Pharmaceutical drug development is a costly and time consuming process. Reportedly, it takes about 10-15 years and ~900 million dollars of investment to launch a new drug in the world market. Any measure that increases the power and also decreases uncertainty about that power also increases drug net present value. For some time now, it has been argued that judicious utilization of available data might lead to more efficient use of resources during drug development. Conventionally, assessment of effectiveness has been based on comparing change from baseline at some pre-specified time for the control and test treatment (SPA). The last observation carry forward (LOCF) is a widely used technique if the data are missing due to any reason. Although, LOCF is known to introduce bias, the direction and magnitude is debatable.The primary aim of the proposed simulation experiments was to assess the properties of the random effects model (REM) and mixed model repeated measures (MMRM) methods that utilize all the data collected during pivotal trials. A total of 43 scenarios based on disease progression, magnitude of drug effect, between and within subject variability and patient drop-outs were analyzed. Three analysis methods, viz. SPA, REM and MMRM, were investigated. For the SPA method, the missing data were imputed with four different methods, such as LOCF, mean imputation, population and individual regression. The false-positive, false-negative inferences and bias in estimating the effect size for each method was assessed.The most important finding of this report is that the REM and MMRM methods are efficient alternatives to the SPA methods with ~50% savings on sample size. These methods are based on sound scientific principles and provide stronger evidence against the null hypothesis. The choice of the REM versus MMRM method is dependent on the purpose of the analysis and data gathered from the experimental design. The results support the use of likelihood-based MMRM methods for regulatory decision making. The REM methods are useful in understanding the time course of the disease and drug effect, making predictions based on the data and gaining insights into time to steady state effect for rational decision making. The SPA methods are less powerful across all the scenarios. The SPA-LOCF yielded anticonservative results in some cases with type-1 error rate exceeding 15% if data were missing due to toxicity. On the other hand, the drug effect was consistently underestimated (~40%), if data were missing due to lack of effectiveness. The results demonstrate that the SPA-LOCF methods make it practically impossible to establish effectiveness in these areas with a reasonable sample size.

Orientador: Rosângela Gonçalves Peccinini / Banca: Pedro José Rolim Neto / Banca: Antonio José de Araujo Aguiar / Resumo: O efavirenz (EFZ), fármaco de primeira escolha utilizado no tratamento da imunodeficiência adquirida, é um fármaco de Classe II segundo o Sistema de Classificação Biofarmacêutica. A baixa solubilidade desta classe de fármacos tem significativo impacto na sua absorção enteral, resultando principalmente em biodisponibilidade errática, característica que pode contribuir para a variabilidade de resposta ao tratamento. Frente a esse problema, o Laboratório de Tecnologia de Medicamentos (LTM) da Universidade Federal de Pernambuco complexou o EFZ em dispersão sólida (DS) com o objetivo de aumentar sua solubilidade e melhorar suas características de absorção. Para avaliar os resultados dessa inovação, o estudo da disposição cinética na administração por diferentes vias e diferentes modelos animais é indicado. Neste sentido, o presente estudo teve como objetivo avaliar e comparar a farmacocinética pré-clínica do EFZ em coelhos albinos (machos; 2,8 kg; n=21) após administração intravenosa (2,7 mg/kg) e oral do insumo farmacêutico ativo (50 mg) e do EFZ carreado pela DS (50 mg - 10% EFZ). A quantificação de EFZ no plasma dos animais foi realizada através de método cromatográfico previamente validado e os parâmetros farmacocinéticos foram obtidos utilizando cálculos farmacocinéticos para modelo monocompartimental. O grupo EFZ-IV mostrou-se diferente estatisticamente em todos os parâmetros farmacocinéticos em relação às duas administrações orais; e esses resultados são esperados pois na a... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Efavirenz (EFZ), the first-choice drug used to treat acquired immunodeficiency, is a Class II drug according to the Biopharmaceutical Classification System. The low solubility of this class of drugs has a significant impact on its enteral absorption, resulting mainly in erratic bioavailability, a characteristic that may contribute to the variability of response to treatment. Faced with this problem, the Laboratory of Medication Technology (LTM) of the Federal University of Pernambuco produced a new solid dispersion (DS) with the objective of increasing EFZ solubility and improving its absorption characteristics. To evaluate the results of this innovation, the kinetic arrangement in the administration by different routes and different animal models is indicated. The aim of the present study was to evaluate and compare the pre-clinical EFZ pharmacokinetics in albino rabbits (male, 2.8 kg, n = 21) after intravenous (2.7 mg/kg), oral active pharmaceutical ingredient (50 mg) and carried by DS (500 mg - 10% EFZ). EFZ quantification was performed using a previously validated chromatographic method and the pharmacokinetic parameters were obtained and compared to each other using pharmacokinetic calculations for onecompartmental models. The EFZ-IV group was statistically different in all pharmacokinetic parameters relative to the two oral administrations, these results are expected since intravenous administration does not undergo the absorption process, leading to the immediate occurrence of the distribution and elimination processes. For the ORAL-IFA and ORAL-DS groups, no statistically significant difference was observed either, but less intra-animal variability was observed in the pharmacokinetic parameters from administration... (Complete abstract click electronic access below) / Mestre

Monte Carlo (MC) and Pencil Beam (PB) calculations are compared to their measured planar dose distributions using a 2-D diode array for lung Stereotactic Body Radiation Therapy (SBRT). The planar dose distributions were studied for two different phantom types: an in-house heterogeneous phantom and a homogeneous phantom. The motivation is to mimic the human anatomy during a lung SBRT treatment and incorporate heterogeneities into the pre-treatment Quality Assurance process, where measured and calculated planar dose distributions are compared before the radiation treatment. Individual and combined field dosimetry has been performed for both fixed gantry angle (anterior to posterior) and planned gantry angle delivery. A gamma analysis has been performed for all beam arrangements. The measurements were obtained using the 2-D diode array MapCHECK 2™. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2015. / FAU Electronic Theses and Dissertations Collection

The development of essential medicines is being slowed by a lack of efficiency in drug development as ninety per cent of drugs fail at some stage during clinical evaluation. This attrition in drug development is seen not because of a reduction in pharmaceutical research expenditure nor is it caused by a declining understanding of biology, if anything, these are both increasing. Instead, drugs are failing because we are unable to effectively predict how they will work before they are given to patients. This is due to limitations of the current methods used to evaluate a drug's toxicity and efficacy prior to its development. Quite simply, these methods do not account for the full complexity of biology in humans. Systems pharmacology models are a likely candidate for increasing the efficiency of drug discovery as they seek to comprehensively model the fundamental biology of disease mechanisms in a quantit- ative manner. They are computational models, designed and hailed as a strategy for making well-informed and cost effective decisions on drug viability and target druggability and therefore attempt to reduce this time-consuming and costly attrition. Using text mining and text classification I present a growing landscape of systems pharmacology models in literature growing from humble roots because of step-wise increases in our understanding of biology. Furthermore, I develop a case for the capability of systems pharmacology models in making predictions by constructing a model of interleukin-6 signalling for rheumatoid arthritis. This model shows that druggable target selection is not necessarily an intuitive task as it results in an emergent but unanswered hypothesis for safety concerns in a monoclonal antibody. Finally, I show that predictive classification models can also be used to explore gene expression data in a novel work flow by attempting to predict patient response classes to an influenza vaccine.

