Introdução: A ceratectornia fotorrefrativa (PRK) é uma das técnicas de cirurgia refrativa mais empregadas no mundo. A despeito de sua efetividade e segurança no tratamento de miopia, hipermetropia e astigmatismo, a dor permanece ainda como um dos grandes desafios no período pós-operatório da PRK. Embora a associação dos fármacos codeína (opióide oral) e paracetamol (analgésico) seja amplamente empregada no período pós-cirúrgico de várias especialidades médicas. a eficácia e segurança dessa associação não foi avaliada no manejo da dor no pós-PRK. Objetivo: O objetivo da presente tese foi testar a combinação codeína + paracetamol no manejo da dor pós-PRK. Métodos: Trata-se de um ensaio clínico controlado por placebo, randomizado, paralelo e duplo-cego. O subdelineamento é do tipo \"add-on \", isto é. o grupo da intervenção recebeu a terapia padrão + a intervenção. enquanto o grupo controle recebeu a terapia padrão + placebo. A amostra foi composta por 41 participantes (82 olhos) - por meio do delineamento \"olhos pareados\" (paired-eye design), ou seja, o olho foi a unidade de análise. As cirurgias foram realizadas com duas semanas de intervalo. Um olho recebeu codeína (30 mg) + paracetamol (500 mg) 4x1dia por quatro dias (período A), enquanto o outro olho recebeu placebo 4x/dia por quatro dias (período B). Tanto a alocação (intervenção ou placebo) quanto a ordem (A-B ou B-A) foram aleatorizadas. A dor foi avaliada por meio de três escalas: questionário de dor McGill (MPQ). Inventário Resumido da Dor (I3PI) e escala visual análoga (EVA) nos períodos I, 24, 48 e 72 horas após a cirurgia. O período de seguimento total foi de quatro meses. Resultados: A idade média dos pacientes foi de 30 anos (rnin-máx: 22-52), dos quais 67% foram mulheres. Dos 82 olhos inicialmente arrolados no estudo, 80 completaram os quatro meses de seguimento (40 na intervenção e 40 no placebo). Os escores medianos de dor mensurados pela EVA foram significativamente mais baixos no grupo da intervenção comparado com o grupo placebo - durante todo o período do pós- cirúrgico imediato (1-48 horas). Os eventos adversos foram brandos e de fácil manejo clínico; os mais comuns foram sonolência, náusea e constipação. Após um seguimento de quatro meses, não foi observado nenhum retardo na resposta de cicatrização da córnea ou haze. Conclusões: A combinação de codeína (30mg) e paracetamol (500mg) via oral (4x/dia) é segura e significativamente superior ao placebo para o controle da dor após a PRK / Introduction: Photorefractive keratectomy (PRK) is one of most widely performed types of refractive surgery in the world. In spite of its effectiveness and safety for the treatment of myopia, hypermetropia and astigmatism, pain remains one of the biggest clinical challenges during the early postoperative period after PRK. Although the combination of codeine (an oral opioid) plus acetaminophcn (an analgesic) has been widely used during the postoperative period in many medical specialties, both its efficacy and safety have not been formally investigated for pain control after PRK. Objective: To carry out a randomized, controlled c1inical trial, specifically dcsigned to test whether the combination of codeine + acetaminophen is efficacious and safe for pain control after PRK. Methods: Double-blind (patients and outcome assessors), randomized, parallel, placebo-controlled trial. An add-on design was adopted. tl.at is, the intervention group received the standard of care therapy + codeine/acetaminophen, whereas the control group received the standard o[ care therapy + placebo. The sample encompassed 41 participants (82 eyes) through the \"paired-eye design\". In other words, the eye was the unity of analysis. Surgeries were performed two weeks ap311. One eye received codeine (30mg) + acetaminophen (500mg) 4x/day for four days (period A), whereas the fellow (control) eye received placebo 4x/day for four days (period B). Both treatrnents (intervention or placebo) and treatment order (A-B or B-A) were randomly chosen. Pain was asscsscd at 1, 24, 48 and 72h postopcrativcly by three scales: visual analogue scale (VAS), McGill Pain Questionnaire (MQP) and Brief Pain Inventory (BPI). The total follow-up period was 4 months. Results: The mean age of patients was 30 years (rnin-max: 22-52) and 67% (27/40) were female. Ofthe initial 82 eyes, 80 completed the trial (40 in the intervention 31m, 40 in the placebo arm). Median pain scores as measured by the VAS were significantly lower during treatment with codeine/acetaminophen compared to the placebo throughout the early postoperative period (1-48h). Virtually identical results were obtained by the MQP and BPI scales, suggesting that the intervention can have a positive impact not only on the pain intensity, but also on the multidimensional aspects of pain, such as interference on activities of daily living as well as emotional status. Adverse events (AEs) were usually mild and easily managed. The most common AEs were drowsiness, nausea and constipation. After a follow- up period of four months, no case of delayed epithelial healing or haze was observed in both treatment arms. Conclusions: When added to the standard of care therapy, the oral combination of codeine (30mg) and acetaminophen (500mg) given 4x/day was safe and significantly superior to placebo for pain control after PRK

