Polymorphism can influence every aspect of the properties of a solid including the shelf life, dissolution rate, solubility, formulation properties and processing properties of a solid drug. A deeper understanding of polymorphism and related solid state properties would ensure an improved quality of the materials used throughout drug preparation, dosage form formulation and clinical trials. Therefore, determination of the existence of polymorphs and pseudopolymorphs, characterization of different solid state forms and their respective properties, and controlling the existing form in the resulting formulation all form part of a rapidly growing field within pharmaceutical research and industry. Carbamazepine (CBZ) was the model drug used in this study. FT-Raman spectroscopy was chosen as a main investigative technique in this study to evaluate its potential in monitoring (pseudo)polymorphic conversions in aqueous suspensions in the absence or presence of various pharmaceutical excipients. Partial least squares analysis (PLS) was used for quantitative analysis of the spectral data. Earlier it has been found that CBZ converts rapidly to the dihydrate (DH) when exposed to humidity or water, and this has been reported to be the main reason for the sometimes observed greatly decreased bioavailability of marketed CBZ tablets. In this study, the conversion kinetics of CBZ (forms I, II and III) to DH in aqueous suspension were found to be first order kinetics with an unconverted portion (R� [greater than or equal to] 0.95), where the crystal morphology appeared to play a more important role in its conversion kinetics than the polymorphic form. The influence of pharmaceutical excipients on the conversion of CBZ in aqueous suspension was also explored. For excipients such as methylcellulose (MC), hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) which have both a low solubility parameter (< 27.0 MPa[1/2]) and strong hydrogen bonding groups, complete inhibition of the conversion of CBZ was possible even at a very low concentration (0.1 % w/v). Raman spectroscopy showed its high applicability in investigating CBZ conversion kinetics and screening of excipient effects in aqueous environment. It was demonstrated that Raman has a robust nature in quantitative analysis since problems such as different particle size, morphology, and spatial distribution of the two solid state forms of the drug seemed not to have significant influence on Raman scattering. This study has also clarified the relative importance of many contributing factors (type of crystalline form (CBZ or DH), crystal morphology, surface area, and excipient interactions with drug particles) influencing the in vitro dissolution of CBZ. The solid state characterization approach taken in this study will provide a deeper insight into the dissolution performance of drugs and should thus lead to a better understanding of in vitro/in vivo behavior of drugs.

Thesis (Ph.D. (Pharmacy)) - Rhodes University, 2006.

Modifications to the GCMS assay for valproic acid and 12 metabolites were attempted with respect to internal standards and derivatizing reagents. Four new internal standards, octanoic acid and 2-methylglutaric acid for analysis of VPA and metabolites and hexanoic acid and di-ռ-butylacetic acid for the analysis of hexadeuterated VPA and metabolites were used. Two new derivatizing reagents, MSTFA and MTBSTFA, were tested as alternatives to the reagent previously used. TMS (MSTFA) and tBDMS derivatives were compared with respect to sensitivity, stability, and chromatographic time. The derivatives formed from MTBSTFA were extremely stable a major drawback was the formation of a diderivative of 3-keto VPA upon increased heating time and storage. Preliminary data on the metabolism of D₆-VPA was obtained in one volunteer. The substitution of six deuterium atoms for six hydrogen atoms resulted in an isotope effect with decreased serum trough concentrations of 4-ene VPA and 2,4-diene VPA. Valproic acid and carbamazepine are frequently coadministered in efforts to optimize seizure control. VPA is extensively metabolized while CBZ is known to induce the hepatic microsomal enzyme system, and thus, this is a potentially toxic interaction. Pharmacokinetic parameters for VPA were obtained before and after CBZ administration in five, healthy male volunteers. Increased plasma clearance of VPA accompanied by decreased plasma concentrations, serum half-life, and AUC values were observed after CBZ comedication. This was consistent with the ability of CBZ to induce the hepatic microsomal enzyme systems in a manner similar to phenobarbital. Serum trough and steady state concentrations and AUC values for 12 metabolites were determined before and after CBZ administration. The AUC values for the monounsaturated metabolites decreased after CBZ administration while the AUC values of the polar metabolites increased. The amount of 4-ene VPA, a potential hepatotoxin, was not increased in the serum after administration of CBZ. The amounts of the two diunsaturated metabolites, 2,3'-diene VPA and 2,4-diene VPA, were increased in the serum of the volunteers after CBZ administration. The amount of 2-ene trans VPA in the serum was significantly decreased after CBZ administration, while the amount of 3-keto VPA did not increase. Urinary metabolic profiles were determined individually and grouped in pathways for the five volunteers before and after CBZ administration. Increased recoveries of 4-ene VPA, 4-keto VPA, and 2-PSA after CBZ administration were consistent with enhanced ω-1 oxidation. Formation clearance, metabolic clearance, and fraction metabolized were determined for the metabolic pathways and for the individual metabolites. CBZ adminstration resulted in increased formation clearances for all pathways. The results obtained from this study indicate that CBZ caused a general induction of VPA metabolism and did not specifically affect a particular pathway. The effect of CBZ on the beta-oxidation pathway is not clearly understood. CBZ may cause a metabolic shift away from beta-oxidation, or actually inhibit beta-oxidation to some extent. As well, peroxisomal beta-oxidation may be involved. / Pharmaceutical Sciences, Faculty of / Graduate

No description available.

