Lab Module 11 SYNTHESIS OF ASPIRIN

SCENARIO Hofmann Pharmaceutical Company makes generic pharmaceutical products, which it markets under its own brand names, and they also sell their products to other companies that market them under their brand names. A generic drug is a drug for which the patent has expired and which is not sold under the original brand name. For instance, acetaminophen was patented by McNeil PPC, Inc. and sold under the brand name, Tylenol. When the patent expired (17 years after patent was granted), acetaminophen could be made and sold by any company after getting FDA (Food and Drug Administration) approval. When acetaminophen is sold under any name but Tylenol, it is referred to as a generic drug. http://www.enotes.com/how-products-encyclopedia/aspirin/print Aspirin Synthesis In this module, aspirin will be synthesized. Aspirin is a generic name, like acetaminophen. Generic drug names are not usually systematic chemical names. From the name aspirin, there are no rules by which one can determine the chemical structure of aspirin. A systematic chemical name for aspirin is acetylsalicylic acid, which is made by reacting salicylic acid with acetic anhydride, using sulfuric acid as a catalyst.

Whats in a Drug Tablet? When you take an aspirin tablet, the tablet contains more than aspirin. Aspirin is referred to as the active ingredient in an aspirin tablet. (Some pharmaceutical products have more than one active ingredient.) A tablet is a convenient way to take a drug. The other ingredients (called excipients) in a drug tablet are added to make the powdered mixture flow into a tableting machine, to keep the compressed tablet from sticking to the tableting machine, and to cause the tablet to rapidly break up in the stomach so that the active ingredient can be absorbed by the body. Some tablets (such as ibuprofen) are coated to avoid a bad taste. Others are coated so that they will go through the stomach and break up in the intestine. There are generally four to ten processing steps in making drug tablets. Originally, in 1899, aspirin was sold as a powder in paper wrappings, like in BC Powder. Hofmann Pharmaceutical is involved in all phases of the manufacture of drugs that they market. They do all the tableting and packaging of their products. They synthesize the active drug ingredients, e.g., aspirin. In the case of aspirin, they also synthesize the salicylic acid and the acetic anhydride used to make aspirin. They make the salicylic acid because they can make salicylic acid more cheaply than they can purchase it. They make the acetic anhydride, because they have a large amount of acetic acid solution after the aspirin is made, and they can convert the acetic acid from this solution back into acetic anhydride. FDA Regulations The FDA requires that all aspects of drug manufacture be carried out under Good Manufacturing Practices (GMP). GMPs are regulations made by the FDA regarding the manufacture of drugs (active ingredients and tablet, liquid or emulsion consumer products). Records must be kept of the weights of all chemicals (raw materials) fed into each batch of a processing step, plus records of which Lot No. of a purchased raw material was used in each batch. Certification of all raw materials must be done either by the raw material producer or the drug company. Records of analyses performed in the quality control laboratory and records of each batch process step of the drug synthesis must be saved for five years. These records are kept for investigation purposes, should any product batch be found defective. The number of analyses required on active drug compounds is much higher than for other chemicals produced by the chemical industry. The final active drug will have from 12-15 analyses, all with specifications that must be met. The drug tablets must also be assayed for amount of active ingredient, and for bioavailability. Bioavailability is determined by giving patients the drug tablet and then drawing blood at certain times. The blood is then analyzed to determine the blood level of the active ingredient. Bioavailability is a type of performance test. 2