<p>Studies have been performed to evaluate the use of micellar electrokinetic chromatography (MEKC), one mode of capillary electrophoresis (CE), as an analytical technique in industrial pharmaceutical analysis. The potential for using chemometrics for the optimisation of MEKC methods has also been studied as well as the possibilities of coupling MEKC with mass spectrometry (MS). </p><p>Two methods were developed, one for the determination of ibuprofen and codeine and another for pilocarpine, together with their degradation products and impurities in both cases. MEKC was found to be the most suitable mode of CE for the methods. Both methods were optimised by means of experimental design. Valuable information was gathered and optimum conditions were defined which resulted in fast systems with baseline-separated peaks. The ibuprofen-codeine method was validated according to the recommended validation procedures of the International Conference of Harmonisation. The validation was performed on a commercially available tablet formulation to verify the suitability of the method, i.e. for quantification of the two main compounds and to determine the degradation products and impurities in area% of each main peak. The following parameters were determined: selectivity, linearity, accuracy, precision, detection limit, quantitation limit, robustness and range. The results confirm that the method is highly suitable for its intended purpose, i.e. as a routine method for assay and impurity determination. The MEKC method for ibuprofen-codeine was coupled to a mass spectrometer in order to evaluate the potential of partial filling (PF)-MEKC-MS for identification of impurities in pharmaceutical substances and products. The so-called partial-filling technique was used to prevent the non-volatile micelles from entering the MS and was shown to fulfil its purpose of providing detection limits of about 10 pg. </p><p>The study clearly shows that micellar electrokinetic chromatography is well-suited as an analytical technique in industrial pharmaceutical analysis. </p>

Studies have been performed to evaluate the use of micellar electrokinetic chromatography (MEKC), one mode of capillary electrophoresis (CE), as an analytical technique in industrial pharmaceutical analysis. The potential for using chemometrics for the optimisation of MEKC methods has also been studied as well as the possibilities of coupling MEKC with mass spectrometry (MS). Two methods were developed, one for the determination of ibuprofen and codeine and another for pilocarpine, together with their degradation products and impurities in both cases. MEKC was found to be the most suitable mode of CE for the methods. Both methods were optimised by means of experimental design. Valuable information was gathered and optimum conditions were defined which resulted in fast systems with baseline-separated peaks. The ibuprofen-codeine method was validated according to the recommended validation procedures of the International Conference of Harmonisation. The validation was performed on a commercially available tablet formulation to verify the suitability of the method, i.e. for quantification of the two main compounds and to determine the degradation products and impurities in area% of each main peak. The following parameters were determined: selectivity, linearity, accuracy, precision, detection limit, quantitation limit, robustness and range. The results confirm that the method is highly suitable for its intended purpose, i.e. as a routine method for assay and impurity determination. The MEKC method for ibuprofen-codeine was coupled to a mass spectrometer in order to evaluate the potential of partial filling (PF)-MEKC-MS for identification of impurities in pharmaceutical substances and products. The so-called partial-filling technique was used to prevent the non-volatile micelles from entering the MS and was shown to fulfil its purpose of providing detection limits of about 10 pg. The study clearly shows that micellar electrokinetic chromatography is well-suited as an analytical technique in industrial pharmaceutical analysis.