Increasing concentrations of pharmaceutical compounds and their metabolites in aquatic environment threatens both aquatic species and human health. Many pharmaceuticals are persistent in the environment and resistant to conventional water treatment; hence, alternate treatment techniques are required to remove these compounds from water. Aqueous phase electrical discharge has been demonstrated to successfully remove a range of pharmaceutical compounds from water. This technique is characterized by the simultaneous generation of highly reactive species and physical effects within the aqueous solution to be treated. The present study investigates and optimizes the efficacy of pulsed corona discharges generated in water for the treatment of carbamazepine (CBZ) in a relatively clean water matrix by varying the solution pH, solution conductivity, gas type injected, and gas flow rate injected. A point-to-plane reactor configuration was employed to produce plasma channel- streamers. In this geometry, the electrical discharges were produced directly within the aqueous phase to be treated by charging a 1nF pulse forming capacitor using a high voltage (25 KV) DC power supply through 10 MΩ resistor to generate discharges within the water at a 30 HZ pulse repetition rate. Solution pH, solution conductivity, gas type, and gas flow rate were optimized to maximize the removal efficacy of CBZ removal by pulsed corona at the laboratory scale. The CBZ degradation rate (concentration decrease over time) was monitored using LC/MS/MS, with overall degradation ranging from 14-94% depending on the experimental conditions. The results demonstrate that higher CBZ removal efficiency is achieved under lower pH and conductivity conditions. Moreover, enhanced degradation efficiency is obtained when gas, and particularly oxygen, is bubbled through the high voltage hollow electrode, especially at higher flow rates. / Thesis / Master of Applied Science (MASc) / Pharmaceuticals are being released into the environment at an increasing rate due to population growth and a rising dependence on these compounds. Pharmaceuticals are resistant to many common water treatment methods; however, electrical discharge generated within the water to be treated (pulsed corona discharge) is an emerging water treatment technology that has been shown to successfully treat many pharmaceuticals. In the present work, pulsed corona discharge has been used to treat carbamazepine present in a relatively clean water matrix. Removal was maximized by optimizing the solution pH, solution conductivity, type of gas bubbled through the electrode, and gas flow rate. The best removal was achieved in solutions with lower pH and conductivities where oxygen was bubbled through the electrode at a relatively high rate.

Crystal engineering study using spray dryer was performed for scale-up and rapid, continuous crystallisation of co-crystals from solution. The study emphasise on developing co-crystals of two structurally similar compounds, caffeine (CAF) and theophylline (THEO) with various di-carboxylic acids. The incongruently soluble pair of CAF and THEO with di-carboxylic acids acquires large solubility difference which is important to consider for its utility in product development. Based on previous assumption that maleic acid (MAL) elevates CAF’s solubility; solubility of the two similar compounds was tested in various dicarboxylic acids. Other solubility enhancement strategies such as introduction of surfactant and binary solvents were also scrutinised. A kinetically similar bench-scale technique, rotary evaporator (rotavap) was investigated as a pre-screening tool for the production of co-crystals via spray drying. Furthermore, various process parameters within the spray dryer were optimised to control the kinetic conditions which influence co-crystallisation and quality of the product. Another polymorphic co-crystal pair, CBZ (carbamazepine) and SAC (saccharin) was examined in various solvents and its degradation was evaluated over a period of few months. In this study, a two-step conversion of CBZ into its degradate was hypothesised. Rotavap delivered a true reflection of co-crystal favoured via spray drying apart from co-crystal pairs depicting polymorphism. Spray dryer offered a unique environment favouring metastable forms of co-crystals irrespective of the starting component stoichiometry; generating CAF:MAL 2:1. However, due to process limitation and solubility constraint, the impurity of CAF in CAF:MAL 2:1 co-crystals could not be abolished.

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 134-149).

