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1、MSc Pharmaceutical and Chemical Process Technology(DT275)Pharmaceutical Processes Module CPPT9001A process for the production of aspirinEmilia KliszewskaContents Page1.0 Abstract32.0 Introduction33.0 Calculations for annual mass balance54.0 Batch Balance Calculations for each stream125.0 Energy Bala
2、nce Calculations 125.1 Energy Balance for reactor135.2 Crystalliser Energy Balance155.3 Centrifuge Energy Balance165.4 Wash Energy Balance175.5 Drier Energy Balance175.6 Distillation Energy Balance186.0 Energy Balance Summary207.0 Analysis of the assumptions218.0 Bibliography23Appendix 1: Flow sheet
3、 of aspirin productionAppendix 2: Calculations for annual mass balanceAppendix 3: Tabulated mass batch balance for each stream1.0 Abstract It is required to prepare a PFD flow sheet and carry out an annual, batch mass balance and heat balance for a process to manufacture 1 million kilograms of aspir
4、in (acetyl salicylic acid).Aspirin can be product by the reaction of salicylic acid with acetic anhydride in the presence of sulphuric acid. The products of the reaction are: aspirin (acetyl salicylic acid), acetic acid and unreacted acetic anhydride and sulphuric acid.The process is based on the re
5、action between salicylic acid and 20% stoichiometric excess of acetic anhydride and 10% by weight concentrated sulphuric acid (based on the mass of salicylic acid).The main reaction takes place in glass-lined or stainless-steel batch reactor, in which the temperature is 90C. At the end of the reacti
6、on period (5 hours) the liquid product mixture is transferred to crystalliser where it is cooled from 90C to 0C. The aspirin crystallizes from the acetic acid/acetic anhydride mother liquor. The resulting suspension is transferred to a filter for removal of acetic acid and solvent. After washing wit
7、h solvent, the aspirin crystals are slurried and filtered again. The aspirin crystals are then dried and sent to sifting, granulation and tableting. Acetic acid, which is formed as a by product, is recovered for sale. 1 22.0 IntroductionAspirin is one of the safest and least expensive pain relievers
8、 on the marketplace. While other pain relievers were discovered and manufactured before aspirin, they only gained acceptance as over-the-counter drugs in Europe and the United States after aspirins success at the turn of the twentieth century. Today, Americans alone consume 16,000 tons of aspirin ta
9、blets a year, equalling 80 million pills, and we spend about $2 billion a year for non-prescription pain relievers, many of which contain aspirin or similar drugs. Currently, the drug is available in several dosage forms in various concentrations from 0.0021 to 0.00227 ounces (60 to 650 milligrams),
10、 but the drug is most widely used in tablet form. Other dosage forms include capsules, caplets, suppositories and liquid elixir. Aspirin can be used to fight a host of health problems: cerebral thromboses (with less than one tablet a day); general pain or fever (two to six tablets a day; and disease
11、s such as rheumatic fever, gout, and rheumatoid arthritis. The drug is also beneficial in helping to ward off heart attacks. In addition, biologists use aspirin to interfere with white blood cell action, and molecular biologists use the drug to activate genes. The wide range of effects that aspirin
12、can produce made it difficult to pinpoint how it actually works, and it wasnt until the 1970s that biologists hypothesized that aspirin and related drugs (such as ibuprofen) work by inhibiting the synthesis of certain hormones that cause pain and inflammation. Since then, scientists have made furthe
13、r progress in understanding how aspirin works. They now know, for instance, that aspirin and its relatives actually prevent the growth of cells that cause inflammation. 3A batch process is any manufacturing process that runs in short time bursts, where the quantity or scale of manufacture does not j
14、ustify continuous operation. Nearly all pharmaceutical production is done in batches, for both the active pharmaceutical ingredient (the chemical) and the drug product (the pill). Specialty chemicals, by their nature of being specialty, are commonly produced in batches. These might be high-performan
15、ce materials, new chemicals looking for a market, some agricultural chemicals, inks and paints, and many others. Biochemical processes, depending on their scale, are run in batches or semi-continuously. Commercial food production is often done in batches, though there are aspects that appear semi-co
