Foram analisados 84 lotes de especialidades fitoterápicas de uso oral, na forma de cápsula, comprimido e pó, contendo 17 drogas vegetais, produzidas por 20 fabricantes e comercializadas em farmácias, drogarias, lojas de produtos naturais e supermercados da cidade de são Paulo. O confronto da apresentação comercial das mesmas em relação à legislação nacional, indicou que a minoria (15/84) atendeu a tais exigências, além de ter demonstrado total falta de padronização de qualidade pelos produtores, inclusive com ausência de definição e conceituação, enquadrando-as indistintamente como medicamentos alopáticos, homeopáticos, produtos dietéticos ou alimentos. Efetuou-se a quantificação de bactérias aeróbias mesófilas (forma vegetativa e esporulada) e de fungos (bolores e leveduras), através da técnica de tubos múltiplos, bem como a pesquisa de Escherichia coli e Salmonella sp. pela metodologia oficial internacional. A contaminação fúngica, predominantemente de bolores, foi inferior em relação à bacteriana aeróbia mesófila, pois o máximo detectado para aquela foi de 4,6 X 105, enquanto que para esta 5,1 X 109/g. A incidência fúngica com carga maior ou igual a 102/g foi de 34,5%, contra 53,6% da carga bacteriana vegetativa com 104/g ou mais e 45,2% da bacteriana esporulada, com o mesmo nível. A determinação do Número Mais Provável de Escherichia coli indicou incidência de 6,0% com a carga maior igual a 1,5 X 102/g. Houve estreita relação entre a carga bacteriana vegetativa total e o número de esporos, assim como a presença de patogênicos específicos em produtos altamente contaminados. Amostras sob a forma de pó foram as mais afetadas, seguidas de cápsulas e comprimidos. Pelo confronto dos dados encontrados, com os diversos padrões microbianos aplicados para medicamentos não estéreis de uso oral, para insumos e produtos fitoterápicos, o índice de aprovação variou de 29,8 a 94,0%. Mesmo frente ao padrão da FIP, a rejeição especialidades fitoterápicas analisadas foi da ordem de 59,5%. Em vista da qualidade sanitária de muitos destes produtos ser imprópria para o consumo, e após análise crítica dos vários padrões microbianos, discutiu-se a necessidade de implantação de especificações nacionais, ainda que a caráter provisório, sugerindo-se limites de tolerância para medicamentos fitoterápicos de uso oral. / 84 samples of phytotherapic products of oral solid dosage forms (capsules, tablets and powders) containing 17 different crude drugs and produced by 20 laboratories, marketed in drugstores, herborist\'s and supermarkets at são Paulo-Brazil were analysed with regard to legal marketing requirements, only 15 samples were in accordance. A complete lack of quality standard was attributed to the manufacturers, including indefinition as to the classification of products among allopathic or homeopathic pharmaceuticals or foods or dietetics. The total aerobic bacterial (vegetative and sporulated forms) and fungal (moulds and yeasts) contents were determined by multiple tube technique; moreover tests were carried out for Escherichia coli and Salmonella sp. by official international methods. The fungal contamination was predominantly of moulds and lower than the aerobic bacterial one. The maximum counts were 4,6 X 105 and 5,1 X 109/g, respectively, for fungi and bacteria. The frequency of samples with or more than 102/g fungi/g was 34,5% that for vegetative and sporulated bacterial counts with or more than 104/g was respectively, 53,6 and 45,2%. The incidence of Escherichia coli was about 6,0% with the highest level at 1,5 X 102/g. There was a tight relation between the vegetative and sporulated bacterial counts as well as the presence of specific pathogenic microorganisms in highly contaminated samples. The highest contamination occured in powders followed by capsules and tablets. Comparing our experimental data with the corresponding microbial standards for oral non sterile pharmaceuticals, crude drugs and phytotherapic products, the index of approval varied between 29,8 and 94,0%. Even by FIP\'s standards 59,5% of the phytotherapic specialties analysed had to be rejected. As many of these products showed innadequate sanitary quality for consumption, coupled to a critical analysis of the different microbial standards, the discution was raised about the necessity of establishing national specifications, even if provisional. Suggestions are made as to the contamination limits of oral phytotherapic pharmaceuticals.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2016-01-08T10:41:46Z No. of bitstreams: 2 Dissertação - Denise Vaz Ferreira da SILVA Crispim - 2015.pdf: 1185283 bytes, checksum: 45a58d0e5020c6f20f896c9d1e286b97 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2016-01-08T10:46:23Z (GMT) No. of bitstreams: 2 Dissertação - Denise Vaz Ferreira da SILVA Crispim - 2015.pdf: 1185283 bytes, checksum: 45a58d0e5020c6f20f896c9d1e286b97 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2016-01-08T10:46:23Z (GMT). No. of bitstreams: 2 Dissertação - Denise Vaz Ferreira da SILVA Crispim - 2015.pdf: 1185283 bytes, checksum: 45a58d0e5020c6f20f896c9d1e286b97 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2015-03-30 / Paracetamol (N-acetyl-p-aminophenol or acetaminophen) is a drug with antipyretic, analgesic and anti-inflammatory, stands out as one of the most consumed worldwide. Because of this demand, the development and registration of new formulations by the pharmaceutical sector is ongoing. The process control and final product is an obligatory part of quality control. The official methods for quantitative determination of paracetamol include spectrophotometric and chromatographic techniques. In turn, due to the inherent electroactivity of this compound, the scientific literature involving electroanalytical methods is also large. Our objective was to demonstrate the efficiency of carbon electrodes modified with silica sonogel compared to conventional electrodes and official methods. The development and validation of an electroanalytical method for quantitative determination of paracetamol in liquid formulations. Apply the method in different product development phases, like product and reference, comparing the method developed with the official method of CLAE using conventional glassy carbon electrodes and carbon and sonogel folder. The samples consisted of a formulation drops reference (Tylenol®), 5 test formulations, standard solution of Paracetamol, all the 200 mg/mL. For differential pulse voltammetry (DPV) was used a potentiostat/galvanostat. Electrochemical cell with 5.0mL capacity, with three-electrode system, glassy carbon electrodes or sonogel, Pt ring and calomel (SCE), represented the electrodes working, auxiliary and reference, respectively. The VPD conditions were: 75mV pulse amplitude, pulse width of 0.4 is scanning speed of 5 mV/s. For chromatographic testing was performed using a UV detector at 272 nm, C18 column (200 mm x 4.6 mm x 10 microns) with a mobile phase flow 2 ml/min. The observed voltammetric profiles showed an anodic peak at 293 mV (vs. Ag/AgClsat, pH = 6.0), whose potential and current levels was lower than that observed for cabono of electrode. Have excipients showed no do not constitute interfering peaks. Carbon electrodes with nanostructured silica sonogel also showed good linearity and recovery rate (CV <5%) compared to standard solution and official method (CLAE). This fact combined with good selectivity, sensitivity, and low overall cost makes this very promising device for analysis of paracetamol formulations. / O paracetamol (acetaminofeno) é um fármaco com propriedades antitérmica, analgésica e anti-inflamatória, destaca-se como um dos mais consumidos mundialmente. Em virtude desta demanda, o desenvolvimento e registro de novas formulações por parte do setor farmacêutico é contínuo. O controle de processos e do produto final é parte obrigatória do controle de qualidade. Os métodos oficiais para determinações quantitativas do paracetamol englobam técnicas espectrofotométricas e cromatográficas. Igualmente, dada a sua inerente eletroatividade, o uso de métodos eletroanalíticos é vasto. No presente trabalho pretende-se demonstrar a eficiência de eletrodos de carbono modificados com sílica sonogel em comparação a eletrodos convencionais e métodos oficiais. O desenvolvimento e validação de um método eletroanalítico para determinação quantitativa de paracetamol em formulações líquidas sob diferentes fases de desenvolvimento, comparando o método desenvolvido com o método oficial de Cromatografia Líquida de Alta Eficiência (CLAE), usando eletrodos convencionais de carbono vítreo e pasta de carbono e sonogel. As amostras consistiram em soluções preparadas a partir de formulação gotas de referência, 5 formulações teste e padrão SQR, todas a 200mg de paracetamol/mL. Para voltametria de pulso diferencial (VPD), utilizou-se um Potenciostato/galvanostato. Uma cela eletroquímica com capacidade de 5,0 mL, com sistema de três eletrodos, eletrodos de carbono vítreo ou sonogel, anel de Pt e calomelano (SCE), representado os eletrodos de trabalho, auxiliar e de referência, respectivamente. As condições para VPD foram: amplitude de pulso 75 mV e velocidade de varredura de 5 mV/s. Para ensaios cromatográficos foi utilizado um detector ultravioleta a 272 nm, coluna C18 (200 mm X 4,6mm X 10 μm), com fluxo de fase móvel 2 mL/minuto. Os perfis voltamétricos observados apresentaram um pico anódico em 293 mV (vs. Ag/AgClsat, pH = 6,0), cujo potencial e níveis de corrente foi inferior ao observado para eletrodo de carbono não modificado. Já os excipientes, não apresentaram picos não se constituindo em interferentes. Os eletrodos de sonogel apresentaram também boa linearidade e taxa de recuperação (CV < 5%) frente a solução padrão e método oficial (CLAE). Tal fato aliado a boa seletividade, sensibilidade e baixo custo geral torna o dispositivo promissor à análise de formulações de paracetamol. Palavras-chave: Eletrodos modificados; desenvolvimento farmacêutico; formas de dosagem; controle de qualidade.