Submitted by Jos? Henrique Henrique (jose.neves@ufvjm.edu.br) on 2017-02-14T16:13:27Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) thiago_cesar_lima.pdf: 1162775 bytes, checksum: 1299abb85838ff2827416270126f508d (MD5) / Approved for entry into archive by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2017-03-06T12:23:26Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) thiago_cesar_lima.pdf: 1162775 bytes, checksum: 1299abb85838ff2827416270126f508d (MD5) / Made available in DSpace on 2017-03-06T12:23:26Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) thiago_cesar_lima.pdf: 1162775 bytes, checksum: 1299abb85838ff2827416270126f508d (MD5) Previous issue date: 2016 / A remo??o de terceiros molares inferiores retidos ? um procedimento invasivo com extenso trauma tecidual e resposta inflamat?ria p?s-operat?ria consider?vel. O objetivo deste estudo foi comparar o efeito da dexametasona 8mg (grupo controle) com o diclofenaco s?dico 50mg associados com fosfato de code?na 50mg (grupo experimental) para o controle da dor, edema e trismo, ap?s a exodontia dos terceiros molares inferiores impactados. Trinta terceiros molares inferiores de quinze pacientes saud?veis, com idade m?dia de 22,8 anos (desvio padr?o 12,62) receberam dose oral e ?nica de um dos f?rmacos uma hora antes de cada procedimento cir?rgico (dentes do lado esquerdo ou direito). Ap?s a cirurgia o edema foi aferido em 24, 48, 72 horas e 7 dias, sendo determinado por medidas lineares sobre o rosto, o trismo foi determinado pela abertura m?xima de boca. A dor p?s-operat?ria foi determinada pelo paciente atrav?s de uma escala visual de anal?gica, em intervalos de 24 horas, dentro de um per?odo total de 72 horas. A an?lise dos dados envolveu estat?stica descritiva, teste de Shapiro-Wilk, Wilcoxon, e teste T emparelhado (P<0,05). A dexametasona obteve melhores resultados nas an?lises de dor (p = 0,016) e edema (p = 0,08) no per?odo de 48 horas. N?o houve diferen?as estatisticamente significativas entre as drogas em rela??o ao trismo e ao n?mero de analg?sicos consumidos. Em conclus?o, a administra??o preventiva da dexametasona 8mg apresentou melhor controle da dor e edema nas exodontias bilaterais de terceiros molares inferiores impactados. / Disserta??o (Mestrado) ? Programa de P?s-Gradua??o em Odontologia, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 2016. / Removing third retained molars is an invasive procedure with extensive tissue trauma and considerable postoperative inflammatory response. The aim of this study was to compare the effect of dexamethasone 8mg (control group) with diclofenac sodium 50mg associated with codeine phosphate 50 mg (experimental group) to control pain, swelling and trismus after extraction of third molars impacted. Thirty third molars fifteen healthy subjects with a mean age of 22.8 years (standard deviation 12.62) and received oral single dose of one of the drugs an hour before each surgery (teeth on the left or right). After surgery the edema was measured at 24, 48, 72 hours and 7 days, being determined by linear measurements on the face, trismus was determined by the maximum mouth opening. Postoperative pain was determined by the patient using a visual analogue scale at intervals of 24 hours, within a total period of 72 hours. The data analysis involved descriptive statistics, Shapiro-Wilk test, Wilcoxon test, and paired t-test (P <0.05). Dexamethasone better results in pain analysis (p = 0.016) and edema (p = 0.08) within 48 hours. There were no statistically significant differences between the drug relative to trismus, and the number of analgesics consumed. In conclusion, the preventive administration of dexamethasone 8mg showed better control of pain and edema in bilateral extractions of third molars impacted.

Introdução: A ceratectornia fotorrefrativa (PRK) é uma das técnicas de cirurgia refrativa mais empregadas no mundo. A despeito de sua efetividade e segurança no tratamento de miopia, hipermetropia e astigmatismo, a dor permanece ainda como um dos grandes desafios no período pós-operatório da PRK. Embora a associação dos fármacos codeína (opióide oral) e paracetamol (analgésico) seja amplamente empregada no período pós-cirúrgico de várias especialidades médicas. a eficácia e segurança dessa associação não foi avaliada no manejo da dor no pós-PRK. Objetivo: O objetivo da presente tese foi testar a combinação codeína + paracetamol no manejo da dor pós-PRK. Métodos: Trata-se de um ensaio clínico controlado por placebo, randomizado, paralelo e duplo-cego. O subdelineamento é do tipo \"add-on \", isto é. o grupo da intervenção recebeu a terapia padrão + a intervenção. enquanto o grupo controle recebeu a terapia padrão + placebo. A amostra foi composta por 41 participantes (82 olhos) - por meio do delineamento \"olhos pareados\" (paired-eye design), ou seja, o olho foi a unidade de análise. As cirurgias foram realizadas com duas semanas de intervalo. Um olho recebeu codeína (30 mg) + paracetamol (500 mg) 4x1dia por quatro dias (período A), enquanto o outro olho recebeu placebo 4x/dia por quatro dias (período B). Tanto a alocação (intervenção ou placebo) quanto a ordem (A-B ou B-A) foram aleatorizadas. A dor foi avaliada por meio de três escalas: questionário de dor McGill (MPQ). Inventário Resumido da Dor (I3PI) e escala visual análoga (EVA) nos períodos I, 24, 48 e 72 horas após a cirurgia. O período de seguimento total foi de quatro meses. Resultados: A idade média dos pacientes foi de 30 anos (rnin-máx: 22-52), dos quais 67% foram mulheres. Dos 82 olhos inicialmente arrolados no estudo, 80 completaram os quatro meses de seguimento (40 na intervenção e 40 no placebo). Os escores medianos de dor mensurados pela EVA foram significativamente mais baixos no grupo da intervenção comparado com o grupo placebo - durante todo o período do pós- cirúrgico imediato (1-48 horas). Os eventos adversos foram brandos e de fácil manejo clínico; os mais comuns foram sonolência, náusea e constipação. Após um seguimento de quatro meses, não foi observado nenhum retardo na resposta de cicatrização da córnea ou haze. Conclusões: A combinação de codeína (30mg) e paracetamol (500mg) via oral (4x/dia) é segura e significativamente superior ao placebo para o controle da dor após a PRK / Introduction: Photorefractive keratectomy (PRK) is one of most widely performed types of refractive surgery in the world. In spite of its effectiveness and safety for the treatment of myopia, hypermetropia and astigmatism, pain remains one of the biggest clinical challenges during the early postoperative period after PRK. Although the combination of codeine (an oral opioid) plus acetaminophcn (an analgesic) has been widely used during the postoperative period in many medical specialties, both its efficacy and safety have not been formally investigated for pain control after PRK. Objective: To carry out a randomized, controlled c1inical trial, specifically dcsigned to test whether the combination of codeine + acetaminophen is efficacious and safe for pain control after PRK. Methods: Double-blind (patients and outcome assessors), randomized, parallel, placebo-controlled trial. An add-on design was adopted. tl.at is, the intervention group received the standard of care therapy + codeine/acetaminophen, whereas the control group received the standard o[ care therapy + placebo. The sample encompassed 41 participants (82 eyes) through the \"paired-eye design\". In other words, the eye was the unity of analysis. Surgeries were performed two weeks ap311. One eye received codeine (30mg) + acetaminophen (500mg) 4x/day for four days (period A), whereas the fellow (control) eye received placebo 4x/day for four days (period B). Both treatrnents (intervention or placebo) and treatment order (A-B or B-A) were randomly chosen. Pain was asscsscd at 1, 24, 48 and 72h postopcrativcly by three scales: visual analogue scale (VAS), McGill Pain Questionnaire (MQP) and Brief Pain Inventory (BPI). The total follow-up period was 4 months. Results: The mean age of patients was 30 years (rnin-max: 22-52) and 67% (27/40) were female. Ofthe initial 82 eyes, 80 completed the trial (40 in the intervention 31m, 40 in the placebo arm). Median pain scores as measured by the VAS were significantly