Particle fabrication techniques for pharmaceutical applications

PARTICLE FABRICATION VIA ELECTROHYDRODYNAMIC ATOMIZATION FOR PHARMACEUTICAL APPLICATIONS ALIREZA REZVANPOUR (M.S., B.S., Sharif University of Technology, Iran) A THESIS SUBMITED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMICAL AND BIOMOLECULAR ENGINEERING NATIONAL UNIVERSITY OF SINGAPORE 2012 ii Acknowledgements First and foremost, I would like to truthfully express my gratitude to my highly respected supervisor Professor Chi-Hwa Wang, for his constant guidance, moral support, supervision, comments and suggestions throughout my whole PhD studies. Definitely, without his support, the completion of this thesis would not have been possible. I would also like to sincerely thank Professor William B. Krantz (Department of Chemical & Biological Engineering, University of Colorado, Boulder) for his invaluable guidance and comments during my studies. I don’t hesitate to say that I have learnt many precious points during several discussions with him. I am specially grateful to Professor Wuqiang Yang (School of Electrical and Electronic Engineering, The University of Manchester) and Professor Yung C. Liang (Department of Electrical and Computer Engineering, National University of Singapore) for their invaluable discussions and comments during the work. The support from Mr. Kok Hong Boey, Ms. How Yoke Leng, Ms. Fengmei Li and other lab technicians and administrative staff is greatly appreciated. I would like to thank Dr. Lim Wee Chuan, Dr. Sudhir Hulikal Ranganath, Dr. Nie Hemin, Dr. Davis Yohanes Arifin, Dr. Lim Liang Kuang, Dr. Jingwei Xie, Dr. Cheng Yongpan, Ms. Lei Chenlu, Mr. Qiao Gian, Mr. Xu Qingxing Noel and other group members for helpful technical support and discussions. And I would like to thank students Mr. Tan Guowei, Ms. Amalina Bte Ebrahim Attia, Mr. Lee Teng Yong Jeffrey, Mr. Luo Yu, Ms. Nancy Liliana Setiawan and Mr. Jun Wei for their participation on various experiments and simulations in this project. The research scholarship from the National University of iii Singapore, Department of Chemical and Biomolecular Engineering, is deeply acknowledged. Lastly but definitely not the least, I would like to truthfully express my thanks to my lovely wife, Mrs. Shima Najafi Nobar, and other family members for providing me inexhaustible support and love during my PhD study. iv Table of Contents Title page i Acknowledgements iii Table of contents Summary v viii List of Tables xi List of Figures xiii Nomenclature xxi Chapter 1: Introduction 1.1 Background 1.2 Overview of this thesis Chapter 2: Experimental and Computational Studies of Electrohydrodynamic Atomization process in Encapsulation Chamber for Pharmaceutical Particle Fabrication to Enhance the Particle Collection Efficiency 2.1 Introduction 12 2.2 Experimental observations 2.2.1 EHDA Setup, Materials and methods 2.2.2 Experimental design 2.2.3 Results and Discussion 2.2.3.1 Effect of solution flow rate 2.2.3.2 Effect of nitrogen flow rate 2.2.3.3 Effect of nozzle and ring voltages 2.2.3.4 Effect of electrical conductivity and polymer material 2.2.3.5 Particle size analysis 2.2.3.6 Concentration of residual DCM in particles 18 18 22 25 28 30 33 37 40 45 2.3 Computational studies 2.3.1 Mathematical model 2.3.1.1 Computational Fluid Dynamics (CFD) 2.3.1.2 Droplet Dynamics 2.3.1.3 Droplet Collision and Breakup Model 47 47 48 50 52 v 2.3.2 2.3.1.4 Electric Force Model 2.3.1.5 Initial Conditions for Particle Trajectory Simulations 2.3.1.6 Solvent Evaporation from Droplets Results and Discussions 2.3.2.1 Electric field Distribution 2.3.2.2 Particle Residence Time 2.3.2.3 Operational Parameters 54 55 57 59 59 60 64 2.4 The Effect of Auxiliary Electric Field (AEF) 2.4.1 Main zones in encapsulation chamber 2.4.2 Materials and methods 2.4.2.1 Electrical mobility 2.4.3 Results and discussion 2.4.3.1 Particle collection efficiency 2.4.3.2 Particle size and morphology 75 76 77 78 79 79 86 2.5 Conclusions 94 Chapter 3: Scaling analysis of the Electrohydrodynamic Atomization (EHDA) process for pharmaceutical particle fabrication 3.1 Introduction 3.1.1 Experimental studies of EHDA in the encapsulation chamber 3.1.2 Experimental studies of the fabrication of biomaterials by EHDA 3.1.3 Modeling studies on EHDA phenomenon 3.1.4 Critique of the State-of-the-Art 98 99 100 101 105 3.2 Describing equations 106 3.3 Scaling analysis 107 3.4 Use of scaling analysis to correlate the particle collection efficiency 113 3.5 Conclusions 117 Chapter 4: Computational and Experimental Studies of Electrospray Deposition Process in Pharmaceutical Micro-Pattern Formation 4.1 Introduction 119 4.2 Materials and Methods 4.2.1 Chemicals 4.2.2 Experimental procedures 4.2.3 Mathematical Model 4.2.4 Definition of PDE for mathematical model 122 122 123 126 134 vi 4.3 Results and Discussion 4.3.1 Deposition on the substrate 4.3.2 Simulation results 4.3.3 Deposition on the mask 134 135 142 145 4.4 Applying scaling analysis to electrospray deposition process 151 4.5 Conclusions 163 Chapter 5: Investigation of droplet distribution in EHDA encapsulation chamber using AC-based Electrical Capacitance Tomography (AC-ECT) system with internal-external electrode sensor 5.1 Introduction 5.1.1 ECT systems 5.1.2 ECT sensor 165 166 167 5.2 Experimental procedures 169 5.3 Results and discussion 5.3.1 Sensitivity maps 5.3.2 Results of water-air/DCM-air system 5.3.3 Results of EHDA process 171 171 173 179 5.4 Conclusions 180 Chapter 6: Conclusions and Recommendations 6.1 General conclusions 183 6.2 Recommendations for future works 188 Bibliography 192 List of Journal Publications 211 List of Journal Publications 213 vii Summary In the present work, Electrohydrodynamic Atomization was employed to produce biodegradable polymeric microparticles in a new generation of shuttle glass chamber. The effects of different operational parameters on the particle collection efficiency and residual amount of organic solvent in collected particles were investigated systematically. The Taguchi method was used to design the experiments. It was found that the important factors affecting particle collection efficiency were given in the following orders: solution flow rate, nitrogen flow rate, ring, and nozzle voltage. It was found that solution flow rate and nozzle voltage can considerably affect the size of fabricated particles. For all the trials, the residual DCM content of the particles fabricated using the EHDA method was well within the limit of safety standards at the end of process without engaging any additional freeze-drying process. A computational model (using FLUENT and COMSOL as computational fluid dynamic software) was developed in this study to simulate the fluid and particle dynamics in an EHDA chamber. It was found that nitrogen flow rate, solution flow rate and voltage difference between the nozzle and ring can significantly affect the particle collection efficiency of the EHDA process. Electric field and electric potential profiles in the chamber were significantly affected by the combined voltages of the nozzle and ring. The computational model developed in this study provided a means of understanding the various processes involved in particle fabrication using the EHDA methodology. In a new set of experiments, an additional aluminum plate was located a few centimeters above the collecting plate in EHDA chamber which was connected to positive high voltage generator. This work aimed to investigate the effect of the auxiliary electric field viii on particle collection efficiency, morphology and size distribution. The final results show that application of the auxiliary electric field can clearly enhance particle collection efficiency in comparison to the EHDA process without auxiliary electric field. Additionally, it was established that the particle size distribution was not considerably influenced by the auxiliary electric field. On the contrary, the smoothness of the particles can be affected by the auxiliary electric field especially when a high voltage is applied to the flat plate. Scaling analysis was used to assess the relative importance of the terms in the particle force balance. The collection efficiency of the EHDA process was determined from a force balance on the particles that in turn depends on the fluid dynamics and electric field. It led to a unique dimensionless group that permits collapsing all the experimental data for the effect on the particle collection efficiency of the carrier gas flow rate, liquid solution flow rate and electric field strength onto a generalized plot for which a cubic trendline fits the data with a coefficient of determination R  . Electrospray deposition on a substrate through a mask, to generate biodegradable polymeric particle patterns, was also considered in this study to investigate the effect of different operational parameters. Moreover, a mathematical model was developed to track the particle trajectories and focusing effect in electrospray deposition process on the substrate. The final results confirm that the clearest particle pattern and the best focusing effect on the substrate can be achieved with long distance between the nozzle and the substrate, high voltage difference between the nozzle and the mask, short process time and low solution flow rate. 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Computational and Experimental Studies of Electrospray Deposition Process in Pharmaceutical Micro-Pattern Formation. Chemical Engineering Science, 66 (2011) 3836-384. 4- Alireza Rezvanpour, Eldin Wee Chuan Lim and Chi-Hwa Wang. Computational and Experimental Studies of Electrohydrodynamic Atomization for Pharmaceutical Particle Fabrication. AICHE Journal, 2012, 10.1002/aic.13727. 5- Alireza Rezvanpour and Chi-Hwa Wang. The Effects of Auxiliary Electric Field within the Electrohydrodynamic Atomization Encapsulation Chamber on Particle Size, Morphology and Collection Efficiency. Powder Technology, November 2011 (submitted, under review). 6- Alireza Rezvanpour, William B. Krantz and Chi-Hwa Wang. Scaling analysis of the Electrohydrodynamic Atomization (EHDA) process for pharmaceutical particle fabrication. Chemical Engineering Science, October 2011 (submitted, under review). 211 7- Alireza Rezvanpour, Chi-Hwa Wang, Yung C. Liang and Wuqiang Yang. Investigation of droplet distribution in electro-hydro-dynamic atomization (EHDA) encapsulation chamber using AC-based electrical capacitance tomography (ECT) system with internal-external electrode sensor. Measurement Science and Technology, 23, 2012, 015301. 212 List of Conference Presentations 1- A. Rezvanpour, William B. Krantz and C.H. Wang. Design and Analysis of a Modified Electrospray Process for Fabricating Polymeric Nano- and Microparticles for Drug Encapsulation. AICHE Annual Meeting 2011, Minneapolis, USA. 2- A. Rezvanpour and C.H. Wang. Application of Auxiliary Electric Field in Electrohydrodynamic Atomization Encapsulation Chamber to Enhance Particle Collection Efficiency. AICHE Annual Meeting 2010, Salt Lake City, USA. 3- A. Rezvanpour and C.H. Wang. Simulation of Electrospray Particle Deposition Process in Pharmaceutical Micro-Patterning. AICHE Annual Meeting 2010, Salt Lake City, USA. 4- A. Rezvanpour and C.H. Wang. Enhancement of Particle Collection Efficiency in Electrohydrodynamic Atomization Processes for Pharmaceutical Particle Fabrication. Accepted for presentation, AICHE Annual Meeting 2009, Nashville, USA. 5- A. Rezvanpour and C.H. Wang. Simulation of Electrohydrodynamic Atomization for Enhanced Particle Collection Efficiency in an Encapsulation Chamber. Accepted for presentation, AICHE Annual Meeting 2009, Nashville, USA. 6- A. Rezvanpour and C.H. Wang. Electric Field Controlled Electrospray Deposition for Precise Micropattern Formation. Accepted for presentation, 8th World Congress of Chemical Engineering 2009, Montreal, Canada. 213 7- A. Rezvanpour and C.H. Wang. Applications of Electrical Capacitance Tomography for On-line Monitoring of Pharmaceutical Particle Fabrications. International Workshop on Process Tomography 2009, Tokyo, Japan. 214 [...]... used for pharmaceutical particle fabrication are expensive, higher particle collection efficiency is extremely desirable Therefore, research gap for the current study of pharmaceutical particle fabrication by electrohydrodynamic atomization (EHDA) process is particle collection efficiency The present work mainly aimed to develop a deeper understanding of the EHDA process for polymeric particle fabrication. .. vector, m s-1 up = particle velocity vector, m s-1 ud = droplet velocity vector, m s-1 mp= mass of the particle, kg md= mass of the droplet, kg Fq = columbic repulsion force, kg m s-2 FE = electrical field force, kg m s-2 Fb = buoyancy force, kg m s-2 Fg = gravitational force, kg m s-2 FD = drag force, kg m s-2 FB = thw body forces acting in the system, kg m s-2 C D = drag coefficient R p = particle radius,... each trial 23 Table 2.4 S/N ratio for levels of each factor and S/N differences between these levels where particle fabrication has been optimized 26 Table 2.5 Results of analysis of variance (ANOVA) for particle collection efficiency for each factor 27 Table 2.6 Estimated performance at the optimum conditions 28 Table 2.7 Summary of factors, levels, obtained results (particle size) and S/N ratio in... al., 1999), pharmaceutical productions (Ijsebaert et al 2001; Tang and Gomez 1994), and polymeric particle fabrications for drug encapsulation (Ding et al 2005; Rezvanpour et al 2010 ; Yao et al 2008 ; Farook et al 2007) With controlled solvent evaporation during the particle fabrication process, further enhancements in terms of narrow polydispersities and smooth, spherical morphologies of particles... between nozzle and ring on the particle size and particle collection efficiency (a) trial 7: voltage difference: 2.5 kV; average CE: 78.6%; particle size: 4-5 μm (b) trial 1; voltage difference: 2 kV; average CE: 75.8%; particle size: 5-6 μm (c) trial 15; voltage difference: 1.5 kV; average CE: 62.2%; particle size: 6-8 μm (d) trial 9; voltage difference: 1 kV; average CE: 63.5%; particle size: 8-10 μm Detailed... the particle distribution in cross-section of the chamber is important to control the particle collection efficiency Finally, Chapter 6 gives general conclusions and recommendations for future works 10 Figure 1.1: Schematic diagram of overview of this thesis 11 Chapter 2 Experimental and Computational Studies of Electrohydrodynamic Atomization process in Encapsulation Chamber for Pharmaceutical Particle. .. 2004), deposition of nanoparticle clusters (Jayasinghe et al 2004), micro/nano encapsulation (Loscertales et al 2002; Berkland et al 2004) and production of pharmaceutical particles (Ijsebaert et al 2001) Due to the recent emergence of the application of electrospray, only a few researchers are studying polymeric particle fabrication using electrospray It is reported that PLGA particles could be obtained... particle charge, C qd = droplet charge, C  q = the space charge density, C m-3 μ = the electric mobility of a charged particle ri = distance between the particle of concern and surrounding particles, m ri = unit vector showing the direction of the exerted repulsive force between the particles K = electrical conductivity, S m-1 I = current, C s-1  = liquid surface tension, N m-1  d = droplet surface... Direct dialysis method was developed for the simple preparation of drug carriers such as lipsomes and polymeric micelle (Jeong et al 2001) More recently, surfactant free nanoparticles of Poly (D, L-lactide-co-glycolic acid) or PLGA were prepared for controlled released drug delivery systems (Jeong et al 1998; Jeong et al 2003) Their work mainly focused on particle fabrication, characterization and in... Variation of arithmetic particle mean size versus solution flow rate for different nozzle voltages at ring voltage 6 kV and nitrogen flow rate 25 L/min 43 Figure 2.12 Variation of arithmetic particle mean size versus nozzle voltage for different solution flow rates at ring voltage 6 kV and nitrogen flow rate 25 L/min 44 Figure 2.13 Variation of residual concentration of DCM in collected particles versus nitrogen . PARTICLE FABRICATION VIA ELECTROHYDRODYNAMIC ATOMIZATION FOR PHARMACEUTICAL APPLICATIONS ALIREZA REZVANPOUR (M.S., B.S., Sharif. of Electrohydrodynamic Atomization process in Encapsulation Chamber for Pharmaceutical Particle Fabrication to Enhance the Particle Collection Efficiency 2.1 Introduction 12 2.2 Experimental. S/N ratio for levels of each factor and S/N differences between these levels where particle fabrication has been optimized. 26 Table 2.5 Results of analysis of variance (ANOVA) for particle