Submitted by Izabel Monteiro (izabel_22@hotmail.com) on 2016-08-03T15:40:38Z No. of bitstreams: 1 Dissertação - Jackeline de Souza Marinho.pdf: 2225410 bytes, checksum: 7a6f9be92271f2c88a3bc632cfead114 (MD5) / Approved for entry into archive by Divisão de Documentação/BC Biblioteca Central (ddbc@ufam.edu.br) on 2016-08-17T15:57:58Z (GMT) No. of bitstreams: 1 Dissertação - Jackeline de Souza Marinho.pdf: 2225410 bytes, checksum: 7a6f9be92271f2c88a3bc632cfead114 (MD5) / Approved for entry into archive by Divisão de Documentação/BC Biblioteca Central (ddbc@ufam.edu.br) on 2016-08-17T16:10:32Z (GMT) No. of bitstreams: 1 Dissertação - Jackeline de Souza Marinho.pdf: 2225410 bytes, checksum: 7a6f9be92271f2c88a3bc632cfead114 (MD5) / Made available in DSpace on 2016-08-17T16:10:32Z (GMT). No. of bitstreams: 1 Dissertação - Jackeline de Souza Marinho.pdf: 2225410 bytes, checksum: 7a6f9be92271f2c88a3bc632cfead114 (MD5) Previous issue date: 2016-02-05 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Libidibia ferrea is an important plant species from Brazil, as pharmacology studies demonstrating potential therapeutic effects, such as anti-inflammatory and hypoglycemic associated with active substances, particularly in the stem bark and fruit. However, there are a few studies of the technological knowledge from transformation of the plant in a final dosage. Therefore, the aim of this study was to develop and assess the feasibility of obtaining solid dosage forms containing high spray dried product from fruit Libidibia ferrea. The plant material was collected, processed and characterized according to the quality control parameters. The spray dried extract (PSA) was produced from the optimization of the drying process of the extraction solution, which aimed to improve the yield and the physicochemical characteristics of the powder. The improved PSA was used to produce granulates, evaluating the efficiency of the method by wet and suitable granulating agent. The granules produced were characterized from a technological point of view and used as an intermediate for handling capsules. The influence of different flow regulators in the formulation of capsules (magnesium stearate, sodium lauryl sulfate and colloidal silicon dioxide) was studied by means of tests recommended by the Brazilian Pharmacopoeia (weight average, disintegration and liodisponibility). In order to evaluate the chemical stability during the production process it was determined content of total polyphenols in all process steps. The results obtained showed that the raw material is within the required quality standards and can be used for the production of pharmaceutical forms. The polyphenols content has not changed significantly during the drying process of the extraction solution, indicating that there was no degradation of constituents. The Eudragit E® proved to be a good granulation agent at a concentration of 15%, resulting in somewhat friable granules (1.68%) and high yield (80.6%) granulating the wet method. The presence of the flow regulators in the formulations did not cause significant differences in accordance with the tests performed demonstrate that the use thereof does not imply changes which impair the quality and efficacy of the product. The dissolution profile showed that the capsules did not suffer total dissolution (up 78.676%), which may be associated with several factors related to the formulation, dissolution medium, among others. Thus, the present study demonstrated that it is feasible the production of solid dosage forms, such as granules and capsules from the PSA given plant species, however further studies are still needed, particularly for the determination of chemical markers in order to analyze the stability of analytical method. / Libidibia ferrea é uma espécie vegetal de destaque no Brasil, uma vez que estudos farmacológicos demonstram potenciais efeitos terapêuticos, tais como anti-inflamatório e hipoglicemiante, atribuídos a substâncias ativas presentes, principalmente, na casca do caule e nos frutos. No entanto, os conhecimentos tecnológicos que propiciam a transformação da planta em uma forma farmacêutica final ainda são bastante incipientes. Por conseguinte, o objetivo desse estudo foi desenvolver e avaliar a viabilidade de obtenção de formas farmacêuticas sólidas contendo alto teor de produto seco por aspersão de frutos de Libidibia ferrea. O material vegetal foi obtido, processado e caracterizado de acordo com os parâmetros de controle de qualidade. O produto seco por aspersão (PSA) foi produzido a partir da otimização do processo de secagem da solução extrativa, que teve por finalidade melhorar o rendimento e as características físico-químicas do pó. O PSA otimizado foi utilizado para a produção de granulados, avaliando-se a eficiência do método por via úmida e o agente de granulação adequado. Os granulados produzidos foram caracterizados do ponto de vista tecnológico e utilizados como produto intermediário para a manipulação das cápsulas. Foi estudada a influência de diferentes reguladores de fluxo na formulação das cápsulas (estearato de magnésio, lauril sulfato de sódio e dióxido de silício coloidal) por meio de ensaios preconizados pela Farmacopeia Brasileira (peso médio, desintegração e liodisponibilidade). A fim de avaliar a estabilidade química durante o processo de produção, determinou-se o teor de polifenois totais em todas as etapas do processo. Os resultados obtidos permitiram verificar que a matéria-prima atende aos padrões de qualidade exigidos, podendo ser utilizada para a produção de formas farmacêuticas. O teor de polifenois não sofreu grandes alterações durante o processo de secagem da solução extrativa, indicativo de que não houve degradação