16、ntinuous. Alcohol production is batch wise-even mass produced beers are fermented in large batches. 4 It is required to prepare a PFD flow sheet and carry out an annual and batch mass balance, and heat balance for a process to manufacture 1 million kilograms of aspirin (acetyl salicylic acid).Mass b
17、alances are the basis of process design. A mass balance taken over the complete process will determine the quantities of raw materials required and products produced. Balances over individual process units set the process stream flows shown in the appendix 1.It is given that PA Pharmaceuticals have
18、developed a process to produce 1 million kg of acetyl salicylic acid (aspirin) per year. The process is based on the reaction between salicylic acid and 20% stoichiometric excess of acetic anhydride and 10% by weight concentrated sulphuric acid (based on the mass of salicylic acid). It is required t
19、o prepare a PFD flow sheet and carry out mass balance and heat balance for below processes.Following directions and assumptions have been given: Plant runs 24 hour per day, 8000 hour per year Reaction is exothermic (-84kJ/mol) Reaction is carry out in a batch reactor operating in semi- batch mode As
20、sume reaction yield is 95% Batch reaction cycle is 5 hours One reactor only in use At the end of the reaction period (5 hours) contents are transferred to crystalliser, where are cooled from 90C to 0C at a rate of 0.1C per minute All materials entering the reactor are at room temperature Number of c
21、rystallisers are required to avoid a delay before next batch is started All aspirin is recovered at crystallisation Other processes are required: centrifugation (or filtration), including a washing and drying. These processes take a total of 5 hours. After initial centrifugation (or filtration) soli
22、d is 98% aspirin and 2% mother liquor by weight After washing cycle in centrifugation (or filtration) solid is 98% aspirin and 2% water by weight, i.e. traces of mother liquor in solid are removed into a waste water stream. Mother liquor from initial centrifugation is recycled in process after remov
23、al of acetic acid by distillation Mixture for distillation consists acetic acid and acetic anhydride only, other components are ignored.3.0 Calculations for annual mass balanceIt is required to produce 1000 000kg of acetyl salicylic acid (aspirin). According to the British Pharmacopoeia 2010 9, the
24、final product must be min. 99.5% pure (995000kg of aspirin).The process is based on the reaction between salicylic acid and 20% stoichiometric excess of acetic anhydride and 10% by weight concentrated sulphuric acid (based on the mass of salicylic acid). Sulphuric acid (H2SO4) is used as catalyst an
25、d it is not part of the reaction. Salicylic acid and acetic anhydride react according to:C7H6O3 + C4H6O3 C9H8O4 + C2H4O2Salicylic Acid Acetic Anhydride Acetylsalicylic Acid Acetic AcidThe molecular weight in grams for each reactant:C7H6O3 = 7*12+6*1+3*16=138gC4H6O3 = 4*12+6*1+3*16=102gand products:
26、C9H8O4 = 9*12+8*1+4*16=180gC2H4O2 = 2*12+4*1+2*16=60gThe reaction is carried out at a temperature of 90C.The reaction delivers a 95% yield of acetylsalicylic acid. Therefore 5% of the initial mass of reactants remains after the reaction is completed, and there is a corresponding reduction in the qua
27、ntity of products.To produce 995000 kg aspirin (5528 kmol) in reactor exit stream at 95% yield we need in reactor feed (F+R): 712210kg acetic anhydride ( 20% stoichiometric excess) 803015 kg salicylic acid (95%) 80302 kg sulphuric acid (10% by weight concentrated sulphuric acid (based on the mass of
28、 salicylic acid).This quantity of reactants will give a reactor product (P) of: 995000kg aspirin 148389 kg acetic anhydride 331680 kg acetic acid 40151 kg salicylic acid 80302 kg sulphuric acid Reactor MATERIALS IN stream 1 (F+R) OUT stream 2SALICYLIC ACIDKmol5819Kg 803015Kmol291Kg40151ACETIC ANHYDR
29、IDE69837122101455148389SULPHURIC ACID-80302-80302ACETIC ACID _5528331680ASPIRIN _5528995000TOTALS15955271595522 Table 1: Annual Mass Balance for the aspirin production process-step1The reaction is carried out at a temperature of 90C and takes 5 hours, after which the products are transferred to crys
30、talliser and cooling takes place from 90C to 0C at a rate of 0.1 0C. The crystallization process will take 15 hours and this is three times longer than reactor step. To avoid a delay before the next batch is started, 3 crystallisers will be required. Crystalliser should be free every 5 hours to take