lower during treatment with codeine/acetaminophen compared to the placebo throughout the early postoperative period (1-48h). Virtually identical results were obtained by the MQP and BPI scales, suggesting that the intervention can have a positive impact not only on the pain intensity, but also on the multidimensional aspects of pain, such as interference on activities of daily living as well as emotional status. Adverse events (AEs) were usually mild and easily managed. The most common AEs were drowsiness, nausea and constipation. After a follow- up period of four months, no case of delayed epithelial healing or haze was observed in both treatment arms. Conclusions: When added to the standard of care therapy, the oral combination of codeine (30mg) and acetaminophen (500mg) given 4x/day was safe and significantly superior to placebo for pain control after PRK

Indiana University-Purdue University Indianapolis (IUPUI) / Pharmacogenetic testing has the potential to improve pain management through addressing wide interindividual variations in responses to pharmacogenetically actionable opioids, ultimately decreasing costly adverse drug effects and improving responses to these medications. A recent review of pharmacogenomics in the nursing literature highlighted the need for nurses to more fully embrace the burgeoning field of pharmacogenomics in nursing research, clinical practice, and education. Despite the promise of pharmacogenetic testing, significant challenges exist for evaluating outcomes related to its implementation, including oversimplification of medication exposure, the complexity of patients' clinical profiles, and the characteristics of healthcare contexts in which medications are prescribed. A better understanding of these challenges could enhance the assessment and documentation of the benefits of pharmacogenetic testing in guiding opioid therapies. This dissertation is intended to address the challenges of evaluating outcomes of pharmacogenetic testing implementation and the need for nurses to lead pharmacogenomic-related research. The dissertation purpose was to advance the sciences of nursing, pain management, and pharmacogenomics through the development of a typology of common patterns of medication exposure to known pharmacogenetically actionable opioids (codeine &amp; tramadol). A qualitative, person-oriented approach was used to retrospectively analyze six months of electronic health record and pharmacogenotype data in 30 underserved adult patients. An overarching typology with eight groups of patients that had one of five opioid prescription patterns (singular, episodic, switching, sustained, or multiplex) and one of three types of medical emphasis of care (pain, comorbidities, or both) were identified. This typology consisted of a description of multiple common patterns that compare and contrast salient factors of exposure and the emphasis of why individuals were seeking care. Furthermore, in an aggregate descriptive analysis evaluating key clinical profile factors, these patients had complex medical histories, extensive healthcare utilization, and experienced significant polypharmacy. These findings can aid in addressing challenges related to the implementation of pharmacogenetic testing in clinical practice and point to ways in which nurses can take the lead in pharmacogenomics research. Findings also provide a foundation for future studies aimed at developing medication exposure measures to capture its dynamic nature and identifying and tailoring interventions in this population.

Fundação de Amparo a Pesquisa do Estado de Minas Gerais / The present thesis demonstrates, for the first time, the possibility of using of the internal standard method in FIA or BIA systems with amperometric detection. The method allows to obtain accurate results in the presence of fluctuations in the system parameters (injected volume, dispensing rate, ionic strength and accidental insertion of air bubbles) and in the presence of contamination and/or gradual passivation of the working electrode surface. Methods for determination of diclofenac (DCF) using FIA with amperometric detection and simultaneous determination of DCF and codeine (CO) by BIA with amperometric detection have also been developed. The internal standard method was implemented in the flow injection analysis with multiple pulse amperometric detection (FIA-MPA) system by applying a sequence of potential pulses of the working electrode as a function