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Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biophysics and Physical Chemistry Candidate: Kateřina Brokešová Supervisor: Ing. Martin Drastík, Ph. D. Thesis title: The use of core-shell columns for fluconazole determination A novel HPLC method for determination of fluconazole in dissolution test samples was developed and partly validated. A matrix formed by lactic and glycolic acid copolymer branched by different compounds was used as a drug carrier. Fluconazol was incorporated as the model drug. The concentration profile of fluconazole was studied by developed HPLC method during the dissolution test. A modern core-shell column Ascentis Express RP-Amide, 10 cm × 3.0 mm; 2.7 μm was employed. A mixture of acetate buffer pH 5.0:methanol (80:20) served as the mobile phase. The flow rate was 0.70 ml/min and the detection wavelength was 260 nm. The temperature of analysis was 50 řC. The retention time of fluconazole was 3.3 min and the whole analysis took just 4 min. Keywords: fluconazole, core-shell column, HPLC, PLGA

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biophysics and Physical Chemistry Candidate: Andrea Malovaná Supervisor: Ing. Martin Drastík, Ph. D. Diploma thesis: Simplification of terbinafine HPLC analysis of samples based on biodegradable polyesters A HPLC method for determination of terbinafine in samples consisting of copolymers of lactic and glycolic acid was optimized and validated. The development of the method was based on the finding of suitable chromatographic conditions for separation of terbinafine. The separation was performed on the Ascentis Express ES-CN, 15 cm × 4.6 mm; 2.7 μm core- shell column. The mixture of the citrate phosphate buffer pH 4 and acetonitrile in ratio 40:60 (v/v) was chosen as the mobile phase. The mobile phase flow rate was set to 1.4 ml/min and the temperature to 30 řC. The injection volume of samples containing terbinafine was 5 µl. The UV detection at 226 nm was employed. The retention time of terbinafine was 3.3 min. The whole analysis was completed within 4 min. The method was validated, following parameters were tested: column efficiency, factor of symmetry, LOD, LOQ, linearity, repeatability and robustness. Keywords: terbinafine, HPLC, core-shell column, PLGA

BSc. Martina Hloušková Supervisor: Ing. Martin Drastík, Ph.D. The aim of this diploma thesis was the optimization and validation of a HPLC method for miconazole determination in samples supplied by the Department of Pharmaceutical Technology. A gradual miconazole release dependent on the composition of the copolymere of glycolic and lactic acid was studied. HPLC analysis was performed using a modern core-shell Column Ascentis Express RP- Amide, 10 cm x 3.0 mm; 2.7 μm. Optimized analytical conditions were: mobile phase methanol:water 70:30, flow rate 0.8 ml/min, temperature 45 řC, injection 5 l and UV detection at 220 nm. Miconazole retention time was 5.65 min. The entire analysis was carried out in 7 minutes. When the optimal conditions of analysis were determined, the method could be validated. The following parameters were monitored during validation: linearity, selectivity, efficiency, LOD, LOQ, repeatability and tailing factor. All of the monitored parameters met the requirements of the Czech Pharmacopoeia.

