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The objective of the present work was to develop an artificial neural network (ANN) model to accurately predict the dissolution profile of immediate release tablets based on non-destructive spectral data. Six different tablet formulations with varying API (caffeine) and disintegrant (potato starch) concentrations were prepared. The near-infrared (NIR) and Raman spectra of each tablet were collected in both reflection and transmission modes, then principal component analysis (PCA) was conducted. The training of the ANN was performed at each hidden neuron number from 1 to 10 in order to determine the optimal number of neurons in the hidden layer. The best results were obtained when a small number of neurons (1–3) was used. In the case of all four spectroscopic methods, the average similarity values (f2) of the optimized ANN models were above 59 for the validation tablets, indicating that the predicted dissolution profiles were similar to the measured dissolution curves. The optimized model based on reflection Raman spectra exhibited the best predictive ability. The results demonstrated the potential of ANN models in the implementation of the real-time release testing of tablet dissolution. more...

This study aimed at the preparation and characterization of co-amorphous loratadine–citric acid orally disintegrating dosage forms (ODx). A co-amorphous loratadine–citric acid was prepared by solvent evaporation method in three different molecular ratios. DSC, FTIR, and dissolution studies have been conducted for the binary system. The co-amorphous system was used to obtain oral lyophilizates and orally disintegrating tablets by direct compression. Diameter, thickness, hardness, disintegration time, uniformity of mass, and dissolution was determined for the dosage forms. DSC curves showed a lack of sharp endothermic peaks for the binary systems. FTIR spectra presented a hypsochromic modification of the characteristic peaks. Dissolution studies indicated a five-fold increase in the dissolved amount compared to pure loratadine in water. Disintegration times of direct compression ODx varied in the range of 34–41 s and for freeze-dried ODx in the range of 8–9 s. Friability was under 1% in all cases. The dissolution of loratadine in buffer solution at pH = 1 was almost complete. In conclusion binary systems of loratadine and citric acid enhance solubility and combined with the orally disintegrating pharmaceutical form also increase patient compliance. more...

There are several potential advantages of using experimental design-based retention modeling for chromatographic method development. Most importantly, through the model-delivered systematic understanding (Design Spaces), users can benefit from increased method consistency, flexibility and robustness that can efficiently be achieved at lesser amount of development time. As a result, modeling tools have always been great supplementary assets and welcomed by both the pharmaceutical industry and the regulatory authorities. Most recently published chapters of ICH however - Q2(R2) and Q14 (both currently drafts) - evidence a further paradigm shift, specifying the elements of model-based development strategies in the so-called "enhanced approach". The main aim of this study was to investigate the impact of stationary phase chemistries on chromatographic method performance in the application example of ezetimibe and its related substances. A commercial modeling software package (DryLab®) was used to outline three-dimensional experimental design frameworks and acquire model Design Spaces (DSs) of 9 tested columns. This was done by performing 12 input calibration experiments per column, systematically changing critical method parameters (CMPs) as variables such as the gradient time (tG), temperature (T) and the ternary composition (tC) of the mobile phase. The constructed models allowed studying retention behaviors of selected analytes within each separation systems. In the first part of our work, we performed single optimizations for all nine stationary phases with substantially different surface modifications based on their highest achievable critical resolution values. For these optimum points in silico robustness testing was performed, clearly showing a change of CMPs, depending on the column, and specified optimum setpoint. In the second part of our work, we simultaneously compared the three-dimensional virtual separation models to identify all method parameter combinations that could provide at least baseline separation (R more...

Around 5% of the population of the world is affected with the disease called diabetes mellitus. The main medication of the diabetes is the insulin; the active form is the insulin monomer, which is an instable molecule, because the long storage time, or the high temperature, can cause the monomer insulin to adapt an alternative fold, rich in β-sheets, which is pharmaceutically inactive. The aim of this study is to form different insulin complexes with all the cyclodextrin used for pharmaceutical excipients (native cyclodextrin, methyl, hydroxyethyl, hydroxypropyl and sulfobutylether substituted β-cyclodextrin), in silico condition, with the AutoDock molecular modeling program, to determine the best type of cyclodextrin or cyclodextrin derivate to form a complex with an insulin monomer, to predict the molar ratio, the conformation of the complex, and the intermolecular hydrogen bonds formed between the cyclodextrin and the insulin. From the results calculated by the AutoDock program it can be predicted that insulin can make a stable complex with 5–7 molecules of hydroxypropyl-β-cyclodextrin or sulfobutylether-β-cyclodextrin, and by forming a complex potentially can prevent or delay the amyloid fibrillation of the insulin and increase the stability of the molecule. more...

Moxifloxacin (MOX), a novel fourth-generation fluoroquinolone antibacterial was characterized in terms of β-cyclodextrin (β-CD) complexation in order to improve its antibacterial activity. The inclusion complexation has been examined with a wide variety of state-of-the-art analytical techniques, such as nuclear magnetic resonance spectroscopy (NMR), affinity capillary electrophoresis (ACE), mass spectrometry (MS), infrared spectroscopy (IR) and differential scanning calorimetry (DSC). The stoichiometry of the complex was investigated by two different techniques. NMR Job plot method indicated 1:1 stoichiometry in liquid state, however MS study revealed that a complex with 2:1 (MOX:β-CD) stoichiometry can also be formed in gas phase. The stability constants were determined by 1H NMR titration and ACE at different pH values, where MOX exists predominantly in monocationic, neutral and monoanionic form, respectively, indicating that the neutral macrospecies forms the most stable complex with the host (logK = 2.51 ± 0.03). Geometric aspects of the inclusion complex were assessed by 2D ROESY NMR and proved that the tricyclic moiety of guest can enter the host cavity. To understand the interaction of different protonation forms of MOX with β-CD at atomic level molecular modeling studies were also performed. Solid state complexation in 1:1 M ratio was carried out by lyophilization and investigated by DSC and IR, which also confirmed the inclusion complex formation in solid state. The antibacterial activity of the complex was tested against Gram-negative and Gram-positive bacteria by determination of minimum inhibitory concentrations, which revealed that supramolecular interactions do not affect significantly the antibacterial activity of the drug. more...

Objective: The study aimed at obtaining and characterizing levofloxacin-loaded, poly(ε-caprolactone) electrospun nanofiber formulations to be used as antibacterial wound dressings. Methods: Drug-loaded nanofibers were obtained by the electrospinning process and their morphology was determined using scanning electron microscopy. Structural analysis of the prepared nanofibers was carried out using differential scanning calorimetry and dissolution testing was performed in order to determine drug release. Results: Both nanofiberous formulations (containing 20 % and 50 % w/w levofloxacin) showed dimensions in the range of few hundred nanometers. Thermograms indicated that the formulation containing 20% levofloxacin was totally amorphized, showing a rapid release of the active, in 20 minutes. Conclusions: The poly(ε-caprolactone)-based electrospun nanofibers, containing levofloxacin presented suitable characteristics for obtaining potential antibacterial wound dressings. more...

Pediatric, ibuprofen containing orodispersible tablets (ODTs) were prepared using the SeDeM expert system methodology. In order to facilitate formulation, directly compressible ibuprofen was employed (Ibuprofen DC 8TM) and characterized using its SeDeM profile. The mannitol based superdisintegrant Ludiflash®was characterized by the SeDeM-ODT expert system, which also allowed calculation of the optimal excipient concentration in order to obtain suitable tablet hardness and disintegration time. After adding a sweetener and a standard combination of lubricants, the optimized formulation was directly compressed into tablets and evaluated in terms of tablet hardness, friability, disintegration time and dissolution profile. The SeDeM method was applied to determine the amount of corrective excipient (Ludiflash®) required for the compression of Ibuprofen DC 85TMin order to achieve suitable ODTs. Adequate tablet hardness, disintegration time, friability and dissolution profiles were found during tablet evaluation. more...

Rufinamide (RUF) was characterized in terms of cyclodextrin (CD) complexation in order to improve its aqueous solubility. Binary systems of RUF with three CDs—β-cyclodextrin (β-CD), randomly methylated-β-cyclodextrin (RAMEB) and sulfobutylether-β-cyclodextrin (SBE-β-CD)—were characterized with a wide variety of analytical techniques. Liquid state characterization was carried out by complementary techniques such as nuclear magnetic resonance spectroscopy (NMR), capillary electrophoresis (CE), mass spectrometry (MS) and phase solubility studies. The latter revealed that the stability of the complexes decreased in the order of RAMEB > β-CD > SBE-β-CD. AL-type diagrams were obtained in all cases, characteristic of 1:1 stoichiometry, with a maximum of over 15-fold increase in RUF solubility, when complexed with RAMEB. NMR Job plot and MS studies confirmed phase solubility results, regarding the binding stoichiometry. 1H NMR and 2D ROESY investigations revealed the inclusion of the triazole moiety of RUF, confirmed by molecular modeling. Solid state complexation in 1:1 molar ratio was carried out by kneading method and investigated by differential scanning calorimetry (DSC) and infrared spectroscopy (IR). Comparative dissolution studies indicated an over two-fold improvement in dissolution efficacy of the kneaded products, when compared to the pure drug. Results of the present study might pave the way for a drug formulation with improved bioavailability. more...

Aceclofenac-loaded poly(vinyl-pyrrolidone)-based nanofiber formulations were prepared by electrospinning to obtain drug-loaded orally disintegrating webs to enhance the solubility and dissolution rate of the poorly soluble anti-inflammatory active that belongs to the BCS Class-II. Triethanolamine-containing ternary composite of aceclofenac-poly(vinyl-pyrrolidone) nanofibers were formulated to exert the synergistic effect on the drug-dissolution improvement. The composition and the electrospinning parameters were changed to select the fibrous sample of optimum fiber characteristics. To determine the morphology of the nanofibers, scanning electron microscopy was used. Fourier transform infrared spectroscopy (FT-IR), and differential scanning calorimetry (DSC) were applied for the solid-state characterization of the samples, while the drug release profile was followed by the in vitro dissolution test. The nanofibrous formulations had diameters in the range of few hundred nanometers. FT-IR spectra and DSC thermograms indicated the amorphization of aceclofenac, which resulted in a rapid release of the active substance. The characteristics of the selected ternary fiber composition (10 mg/g aceclofenac, 1% w/w triethanolamine, 15% w/w PVPK90) were found to be suitable for obtaining orally dissolving webs of fast dissolution and potential oral absorption. more...

Computer-aided ultrahigh performance liquid chromatographic (UHPLC) method development and optimization was undertaken in order to replace an underperforming European Pharmacopoeia method for the determination of albendazole and its related substances. In the preliminary screening, a temperature-gradient time bidimensional model was chosen to aid selection of the proper stationary phase. Hereinafter temperature-gradient time-ternary composition and temperature-gradient time-pH tridimensional models were applied for the optimization of critical method parameters. The simulation and in silico robustness testing were realized using DryLab modeling software. The final method was validated for quantification of impurities and assay of the active substance according to the current ICH guidance. The validated methods were tested on a real, commercial tablet formulation. The experimental design-based and software-assisted method development proved to be a fast and reliable way of replacing a method with inadequate selectivity and long runtime with a robust UHPLC-based method, which offers baseline separation for all monitored impurities in 10 min. Results confirm that software-based chromatographic modelling can not only speed up the analytical method development process, but also improve the reliability of the developed method. more...

To evaluate the influence of different variables on tablet formulations containing enalapril maleate and indapamide as active substances, two separate experimental designs were employed: one for evaluating powder properties and the other for tablet characteristics. Because of the low active pharmaceutical ingredient content, it was hypothesized that both powder and tablet properties could be determined only by the characteristics of excipients. In order to test this assumption, both experimental designs were done with placebo mixtures. The optimized formulation was then evaluated both with and without APIs. Results indicated that filler and lubricant percentage, along with compression force, were the most important variables during the formulation study. The optimized formulation showed similar characteristics in both cases for all responses, except for angle of repose and friability where only minor differences were observed. The combination of the applied approaches (using placebo composition and fractional experimental design) proved to be efficient, cost effective and time saving. more...

Local inflammation is a well-known symptom of envenomation by snakes of the family Viperidae, attributed primarily to the phospholipase A2s, metalloproteinases and L-amino acid oxidases contained in their venom. The inflammatory effect of snake venoms has been associated with a marked increase of the cytokines IL-1β, IL-6, IL-8, IL-10 and TNF-α. To determine the impact of Vipera ammodytes ammodytes snake venom on the expression of inflammation-related genes, we incubated human U937 monocyte cells with dilutions of snake venom. Gene expression was quantified for 28 different genes using a TaqMan® Array Human Cytokine Network 96-well Plate in a RT-qPCR system. Our results have demonstrated that 1.0 μg/mL Vipera ammodytes ammodytes venom solution induces a notable change in the expression of several cytokine network genes. Among the upregulated genes, there were several that encode interleukins, interferons, and tumor necrosis factors. We further report the downregulation of three interleukin-related genes. Our findings come as supportive information for the known complex effect of snake venoms on the human cytokine network. It also provides relevant new information regarding the expression of genes that have not been previously associated with the effect of snake venoms. more...

