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Attenuated Total Reflection Infrared Spectroscopy (ATR-IR) As an in Situ Technique for Dissolution Studies Abe S

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Attenuated Total Reflection Infrared Spectroscopy (ATR-IR) As an in Situ Technique for Dissolution Studies Abe S Seton Hall University eRepository @ Seton Hall Seton Hall University Dissertations and Theses Seton Hall University Dissertations and Theses (ETDs) Summer 8-2011 Attenuated Total Reflection Infrared Spectroscopy (ATR-IR) as an In Situ Technique for Dissolution Studies Abe S. Kassis Seton Hall University Follow this and additional works at: https://scholarship.shu.edu/dissertations Part of the Biochemistry Commons Recommended Citation Kassis, Abe S., "Attenuated Total Reflection Infrared Spectroscopy (ATR-IR) as an In Situ Technique for Dissolution Studies" (2011). Seton Hall University Dissertations and Theses (ETDs). 1432. https://scholarship.shu.edu/dissertations/1432 Attenuated Total Reflection Infrared Spectroscopy (ATR-IR) as an In Situ Technique for Dissolution Studies by Abe S. Kassis Ph.D. DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry and Biochemistry of Seton Hall University Seton Hall University Department of Chemistry and Biochemistry 400 South Orange Avenue South Orange, New Jersey 07079 August 2011 DISSERTATION COMMITTEE APPROVALS We certify that we have read this thesis and that in our opinion it is sufficient in scientific scope and quality as a dissertation for the degree of Doctor of Philosophy APPROVED BY: Advisor, Seton Hall University Nicholas H. Snow, Ph.D. Member of Dissertation Committee, Seton Hall University Tarun ~el, Ph.D. Member of Dissertation Committee, Novartis Pharmaceuticals Corporation Q\A"b A lM~ en P. KeI;y, Ph.D. Chair, Department ofChemistry and Biochemistry, Seton Hall University [ii] "Although nature commences with reason and ends in experience it is necessary for us to do the opposite, that is to commence with experience and from this to proceed to investigate the reason." -Leonardo da Vinci [iii] Abstract Attenuated Total Reflection Infrared Spectroscopy (ATR-IR) as an in situ Technique for Dissolution Studies Dissolution studies are critical tests for measuring the performance, or rate of release, of a drug product. There are many variables that affect the dissolution rate of the drug. Such variables may include characteristics of the active pharmaceutical ingredient (API) (e.g., particle size, crystal form, and bulk density), drug product composition (e.g., drug loading, and the identity, type, and levels of excipients), the drug product manufacturing process (e.g., compreSSIon forces, equipment), and the effects of stability storage conditions (e.g., temperature, humidity). Since dissolution has the ability to detect these variables, the regulatory agencies (i.e. FDA and EMEA) have placed great emphasis on the test. Moreover, the regulatory agencies have increased the monitoring and auditing ofthe dissolution test. A novel technique using in situ attenuated total reflection-infrared spectroscopy (ATR-IR) to monitor dissolutions of pharmaceutical drug products was developed. The accuracy of this technique is ±3% relative to HPLC. Salicylic acid calibrator tablets were studied and two over-the-counter (OTe) formulations containing acetaminophen, and/or acetylsalicylic acid were tested during the research. This novel approach was also used to analyze multiple components in a single tablet. For example, dissolution of the individual components of caffeine-free version of Excedrin® tablets, acetaminophen and acetylsalicylic acid were easily distinguished. [iv] Furthermore, the system has the capability of monitoring the drug transformations during dissolution. For instance, this technique was used to monitor the dissolution and hydrolysis of aspirin to salicylic acid. The ATR-IR system was found to have good sensitivity and can analyze samples as low as 0.03 mg/mL (2 x 10-4 M) based on the limit of detection ("LOD") studies. This will be discussed in details in chapter four. This technique allows deeper insight into spectroscopy, reaction analysis, kinetics and dynamics of the dissolution of active components in a pharmaceutical formulation. In addition, this novel system was used to support research related to the BP oil spill that occurred in the Gulf of Mexico during April 20th - June 3rd, 2010. Specifically, the system was used to study dispersion of oil in the presence of dishwashing soaps as preliminary models for commercial dispersants. Dawn® dishwashing soap was used because of its powerful claim to clean wildlife affected by oil spills. Dawn® specifically uses anionic surfactants, such as alkyl dimethyl amine oxide, to break down oil samples. These surfactants reduce the surface tension of water and can weaken the barrier that automatically forms between oil and water, allowing them to unnaturally mix. Furthermore, in recognition of the potential of this technique to be widely used in the pharmaceutical industry for drug dissolution studies, an instrument was designed and the design is presented as a chapter in this dissertation. Overall, this work has discovered and validated the use of ATR-IR as a technique for monitoring to dissolution and dissolution/hydrolysis reactions of pharmaceutical formulations. It has excellent potential for studies of the dissolution of tablets especially multi-component tablets and tablets with ingredients that undergo subsequent hydrolysis. [v] Acknowledgments During my graduate career at Seton Hall University, I have had the privilege and opportunity to develop myself as a research scientist and strategic thinker. This would not have been possible without the support I received from my great employer Novartis Pharmaceuticals Corporation, for giving me the financial support and opportunity to obtain my doctorate degree. Moreover, I would like to give special thanks to Cynthia Cetani, Andre Wyss, Colleen Ruegger, Steffen Lang, Lynne Delisi and many others for their support and mentorship. Also, I would like to give special thanks to my research advisor Dr. John R. Sowa, Jr. for his valuable guidance, expertise, encouragement, and his dear friendship. Dr. Sowa inspires me to become a better scientist and individual. I would also like to acknowledge Dr. Sowa's research group as well as the faculty members of the Department of Chemistry and Biochemistry at Seton Hall University. Specifically, I would like to give special appreciation to; Dr. Snow for encouraging, motivating and supporting my research ambitions, Dr. Kazakevich for his great guidance and teachings in HPLC, Dr. Kelty, Dr. Murphy, Dr. Fadeev and Dr. Marzabadi. I would also like to acknowledge Dr. Tarun Patel from the Novartis Pharmaceuticals Corporation for his guidance and mentoring throughout my studies. I will forever be indebted to those who have supported me through the years in this endeavor. It is with great appreciation that I offer my gratitude to all. To my Dad and Mom, Sam and Nina Kassis for opening the door to science and motivating me to reach further in life. To my dear sisters, family and close friends. [vi] Finally, I want to thank my wife, Cindy for her unwavering support. Also, I want to thank my daughter Amber and my son Neil for their support and understanding. Without them none of this would have been possible. I would like to acknowledge Wes Walker and Jane Riley from Mettler-Toledo for technical support for the iCIOIR Instrument. [vii] Table of contents Table of contents ..............................................................................................................viii List of figures ....................................................................................................................xii List of tables ................................................................................................................... xviii Introduction and Literature Overview ................................................................................. 1 1.1 History ..................................................................................................................... 5 1.2 Infrared Spectroscopy ............................................................................................ 28 1.3 Literature background: in situ ATR-IR and dissolution ........................................ 32 2 Dissolution of salicylic acid, acetylsalicylic acid and acetaminophen using In Situ ATR-IR spectroscopy ........................................................................................................ 35 2.1 Experimental section ............................................................................................. 38 2.1.1 Chemical and materials ......................................................................... 38 2.1.2 Instrumentation ..................................................................................... 39 2.1.3 Buffered solutions .................................................................................40 2.1.4 Dissolution experiments ........................................................................ 40 2.1.5 HPLC analysis ....................................................................................... 41 2.1.6 ATR-IR analysis ................................................................................... 42 2.2 Results and discussion ...........................................................................................44 2.2.1 Single-component analysis ................................................................... 44 2.2.2 Dissolution results for salicylic acid using pH 7.4 phosphate buffer .. .47 [viii] 2.2.3 Multi-tablet analysis .............................................................................
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