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

Hypromellose matrices exhibit extended burst effect immediately after contact with aqueous medium, especially when a water-soluble drug is incorporated. The objective of this study was to reduce burst effect and maintain complete dissolution of a very soluble levetiracetam over 12 h period from hypromellose K4M matrices to obtain zero-order kinetics. Desired changes were achieved by applying water dispersions of insoluble Eudragits® (NE, NM, RL, RS) as a granulation liquid to the drug/microcrystalline cellulose mixture during high-shear granulation (non-thermal treated set) and consequently by thermally treating granules or final tablets (TT), respectively. Applying Eudragit® water dispersions to the drug/microcrystalline cellulose mixture was recognized as an effective method of significantly reducing the burst release (25.4-33.7%) of levetiracetam in comparison with a reference sample without Eudragit®. Multivariate data analysis showed that the addition of Eudragit® reduced burst effect, increased fitting with zero-order kinetics, and supported matrix erosion as the supplementary mechanism to predominant diffusion. Moreover, resulting PCA sub-model revealed the addition of Eudragit® RL and thermal treatment of tablets to be the most suitable method of all. For a 12 h dissolution profile, characterized by low burst effect and drug release close to 100% at the 12th hour, sample RL_TT was the most suitable.

• Klíčová slova
• Eudragit® NE, HPMC, NM, Prolonged drug release, RL, RS, burst effect, levetiracetam, matrix tablets, multivariate data analysis, thermal treatment,
• MeSH
• antikonvulziva aplikace a dávkování   chemie   MeSH
• celulosa chemie   MeSH
• deriváty hypromelózy chemie   MeSH
• kyseliny polymethakrylové chemie   MeSH
• léky s prodlouženým účinkem chemie   MeSH
• levetiracetam MeSH
• multivariační analýza MeSH
• piracetam aplikace a dávkování   analogy a deriváty   chemie   MeSH
• příprava léků metody   MeSH
• rozpustnost MeSH
• tablety MeSH
• teplota MeSH
• uvolňování léčiv MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antikonvulziva MeSH
• celulosa MeSH
• deriváty hypromelózy MeSH
• kyseliny polymethakrylové MeSH
• léky s prodlouženým účinkem MeSH
• levetiracetam MeSH
• methylmethacrylate-methacrylic acid copolymer MeSH Prohlížeč
• microcrystalline cellulose MeSH Prohlížeč
• piracetam MeSH
• tablety MeSH

A fully automated sequential injection system was tested in terms of its application in liberation testing, and capabilities and limitations were discussed for clotrimazole liberation from three semisolid formulations. An evaluation based on kinetic profiles obtained in short and longer sampling intervals and steady-state flux values were applied as traditional methods. The obtained clotrimazole liberation profile was faster in the case of Delcore and slower for Clotrimazol AL and Canesten cream commercial formulations. The steady-state flux values for the tested formulations were 52 µg cm-2 h-1 for Canesten, 35 µg cm-2 h-1 for Clotrimazol AL, and 7.2 µg cm-2 h-1 for Delcore measured in 4 min sampling intervals. A simplified approach for the evaluation of the initial rate based on the gradient between the second and third sampling points was used for the first time and was found to correspond well with the results of the conventional methods. A comparison based on the ratio of the steady-state flux and the initial rate values for Canesten and Clotrimazol AL proved the similarity of the obtained results. The proposed alternative was successfully implemented for the comparison of short-term kinetic profiles. Consequently, a faster and simpler approach for dissolution/liberation testing can be used.

• Klíčová slova
• Franz cell, clotrimazole, kinetic profile, liberation study, sequential injection analysis,
• MeSH
• antifungální látky analýza   MeSH
• kinetika MeSH
• klotrimazol analýza   MeSH
• laboratorní automatizace metody   MeSH
• pleťový krém MeSH
• příprava léků MeSH
• průtoková injekční analýza metody   MeSH
• uvolňování léčiv MeSH
• Publikační typ
• časopisecké články MeSH
• hodnotící studie MeSH
• Názvy látek
• antifungální látky MeSH
• klotrimazol MeSH