Local inflammation is a well-known symptom of envenomation by snakes of the family Viperidae, attributed primarily to the phospholipase A2s, metalloproteinases and L-amino acid oxidases contained in their venom. The inflammatory effect of snake venoms has been associated with a marked increase of the cytokines IL-1&beta, IL-6, IL-8, IL-10 and TNF-&alpha, To determine the impact of Vipera ammodytes ammodytes snake venom on the expression of inflammation-related genes, we incubated human U937 monocyte cells with dilutions of snake venom. Gene expression was quantified for 28 different genes using a TaqMan&reg, Array Human Cytokine Network 96-well Plate in a RT-qPCR system. Our results have demonstrated that 1.0 &mu, g/mL Vipera ammodytes ammodytes venom solution induces a notable change in the expression of several cytokine network genes. Among the upregulated genes, there were several that encode interleukins, interferons, and tumor necrosis factors. We further report the downregulation of three interleukin-related genes. Our findings come as supportive information for the known complex effect of snake venoms on the human cytokine network. It also provides relevant new information regarding the expression of genes that have not been previously associated with the effect of snake venoms. more...

Chloramphenicol eye drops are commonly prescribed in concentrations of 0.5-1% in the treatment of infectious conjunctivitis. In terms of ophthalmic solution preparation, the major disadvantage of chloramphenicol consists in its low solubility in water. The solubility is increased by substances that form chloramphenicol-complexes, for example: boric acid/borax or cyclodextrins. Objective: Experimental studies aimed to evaluate the potential advantages of enhancing the solubility and stability of chloramphenicol (API) by molecular encapsulation in b-cyclodextrin (CD), in formulation of ophthalmic solutions buffered with boric acid/borax system. Methods and Results: We prepared four APIb- CD complexes, using two methods (kneading and co-precipitation) and two molar ratio of API/b-cyclodextrin (1:1 and 1:2). The formation of complexes was proved by differential scanning calorimetry (DSC) and the in vitro dissolution tests. Using these compounds, we prepared eight ophthalmic solutions, formulated in two variants of chloramphenicol concentrations (0.4% and 0.5%). Each solution was analyzed, by the official methods, at preparation and periodically during three months of storing in different temperature conditions (4°C, 20°C and 30°C). Conclusions: Inclusion of chloramphenicol in b-cyclodextrin only partially solves the difficulties due to the low solubility of chloramphenicol. The protection of chloramphenicol molecules is not completely ensured when the ophthalmic solutions are buffered with the boric acid/borax system. more...

Pediatric, ibuprofen containing orodispersible tablets (ODTs) were prepared using the SeDeM expert system methodology. In order to facilitate formulation, directly compressible ibuprofen was employed (Ibuprofen DC 85™) and characterized using its SeDeM profile. The mannitol based superdisintegrant Ludiflash® was characterized by the SeDeM-ODT expert system, which also allowed calculation of the optimal excipient concentration in order to obtain suitable tablet hardness and disintegration time. After adding a sweetener and a standard combination of lubricants, the optimized formulation was directly compressed into tablets and evaluated in terms of tablet hardness, friability, disintegration time and dissolution profile. The SeDeM method was applied to determine the amount of corrective excipient (Ludiflash®) required for the compression of Ibuprofen DC 85™ in order to achieve suitable ODTs. Adequate tablet hardness, disintegration time, friability and dissolution profiles were found during tablet evaluation. more...

A novel stability indicating gradient reverse-phased high-performance liquid chromatographic method has been developed for the quantification of impurities of perindopril tert-butylamine (PER) in pharmaceutical dosage form. Separation of the active substance and its known (Impurities B, C, D, E, F) and unknown impurities was achieved on a BDS Hypersil C18 column (250 mm × 4.6 mm, 5 µm), thermostated at 70°C, using a mobile phase comprised of aqueous solution of sodium 1-heptanesulfonate adjusted to pH 2 with perchloric acid and acetonitrile. The flow rate was maintained at 1.5 mL min(-1), injection volume of 20 µL was utilized and detection of analytes was performed at 215 nm. The developed method was validated in accordance with current ICH Guidelines for all suggested parameters, including forced degradation studies and proved to be linear, accurate, precise and suitable for the impurity testing of PER, being subsequently applied during on-going stability studies of a newly developed generic formulation. more...

The use of dry powder formulations presents an alternative through which to achieve better deposition and residence time in the nasal cavity, increased stability and possible absorption enhancement. The most important factors involved in the preformulation are particle size and physical stability. Propranolol hydrochloride a model drug was subjected to spray-drying technology to form an intranasal dry powder. Particle size reduction of the drug was carried out by integration (spray-drying) methods, using different excipients. The micrometric properties were characterized by size and morphology. The structure was determined through the use of differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy investigations. It was concluded that the intranasal dry powder formulation of propranolol hydrochloride can be achieved with a suitable particle size without polymorph modification or chemical decomposition. more...