of time. The analyte (+0.80 V/300ms) and internal standard (-0.05 V/400ms) were detected selectively, one at each potential pulse. Significant improvements were obtained in the accuracy of the system when the results before and after normalization (using the internal standard method), were compared. The following errors were calculated, respectively, before and after normalization of the results using the internal standard method. Change in flow rate from 3.0 to 1.0 ml min-1 (-57% e < 1%); volume injection from 300 to 100 &#956;L (-63% and 3%); ionic strength from 0.60 to 0.77 mol L-1 (-44 and 0,2%) and before and after the introduction of air bubbles into the system (-9,6% and 1,7%). A significant improvement was also obtained in the correlation coefficient of the calibration curve in the presence of problems of passivation or contamination of the working electrode. The correlation coefficient was calculated, respectively, as 0,975 and 0,998, before and after the normalization of the results by the IS method. The internal standard method was also applied to correct errors derived from the injection procedure (dispensing rate and injected volume) in batch injection analysis systems (BIA) with amperometric detection when disposable syringes were used. The results obtained before and after normalization of the results by the IS method were the following, respectively: repeatability test (RSD = 6.4 and 1.8%; n = 8), correlation coefficients (R=0.954 and 0.997) and errors obtained in analysis of synthetic samples (E = 9.4 ± 1.5 and 3.5 ± 0.7%; n = 8). The determination of DCF by FIA-MPA was implemented by applying two potential pulses to the BDD electrode using H2SO4 0.1 mol L-1 as supporting electrolyte: (i) + 1.2 V / 50 ms for oxidation and quantification of DCF, and (ii) 0.0 V / 50 ms for constant electrochemical cleaning of the electrode surface. The system showed good stability (RSD = 1.0%, n = 10) and high analytical frequency (135 injections h-1). The method showed a linear response between 5 and 50 &#956;mol L-1 and the detection and quantification limits were as 0.14 and 0.46 mmol L-1, respectively. The proposed method was applied to determine of DCF in pharmaceutical formulations and the obtained results were similar to those obtained by HPLC with a confidence level of 95%. The simultaneous determination of DCF and CO was performed using the following potential pulses: (i) +1.1 V / 50 ms: oxidation and quantification of DCF; (ii) +1.4 V / 50 ms: simultaneous oxidation of DCF and CO, (iii) 0.0 V / 200 ms: for constant electrochemical cleaning of the BDD electrode. The oxidation current from CO was obtained by the difference between currents detected at 1.4 and 1.1 V by using a correction factor. The system showed good stability (RSD = 0.9% and 1.1 for DCF and CO respectively, n = 10) and high analytical frequency (~ 300 injections h-1). The method showed a linear response between 10 and 50 &#956;mol L-1 for DCF and 7.1 and 35.7 &#956;mol L-1 for CO. The LQ and LD were calculated, respectively, at 1.1 and 3.7 &#956;mol L-1, for DCF and 1.0 and 3.3 mol L-1 for CO. The proposed method was applied for simultaneous determination of DCF and CO in pharmaceutical formulations and the obtained results were similar to those obtained by HPLC with a confidence level of 95%. Keywords: Multiple pulse amperometry, FIA, BIA, internal standard, simultaneous analysis, boron doped diamond (BDD), codeine, diclofenac. / Esta tese apresenta, pela primeira vez, a possibilidade de usar o método do padrão interno em sistemas FIA ou BIA com detecção amperométrica. O método permite a obtenção de resultados precisos na presença de flutuações em parâmetros dos sistemas (volume injetado, velocidade de injeção, força iônica e inserção acidental de bolhas de ar) e na presença de contaminação e/ou passivação gradual do eletrodo de trabalho. Métodos para determinação de diclofenaco (DCF) usando FIA com detecção amperométrica e simultânea de DCF e codeína (CO) por BIA com detecção amperométrica também foram desenvolvidos. O método do padrão interno foi implementado no sistema de análise por injeção em fluxo com detecção por amperometria de múltiplos pulsos (FIA-MPA) mediante a aplicação de uma sequência de pulsos de potenciais ao eletrodo de trabalho em função do tempo. O analito (+0,80 V/300ms) e o padrão interno (-0,05 V/400ms) foram detectados seletivamente, um em cada pulso de potencial. Melhoras significativas foram obtidas na precisão do