O presente trabalho apresenta resultados do estudo que objetivou desenvolver blendas poliméricas compostas por dois polimeros biodegradáveis, o poli (butileno succinato - co - adipato) (PBSA) copolímero de poliésteres alifáticos e a policaprolactona (PCL). O estudo desenvolveu a tecnologia para a incorporação de nanowhiskers de celulose (NWC) enxertados com PCL (NWC - g - PCL), com objetivo de melhorar a adesão nanowhisker/matrix, e otimizar as propriedades mecânicas destes polímeros. As composições utilizadas foram 30PCL/70PBSA e 50PCL/50PBSA (em % de massa), com 1, 3 e 5% de NWC - g - PCL. As blendas e compósitos foram preparadas na forma de filmes por evaporação de solvente clorofórmio (casting) e via extrusão e moldagem por injeção, e caracterizadas quanto a suas propriedades térmicas, mecânicas e morfológicas através de calorimetria exploratória diferencial (DSC), análise termogravimétrica (TGA) e análise termodinâmica mecânica (DMTA), ensaio mecânico de tração e microscopia eletrônica de varredura (MEV). Os resultados obtidos através das análises de espectroscopia no infravermelho (IV) e difração de raios-X (DRX) sugerem a enxertia de cadeias de PCL nos NWC. Os polímeros puros, na forma de filmes, obtidos por evaporação de solvente, apresentaram estabilidade térmica semelhantes com início de decomposição em 290°C e decomposição máxima em torno de 420°C. Os filmes dos compósitos apresentaram uma diminuição da estabilidade térmica com o aumento dos teores de NWC - g - PCL nas formulações. As curvas DSC apresentaram dois picos de fusão e de cristalização o que indica a imiscibilidade dos polímeros, as análises térmicas dos filmes, mostraram também um aumento no grau de cristalinidade conforme os teores de nanowhiskers enxertados aumentaram, isso para composição 30/70. No caso dos compósitos com composição 50/50 (PCL/PBSA) houve uma diminuição do grau de cristalinidade dos polímeros. A imiscibilidade dos polímeros nos filmes foi confirmada também através das análises DMTA onde dois picos distintos de tanδ foram encontrados, para as composições 30/70, próximos das temperaturas de transição vítrea dos dois polímeros. As mesmas composições processadas via extrusão, e corpos de prova moldados por injeção, apresentaram uma queda na estabilidade térmica detectada pelas análises TGA. Houve um aumento no grau de cristalinidade da PCL conforme maior quantidade de nanowhisker nos compósitos. A maior rigidez do material foi confirmada a partir dos ensaios mecânicos de tração, onde o módulo elástico aumentou aproximadamente duas vezes com o aumento da porcentagem de nanocargas nos compósitos, assim como a diminuição da porcentagem de alongamento e a resistência à tração não sofreu grandes alterações. / In this dissertation results of the study aimed to develop polymer blends composed of two biodegradable polymers, poly (butylene succinate - co - adipate) (PBSA) and aliphatic polyester polycaprolactone (PCL). The study developed the technology for the incorporation of cellulose nanowhiskers (NWC) grafted PCL (NWC - g - PCL), aiming to improve adherence nanowhisker / matrix, and improve mechanical properties of these polymers. The compositions used were 30PCL/70PBSA and 50PCL/50PBSA (in mass%), with 1, 3 and 5% of NWC - g - PCL. The blends and composites were prepared as films by evaporation of solvent chloroform (casting) and via extrusion and injection molding, and characterized their thermal, mechanical and morphological means of differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) mechanical and thermodynamic analysis (DMTA), mechanical tests and scanning electron microscopy (SEM). The results obtained by analysis of infrared spectroscopy (IR) and X -ray diffraction (XRD) suggest the grafting of PCL chains in the NWC. The pure polymers in the form of films obtained by solvent evaporation, showed similar thermal stability with decomposition onset at 290°C and decomposition maximum at around 420°C. The films of the composites showed a decrease in thermal stability with increased levels NWC - g - PCL in the formulations. The DSC curves show two melting peaks and crystallization which indicates immiscibility of the polymers, the thermal analysis of the film showed also an increase in degree of crystallinity as the content of grafted nanowhiskers increased, this composition to 30/70. In the case of composites with composition 50/50 (PCL / PBSA) there was a decrease in the degree of crystallinity of polymers. The immiscibility of the polymers in the film was also confirmed by analysis DMTA where tanδ two distinct peaks were found for compositions 30/70, close to the glass transition temperatures of the two polymers. The same compositions processed via extrusion, and specimens injection molded, showed a decrease in thermal stability detected by TGA analysis. There was an increase in the degree of crystallinity of the PCL as the largest quantity of nanowhisker composites. The rigidity of the material was confirmed from the tensile test, where the elastic modulus increased approximately twice the percentage increase of nanofiller in the composites, as well as the decrease in percentage elongation and tensile strength has not changed much.

