Msc Pharmaceutical and Chemical Process Technology

MSc Pharmaceutical and Chemical Process Technology

(DT275)

Pharmaceutical Processes Module CPPT9001

A process for the production of aspirin

Emilia Kliszewska

Contents Page

1.0 Abstract...... 3

2.0 Introduction...... 3

3.0 Calculations for annual mass balance...... 5

4.0 Batch Balance Calculations for each stream...... 12

5.0 Energy Balance Calculations...... 12

5.1 Energy Balance for reactor...... 13

5.2 Crystalliser Energy Balance...... 15

5.3 Centrifuge Energy Balance...... 16

5.4 Wash Energy Balance...... 17

5.5 Drier Energy Balance...... 17

5.6 Distillation Energy Balance...... 18

6.0 Energy Balance Summary...... 20

7.0 Analysis of the assumptions...... 21

8.0 Bibliography...... 23

Appendix 1: Flow sheet of aspirin production

Appendix 2: Calculations for annual mass balance

Appendix 3: Tabulated mass batch balance for each stream

1.0 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 aspirin (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 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).The main reaction takes place in glass-lined or stainless-steel batch reactor, in which the temperature is 90°C. At the end of the reaction period (5 hours) the liquid product mixture is transferred to crystalliser where it is cooled from 90°C to 0°C. 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 with 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][2]

2.0 Introduction

Aspirin is one of the safest and least expensive pain relievers 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 aspirin's success at the turn of the twentieth century. Today, Americans alone consume 16,000 tons of aspirin tablets 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), 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 diseases 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 can produce made it difficult to pinpoint how it actually works, and it wasn't 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 further 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. [3]

A batch process is any manufacturing process that runs in short time bursts, where the quantity or scale of manufacture does not justifycontinuous operation. Nearly all pharmaceutical production is done in batches, for both the active pharmaceutical ingredient (thechemical) and the drug product (the pill). Specialty chemicals, by their nature of being "specialty," are commonly produced in batches.These might be high-performance materials, new chemicals looking for a market, some agricultural chemicals, inks and paints, andmany others. Biochemical processes, depending on their scale, are run in batches or semi-continuously. Commercial food production isoften done in batches, though there are aspects that appear semi-continuous. Alcohol production is batch wise-even mass producedbeers are fermented in large batches. [4]

It is required to prepare a PFD flow sheet and carry out an annual and batchmass balance,and heat balance for a process to manufacture 1 million kilograms of aspirin (acetyl salicylic acid).Mass balances 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 appendix1].

It is given that PA Pharmaceuticals have 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 to 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
Assume 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 90°C to 0°C at a rate of 0.1°C per minute
All materials entering the reactor are at room temperature
Number of crystallisers 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) solid 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 removal 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 balance

It is required to produce 1000 000kg of acetyl salicylic acid (aspirin). According to the British Pharmacopoeia 2010 [9], the 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 and it is not part of the reaction. Salicylic acid and acetic anhydride react according to:

C7H6O3 + C4H6O3  C9H8O4 + C2H4O2

Salicylic Acid Acetic Anhydride Acetylsalicylic Acid Acetic Acid

The molecular weight in grams for each reactant:

C7H6O3 = 7*12+6*1+3*16=138g

C4H6O3 = 4*12+6*1+3*16=102g

and products:

C9H8O4 = 9*12+8*1+4*16=180g

C2H4O2 = 2*12+4*1+2*16=60g

The reaction is carried out at a temperature of 90°C.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 quantity 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 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 2
SALICYLIC ACID / Kmol
5819 / Kg
803015 / Kmol
291 / Kg
40151
ACETIC ANHYDRIDE / 6983 / 712210 / 1455 / 148389
SULPHURIC ACID / - / 80302 / - / 80302
ACETIC ACID / _ / _ / 5528 / 331680
ASPIRIN / _ / _ / 5528 / 995000
TOTALS / 1595527 / 1595522

Table 1: Annual Mass Balance for the aspirin production process-step1

The reaction is carried out at a temperature of 90°C and takes 5 hours, after which the products are transferred to crystalliser and cooling takes place from 90°C to 0°C at a rate of 0.1 0°C. 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 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).

