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A modified method for ibuprofen/β-cyclodextrin (IBU/β-CD) complex formation, based on ball milling (BM) under controlled conditions was developed and its efficiency with respect to the drug encapsulation yield was compared with the well-known kneading and solid dispersion synthetic approaches. Quantitative evaluation of the efficiency of drug-cyclodextrin interaction applying various methods and experimental conditions as well as characterization of the inclusion complexes were carried out by X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetry (TG), scanning electron microscopy (SEM), infrared (IR) and nuclear-magnetic resonance (1HNMR) spectroscopy. It was found that the yield of the formed IBU/β-CD complex varies in a large range, depending on the techniques applied. The degree of complexation between IBU and β-CD using the proposed optimized BM method is very high and close to the complete inclusion complex formation achieved by a modified solid dispersion method. Furthermore, using DSC, TG and 1HNMR we proved that the ibuprofen molecules enter the β-CD hydrophobic cavities replacing completely the water molecules present naturally inside, which we determined to be 7.

A ternary melt-derived inorganic glass system (Igl) of composition corresponding to 62SiO(2), 35Na(2)O, 3Al(2)O(3 )(wt.%) has been formulated and studied as a drug carrier. The [Al(2)O(3)/Na(2)O] ratio is less than one and the aluminium ion is a network former that retards the glass dissolution. The processing conditions lead to a brittle, easily grinding, amorphous product. The Igl structure was proven by IR-spectroscopy, energy-dispersive spectrometry, X-ray diffraction, scanning electron microscopy. A very important fact established is that the Igl corrosion (dissolution) is pH-dependent. Inorganic glass system was transformed into model acetaminophen (APH) adsorbate (APH/Igla 1:1(w/w)) with mild experimental conditions and evaluated as a drug carrier. No interactions between Igl and APH during the processing were proven. Besides, APH settles onto the glass surface as crystalline phase. A lower extent of corrosion, apparent solubility and delayed in vitro APH release from the adsorbate in water and artificial gastric juice in comparison to the samples untreated drug and APH/Iglm physical mixture were established. It is hypothesized that the glass decomposition products, formed into contact with a solvent, initiate interactions with APH at the glass/solution interface. Similar behaviour of the Igl and its drug adsorbates could be expected in gastro-intestinal tract.

The influence of the water structure promoters, mannitol and sucrose, on the indomethacin/β-cyclodextrin inclusion process at different pH values was evaluated using the phase solubility method and circular dichroism spectroscopy. The effect of mannitol and sucrose on the total solubilizing activity of β-cyclodextrin as well as on the stabilization of the complex was moderate, and depended strongly on the pH value of the medium. The most pronounced effect on the association constant of the indomethacin inclusion compound was observed in KCl/HCl buffer of pH 1.6, because mannitol and sucrose, in the absence of β-cyclodextrin, approximately double the indomethacin solubility so that the constant value decreases. On the other hand, a very strong complex formation between indomethacin and β-cyclodextrin was observed in acid medium (KCl/HCl buffer, pH = 1.6), a fact not much discussed in the literature. The apparent association constant of the inclusion compound formed in the absence of mannitol or sucrose was found to be of the same order of magnitude as for the complex formed at pH 6.8. Changes in the optical activity of the indomethacin/β-cyclodextrin inclusion complex were registered in the presence of sucrose, which interacts more strongly than mannitol with water molecules, and could probably adhere to the surface of the inclusion complex, thus changing its configuration and environment.

A novel method of preparing modified chitosan films was developed. Bi- and tri-component chitosan films were prepared by blending chitosan with high molecular weight polyoxyethylene. The films were loaded with 8-hydroxy-7-iodoquinoline-5-sulfonic acid which was chosen as a model drug. The properties of the films were studied with respect to crystallinity, thermal stability and swelling degree. These properties were shown to depend on the ratio of polyoxyethylene/chitosan. The drug release profile from the films was measured in a buffer at pH 6.8 and 37°C. The antimycotic effect of the films against Candida albicans was determined.

High-molecular weight polyoxyethylene (POE) was evaluated for potential use as an additive in ophthalmic solutions of indomethacin. The basic drug model was formulated on the basis of hydrotropic and micellar interactions. The influence of POE on the solution viscosity and stability, as well as on in vitro diffusion of indomethacin through an artificial lipid membrane, was comparatively studied with other hydrophilic polymers. It was established that POE shows advantages over hydroxypropylmethylcellulose and polyvinyl alcohol and can be used as a polymeric additive in ophthalmic aqueous solutions of indomethacin.

