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In order to improve the delivery of topical corticosteroids into inflammatory skin lesions while reducing the likelihood of adverse effects, lipid nanocarriers have received increasing attention. Hence, this study aimed to develop biocompatible nanoemulsions (NEs) and nanostructured lipid carriers (NLCs) as carriers for fluocinolone acetonide (FA) by carefully optimizing the formulation and process parameters. After an analysis of the relevant physicochemical parameters and stability testing, in vitro release and permeation tests were performed to evaluate whether the nanocarriers affected the penetration of FA into/through the skin compared to a conventional reference product (Sinoderm® cream). The developed NEs exhibited satisfactory physicochemical properties (droplet size |-30| mV, pH ~ 4.75) and long-term stability. Although the developed NLCs initially had satisfactory properties, gelation was observed within 3 months of storage, implying that further formulation testing is required to resolve the limited stability of these systems. In vitro release/permeation findings suggest that the developed nanocarriers (especially NEs) provide better delivery of FA into/though the skin compared to the Sinoderm® cream. Therefore, a lecithin-based NE with a 10% lipid phase (medium-chain triglycerides/oleic acid 3:1) is a promising strategy for improved delivery of FA to the inflamed skin, allowing for ease of application, especially to larger skin surfaces and hairy regions.

Polyelectrolyte complexes (PECs) are attractive carriers with recognized potential to enhance oral delivery of poorly soluble high-dosed low-molecular-weight drugs. The formulation of solid oral dosage forms requires the drying of PECs, which may affect their physicochemical and biopharmaceutical properties. The aim of this study was to investigate the effect of spraydrying on the properties of ibuprofen-loaded chitosan/xanthan gum PECs and to assess the drug release kinetics from such PECs filled into hard capsules in comparison with corresponding PECs which are dried under ambient conditions. The yield, ibuprofen content, entrapment efficiency, and residual moisture content of spray-dried PECs were lower than those of ambient-dried PECs. Better flowability of spray-dried PECs was attributed to the almost spherical particle shape, shown by scanning electron microscopy. DSC and PXRD analysis confirmed the amorphization of ibuprofen during spray-drying. All the investigated PECs, obtained by drying under ambient conditions as well as by spray-drying, had high rehydration capacity both in 0.1 M hydrochloric acid (pH 1.2) and phosphate buffer pH 7.4. In vitro ibuprofen release from dried PECs was controlled during 12 h with the release of approximately 30% of entrapped ibuprofen. Spray-dried PECs provided better control of ibuprofen diffusion from the carrier compared to the ambientdried ones.

Drug discovery and development is a very challenging, expensive and time-consuming process. Impressive technological advances in computer sciences and molecular biology have made it possible to use computer-aided drug design (CADD) methods in various stages of the drug discovery and development pipeline. Nowadays, CADD presents an efficacious and indispensable tool, widely used in medicinal chemistry, to lead rational drug design and synthesis of novel compounds. In this article, an overview of commonly used CADD approaches from hit identification to lead optimization was presented. Moreover, different aspects of design of multitarget ligands for neuropsychiatric and anti-inflammatory diseases were summarized. Apparently, designing multi-target directed ligands for treatment of various complex diseases may offer better efficacy, and fewer side effects. Antipsychotics that act through aminergic G protein-coupled receptors (GPCRs), especially Dopamine D2 and serotonin 5-HT2A receptors, are the best option for treatment of various symptoms associated with neuropsychiatric disorders. Furthermore, multi-target directed cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors are also a successful approach to aid the discovery of new anti-inflammatory drugs with fewer side effects. Overall, employing CADD approaches in the process of rational drug design provides a great opportunity for future development, allowing rapid identification of compounds with the optimal polypharmacological profile.

This paper presents study of losartan potassium stability evaluation by liquid chromatography with UV/VIS and MS-MS detection and its degradation profile. A solution of losartan potassium was exposed to the following stress agents: 0.1 M HCl, 0.1 M NaOH, and 3% (v/v) H2O2. The analyses of losartan potassium solutions were carried out in a gradient elution mode with acetonitrile and 0.1% (v/v) CF3COOH aqueous solution and constant flow rate of 0.5 mL min-1 within 22 min run time. After 7 days of losartan potassium solutions exposure to the stress agents at room temperature, it was found that the degree of degradation in the presence of 0.1 M HCl and 0.1 M NaOH was less than 1%, while in the presence of 3% H2O2 degradation was significantly higher (about 10%). Chemical structure elucidation of the major degradation products of losartan potassium was performed using LC-MS/MS method. The concentration versus time plot indicated that in 3% (v/v) H2O2 solution losartan potassium was degraded according to the pseudo zero-order reaction kinetics with 1.48·10-8 mol L-1 day-1 rate constant.

Acetylsalicylic acid belongs to nonsteroidal anti-inflammatory drugs with antiinflammatory, analgesic and antipyretic properties. The aim of this work was development and validation of HPLC method for qualitative and quantitative analysis of acetylsalicylic acid and its major degradation product, salicylic acid, in dosage forms. The optimal separation was achived using Zorbax Eclipse XDB-C18 Analytical column (4,6x150 mm, particle size 5 μm) thermostated at 35°C. Mobile phase consisted of eluents A and B in ratio 65:35 (V/V). As the eluent A, water of HPLC purity and 85% phosphoric acid in ratio 80:0.5 (V/V) were used, while acetonitrile was used as the eluent B. The flow rate was 1.0 mL/min and UV detection was performed at 240 nm. The method was validated in terms of selectivity, linearity, precision, accuracy and robustness for both analytes, as well as limits of detection and quantification for salicylic acid. The obtained results meet the requirements of analytical procedures validation. The proposed HPLC method was applied in qualitative and quantitative analysis of acetylsalicylic and salicylic acids in six different forms of drugs. All obtained results meet the requirements of manufacturer specifications. The established HPLC method was found to be rapid, simple, accurate and selective for simultaneous determination of acetylsalicylic and salicylic acids in dosage forms.

