Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 1998 Process analysis and yield enhancement for the production of beta-hydroxy-beta-methyl-butyrate (HMB) George Barac Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Chemical Engineering Commons, and the Organic Chemistry Commons Recommended Citation Barac, George, "Process analysis and yield enhancement for the production of beta-hydroxy-beta-methyl-butyrate (HMB) " (1998). Retrospective Theses and Dissertations. 11594. https://lib.dr.iastate.edu/rtd/11594 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. 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This microform edition is protected against unauthorized copying under Title 17, United States Code. UMI 300 North Zeeb Road Ann Arbor, MI 48103 ii Graduate College Iowa State University This is to certify that the Doctoral dissertation of George Barac has met the dissertation requirements of Iowa State University Signature was redacted for privacy. Major Professorf^rof Signature was redacted for privacy. For the Major Pro] Signature was redacted for privacy. For the Graduate College iii To my parents, who always have taught me to aim high. To my sister, without whom I never would have come to the United States. To my wife, for being so incredibly supportive. iv TABLE OF CONTENTS CHAPTER 1. INTRODUCTION 1 CHAPTER 2. HMB APPLICATIONS AND IMPORTANCE 4 CHAPTER 3. PROCESS ANALYSIS 9 CHAPTER 4. THE HALOFORM REACTION 23 CHAPTER 5. SYNTHESIS OF p-HYDROXY-p-METHYL-BUTYRATE BY THE 28 HALOFORM REACTION CHAPTER 6. REACTION YIELD ENHANCEMENT 37 CHAPTER 7. STATUS-QUO OF THE EXTRACTION OPERATION 75 AND OPPORTUNITIES FOR IMPROVEMENT CHAPTER 8. CONCLUSIONS AND RECOMMENDATIONS 105 APPENDIX A. PROPERTY ESTIMATION 117 APPENDIX B. SETUP AND PROCEDURE USED IN THE LIQUID 121 EXTRACTION EXPERIMENTS APPENDIX C. SETUP AND PROCEDURE USED IN THE 123 REACTION KINETICS EXPERIMENTS APPENDIX D. ANALYTICAL PROCEDURE FOR THE 125 DETERMINATION OF AVAILABLE CHLORINE IN BLEACH SOLUTIONS REFERENCES 126 ACKNOWLEDGMENTS 132 1 CHAPTER 1. INTRODUCTION The development of a viable manufacturing process is a complex task that must address and solve a plethora of problems related to the individual steps to full-scale market production. The ultimate purpose of the activities that constitute the development of a process is usually to create a product that can be sold at a profit. The magnitude of the profit depends on the market value of tiie product itself, the scale of production and manufacturing costs. Once product value is established by the market, the only means to maximize profits are to increase the production scale and to minimize production costs. However, in most cases, the scale of production is imposed by market demand, so reduction of manufacturing costs becomes the principal target to boost profits. Also, decreasing sales price is often a factor that greatiy influences the penetration of the product in all potential markets. Evidentiy, the type, structure and efficiency of the manufacturing process are key elements that affect both the profit itself and the very fate of the product on the market. An efficient, coherent process will insure stable, good quality production and will allow the manufacturer to explore new markets and new uses. But, in addition to this, any process, no matter how efficient or profitable, will not be acceptable if environmental standards are not met. From this perspective, the development of a chemical process has to take into consideration a variety of aspects that are related to the setup of the manufacturing facility, the mode of operation, the type of equipment used, the nature and 2 degree of hazardousness of the reagents, auxiliary materials, by-products and waste, recovery/reuse of materials as opposed to disposal etc. Therefore, for a process to be viable, both aspects of efficiency and environmental acceptability must be assessed in conjunction with each other. The task of elaborating a chemical process becomes even more complicated when the product is new and is to be produced at a low to intermediate scale. One reason for this is that all development activities must "start from scratch", with very limited physical and thermo-chemical information and with almost non-existent design data. Moreover, the reduced production scale and unsecured market dramatically increase the importance of issues such as yield, which is directly related to cost per unit product and overall materials and energy efficiencies. A typical example in this respect is the manufacture of p-hydroxy-p-methyl- butyrate (HMB) for human consumption as a nutritional supplement or as an animal feed additive. HMB, labeled as a protein breakdown suppresser, is being manufactured for Metabolic Technologies, Inc., (MTI), a company located in Ames, Iowa. The current process, comprising three major steps-reaction of diacetone alcohol and sodium hypochlorite, separation of the product by batch, cross-current extraction and crystallization-displays very low efficiency and has to deal with hazardous reagents and by-products. Currently, the high costs related to this process, as well as the environmental safety problems associated with it negatively infringe upon the price of the product on the human market and constitute the main obstacle in the way of exploiting the animal 3 market. The purpose of this project is to develop an optimum chemical process philosophy for the manufacture of HMB, using the existing synthesis and purification schemes as a starting point. Process analysis and improvement will be performed as a means to increase overall efficiency and to address environmental concerns. The first two steps, reaction and extraction, will be studied in detail as they are of crucial importance for the outcome of the entire operation. Finally, the findings of this investigation will be used to propose several process schemes that could lead to dramatic improvements in overall yield, product purity and material costs. 4 CHAPTER 2. HMB-APPLICATIONS AND IMPORTANCE 2.1. The Role of HMB in the Human and Animal Metabolism P-hydroxy-P-methyl-butyrate is one of the latest and most successful dietary supplements available today. The increasing attention and popularity it has gained in recent years stem from its wide range of uses and from the fact that it is a natural compound, being consumed and produced by the human body. In an era of mounting awareness and concern regarding the effectiveness, potential side-effects and health hazards associated with new drugs, HMB stands out as a powerful and safe nutrient for both humans and animals. HMB (also known as P-hydroxy-isovaleric acid) plays a key role in muscle protein synthesis and protein breakdown, as a metabolite of the amino acid leucine. Initially, this role was attributed to leucine, a branched-chain amino acid (BCAA). Certain studies showed that leucine, as well as other select BCAA, have anabolic effects similar to those of insulin. Thus, for example, it was proven that heart protein synthesis increases by approximately 40% when leucine alone or all of the amino acids are increased between 1 and 5 times the normal concentration [1]. Similar findings were observed in liver slices and skeletal muscle preparations, and the use of leucine was suggested for the treatment of chronic liver disease. Other studies have shown variable results in the benefits of supplementing leucine, isoleucine and valine, during stressful situations such as infections and trauma. Additionally, several investigators inferred that 5 plasma amino acids, and BCAA, in particular, have a role in regulating the rates of whole body and regional protein turnover. However, dietary leucine supplementation in pigs, fish and lambs did not generate an increase in muscle growth. Moreover, higher levels of leucine in humans indicate little or no effect on muscle mass or strength.