Orientador: Ronei Jesus Poppi / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-22T20:20:45Z (GMT). No. of bitstreams: 1 Terra_LucianaAssis_M.pdf: 5662002 bytes, checksum: 969f678029bf9ac1f5d8f5fadf9727f9 (MD5) Previous issue date: 2013 / Resumo: A Espectroscopia de Imagem na região do Infravermelho Próximo juntamente com ferramentas quimiométricas foi utilizada para estudar a transformação polimórfica do fármaco carbamazepina (forma III para forma I) em formulações farmacêuticas do comprimido, geradas por aquecimento. Os mapas de distribuição de concentração das formas polimórficas I e III da carbamazepina no comprimido foram estimados por Mínimos Quadrados Parciais (PLS), Resolução Multivariada de Curvas (MCR) e Análise de Fatores Paralelos (PARAFAC), assim como o perfil de concentração em função do tempo durante o aquecimento, comparando os resultados obtidos quanto à eficácia na quantificação das formas polimórficas. Para o estudo da homogeneidade da distribuição do fármaco ao longo do comprimido, foram construídos histogramas. O trabalho está dividido em duas partes: na primeira parte foi realizado o mapeamento completo de um comprimido antes e após o aquecimento a 160 ºC, por 3 horas e os dados foram analisados por MCR. Na segunda parte do trabalho estudou-se a transformação polimórfica com o tempo a 140 ºC, em que foi realizado o mapeamento da parte central do comprimido, sendo nesse caso obtidas imagens a cada hora, com tempo total de 7 horas. Os resultados mostraram que os métodos PLS, MCR e PARAFAC foram capazes de obter informações sobre a transformação polimórfica, sendo MCR e PARAFAC capazes de estudar o processo dinâmico envolvido. Além disso, o MCR também foi capaz de fornecer os mapas de distribuição de concentrações em cada tempo de aquisição de dados, acompanhando a transformação polimórfica na superfície do comprimido / Abstract: The Near Infrared Chemical Imaging in conjunction with chemometric tools was used to study the polymorphic transformation of the drug carbamazepine (form III to form I) in pharmaceutical formulations tablets, generated by heating. The concentration distribution maps of the polymorphic forms I and III of carbamazepine in the tablet were estimated by Partial Least Squares (PLS), Multivariate Curve Resolution (MCR) and Parallel Factor Analysis (PARAFAC), as well as the concentration profile as a function of the heating time and the results were compared regarding the efficacy in quantification of the polymorphic forms. For the study of the homogeneity of distribution of the drug in the tablet, histograms were built. The work was divided into two parts: in the first part, it was conducted the mapping of the whole tablet before and after heating at 160 ºC for 3 hours and the data were analysed by MCR. In the second part, it was studied the polymorphic transformation over the time at 140 °C. Images of the central part of the tablet were obtained every hour during 7 hours. The results showed that the PLS, MCR and PARAFAC were able to obtain information about the polymorphic transformation and the MCR and PARAFAC were able to study the dynamic process involved as well. Furthermore, the MCR provided the concentration distribution map at each time of data acquisition, providing the polymorphic transformation on the tablet surface / Mestrado / Quimica Analitica / Mestra em Química

Carbamazepine (CBZ) is an antiepileptic drug widely detected in drinking water supplies and wastewater effluent. It has been previously found that CBZ is recalcitrant to biological removal processes. Therefore, active CBZ will be exposed to wastewater effluent disinfection processes, which for most treatment plants in the United States involves the addition of free chlorine. However, the chlorination mechanisms of CBZ have not been fully investigated and are currently poorly understood. Our experimental studies were conducted to examine the chlorination of CBZ under controlled conditions. The kinetics, products, and reactivity of CBZ/free chlorine reactions were investigated over the pH range of 5.5-10. Results show that free chlorine reacts with CBZ and the reactivity is pH dependent. Furthermore, the results indicate that temperature affects the reactivity of CBZ with free chlorine. The temperature experiment results were fitted with the Arrhenius equation. The calculated Ea and A values are 48.8 kJ/mol and 1.41x104 s-1, respectively. Four common intermediates were detected based on both UV and mass spectral analysis proposed structures were developed based on m/z from mass spectra. / Master of Science

Crystal engineering study using spray dryer was performed for scale-up and rapid, continuous crystallisation of co-crystals from solution. The study emphasise on developing co-crystals of two structurally similar compounds, caffeine (CAF) and theophylline (THEO) with various di-carboxylic acids. The incongruently soluble pair of CAF and THEO with di-carboxylic acids acquires large solubility difference which is important to consider for its utility in product development. Based on previous assumption that maleic acid (MAL) elevates CAF’s solubility; solubility of the two similar compounds was tested in various dicarboxylic acids. Other solubility enhancement strategies such as introduction of surfactant and binary solvents were also scrutinised. A kinetically similar bench-scale technique, rotary evaporator (rotavap) was investigated as a pre-screening tool for the production of co-crystals via spray drying. Furthermore, various process parameters within the spray dryer were optimised to control the kinetic conditions which influence co-crystallisation and quality of the product. Another polymorphic co-crystal pair, CBZ (carbamazepine) and SAC (saccharin) was examined in various solvents and its degradation was evaluated over a period of few months. In this study, a two-step conversion of CBZ into its degradate was hypothesised. Rotavap delivered a true reflection of co-crystal favoured via spray drying apart from co-crystal pairs depicting polymorphism. Spray dryer offered a unique environment favouring metastable forms of co-crystals irrespective of the starting component stoichiometry; generating CAF:MAL 2:1. However, due to process limitation and solubility constraint, the impurity of CAF in CAF:MAL 2:1 co-crystals could not be abolished.