O constante crescimento mundial da Pesquisa Clínica no desenvolvimento de novas drogas foi responsável pelo aumento do interesse em traçar as atividades desenvolvidas pelas Autoridades Regulatórias. Os dados foram obtidos através de revisão bibliográfica sistemática, destacando o tempo de aprovação dos protocolos clínicos e as normatizações vigentes: no Brasil, Estados Unidos da América, União Europeia, Canadá e Japão. Além disso, observou-se a atuação de profissionais experientes na realização de atividades no Comitê de Ética para Análise de Projetos de Pesquisa (CAPPesq) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP). Com isso, foi possível identificar as diferenças significantes em relação à legislação e ao sistema regulatório dos países em questão. Deficiências no sistema regulatório brasileiro responsáveis pela demora no tempo de aprovação foram constatadas. Com a identificação destes fatores, foram elaboradas sugestões relacionadas à qualificação dos profissionais atuantes, organização das atividades desempenhadas pelas Autoridades Regulatórias e possíveis alterações administrativas. A diferente atuação das autoridades analisadas pode servir como fonte de aprimoramento do sistema regulatório nacional e, consequentemente, aprimorar o processo para aprovação e realização de protocolos clínicos com medicamentos testados no Brasil. / The world-wide Clinical Research for new drug development growth was responsible for the increase of interest in following the regulatory authorities activities. Data were collected through a systematic literature review.The main facts observed were clinical protocols time approval and guidelines in Brazil, United States of America, European Union, Canada and Japan. In addition, it was observed the activities realized by experienced professionals of the IRB of the University of São Paulo School of Medicine. Significant legislation and regulatory system differences between the countries were identified. Some deficiencies at Brazilian regulatory system, suggestions regarding the acting professionals qualification, organization of the regulatory authorities activities and possible administrative changes were discussed. The different performance of the regulatory authorities can serve as a source to upgrade the national regulatory system and consequently lead to improvements in process of approval and realization of clinical protocol with drugs tested in Brazil.

Submitted by Joana Azevedo (joanad@id.uff.br) on 2017-06-29T17:40:02Z No. of bitstreams: 1 Dissert Ana Carolina Felizardo Lima.pdf: 1609943 bytes, checksum: 8507dcda10086eb77a81018410234127 (MD5) / Rejected by Biblioteca da Escola de Engenharia (bee@ndc.uff.br), reason: Item rejeitado, pois a ficha catalográfica está fora do padrão. Atenciosamente, Catarina Ribeiro Bibliotecária BEE - Ramal 5992/5993/5994 on 2017-07-07T13:12:20Z (GMT) / Submitted by Joana Azevedo (joanad@id.uff.br) on 2017-07-26T19:37:01Z No. of bitstreams: 1 Dissert Ana Carolina Felizardo Lima.pdf: 1641149 bytes, checksum: ff9e077bbc5f7321ffad9983e9465431 (MD5) / Approved for entry into archive by Biblioteca da Escola de Engenharia (bee@ndc.uff.br) on 2017-07-28T14:42:57Z (GMT) No. of bitstreams: 1 Dissert Ana Carolina Felizardo Lima.pdf: 1641149 bytes, checksum: ff9e077bbc5f7321ffad9983e9465431 (MD5) / Made available in DSpace on 2017-07-28T14:42:57Z (GMT). No. of bitstreams: 1 Dissert Ana Carolina Felizardo Lima.pdf: 1641149 bytes, checksum: ff9e077bbc5f7321ffad9983e9465431 (MD5) / Para que um medicamento seja considerado apto ao comércio no Brasil e esteja disponível para a população, este precisa obter um registro no órgão regulador nacional, que é a Agência Nacional de Vigilância Sanitária (ANVISA). Nesta etapa de registro, a segurança, eficácia e qualidade do medicamento são avaliadas, visando garantir a saúde pública. Acredita-se que se a fase de desenvolvimento do medicamento for devidamente planejada e controlada, possibilitará a obtenção de produtos farmacêuticos com estas características e com custo reduzido, já que acarretará na diminuição de retrabalhos ou de possíveis necessidades de alterações pós-registro. A área de desenvolvimento farmacêutico de uma indústria farmacêutica pública do Rio de Janeiro hoje trabalha com aproximadamente metade de sua capacidade dedicada à projetos de redesenvolvimentos, o que representa um problema para a indústria, já que grande parte do tempo e do montante financeiro destinados ao desenvolvimento de produtos, acabam por ser reinvestidos em produtos que já foram ou são parte do portfólio da empresa, em detrimento da adesão de novos produtos. Trata-se de um alto custo em recursos materiais e humanos investidos em retrabalho. Esta pesquisa explicativa e aplicada objetivou esclarecer as causas da grande quantidade de projetos de redesenvolvimento e delinear propostas de ações corretivas para as principais, através do estudo de caso, documental e de campo, da aplicação de parte do método de análise e solução de problemas (MASP), de modo a reduzir a quantidade de redesenvolvimentos, e assim contribuir para a melhoria do processo e aumento da viabilidade de desenvolvimento de novos medicamentos. Essa pesquisa demonstrou que o método e as ferramentas escolhidas foram eficazes dentro do esperado. Através deles, foi possível evidenciar uma interligação entre as causas principais dos problemas levantados, um plano de ação foi proposto e sua viabilidade foi validada / A drug will be approved to trade in Brazil and be available to the population if it gets registry in the national regulator agency, Agência Nacional de Vigilância Sanitária (ANVISA). At this registry step, the drugs will be evaluated for their safety, effectiveness and quality, in order to ensure the public health. It is believed that if the drug development is properly planned and controlled, it makes possible to obtain pharmaceutical products with these characteristics and low cost, because it will result in reduction of reworks and possibles changes needs after registry. The pharmaceutical development area in a pharmaceutical industry in Rio de Janeiro works nowadays with almost half of its capacity dedicated to redevelopment, which represents a problem to the organization, because of the time and financial amount that is reinvested in products that are, or have been, part of organization’s portfolio, instead of supporting new products. This is a high cost in human and material resources invested in rework. This explanatory and applied research aimed to clarify the causes of the large number of redevelopment projects and to outline proposals for corrective actions to the majors causes of redevelopment in the public pharmaceutical industry target of this study, through the application of analysis and troubleshooting method MASP, in order to reduce the amount of redevelopment projects, contribute to the process improvement and increase the feasibility of developing new drugs. This research has shown that the selected method and tools were effective as expected. Through them, it was possible to show an interconnection between the main causes of the problems raised, a plan of action was proposed and its feasibility was validated.

This study addressed the factors that predict employee response to large-scale change in the United States pharmaceutical industry. When poorly executed, major organizational changes such as mergers and acquisitions are often disruptive and costly to organizations and demoralizing to employees. Although employee responses to change have been studied in several industries, employee responses during change execution in the pharmaceutical industry have not been subject to study. The purpose of this correlational study was to reduce the knowledge gap related to organizational change in the pharmaceutical industry by evaluating key predictors of employee response to large-scale change. The theoretical framework consisted of transformational leadership, stakeholder, and change management theories. The research questions focused on 4 key predictors (initial change reaction, change communication, involvement in change development, and perceived change success) and their effect on 2 primary dependent variables: reaction to change (RC) and support of change (SC). Ninety-eight participants completed the survey and multiple regression was used to measure associations between predictor variables and dependent variables. The 4 independent variables in the aggregate predicted RC and the championing subscale of SC. Individually, none of the independent variables predicted RC, SC, or any of the SC subscales. The study contributes to positive social change by providing leadership with information in guiding creation of a supportive work environment during organizational change and to inspire employees developing medical innovations to fulfill global health needs, while creating skilled jobs and generating profit.

University of Macau / Institute of Chinese Medical Sciences

En aquesta tesi s’ha realitzat una aproximació terapèutica per a la malaltia de Gaucher, basada en xaperones farmacològiques. La malaltia de Gaucher és una malaltia d’acúmul lisosòmic d'herència autosòmica recessiva, causada per mutacions en el gen GBA, o en alguns pocs casos, per mutacions en el gen PSAP. El gen GBA codifica la hidrolasa lisosòmica glucocerebrosidasa i el gen PSAP codifica la proteïna activadora de l'enzim anterior, la Saposina C. Fins al moment s'han descrit més de 300 mutacions en el gen GBA causants de la malaltia de Gaucher, que han permès desenvolupar un diagnòstic molecular de la malaltia, i unes poques en el gen PSAP. Aquestes mutacions produeixen una deficiència en alguna d'aquestes dues proteïnes, la glucocerebrosidasa o la Saposina C, que estan implicades en la via de degradació dels glicoesfingolípids. La manca d’una bona correlació genotip-fenotip fa que els estudis d’expressió puguin aprofundir en el coneixement sobre la fisiopatologia de la malaltia de Gaucher. En aquest treball presentem els estudis cel•lulars que han permès expressar els al•lels mutats en cèl•lules COS així com establir l’origen de l’al•lel doble D409H;H255Q. A més a més, hem confirmat l’efecte negatiu acumulatiu d’aquestes dues mutacions a nivell d’activitat enzimàtica, gràcies a l’expressió heteròloga dels al•lels únics i doble mutant. Una de les teràpies que actualment s'està utlitzant en la malaltia de Gaucher és la teràpia de reducció de substrat com a complement o alternativa a la teràpia de reemplaçament enzimàtic. En els darrers anys, una nova estratègia terapèutica basada en l’ús de xaperones farmacològiques ha aparegut. Aquesta nova aproximació es basa en la hipòtesi que les xaperones farmacològiques impedeixen que els enzims amb mutacions que impedeixen el bon plegament podien estabilitzar-se i arribar a seu destí, el lisosoma. Els dos objectius principals han estat: 1. L’expressió in vitro, mitjançant cèl•lules COS-7, de diversos al•lels mutats del gen GBA i la caracterització de les proteïnes GBA mutades. 2. Assajar l’efecte dels iminosucres (NN-DNJ i NB-DNJ), aminociclitols i dels seus derivats com a possibles xaperones farmacològiques sobre les proteïnesmutades, tant en cèl•lules COS-7 transfectades amb cDNAs mutats com en fibroblasts de pacients. Els resultats s’han presentat en els articles següents: 1. Homozygosity for the double D409H+H255Q allele in type II Gaucher disease Autors: Helen Michelakakis, Marina Moraitou, Evagelia Dimitriou, Raül Santamaria, Gessamí Sànchez, Laura Gort, Amparo Chabás, Daniel Grinberg, Maria Dassopoulou, Spyros Fotopoulos, Lluïsa Vilageliu. Publicació: Journal of Inherited and Metabolic Diseases (2006) 29:591 2. Haplotype Analysis Suggests a Single Balkan Origin for the Gaucher Disease [D409H;H255Q] Double Mutant Allele Autors: Raül Santamaria, Helen Michelakakis, Marina Moraitou, Evangelia Dimitriou, Silvia Dominissini, Serena Grossi, Gessamí Sánchez-Ollé, Amparo Chabás, María Gabriela Pittis, Mirella Filocamo, Lluïsa Vilageliu, Daniel Grinberg Publicació: HUMAN MUTATION Mutation in Brief #1010, 29:E58-E67, 2008 3. Promising results of the chaperone effect caused by imino sugars and aminocyclitol derivatives on mutant glucocerebrosidases causing Gaucher disease. Autors: Gessamí Sánchez-Ollé, Joana Duque, Meritxell Egido-Gabás, Josefina Casas, Montserrat Lluch, Amparo Chabás, Daniel Grinberg, Lluïsa Vilageliu Publicació: Blood Cells, Molecules, and Diseases 42 (2009) 159–166 4. Chaperone effects caused by new aminocyclitol derivatives on mutant glucocerebrosidases causing Gaucher disease. Autors: Lucía Díaz, Gessamí Sánchez-Ollé, Josefina Casas, Daniel Grinberg, Antonio Delgado and Lluïsa Vilageliu Publicació: In press. Les dades recents presentades fan pensar que les xaperones farmacològiques podrien arribar a ser un tractament tant per les formes no neuronopàtiques com per a les neuronopàtiques de la malaltia de Gaucher. / Lysosomal storage diseases are a group of disorders caused by the loss of function of lysosomal enzymes, which leads to the intralysosomal storage of non-degraded substrates. Gaucher disease (GD, OMIM 230800) is the most prevalent sphingolipidosis caused by deficiency of glucocerebrosidase (GBA, E.C. 3.2.1.45), which produces the progressive accumulation of glucosylceramide. Clinically, GD is classified into three major types depending on the absence (Type I) or presence (Type II and III) of central nervous system involvement. The main symptoms of GD are anaemia, thrombocytopenia, hepatosplenomegaly and skeletal disease. Two disease-specific therapies have been approved to treat GD. Enzyme replacement therapy (ERT) has been applied for more than 15 years and has proved successful mainly for symptoms of type I patients. The other approved treatment is substrate reduction therapy, which is based on the inhibition of glucosylceramide synthase (GCS), the rate-limiting first step in the glycosphingolipid biosynthetic pathway, by the oral administration of N-butyl-deoxynojirimycin (NB-DNJ). This reduction therapy is used for type I patients for whom ERT is not a therapeutic option. The small size of NB-DNJ makes it of potential use for neurological cases. To date, other alternative strategies, such as gene therapy, have had very limited success in the treatment of GD. However, new experimental approaches in cellular and animal models have been assayed either for conventional gene therapy or based on the partial inhibition of the GCS gene using siRNAs. Recently, a new line of research, using small molecules that act as chemical chaperones, has emerged. This approach is based on the assumption that some mutations cause the misfolding of lysosomal enzymes after their synthesis. Misfolding is responsible for enzyme degradation in the endoplasmic reticulum (ER), thereby preventing enzyme transport to the lysosome. In this scenario, the chaperone stabilizes the mutant protein, thereby allowing that, at least, some molecules reach their final destination. Here we analyzed the effect of iminosugars NB-DNJ and NN-DNJ and aminocyclitols, on COS cells transfected with either the wild-type or mutant GBA cDNAs. The effect of these compounds was also tested on the residual β-glucosidase activity of fibroblasts from patients with diverse genotypes.

The aim of the present work was to contribute to establish robust and high throughput methodology of interest in the "Drug Discovery" step commonly done in pharmaceutical laboratories. This purpose involves the exploration of the possibilities of the potentiometric Sirius methodology to determine both acidity constants and solubilities of drugs and other bioactive compounds and also to do a study about how to improve bioavailability of a model drug, Amphotericine 8, by increasing its dissolution rate. In the first part of this project, the acidic dissociation enthalpies and constants of anilinium, protonated tris (hydroxymethyl)- aminomethane (HTris+), benzoic and acetic acids, have been determined at several temperatures in pure water and in methanol/water mixtures by potentiometry method. The pK(a) values determined by this technique are in accordance with those values determined by ITC method in our laboratory and also with those other values from literature. Also dissociation enthalpies can be obtained from potentiometric pK(a) values by means of the Van't Hoff approach and these obtained values are in agreement with those ones determined directly by calorimetry in our laboratory. In the second part, we focused on studying about solubility. The Chasing Equilibrium method offers an alternative to the classical procedures to measure the solubility of compounds with acid-base properties. The method is fast and yields accurate results. In this work, the solubility of several compounds including acids and bases was determined through the Chasing Equilibrium approach. A study of experimental conditions in terms of sample weight was performed to measure solubilities. The study shows that only a limited range of weights, depending on the nature and solubility of the compounds, is adequate to obtain reliable results. In the third part of this work, the solubility vs. pH profiles of five ionizable drugs of different nature (a monoprotic acid, a monoprotic base, a diprotic base and two amphoteric compounds showing a zwitterionic species each one) have been determined through two different methodologies: the classical Shake-Flask (S-F) and the potentiometric Cheqsol methods using in both instances the appropriate Henderson-Hasselbalch (H-H) or derived relationships. The results obtained independently from both approaches are consistent. A critical revision about the influence of the electrolyte used as buffering agent in the S-F method on the obtained solubility values is also performed. Thus, some deviations of the experimental points with respect the H-H profiles can be attributed to specific interactions between the buffering electrolyte and the drug due to the hydrotrophic character of citric and lactic acids. In other cases, the observed deviations are independent of the buffers used since they are caused by the formation of new species such as drug aggregates (cefadroxil) or the precipitation of a salt from a cationic species of the analysed compound (quetiapine). In the forth part, the objective was to compare the