8,772 research outputs found
Development and optimization of HPLC methods in drug development using Quality by design approach
No full textRazvoj novega zdravila v farmacevtski industriji je sestavljen iz različnih procesov, med katere uvrščamo tudi razvoj analiznih metod. Rezultati, ki jih dobimo z njihovo uporabo, nam omogočajo odločitev glede strategije za nadaljnji razvoj zdravila oziroma podajo informacijo, ali je zdravilo primerno za sprostitev na trg. Zato je bistveno, da so analizne metode natančne, točne in zanesljive. Ključna analizna metoda za analizo in sproščanje zdravil je tekočinska kromatografija visoke ločljivosti (HPLC), katere razvoj je zaradi kompleksne sestave vzorcev tekom razvoja lahko zelo zahteven. S tradicionalnim pristopom (>>one factor at a time>sweet spot>central composite face design>design space>central composite face-centered design>design space<<) v odvisnosti od vrstnega reda elucije nečistote C in neznanega razkrojnega produkta. Za POVZETEK 3 končno metodo smo izbrali optimalno kombinacijo faktorjev, ki leži v robustnejšem območju ter potrdili ustrezno ponovljivost, točnost, linearnost in občutljivost razvite metode UHPLC. Z uporabo AQbD smo razvili dve novi robustni metodi in s tem odpravili težave obstoječih farmakopejskih metod. Z uporabo DoE smo zmanjšali število izvedenih eksperimentov, ki bi bili potrebni pri uporabi OFAT načina, matematični model pa nam je omogočil pridobitev podrobnih informacij glede vplivov faktorjev in faktorskih interakcij na posamezen odziv, česar z OFAT načinom ni mogoče ugotoviti. Na ta način smo določili območje robustnosti. V primeru ropinirolijevega klorida smo bistveno skrajšali čas analize in zmanjšali porabo organskih topil, kar je v skladu z aktualnimi trendi v analizni kemiji. Na obeh primerih smo dokazali učinkovitost uporabe AQbD pri razvoju in optimizaciji metod HPLC.The development of a new drug product in pharmaceutical industry consists of many processes, including analytical methods. The results obtained by using analytical methods allow us to determine the strategy for further development or provide information on whether the drug product may be released. It is therefore essential that analytical methods are precise, accurate and reliable. High performance liquid chromatography (HPLC) method is the key analytical method for drug product analysis and release. The development of HPLC method may be a challenge because of the complexity of the samples in development. Using the traditional approach (OFAT) the process of HPLC method development and optimization is time consuming and non-transparent, as well as it is impossible to determine factor interactions that affect method performance. In 2004, the FDA first introduced Quality by Design (QbD), the purpose of which is to improve the quality of the drug product by designing it directly into the pharmaceutical process. In June 2018, ICH announced a new ICH Q14 guideline that will include the use of QbD for analytical methods, called Analytical Quality by Design (AQbD). In the introduction part, as a review scientific article, we introduced the theoretical background of AQbD and presented in detail the recent cases, which systematically show the methodology of the AQbD approach to the development and optimization of HPLC methods. In chapter one of experimental part, we focused on the HPLC method from the EP for the determination of related substances in celecoxib. Using the prescribed analytical method the system suitability test (SST) criteria cannot be met: inadequate resolution between celecoxib and impurity B, barely adequate resolution between impurity A and celecoxib. Using the Design of Experiments (DoE) we optimized the pharmacopeial method within the acceptable limits prescribed in the EP. Four critical method parameters were varied using DoE: the ratio of methanol and acetonitrile in the mobile phase, column temperature and mobile phase flow rate. We determined the sweet spot, in which both resolution meet the SST criteria. However, the sweet spot was narrow and the analysis time had to be increased for a factor of 1.5. In chapter two, we started with the development and optimization of a new HPLC method for celecoxib, since the pharmacopeial optimized method was too long and non-robust. In the USP forum, we found the HPLC method for celecoxib capsules, that can be used for the determination of six process related impurities but not also impurity A, as it was not separated from the peak of celecoxib. Our goal was to develop one HPLC method able to determine all seven process related impurities of celecoxib from EP and USP. Due to structural similarity of some investigated process-related impurities (positional isomers), we had to find a more suitable stationary phase for their separation. Using a chiral column in reversed phase, we achieved satisfactory separations. In order to optimize the method and determine the design space, we performed 17 experiments according to a central composite face design, in which the values of three CMPs (the ratio of acetonitrile in the mobile phase, column temperature and mobile phase flow rate) were varied. Three critical resolutions and the retention time of the last eluting impurity were monitored as CMAs. Using the multiple linear regression (MLR) method, we established a statistically significant mathematical model with excellent prediction abilities. Using the Monte Carlo simulations method, we determined the design space, in which all responses meet the criteria with 99 % probability. We also determined a combination of factors that give the optimal response and confirmed the suitable precision, accuracy, linearity and sensitivity of the developed HPLC method. In chapter three, we focused on the HPLC method from the EP for the determination of related substances in ropinirole hydrochloride. The pharmacopeial method did not separate two pairs of impurities and the analysis time was too long. A UHPLC analytical technique was used to develop a new method. Due to a relatively large number of CMPs (buffer molarity, buffer pH, ratio of methanol in the mobile phase, column temperature, initial ratio of organic phase and gradient slope) we performed 19 experiments according to a fractional factorial screening design. Using DoE, we determined the effects of factors, among which the ratio of methanol in the mobile phase, column temperature and gradient slope turned out as highly significant. In this step, we already determined the optimal values for the three less significant factors. In the method optimization step, we performed 17 experiments according to a central composite face-centered response-surface design. Using the MLR method, we established a statistically significant mathematical model with very good prediction abilities. Using the Monte Carlo simulations method, we determined two design spaces according to the elution order of impurity C and unknown degradation impurity. For the final method, we chose the optimal combination of factors from the wider design space and confirmed the suitable precision, accuracy, linearity and sensitivity of the developed UHPLC method. Using AQbD, we developed and optimized two new robust methods, which eliminate the issues of the existing pharmacopeial methods. Using DoE reduced the number of experiments that would otherwise be performed if using OFAT approach, and that the established mathematical model allowed us to obtain detailed information on the effects of factors and factor interactions on a particular response, which is impossible to determine using OFAT. Using DoE, we determined the design space. In the case of ropinirole hydrochloride, we significantly shortened the analysis time and reduced organic solvent consumption, which is in line with current trends of analytical chemistry. For both cases, we have proven the effectiveness of the AQbD approach to the development and optimization of HPLC methods
Do dolphins benefit from nonlinear mathematics when processing their sonar returns?
No full textAn interview with author Tim Leighton about the paper
Opportunities for linking young surveyors across professional surveying member organisations and FIG
No full textTim Di Muzio on 'Sabotage'
No full textIn a series of essays published in 2013 and 2014 on capitaspower.com, political economist Tim Di Muzio explored the concept of ‘sabotage’ as it applies to capitalist power. I recently rediscovered these essays and was so impressed by them that I have reposted them here as a single piece.
About the author: Tim Di Muzio is a researcher at the University of Wollongong. He is the author of numerous books, including Debt as power, Carbon capitalism, and The 1% and the Rest of us
1996-1997 Tim Gautreaux
No full textTim Gautreaux is the author of three novels and two earlier short story collections. His work has appeared in The New Yorker, The Best American Short Stories, The Atlantic, Harper’s, and GQ. After teaching for thirty years at Southeastern Louisiana University, he now lives, with his wife, in Chattanooga, Tennessee. (Photo credit: Randy Bergeron)https://egrove.olemiss.edu/grisham_res/1023/thumbnail.jp
First person - Tim Petzold
No full textFirst Person is a series of interviews with the first authors of a selection of papers published in Biology Open, helping researchers promote themselves alongside their papers. Tim Petzold is first author on ‘ Connexin 41.8 governs timely haematopoietic stem and progenitor cell specification’, published in BiO. Tim conducted the research described in this article while a PhD student in Julien Bertrand's lab at the Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland. He is now a postdoc in the lab of Holger Gerhardt at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany, investigating developmental biology – previously his focus was on how blood stem cells develop and now it has shifted to how the vascular system develops
Tim Seibles, 40th Annual ODU Literary Festival
No full textTim Seibles is the author of several poetry collections including Hurdy-Gurdy, Hammerlock, Buffalo Head Solos, and Fast Animal, which was a finalist for the 2012 National Book Award. In 2013 he received both the Pen Oakland Josephine Miles Award for poetry and an honorary Doctorate of Humane Letters from Misericordia University for his literary accomplishments. His latest collection, One Turn Around the Sun, has just been released. Tim is the current Poet Laureate of Virginia and is a Professor of English at Old Dominion University where he teaches literature as well as classes in the MFA in writing program
Tim Seibles, 39th Annual ODU Literary Festival
No full textTim Seibles is the author of several poetry collections including Hurdy-Gurdy, Hammerlock, Buffalo Head Solos, and Fast Animal, which was a finalist for the 2012 National Book Award. In 2013 he received both the Pen Oakland Josephine Miles Award for poetry and an honorary Doctorate of Humane Letters from Misericordia University for his literary accomplishments. His latest collection, One Turn Around the Sun, has just been released. Tim is the current Poet Laureate of Virginia and is a Professor of English at Old Dominion University where he teaches literature as well as classes in the MFA in writing program
Global Media Ideas - Infinite Pathways to Creative Succes - Tim Chang - Part One.mp4
No full textDuring the X Media Lab: Global Media Ideas summit in June 2011 media and technology writer Brad Howarth conducted interviews with industry experts for Creativeinnovation. This video is part one of Brad Howarth's interview with Tim Chang about his role as Partner at Norwest Venture Partners (Palo Alto). Tim focuses on investments in mobile, gaming, digital media, and also leads Norwest Venture Partners's investment practice in China and Asia-Pacific. Tim shares tips on how to get an introduction to a Venture Capital; the elements of a good pitch and follow-up. And what he looks at when considering a deal - The 3Ts: Team, Traction, Tier 1 co-investors
2015 MLK Lecture: Tim Wise
No full text2015 MLK Series Lecturer, anti-racism author and activist Tim Wise speaks on privilege and the harms of inequity
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