de constituintes. O Eudragit E® demonstrou ser um bom agente de granulação na concentração de 15%, originando granulados pouco friáveis (1,68%) e de elevado rendimento (80,6%) pelo método de granulação por via úmida. A presença dos reguladores de fluxo nas formulações não ocasionou diferenças significativas de acordo com os ensaios realizados, demonstrando que a utilização destes não implica em alterações que comprometam a qualidade e eficácia do produto. O perfil de dissolução demonstrou que as cápsulas não sofreram dissolução total (máximo 78,676%), fato que pode estar associado a diversos fatores relacionados à formulação, meio de dissolução, entre outros. Dessa forma, o presente estudo demonstrou que é viável a produção de formas farmacêuticas sólidas, como granulados e cápsulas, a partir do PSA da dada espécie vegetal. No entanto, estudos mais aprofundados ainda são necessários, principalmente quanto ao doseamento de marcadores químicos, a fim de analisar a estabilidade por método analítico.

Natural products are complex mixtures of compounds with therapeutic effects which are often reported to be due to the synergistic action of multiple and sometimes unknown components. Consequently, standardization of these products is complex and a lack of effective quality control (QC) criteria in most countries has led to marketing of commercial products with questionable quality, safety and efficacy (QSE). The aim of this study was therefore to develop qualitative and quantitative analytical methods for use in the QC of Ginkgo biloba solid oral dosage forms. Initially, a micellar electrokinetic chromatography (MEKC) method was developed for the identification of the flavonol glycosides, rutin and quercitrin as well as 3 flavonol aglycones, quercetin, kaempferol and isorhamnetin in crude extracts of 4 Ginkgo biloba solid oral dosage forms using ultraviolet (UV) detection. A reversed-flow cyclodextrin-modified MEKC method was subsequently developed for the simultaneous determination of the aforementioned flavonols as well as ginkgolide A, B, C, J and bilobalide (all positive markers) in Ginkgo commercial products. A non-aqueous capillary electrophoresis (CE) method was also developed for fingerprinting the presence of ginkgolic acids (negative markers) in Ginkgo biloba leaf extracts, which are purported to be associated with toxic properties. This method was also applied to 2 Ginkgo biloba commercial products. Since the flavonols have strong UV absorbing chromophores, a reversed phase high-performance liquid chromatographic (RP-HPLC) method was developed and validated using photo-diode-array (PDA) detection which was then successfully applied to fingerprint commercially available Ginkgo biloba solid oral dosage forms as well as quantify the relevant flavonol markers present in these extracts. Sample preparation was simple, rapid and cost efficient with minimal clean-up and the employment of a minibore column which requires low mobile phase flow rates contributed to the economy of the method. Unlike the conventional QC approach, samples were not hydrolyzed and direct determination of 2 intact flavonol glycosides, together with the usual aglycone markers was facilitated which provided maximal content information for fingerprint comparisons. On the other hand, terpene trilactones possess poor chromophores and an alternative detection method to UV was required in order to obtain suitable sensitivity. RP-HPLC with evaporative light scattering detection (ELSD) was selected for quantification of these non-volatile constituents in Ginkgo dosage forms and this method was deemed suitable for the routine QC analysis of these positive markers in commercial products. Since approximately 33 flavonoids have been identified in Ginkgo biloba leaf extracts, baseline separation using UV/PDA detection normally requires complex gradient programs and long analysis times. In addition, unequivocal identification of the flavonoids with similar UV spectra and elution times cannot be guaranteed. A liquid chromatographic tandem mass spectrometric (LC-MS-MS) method was therefore developed and validated in order to ensure accurate quantification of the selected flavonol marker compounds in Ginkgo commercial products. LC-MS-MS analysis of Ginkgo extracts revealed, in addition to rutin, the possible presence of other quercetin analogues, quercetin-3-Orhamnoside-7-O-glucoside or quercetin-3-O-glucoside-7-O-rhamnoside, previously unreported in Ginkgo biloba leaf extracts or dosage forms. In terms of evaluating the most suitable analytical method for QC, CE shows exceptional potential in the future analysis of Ginkgo biloba dosage forms while HPLC-PDA and HPLC-ELSD are currently the most affordable and practical instruments for the routine analysis of the flavonols and terpenoids, respectively. LC-MS-MS proved to be pivotal for the accurate identification and quantification of the flavonols due to interference by other flavonoid compounds with similar retention times and UV spectra to the peaks of interest. All quantitative and qualitative results revealed large discrepancies in the marker content between the products regardless of which batch was analysed and product labels disclosed little relevant information. Although currently not required by most regulatory agencies, some of the usual quality criteria applied to orthodox medicines was evaluated. In particular, dissolution analysis, disintegration, tablet hardness and weight uniformity were assessed and revealed similar inconsistencies. This thesis emphasises that implementation of effective QC criteria is long overdue and is essential to ensure consistent product QSE of commercially available Ginkgo biloba solid oral dosage forms.

Thesis (M. Pharmacy ((Pharmaceutics)) -- University of Limpopo, 2022 / According to the biopharmaceutical classification system, Clarithromycin is considered a class II molecule with low solubility. Poorly soluble drugs result in low bioavailability. Various techniques have been studied to improve the solubility of drugs and subsequently bioavailability. Of these techniques, preparation of amorphous form is the preferred method because it is a more effortless and convenient way to improve the aqueous solubility and dissolution of poorly water soluble drugs. The only disadvantage of amorphous materials is that they are less thermodynamically stable and can recrystallize during processing and storage. Aim: The aim of this study is to prepare amorphous form of clarithromycin to improve its solubility, dissolution rate, and, subsequently, bioavailability. Methods: In this study, preparation of amorphous form of clarithromycin was conducted using the quench cooling method in which the purchased anhydrous crystalline clarithromycin was spread on an aluminum foil and heated to a melting point (217˚C - 220˚C) and then rapidly cooled. Various techniques were conducted to characterize the prepared amorphous clarithromycin, and these include Differential Scanning Calorimetry (DSC), Fourier-Transform Infrared Spectroscopy (FTIR), and X-Ray Powder Diffraction (XRPD). In addition, tablets were formulated using the amorphous clarithromycin mixed with selected excipients from compatibility studies, and in vitro dissolution and stability studies were conducted over a period of 6 months. Results: The DSC thermogram results confirmed that the material prepared using the quench cooling process is an amorphous solid-state. Furthermore, the XRPD confirmed an amorphous solid-state with scattering halo peaks. The FTIR also depicted some broader and lower intensity peaks that indicated a formation of an amorphous material. The dissolution rate of amorphous clarithromycin tablets improved by more than 30% when compared to commercial crystalline clarithromycin tablets. The study revealed a drop in dissolution rate at months 3 to 6 under accelerated conditions due to recrystallization. The 6 monthly stability study at long term conditions showed no change in the integrity of the tablets and their contents. Conclusion: As indicated by the study, it can be concluded that the amorphous clarithromycin remained stable during processing and storage under long-term stability for 6 months. Furthermore, based on dissolution results, it can be concluded that amorphous solids have an improved dissolution rate. / Medical Research Council CHIETA

Hot-melt extruded solid dispersion technique is increasingly employed to improve the solubility of poorly water-soluble drugs. The technique relies on the enhanced solubility of the amorphous form of the drug compared to its crystalline counterpart. These systems however are thermodynamically unstable. This means that the drug crystallises with time. Therefore, efforts to measure the stability of these systems over the life span of the product are crucial. This study focused on investigating the use of Hansen Solubility Parameters to quantify polymer-drug interaction and to predict the stability of solid dispersions. This was achieved through a systematic review of hot-melt extruded solid dispersion literature. The study also investigated the use of a combined mechanical and rheological model to characterise the physicochemical and release behaviour of three solid dispersion immediately after preparation and after storage for one month at 40oC or three months at room temperature. Results revealed that the total solubility parameter |ΔбT| was able to predict the stability of the systems for more than 4 months using a cut-off point of 3 MPa-1 with a negative predictive value of 0.9. This was followed by ΔбD with a cut-off point of 1.5 MPa- 1. Moreover, Dynamic Mechanical Analyser and shear rheometry data were shown to be more sensitive than Differential Scanning Calorimetry, Powder X-Ray Diffraction, Scanning Electron Microscope and Fourier Transform Infrared in detecting crystallisation and the interaction between the drug and the polymer. The Dynamic Mechanical Analyser data were consistent with the dissolution behaviour of the samples when comparing the freshly prepared samples with those after storage. The results highlight the need for a unified characterisation approach and the necessity of verifying the homogeneity of mixing during the extrusion process.