Acridine ring can be found in molecules used in many different spheres, including industry and medicine. Nowadays, even acridines with antibacterial activity are of research interest due to increasing bacterial resistance. Some acridine derivatives showed antimalarial or antiviral activity. Acridine derivatives were also investigated for antitumor activity due to the interaction with topoisomerase II and DNA base pairs. Considering these possible uses of acridine derivatives, this work was made as overview of all significant structure characteristics for specific action of these compounds.

Two types of biocompatible surfactants were evaluated for their capability to formulate skin-friendly/non-irritant microemulsions as vehicles for two poorly water-soluble model drugs differing in properties and concentrations: alkyl polyglucosides (decyl glucoside and caprylyl/capryl glucoside) and ethoxylated surfactants (glycereth-7-caprylate/ caprate and polysorbate 80). Phase behavior, structural inversion and microemulsion solubilization potential for sertaconazole nitrate and adapalene were found to be highly dependent on the surfactants structure and HLB value. Performed characterization (polarized light microscopy, pH, electrical conductivity, rheological, FTIR and DSC measurements) indicated a formulation containing glycereth- 7-caprylate/caprate as suitable for incorporation of both drugs, whereas alkyl polyglucoside-based systems did not exhibit satisfying solubilization capacity for sertaconazole nitrate. Further, monitored parameters were strongly affected by sertaconazole nitrate incorporation, while they remained almost unchanged in adapalene-loaded vehicles. In addition, results of the in vivo skin performance study supported acceptable tolerability for all investigated formulations, suggesting selected microemulsions as promising carriers worth exploring further for effective skin delivery of model drugs.

Development and validation of a liquid chromatography - tandem mass spectrometry (LC-MS/MS) method for the determination of adapalene in pharmaceutical forms for skin application were presented. The MS/MS analysis of adapalene was performed by use of three mobile phases, consisted of acetonitrile and (a) 0.1 % formic acid, (b) 0.1 % trifluoroacetic acid and (c) 20 mM ammonium acetate. The strongest signals of parent ion and dominant product ion were obtained in negative mode by use of the mobile phase (c). Validation of this method was performed according to the ICH guidelines. Small variations of selected chromatographic parameters (concentration of ammonium acetate, mobile phase composition, column temperature and flow rate) did not affect qualitative and quantitative system responses significantly, which proved method’s robustness. The method is specific for the determination of adapalene. Linearity was proved in the concentration range 6.7 - 700.0 ng mL-1 (r = 0.9990), with limits of detection and quantification 2.0 ng mL-1 and 6.7 ng mL-1, respectively. Accuracy was confirmed by calculated recoveries (98.4 % - 101.5 %). Precision was tested at three levels: injection repeatability, analysis repeatability and intermediate precision. Calculated relative standard deviations were less than 1, 2 and 3 %, respectively. [Projekat Ministartsva nauke Republike Srbije, br. OI172041 i br. TR34031]

Cortienic acid was obtained by periodic acid oxidation of fluocinolone acetonide, whereas corresponding amide was synthesized from the cortienic acid and ethyl ester of b-alanine by dicyclohexylcarbodiimide - hydroxybenzotriazole coupling procedure. Lipophilicity of the amide was evaluated by using reversed-phase thin-layer chromatography systems, consisting of ethanol and water in various ratios, and was higher in comparison to fluocinolone acetonide and cortienic acid.

L-phenylalanine methyl ester derivative of dexamethasone - derived cortienic acid (DF) was synthesized and its crystal structure was characterized by X-ray diffraction method. The crystal system is orthorhombic with space group P212121 and cell constants a = 8.2969 (3) Å, b = 18.9358 (8) Å, c = 20.0904 (6) Å, V = 3156.4 (2) Å3 and Z = 4. Ring A of the steroid nucleus and phenyl ring in the 17β-side chain are almost planar. Rings B and C have a slightly distorted chair conformation, whereas ring D has an envelope conformation. The packing of DF is characterized by a network of intermolecular hydrogen bonds involving the O4 atom from one side of the steroid nucleus and O1 and F1 atoms from the other side as hydrogen bond acceptors. Apart from the intermolecular hydrogen bonds in the crystal packing, there are also numerous intramolecular hydrogen bonds of the N-H...O, C-H...O and C-H...F type. Local anti-inflammatory activity of DF was evaluated by use of croton oil-induced ear edema test. This derivative achieved maximal inhibition of ear edema at significantly lower concentration in comparison with dexamethasone. [Projekat Ministarstva nauke Republike Srbije, br. 172041, 172014 i 172035]

Soft ('antedrug') glucocorticoids are pharmacologically active compounds which are biotransformed in a predictable and controllable way to inactive and non-toxic metabolites. Amides of cortienic acids (17(-carboxamide derivatives of glucocorticoids) are potential soft drugs with fewer side effects than traditional glucocorticoids. The purification of 17(- carboxamide derivatives of hydrocortisone was explained using the amide of hydrocortisonederived cortienic acid and ethyl ester of L-glycine as an example and performed by use of column chromatography and preparative thin-layer chromatography (TLC). The optimization of purification process was performed employing analytical TLC and reversed-phase highperformance liquid chromatography (RP-HPLC). The mobile phase that enables best chromatographic separation of the amide from impurities on TLC plate (chloroform-methanol (95:5 V/V)) was selected and modified (reduction of polarity and addition of glacial acetic acid) to be used for the column chromatography and preparative TLC purification. It was confirmed by use of RP-HPLC that purification procedures applied in this study resulted in pure (96.2 %) amide.