Crystalliser

MATERIALS / IN stream 2 / OUT stream 3
SALICYLIC ACID / Kmol
291 / Kg
40151 / Kmol
291 / Kg
40151
ACETIC ANHYDRIDE / 1455 / 148389 / 1455 / 148389
SULPHURIC ACID / - / 803015 / - / 803015
ACETIC ACID / 5528 / 331680 / 5528 / 331680
ASPIRIN
solution / 5528 / 995000
solution / 5528 / 995000
solid
TOTALS / 1595516 / 1595516

Table 2: Annual Mass Balance for the aspirin production process-step 2

Aspirin is recovered at crystallisation so it is possible to separate it out completely after 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% mother 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 split in two streams (stream 7 and stream 6).The aspirin stream (stream 7) is delivered to a drier.

Centrifuge

MATERIALS / IN stream 3 / IN stream 4 / OUT stream 5 / OUT stream 6 / OUT stream 7
SALICYLIC ACID / Kmol
291 / Kg
40151 / Kmol
- / Kg
- / Kmol
2943,094 / Kg
406147 / Kmol
10,300 / Kg
1421,42 / Kmol
- / Kg
ACETIC ANHYDRIDE / 1455 / 148389 / - / - / 1422,083 / 145052,5 / 49,7697 / 5076,5 / - / -
SULPHURIC ACID / - / 803015 / - / - / 769,666 / 75427,3 / 26,936 / 2639,78 / - / -
ACETIC ACID / 5528 / 331680 / - / 5318,591 / 319115,5 / 186,138 / 11168,3 / - / -
ASPIRIN / 5528 / 995000 / - / - / - / - / - / - / - / 995000
WATER / - / - / - / 995000 / - / - / 974694 / 20306
TOTALS / 1595516 / 995000 / 580210 / 995000 / 1015306
TOTAL IN / 2590516
TOTAL OUT / 2590516

Table 3: Annual Mass Balance for the aspirin production process-step 3

According 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 remaining 15306 kg (20306-5000) water is evaporated off during the drying process (stream 8)

Drier

MATERIALS / IN (7) / OUT (8) / OUT (9)
SALICYLIC ACID / Kmol / Kg
- / Kmol / Kg
- / Kmol / Kg
-
ACETIC ANHYDRIDE / - / - / -
SULPHURIC ACID / - / - / -
ACETIC ACID / - / - / -
ASPIRIN / 5528 / 995000 / - / 5528 / 995000
WATER / 20306 / 15306
vapour / 5000
liquid
TOTALS / 1015306 / 15306 / 1000000
TOTAL IN / 1015306
TOTAL OUT / 1015306

Table 4: Annual Mass Balance for the aspirin production process-step 4

The 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 returned to the reactor.

Distillation Column (Recovery)

MATERIALS / IN steam 5 / OUT recycle steam 10 / OUT steam 11
SALICYLIC ACID / Kmol
2943,094 / Kg
406147 / Kmol
2943,094 / Kg
406147 / Kmol
- / Kg
-
ACETIC ANHYDRIDE / 1422,083 / 145052,5 / 1422,083 / 145052,5 / - / -
SULPHURIC ACID / 769,666 / 75427,3 / 769,666 / 75427,3 / - / -
ACETIC ACID / 5318,591 / 319115,5 / 5318,591 / 319115,5
TOTALS / 580210 / 261094,5 319115,5
TOTALS IN / 580210
TOTALS OUT / 580210

Table 5: Annual Mass Balance for the aspirin production process-step 5

The 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 referred 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 distillation 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 batch required 995000kg/16000batches= 621.19 kg per batch. Batch balances for each stream in and out of each process as shown in appendix 3

5.0 Energy Balance Calculations:

Kopp’s 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-1°C-1)
Element / Solid / Liquid
Carbon / 7.5 / 12
Hydrogen / 9.6 / 18
Oxygen / 17 / 25
Sulphur / 26 / 33

For example, the head capacity for salicylic acid (solid) is calculated:

Cp (C7H6O3) =7(Cpa)C+ 6(Cpa)H +3 (Cpa)O =7x7.5 +6 x 9.6+3 x17=161.1(J/mol/°C)

Compound / Formula / Solid Heat Capacity
(J.mol-1°C-1) / Liquid Heat
Capacity
(J.mol-1°C-1)
Salicylic Acid (solid) / C7H6O3 / 161.1 / 267.0
Acetic Anhydride (liquid) / C4H6O3 / 138.6 / 231.0
Sulphuric Acid (liquid) / H2SO4 / 113.2 / 169.0
Acetylsalicylic Acid (solid) / C9H8O4 / 212.3 / 352.0
Acetic Acid (liquid) / C2H4O2 / 87.4 / 146.0

Unit (J/mol/°C) needs to be converted to unitJ/kg/k dividing heat capacities by weight of mole

Compound / Molecular Weight (g/mol)
Salicylic Acid (solid) / 138.1
Acetic Anhydride (liquid) / 102.1
Sulphuric Acid (liquid) / 98.1
Acetylsalicylic Acid (solid) / 180.2
Acetic Acid (liquid) / 60.06

After dividing heat capacities by weight of mole heat capacity for each compound is follow:

Compound / Solid Heat Capacity
(Jkg-1°C-1) / Liquid Heat
Capacity
(Jkg-1°C-1)
Salicylic Acid / 1166.3 / 1933.0
Acetic Anhydride / 1357.5 / 2262.5
Sulphuric Acid / 1154.2 / 1723.1
Acetylsalicylic Acid / 1178.3 / 1953.7
Acetic Acid / 1455.2 / 2430.9

5.1 Reactor energy balance:

Basis of calculations throughout is per batch. Batch balance for each stream in reactor is shown in appendix 2.

It is assumed that that temperature of reactants at start of batch reactor cycle is 15°C. Reactants are heated up from 15°C to 25°C. Reaction is assumed to take place at 25℃. Products remaining after reaction are heated up from25℃ to 90℃.

Figure 1:Block Diagram for the Reactor

Mass at start of reactor process:

Compound / Stream 1 (R+F) (kg) / Specific Heat Capacity (Jkg-1°C-1) / Δt (15-25) (°C)
Salicylic Acid / 501.88 / 1166.3 / 10
Acetic Anhydride / 445.13 / 2262.5 / 10
Sulphuric Acid / 50.19 / 1723.1 / 10

To calculate change in enthalpy of reactants from 15°C to 25°C∆H as follows:

∆H= mCpΔt

Where:

m= mass (kg)

Cp= Specific Heat Capacity (Jkg-1°C-1)

Δt = temperature difference (°C)

Compound / Heat Added (kJ)
Salicylic Acid / 5853
Acetic Anhydride / 10071
Sulphuric Acid / 865
Total / 16,789kJ

Next step is to calculate heat of reaction for the process QR:

The reaction is exothermic and heat of reaction is given and equal – 85 kJ/mol

Total no. of moles in reaction per batch (n) :

621.19 kg acetylsalicylic acid /0.1802kg per mole acetylsalicylic acid =3447.2 moles.

Heat of reactionQR = -n∆H0R

QR=– 85 kJ/mol x3447.2 moles =- 293012kJ

To calculate change in enthalpy of products from 25°C to 90°C∆H as follows:

∆H= mCpΔt

Compound / Stream 2 (kg) / Specific Heat Capacity (J/kg/°C) / Δt (°C) / Heat Added (kJ)
Salicylic Acid / 25.09 / 1166.3 / 65 / 1902
Acetic Anhydride / 92.74 / 2262.5 / 65 / 13638
Sulphuric Acid / 50.19 / 1723.1 / 65 / 5621
Acetylsalicylic Acid / 621.19 / 1178.3 / 65 / 47576
Acetic Acid / 207.3 / 2430.9 / 65 / 32756
Total / 101,493kJ

Next step is to calculate total heat transferred to reactor QP:

QP = H products - H reactants + QR

Where :

QP = heat transferred to the reactor,

HP = total enthalpy of the products,

HR = total enthalpy of the reactants and

QR = reaction heat

QP = 101,493kJ -16,789kJ +(- 293012kJ) =-208308kJ

5.2 Energy Balance for crystalliser

Basis of calculations throughout is per batch. Contents in crystalliserare cooled from 90℃ to 0℃. Heat of crystallisation of acetylsalicylic acid is assumed to be negligible.

Figure 2: Block diagram for the crystalliser process

To calculate change in enthalpy of crystalliser products∆H as follows:

∆H= mCpΔt

Compound / Stream 2 (kg) / Specific Heat Capacity (J/kg/°C) / Δt (°C) / Heat Added (kJ)
Salicylic Acid / 25.09 / 1166.3 / -90 / -2630
Acetic Anhydride / 92.74 / 1357.5 / -90 / -11330
Sulphuric Acid / 50.19 / 1723.1 / -90 / -7783
Acetylsalicylic Acid / 621.19 / 1178.3 / -90 / -65875
Acetic Acid / 207.3 / 2430.9 / -90 / -45353
Total / -132,971kJ

Heat transferred to crystalliser process = -132,971kJ

5.3 Centrifuge Energy Balance

Products from crystalliser are delivered to the centrifuge at 0℃.Product are assumed to remain at 0℃. No heat is actively added. For purposes of this calculation, no energy is assumed to be delivered to the process.

5.4 Wash energy balance

Products delivered to the washing stage are assumed to be at 0℃.Products are assumed to remain at 0℃.For purposes of this calculation no energy is assumed to be delivered to this process.

5.5 Drier energy balance

Heat is added to the materials in the drier. Initial temperature of acetylsalicylic acid is 0℃, while the water content is at 10℃.

Figure 3: Block diagram for the drier

To calculate change in enthalpy ∆H of drier in stream 9 as follows:

Compound / Stream 9 (kg) / Specific Heat Capacity (J/kg/°C) / Δt (°C) / Heat Added (kJ)
Acetylsalicylic Acid (solid) / 621.19 / 1178.3 / 100 / 73,194
Water (liquid) / 3.12 / 3360.5 / 90 / 943
Total / 74,137kJ

The specific enthalpy change between the liquid and vapour forms of a species at T and P is defined as Heat of Vaporization∆HV(T and P) and for water is equal 2257kJ/kg [3]

To calculate change in enthalpy ∆H of drier in stream 8 as follows:

Compound / Stream 8 (kg) / Specific Heat Capacity (J/kg/°C) / Δt (°C) / Heat Added (KJ)
Water / 9.57 / 3360.5 / 100 / 3,215kJ
Latent Heat of Vaporization(J/kg)
Water (vapour) / 9.57 / 2257000 [3] / 21,599kJ
Total / 24,814kJ

Heat transferred to drier =74,137kJ+24,814kJ=98,951kJ

5.6 Distillation Energy Balance

It is assumed that products delivered from the centrifuge process remain at 0℃ (except water). There are three liquids present in the stream 5 going to the distiller; acetic acid, acetic anhydride and sulphuric acid. Following are boiling points at atmospheric pressure for the components fed into the distiller:

Compound / Boiling Point (°C)
Acetic Acid / 118.1[4]
Acetic Anhydride / 139.8[5]
Sulphuric Acid / 338 [6]

Material fed into the distiller is to be heated to 118.1(°C) in order to boil off the acetic acid, while leaving the remaining materials unevaporated.

Figure 4: Block diagram for the distiller

To calculate change in enthalpy ∆H of drier in stream 10 as follows:

Compound / stream 10(kg) / Specific Heat Capacity (J/kg/°C) / Δt (°C) / Heat Added (kJ)
Salicylic Acid / 253.84 / 1166.3 / 118.1 / 34,963
Acetic Anhydride / 90.65 / 2262.5 / 118.1 / 24,221
Sulphuric Acid / 47.14 / 1723.1 / 118.1 / 9,592
Total / 68,776 kJ

To calculate change in enthalpy ∆H of drier in stream 11 as follows:

Compound / stream 11 (kg) / Specific Heat Capacity (J/kg/°C) / Δt (°C) / Heat Added (kJ)
Acetic Acid / 199.45 / 2430.9 / 118.1 / 57,259 kJ
Latent Heat of Vapourisation (J/kg)
Acetic Acid / 199.45 / 402000[6] / 80,178 kJ
Total / 137,437 kJ

Stream 11 contains reflux @ 10% = (199.45/0.9)-199.45=22.16 kg of acetic acid will be cooled from 118.1°Cto 25°C and then returned to distiller for re-distillation as follows:

Compound / 10% reflux (kg) / Specific Heat Capacity (J/kg/°C) / Δt (°C) / Heat Added (kJ)
Acetic Acid / 22.16 / 2430.9 / 93.1 / 5,015 kJ
Latent Heat of Vapourisation (J/kg)
Acetic Acid / 22.16 / 402000 / 8,908 kJ
Total / 13,923 kJ

Heat transferred to distiller heating process =68,776+137437+13923= 220,136kJ

Distiller condenser will be required to remove heat from the evaporated acetic acid (plus the 10% reflux) and cool down to 25°C as follows:

Compound / Stream 11 +10% reflux (kg) / Specific Heat Capacity (J/kg/°C) / Δt (°C) / Heat Added (kJ)
Acetic Acid / 221.61 / 2430.9 / -93.1 / -50,154kJ
Latent Heat of Condensation (J/kg)
Acetic Acid / 221.61 / -402000 / -89,0875kJ
Total / -139,241kJ

Heat transferred to distiller condensing process = -139241kJ

It is assumed that temperature rise of water passing through the condenser is 35°C, and then mass of water required for condenser is as follows: