In vitro dissolution testing is commonly performed to ensure that oral solid dosage medicines are of high quality and will achieve their targeted in vivo performance. However, this testing is time and material consuming. Therefore, pharmaceutical companies have been developing predictive dissolution models (PDMs) for drug product release based on fast at- and/or on-line measurements, including real-time release testing of dissolution (RTRT-D). Recently, PDMs have seen acceptance by major regulatory bodies as release tests for the dissolution critical quality attribute. In this paper, several methodologies are described to develop and validate a fit-for-purpose model, then to implement it as a surrogate release test for dissolution. These approaches are further exemplified by real-life case studies, which demonstrate that PDMs for release are not only viable but more sustainable than in vitro dissolution testing and can significantly accelerate drug product release. The rise of continuous manufacturing within the pharmaceutical industry further favors the implementation of real-time release testing. Therefore, a steep uptake of PDMs for release is expected once this methodology is globally accepted. To that end, it is advantageous for global regulators and pharmaceutical innovators to coalesce around a harmonized set of expectations for development, validation, implementation, and lifecycle of PDMs as part of drug product release testing.

• Klíčová slova
• dissolution, predictive dissolution modelling, real-time release testing,
• MeSH
• aplikace orální MeSH
• farmaceutická chemie metody   MeSH
• léčivé přípravky chemie   aplikace a dávkování   MeSH
• lidé MeSH
• příprava léků MeSH
• rozpustnost MeSH
• schvalování léčiv MeSH
• uvolňování léčiv * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• léčivé přípravky MeSH

Roller compaction is often utilized as the first step to improve flow properties and homogeneity of pharmaceutical mixtures. Since the dry granulation process is less complicated than its counterparts in the industry, it is possible to perform screening experiments readily to investigate granulate quality for further operations. In this study, the aim of the investigation focused on the effect of roller compaction on the dissolution of granules and tablets of two pharmaceutical formulations that contain APIs of different biopharmaceutical classification. This study underscores the benefits of granule dissolution testing as a crucial early-stage technique for optimizing granulate quality and facilitating progression through formulation manufacturing operations. For active pharmaceutical ingredients characterized by poor dissolution properties, this approach provides valuable insights during the initial development phases. By integrating granule dissolution testing into the development process, product manufacturability can be enhanced and optimal product performance can be ensured.

• Klíčová slova
• Disintegration kinetics, Dissolution behavior, Dissolution rate, Dry granulation, Flow-through cell, Granule dissolution, Granule properties, Paddle dissolution, Poller compaction, Porosity, Process engineering, Process parameters, Tablet dissolution, USP2 dissolution, USP4 dissolution,
• MeSH
• farmaceutická chemie metody   MeSH
• farmaceutická technologie metody   MeSH
• pomocné látky chemie   MeSH
• prášky, zásypy, pudry chemie   MeSH
• příprava léků * metody   MeSH
• rozpustnost MeSH
• tablety * chemie   MeSH
• uvolňování léčiv MeSH
• velikost částic MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• pomocné látky MeSH
• prášky, zásypy, pudry MeSH
• tablety * MeSH

Biorelevant dissolution instruments represent an important tool for pharmaceutical research and development. These instruments are designed to simulate the dissolution of drug formulations in conditions most closely mimicking the gastrointestinal tract. In this work, we focused on the optimization of dissolution compartments/vessels for an updated version of the biorelevant dissolution apparatus-Golem v2. We designed eight compartments of uniform size but different inner geometry. The dissolution performance of the compartments was tested using immediate release caffeine tablets and evaluated by standard statistical methods and principal component analysis. Based on two phases of dissolution testing (using 250 and 100 mL of dissolution medium), we selected two compartment types yielding the highest measurement reproducibility. We also confirmed a statistically ssignificant effect of agitation rate and dissolution volume on the extent of drug dissolved and measurement reproducibility.

• Klíčová slova
• Golem, biorelevant, caffeine, dissolution, multivariate data analysis,
• MeSH
• biologické modely * MeSH
• design vybavení MeSH
• farmaceutická chemie * MeSH
• farmakokinetika * MeSH
• gastrointestinální absorpce MeSH
• gastrointestinální trakt metabolismus   MeSH
• multivariační analýza MeSH
• počítačová simulace MeSH
• rozpustnost * MeSH
• Publikační typ
• časopisecké články MeSH

It is established that the rates of solvent exchange at interfaces correlate with the rates of a number of mineral reactions, including growth, dissolution and ion sorption. To test if solvent exchange is limiting these rates, quasi-elastic neutron scattering (QENS) is used here to benchmark classical molecular dynamics (CMD) simulations of water bound to nanoparticulate calcite. Four distributions of solvent exchanges are found with residence times of 8.9 ps for water bound to calcium sites, 14 ps for that bound to carbonate sites and 16.7 and 85.1 ps for two bound waters in a shared calcium-carbonate conformation. By comparing rates and activation energies, it is found that solvent exchange limits reaction rates neither for growth nor dissolution, likely due to the necessity to form intermediate states during ion sorption. However, solvent exchange forms the ceiling for reaction rates and yields insight into more complex reaction pathways.

