The rising demands on discriminatory and prediction abilities of dissolution methods and the increasing complexity of new drug products are the main driving forces of the progress in this field. The research moves forward as imperfections and shortcomings of classical methods are being described, and where the capabilities of the contemporary methods are insufficient, new methods are being developed. The review discusses these advances with respect to the issues that currently draw the most attention, i.e. correct simulation of hydrodynamics and stress forces, maintenance of sink conditions, study of precipitation, use of biorelevant media and the employment of more physiologically relevant methods in general.
- Keywords
- Apparatus, biorelevant, dissolution, precipitation, sink conditions,
- MeSH
- Chemistry, Pharmaceutical instrumentation methods MeSH
- Hydrodynamics MeSH
- Pharmaceutical Preparations chemistry MeSH
- Humans MeSH
- Drug Design * MeSH
- Drug Liberation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Names of Substances
- Pharmaceutical Preparations 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.
- Keywords
- Golem, biorelevant, caffeine, dissolution, multivariate data analysis,
- MeSH
- Models, Biological * MeSH
- Equipment Design MeSH
- Chemistry, Pharmaceutical * MeSH
- Pharmacokinetics * MeSH
- Gastrointestinal Absorption MeSH
- Gastrointestinal Tract metabolism MeSH
- Multivariate Analysis MeSH
- Computer Simulation MeSH
- Solubility * MeSH
- Publication type
- Journal Article MeSH
Meloxicam (MLX) is a poorly soluble drug exhibiting strong hydrophobicity. This combination of properties makes dissolution enhancement by particle size reduction ineffective; therefore, combined formulation approaches are required. Various approaches were investigated in this study, including milling, solid dispersions, and self-emulsified lipid formulations. Whereas milling studies of MLX and its co-milling with various polymers have been reported in recent literature, this study is focused on investigating the dissolution kinetics of particulate formulations obtained by co-milling MLX with sodium lauryl sulfate (SLS) in a planetary ball mill with 5-25 wt.% SLS content. The effects of milling time and milling ball size were also investigated. No significant reduction in drug crystallinity was observed under the investigated milling conditions according to XRD data. For the dissolution study, we used an open-loop USP4 dissolution apparatus, and recorded dissolution profiles were fitted according to the Weibull model. The Weibull parameters and a novel criterion-surface utilization factor-were used to evaluate and discuss the drug release from the perspective of drug particle surface changes throughout the dissolution process. The most effective co-milling results were achieved using smaller balls (2 mm), with a co-milling time of up to 15 min SLS content of up to 15 wt.% to increase the dissolution rate by approximately 100 times relative to the physical mixture reference. The results suggest that for hydrophobic drugs, particle performance during dissolution is very sensitive to surface properties and not only to particle size. Co-milling with SLS prepares the surface for faster drug release than that achieved with direct mixing.
- Keywords
- co-milling, dissolution kinetics, dissolution rate, enhanced dissolution, meloxicam, sodium lauryl sulfate, surface modification,
- Publication type
- Journal Article MeSH
The aim of this study was to improve rivaroxaban water-solubility by cocrystal preparation and to understand this process. The screening with water-soluble coformers was performed via both mechanochemical and solution-mediated techniques. Two cocrystals of rivaroxaban with malonic acid and oxalic acid were prepared, and the structure of the cocrystal with oxalic acid was solved. Both cocrystals exhibit improved dissolution properties. The mechanism of the supersaturation maintenance was studied by in-situ Raman spectroscopy. The transformation into rivaroxaban dihydrate was identified as the critical step in the improved dissolution properties of both cocrystals. Moreover, the transformation kinetics and solubilization effects of the coformers were identified as responsible for the differences in the dissolution behavior of the cocrystals. In-vivo experiments proved that the use of cocrystal instead of form I of free API helped to increase the bioavailability ofrivaroxaban.
- Keywords
- Cocrystal, Dissolution, In-vivo studies, Rivaroxaban, Solid form transformation, Solubilization,
- MeSH
- X-Ray Diffraction MeSH
- Crystallization MeSH
- Oxalic Acid MeSH
- Rivaroxaban * MeSH
- Solubility MeSH
- Water * chemistry MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Oxalic Acid MeSH
- Rivaroxaban * MeSH
- Water * 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.
- Keywords
- Ball milling, Co-grinding, Co-milling, Dissolution rate enhancement, In silico modelling, Multiple linear regression, Partial least squares regression,
- MeSH
- Pharmaceutical Preparations chemistry MeSH
- Least-Squares Analysis MeSH
- Computer Simulation MeSH
- Povidone chemistry MeSH
- Drug Compounding * methods MeSH
- Solubility * MeSH
- Drug Liberation * MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Pharmaceutical Preparations MeSH
- Povidone MeSH
Transforming poorly soluble active pharmaceutical ingredients (APIs) into a nanoparticulate form is a proven way of improving their dissolution characteristics. The preparation of API nanosuspensions is commonly achieved by wet-stirred media milling. The challenge lies in converting the nanosuspension into a solid dosage form without compromising its re-dispersibility. In the present work, an API nanosuspension was combined with additional excipients and used as abinder in fluid-bed granulation to obtain granules with systematically varying dissolution properties. Specifically, polymeric excipients (hydroxypropyl methylcellulose grade E5 and polyvinylpyrrolidone grade K30) were used in the nanosuspension binder to granulate microcrystalline cellulose or Pearlitol CR-H substrate. The resulting granules were used as feed material to prepare minitablets whose combination enabled the formation of multi-unit dosage form (MUDF) capsules with tuneable drug release profiles, paving the way to rational design and manufacturing of precision medicines.