método quando os resultados obtidos antes e após a normalização (usando o método do padrão interno) foram comparados. As seguintes variações foram calculadas, respectivamente, antes e após a normalização dos resultados usando o método do padrão interno. Variação na velocidade de vazão de 3,0 para 1,0 mL min-1 (-57% e < 1%); no volume de injeção de 300 para 100 &#956;L (-63% e 3%); força iônica de 0,60 para 0,77 mol L-1 (-44 e 0,2%) e antes e após a inserção de bolhas de ar no sistema (-9,6% e 1,7%). Uma melhora significativa também foi obtida no coeficiente de correlação da curva de calibração na presença de problemas de passivação ou contaminação do eletrodo de trabalho. O coeficiente de correlação foi calculado, respectivamente, em 0,975 e 0,998, antes e após a normalização dos resultados pelo método do PI. O método do padrão interno também foi aplicado para corrigir erros em sistemas de análise por injeção em batelada (BIA) com detecção amperométrica provenientes do procedimento de injeção (velocidade de injeção e volume injetado) quando seringas descartáveis foram utilizadas. Os resultados obtidos antes e após a normalização dos resultados pelo método do PI foram os seguintes, respectivamente: estudo de repetibilidade (DPR=6,4 e 1,8%; n = 8), coeficientes de correlação (R=0,954 e 0,997) e erros obtidos na análise de amostras sintéticas (9,4 ± 1,5% e 3,5 ± 0,7; n = 8). A determinação de DCF por FIA-MPA foi implementada através da aplicação de dois pulsos de potenciais ao eletrodo de BDD em meio de H2SO4 0,1 mol L-1 como eletrólito suporte: (i) +1,2 V / 50 ms para oxidação e quantificação do DCF e, (ii) 0,0 V / 50 ms para constante limpeza eletroquímica do eletrodo de trabalho. O sistema apresentou boa estabilidade (RSD = 1,0%; n=10) e elevada frequência analítica (135 injeções h-1). O método apresentou resposta linear entre 5 e 50 &#956;mol L-1 e os limites de detecção e quantificação foram calculados em 0,14 e 0,46 &#956;mol L-1, respectivamente. O método proposto foi aplicado na determinação de DCF em formulações farmacêuticas e os resultados obtidos foram similares ao obtidos por HPLC a um nível de confiança de 95%. A determinação simultânea de DCF e CO foi realizada usando os seguintes pulsos de potenciais: (i) +1,1 V / 50 ms: oxidação e quantificação de DCF; (ii) +1,4 V / 50 ms: para oxidação simultânea de DCF e CO; (iii) 0,0 V / 200 ms: para constante limpeza eletroquímica do eletrodo de BDD. A corrente de oxidação da CO foi obtida pela subtração entre as correntes detectadas em 1,4 e 1,1 V mediante uso de um fator de correção. O sistema apresentou boa estabilidade (RSD= 1,1 e 0,9% para DCF e CO, respectivamente, n=10) e elevada frequência analítica (~300 injeções h-1). O método apresentou resposta linear entre 10 e 50 &#956;mol L-1 para o DCF e entre 7,1 e 35,7 &#956;mol L-1 para CO. O LD e o LQ foram calculados, respectivamente, em 1,1 e 3,7 &#956;mol L-1, para DCF e 1,0 e 3,3 &#956;mol L-1 para CO. O método proposto foi aplicado na determinação simultânea de DCF e CO em formulações farmacêuticas e os resultados obtidos foram similares ao obtidos por HPLC a um nível de confiança de 95%. / Doutor em Química

(EN) In the first part of this work, analytical methods for determination of impurities of active pharmaceutical ingredients (API) in combined pharmaceutical dosage forms were developed and validated. Development of the methods covered both the optimization of sample preparation procedure and chromatographic conditions. The methods were validated according to International Conference on Harmonization guideline and both of them were confirmed to be able to analyze stability samples. Impurities in paracetamol, codeine phosphate hemihydrate and pitophenone hydrochloride in the presence of fourth API fenpiverinium bromide were separated by using ion-pair reversed phase chromatography with gradient elution. Symmetry C18, 250 x 4,6 mm, 5 µm heated to 35 řC was used as a separation column. A diode array detector was used. The detection wavelengths were set as follows: 220 nm for paracetamol impurity K, 245 nm for paracetamol and its other impurities and 285 nm for codeine, pitophenone and their impurities. Impurities in valsartan, amlodipine besylate and hydrochlorothiazide were separated by reversed phase UHPLC method with gradient elution. Chromatographic column Zorbax Eclipse C8 RRHD, 100 x 3,0 mm, 1,8 µm heated to 30 řC and spectrophotometric detection were used. The detection wavelengths were set as...