• Publikační typ
• časopisecké články MeSH

Co-milling is an effective technique for improving dissolution rate limited absorption characteristics of poorly water-soluble drugs. However, there is a scarcity of models available to forecast the magnitude of dissolution rate improvement caused by co-milling. Therefore, this study endeavoured to quantitatively predict the increase in dissolution by co-milling based on drug properties. Using a biorelevant dissolution setup, a series of 29 structurally diverse and crystalline drugs were screened in co-milled and physically blended mixtures with Polyvinylpyrrolidone K25. Co-Milling Dissolution Ratios after 15 min (COMDR15 min) and 60 min (COMDR60 min) drug release were predicted by variable selection in the framework of a partial least squares (PLS) regression. The model forecasts the COMDR15 min (R2 = 0.82 and Q2 = 0.77) and COMDR60 min (R2 = 0.87 and Q2 = 0.84) with small differences in root mean square errors of training and test sets by selecting four drug properties. Based on three of these selected variables, applicable multiple linear regression equations were developed with a high predictive power of R2 = 0.83 (COMDR15 min) and R2 = 0.84 (COMDR60 min). The most influential predictor variable was the median drug particle size before milling, followed by the calculated drug logD6.5 value, the calculated molecular descriptor Kappa 3 and the apparent solubility of drugs after 24 h dissolution. The study demonstrates the feasibility of forecasting the dissolution rate improvements of poorly water-solube drugs through co-milling. These models can be applied as computational tools to guide formulation in early stage development.

• Klíčová slova
• Ball milling, Co-grinding, Co-milling, Dissolution rate enhancement, In silico modelling, Multiple linear regression, Partial least squares regression,
• MeSH
• léčivé přípravky chemie   MeSH
• metoda nejmenších čtverců MeSH
• počítačová simulace MeSH
• povidon chemie   MeSH
• příprava léků * metody   MeSH
• rozpustnost * MeSH
• uvolňování léčiv * MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• léčivé přípravky MeSH
• povidon MeSH

Long-acting injectable formulations represent a rapidly emerging category of drug delivery systems that offer several advantages compared to orally administered medicines. Rather than having to frequently swallow tablets, the medication is administered to the patient by intramuscular or subcutaneous injection of a nanoparticle suspension that forms a local depot from which the drug is steadily released over a period of several weeks or months. The benefits of this approach include improved medication compliance, reduced fluctuations of drug plasma level, or the suppression of gastrointestinal tract irritation. The mechanism of drug release from injectable depot systems is complex, and there is a lack of models that would enable quantitative parametrisation of the process. In this work, an experimental and computational study of drug release from a long-acting injectable depot system is reported. A population balance model of prodrug dissolution from asuspension with specific particle size distribution has been coupled with the kinetics of prodrug hydrolysis to its parent drug and validated using in vitro experimental data obtained from an accelerated reactive dissolution test. Using the developed model, it is possible to predict the sensitivity of drug release profiles to the initial concentration and particle size distribution of the prodrug suspension, and subsequently simulate various drug dosing scenarios. Parametric analysis of the system has identified the boundaries of reaction- and dissolution-limited drug release regimes, and the conditions for the existence of a quasi-steady state. This knowledge is crucial for the rational design of drug formulations in terms of particle size distribution, concentration and intended duration of drug release.

• Klíčová slova
• Hydrolysis, Injectable depot systems, Nanosuspension, Paliperidone palmitate, Particle size distribution, Reactive dissolution,
• MeSH
• antipsychotika * MeSH
• injekce intramuskulární MeSH
• léky s prodlouženým účinkem MeSH
• lidé MeSH
• prekurzory léčiv * MeSH
• rozpustnost MeSH
• suspenze MeSH
• uvolňování léčiv MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antipsychotika * MeSH
• léky s prodlouženým účinkem MeSH
• prekurzory léčiv * MeSH
• suspenze MeSH

Development of new pharmaceutical compounds and dosage forms often requires in vitro dissolution testing with the closest similarity to the human gastrointestinal (GI) tract. To create such conditions, one needs a suitable dissolution apparatus and the appropriate data on the human GI physiology. This review discusses technological approaches applicable in biorelevant dissolutions as well as the physiology of stomach and small intestine in both fasted and fed state, that is, volumes of contents, transit times for water/food and various solid oral dosage forms, pH, osmolality, surface tension, buffer capacity, and concentrations of bile salts, phospholipids, enzymes, and Ca(2+) ions. The information is aimed to provide clear suggestions on how these conditions should be set in a dynamic biorelevant dissolution test.

