Good afternoon review committee my name is sean rickson and presenting alongside me are nathan chao and sean bayabado over the last semester we’ve created a new way to manufacture acetaminophen the pharmaceutical market is one of the largest industries in the world and continues to grow rapidly owing to increasing consumer health awareness improving distribution
Channels urbanizing lower middle income nations and the lasting effects of the pandemics analgesics are a class of drugs within the pharmaceutical market that have seen the most significant increase in demand over the last three years these drugs relieve pain and reduce inflammation with both prescription and over-the-counter products available acetaminophen is
Not only one of the most demanded analgesics but one of the most demanded over-the-counter drugs on the market a familiar brand is shown as tylenol the global acetaminophen market was valued in 2021 at an estimated 9.4 billion us dollars and it’s expected to reach nearly 15 billion us dollars growing at a staggering seven percent kicker the upstream sector is
Primarily focused on the formulation of active pharmaceutical ingredients or apis which is the drug component that produces the desired biological effect the api acetaminophen is going to be man is manufactured in powder form with bulk demand composing around 80 000 metric tons globally within this market manufacturing cost is a critical factor to success because
Consumer behavior is strongly dictated by price as such a clear economic opportunity is present to revolutionize acetaminophen manufacturing to be a cheaper and greener process the production process is historically and presently performed as a batch process however continuous manufacturing is thought to present a multitude of potential benefits spanning time and
Resource savings flexibility and control over reaction conditions which include concentration pressure and temperature it is proposed that a continuous process could be cheaper and more sustainable thus this project designs both a batch process and continuous process to determine whether and under what conditions the property benefits can be achieved the batch
And continuous plans are designed 30 000 metric tons per year of dry powder acetaminophen targeting 30 of global demand there are several routes for acetaminophen synthesis project authors recommended to focus on a process that begins with p nitrofunnel which undergoes hydrogenation to p aminophenol to which acidic anhydride is added to yield the api however
A thorough analysis of many synthetic pathways was conducted in an exercise to reduce cost and limit hazardous operation these reasons support the decision to procure from pmn phenol as opposed to manufacture the monaco molecule and begin with the acetylation step with this reaction pathway the first step in the synthesis is to acetylate pmenophenol this is
Done with acetic anhydride in excess and water to convert the acetic anhydride to acetic acid to optimize the ratio of reactants to achieve maximum yields multiple coupled variables were evaluated and are presented on the succeeding slide their optimization led to the most economical overall mass and energy balances which the values are shown here after making
Acetaminophen the solution is crystallized and filtered before being purified and then re-crystallized and dried the acetic acid solution as a byproduct is then distilled for resale now acetaminophen crystallization presents numerous challenges as a small molecule is polymorphic with five variations form 1 and form 2 are the only polymorphs that form under the
Operating conditions of this plant however consistent form 2 growth has not been achieved on a bulk scale to elute a purity higher than fifty percent whereas form one can obtain impurities greater than ninety nine percent thus this project will build on established processes of obtaining high purity form one crystals and this is the market standard to build the
Necessary balances it was important to make a sound decision on which composition to use presented in the five fingers one can see that solvent composition impacts solubility nucleation orders growth rates and purity optimizing these five variables it was found that the larger the solvent ratio the most overall benefit and an analysis revealed that an 8 to 2 ratio
Would result in the most crystal yield and from this the kinetic data was obtained with this composition following the balances to ensure all aspects of the process could be optimized a series of hand calculated numerical solutions were developed and linked the numerical solutions made use of thermodynamic first principles to keep consistent reaction profiles and
Conditions between processes as pricing became integrated into these sheets minimization functions ensured the process operated as efficiently as possible with those preceding calculations presented here is the complete batch flow diagram the plant’s staggering of reactors is not shown but the succeeding economic analysis accounts for having multiple of the same
Process units to optimize both time and cost to develop the continuous plant the following considerations were made many of the processes were kept identical but the reactors now used a cstr continuous stirred reactor model screw press filters and a fluid bed dryer very conservative estimations were also used for their respective throughputs here the continuous
Process is modeled one to one to the batch process the true novelty in this project is not displayed on any singular reactor rather the small changes made to each process that ensure purity and yield it is important now to highlight the optimizations that were completed for both processes for the batch a batch time of two hours was optimal for reactor sizing for
The continuous two cstrs and crystallizers were selected to ensure reaction control and fluidity even with the added capital cost for heating and cooling agents sodium chloride brine and calcium chloride brine were selected where the slightly increased operating costs were favored to minimize capital costs understanding the full plant development we can now present
The true economic superiority of the continuous process to elude some of the major cost differences the continuous process does not require intermediary storage vessels which total to 14.3 million dollars in the batch process and instead make use of cheap inline heat exchangers further the batch reactor and filter costs total to 35.2 million compared to the 29.9
Million of the continuous process this 20 percent difference is attributed to more efficient heat transfer leading to less equipment and smaller reactors in the continuous scheme further the batch process is 82 process units compared to the 69 for the continuous process additionally the continuous process also sees significant operation benefits with fewer moving
Parts the plant can run for a larger portion of the year and requires less maintenance additionally the process sections require two-thirds the number of operators compared to batch combined these benefits attribute to just over two million dollars in annual cost savings so at a price of four dollars a kilo the continuous process will see a 15-year npv of 38
Million with an irr of 33 compared to the grim 7.3 million and 18 for batch sensitivity analyses demonstrate that the continuous remains a more profitable investment across all the respective tested variables fixed costs were used as a proxy to plant scale to reach an understanding of what production conditions may prefer batch to continuous while the difference
Between batch and continuous irr appeared to converge as planned scale reduced it was found that even a 50 reduction in output showed continues to be 10 more profitable additionally if the economy of scale correlations used for the continuous process happened to be an underestimation of the actual cost the continuous process can become 50 percent more expensive
And still have an irr five percent greater than match recognizing the significant scale of this plant india was the chosen location and with wharton healthcare professors a plan to make partnership with ngos to facilitate community development was developed we also considered current good manufacturing processes with the design of the plant to ensure public safety
With our product and also ensure that we could receive approval from fda for sale in the us lastly given that we are producing powders it was important to ensure that dust does not impact workers health through the use of appropriate ppe dust collectors and de-dusting booths for further optimizations there is possibility for further exploration of semi-continuous
Processes to further reduce costs by integrating patch and continuous process units lastly to facilitate recalls resonance time distribution can ensure pseudo batches providing product protection it is recommended that future analyses gain true understanding of activated carbon needs and composition pilot scale tests should be performed to understand the degree
Of variability to the theoretical model additionally the pilot scale should include polymorph sensors and examine purity in summary not only does the continuous process result in lower equipment costs but it requires less maintenance and fewer operators the continuous process also offers more control over the temperature and reaction profile finally there is a
Greater ability to be flexible to demand fluctuations overall the positive social and environmental impact justifies further exploration of continuous manufacturing processes in the pharmaceutical industry all of this has the hope of lowering the price of generic drugs for all
Transcribed from video
Production of Acetaminophen By Sean Riksen
