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APPLICABILITY OF MASS SPECTROMETRY TO DETECT COELUTING IMPURITIES IN HIGH PERFORMANCE LIQUID CHROMATOGRAPHYANTONOVICH, ROBERT STEVEN 16 September 2002 (has links)
No description available.
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Elektroforetické stanovení rivaroxabanu / Electrophoretic determination of rivaroxabanPetrák, Ondřej January 2021 (has links)
Capillary electrophoresis is a method used in pharmaceutical analysis because of its low cost, speed and environmental friendliness. This diploma thesis deals with development of electrophoretic method for rivaroxaban determination. After several optimizations, a method suitable for rivaroxaban determination inside its dosage forms was developed. Optimizations involved change of background electrolyte's composition from aqueous solution of low molecular weight organic acids to non-aqueous solution of acetic acid and cetyltrimethylammoniumbromide in acetonitrile in multiple steps. Final conditions of analysis included background electrolyte composed of 1M acetic acid and 40mM cetyltrimethylammoniumbromide in acetonitrile, sample injection carried out hydrodynamically by pressure of 5,0 kPa for period of 3 s and subsequent insertion of separation voltage of 30,0 kV for entire duration of analysis. Capillary content was mobilized by pressure of 0,50 kPa for entire duration of analysis. With aforementioned optimizations a selective method for determination of dosage forms of rivaroxaban was obtained. This method provides limit of detection 0,0056 mg/ml and limit of quantification 0,019 mg/ml and is linear in 0,01 - 0,40 mg/ml range with a recovery of 93,2 %. Keywords capillary electrophoresis,...
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Fundamental and Regulatory Aspects of UHPLC in Pharmaceutical AnalysisÅsberg, Dennis January 2017 (has links)
Ultra-high performance liquid chromatography (UHPLC) provides a considerable increase in throughput compared to HPLC and a reduced solvent consumption. The implementation of UHPLC in pharmaceutical analysis, e.g. quality control, has accelerated in recent years and there is currently a mix of HPLC and UHPLC instrumentation within pharmaceutical companies. There are, however, technical and regulatory challenges converting a HPLC method to UHPLC making it difficult to take full advantage of UHPLC in regulatory-focused applications like quality control in pharmaceutical production. Using chromatographic modelling and fundamental theory, this thesis investigated method conversion between HPLC and UHPLC. It reports on the influence of temperature gradients due to viscous heating, pressure effects and stationary phase properties on the separation performance. It also presents a regulatory concept for less regulatory interaction for minor changes to approved methods to support efficient life cycle management. The higher pressure in UHPLC gave a retention increase of up to 40% as compared to conventional HPLC while viscous heating, instead, reduced retention and the net result was very solute dependent. Selectivity shifts were observed even between solutes with similar structure when switching between HPLC and UHPLC and an experimental method to predict such selectivity shifts was therefore developed. The peak shape was negatively affected by the increase in pressure for some solutes since secondary interactions between the solute and the stationary phase increased with pressure. With the upcoming ICH Q12 guideline, it will be possible for the industry to convert existing methods to UHPLC in a more flexible way using the deeper understanding and the regulatory concept presented here as a case example. / Ultra-high performance liquid chromatography (UHPLC) provides a considerable increase in throughput compared to conventional HPLC and a reduced solvent consumption. The implementation of UHPLC in pharmaceutical analysis has accelerated in recent years and currently both instruments are used. There are, however, technical and regulatory challenges converting a HPLC method to UHPLC making it difficult to take full advantage of UHPLC in regulatory-focused applications like quality control in pharmaceutical production. In UHPLC, the column is packed with smaller particles than in HPLC resulting in higher pressure and viscous heating. Both the higher pressure and the higher temperature may cause changes in retention and selectivity making method conversion unpredictable. Using chromatographic modelling and fundamental theory, this thesis investigates method conversion between HPLC and UHPLC. It reports on the influence of temperature gradients due to viscous heating, pressure effects and stationary phase properties on the separation performance. It also presents a regulatory concept for less regulatory interaction for minor changes to approved quality control methods and how predicable method conversion is achieved by improved understanding.
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Vibrational spectroscopic techniques (Raman, FT-IR and FT-NIR spectroscopy) as a means for the solid-state structural analysis of pharmaceuticals]Ali, H. R. H. January 2009 (has links)
The aim of this work was to assess the suitability of vibrational spectroscopic techniques (Raman, FT-IR and FT-NIR spectroscopy) as a means for the solid-state structural analysis of pharmaceuticals. Budesonide, fluticasone propionate, salbutamol hemisulfate, terbutaline hemisulfate, ipratropium bromide, polymorphic forms of salmeterol xinafoate and two polymorphic forms of sulfathiazole were selected since they are used in the management of certain respiratory disorders and from different chemical and pharmacological entities along with some pharmaceutical excipients. Conventional visual examination is not sufficient to identify and differentiate spectra between different pharmaceuticals. To confirm the assignment of key molecular vibrational band signatures, quantum chemical calculations of the vibrational spectra were employed for better understanding of the first five selected drugs. The nondestructive nature of the vibrational spectroscopic techniques and the success of quantum chemical calculations demonstrated in this work have indeed offered a new dimension for the rapid identification and characterisation of pharmaceuticals and essentially warrant further research. The application of simultaneous in situ Raman spectroscopy and differential scanning calorimetry for the preliminary investigation of the polymorphic transformation of salmeterol xinafoate polymorphs and two polymorphic forms of sulfathiazole has also been explored in this work leading to the development of a new method for the solid-state estimation of the transition temperature of entantiotropically related pharmaceutical polymorphs which represents the first analytical record of the use of this approach for pharmaceutical polymorphs.
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Vibrational spectroscopic techniques (Raman, FT-IR and FT-NIR spectroscopy) as a means for the solid-state structural analysis of pharmaceuticalsAli, H.R.H. January 2009 (has links)
The aim of this work was to assess the suitability of vibrational spectroscopic
techniques (Raman, FT-IR and FT-NIR spectroscopy) as a means for the solid-state
structural analysis of pharmaceuticals. Budesonide, fluticasone propionate, salbutamol
hemisulfate, terbutaline hemisulfate, ipratropium bromide, polymorphic forms of
salmeterol xinafoate and two polymorphic forms of sulfathiazole were selected since
they are used in the management of certain respiratory disorders and from different
chemical and pharmacological entities along with some pharmaceutical excipients.
Conventional visual examination is not sufficient to identify and differentiate spectra
between different pharmaceuticals. To confirm the assignment of key molecular
vibrational band signatures, quantum chemical calculations of the vibrational spectra
were employed for better understanding of the first five selected drugs. The nondestructive
nature of the vibrational spectroscopic techniques and the success of
quantum chemical calculations demonstrated in this work have indeed offered a new
dimension for the rapid identification and characterisation of pharmaceuticals and
essentially warrant further research.
The application of simultaneous in situ Raman spectroscopy and differential
scanning calorimetry for the preliminary investigation of the polymorphic
transformation of salmeterol xinafoate polymorphs and two polymorphic forms of
sulfathiazole has also been explored in this work leading to the development of a new
method for the solid-state estimation of the transition temperature of
entantiotropically related pharmaceutical polymorphs which represents the first
analytical record of the use of this approach for pharmaceutical polymorphs.
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Studies of Micellar Electrokinetic Chromatography as an Analytical Technique in Pharmaceutical Analysis - an Industrial PerspectiveStubberud, Karin January 2002 (has links)
<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>
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Studies of Micellar Electrokinetic Chromatography as an Analytical Technique in Pharmaceutical Analysis - an Industrial PerspectiveStubberud, Karin January 2002 (has links)
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.
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Separation of Pharmaceuticals by Capillary Electrophoresis using Partial Filling and Multiple-injectionsLodén, Henrik January 2008 (has links)
Different multiple-injection methodologies and the partial filling technique (PFT) have been utilized for separation of pharmaceuticals by capillary elec-trophoresis. In multiple-injection capillary zone electrophoresis (MICZE), the samples and all standards, used for construction of the calibration curve, are analyzed within a single run. Four different modes of MICZE have been described by means of equations, which were experimentally verified. The developed equations facilitate the transfer from conventional single-injection CZE to one or more of these MICZE-modes, depending on the selectivity between the analyte and the injection marker. The applicability of two of these modes was then demonstrated by quantification of buserelin and salbutamol, re-spectively in commercially available pharmaceutical products. The content of buserelin in an injection solution was determined to 0.94 mg/ml, which only deviated slightly from the declared concentration (1 mg/ml). An alter-native mode of MICZE, offering a higher number of sequential sample injec-tions, was then utilized for single-run determination of salbutamol in 15 tab-lets, with a labelled content of 8 mg. The average content of the tablets was determined to 7.8 mg, with an intra-tablet variation of 3 % or less. Moreover, UV- and mass-spectrometric detection of enantiomeric amines, resolved by non-aqueous capillary electrophoresis (NACE), was demon-strated. Separation of enantiomeric amines was achieved using the chiral selector (-)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid, (-)-DIKGA. Introduction of the non-volatile (-)-DIKGA into the mass-spectrometer was avoided by using the PFT, where the capillary is only partially filled with electrolyte containing the chiral selector.
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The role of drug metabolism in drug discovery and development:case ospemifeneUusitalo, J. (Jouko) 24 November 2015 (has links)
Abstract
Drug metabolism is one of the most important events a drug faces after administration. Traditionally, drug metabolism has only been considered as a major clearance and elimination step in the pharmacokinetics of a drug. However, drug metabolism is also one of the important factors behind safety and toxicity issues in drug discovery and development. Some of the mechanisms behind metabolism-related toxicity we do understand well while others, especially the role of reactive metabolites, need further research. The thesis reviews the role of drug metabolism in the drug discovery and development process from the point of view of metabolism and metabolites. Special emphasis is put on reviewing the metabolism behind human toxicity and safety, and the roles of circulating and reactive metabolites in particular.
Ospemifene is a nonsteroidal selective estrogen receptor modulator recently approved for the treatment of vulvar and vaginal atrophy in postmenopausal women with moderate to severe dyspareunia. The present study characterized the in vitro and in vivo metabolism and potential drug interactions of ospemifene. The principal human metabolites were identified and the adequacy nonclinical animal exposure was evaluated. The major human cytochrome P450 enzymes involved in the formation of principal metabolites were also identified and the clinical consequences assessed. Finally, the interaction potential of ospemifene as a cytochrome P450 enzyme inducer or inhibitor was investigated. As a result, ospemifene was considered to be safe drug from a metabolic interaction point of view.
This study was part of the drug development program of ospemifene and practically all of the in vitro study data were included in the marketing authorization application of ospemifene. Ospemifene was also a case molecule in the development of new methodologies to study drug metabolism and drug-drug interactions. / Tiivistelmä
Lääkeainemetabolia on lääkeaineen farmakokinetiikassa tärkeä puhdistuma- ja eliminaatioaskel, jonka rooli on ymmärretty varsin hyvin. Lääkeainemetabolialla on myös merkittävä vaikutus lääkeaineen toksisuuteen ja lääkkeen käytön turvallisuuteen. Osa lääkeainemetaboliaan liittyvistä toksisuusmekanismeista selvitetty hyvin, mutta erityisesti reaktiivisiin metaboliitteihin liittyvä osa vaatii vielä tutkimusta. Tämän työn kirjallisuusosassa katselmoidaan lääkeainemetabolian merkitystä lääkekehitysprosessissa painottaen erityisesti lääkeainemetabolian sekä reaktiivisten ja verenkierrossa kiertävien metaboliatuoteiden vaikutusta toksisuuteen ihmisellä ja merkitystä turvalliseen lääkkeiden käyttöön.
Ospemifeeni on uusi ei-steroidinen selektiivinen estrogeenireseptorimodulaattori, joka on hyväksytty yhdynnänaikaisesta kivusta kärsivien postmenopausaalisten naisten vulvan ja vaginan limakalvojen kuivumisen hoitoon. Tässä tutkimuksessa selvitettiin ospemifeenin lääkeainemetaboliaa ihmisellä ja koe-eläimillä sekä mahdollisia lääkeinteraktioita. Tutkimuksessa tunnistettiin tärkeimmät metaboliitit ihmisellä ja arvioitiin eläinkokeissa käytettyjen koe-eläinten altistumisen kattavuus niille. Työssä selvitettiin myös tärkeimmät päämetaboliitteja katalysoivat sytokromi P450 -entsyymit ja arvioitiin löydösten kliinistä merkitystä. Lisäksi tutkittiin aiheuttaako ospemifeeni lääkeinteraktioita muille lääkeaineille indusoimalla tai inhiboimalla sytokromi P450 -entsyymejä. Tutkimustulosten perusteella ospemifeenia voidaan pitää lääkeainemetabolian suhteen turvallisena lääkkeenä.
Tämä tutkimus oli osa ospemifeenin lääkekehitysohjelmaa ja käytännössä kaikki tutkimustyön in vitro -tietoaineisto oli mukana ospemifeenin myyntilupa-hakemuksissa lääketurvallisuusviranomaisille. Ospemifeenia käytettiin tutkimustyön aikana myös yhtenä esimerkkimolekyylinä kehitettäessä uusia menetelmiä lääkeainemetabolian ja lääkeinteraktioiden tutkimiseen.
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