• Klíčová slova
• bioavailability, bioequivalence, biorelevant dissolution, dissolution, dynamic dissolution, gastrointestinal physiology, gastrointestinal transit, in vitro models,
• MeSH
• farmaceutická chemie metody   MeSH
• farmakokinetika * MeSH
• gastrointestinální trakt fyziologie   MeSH
• léčivé přípravky chemie   MeSH
• lidé MeSH
• rozpustnost MeSH
• tenké střevo fyziologie   MeSH
• žaludek fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• léčivé přípravky MeSH

A drug dissolution profile is one of the most critical dosage form characteristics with immediate and controlled drug release. Comparing the dissolution profiles of different pharmaceutical products plays a key role before starting the bioequivalence or stability studies. General recommendations for dissolution profile comparison are mentioned by the EMA and FDA guidelines. However, neither the EMA nor the FDA provides unambiguous instructions for comparing the dissolution curves, except for calculating the similarity factor f2. In agreement with the EMA and FDA strategy for comparing the dissolution profiles, this manuscript provides an overview of suitable statistical methods (CI derivation for f2 based on bootstrap, CI derivation for the difference between reference and test samples, Mahalanobis distance, model-dependent approach and maximum deviation method), their procedures and limitations. However, usage of statistical approaches for the above-described methods can be met with difficulties, especially when combined with the requirement of practice for robust and straightforward techniques for data evaluation. Therefore, the bootstrap to derive the CI for f2 or CI derivation for the difference between reference and test samples was selected as the method of choice.

• Klíčová slova
• EMA and FDA strategy, dissolution profile comparison, drug dissolution,
• Publikační typ
• časopisecké články MeSH

Modern pharmaceutical technology still seeks new excipients and investigates the further use in already known ones. An example is magnesium aluminometasilicate Neusilin® US2 (NEU), a commonly used inert filler with unique properties that are usable in various pharmaceutical fields of interest. We aimed to explore its application in hypromellose matrix systems (HPMC content 10-30%) compared to the traditionally used microcrystalline cellulose (MCC) PH 102. The properties of powder mixtures and directly compressed tablets containing individual fillers NEU or MCC, or their blend with ratios of 1.5:1, 1:1, and 0.5:1 were investigated. Besides the routine pharmaceutical testing, we have enriched the matrices' evaluation with a biorelevant dynamic dissolution study and advanced statistical analysis. Under the USP apparatus 2 dissolution test, NEU, individually, did not provide advantages compared to MCC. The primary limitations were the burst effect increase followed by faster drug release at the 10-20% HPMC concentrations. However, the biorelevant dynamic dissolution study did not confirm these findings and showed similarities in dissolution profiles. It indicates the limitations of pharmacopoeial methods in matrix tablet development. Surprisingly, the NEU/MCC blend matrices at the same HPMC concentration showed technologically advantageous properties. Besides improved flowability, tablet hardness, and a positive impact on the in vitro drug dissolution profile toward zero-order kinetics, the USP 2 dissolution data of the samples N75M50 and N50M50 showed a similarity to those obtained from the dynamic biorelevant apparatus with multi-compartment structure. This finding demonstrates the more predictable in vivo behaviour of the developed matrix systems in human organisms.

• Klíčová slova
• HPMC, Neusilin® US2, USP apparatus 2 dissolution test, dynamic dissolution study, matrix tablets, microcrystalline cellulose,
• Publikační typ
• časopisecké články MeSH

The vaginal rings research is almost exclusively focused on rings for human medicine, although the dosage form offers improvement of therapeutic effect in other mammals as well. This contribution studied an effect of varying dimension parameters (diameter 20, 30 or 40 mm; height 3, 4 or 5 mm; width of annulus 5, 7.5 or 10 mm) on mechanical properties and dissolution behaviour of silicone vaginal rings with constant drug amount, intended for use in dogs. Results showed that altering dimensions influenced mechanical properties (compressive force, tensile strength and resistance of removal thread), in vitro drug release and water uptake. The removal thread resistance was increasing with increasing height and width. Compression force was higher for the rings with smaller diameter. The total drug release was increasing with decreasing height and rising diameter, surface area and water uptake during dissolution test. The initial dissolution rate was slower for the rings with higher width. As the best candidate for use in model dog subjects, the ring with 30 mm diameter, 3 mm height and 7.5 mm width was found. These drug-free vaginal rings were further tested in in vivo safety study. The results did not show any major deviation from the physiological conditions. Graphical abstract.

• Klíčová slova
• DOE, design of experiment, dimension parameters, drug release, silicone elastomer, vaginal ring,
• MeSH
• antikoncepční prostředky ženské * MeSH
• mechanické jevy MeSH
• pevnost v tahu MeSH
• psi MeSH
• rozpustnost MeSH
• testy toxicity MeSH
• uvolňování léčiv MeSH
• zvířata MeSH
• Check Tag
• psi MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH