Tablets were exposed to five different storage conditions from 37∘C/30% relative humidity (RH) to 70∘C/75%RH with testing after 2 and 4 weeks of storage. Each formulation contained two different fillers (47% w/w each), a disintegrant (5% w/w) and magnesium stearate (1% w/w). The results show that tablets stored at high humidity show increases in porosity and decreases in tensile strength, particularly if they contain a highly hygroscopic filler such as microcrystalline cellulose (MCC). For tablets stored at high temperature, the most commonly affected property was the tablet wettability, measured by sessile drop contact angle measurements. These results are considered in combination with the performance-controlling disintegration mechanism (Maclean et al., 2021) to identify the critical properties which influence the performance after storage.

BACKGROUND:Early assessment of pH-dependent drug-drug-interactions (DDIs) for salts of poorly soluble weakly acidic compounds offers various advantages for patient safety, the pharmaceutical industry, and regulatory bodies. Biorelevant media and tests reflecting physiological changes during acid-reducing agent (ARA) co-administration can be used to explore and predict the extent of the pH effect during therapy with ARAs.METHODS:Solubility, one-stage and two-stage dissolution of tablets containing potassium raltegravir, the marketed salt form of this poorly soluble, weakly acidic drug, was investigated using biorelevant media specially designed to reflect administration without and during ARA co-therapy. The dissolution data were then converted into parameters suitable for input into an in silico model (Simcyp™) and the simulated plasma profiles were compared with available pharmacokinetic (PK) data from the literature.RESULTS:Dissolution of the potassium raltegravir formulation in media reflecting ARA co-administration, and thus elevated gastric pH, was faster and more complete than in experiments reflecting the low gastric pH observed in the absence of ARA co-administration. Simulations using data from dissolution experiments with ARA media appropriately bracketed the in vivo data for ARA co-administration in healthy volunteers.CONCLUSION:Dissolution data from in vitro experiments in biorelevant media reflecting physiological changes due to ARA co-administration provide valuable information about potassium raltegravir's behavior during concomitant ARA therapy. The approach may also be suitable for salts forms of other poorly soluble, weakly acidic drugs.

Acalabrutinib is a Bruton tyrosine kinase (BTK) inhibitor approved to treat adults with chronic lymphocytic leukemia, small lymphocytic lymphoma, or previously treated mantle cell lymphoma. As the bioavailability of the acalabrutinib capsule (AC) depends on gastric pH for solubility and is impaired by acid-suppressing therapies, coadministration with proton-pump inhibitors (PPIs) is not recommended. Three studies in healthy subjects (N = 30, N = 66, N = 20) evaluated the pharmacokinetics (PKs), pharmacodynamics (PDs), safety, and tolerability of acalabrutinib maleate tablet (AT) formulated with pH-independent release. Subjects were administered AT or AC (orally, fasted state), AT in a fed state, or AT in the presence of a PPI, and AT or AC via nasogastric (NG) route. Acalabrutinib exposures (geometric mean [% coefficient of variation, CV]) were comparable for AT versus AC (AUC(inf) 567.8 ng h/mL [36.9] vs 572.2 ng h/mL [38.2], C-max 537.2 ng/mL [42.6] vs 535.7 ng/mL [58.4], respectively); similar results were observed for acalabrutinib's active metabolite (ACP-5862) and for AT-NG versus AC-NG. The geometric mean C-max for acalabrutinib was lower when AT was administered in the fed versus the fasted state (C-max 255.6 ng/mL [%CV, 46.5] vs 504.9 ng/mL [49.9]); AUCs were similar. For AT + PPI, geometric mean C-max was lower (371.9 ng/mL [%CV, 81.4] vs 504.9 ng/mL [49.9]) and AUC(inf) was higher (AUC(inf) 694.1 ng h/mL [39.7] vs 559.5 ng h/mL [34.6]) than AT alone. AT and AC were similar in BTK occupancy. Most adverse events were mild with no new safety concerns. Acalabrutinib formulations were comparable and AT could be coadministered with PPIs, food, or via NG tube without affecting the PKs or PDs.