Warfarin is intensively discussed drug with narrow therapeutic index. In the past, its generic substitution was identified as a cause of bleeding. Altered quality of the active substance or varying drug content was discussed. The substance quality can be evaluated with adequate dissolution method. An official dissolution method with aqueous medium exists, however this method is non-discriminatory. In the first 15 minutes the whole amount of the active pharmaceutical ingredient is released from a tested dosage form, which does not allow comparison between tablets from different producers and it also makes difficult to track the changes throughout stability testing. In the literature, there is a well known method using pH 6.8 buffer, which seems to be a suitable alternative to water. The aim of this study was to prove, that this alternative medium, when two stirring speeds for dissolution (50 or 25 rpm) are used, will be suitable for calculation of similarity and difference factor and if it will be eventually discriminatory with regard to particle size and radial hardness. For this purpose we prepared tablets with 10 mg of warfarin sodium in form of crystalline clathrate with isopropanol. Tablets differed by particle size of active pharmaceutical ingredient (d50 = 4.8, or d50 = 22.5 μm respectively) and by radial hardness (30, or 100 N respectively). The content uniformity of the tablets was determined using process capability index (Cpk) and Bergum method. It was confirmed that the dissolution medium with pH of 6.8 allows comparison of dissolution profiles by similarity and difference factors but under given conditions it is not discriminatory.Key words: warfarin dissolution method particle size distribution radial hardness similarity factor difference factor.

• MeSH
• farmaceutická technologie MeSH
• rozpustnost MeSH
• tablety MeSH
• velikost částic MeSH
• warfarin chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• tablety MeSH
• warfarin MeSH

Warfarin is intensively discussed drug with narrow therapeutic range. There have been cases of bleeding attributed to varying content or altered quality of the active substance. Factor analysis is useful for finding suitable technological parameters leading to high content uniformity of tablets containing low amount of active substance. The composition of tabletting blend and technological procedure were set with respect to factor analysis of previously published results. The correctness of set parameters was checked by manufacturing and evaluation of tablets containing 1-10mg of warfarin sodium. The robustness of suggested technology was checked by using "worst case scenario" and statistical evaluation of European Pharmacopoeia (EP) content uniformity limits with respect to Bergum division and process capability index (Cpk). To evaluate the quality of active substance and tablets, dissolution method was developed (water; EP apparatus II; 25rpm), allowing for statistical comparison of dissolution profiles. Obtained results prove the suitability of factor analysis to optimize the composition with respect to batches manufactured previously and thus the use of metaanalysis under industrial conditions is feasible.

• Klíčová slova
• Common blend, Content uniformity, Dissolution method, Factor analysis, Process optimization, Sampling error, Worst case,
• MeSH
• antikoagulancia chemie   MeSH
• faktorová analýza statistická MeSH
• příprava léků statistika a číselné údaje   MeSH
• tablety MeSH
• uvolňování léčiv MeSH
• warfarin chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antikoagulancia MeSH
• tablety MeSH
• warfarin MeSH

This study was designed to assess both the quality and cost aspects of various branded and generic formulations of angiotensin receptor blockers, specifically Irbesartan, Losartan Potassium, Olmesartan Medoxomil, Telmisartan, and Valsartan. The collected samples underwent distinct quality evaluations using the methods outlined in different global Pharmacopoeias (British Pharmacopoeia/European Pharmacopoeia, Indian Pharmacopoeia and United States Pharmacopoeia). These drugs were characterized using Fourier-Transform Infrared Spectroscopy and Nuclear Magnetic Resonance techniques, while their quality and concentration were analysed using High Performance Liquid Chromatography. The release profile of the drugs was examined through dissolution testing. Additionally, a cost comparison analysis was carried out by determining the prevailing market prices of the drugs. The evaluated branded and generic angiotensin receptor blockers were found to meet the established standards for impurities, active drug content, and dissolution as set by these Pharmacopoeias, indicating their optimal quality. Notably, the generic drugs exhibited significantly lower costs compared to their branded counterparts. This study confirms that the quality of generic angiotensin receptor blockers is equivalent to that of their branded counterparts. Consequently, these findings support the practicality of utilizing generic drugs as a more economically sustainable and cost-effective approach to managing diseases, especially those of chronic nature.

• Klíčová slova
• Drugs, High-Performance Liquid Chromatography, Nuclear Magnetic Resonance, Pharmaceutical Quality Control,
• Publikační typ
• časopisecké články MeSH

The dissolution mechanism of a poorly aqueous soluble drug from amorphous solid dispersions was investigated using a combination of two imaging methods: attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopic imaging and magnetic resonance imaging (MRI). The rates of elementary processes such as water penetration, polymer swelling, growth and erosion of gel layer, and the diffusion, release and in some cases precipitation of drug were evaluated by image analysis. The results from the imaging methods were compared with drug release profiles obtained by classical dissolution tests. The study was conducted using three polymeric excipients (soluplus, polyvinylpyrrolidone - PVP K30, hydroxypropylmethyl cellulose - HPMC 100M) alone and in combination with a poorly soluble drug, aprepitant. The imaging methods were complementary: ATR-FTIR imaging enabled a qualitative observation of all three components during the dissolution experiments, water, polymer and drug, including identifying structural changes from the amorphous form of drug to the crystalline form. The comparison of quantitative MRI data with drug release profiles enabled the different processes during dissolution to be established and the rate-limiting step to be identified, which - for the drug-polymer combinations investigated in this work - was the drug diffusion through the gel layer rather than water penetration into the tablet.

