AC 2012-3298: WORKSHOP MODULES ON PHARMACEUTICAL ENGI- NEERING FOR UNDERGRADUATE EDUCATION

Dr. Stephanie Farrell, Rowan University

Stephanie Farrell is an Associate Professor in chemical engineering at Rowan University. Prior to joining Rowan in 1998, she was an Assistant Professor in chemical engineering and Adjunct Professor in biomed- ical engineering at Louisiana Tech University. She received her bachelor’s, M.S., and Ph.D. degrees in chemical engineering from the University of Pennsylvania, Stevens Institute of Technology, and New Jer- sey Institute of Technology, respectively. Farrell’s educational interests are in laboratory development and experiential learning, particularly in the areas of biomedical and sustainable engineering.

Dr. C. Stewart Slater, Rowan University

C. Stewart Slater is a professor of chemical engineering and Founding Chair of the Chemical Engineering Department at Rowan University. He has an extensive research and teaching background in separation process technology with a particular focus on membrane separation process research, development and design for green engineering, and pharmaceutical and consumer products. He received his Ph.D., M.S., and B.S.in chemical and biochemical engineering from Rutgers University. Prior to joining Rowan Uni- versity he was a professor at Manhattan College.

Dr. Zenaida Otero Gephardt, Rowan University Dr. Mariano Javier Savelski, Rowan University

Mariano J. Savelski is a professor in the Chemical Engineering Department at Rowan University, Glass- boro, N.J.. His research and teaching interests are in optimizing processes for water and energy reduction; lean manufacturing in food, consumer products, and pharmaceutical industry; and developing renewable fuels from biomass. He received his Ph.D. in chemical engineering from the University of Oklahoma, M.E. in chemical engineering from the University of Tulsa, and B.S. in chemical engineering from the University of Buenos Aires. Page 25.1500.1

c American Society for Engineering Education, 2012

Workshop Modules on Pharmaceutical Engineering for Undergraduate Education

Page 25.1500.2 Abstract

This paper will describe workshop modules developed for use at the ASEE-Chemical Engineering Division (CHED) 2012 Summer School. These materials will introduce faculty to the essential concepts of pharmaceutical engineering in a way that they can be easily integrated into the undergraduate curricula at their home institution. This will be accomplished through interactive exercises where workshop participants will learn new concepts and be engaged in seeing how they can improve the courses they teach. We will use the approach that we have practiced at Rowan University, to integrate concepts of new technologies into the traditional undergraduate chemical engineering curriculum through laboratories/demonstrations, in- class/homework problems, and case studies. The proposed modules are self contained and attendees may choose to participate in any or all modules depending on their interests.

Introduction

Over the past several years Rowan University faculty members have been engaged as Educational Outreach Partners with the NSF-sponsored ERC on Structured Organic Particulate Systems hosted by Rutgers University (with member schools: New Jersey Institute of Technology, Purdue Univ. and Univ. Puerto Rico-Mayaguez). Our goal has been to develop and disseminate undergraduate materials related to pharmaceutical technology and seek ways to integrate this into the curriculum 1, 2, 3. We have had positive assessment results from our own pilot testing at Rowan University and with the use of some of the materials in the Freshman Chemical Engineering course at the State University of New York-Stony Brook 4. We have disseminated some of our results through ASEE conference papers, and some of the problem sets described in this paper will be used in the next edition of Felder, Rousseau and Newell, Elementary Principles of Chemical Processes, 4th ed 5.

Our current efforts are to expand our dissemination through the ASEE Chemical Engineering Division (CHED) Summer School. This will help extend the reach of our materials to an audience of educators early in their careers who will be able to directly impact the students that they teach. The Summer School is held every five years and attracts faculty from across the country to learn about new approaches to engineering education. This is done through workshops and lectures on various topics, from K-12 outreach to senior design courses.

The pharmaceutical industry employs one in eight chemical engineers, second only to the chemical process industry. The expanding role of chemical engineering in pharmaceutical production demands the inclusion of pharma-related concepts in chemical engineering courses throughout the curriculum. Successful curriculum improvement requires a new approach to integrating concepts of batch processing, solid-liquid separation techniques, solid-solid particulate processing, drug formulation and delivery, and technology at the nano-scale. Students must possess a solid grasp of chemical engineering fundamentals and the perspective necessary to work successfully side-by-side with pharmacists, pharmacologists, medicinal chemists, and materials chemists in this highly multidisciplinary field.

The field of pharmaceutical engineering is quite broad and involves the manufacture of the active Page 25.1500.3 pharmaceutical ingredients (API) and drugs in the final dosage form as well as their therapeutic delivery. The interface of pharmaceutical science and chemical engineering is crucial for understanding the basis of structured organic particulate systems (SOPS), a term that describes the multicomponent organic system that comprises a drug, nutraceutical, or medicine formulation.

The workshop modules proposed for the 2012 Summer School will introduce faculty to the essential concepts of pharmaceutical engineering in a way that they can be easily integrated into the undergraduate curricula at their home institution. This will be accomplished through interactive exercises where workshop participants will learn new concepts and then be engaged to explore ways to improve the courses they teach. We will use the approach that we have practiced at Rowan University, to integrate concepts of new technologies into the traditional undergraduate chemical engineering curriculum through laboratories/demonstrations, in- class/homework problems, and case studies.

Workshop Modules

Incorporating Pharmaceutical Engineering Concepts into the Lower Level Curriculum

This workshop module consists of an interactive presentation integrated with example problems and demonstrations to teach concepts of pharmaceutical engineering relevant to material and energy balances. An introduction will include an overview of the pharmaceutical industry with a particular focus on drug development. This will be followed by a discussion of active pharmaceutical manufacture, drug formulation and drug delivery. The introductory lecture materials have been developed into a Powerpoint® slide set comprised of over 30 slides (Figure 1). The workshop will conclude with a breakout session in which participants work to modify a course they teach.

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Figure 1. Example introductory slide illustrating complex organic structure of a drug tablet showing active pharmaceutical ingredient (API) and excipients.

The active learning exercises and demonstrations can be used directly in a material and energy balance course or in a freshman engineering course. These educational materials convey essential concepts in pharmaceutical terminology, drug delivery, and manufacturing within the context of a material and energy balance calculation. For example, one problem explores the role of active pharmaceutical ingredient (API) and excipients (binders, filler, lubricants) in the formulation of drugs through unit conversions and mass/mole/volume composition problems. The accompanying demo shows how to compare total mass of a drug to its active ingredient dose and then use a medical formulary to determine the role of the excipients. A related experiment explores the effect of excipients and drug loading on the drug release rate from a tablet.

The following sample problem /experimental demo illustrates Higuchi model for API release using a caffeine dissolution experiment6. This type of demo can be performed with caffeine tablets, 2 liter beaker of water, and a spectrophotometer.

Higuchi Model for Drug Release Rate

The following data was gathered from an experiment in which a caffeine tablet weighing 1.2 g was dissolved in a beaker with 2 liters of water. The caffeine is released through a polymer matrix in the tablet so that the release of caffeine follows the Higuchi model:

Where M is the mass of the drug released in mg, D is the diffusivity constant, CSat is the concentration at saturation in mg/ml, CTot is the total possible concentration in mg/ml, and t is time in minutes. D, CSat, and CTot are constants.

Samples of the water were taken at different times and evaluated for concentration with the use of a spectrophotometer. After 140 minutes, the tablet was completely dissolved. a) Given the data below and the relationship between M and t expressed by the Higuchi model, calculate the time (min) it takes for 95% of the caffeine that is released to be released into the beaker?

Mass of Caffeine Time Released (min) (mg) 20 22.648 40 61.428 60 92.578 80 116.164 100 127.936 120 141.578 140 153.088

b) Caffeine made up what percentage of the tablet’s mass? (Assume all of the caffeine was

released into the water.) Page 25.1500.5

c) What would be the units on the diffusivity constant?

Solution

a) How long does it take for 95% of the caffeine that is released to be released into the beaker?

The total mass of caffeine released is 153.088 mg. (From table given at 140 min when the tablet was completely dissolved) 95% of the caffeine released is:

The Higuchi model gives the relationship between the mass released and time and can be rewritten in the following form:

This shows there is a direct relationship between M and t1/2.

is a constant because D, CSat, and CTot are constants.

Because values for D, CSat, and CTot are not given, the data must be used to find the proportionality constant.

Mass of Caffeine Time t1/2 Released (min) (min1/2) (mg) 20 4.472136 22.648 40 6.324555 61.428 60 7.745967 92.578 80 8.944272 116.164 100 10 127.936 120 10.95445 141.578 140 11.83216 153.088

Plot mass of caffeine released (M) vs. t1/2.

The trend line gives the relationship between mass released and the square root of time:

Where M is mass in mg and t is time in minutes.

Page 25.1500.6 Using the value of 145.4336 mg for M and solve for t to find how long it would take for 95% of the caffeine to be released:

b) Caffeine made up what percentage of the tablet’s mass?

Caffeine contributes to 12.8% of the tablet’s mass.

c) What would be the units on the diffusivity constant?

Rearrange the Higuchi model to solve for D:

Insert the units and cancel:

The workhsop module also provides training on how to use PharmaHUB (www.PharmaHUB.org), the pharmaceutical training and education web site, to access materials developed by schools across the county. Most of the teaching resource materials provided on PharmaHUB are in a format that can be easily utilized in courses (Powerpoint presentations, etc). The example problems developed on material and energy balance calculations used at the workshop are available through PharmaHUB as shown in Figure 2. If someone is teaching a course in another topic, such as fluid transport, this can be easily accessed through the Tags and the Particle and Powder Flow module will be displayed.

We will conclude our workshop session by asking faculty to form small groups and we will work with them to develop some educational materials or help them adapt those from PharmaHUB for the courses they teach. This way they will have an action plan for course integration.

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Figure 2 Screen image of PharmaHUB accessing a course module for problem sets related to integrating pharmaceutical concepts into introductory chemical engineering courses (www.Pharma HUB.org).

V-Mixing: An Introduction to Powder/Particulate Mixing and Design of Experiments (DOE)

V-mixers are commonly used in the pharmaceutical industry to mix powders. The mixing of large amounts of excipients with relatively small amounts of active ingredients, and the strict requirements associated with pharmaceutical products make V-mixing an important component in pharmaceutical processing. V-mixing technology provides an important opportunity to expose students to the pharmaceutical industry, powder and particulate technology, and to the challenges in developing accurate measures of mixing quality. In general, V-mixing will be a new technology for students and it is possible to capitalize on the unusual nature of the process to engage and interest students in aspects of the experimentation, measures of mixing quality and statistical data analysis. This workshop module offers participants tools to use V-mixing technology as a means to familiarize students with powder technology and to introduce students to design of experiments (DOE).

The module will start with an interactive discussion on the background of V-mixers and V- mixing technology. Through interactive group exercises, the powder properties and process parameters associated with V-mixing operations will be identified and ranked according to their Page 25.1500.8 likely impact on mixing quality. Three variables will be investigated: percent loading, particle loading order, and number of mixer revolutions. The mixing process will be illustrated using small, clear V-mixers with pneumatic powered motors. Figure 3 shows one of the mixers designed and constructed for the workshop. The mixers were constructed from 4 in diameter Lexan® tubes (1/8 in thickness) with a 40° angle.

Figure 3. V-mixer with pneumatic motor

A lid was especially designed to ensure a closed system and for ease of mixer loading and cleaning. Figure 4 and Figure 5 show the lid and the lid assembly including the rubber gasket.

Figure 4. V- mixer lid assembly

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Figure 5. V-mixer lid fully assembled.

Two powders will be used: NaCl and silica powder. This will allow for the use of solution conductivity as a measure of salt concentration in samples, and this measurement will be used to quantify mixing quality.

The module also will include an introduction to experimental design. Factorial designs, the simplest of experimental designs, will be used to develop a series of experiments that will allow the investigation of the effects of the three variables discussed above on mixing quality. The experiments will be divided among workshop groups and each group will carry out the appropriate experiments. The data from all groups will be combined and analyzed using Statgraphics® software.

At the conclusion of the workshop module, participants will be familiar with V-mixing technology and be able to integrate a self-contained powder technology/V-mixing module in appropriate courses. They will have information on how to design and build a small V-mixer for laboratory and demonstration use. In addition, they will be able to introduce experimental design to students in any course.

Sustainability Analysis of Pharmaceutical Synthesis and Process Design

The pharmaceutical industry has one of the highest waste generation rates per pound of product produced and the highest amount of organic solvents used per pound of product produced for any commercial sector. Typical waste streams from drugs made through organic synthesis contain over 80% organic solvents. The majority of drug products made through organic synthesis routes require many sequential reaction steps, large quantities and multiple organic solvents (with varying degrees of toxicity), and are made in batch processes 7. Among the processes that generate liquid waste streams containing the organic solvents are crystallization, extraction, and solid washing and cleaning processes as well as byproducts from inefficiencies in the reactions. Solvent waste released in the air as VOC’s is produced from the solid active pharmaceutical ingredient (API) drying processes, tableting and coating operations, and from fugitive emissions from the manufacturing process. These solvents also result in wastes released into the environment through the life cycle of their production and disposal which extend beyond the pharmaceutical plant boundaries but significantly impact the environment in a negative way 8, 9. Page 25.1500.10

This Workshop module will consist of a session that uses a case study in drug manufacture to illustrate how a sustainability analysis is performed and how to select the design with the lower overall carbon footprint. Through this session attendees will understand the key issues driving green chemistry and engineering solutions in process design and sustainability analysis. A tutorial will be conducted to show how a life cycle assessment is performed in a process and the key issues such as defining the boundaries of the system and calculating the appropriate life cycle inventory data for all chemicals involved in the analysis (Figure 6). The software package, SimaPro 7.2® (PRé Consultants, Amersfoort, Netherlands), is used to determine life cycle inventories for the raw materials, energy and waste. The case study developed involves the production of the active ingredient in aspirin, acetylsalicylic acid (Figure 7 ). The version presented at the workshop can be used in a condensed format for lower level instruction or expanded for upper level process design classes. The tutorial shows how changes made in manufacturing, e.g., recycling byproducts, can lead to environmental impacts well beyond the production plant and define the true carbon footprint of a manufacturing operation (Figure 8).

Figure 6. Example slide from LCA tutorial showing the stages in life cycle assessment that are analyzed from extracting the raw materials used to make a product to the product’s final disposal.

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Figure 7. Introductory slide for the case study to determine the life cycle assessment to produce on 1 kg of acetylsalicylic acid, the API in aspirin. The input raw materials: acetic anhydride, toluene, salicylic acid; waste produced: acetic anhydride, acetic acid.

Figure 8. Life cycle assessment output showing comparison between manufacturing with and Page 25.1500.12 without waste recovery.

Summary

Modular educational materials have been developed for pharmaceutical engineering to be included in the ASEE CHED Summer School. A tutorial on pharmaceutical engineering with introductory course material supported by example problems and demonstrations has been developed. An introduction to pharmaceutical engineering problem set includes over 50 examples for a material and energy balance course mapped to individual course topics. Simple demonstrations in drug delivery be effectively and combined with illustrative example problems. A small-scale V-mixer experiment is used to demonstrate a unit operation common to powder mixing in drug formulation. The demonstration integrates topics from particle properties to design of experiments. A tutorial on life cycle assessment demonstrates how to use life cycle modeling software and apply it to the manufacture of the active ingredient in aspirin.

Acknowledgements

This project has been supported by a National Science Foundation Engineering Research Center grant, NSF grant #ECC0540855

References

1 Savelski, M.J., Slater, C.S., Del Vecchio, C.A., Kosteleski, A.J., Wilson, S.A., “Development of Problem Sets for K-12 and Engineering on Pharmaceutical Particulate Systems,” Chemical Engineering Education, 44, 50-57, 2010 2 McIver, K. Whitaker, K. DeDelva, V. Farrell, S. Savelski, M. J. Slater C. S. “Introductory Level Problems Illustrating Concepts in Pharmaceutical Technology,” Advances in Engineering Education, 5 (1) 2011 3 Otero Gephardt, Z. Farrell, S. Savelski, M.J. Slater, C.S. Rodgers, M. Kostetskyy, P. McIver, K. Diallo, H. Zienowicz, K. Giacomelli, J. DeDelva V. “Integration of Particle Technology with Pharmaceutical Industry Applications in the Chemical Engineering Undergraduate Curriculum and K-12 Education,” Proceedings of the 2011 American Society for Engineering Education Annual Conference, Vancouver, BC, June 2011. 4 Farrell, S. Slater, C.S. Savelski, M.J. Calvo W.J. “Introductory Level Textbook Problems Illustrating Concepts in Pharmaceutical Engineering,” Proceedings of the 2011 American Society for Engineering Education Annual Conference, Vancouver, BC, June 2011. 5 Felder, R. M., Rousseau, R. W., Newell, J.A., Elementary Principles of Chemical Processes, 4th ed. , John Wiley & Sons, Hoboken, NJ, 2012 6 Farrell, S. Savelski, M. Slater, C.S. De Delva, V. Kostetskyy, P. McIver, K. Whitaker, K. Zienowicz, K. “Problem sets on Pharmaceutical Engineering for Introductory Chemical Engineering Courses - Part III,” PharmaHUB, 85 pp, May 2011 7 Slater, C.S., Savelski, M.J., A Method to Characterize the Greenness of Solvents used in Pharmaceutical Manufacture,” Journal of Environmental Science and Health, Part A, 42, 1595-1605, 2007 8 Slater, C.S., Savelski, M.J. Carole, W.A. Constable, D.J.C. “Solvent Use and Waste Issues,” Chapter 3, in Green Chemistry in the Pharmaceutical Industry, P. Dunn, A. Wells, T. Williams, Eds., Wiley-VCH Verlag Publishers, Weinheim, Germany, 49-82 2010, 9 Raymond, M.J. Slater, C.S. Savelski, M.J. “LCA Approach to the Analysis of Solvent Waste Issues in the Pharmaceutical Industry,” Journal of Green Chemistry, 12, 1826-1834, 2010. Page 25.1500.13