The aim of this research was to develop a solid dosage form containing 1.5 g of the pesticide cypermethrin. The dosage should be stable in a tropical climate. In addition, it is to disintegrate and disperse in 10 L of tap water within 3 minutes. Such dissolution should yield a 150 ppm dispersion of cypermethrin, stable for at least one week. This provides for a dip dispersion to treat ticks and fly infestation on livestock. A new solid dosage was formulated as the scope of this research. It is a gel-based solid dosage form. Polymer electrolyte ASP4 - a copolymer of methacrylic acid, ethyl acrylate and diethyl maleate, was used to produce the gel. Preliminary tests revealed that ASP4- based gel, on its own, failed to meet the required dissolution time of 3 minutes. Strong entanglements of ASP4 chains impeded rapid dissolution. These strong entanglements occurred owing to the use of a high concentration of ASP4. Reducing the concentration of ASP4 yielded a solution of high viscosity instead of a gel. It was therefore decided to Gel-based solid dosage form for pesticide delivery use a superabsorbent (Product Z1069) in conjunction with ASP4 to produce the gel. Product Z1069 is a cross-linked sodium polyacrylate. Before producing the gel, a 1:1.5 by mass oil/water (O/W) emulsion was prepared using the phase-inversion route. The water (W) phase comprised 85.9% distilled water, 3.9% ASP4 at 20% dispersion, 8.6% sodium carbonate (0.5 M) and 1.6% Emulsogen EL. All concentrations are indicated in mass %. The oil (O) phase consisted of 76.9% cypermethrin, 19.3% Solvesso S200 and 3.8% Phenyl Sulphonate CA, also by mass. This emulsion was gelled by adding the superabsorbent Product Z1069 (ca. 37.5% by mass relative to the W phase of the emulsion). The superabsorbent strongly absorbed water, depleting it from the emulsion. This resulted in an increase of the effective concentration of ASP4 in the water phase of the emulsion. This increase of the polymer electrolyte concentration brought about a gel-like state corresponding to the desired solid dosage form. Rheometry confirmed that the dosage form maintained a solid gel-like consistency at 50°C. The dosage contained 24.6% m/m cypermethrin. Thus, the required dosage of 1.5 g was achieved in pellets weighing ca. 6.1 g. Such pellets rapidly disintegrated with mild stirring in 10 L of tap water. Complete pellet disintegration and active dispersion occurred within 2.5 minutes at ambient temperature (25 ± 2°C). / Dissertation (MSc)--University of Pretoria, 2008. / Chemistry / unrestricted

Controlled-release formulations for pesticide applications act as depot systems that continuously release the active ingredients into the environment over a speci ed period, usually from months to years. However, some applications require fast-dissolving drug delivery. The interest of this research is in fast-release of water-insoluble pesticides into aquatic environments. This study considered the use of dextrin starch and urea eutectics as fast release, solid dosage carrier forms that contain an active ingredient. The chosen active for this study is an acaricide called amitraz (N-methylbis-(2,4-xylyliminomethyl)- methylamine). The focus is on matrix-based dosage forms such as tablets, granules or bres that either disintegrate or dissolve to release a water-insoluble active. These types of dosage forms can be fabricated using processes such as lyophilisation, spray drying, solvent casting, hot melt extrusion, compression moulding, wet granulation, compaction and electrospinning. A simple melt-casting procedure has been discussed in the present work. Dextrin is a water-soluble form of partially hydrolysed starch and is a promising candidate matrix material for dissolving solid dosage forms. The molecular weight of the dextrin was analysed with MALDI-TOF methods and rheological relations. Glycerolplasticized thermoplastic dextrin-based nanocomposites were prepared with a twin-screw extrusion-compounding process. The nano llers included a layered double hydroxide (LDH), cellulose nano bres (CNF) and stearic acid. The time-dependent retrogradation of the compounds was monitored by X-ray di raction (XRD) and dynamic mechanical thermal analysis (DMA). XRD showed that the inclusion of stearic acid in the formulations led to the formation of an amylose-lipid complex and a stable crystallinity during ageing. Dissolution rates in water for samples containing dextrin starch, were characterised using an iodine indicator and UV-visible spectroscopy. High pressure di erential scanning calorimetry (HPDSC) indicated that the addition of stearic acid led to the formation of amylose-lipid complexes (ALC's). An additive system containing stearic acid and CNF was deemed suitable for compounding with amitraz. Compounding at temperatures above the melting point of the latter led, on dissolution in water, to the release of much ner particles of the acaricide, which was con rmed with particle size analysis (PSA). The addition of the acaricide caused an apparent increase in the dissolution rate of the thermoplastic dextrin. Two eutectic urea systems were considered for casting with amitraz. A eutectic system of urea and acetamide was found to display a melting point of 44 C at a 37 wt.