The Aspirin Production Process There are two parts to the aspirin plant: (1) the reactor in which the reaction takes place, and (2) the product recovery area. Lets look each section. A process flow diagram is on page 6. The Reactor The operator first pumps 950 gallons of acetic anhydride from the acetic anhydride storage tank, whose contents had been approved, into the 2000 gallon reactor. The reactor agitator (stirrer) is then turned on. A charge of 25 gallons of approved concentrated sulfuric acid, the reaction catalyst, is then added to the reactor by applying nitrogen pressure to the 25 gallon sulfuric acid charge pot. Handling Solids Solids handling poses a problem for chemical plants. Liquids and gases are much more suitable for a chemical plant, simply because they are fluids and can be pumped through piping from one place to another. Salicylic acid, one of the reactants for making aspirin, is a solid. The salicylic acid is received in 1000 lb net bins from the salicylic acid area of the Hofmann plant. The salicylic acid is certified and labeled APPROVED before being sent to the aspirin production area. The bins are weighed, hoisted by a motor to the top of the reactor, attached to the reactor and emptied. Then the bin is lowered and reweighed to get the net weight of salicylic acid. Five bins must be emptied into the 2000 gallon reactor for each batch. This procedure is much more difficult than adding the acetic anhydride, which can be done by setting a flow meter to 950 gallons and then turning on a pump. The operator enters the weight of salicylic acid and gallons of acetic anhydride into the log book along with the time and date. (S)he then initials the entry. The operator does this after each operation in the process. The reactor is a glass-lined reactor, glass being suitable for the acidic reaction mass (contents of the reactor). The reactor has coils inside the reactor through which steam flows in order to heat the reactor. The steam valve is actuated by a temperature controller (thermostat) set to keep the reactor temperature at 100C. The reaction is allowed to ride for fifteen minutes after the reaction mass reaches 100C. Then the steam valve is turned off and cooling water (ambient temperature) is circulated through the coils to bring the temperature of the reaction mass down to 40C. The reaction mass is then transferred to another vessel, called a crystallizer. Steam Producing Boilers The white smoke seen coming out of chemical plants is simply a cloud formed when steam is released from the boiler. It is not air pollution. The steam boiler is like a pressure cooker. The steam boiler has a pressure control valve set at maybe 50 psig (138 C steam). (Psig is gauge pressure. Like with a tire pressure gauge, its the pressure above atmospheric pressure.) When the pressure exceeds 50 psig, some steam is released, just like with a pressure cooker (generally set at about 5 psig, 109C). The relationship between pressure and temperature of the steam is simply the temperature at which the vapor pressure of water equals the set pressure, in other words, the boiling point of water at the set pressure). Chemical engineers jargon is 50 pound steam. Aspirin Process Flow Diagram (PFD) 3

Salicylic Acid Bins Acetic Anhydride Storage Tank 10 000gal Aspirin Reactor 2000 gal Crystallizer 12 000 gal Dryer Centrifuge

Clean Room Packaging

The Product Recovery Area The Crystallizer The crystallizer is a vessel similar to the reactor. It is called a crystallizer because that is its function. The crystallizer is a jacketed 12 000 gallon glass-lined vessel. While the reaction is taking place, 9 500 gallons of water are pumped into the crystallizer. The agitator is turned on and -25 C brine (CaCl2 solution) is circulated through the reactor jacket to bring the temperature of the water down to 5C. (CaCl2 is used instead of NaCl because the lowest temperature a NaCl solution can reach is -21 C, whereas a CaCl2 solution can be kept liquid to -55C.) When the reaction mass of the reactor reaches 40 C or lower, it is pumped to the crystallizer. A large excess of acetic anhydride, relative to the salicylic acid, was added to the reactor in order to drive the equilibrium reaction to completion. Any salicylic acid remaining after the reaction is difficult to remove, because both salicylic acid and aspirin are insoluble in water. In order to produce pure aspirin in one crystallization, there must be very little salicylic acid left after the reaction. The excess acetic anhydride reacts quite exothermically with the water in the crystallizer to produce acetic acid. The pumping of the reaction mass is temperature controlled at <10 C, because aspirin reacts with water to produce salicylic acid and acetic acid. Keeping the temperature low minimizes this undesirable reaction. Environmental Activity At the waste water treatment system at a chemical plant, and at municipal waste water treatment plants, the organic compounds are broken down in activated sludge systems. (Human waste contains primarily organic compounds and water.) In this system, bacteria (microbes) developed for this purpose metabolize (eat) the organic compounds and make more microbes which are filtered out and land filled. This process is an aerobic process, which means it needs oxygen or air. There are big aeration pumps in the treatment ponds, pumping in large amounts of air, producing the fountain effect. The pH of the waste water must be controlled at slightly above seven. So, before acidic streams can be added to the activated sludge ponds, they must be neutralized. Such would be the case for the wash water from the centrifuges in the aspirin process since it contains acetic acid. 4

The aspirin plant at Hofmann recycles its mother liquor, and they would only have to neutralize the centrifuge wash water. Since you will be washing most of your mother liquor and the wash water down the drain, lets pretend you are sending it directly to a waste water treatment system. You will need to make these streams basic. Add a couple of drops of phenolphthalein indicator, and add 5% NaOH until there is a color change. You dont want it too basic, so try to add just enough solution to change the color of the solution. You will have about three grams of acetic acid in your combined mother liquor and wash water. A rough calculation shows that about 40 mL of 5% caustic will be needed to neutralize your waste stream. So, after you get past 30 mL of NaOH (use a graduated cylinder) add the NaOH about a mL at a time. Measure the pH of your neutralized solution with a pH meter or pH paper. Then wash the neutralized solution down the drain.

Synthesis of Aspirin Aspirin Production Questions Answer the following using complete sentences. Answer on paper. You must print out!! Refer to the above article And the lab for answers. 1. What are generic drugs? 2. Define catalyst. 3. Distinguish between active ingredients and excipients. 4. If a drug is synthesized, what is happened? 5. What are GMPs and who requires them? What purpose do they serve? 6. What does OSHA stand for? 7. What are the Right to Know regulations, and who requires them? 8. What are the two main parts of an aspirin plant? 9. In the reactor what is the operators job? 10. Define ambient temperature. 11. What would the phrase 50 pound steam mean to a chemical engineer? 12. Describe what happens in the Product Recovery Room. 13. Why must the temperature be kept so low in the crystallizer? 14. Crystallization can serve what two purposes? 15. Differentiate between the slurry, mother liquor, and wash water. 16. What is meant by a clean room? 17. Why are acidic streams neutralized before being sent to the activated sludge treatment pond? 18. What are the specific hazards and protective measures to be take for the following acids: a. sulfuric acid b. acetic anhydride Show all calculation sot-ups for the following problems. Moles of solute = masssolute formula mass grams of salicylic acid convert to moles WOG convert to grams aspirin %Yield = actual yield x 100 theoretical yield

17. 18. 19. 20.

What is the formula mass of aspirin, C9H8O4 What is the formula mass of salicylic acid, C7H8O3? If 3.50 g of salicylic acid are used, how many moles of salicylic acid are used? If there is a 1:1 mole ratio between salicylic acid and aspirin, how much aspirin would be theoretically produced if 3.50 g of salicylic acid was used? 21. If only 0.85 g of aspirin was actually produced in the lab, what was the % yield for the experiment?

Synthesis of Aspirin LABORATORY INVESTIGATION 11-1 Title: Purpose: Synthesis of Aspirin To gain an appreciation of the process operations that are involved in producing a solid product. To synthesize aspirin and isolate it in a pure, dry form. To calculate a % yield of the production of aspirin.

Materials and Equipment: salicylic acid acetic anhydride 12 M H2SO4 125 mL Erlenmeyer flask 10 mL graduated pipet centigram balance pipet pump three 600 mL beakers 250 mL beaker 25 mL graduated cylinder 500 mL suction flask aspirator vacuum tubing 100 mL graduated cylinder water trough glass stirring rod Buchner (suction) funnel thermometer spatula hot plate ring stand filter paper to fit Buchner funnel Safety and Environmental Concerns:
MSDS for Salicylic Acid, Acetic Anhydride, Sodium Hydroxide must be reviewed by the teacher and student for safety before any part of the activity is undertaken. Any items dropped on the uncarpeted floor should be cleaned up immediately to help prevent slipping and falls. Be very careful to clean up any liquid spilled on the floor also. This can create very slippery conditions also. Wear appropriate eye protection as directed by your teacher and lab apron at all times. No food or drink is allowed in the laboratory. No horseplay. Do not perform any unauthorized experiments. Know the location and proper use of fire extinguisher, fire blanket, eye wash fountain, chemical fume hood, and safety shower are located, and that they are accessible (not blocked). Be certain that the fume hood has been checked and is functioning properly. Know two routes out of the lab in the event of an emergency. Sulfuric acid is corrosive to the skin and eyes, and may cause burns. It will also put holes in clothing. Immediately wash off any sulfuric acid that gets on your skin. If even one drop of sulfuric acid gets in the eye, wash the eye thoroughly at the eye wash fountain IMMEDIATELY. Do not ingest or taste any of the chemicals used in the laboratory. SOME ITEMS COULD BE INJURIOUS OR poisonous. Acetic anhydride, liquid and vapor, is strongly corrosive to the skin, eyes and mucous membranes. Read the MSDS on acetic anhydride and be sure you understand the hazards and how to protect yourself. Acetic anhydride is also a lachrymator, which means its vapors will cause the eyes to tear up and bum. Perform the transfer of acetic anhydride in a fume hood. Wash hands after handling acetic anhydride. Concentrated sulfuric acid will rapidly cause burns to the skin and eyes. If any sulfuric acid gets on the skin, wash it off immediately with lots of water. If the skin has been burned, apply ice and get medical attention. Read the MSDS on sulfuric acid and be sure that you understand the hazards. If even one drop of sulfuric acid or

Synthesis of Aspirin
acetic anhydride gets in the eye, immediately irrigate the eye thoroughly at the eye wash fountain. Notify the teacher and get medical attention. Salicylic acid is much less hazardous than these other two chemicals, but it is not completely innocuous. Again, read the MSDS to find out what precautions you need to take when handling salicylic acid. When you do the suction filtration, check to see if your suction flask has any cracks in it. If it has any cracks it could implode during the suction filtration.

Procedure: 1. Get a distilled water bottle and fill full with distilled water. Place in tub of ice water for later 2. Prepare a water bath by halfway filling a 600 mL beaker with tap water. Place the beaker on a hot plate and heat to boiling. Maintain a gentle boiling action. 3. Weigh accurately (to three decimals; record!) 2.### g of salicylic acid and transfer to a 125 mL Erlenmeyer flask. 4. In a fume hood, use a pipet to add 4.0 mL of acetic anhydride to the same Erlenmeyer flask. Gently swirl the flask or stir with a glass stirring rod to mix the contents of the flask. Some of the salicylic acid will remain undissolved. 5. Carefully add five drops of 12 M H2SO4 to the flask (in hood), and again mix the contents of the flask. 6. Place the Erlenmeyer flask in the boiling water bath. Heat the flask and its contents for 15 minutes. (Heating for more than 20 minutes will cause excessive impurities to form.) 7. After the reaction mass has been heated for 15 minutes, remove the hot Erlenmeyer flask using the clamp as a handle. (Be careful. The clamp may also be hot. Use paper towels to hold the clamp if it is hot.) Cool the flask by swirling it in a water trough (tap water in 600 mL beaker) until the temperature is below 50C. 8. Add 10 mL of cold distilled water (from your distilled water bottle) to a graduated cylinder. In 1-2 mL portions, pour the cold water into the Erlenmeyer flask, swirling the flask after each portion of cold water is added. 9. Chill the flask in the ice bath (you may need to add more ice to bath) for 15 minutes to crystallize the aspirin. Swirl the flask frequently during this time to optimize the heat transfer. After 5 minutes of cooling, add 25 mL of cold distilled water. The temperature of the reaction mass at the end of the cooling should be 5C or colder. Check the temperature with a thermometer. Continue to cool until the desired temperature is reached. 10. While the aspirin is crystallizing, assemble an apparatus for suction filtration. A small Buchner (suction) funnel is fitted with a rubber stopper and pushed firmly into the top of a suction flask. The suction flask is connected to an aspirator with vacuum (thick-walled) tubing. The system can be stabilized (kept from turning over) by clamping the neck of the suction flask to a ring stand.

Synthesis of Aspirin

http://www.dartmouth.edu/~chemlab/techniques/buret.html 11. Weigh a piece of slow (fine pore) filter paper and doubled paper towel record mass. Place the paper towel aside for now. Place a piece of slow (fine pore) filter paper in the Buchner funnel. (If coarse filter paper is used, small aspirin crystals will go through the filter.) The filter paper should be flat on the funnel, covering all the holes. Use a stirring rod to break up any lumps of crystals. Swirl the mixture to form a slurry. Turn on the aspirator by opening the water valve completely. Pour about 2-3 mL of cold distilled water onto the filter paper to seal it. Slowly pour the slurry (swirl the Erlenmeyer flask occasionally to maintain a good slurry) onto the filter paper so that a uniform layer of aspirin is formed. Continue the suction for about a minute after all the mother liquor (filtrate) has been drawn through the funnel. 12. Pour 10 mL of cold distilled water into the Erlenmeyer flask. Slurry the remaining aspirin crystals and pour into the Buchner funnel. With the aspirator still off, use a spatula to mix the water and crystals so that good contact of the wash water is made with all the crystals. This will give a good wash to remove the residual mother liquor. Then turn on the aspirator and remove the wash water, allowing the suction to take place for about a minute. Turn off the aspirator, add 10 more mL of cold water, and mix with the spatula. Turn on the aspirator for about 3 more minutes. This will draw air through the crystals and partially dry them. 13. Remove the Buchner funnel from the suction flask, and invert it over the paper towel. Dislodge the filter paper with the aspirin onto the paper towel. Scrape any crystals left in the Buchner funnel onto the watch glass with a spatula or stir rod. Put the paper towel with the aspirin in a safe place and cover it with a paper towel. Let the aspirin dry until the next lab session. 9

Synthesis of Aspirin 14. After the crystals are dry, weigh the aspirin crystals, filter paper, and paper towel. Calculate your experimental yield (weight) of aspirin. Save the aspirin in a jar or a beaker covered with plastic film. You will analyze your aspirin in the next module. 15. Calculate the theoretical yield of aspirin, based on the salicylic acid, which was the limiting reagent. Then calculate the % yield. % yield = experimental yield theoretical yield x 100

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Synthesis of Aspirin Synthesis of Aspirin Report Sheet Show all calculations on separate sheet. Molecular Formula of salicylic acid _______________ MM salicylic acid_______ Molecular Formula of acetic anhydride _______________ MM acetic anhydride_______ Molecular Formula of aspirin _______________ MM aspirin_______

Weight of salicylic acid Moles of salicylic acid (use circle) Weight of acetic anhydride (density = 1.08 g/mL) Moles of acetic anhydride (use circle) Initial wt of filter paper and paper towel Wt of aspirin, filter paper, and paper towel Experimental yield (weight) of dry aspirin Theoretical yield of aspirin (from calculations) % yield of aspirin

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