dissolution behavior of tablets prepared from solid dispersions prepared in DMSO dissolvent with and without drug-carrier and also with and without surfactants in aqueous and acidic solutions. Amphotericine B was used as a model drug. Two types of carriers were used; mannitol, inulin. Solid dispersions with two different drug loads were prepared by freeze drying method. It was found that the drug dissolution rate in aqueous and acidic solutions was significantly increased in the presence of drug-carrier and surfactants. X-ray powder diffraction revealed that all solid dispersions were fully amorphous. / El objetivo del presente trabajo ha sido contribuir a establecer metodología robusta y de high throughput de interés en la etapa conocida como "Drug Discovery" que tiene lugar en los laboratorios farmacéuticos al inicio del proceso de desarrollo de nuevos fármacos. Este objetivo ha implicado la exploración de las posibilidades de la metodología potenciométrica establecida y comercializada por Sirius Analytical Ltd. para la determinación de las constantes de acidez y de la solubilidad de compuestos bioactivos y también un estudio sobre la mejora de la biodisponibilidad de un fármaco muy insoluble tomado como modelo mediante el aumento de su velocidad de disolución. En la primera parte de esta Tesis se han determinado potenciométricamente las constantes de disociación ácida y la variación de entalpía asociada de dos bases y dos ácidos tomados como modelo en agua pura y en mezclas de metanol/agua (0-60% w/w) a varias temperaturas (25-55°C). Esto ha implicado la puesta a punto de la estandarización del sistema potenciométrico en las condiciones de trabajo. Los valores de pK(a) determinados son concordantes con los que ofrece la literatura. Se han calculado también las entalpias de disociación en los distintos solventes binarios estudiados mediante la ecuación de Van't Hoff a partir de los valores experimentales de pK(a). La consistencia de los resultados obtenidos con los de la literatura, obtenidos directamente por calorimetría, confirma la robustez de la metodología. En la segunda parte de este trabajo, el estudio se centró sobre la determinación potenciométrica de la solubilidad de ácidos y bases mediante el método conocido como Chasing Equilibrium, como alternativa a los procedimientos clásicos de equilibración. El método es rápido y produce resultados precisos. Se ha realizado un estudio sobre las condiciones experimentales óptimas en términos de peso de la muestra para medir eficazmente la solubilidad. El estudio muestra que, en función de la naturaleza y solubilidad de los compuestos, existe un intervalo limitado de peso de muestra adecuado para obtener resultados fiables. En la tercera parte de la presente memoria, se estudian los perfiles de solubilidad en función del pH de cinco fármacos ionizables de naturaleza diferente, un ácido y una base monopróticos, una base diprótica y dos compuestos anfóteros que muestran una especie zwitteriónica cada uno. Se han determinado los perfiles de solubilidad mediante el método clásico de equilibración (Shake-Flak, S-F) y el potenciómétrico y, en ambos casos, se han utilizado las relaciones apropiadas de Henderson-Hasselbalch (H-H) o derivadas. Los resultados obtenidos de forma independiente por ambos métodos son consistentes. Se ha hecho un estudio crítico acerca de la influencia del electrolito utilizado como agente tampón en el método S-F en los valores de solubilidad obtenidos y se han observado algunas desviaciones de los puntos experimentales con respecto a los perfiles esperados que pueden ser debidas a interacciones específicas entre el electrolito tampón y el fármaco. En otros casos, las desviaciones observadas son independientes de los tampones utilizados y se pueden atribuir a la formación de nuevas especies tales como agregados iónicos del fármaco en estudio o la precipitación de una sal a partir de una especie catiónica del compuesto analizado. En la cuarta parte de esta memoria el objetivo ha sido estudiar la velocidad de disolución de comprimidos preparados a partir de dispersiones sólidas de un fármaco modelo con y sin portador del fármaco y también en presencia y en ausencia de tensioactivo en soluciones acuosas neutras y ácidas. Como fármaco modelo se estudió la Anfotericina B y se utilizaron como portadores manitol e inulina y como tensioactivos se ensayaron el deoxicolato de sodio (SDC) y el laurilsulfato de sodio (SLS). La difracción de rayos X reveló que el fármaco en estudio se hallaba en estado amorfo en todas las dispersiones sólidas estudiadas. Se puede concluir que la velocidad de disolución del fármaco se incrementa significativamente en presencia de portador y tensioactivo.