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Refereed Articles
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Simon, L., Bolisetty, P. and Erazo, M.N. (2010), Dynamics of dissolution and diffusion-controlled drug release systems
, Current Drug Delivery, accepted.
Pharmaceutical companies are seeking new ways to manage product life cycles by developing innovative controlled-release devices. The name of the game is generic defense through sound reformulation strategies… And for market innovators timing is everything! Pharmaceutical industries are focusing on hydrophilic matrices to reformulate the drug, provide once-a-day dosing and achieve a desired release profile. These materials present several advantages, such as a cost-effective manufacturing process and suitability for a host of active pharmaceutical ingredients. However, the influence of the pertinent decision parameters (i.e., product and process quality attributes) on the steady-state drug penetration rate is difficult to assess in the current framework. This contribution introduces tools to modulate the rate at which drug molecules dissolve and diffuse in a polymeric system.
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Simon, L., Kanneganti, K., Simon, L. and Kim, K.S. (2010), Drug transport and Pharmacokinetics for Chemical Engineers, Chemical Engineering Education, in press.
Experiments in continuous-stirred vessels are conducted to introduce chemical engineering students to clinical pharmacokinetics. These activities are designed to enable students to use their knowledge of process dynamics in developing drug-dosage regimens that meet certain criteria. The projects can be incorporated into the curriculum to illustrate concepts learned in the classroom.
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Kimmel, H., Hirsch, L.S., Simon, L., Burr-Alexander, L. and Dave, R. (2009), Implementing concepts of pharmaceutical engineering into high school science classrooms, Chemical Engineering Education, 43, 187-193.
A Research Experience for Teachers (RET) program, to help high school science and technology teachers develop and strengthen skills and knowledge in research, science and engineering, is described.
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Kim, K.S. and Simon, L. (2009), Optimal intravenous bolus-infusion drug dosage regimen based on two-compartment pharmacokinetic models, Computers & Chemical Engineering, 33, 1212-1219.
There has been much written about ongoing investigation of drug safety, efficacy, pharmacokinetics and pharmacodynamics as clinicians tirelessly work to assure proper dosage of medicaments for patients. However, what is conspicuously lacking from the literature is a balanced discussion of the need to develop a sound computational framework that helps to critically evaluate the results of clinical studies. In this paradigm, the challenges of accurately prescribing drug doses and times of intake can be thoroughly addressed. The Simon group brings to light the development of user-friendly computer software for facilitating the design of optimal drug-dosage regimens. These programs will not only save time and money but will make it easier for clinicians, who may not be familiar with advanced mathematical tools, to determine appropriate administration protocols that meet patient needs.
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Simon, L. (2009), Timely drug delivery from controlled-release devices: Dynamic analysis and novel design concepts, Mathematical Biosciences, 217, 151-158.
Science Direct Top 25 Hottest Articles - Agricultural and Biological Sciences - Mathematical Biosciences; January - March 2009
Chemical permeation enhancers (e.g. oleic acid, polyethylene glycol, ethanol, acetone, etc.) are currently used by pharmaceutical scientists to increase percutaneous absorption of the therapeutic agent in a drug. Flexible polymers, such as EUDRAGIT® release products, are developed to help design drug-delivery devices that match a targeted release profile. Heat-aided and electrically-assisted mechanisms have also been applied to overcome the resistance of the stratum corneum thereby increasing the number of drugs that are delivered transdermally. This article suggests a dynamic framework and novel design concepts that will facilitate the control of both the appropriate flux and the rate at which a desired effect is achieved.
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Simon, L. and Goyal, A. (2009), Dynamics and control of percutaneous drug absorption in the presence of epidermal turnover, Journal of Pharmaceutical Sciences, 98, 187-204.
Scheindlin wrote*: "Very few companies, even "big pharma," possess the know-how and equipment to deal with the unusual ingredients involved, to work out the parameters needed to obtain the desired absorption rates, and to assemble the patches. Therefore, development and manufacture of these products are generally outsourced." This contribution suggests an optimum treatment protocol for the transdermal delivery of local anesthetics even when epidermal turonover is likely to reduce their absorption into the systemic circulation. Instead of prescribing short- and long-acting drugs after surgery, a single medicament can be prescribed and administered in a manner to control chronic and breakthrough pain. The suggested method relies more on the dose and administration schedules than on the process-design parameters.
*Transdermal drug delivery: PAST, PRESENT, FUTURE. Mol Interv. 2004 Dec; 4(6): 308-12.
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Simon, L. (2007), Analysis of heat-aided membrane-controlled drug release from a process control perspective, International Journal of Heat and Mass Transfer, 50, 2425-2433.
In an article entitled: "Transdermal Market: The Future of Transdermal Drug Delivery Relies on Active Patch Technology*" Jason McKinnie (Pharmaceutical Research Analyst for Frost & Sullivan) discussed how some companies are now developing active patches that rely on external sources of energy, such as heat, to overcome limitations associated with passive patches. However, because these technologies can no longer be explained in terms of passive diffusion, the Simon group has deployed new analytical tools and constructed the necessary framework designed to help with the development of clinical trial simulations. Our method can assist in the selection of optimum dosing strategies and the best trial design among equally viable alternatives, thus alleviating costly production delays. This contribution addresses the effect of heat on the delivery of drugs across membranes. We also show that, when a specific sequence of temperatures is applied to the skin, a desired delivery rate is achieved in a relatively short period of time. This optimum temperature profile is generated by an in-house computer program written explicitly for this purpose.
*Drug Delivery Technology, September 2006, Vol. 6, No. 8.
- Goyal, A. Mandapuram, S., Michniak, B. and Simon, L. (2007), Application of orthogonal collocation and regression techniques for recovering parameters of a two-pathway transdermal drug-delivery model, Computers & Chemical Engineering, 31, 107-120.
The estimation of critical pharmacokinetic parameters and the identification of drug delivery mechanisms are essential for medical breakthroughs. These initiatives are, however, cost- and time-prohibitive as they involve numerous laboratory experiments. This work proposes and tests computational methods to assess the contribution of particular pathways of transdermal drug penetration and to evaluate key physicochemical properties. The applications of this contribution range from cosmetic skin care to dermal toxicology.
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Gautam, S. and Simon, L. (2007), Prediction of equilibrium phase compositions and ß-glucosidase partition coefficient in aqueous two-phase systems, Chemical Engineering Communications, 194, 117-128.
This contribution offers predictive tools inspired by advances in artificial intelligence computing and the thermodynamics of polymer solutions to model the partitioning of biomolecules in Aqueous Two-phase Separation System (ATPS). The work promotes the industrial implementation of ATPS-based protein separation.
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Gautam, S. and Simon, L. (2006), Partitioning of ß-glucosidase from Trichoderma reesei in poly(ethylene glycol) and potassium phosphate aqueous two-phase systems: Influence of pH and temperature, Biochemical Engineering Journal, 30, 104-108.
Science Direct Top 25 Hottest Articles - Chemical Engineering - Biochemical Engineering Journal; April - June 2006
Beta-glucosidase was optimized in an Aqueous Two-phase Separation System (ATPS) based on conditions such as pH and temperature. Although tested on this particular enzyme, the methodology outlined can be adopted to help meet the world demand for pharmaceutical enzymes.
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Simon, L., Weltner, A.W., Wang, Y. and Michniak, B. (2006), A parametric study of iontophoretic transdermal drug-delivery systems, Journal of Membrane Science, 278, 124-132.
A method for extracting pertinent design information from iontophoretic transdermal delivery experiments is proposed and tested. The findings can help to accelerate the development and commercialization of iontophoretic products.
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Simon, L. and Loney, N.W. (2005), An analytical solution for percutaneous drug absorption: Application and removal of the vehicle, Mathematical Biosciences, 197, 119-139.
Science Direct Top 25 Hottest Articles - Agricultural and Biological Sciences - Mathematical Biosciences; October - December 2005
The penetration and distribution of drugs in the skin following application and removal of transdermal patches is studied. A user-friendly platform was created to help pharmaceutical industries and researchers to conduct a quick performance assessment of drug-delivery devices with a minimum number of experiments saving both time and money. This research will help manufacturers of controlled release devices to get their products from R&D to full-scale manufacturing.
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Fernandes, M., Simon, L. and Loney, N.W. (2005), Mathematical modeling of transdermal drug delivery systems: Analysis and applications, Journal of Membrane Science, 256, 184-192.
Science Direct Top 25 Hottest Articles - Chemical Engineering - Journal of Membrane Science; April - June 2005
A simulation environment is provided to investigate the relative impact of different physicochemical parameters on drug-release profiles. This research could lead to new formulation strategies to improve the safe delivery of a constant amount of drug through the skin.
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Loney, N.W., Huang, C. R. and Simon, L. (2005), Mathematical model of a counter current flow multi-fiber dialyzer, World Journal of Microbiology and Biotechnology, 21, 791-796.
Factors affecting the design and operation of countercurrent flow dialyzers are studied. The ensuing knowledge can be used to achieve greater efficiency in the treatment of hemodialysis patients.
- Simon, L. and Fernandes, M. (2004), Neural network-based prediction and optimization of estradiol release from ethylene-vinyl acetate membranes, Computers & Chemical Engineering, 28, 2407-2419.
A central question in transdermal drug formulation technology is addressed: What are the key membrane and solvent properties necessary to achieve a specific drug-release rate? This contribution offers a methodology, tested using estradiol, that promotes the transdermal absorption of drugs and facilitates the design of customized patches to meet the daily needs of consumers.
- Simon, L. and Gautam, S. (2004), Modeling continuous aqueous two-phase systems for control purposes, Journal of Chromatography A., 1043, 135-147.
An analytical approach was proposed to help improve the efficiency and yield of large-scale biopharmaceutical protein purification in aqueous biphasic systems (ATPS). The simulation platform makes it easy to identify, with minimal experimental trials, the optimal operating conditions for multi-component proteins. This approach has the potential to reduce production costs.
- Simon, L. (2005), Observing biomass concentration in a fixed-bed bioreactor, Chemical Engineering Communications, 192, 272-285.
This contribution focuses on the use of engineering-based strategies to improve pollutant removal efficiency in tubular-fixed bed bioreactors. Immediate industrial applications include the optimization of the rate of contaminant degradation in full-scale biofilters.
- Karim, M.N., Hodge, D. and Simon, L. (2003), Data-based modeling and analysis of bioprocesses: some real experiences, Biotechnology Progress, 19,1591-1605.
The use of advanced computational schemes, such as artificial neural networks and principal component models, in industrial settings are addressed in this contribution. These tools allow for quick data interpretation and the detection of trends and significant correlations among pertinent process variables. The result is a considerable reduction in the time-to-market of new products.
- Simon, L. and Loney, N.W. (2003), Mathematical modeling and process control of distributed parameter systems, Chemical Engineering Education, 37,126-131.
An application of Process Control principles relevant to distributed parameter systems, such as transdermal delivery of drugs, is outlined. The time required to reach a desired in-vivo flux can be estimated. This information plays a critical role in topical drug formulation and product development.
- Loney, N.W., Simon, L. and Gao, L. (2003), Trends in the applications of neural networks in chemical process modeling, Proceedings of the IndianNational Science Academy Part A (Physical Sciences), 69, 285-299.
Although Artificial Neural network-based modeling is widespread among academicians, the pharmaceutical industry has been reluctant to embrace it. This contribution outlines a range of relevant applications to promote industrial collaboration and acceptability.
- Simon, L. and Karim, M.N (2002), Control of starvation-induced apoptosis in CHO cell Cultures, Biotechnology and Bioengineering, 78, 645-657.
This contribution answers a basic question: Can starvation-induced apoptosis be delayed via manipulation of certain amino acids? A new perspective, applicable to the real-time control of apoptosis in bioreactors, is gained with the potential of increasing large-scale production of pharmaceutical products.
- Simon, L. and Karim, M.N. (2001), Identification and control of dissolved oxygen in hybridoma cell culture in a shear sensitive environment, Biotechnology Progress, 17, 634-642.
The productivity of mammalian cells is increased by ensuring an optimum supply of oxygen in the bioreactor. The procedures outlined have immediate application for bio-based industrial products and may help pharmaceutical plants to comply with GMP requirements.
- Simon, L. and Karim, M.N. (2001), Probabilistic Neural Networks using Bayesian decision strategies and a modified Gompertz model for growth phase classification in the batch culture of Bacillus subtilis, Biochemical Engineering Journal, 7, 41-48.
Reliable tools for accurate classification of growth cycles (i.e., lag, logarithmic, or stationary phase) in industrial fermentation processes are developed and tested using a B. subtilis strain. This work paves the way for cost-competitive fermentation technologies and allows for the timely addition of inducers in culture media.
- Simon, L., Karim, M.N., and Schreweis, A. (1998), Prediction and classification of different phases in a fermentation using Neural Networks, Biotechnology Techniques, 12, 301-304.
The growth cycles (i.e., lag, logarithmic, or stationary phase) in industrial fermentation processes are predicted (and correctly classified) within the first few hours. The operator can make informed decisions at an early stage in the process, which may save a pharmaceutical company millions of dollars.
- Simon, L. and Loney, N.W. (1996), An analytical solution for the concentration profile of a sublation process, Separation Science and Technology, 31,1019-1024.
An engineering-based approach to remove pollutant from wastewater is described. The performance of the aerator apparatus used can be evaluated a priori. This tool will assist companies to meet regulatory compliance requirements.
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