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Manufacture of Paracetamol

Introduction
Paracetamol is the most widely accepted medicine for relieves pain and fever in adults and children. This has been used by people in world wide for more than thirty years. It is used either as a medicine prescribed by a doctor or it can be easily purchased as an over-the-counter medicine both in retail pharmacies or grocers shops. Paracetamol can purchase in the form of tablets or syrups and paracetamol injections are also prescribed in certain cases. This product is suitable for all age groups including very young children. They can generally be taken by people who are sensitive to aspirin. There are no side-effects when taken at the recommended dosage and interactions with other treatments are not a problem. Because of their effectiveness and lack of side-effects paracetamol products are frequently prescribed in hospitals and people use as a treatment for relieving mild to moderate pains.

Process of manufacture of paracetamol Commercial Manufacture

The early commercial production of paracetamol relied on the nitration of phenol to p-nitrophenol with a reduction step to produce p-aminophenol followed by acetylation with acetic anhydride. A number of commercial methods of manufacture of Paracetamol are currently in use around the world and four routes are listed below.

Phenol Route Para Nitrochloro Benzene Route Nitrobenzene Route Para Hydroxyacetophenone Hydrazine Route

The following processes describe below are two processes that can be done using starting raw materials as phenol and paranitrochlorobenzene. But there can be differences in the processes even though those are starting with same raw material.

Process using Phenol as a starting raw material Phenol is nitrated by means of sodium nitrite and sulphuric acid to obtain paranitrophenol. This is then reduced by means of iron powder or sodium sulphide to get para-aminophenol. The recovery of paraaminophenol is completed by dissolving the para-aminonphenol hydrochloride salt in water, decolourising the aqua solution and crystallising the para-aminophenol by neutralizing the salt. The resulting para-aminophenol is reacted with acetic anhydride to produce paracetamol. The reactions are summarized as shown below: OH NaNO3 H2SO4 NO2

OH Fe Powder / Na2S

OH

OH

CH3-C-O-C-CH3 NH2 H-N-C-CH3 O Paracetamol

Para aminophenol Process using Paranitrochlorobenzene as a starting raw material

Phenol

Para nitro phenol

Paranitrochlorobenzene is converted to paranitrophenol by means of caustic fusion with caustic soda in an autoclave; paranitrophenol thus obtained is further reduced to paraminophenol by using iron powder. Para-aminophenol crystallises out from the mother liquid which is subsequently centrifuged. Para-aminophencl crystal is then reacted with acetic anhydride to produce crude paracetamol. The reactions are summarised as shown below: Cl NaOH NO2 Para nitro phenol Para aminophenol OH Fe Powder OH O O OH

CH3-C-O-C-CH3 NH2 H-N-C-CH3 O Paracetamol

NO2 Paranitrochlorobenzene

Lab scale manufacture

Paracetamol may be easily prepared in the laboratory by using phenol. Phenol is reacted with sodium nitrate and separate para nitro phenol from outho nitro phenol. Then para nitro phenol is converted to para amino phenol by using sodium borohydride and acetylated with acetic anhydride.

OH

Dil. H2SO4 NaNO3

OH + NO2 25% yield

OH

NO2

36% yield

OH

NaBH4 Pd/1 mol dm-3 NaOH

OH

OH

CH3-C-O--C-CH3 NO2 NH2

Water, Room Temp.

H-N-C-CH3 O

74% yield

60% yield

Costs of raw materials

Process using Phenol as a starting raw material Cost of raw materials is calculated for the above process described. Because lab scale process can be used for the commercial production too. This is a rough estimation and only the costs of main raw materials are considered during this calculation. We assume that 1kg of paracetamol is produced. Number of moles of paracetamol = 1000 / 151 = 6.6225 mol Molecular weight of paracetamol is 151 g/mol

As yield of paracetamol is 60% Number of moles of 4-aminophenol required = 6.6225/ 0.6

= 11.0375mol Weight of the 4-aminophenol required = 11.0375 * 109 = 1203.0905g Molecular weight of 4-aminophenol is 109 g/mol According to the literature, 1.17g of ethanoic anhydride is required to react with 1g of 4-amino phenol. Weight of the ethanoic anhydride required = 1203.0905 * 1.17 =1407.6159g If the yield of 4-amino phenol is 74%, Number of moles of 4-nitrophenol reacted =11.0375/0.74 =14.9155mol Weight of 4-nitrophenol reacted = 14.9155 * 139 = 2073.2545g The reduction of nitro group to amine group is done by reacting it with sodium borohydride. According to the literature, 0.56g of sodium borohydride is required to react with 1g of 4-nitrophenol. Weight of the sodium borohydride required = 2073.2545 * 0.56 = 1161.0225g First step is nitration of phenol and Sodium nitrate and dilute sulfuric acid use for the reaction. Two products 2-nitrophenol and 4-nitropenol can be separated and yield of the products are 25% and 36% respectively. Number of moles of phenol reacted = 14.9155/0.25 = 59.662 mol Weight of phenol required Molecular weight of phenol is 94g/mol. If the stoichiometry between phenol and sodium nitrate is 1:1, 59.662 moles of sodium nitrate are used. =59.662 * 94 = 5608.228g

Weight of sodium nitrate required

=59.662 * 85 = 5071.27g

Item Phenol Sodium nitrate Sodium boro hydride Ethanoic anhydride

Unit cost (LKR / kg) 87.98 80.85 5175 125.50

Qty (kg) / Paracetamol Kg 5.6082 5.0713 1.1610 1.4076

Cost (LKR / Paracetamol Kg) 493.39 410.01 6008.32 176.63

Total cost of raw materials per 1kg of paracetamol = 493.39+410.01+6008.32+176.63 = LKR 7088.36 If price of paracetamol tablet is LKR 2.00, Total revenue from 1kg of paracetamol = (1000/0.5) * 2 = LKR 4000.00

Finally this manufacturing process gives loss. Therefore process should modify to earn profit out of it. During this process sodium boro hydride used for the reducing reaction, which has the highest material cost. If we used low cost substitute for that we could earn profit.

We can use Sn and hydrochloric acid for the reducing reaction instead of sodium borohydride. According to the literature, 0.56g of sodium borohydride is required to react with 1g of 4-nitrophenol during the reducing reaction. Assume that same amount of hydrochloric acid is required for the reaction. Weight of the hydrochloric acid required = 2073.2545 * 0.56* (36.5/38) = 1115.1927g But we cannot purchase 100% purity HCl commercially,36% purity HCl can be purchased commercially. Weight of the hydrochloric acid required = 1115.1927*(100/36) = 3097.7575g

Item Phenol Sodium nitrate Ethanoic anhydride HCl

Unit cost (LKR / kg) 87.98 80.85 125.50 8.40

Qty (kg) / Paracetamol Kg 5.6082 5.0713 1.4076 3.0978

Cost (LKR / Paracetamol Kg) 493.39 410.01 176.63 26.02

If tin and hydrochloric acid used for the reducing reaction, Total cost of raw materials per paracetamol Kg = 493.39+410.01+26.02+176.63 = LKR 1106.05

Total revenue from 1kg of paracetamol

= (1000/0.5) * 2 = LKR 4000.00

Profit from manufacture of pracetamol

= LKR 4000 LKR 1106.05 = LKR 2893.95

Therefore profit will arise from manufacture of paracetamol, if use Sn and hydrochloric acid for the reducing reaction instead of sodium borohydride. But the main raw materials for the manufacturer of paracetamol are directly derived from petroleum;

the price of paracetamol is dependent on the world market situation of petroleum and petrochemicals.