No description available.

No description available.

No description available.

Phoslactomycin B (PLM-B), a potent and selective inhibitor of serine threonine phosphatase is of interest for its antitumor, antifungal and antiviral activity. The objective of this study was to evaluate the stability of phoslactomycin B at various pH and temperature conditions. Phoslactomycin B was produced from the mutant strain NP1 of Streptomyces sp.HK-803 and was purified by semi-preparative HPLC . A study of PLM-B degradation was carried out in the pH range of 2-10 at 30ºC and 50°C using HPLC. The PLM-B decomposition was observed to exhibit a U-shaped pH profile and demonstrated both acid and base-catalyzed decomposition. The decomposition could be described by the equation kOBS = kH x 10-pH + kOH x 10 pH- 14 (kH = 45±7 M-1 h-1; kOH = 448± 73 M-1 h-1). PLM-B was found to be most stable at pH 6.63. The degradation products in both acidic and basic pH have been collected and analyzed. Under basic condition, mass spectroscopic analysis revealed addition of water and NMR was consistent with the major products being formed due to lactone ring opening and/or a Micheal type addition reaction. Under acidic condition MS revealed loss of water for all three compounds. NMR analysis of one product (product 8) was consistant with C9- C11 phosphorinane derivative of PLM-B. The remaining compounds were shown to be mixture of various dehydration products. The degradation products despite containing small structural changes to PLM-B lost all detectable levels of antifungal activity.

No description available.

Oxaliplatin is an anticancer drug widely used in cancer chemotherapy. This thesis evaluates whether a specific dose-banding scheme for oxaliplatin could replace the individual dosing method that is currently used in the oxaliplatin administration. Dose-banding was introduced into UK clinical practice in 2001, as it reduces delays in patients receiving their treatment and, through quality control and end-product testing, safeguards the infusion quality and patient safety. A range of studies were included in this thesis: an extended stability study on oxaliplatin infusions using a sequential temperature cycling design; studies on oxalate, a potential degradation product and metabolite of oxaliplatin which has been linked to oxaliplatin neurotoxicity and the development of an ex vivo pharmacokinetic (PK) simulation model to compare the effect of different oxaliplatin dosing methods on its therapeutic outcomes. The shelf-life of oxaliplatin infusions over a concentration range of 0.2 mg/mL – 0.7 mg/mL is extended to 84 days when stored at 2 – 8℃ plus a further 7 days after being left at room temperature (25℃) for 24 hours. This ensures the unused oxaliplatin infusions are safe to be re-issued to patients, which could reduce drug wastage. The oxalate study suggests that the dose-limiting neurotoxicity of oxaliplatin is unlikely to be directly related to the oxalate produced from oxaliplatin degradation in infusions or from the non-enzymic transformation of oxaliplatin in vivo because the oxalate levels from these routes are minor compared to the endogenous level. The safety and efficacy of dose-banding schemes was demonstrated by comparing the simulated PK characteristics gained from the ex vivo model. Dose-banding with the +10% maximum deviation was selected as the most promising dosing scheme for oxaliplatin. Finally, recommendations are made concerning the introduction of oxaliplatin dose-banding scheme into clinical practice, and on the benefits of harmonised dose-banding schemes.

A duloxetina (DLX) é um duplo inibidor seletivo balanceado da recaptação de serotonina e norepinefrina empregado para o tratamento do transtorno depressivo maior e para o manejo da dor neuropática diabética periférica. O objetivo deste estudo foi desenvolver e validar métodos analíticos para determinação de DLX em cápsulas e realizar estudos da estabilidade do fármaco. A substância usada como padrão de referência nas análises foi caracterizada por espectroscopia no infravermelho, ressonância magnética nuclear (RMN), calorimetria diferencial de varredura e espectrometria de massas. As análises qualitativas foram realizadas por cromatografia em camada delgada (CCD), espectrofotometria na região do ultravioleta (UV) e cromatografia líquida de alta eficiência (CLAE) permitindo a identificação do fármaco no produto farmacêutico. A espectrofotometria UV, CLAE e voltametria de redissolução catódica (CSV) foram validadas para determinação quantitativa de DLX em cápsulas. Estes métodos propostos foram específicos, robustos, lineares, precisos e exatos para determinação de DLX em microgrânulos de revestimento entérico. Estudos preliminares da estabilidade da DLX durante o desenvolvimento do método indicativo de estabilidade por CLAE demonstraram que o fármaco foi rapidamente degradado em meio ácido, na presença de peróxido de hidrogênio e de radiação a luz UVC, enquanto que este foi mais estável em meio alcalino. A cinética de degradação descreveu as mudanças na concentração da DLX em condição ácida e sob fotodegradação. A degradação ácida da DLX, em solução de HCl 0,1 M, mostrou cinética aparente de zero ordem e a fotodegradação demonstrou uma cinética aparente de primeira ordem. O produto de degradação principal observado na hidrólise ácida (PDA-14) foi analisado e isolado por CCD preparativa. Espectros de RMN-1H, RMN-13C e COSY foram avaliados e a estrutura do PDA-14 foi confirmada como 1-naftol. Esta substância produz efeitos citotóxicos e consequentemente o produto farmacêutico é uma cápsula de gelatina contendo microgrânulos com revestimento entérico para evitar a degradação ácida da DLX no estômago. / The duloxetine (DLX) is a double balanced selective serotonin and norepinephrinereuptake inhibitor employed for the treatment of major depressive disorder and for the management of diabetic peripheral neuropathic pain. The aim of this study was to develop and validate analytical methods to the determination of DLX in capsules and accomplish studies of this drug stability. The substance used as reference standard in the analysis was characterized by infrared spectroscopy, nuclear magnetic resonance (NMR), differential scanning calorimetry, and mass spectrometry. The qualitative analyses were performed by thin layer chromatography (TLC), ultraviolet spectrophotometry (UV), and high performance liquid chromatography (HPLC) allowing the identification of the drug in pharmaceutical dosage form. The UV spectrophotometry, HPLC, and cathodic stripping voltammetry (CSV) were validated for quantitative determination of the DLX in capsules. These proposed methods were specific, robust, linear, precise, and accurate to the determination of DLX in entericcoated pellets. Preliminary studies of DLX stability during the development of stability-indicating HPLC method demonstrated that the drug was rapidly degraded in acid medium, in the presence of hydrogen peroxide and light UVC radiation, while it was more stable in alkali medium. The kinetics of degradation described the concentration changes of DLX in acid condition and on photodegradation. The acid degradation of DLX in 0.1M HCl solution showed apparent zero-order kinetics and the photodegradation demonstrated apparent first-order kinetics. The main degradation product observed in acid hydrolysis (DP-14) was analyzed and isolated by TLC preparative. 1H NMR, 13C NMR and COSY spectra were evaluated and the structure of DP-14 was confirmed as 1-naphthol. This substance produces cytotoxic effects and consequently the finished pharmaceutical dosage form is a gelatin capsule containing enteric-coated pellets to avoid the acid degradation of DLX in the stomach.

A duloxetina (DLX) é um duplo inibidor seletivo balanceado da recaptação de serotonina e norepinefrina empregado para o tratamento do transtorno depressivo maior e para o manejo da dor neuropática diabética periférica. O objetivo deste estudo foi desenvolver e validar métodos analíticos para determinação de DLX em cápsulas e realizar estudos da estabilidade do fármaco. A substância usada como padrão de referência nas análises foi caracterizada por espectroscopia no infravermelho, ressonância magnética nuclear (RMN), calorimetria diferencial de varredura e espectrometria de massas. As análises qualitativas foram realizadas por cromatografia em camada delgada (CCD), espectrofotometria na região do ultravioleta (UV) e cromatografia líquida de alta eficiência (CLAE) permitindo a identificação do fármaco no produto farmacêutico. A espectrofotometria UV, CLAE e voltametria de redissolução catódica (CSV) foram validadas para determinação quantitativa de DLX em cápsulas. Estes métodos propostos foram específicos, robustos, lineares, precisos e exatos para determinação de DLX em microgrânulos de revestimento entérico. Estudos preliminares da estabilidade da DLX durante o desenvolvimento do método indicativo de estabilidade por CLAE demonstraram que o fármaco foi rapidamente degradado em meio ácido, na presença de peróxido de hidrogênio e de radiação a luz UVC, enquanto que este foi mais estável em meio alcalino. A cinética de degradação descreveu as mudanças na concentração da DLX em condição ácida e sob fotodegradação. A degradação ácida da DLX, em solução de HCl 0,1 M, mostrou cinética aparente de zero ordem e a fotodegradação demonstrou uma cinética aparente de primeira ordem. O produto de degradação principal observado na hidrólise ácida (PDA-14) foi analisado e isolado por CCD preparativa. Espectros de RMN-1H, RMN-13C e COSY foram avaliados e a estrutura do PDA-14 foi confirmada como 1-naftol. Esta substância produz efeitos citotóxicos e consequentemente o produto farmacêutico é uma cápsula de gelatina contendo microgrânulos com revestimento entérico para evitar a degradação ácida da DLX no estômago. / The duloxetine (DLX) is a double balanced selective serotonin and norepinephrinereuptake inhibitor employed for the treatment of major depressive disorder and for the management of diabetic peripheral neuropathic pain. The aim of this study was to develop and validate analytical methods to the determination of DLX in capsules and accomplish studies of this drug stability. The substance used as reference standard in the analysis was characterized by infrared spectroscopy, nuclear magnetic resonance (NMR), differential scanning calorimetry, and mass spectrometry. The qualitative analyses were performed by thin layer chromatography (TLC), ultraviolet spectrophotometry (UV), and high performance liquid chromatography (HPLC) allowing the identification of the drug in pharmaceutical dosage form. The UV spectrophotometry, HPLC, and cathodic stripping voltammetry (CSV) were validated for quantitative determination of the DLX in capsules. These proposed methods were specific, robust, linear, precise, and accurate to the determination of DLX in entericcoated pellets. Preliminary studies of DLX stability during the development of stability-indicating HPLC method demonstrated that the drug was rapidly degraded in acid medium, in the presence of hydrogen peroxide and light UVC radiation, while it was more stable in alkali medium. The kinetics of degradation described the concentration changes of DLX in acid condition and on photodegradation. The acid degradation of DLX in 0.1M HCl solution showed apparent zero-order kinetics and the photodegradation demonstrated apparent first-order kinetics. The main degradation product observed in acid hydrolysis (DP-14) was analyzed and isolated by TLC preparative. 1H NMR, 13C NMR and COSY spectra were evaluated and the structure of DP-14 was confirmed as 1-naphthol. This substance produces cytotoxic effects and consequently the finished pharmaceutical dosage form is a gelatin capsule containing enteric-coated pellets to avoid the acid degradation of DLX in the stomach.

A duloxetina (DLX) é um duplo inibidor seletivo balanceado da recaptação de serotonina e norepinefrina empregado para o tratamento do transtorno depressivo maior e para o manejo da dor neuropática diabética periférica. O objetivo deste estudo foi desenvolver e validar métodos analíticos para determinação de DLX em cápsulas e realizar estudos da estabilidade do fármaco. A substância usada como padrão de referência nas análises foi caracterizada por espectroscopia no infravermelho, ressonância magnética nuclear (RMN), calorimetria diferencial de varredura e espectrometria de massas. As análises qualitativas foram realizadas por cromatografia em camada delgada (CCD), espectrofotometria na região do ultravioleta (UV) e cromatografia líquida de alta eficiência (CLAE) permitindo a identificação do fármaco no produto farmacêutico. A espectrofotometria UV, CLAE e voltametria de redissolução catódica (CSV) foram validadas para determinação quantitativa de DLX em cápsulas. Estes métodos propostos foram específicos, robustos, lineares, precisos e exatos para determinação de DLX em microgrânulos de revestimento entérico. Estudos preliminares da estabilidade da DLX durante o desenvolvimento do método indicativo de estabilidade por CLAE demonstraram que o fármaco foi rapidamente degradado em meio ácido, na presença de peróxido de hidrogênio e de radiação a luz UVC, enquanto que este foi mais estável em meio alcalino. A cinética de degradação descreveu as mudanças na concentração da DLX em condição ácida e sob fotodegradação. A degradação ácida da DLX, em solução de HCl 0,1 M, mostrou cinética aparente de zero ordem e a fotodegradação demonstrou uma cinética aparente de primeira ordem. O produto de degradação principal observado na hidrólise ácida (PDA-14) foi analisado e isolado por CCD preparativa. Espectros de RMN-1H, RMN-13C e COSY foram avaliados e a estrutura do PDA-14 foi confirmada como 1-naftol. Esta substância produz efeitos citotóxicos e consequentemente o produto farmacêutico é uma cápsula de gelatina contendo microgrânulos com revestimento entérico para evitar a degradação ácida da DLX no estômago. / The duloxetine (DLX) is a double balanced selective serotonin and norepinephrinereuptake inhibitor employed for the treatment of major depressive disorder and for the management of diabetic peripheral neuropathic pain. The aim of this study was to develop and validate analytical methods to the determination of DLX in capsules and accomplish studies of this drug stability. The substance used as reference standard in the analysis was characterized by infrared spectroscopy, nuclear magnetic resonance (NMR), differential scanning calorimetry, and mass spectrometry. The qualitative analyses were performed by thin layer chromatography (TLC), ultraviolet spectrophotometry (UV), and high performance liquid chromatography (HPLC) allowing the identification of the drug in pharmaceutical dosage form. The UV spectrophotometry, HPLC, and cathodic stripping voltammetry (CSV) were validated for quantitative determination of the DLX in capsules. These proposed methods were specific, robust, linear, precise, and accurate to the determination of DLX in entericcoated pellets. Preliminary studies of DLX stability during the development of stability-indicating HPLC method demonstrated that the drug was rapidly degraded in acid medium, in the presence of hydrogen peroxide and light UVC radiation, while it was more stable in alkali medium. The kinetics of degradation described the concentration changes of DLX in acid condition and on photodegradation. The acid degradation of DLX in 0.1M HCl solution showed apparent zero-order kinetics and the photodegradation demonstrated apparent first-order kinetics. The main degradation product observed in acid hydrolysis (DP-14) was analyzed and isolated by TLC preparative. 1H NMR, 13C NMR and COSY spectra were evaluated and the structure of DP-14 was confirmed as 1-naphthol. This substance produces cytotoxic effects and consequently the finished pharmaceutical dosage form is a gelatin capsule containing enteric-coated pellets to avoid the acid degradation of DLX in the stomach.

The issue with maintaining stability of compounds during storage and transportation has been universal across many fields such as clinical, pharmaceutical, food industry and especially in forensic laboratories where case backlogs hinder immediate analysis of samples upon collection. This study compares various storage conditions and analyzes changes in compound stability over 28 days. The various storage conditions compared in this study are temperature (+4 °C and -20 °C); water sample and urine sample and solid state (loading onto Solid Phase Extraction cartridges) and storing in its liquid state (present in the urine or water sample). 51 compounds were analyzed in this study belonging to pharmaceutical and hormone classes. Two Dimensional Liquid Chromatography was used for separation allowing the analysis of varied compounds in terms of chemistry. Mass Spectrometry was used for detection of these compounds. This study conclusively helped determine that there is no significant difference in stability of 42 out of 51 of these compounds on comparing them in solid versus liquid state over a period of 28 days. This helps determine that Solid Phase Extraction (SPE) cartridges can be used as an alternative for storage and transportation of these compounds. 46 compounds showed no significant difference in +4 and -20 °C temperature storage conditions as well. Despite not including a wash step during sample preparation between loading and elution, 11 out of 51 compounds did not show suppression or enhancement due to matrix effect. This study not only highlights the importance of sample preparation prior to analysis but also shows how SPE technique could help maintain stability of compounds during storage. In future studies, stability changes using SPE for long term storage could provide beneficial results to conclude if SPE techniques can provide an advantage over liquid state for a period longer than a month.