The phase state and solubility of indomethacin in adsorbates onto hydroxyethylcellulose have been studied. The characterization of the adsorbates and their relevant physical mixtures was made by the use of DSC, X-ray diffractometry, FT-IR spectrometry, and solubility analysis. The drug-to-polymer ratio determines either a partial crystallization of the metastable alpha-form onto hydroxyethylcellulose surface or complete inhibition of indomethacin crystallization. Significantly improved drug aqueous solubility was achieved. A stable immobilization of indomethacin molecules onto hydroxyethylcellulose due to drug/polymer interactions can be assumed. The changed indomethacin phase state in the adsorbates remains stable for one-year storage at ambient conditions. These results could be of practical importance.

To elucidate the differences in the interaction of chiralic ibuprofen (IBP) and naproxen (NAP) with poly(vinylpyrrolidone) (PVP) in a solid state.Drugs/PVP physical mixtures and solid dispersions were characterized by scanning electron microscope (SEM), Fourier transform infrared spectrometry (FT-IR), solid state (13)C NMR spectroscopy, and x-ray diffractometry. Molecular modeling study of the crystal structures and PVP was performed.A spontaneous conversion of IBP/PVP physical mixtures in a stable glasslike form (solid dispersion) was observed after storage. The enantiomer reacted more strongly than the racemate. NAP did not interact with PVP. The crystal structures of drugs showed differences in the hydrogen bonding, aromatic interactions, molecular energies, and distances inside the crystals. The trimer structure of PVP was built and optimized. It was proposed that each PVP monomer could interact with one IBP dimmer in contrast to NAP, where two out of three PVP monomers faced the catemer carboxylic groups.The differences in the interaction of PVP with racemic IBP, enantiomer IBP, and NAP can be related to the differences in their crystal structures. The correlation between the experimental data and the results of the molecular modeling analysis suggest that the IBP dimmer structures are likely to perform HB and aromatic interactions with PVP.

Ulceroprotective action of several flavonoid compounds isolated from Genista rumelica Vel. (total flavonoid mixture, luteoline-7-glycoside, genistine) was established on five models of gastric ulcer in rats, genistine being the most active. Comparison was made against several standard antiulcer durgs (Succus Liquiritiae, Caved S, Almagel). A combined drug Flavogastrol, containing total flavonoid mixture, Semmen Lini gel and antacid compounds, was prepared and demonstrated ulceroprotective activity and low toxicity.

Дисертационният труд се състои от увод, изложение в три глави, заключение, списък с използвана литература (77 източника, от които 39 на английски език, 16 на български език и 22 интернет източника), справка с приносите на дисертационния труд, справка за излезлите от печат публикации по темата на дисертационния труд. Общият обем на разработката е 188 стандартни страници. В настоящия дисертационен труд е направен пълен преглед на всички предприсъединителни инструменти, от които Албания и България са получили финансиране в предприсъединителните си периоди, както и проблемите, които съпътстват администрирането и усвояването на средствата по тези програми. В заключение са направени основни изводи и са отправени препоръки, базирани на анализите на автора в различните части от дисертационния труд и резултатите от двете собствени изследвания, проведени през 2018 г., относно основните проблеми, които възникват в работата по разработването и изпълнението на проекти, финансирани от Инструмента за предприсъединителна помощ., The dissertation paper consists of introduction, statement in three successive chapters, conclusion, list of literature (77 citations, 39 of them – in English, 16 – in Bulgarian and 22 internet ones), summary of dissertation paper contribution, list of publication son the dissertation thesis. The total volume of the paper is 188 standard pages. The current dissertation paper includes a full review of all pre-accession instruments from which Albania and Bulgaria had been funded over their pre-access on periods as well as the problems a companying thread ministration and implementation of those funds. In conclusion, main find in as and references are given basing on the analyses done by the author in different parts of dissertation paper as well as on the results of two own surveys done in 2018 concerning the main problems arе is in gin the process of work on elaboration and implementation of projects financed by the Instrument for Pre-Accession Assistance.