Nanonization and Characterization of Three Non-Steroidal Anti-Inflammatory Drugs (Ketoprofen, Dexibuprofen and Indomethacin)
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NANONIZATION AND CHARACTERIZATION OF THREE NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (KETOPROFEN, DEXIBUPROFEN AND INDOMETHACIN) A DISSERTATION SUBMITTED TO THE UNIVERSITY OF SARGODHA, SARGODHA IN PARTIAL FULFILLMENT OF THE REQUIREMENT FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN PHARMACEUTICS BY JAHANGIR KHAN COLLEGE OF PHARMACY FACULTY OF PHARMACY UNIVERSITY OF SARGODHA, SARGODHA Session 2011-2014 I DEDICATE THIS THESIS TO MY BROTHERS, SISTERS AND WIFE iii APPROVAL CERTIFICATE It is solemnly described that the dissertation titled “Nanonization and characterization of three non-steroidal anti-inflammatory drugs (ketoprofen, dexibuprofen and indomethacin)” submitted by Jahangir Khan in the partial fulfillment of the requirement for the award of degree of DOCTOR OF PHILOSOPHY in Pharmaceutics is hereby approved. Supervisor: _______________________ Co-Supervisor: ____________________ Prof. Dr. Sajid Bashir Dr. Shahzeb Khan Dean Assistant Professor College of Pharmacy Department of Pharmacy Faculty of Pharmacy University of Malakand, Chakdara University of Sargodha, Sargodha External Examiner: ________________ Principal: _____________________ Dean: _____________________ Associate Prof. Dr. Saira Azhar Prof. Dr. Sajid Bashir College of Pharmacy College of Pharmacy University of Sargodha, Sargodha. Faculty of Pharmacy University of Sargodha, Sargodha. iv DECLARATION I declare that the work described in this thesis was carried out by me under the supervision of Prof. Dr. Sajid Bashir, Dean/Chairman Faculty of Pharmacy University of Sargodha, Sargodha, Pakistan and Dr. Shahzeb Khan Assistant Professor, Department of Pharmacy, University of Malakand, Chakdara Dir(L), Pakistan, in partial fulfillment of the requirement for the degree of “DOCTOR OF PHILOSOPHY in PHARMACEUTICS”. I certify that the main content of this thesis accounts for my own research and has not previously been submitted for a degree at any educational institution. Further, it is submitted that the material taken from other sources has been acknowledged. JAHANGIR KHAN v ACKNOWLEDGEMENTS I offer my humble praise and gratitude to ALLAH Almighty, The Most Beneficent, The Most Merciful for sprinkling His uncountable blessings throughout my life and bestowing upon me the intellectual ability and wisdom to explore for its mysteries. Immeasurable salutations upon “The with Whose Existence and by having the Charity of His ”(ﷺ ) Teacher of the Universe Knowledge, the cosmos got illuminated with the light of insight and wisdom, and journey of human enlightenment became possible. I must express my special thanks to my supervisors Prof. Dr. Sajid Bashir, Dean/Chairman Faculty of Pharmacy, University of Sargodha, Sargodha and Dr. Shahzeb Khan, Assistant Professor Department of Pharmacy, University of Malakand Chakdara Dir(L) for their continuous support, constant inspiration and precious advice and supervision throughout the course of my research work. I am immeasurably delighted to place on record my extensive appreciativeness and enthusiastic recognitions to Dr. Muhammad Isreb School of Pharmacy, University of Bradford, UK for his continuous inspiration, friendly supervision, support and priceless efforts throughout my research work to make my project fruitful. At University of Bradford, I must express my special thanks to Dr. Mohammad Amin Muhammad, Abdul Rahman Mkia and Yuosef Al Ayoub for their motivations, enthusiasm, worthy piece of advices and guidance. I’m grateful to the Prof. Dr. Anant Pardarkar & his Research team included Dr. Khaled hafez Assi for providing research facilities and their appreciated assistance. I must acknowledge the technical support of Stuart Fox, David Benson, Toheed raza, Damian Yeadon and other staff members. vi I am thankful to the HEC Pakistan for the finical support provide to me under the IRSIP program. I am also thankful to University of Malakand Chakdara Khyber Pakhtunkhwa for the award of NOC, study leave and support to pursue my PhD studies. At University of Malakand I am also thankful to Prof. Dr. Mirazam khan, Prof. Dr. Waqar Ahamd, Prof. Dr. Rahmat Ali khan, Prof. Dr. Rashid Ahmad and other friends/ colleagues for their help, inspiration and productive suggestions. I sincerely extend my gratitude to my fellow doctoral colleagues and other friends at UK and Pakistan especially to Shah Hassan, Muthana Obeed, Dr. Farhat ali khan, Naveed Khan and PhD scholar Sajjad Khan. I would like to express my warm thanks to my brothers, sisters and my wife whose indispensable support certainly led me towards completion of my PhD studies. JAHANGIR KHAN vii ABBREVIATIONS AVG Average ANOVA Analysis of variance BCS Biopharmaceutical Classification System cm Centimeter °C Degrees celsius COX Cyclooxygenase Conc Concentration DLS Dynamic light scattering DSC Differential scanning calorimetry Da Dalton Diclo Diclofenac DMSO Dimethyl sulfoxide DXI Dexibuprofen EPAS Evaporative precipitation into aqueous solutions ΔG Gibbs free energy GIT Gastrointestinal tract hr Hour HPMC Hydroxypropyl methyl cellulose ΔH Enthalpy change HPH High pressure homogenization HP--CD hydroxyl propyl dextrin H2O Water viii IND Indomethacin Keto Ketoprofen LSD Least significant difference test mg Milligram min Minute ml Milliliter mp Melting point mol f Molecular Formula mol wt Molecular weight NSAIDs Non-steroidal anti-inflammatory drugs NPXN Naproxen NLC Nanostructured lipid carriers P Particle PXRD Powder X-ray diffraction PCS Photon correlation spectroscopy PDI Polydispersity index PVP Polyvinylpyrrolidone RESS Rapid expansion from supercritical fluids s Second SAS Supercritical anti-solvent precipitation SDS Sodium dodecyl sulfate SEM Scanning electron microscopy ΔS Entropy change ix SD Standard deviation TEM Transmission electron microscope USP United States Pharmacopoeia UV Ultraviolet x LIST OF FIGURES Figure I.1: Biopharmaceutical Classification System Figure 1.2: solubility- diagram (Garside and Davey 2000) Figure 1.3: Alternation in nuclei magnitude effect free energy (Gibbs 1928) Figure 1.4: crystal growth Mechanism (Elwell and Scheel 1975; Dirksen and Ring 1991) Figure 1.5: Imaginary crystal faces (i) flat-F (ii) step-S (iii) kink-K (Dirksen and Ring 1991) Figure 1.6: crystal nuclei creation on emerging crystal surface (Garside and Davey 2000) Figure 1.7: creation of spirals initiating from screw dislocation (Mullin 2001) Figure 1.8: Distinguishing features of nanoparticle (Müller, Shegokar et al. 2011). Figure 1.9: Methods of preparation of Nanoparticles. Figure 1.10: Media Milling (Merisko-Liversidge, Liversidge et al. 2003) Figure 1.11: High Pressure Homogenization (HPH) (Junghanns and Müller 2008) Figure 1.12: Spray freezing into liquid. (Hu, Johnston et al. 2003) Figure 1.13: EPAS process (Sinswat, Gao et al. 2005). Figure 1.14: micro-chip.(Schulte, Bardell et al. 2002). Figure 1.15: Microfluidic reactor water and Dye (Ali, Blagden et al. 2009) Figure 1.16: diffusion process liquid streams Figure 1.17: (Classical DLVO theory). Change in particle distance affects the Potential energy of system. Figure 1.18: absorption comparative study of micro and nanoparticle (Mauludin, Müller et al. 2008). Figure 1.19: Chemical structures of drugs (A) Ketoprofen (B) Dexibuprofen (C) Indomethacin Figure 2.1: Microchannel fluidic reactor Figure 3.1: Polymers effect on ketoprofen nanocrystals Figure 3.2: ketoprofen nanoparticle particle size distribution (Poloxamer 407 (1%) xi Figure 3.3: polymers effect on Dexibuprofen nanocrystals Figure 3.4: Dexibuprofen nanoparticle particle size distribution (Poloxamer 407 (0.5%) Figure 3.5: Polymers effect on Indomethacin nanocrystals Figure 3.6: Indomethacin nanoparticle particle size distribution (PVP k-30 (1%)- HPMC 15cps (0.5%)-SLS (0.5%) Figure 3.7: MR inlet angle Effect on Ketoprofen nanoparticle Figure 3.8: MR inlet angle Effect on Dexibuprofen nanoparticle Figure 3.9: MR inlet angle Effect on Indomethacin nanoparticle Figure 3.10: Effect of flow rate (Antisolvent Variable and solvent constant) on Particle size of ketoprofen nanocrystal Figure 3.11: Effect of Antisolvent and solvent flow rate on size of Dexibuprofen Nanoparticle Figure 3.12: Effect of Antisolvent and solvent flow rate (Antisolvent Variable and solvent constant) on nanocrystal size of Indomethacin Figure 3.13: Effect of Antisolvent and solvent flow rate (solvent Variable and antisolvent constant) on particle size of ketoprofen nanoparticle. Figure 3.14: Effect of Antisolvent and solvent flow rate (solvent Variable and antisolvent constant) on particle size of Dexibuprofen nanoparticle Figure 3.15: Effect of Antisolvent and solvent flow rate (solvent Variable and antisolvent constant) on particle size of Indomethacin nanoparticle. Figure 3.16: Effect of Antisolvent and solvent flow rate (Equal ratio of solvent and antisolvent volume) on ketoprofen nanoparticle Figure 3.17: Effect of Antisolvent and solvent flow rate (Equal ratio of solvent and antisolvent volume) on Dexibuprofen nanoparticle Figure 3.18: Effect of Antisolvent and solvent flow rate (Equal ratio of solvent and antisolvent volume) on Indomethacin nanoparticle Figure 3.19: Drug concentration effect on particle size of Ketoprofen Figure 3.20: Drug concentration effect on particle size of Dexibuprofen Figure 3.21: Drug concentration effect on particle size of Indomethacin Figure 3.22: Effect of Mixing Time on ketoprofen nanoparticle Figure 3.23: Effect of Mixing Time on Dexibuprofen nanoparticle Figure 3.24: Effect of Mixing Time on Dexibuprofen nanoparticle xii Figure 3.25: stability of ketoprofen nanoparticle