31、 feed from the reactor. The mass delivered to the crystalliser is fed out completely to the centrifuge. It is assumed that all the aspirin is recovered at crystallisation (shown Table 2).CrystalliserMATERIALS IN stream 2 OUT stream 3SALICYLIC ACIDKmol291Kg40151Kmol291Kg40151ACETIC ANHYDRIDE145514838
32、91455148389SULPHURIC ACID-803015-803015ACETIC ACID55283316805528331680ASPIRINsolution5528995000solution5528995000solidTOTALS15955161595516Table 2: Annual Mass Balance for the aspirin production process-step 2Aspirin is recovered at crystallisation so it is possible to separate it out completely afte
33、r centrifugation (filtration). The separated mass containing the aspirin is made up of 2% mother liquor by weight. So after centrifugation there are two separate streams (stream 7 and stream 5).The aspirin is further separated in the centrifuge by an additional washing cycle. After the wash the 2% m
34、other liquor present is replaced with the same weight of water. It is considered that a kilogram of washing solvent (water) should be used for each kilogram of product. So there is additional water stream (stream 4) going into the centrifuge and as a result of the washing process the aspirin is spli
35、t in two streams (stream 7 and stream 6).The aspirin stream (stream 7) is delivered to a drier.CentrifugeMATERIALS IN stream 3 IN stream 4 OUT stream 5OUT stream 6OUT stream 7SALICYLIC ACIDKmol291Kg40151Kmol-Kg-Kmol2943,094Kg406147Kmol10,300Kg1421,42Kmol-KgACETIC ANHYDRIDE1455148389-1422,083145052,5
36、49,76975076,5-SULPHURIC ACID-803015-769,66675427,326,9362639,78-ACETIC ACID5528331680-5318,591319115,5186,13811168,3-ASPIRIN5528995000-995000WATER-995000-97469420306TOTALS15955169950005802109950001015306TOTAL IN 2590516TOTAL OUT 2590516Table 3: Annual Mass Balance for the aspirin production process-
37、step 3According to the British Pharmacopoeia 2010 9 the final product (stream 9) must be 99, 5% pure. It has been assumed that the 0.5% impurity remaining with the aspirin prior to drying is water. So the 995000 aspirin must be accompanied by no more than 995000kg*0.005/0,995 = 5000kg of water. The
38、remaining 15306 kg (20306-5000) water is evaporated off during the drying process (stream 8)DrierMATERIALS IN (7) OUT (8) OUT (9)SALICYLIC ACIDKmolKg-KmolKg-KmolKg-ACETIC ANHYDRIDE-SULPHURIC ACID-ACETIC ACID-ASPIRIN5528995000-5528995000WATER2030615306vapour5000liquidTOTALS1015306153061000000TOTAL IN
39、 1015306 TOTAL OUT 1015306Table 4: Annual Mass Balance for the aspirin production process-step 4The mother liquor from centrifugation process is separated by distillation, in order to separate out the acetic acid (stream 11) from the remaining components in the mother liquor (stream 10) that are ret
40、urned to the reactor.Distillation Column (Recovery)MATERIALS IN steam 5 OUT recycle steam 10 OUT steam 11SALICYLIC ACIDKmol2943,094Kg406147Kmol2943,094Kg406147Kmol-Kg-ACETIC ANHYDRIDE1422,083145052,51422,083145052,5-SULPHURIC ACID769,66675427,3769,66675427,3-ACETIC ACID5318,591319115,55318,591319115
41、,5TOTALS 580210 261094,5 319115,5 TOTALS IN 580210TOTALS OUT 580210Table 5: Annual Mass Balance for the aspirin production process-step 5The above information is sufficient to build a process flow diagram with mass balances for each stream in and out of each process as shown in appendix 1 already re
42、ferred to.4.0 Batch balance for each stream:It is required to produce 1000 000kg of finished acetyl salicylic acid (aspirin) product. Plant up time is given as 8000 hours. It is know that the reactor process, crystallising process (assuming three crystallisers) centrifuge/wash, dryer and distillatio
43、n processes can be completed in 5 hours so finished batch of product will be delivered every 5 hours. Therefore a total of 8000 hours per year/5 hours per batch so 1600 batches can be produced per year. It is require 1000000kg of finished product per annum, therefore quantity of finished product per
44、 batch required 995000kg/16000batches = 621.19 kg per batch. Batch balances for each stream in and out of each process as shown in appendix 35.0 Energy Balance Calculations:Kopps rule is a simple empirical method for estimating the head capacity Cp of solid or liquid at or near 20. According to this rule, Cp for molecular compounds is the sum of contributions (given in Table B.10 in 4) for each element of compound.Heat Capacity (Cpa) (J.mol-1C-1)Element SolidLiquidCarbon7.512Hydrogen9.618Oxygen1725Sulphur2633For example, the head capacity for salicyl