A correlação in vitro-in vivo (CIVIV) refere-se ao estabelecimento de uma relação racional entre as propriedades biológicas, ou parâmetros derivados destas, produzidos por uma forma farmacêutica e suas propriedades ou características físico-químicas. O estabelecimento desse tipo de correlação de dados pode possibilitar a substituição dos estudos in vivo, necessários à demonstração da bioequivalência, pelos estudos in vitro, no caso de alterações no processo de fabricação pós-registro. Os sistemas matriciais apresentam, como principal exemplo de material controlador da liberação, substâncias poliméricas formadoras de matrizes hidrofílicas. Hidroxipropilmetilcelulose (HPMC) é um excipiente de escolha para o preparo de matrizes hidrofílicas, devido à capacidade de formação de gel e controle da liberação. O diclofenaco de sódio (DCL) é um antiinflamatório não esteroidal com ação analgésica e antipirética. Considerando suas características físico-químicas e farmacológicas, é objetivo deste trabalho o estabelecimento de uma CIVIV para DCL incorporado em sistemas matriciais. Os comprimidos de DCL com HPMC foram desenvolvidos e submetidos aos ensaios de dissolução utilizando os aparatos 1, 2, 3 e 4 conforme as especificações farmacopeicas. Foi realizado o estudo de biodisponibilidade, seguindo as normas éticas, com as formulações selecionadas. A partir dos dados de absorção obtidos pela técnica de deconvolução e dos dados de dissolução foi estabelecida a correlação. Os resultados demonstraram que o aumento da concentração de HPMC produziu a redução da velocidade de dissolução e, dependendo da condição de estudo, estas diferenças foram mais ou menos significativas. Os comprimidos com concentração intermediária de HPMC (15 a 20%) foram mais sensíveis às alterações de formulação e das condições do ensaio de dissolução. As formulações contendo 30% de HPMC praticamente não modificaram o perfil de dissolução, mesmo com alterações na formulação e condições de estudo. No estudo de biodisponibilidade empregado no estabelecimento da CIVIV, foram utilizadas as formulações F1, F2A, F3 e o medicamento de referência Voltaren® 50 mg. A fração absorvida percentual foi determinada pela técnica de deconvolução. A correlação linear entre a fração absorvida e fração dissolvida apresenta um coeficiente de determinação maior do que 0,7. Foi observado que os perfis de dissolução são mais discriminativos que os perfis de absorção, indicando que uma melhor correlação pode ser obtida através da adequação do método de dissolução. / The term in vitro-in vivo correlation (IVIVC) refers to the establishment of a rational relationship between the biological properties, or a parameter derived from a biological property produced by a dosage form, and a physicochemical characteristic or property of the same dosage form. The establishment of IVIVC enables the substitution of in vivo studies for in vitro studies to evaluate bioequivalence, e.g. in case of post-approval changes. Matrix tablets employ mainly hydrophilic polymers to control drug release. Hydroxypropylmethylcellulose (HPMC) is an excipient of choice for preparation of hydrophilic matrices, due to its gel formation and controlled drug release capacities. Sodium diclofenac (SD) is a non-steroidal anti-inflammatory drug with analgesic and antipyretic effects. Considering its physicochemical and pharmacological characteristics, the objective of this work is to establish an IVIVC for HPMC matrix tablets containing SD. HPMC matrix tablets with SD were formulated and submitted to dissolution testing using apparatus 1, 2, 3 and 4 in accordance with pharmacopoeial specifications. The bioavailability study was carried out under ethical guidelines, using the selected formulations. The correlation was obtained by plotting absorption data, obtained from diclofenac plasmatic curves through a deconvolution technique, against dissolution data. The results showed that the increase of HPMC concentration produces a decrease of the drug dissolution rate and these differences were more or less significant, depending on the study conditions. Tablets with intermediate HPMC concentrations (15 to 20%) were more sensitive to changes in dissolution conditions. Formulations containing 30% HPMC do not present changes in dissolution profiles, even when the formulation or the study conditions change. Formulations F1, F2A, F3 and Voltaren® 50 mg as reference product were used in the bioavailability study to establish IVIVC. The linear correlation between absorbed drug fraction and dissolved drug fraction has a determination coefficient higher than 0.7. It was observed that the dissolution profiles are more discriminative than the absorption profiles, which indicates that a better correlation can be obtained through changes of the dissolution method.