% urea composition. The other system consisting of urea and 1,3-dimethylurea displayed a eutectic point at 32 wt.% urea composition which melted at 59 C. Di erential scanning calorimetry (DSC), however, con rmed a melting point depression due to a high moisture content caused by the compounds high hygroscopicity. The endotherm of the sample containing no excess moisture showed a melting point of 70 C. The 1,3-dimethylurea system was deemed suitable for casting with amitraz. XRD of the eutectic composition indicated a small amount of co-crystallisation. The samples were cast as disks of various diameters while keeping the height of the disks constant. The creation of the cast disks showed automatic generation of a nely dispersed form of the active through the process of melting the deep eutectic solvent, the dissolution of the active and its phase separation on cooling and solidi cation of the eutectic. This implies that ne grinding of the actives might not be necessary. Eutectic casts containing 20 wt.% amitraz dissolved at a slower rate than casts not containing the hydrophobic active ingredient. The advantageous features of these casts were exempli ed using the acaricide incorporated into the urea & 1,3-dimethylurea eutectic. This work provides two safe, biodegradable and water soluble materials for use as a matrix to contain active ingredients. One material, the eutectic organic salt casts, can be produced at low temperatures (<100 C) and can be directly cast into storage containers. The complete dissolution of the cast compounded with a hydrophilic active is rapid (4-6 min). The second material, a thermoplastic dextrin, was melt compounded in an extruder at temperatures not exceeding 120 C. This compound containing 20 wt.% of the active dissolved over a 12 hour period. Dextrin, known to be widely used as an adhesive, will aid in the adhesion of the active ingredient to the surface where it must be used. / Dissertation (MEng (Chemical Engineering))--University of Pretoria, 2020. / PAMSA / Department of Science and Innovation under Grant DST/CON 0004/2019 / Chemical Engineering / MEng (Chemical Engineering) / Unrestricted

Drug delivery systems (DDS) are essentially pharmaceutical products for human therapy, typically involving a mixture of active ingredients and excipients. Based upon quantitative characterization of structure, the thesis introduces the concept of classifying the architecture of DDS into four levels by their spatial scale and the life time period. The primary level is recognised as the static structure of the whole dosage form with a size from μm to cm with the final structure generated by formulation design. The secondary level categorises the structures of particles or sub-units to form a DDS with sizes from nm to mm as key units in processing such as mixing, grinding, granulation and packing; The tertiary level represents the dynamic structures of DDS during the drug release phase in vitro or in vivo incorporating the structure size range from nm to mm, which undergo changes during dissolution, swelling, erosion or diffusion. The spatial scale for the quaternary level is defined as the meso or micro scale architecture of active and non-active molecules within a DDS with sizes from Å to μm for the molecular structure of drug and excipients. Methods combining X-ray tomography, image processing, and 3D reconstructions have been devised and evaluated to study systematically pharmaceutical structures and correlate them with drug release kinetics of DDS. Based on the quantitative structural information of pharmaceutical intermediates and dosage forms, it is possible now to correlate structures with production processing, behaviour and function, and the static and dynamic structures of DDS with the release kinetics. Thus, a structure-guided methodology has been established for the research of DDS. / Chinese Academy of Sciences

Os métodos termo-analíticos são ferramentas úteis na avaliação da compatibilidade entre fármacos e adjuvantes, com destaque à calorimetria exploratória diferencial. Neste trabalho foram avaliados a compatibilidade e o comportamento térmico entre a isoniazida e adjuvantes tecnológicos primários usualmente empregados em formas farmacêuticas sólidas. A compatibilidade foi examinada por meio da preparação de misturas físicas binárias do tipo fármaco/adjuvante. Foi investigada também a influência da granulação por via úmida e do processo de compactação para as misturas de isoniazida e adjuvantes com função de material de enchimento e carga e deslizante. A isoniazida apresentou um comportamento térmico não encontrado na literatura. Os adjuvantes avaliados foram: ácido esteárico, amido, celulose microcristalina, crospovidona, croscarmelose sódica, dióxido de silício coloidal estearato de magnésio, glicolato de amido sódico, hipromelose, lactose, manitol, polidona e talco. Para as misturas físicas, a maioria dos adjuvantes mostrou-se compatível com o fármaco em questão. Foram verificadas interações com o ácido esteárico, o glicolato de amido sódico, a lactose, o manitol e a povidona. A isoniazida mostrou a formação de uma mistura eutética com o manitol e de interação química com a lactose. A agregação por via úmida e o processo de compactação não mostraram influências adicionais na compatibilidade das misturas avaliadas. Os resultados observados foram confirmados por métodos não-térmicos como difratometria de raios X, espectroscopia de infravermelho e ressonância nuclear magnética. / Thermo-analytical methods, and specially Differential Scanning Calorimetry, are useful support for the evaluation of compatibility between drug substances and pharmaceutical excipients. In this work were studied the compatibility and the thermal behavior of isoniazid and pharmaceutical excipients, commonly used for the formulation of solid dosage forms. Colloidal silicon dioxide, corn starch, crospovidone, hypromellose, lactose, magnesium stearate, mannitol, microcrystalline cellulose, povidone, sodium croscarmellose, sodium starch glycolate, stearic acid and talc were the excipients employed in these experiments. The compatibility was analyzed testing binary physical drug/excipient admixtures. The effect of wet granulation and compression was also investigated, in this case especially between isoniazid, fillers and lubricant. For almost all excipients no incompatibilities with isoniazid were observed. Interactions were detected when the drug substance was added to stearic acid, sodium starch glycolate, lactose, mannitol and povidone. Isoniazid formed a euthetic mixture with mannitol, whereas a possible chemical reaction occurred between isoniazid and lactose. Wet granulation and compaction of the tested admixtures did not affect the results observed above. These observations were confirmed by non-thermal techniques, such as X-Ray diffractometry, infrared spectroscopy and nuclear magnetic resonance.

Os métodos termo-analíticos são ferramentas úteis na avaliação da compatibilidade entre fármacos e adjuvantes, com destaque à calorimetria exploratória diferencial. Neste trabalho foram avaliados a compatibilidade e o comportamento térmico entre a isoniazida e adjuvantes tecnológicos primários usualmente empregados em formas farmacêuticas sólidas. A compatibilidade foi examinada por meio da preparação de misturas físicas binárias do tipo fármaco/adjuvante. Foi investigada também a influência da granulação por via úmida e do processo de compactação para as misturas de isoniazida e adjuvantes com função de material de enchimento e carga e deslizante. A isoniazida apresentou um comportamento térmico não encontrado na literatura. Os adjuvantes avaliados foram: ácido esteárico, amido, celulose microcristalina, crospovidona, croscarmelose sódica, dióxido de silício coloidal estearato de magnésio, glicolato de amido sódico, hipromelose, lactose, manitol, polidona e talco. Para as misturas físicas, a maioria dos adjuvantes mostrou-se compatível com o fármaco em questão. Foram verificadas interações com o ácido esteárico, o glicolato de amido sódico, a lactose, o manitol e a povidona. A isoniazida mostrou a formação de uma mistura eutética com o manitol e de interação química com a lactose. A agregação por via úmida e o processo de compactação não mostraram influências adicionais na compatibilidade das misturas avaliadas. Os resultados observados foram confirmados por métodos não-térmicos como difratometria de raios X, espectroscopia de infravermelho e ressonância nuclear magnética. / Thermo-analytical methods, and specially Differential Scanning Calorimetry, are useful support for the evaluation of compatibility between drug substances and pharmaceutical excipients. In this work were studied the compatibility and the thermal behavior of isoniazid and pharmaceutical excipients, commonly used for the formulation of solid dosage forms. Colloidal silicon dioxide, corn starch, crospovidone, hypromellose, lactose, magnesium stearate, mannitol, microcrystalline cellulose, povidone, sodium croscarmellose, sodium starch glycolate, stearic acid and talc were the excipients employed in these experiments. The compatibility was analyzed testing binary physical drug/excipient admixtures. The effect of wet granulation and compression was also investigated, in this case especially between isoniazid, fillers and lubricant. For almost all excipients no incompatibilities with isoniazid were observed. Interactions were detected when the drug substance was added to stearic acid, sodium starch glycolate, lactose, mannitol and povidone. Isoniazid formed a euthetic mixture with mannitol, whereas a possible chemical reaction occurred between isoniazid and lactose. Wet granulation and compaction of the tested admixtures did not affect the results observed above. These observations were confirmed by non-thermal techniques, such as X-Ray diffractometry, infrared spectroscopy and nuclear magnetic resonance.

Os métodos termo-analíticos são ferramentas úteis na avaliação da compatibilidade entre fármacos e adjuvantes, com destaque à calorimetria exploratória diferencial. Neste trabalho foram avaliados a compatibilidade e o comportamento térmico entre a isoniazida e adjuvantes tecnológicos primários usualmente empregados em formas farmacêuticas sólidas. A compatibilidade foi examinada por meio da preparação de misturas físicas binárias do tipo fármaco/adjuvante. Foi investigada também a influência da granulação por via úmida e do processo de compactação para as misturas de isoniazida e adjuvantes com função de material de enchimento e carga e deslizante. A isoniazida apresentou um comportamento térmico não encontrado na literatura. Os adjuvantes avaliados foram: ácido esteárico, amido, celulose microcristalina, crospovidona, croscarmelose sódica, dióxido de silício coloidal estearato de magnésio, glicolato de amido sódico, hipromelose, lactose, manitol, polidona e talco. Para as misturas físicas, a maioria dos adjuvantes mostrou-se compatível com o fármaco em questão. Foram verificadas interações com o ácido esteárico, o glicolato de amido sódico, a lactose, o manitol e a povidona. A isoniazida mostrou a formação de uma mistura eutética com o manitol e de interação química com a lactose. A agregação por via úmida e o processo de compactação não mostraram influências adicionais na compatibilidade das misturas avaliadas. Os resultados observados foram confirmados por métodos não-térmicos como difratometria de raios X, espectroscopia de infravermelho e ressonância nuclear magnética. / Thermo-analytical methods, and specially Differential Scanning Calorimetry, are useful support for the evaluation of compatibility between drug substances and pharmaceutical excipients. In this work were studied the compatibility and the thermal behavior of isoniazid and pharmaceutical excipients, commonly used for the formulation of solid dosage forms. Colloidal silicon dioxide, corn starch, crospovidone, hypromellose, lactose, magnesium stearate, mannitol, microcrystalline cellulose, povidone, sodium croscarmellose, sodium starch glycolate, stearic acid and talc were the excipients employed in these experiments. The compatibility was analyzed testing binary physical drug/excipient admixtures. The effect of wet granulation and compression was also investigated, in this case especially between isoniazid, fillers and lubricant. For almost all excipients no incompatibilities with isoniazid were observed. Interactions were detected when the drug substance was added to stearic acid, sodium starch glycolate, lactose, mannitol and povidone. Isoniazid formed a euthetic mixture with mannitol, whereas a possible chemical reaction occurred between isoniazid and lactose. Wet granulation and compaction of the tested admixtures did not affect the results observed above. These observations were confirmed by non-thermal techniques, such as X-Ray diffractometry, infrared spectroscopy and nuclear magnetic resonance.

The aim of present work is cultivation of probiotic bacteria L. acidophilus, B. breve and B. longum in such a way that the culture forms cells clusters or comprehensive biofilm on the variety of free carriers. Biofilm formation of L. acidophilus on the silica from point of view bile and acid tolerance in gastrointestinal tract was studied. While the number of living cells in planktonic form (planktonic form) at pH 1 fell by 30 %, the viability of the biofilm cells was maintained to 90 % under the same environmental conditions. The biofilm culture showed also the protection against environment contained bile. Furthermore, the possibilities of drying procedures of biofilm cultures used as commercial technologies in pharmaceutical industry were studied. The comparison of freeze-drying and fluidization bed drying showed, that freeze-drying is more suitable method, which is able to achieve higher amount of viable cells after drying than fluidization bed drying. The effectivity of freeze-drying method is dependent on the selection of suitable cryprotective medium. In this case, about 90 % higher viability after freeze drying was achieved in comparison with fluidization bed drying. Finally, the industrial processing of probiotic strains into the solid dosage form was studied. Tablets should be produced at hardness between 70 and 90 N and water activity of tablet mixture can be maintained below 0.3. Consequently, the drying step of the tablets in a hermetically closed space with at least 10 % of silica gel must be ensured. Thereafter, the tablets contain (5.4 ± 0.7)109 viable cells after 6 months of drying process. Capsule production technology has no significant effect on the cell‘s viability during production. The triplex blistering foil for primary blistering of probiotic capsules was chosen. The triplex foil, which has low values of water vapour transition rate (0.07 g H2O / (m2 × day) and oxygen transition rate (0.01 cm3/m2 × day), was chosen. Other studied blistering foils commonly used in the pharmaceutical industry are not suitable for long storage of solid dosage forms contained probiotics.