• Klíčová slova
• Dissolution rate, FT-IR spectroscopy, Magnetic resonance imaging, Solid dispersion, Spray drying, Water penetration,
• MeSH
• aprepitant MeSH
• časové faktory MeSH
• magnetická rezonanční tomografie * přístrojové vybavení   MeSH
• molekulární struktura MeSH
• morfoliny chemie   MeSH
• polymery chemie   MeSH
• spektroskopie infračervená s Fourierovou transformací přístrojové vybavení   MeSH
• uvolňování léčiv MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aprepitant MeSH
• morfoliny MeSH
• polymery MeSH

Drug loading into mesoporous carriers may help to improve the dissolution of poorly aqueous-soluble drugs. However, both preparation method and carrier properties influence loading efficiency and drug release. Accordingly, this study aimed to compare two preparation methods: formulation into liquisolid systems (LSS) and co-milling for their efficiency in loading the poorly soluble model drug cyclosporine A (CyA) into mesoporous magnesium aluminometasilicate Neusilin® US2 (NEU) or functionalized calcium carbonate (FCC). Scanning electron microscopy was used to visualize the morphology of the samples and evaluate the changes that occurred during the drug loading process. The solid-state characteristics and physical stability of the formulations, prepared at different drug concentrations, were determined using X-ray powder diffraction. In vitro release of the drug was evaluated in biorelevant media simulating intestinal fluid. The obtained results revealed improved drug release profiles of the formulations when compared to the milled (amorphous) CyA alone. The dissolution of CyA from LSS was faster in comparison to the co-milled formulations. Higher drug release was achieved from NEU than FCC formulations presumably due to the higher pore volume and larger surface area of NEU.

• Klíčová slova
• Co-milling, Cyclosporine A, Drug loading, Liquisolid systems, Mesoporous carrier,
• MeSH
• difrakce rentgenového záření MeSH
• pomocné látky * MeSH
• poréznost MeSH
• rozpustnost MeSH
• voda * MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• pomocné látky * MeSH
• voda * MeSH

External ionotropic gelation offers a unique possibility to entrap multivalent ions in a polymer structure. The aim of this experimental study was to prepare new drug-free sodium alginate (ALG) particles cross-linked by Cu2+ ions and to investigate their technological parameters (particle size, sphericity, surface topology, swelling capacity, copper content, release of Cu2+ ions, mucoadhesivity) and biological activity (cytotoxicity and efficiency against the most common vaginal pathogens-Herpes simplex, Escherichia coli, Candida albicans) with respect to potential vaginal administration. Beads prepared from NaALG dispersions (3 or 4%) were cross-linked by Cu2+ ions (0.5 or 1.0 M CuCl2) using external ionotropic gelation. Prepared mucoadhesive beads with particle size over 1000 μm exhibited sufficient sphericity (all ˃0.89) and copper content (214.8-249.07 g/kg), which increased with concentration of polymer and hardening solution. Dissolution behaviour was characterized by extended burst effect, followed by 2 h of copper release. The efficiency of all samples against the most common vaginal pathogens was observed at cytotoxic Cu2+ concentrations. Anti-HSV activity was demonstrated at a Cu2+ concentration of 546 mg/L. Antibacterial activity of beads (expressed as minimum inhibition concentration, MIC) was influenced mainly by the rate of Cu2+ release which was controlled by the extent of swelling capacity. Lower MIC values were found for E. coli in comparison with C. albicans. Sample ALG-3_1.0 exhibited the fastest copper release and was proved to be the most effective against both bacteria. This could be a result of its lower polymer concentration in combination with smaller particle size and thus larger surface area.

• Klíčová slova
• alginate beads, copper’s biological effects, dissolution profile, external gelation, vaginal administration,
• MeSH
• algináty chemie   farmakologie   MeSH
• antibakteriální látky farmakologie   MeSH
• gely chemie   MeSH
• kationty MeSH
• kyselina glukuronová chemie   farmakologie   MeSH
• kyseliny hexuronové chemie   farmakologie   MeSH
• měď chemie   farmakologie   MeSH
• polymery chemie   MeSH
• rozpustnost MeSH
• skot MeSH
• velikost částic MeSH
• zvířata MeSH
• Check Tag
• skot MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• algináty MeSH
• antibakteriální látky MeSH
• gely MeSH
• kationty MeSH
• kyselina glukuronová MeSH
• kyseliny hexuronové MeSH
• měď MeSH
• polymery MeSH