differential scanning calorimetric profile and the generation of much less intense and broader peaks in the powder X-ray diffraction pattern compared to beta-CD. FTIR analysis revealed significant physical interactions between CX oil and beta-CD in the granules, possibly due to complexation. Results from phase solubility measurements and proton nuclear magnetic resonance ( 1H-NMR) analysis of pure 3-butylidenephthalide (3-BDPH), a representative CX component, lend some support for the formation of a 1:1 stoichiometric inclusion complex between 3-BDPH and beta-CD. / Rhizoma chuanxiong (CX), the dried rhizome of Ligusticum Chuangxiong Hort. (Umbelliferae), has been extensively used in mainland China as a traditional herbal medicine for treating cardio-/cerebrovascular diseases and gynecological disorders. However, the active components in CX, which are predominantly essential oils, generally exhibit poor stability (mostly photo-oxidation), high volatility, low aqueous solubility, and extensive gut/hepatic metabolism, all of which can significantly reduce their oral bioavailability and therapeutic efficacy. The present project has investigated the feasibility of utilizing three formulation approaches to circumvent the aforementioned problems associated with the peroral delivery of CX (as crude oil mixture or individual components). / The first approach involved inclusion of CX oil in beta-cyclodextrin (beta-CD) as solid granules using a coprecipitation method optimized with the aid of an orthogonal study design. The resulting CX oil granules were colorless and odorless with a median particle size of 11.38mum; were stable to heat, light and moisture, and readily soluble in simulated gastric and intestinal fluids. The granules were largely amorphous, as evidenced by an absence of the melting endotherm for beta-CD in the formulation could be largely explicated by the complexation behavior and hydration properties of the two polymers blended in different weight percentages, as substantiated by turbidity measurement, viscosity determination and FTIR analysis of the pure polymer mixtures as well as swelling measurement of the formulated tablets. The sustained release behavior of 3-BDPH from the tablet was dependent on the relative proportion of the two polymers present, and could be similarly explained by the changes in hydration and complexation behavior of the polymers during the penetration of aqueous fluid into the tablet matrix. / The second approach involved incorporation of CX oil into surfactant micelles and liquid crystals as a self-emulsifying drug delivery system (SEDDS). An optimal formulation was developed through a judicial choice of excipients (lipids and surfactants/cosurfactant) and their proper combination in the correct proportions, as determined by the spontaneity of the emulsification process and the change in emulsion droplet size. The formulation was readily dispersible in water upon mild agitation, free from unpleasant odor, and stable in soft gelatin capsules for a storage period of at least 12 months under ambient condition. The optimal utilization of the lipid and surfactant blends in defined proportions in the formulation was further substantiated by interfacial tension determination and equilibrium phase analysis. / The third approach involved formulation of 3-BDPH (or crude CX oil) into a sustained-release buccoadhesive tablet, based on a systematic evaluation of the adhesive properties of two polymers (Carbopol 974P and hydroxypropyl methylcellulose K4M) used in the formulation. The adhesive properties of the formulation could be largely explicated by the complexation behavior and hydration properties of the two polymers blended in different weight percentages, as substantiated by turbidity measurement, viscosity determination and FTIR analysis of the pure polymer mixtures as well as swelling measurement of the formulated tablets. The sustained release behavior of 3-BDPH from the tablet was dependent on the relative proportion of the two polymers present, and could be similarly explained by the changes in hydration and complexation behavior of the polymers during the penetration of aqueous fluid into the tablet matrix. / Gao Yuan. / "April 2005." / Adviser: Albert H. L. Chow. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1585. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 193-223). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

A correlação in vitro-in vivo (CIVIV) refere-se ao estabelecimento de uma relação racional entre as propriedades biológicas, ou parâmetros derivados destas, produzidos por uma forma farmacêutica e suas propriedades ou características físico-químicas. O estabelecimento desse tipo de correlação de dados pode possibilitar a substituição dos estudos in vivo, necessários à demonstração da bioequivalência, pelos estudos in vitro, no caso de alterações no processo de fabricação pós-registro. Os sistemas matriciais apresentam, como principal exemplo de material controlador da liberação, substâncias poliméricas formadoras de matrizes hidrofílicas. Hidroxipropilmetilcelulose (HPMC) é um excipiente de escolha para o preparo de matrizes hidrofílicas, devido à capacidade de formação de gel e controle da liberação. O diclofenaco de sódio (DCL) é um antiinflamatório não esteroidal com ação analgésica e antipirética. Considerando suas características físico-químicas e farmacológicas, é objetivo deste trabalho o estabelecimento de uma CIVIV para DCL incorporado em sistemas matriciais. Os comprimidos de DCL com HPMC foram desenvolvidos e submetidos aos ensaios de dissolução utilizando os aparatos 1, 2, 3 e 4 conforme as especificações farmacopeicas. Foi realizado o estudo de biodisponibilidade, seguindo as normas éticas, com as formulações selecionadas. A partir dos dados de absorção obtidos pela técnica de deconvolução e dos dados de dissolução foi estabelecida a correlação. Os resultados demonstraram que o aumento da concentração de HPMC produziu a redução da velocidade de dissolução e, dependendo da condição de estudo, estas diferenças foram mais ou menos significativas. Os comprimidos com concentração intermediária de HPMC (15 a 20%) foram mais sensíveis às alterações de formulação e das condições do ensaio de dissolução. As formulações contendo 30% de HPMC praticamente não modificaram o perfil de dissolução, mesmo com alterações na formulação e condições de estudo. No estudo de biodisponibilidade empregado no estabelecimento da CIVIV, foram utilizadas as formulações F1, F2A, F3 e o medicamento de referência Voltaren® 50 mg. A fração absorvida percentual foi determinada pela técnica de deconvolução. A correlação linear entre a fração absorvida e fração dissolvida apresenta um coeficiente de determinação maior do que 0,7. Foi observado que os perfis de dissolução são mais discriminativos que os perfis de absorção, indicando que uma melhor correlação pode ser obtida através da adequação do método de dissolução. / The term in vitro-in vivo correlation (IVIVC) refers to the establishment of a rational relationship between the biological properties, or a parameter derived from a biological property produced by a dosage form, and a physicochemical characteristic or property of the same dosage form. The establishment of IVIVC enables the substitution of in vivo studies for in vitro studies to evaluate bioequivalence, e.g. in case of post-approval changes. Matrix tablets employ mainly hydrophilic polymers to control drug release. Hydroxypropylmethylcellulose (HPMC) is an excipient of choice for preparation of hydrophilic matrices, due to its gel formation and controlled drug release capacities. Sodium diclofenac (SD) is a non-steroidal anti-inflammatory drug with analgesic and antipyretic effects. Considering its physicochemical and pharmacological characteristics, the objective of this work is to establish an IVIVC for HPMC matrix tablets containing SD. HPMC matrix tablets with SD were formulated and submitted to dissolution testing using apparatus 1, 2, 3 and 4 in accordance with pharmacopoeial specifications. The bioavailability study was carried out under ethical guidelines, using the selected formulations. The correlation was obtained by plotting absorption data, obtained from diclofenac plasmatic curves through a deconvolution technique, against dissolution data. The results showed that the increase of HPMC concentration produces a decrease of the drug dissolution rate and these differences were more or less significant, depending on the study conditions. Tablets with intermediate HPMC concentrations (15 to 20%) were more sensitive to changes in dissolution conditions. Formulations containing 30% HPMC do not present changes in dissolution profiles, even when the formulation or the study conditions change. Formulations F1, F2A, F3 and Voltaren® 50 mg as reference product were used in the bioavailability study to establish IVIVC. The linear correlation between absorbed drug fraction and dissolved drug fraction has a determination coefficient higher than 0.7. It was observed that the dissolution profiles are more discriminative than the absorption profiles, which indicates that a better correlation can be obtained through changes of the dissolution method.

Magister Pharmaceuticae - MPharm / Sutherlandia frutescens (tribe Galegeae, Fabaceae), is a popular medicinal plant traditionally used in South Africa. In 2000, a company called Phyto Nova (Pty) Ltd. initiated large-scale cultivation and contract manufacturing of tablets, made from the powdered herb (i.e. thin stems and leaves). Most of these commercial Sutherlandia solid dosage forms are made from the dried leaf powder but recently a new product, viz. Promune™ capsules, made from a freeze-dried aqueous extract, came on the market and was claimed to be “better” as it mimics the traditional tea. However, the pharmaceutical quality and stability of these preparations have not yet been investigated. The objectives of this study were firstly, to develop a validated stability-indicating HPLC assay for sutherlandioside B (SU-B); secondly, to compare the SU-B levels in the two commercially available Sutherlandia products viz, the Phyto Nova Sutherlandia SU1™ tablet and the Promune™ capsule, and, thirdly, to determine the effect of elevated temperature and humidity as well as acid hydrolysis on the SU-B levels in these two products. / South Africa