- Keywords
- Dissolution, Fluid-bed granulation, Minitablets, Nanosuspension, Precision medicine,
- MeSH
- Cellulose chemistry MeSH
- Hypromellose Derivatives * chemistry MeSH
- Chemistry, Pharmaceutical methods MeSH
- Nanoparticles * chemistry MeSH
- Excipients * chemistry MeSH
- Povidone * chemistry MeSH
- Drug Compounding * methods MeSH
- Solubility * MeSH
- Suspensions * MeSH
- Tablets MeSH
- Drug Liberation * MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Cellulose MeSH
- Hypromellose Derivatives * MeSH
- microcrystalline cellulose MeSH Browser
- Excipients * MeSH
- Povidone * MeSH
- Suspensions * MeSH
- Tablets MeSH
CONTEXT: The preparation of liquisolid systems (LSS) represents a promising method for enhancing a dissolution rate and bioavailability of poorly soluble drugs. The release of the drug from LSS tablets is affected by many factors, including the disintegration time. OBJECTIVE: The evaluation of differences among LSS containing varying amounts and types of commercially used superdisintegrants (Kollidon® CL-F, Vivasol® and Explotab®). MATERIALS AND METHODS: LSS were prepared by spraying rosuvastatin solution onto Neusilin® US2 and further processing into tablets. Varying amounts of superdisintegrants were used and the differences among LSS were evaluated. The multiple scatter plot method was used to visualize the relationships within the obtained data. RESULTS AND DISCUSSION: All disintegrants do not showed negative effect on the flow properties of powder blends. The type and concentration of superdisintegrant had an impact on the disintegration time and dissolution profiles of tablets. Tablets with Explotab® showed the longest disintegration time and the smallest amount of released drug. Fastest disintegration and dissolution rate were observed in tablets containing Kollidon® CL-F (≥2.5% w/w). Also tablets with Vivasol® (2.5-4.0% w/w) showed fast disintegration and complete drug release. CONCLUSION: Kollidon® CL-F and Vivasol® in concentration ≥2.5% are suitable superdisintegrants for LSS with enhanced release of drug.
- Keywords
- Data visualization, disintegration time, dissolution profile, liquisolid systems, superdisintegrant,
- MeSH
- Anticholesteremic Agents administration & dosage chemistry MeSH
- Pharmaceutic Aids chemistry MeSH
- Povidone chemistry MeSH
- Drug Compounding MeSH
- Rosuvastatin Calcium administration & dosage chemistry MeSH
- Solubility MeSH
- Silicates chemistry MeSH
- Starch analogs & derivatives chemistry MeSH
- Aluminum Compounds chemistry MeSH
- Magnesium Compounds chemistry MeSH
- Tablets chemistry MeSH
- Drug Liberation MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- aluminum magnesium silicate MeSH Browser
- Anticholesteremic Agents MeSH
- Pharmaceutic Aids MeSH
- Povidone MeSH
- Rosuvastatin Calcium MeSH
- Silicates MeSH
- Starch MeSH
- Aluminum Compounds MeSH
- Magnesium Compounds MeSH
- sodium starch glycolate MeSH Browser
- Tablets 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.
- Keywords
- Hydrolysis, Injectable depot systems, Nanosuspension, Paliperidone palmitate, Particle size distribution, Reactive dissolution,
- MeSH
- Antipsychotic Agents * MeSH
- Injections, Intramuscular MeSH
- Delayed-Action Preparations MeSH
- Humans MeSH
- Prodrugs * MeSH
- Solubility MeSH
- Suspensions MeSH
- Drug Liberation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Antipsychotic Agents * MeSH
- Delayed-Action Preparations MeSH
- Prodrugs * MeSH
- Suspensions 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.
- Keywords
- EMA and FDA strategy, dissolution profile comparison, drug dissolution,
- Publication type
- Journal Article MeSH
The purpose of this study was to specify critical parameters (physicochemical characteristics) of drug substance that can affect dissolution profile/dissolution rate of the final drug product manufactured by validated procedure from various batches of the same drug substance received from different suppliers. The target was to design a sufficiently robust drug substance specification allowing to obtain a satisfactory drug product. For this reason, five batches of the drug substance and five samples of the final peroral drug products were analysed with the use of solid state analysis methods on the bulk level. Besides polymorphism, particle size distribution, surface area, zeta potential, and water content were identified as important parameters, and the zeta potential and the particle size distribution of the drug substance seem to be critical quality attributes affecting the dissolution rate of the drug substance released from the final peroral drug formulation.