A quick and efficient method to eliminate pain is combining complementary action and substances with synergic effect. Such an association is the one between tramadol hydrochloride and paracetamol, in which the rapid reaction time of the paracetamol is combined with the long-term effect of the tramadol hydrochloride.Our aim was to develop and characterize alternative tablet formulations containing tramadol hydrochloride 37.5 mg and paracetamol 325 mg with different excipients in different ratio, and also the development of a new electrophoretic method for the quantitative determination of the active substances.The tablets were evaluated for physical characteristics (weight, thickness, diameter, mechanical strength, friability, disintegration time), drug content and dissolution following Ph.Eur.7 and USP 35 guidelines. A new capillary electrophoretic method was developed for the determination of the two active substances.Capillary electrophoresis proved to be an efficient method for the determination of drug content and also for the dissolution profile. The two substances were separated based on the differences between their own electrophoretic mobilities, and determined in UV at two different wavelengths.Tablet formulation proved to be a significant factor in quality of tramadol hydrochloride/paracetamol tablets, as considerable differences between tablets containing different excipients were found; while capillary electrophoresis can be considered a useful alternative for the quantitative determination of tramadol hydrochloride/paracetamol combinations. more...

The aim of the study was to investigate the stability of some oral liquid formulations containing 1 mg/ml captopril.The oral solutions were prepared using captopril substance, keeping the formulation as simple as possible to avoid potentially undesirable excipients. Samples were stored for 39 days below 8 degrees C and at 22 +/- 3 degrees C and analysed for physical, chemical and microbiological stability.The formulations with ascorbic acid are stable for seven days either at 8 and 22 degrees C and could be prepared in hospital pharmacy as a more safely alternative to children terapy with tablets powders. more...

Thermal and chemical stability of pentoxifylline from modified release tablets were studied. This experimental study observed the influence of temperature and humidity on the stability of pentoxifylline from the proposed formulations. The paper describes the HPLC determination of pentoxifylline from new controlled release tablets with hydrophilic matrix (HPMC, HPC, HEC). A C18 column with a mobile phase containing water : acetonitrile 70:30 (V/V) and UV detection at 280 nm was used. The "in vitro" dissolution test was carried out regarding the officinal stipulations of USP; the machine nr.2 was used (with paddles); as dissolution environment 1000 ml water, a constant temperature of 37 plusmn 0.5degC was kept. In all experiences, the rotation speed was 50 rpm. The studied tablets were kept in the stability chamber at a temperature of 40 plusmn 2degC and a relative humidity of 75 plusmn 5%. At different time intervals (a month, three months, six months), samples were prelevated to accomplish the dissolution test and the quantitative determination of pentoxifylline. From the evaluation of the experimental results, we observed the stability of pentoxifylline from all the prepared tablets. more...

Purpose: To formulate dexpanthenol gels with enhanced in vivo absorption properties via skin.Methods: Carboxyvinyl derivatives (Carbopol 980 and Ultrez 10) and poloxamer (Lutrol F 127) were used as the hydrogel base in the formulations. Changes in rheological properties (apparent viscosity and penetration values) during the storage period were examined by Rheotest RN rotational viscometer and PNR12 penetrometer. In vitro release study using Franz diffusion cell was employed to compare the release characteristics of the formulated hydrogels with those of a reference cream.Results: The flow curves of the gels with Carbopol 980 and Ultrez 10 showed pseudoplastic flow. Lutrol F 127 gels presented thixotropic behaviour. The consistency of the studied gels was in the following rank order: Lutrol F 127 > Ultrez 10 > Carbopol 980. In vitro results showed that dexpanthenol was released in lower amounts from the reference cream than from the three test gels. No significant differences were observed in the amount of active substance released from the gels due probably to the fact that Carbopol 980 and Ultrez 10 are both carboxyvinyl polymers. The highest amount of dexpanthenol was released from Lutrol F 127 gel.Conclusion: The hydrogel made with Lutrol F 127 gel base possesses the best properties of all the gels and is recommended for the formulation of a suitable dexpanthenol gel.Keywords: Hydrogel, Dexpanthenol, Carboxyvinyl polymers, Gels, Carbopol, Poloxamer, Rheology, Drug release, Penetrometer more...