O presente trabalho apresenta resultados do estudo que objetivou desenvolver blendas poliméricas compostas por dois polimeros biodegradáveis, o poli (butileno succinato - co - adipato) (PBSA) copolímero de poliésteres alifáticos e a policaprolactona (PCL). O estudo desenvolveu a tecnologia para a incorporação de nanowhiskers de celulose (NWC) enxertados com PCL (NWC - g - PCL), com objetivo de melhorar a adesão nanowhisker/matrix, e otimizar as propriedades mecânicas destes polímeros. As composições utilizadas foram 30PCL/70PBSA e 50PCL/50PBSA (em % de massa), com 1, 3 e 5% de NWC - g - PCL. As blendas e compósitos foram preparadas na forma de filmes por evaporação de solvente clorofórmio (casting) e via extrusão e moldagem por injeção, e caracterizadas quanto a suas propriedades térmicas, mecânicas e morfológicas através de calorimetria exploratória diferencial (DSC), análise termogravimétrica (TGA) e análise termodinâmica mecânica (DMTA), ensaio mecânico de tração e microscopia eletrônica de varredura (MEV). Os resultados obtidos através das análises de espectroscopia no infravermelho (IV) e difração de raios-X (DRX) sugerem a enxertia de cadeias de PCL nos NWC. Os polímeros puros, na forma de filmes, obtidos por evaporação de solvente, apresentaram estabilidade térmica semelhantes com início de decomposição em 290°C e decomposição máxima em torno de 420°C. Os filmes dos compósitos apresentaram uma diminuição da estabilidade térmica com o aumento dos teores de NWC - g - PCL nas formulações. As curvas DSC apresentaram dois picos de fusão e de cristalização o que indica a imiscibilidade dos polímeros, as análises térmicas dos filmes, mostraram também um aumento no grau de cristalinidade conforme os teores de nanowhiskers enxertados aumentaram, isso para composição 30/70. No caso dos compósitos com composição 50/50 (PCL/PBSA) houve uma diminuição do grau de cristalinidade dos polímeros. A imiscibilidade dos polímeros nos filmes foi confirmada também através das análises DMTA onde dois picos distintos de tanδ foram encontrados, para as composições 30/70, próximos das temperaturas de transição vítrea dos dois polímeros. As mesmas composições processadas via extrusão, e corpos de prova moldados por injeção, apresentaram uma queda na estabilidade térmica detectada pelas análises TGA. Houve um aumento no grau de cristalinidade da PCL conforme maior quantidade de nanowhisker nos compósitos. A maior rigidez do material foi confirmada a partir dos ensaios mecânicos de tração, onde o módulo elástico aumentou aproximadamente duas vezes com o aumento da porcentagem de nanocargas nos compósitos, assim como a diminuição da porcentagem de alongamento e a resistência à tração não sofreu grandes alterações. / In this dissertation results of the study aimed to develop polymer blends composed of two biodegradable polymers, poly (butylene succinate - co - adipate) (PBSA) and aliphatic polyester polycaprolactone (PCL). The study developed the technology for the incorporation of cellulose nanowhiskers (NWC) grafted PCL (NWC - g - PCL), aiming to improve adherence nanowhisker / matrix, and improve mechanical properties of these polymers. The compositions used were 30PCL/70PBSA and 50PCL/50PBSA (in mass%), with 1, 3 and 5% of NWC - g - PCL. The blends and composites were prepared as films by evaporation of solvent chloroform (casting) and via extrusion and injection molding, and characterized their thermal, mechanical and morphological means of differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) mechanical and thermodynamic analysis (DMTA), mechanical tests and scanning electron microscopy (SEM). The results obtained by analysis of infrared spectroscopy (IR) and X -ray diffraction (XRD) suggest the grafting of PCL chains in the NWC. The pure polymers in the form of films obtained by solvent evaporation, showed similar thermal stability with decomposition onset at 290°C and decomposition maximum at around 420°C. The films of the composites showed a decrease in thermal stability with increased levels NWC - g - PCL in the formulations. The DSC curves show two melting peaks and crystallization which indicates immiscibility of the polymers, the thermal analysis of the film showed also an increase in degree of crystallinity as the content of grafted nanowhiskers increased, this composition to 30/70. In the case of composites with composition 50/50 (PCL / PBSA) there was a decrease in the degree of crystallinity of polymers. The immiscibility of the polymers in the film was also confirmed by analysis DMTA where tanδ two distinct peaks were found for compositions 30/70, close to the glass transition temperatures of the two polymers. The same compositions processed via extrusion, and specimens injection molded, showed a decrease in thermal stability detected by TGA analysis. There was an increase in the degree of crystallinity of the PCL as the largest quantity of nanowhisker composites. The rigidity of the material was confirmed from the tensile test, where the elastic modulus increased approximately twice the percentage increase of nanofiller in the composites, as well as the decrease in percentage elongation and tensile strength has not changed much.