The document summarizes the design of a chemical process for producing the analgesic drug paracetamol. It begins with background on paracetamol and then describes its physical and chemical properties. The document outlines the commonly used PNCB production route and provides details of the multi-step chemical process involving neutralization, nitration, reduction, and acetylation reactions. It also discusses process parameters, potential improvements to optimize yields and recovery of paracetamol, and outlines methods for purification to meet pharmaceutical standards.
The document summarizes the design of a chemical process for producing the analgesic drug paracetamol. It begins with background on paracetamol and then describes its physical and chemical properties. The document outlines the commonly used PNCB production route and provides details of the multi-step chemical process involving neutralization, nitration, reduction, and acetylation reactions. It also discusses process parameters, potential improvements to optimize yields and recovery of paracetamol, and outlines methods for purification to meet pharmaceutical standards.
The document summarizes the design of a chemical process for producing the analgesic drug paracetamol. It begins with background on paracetamol and then describes its physical and chemical properties. The document outlines the commonly used PNCB production route and provides details of the multi-step chemical process involving neutralization, nitration, reduction, and acetylation reactions. It also discusses process parameters, potential improvements to optimize yields and recovery of paracetamol, and outlines methods for purification to meet pharmaceutical standards.
The document summarizes the design of a chemical process for producing the analgesic drug paracetamol. It begins with background on paracetamol and then describes its physical and chemical properties. The document outlines the commonly used PNCB production route and provides details of the multi-step chemical process involving neutralization, nitration, reduction, and acetylation reactions. It also discusses process parameters, potential improvements to optimize yields and recovery of paracetamol, and outlines methods for purification to meet pharmaceutical standards.
Krishna Agrawal (11BCH0033) Utsav Saxena (11BCH0012) Introduction • Paracetamol or acetaminophen or APAP, is a widely used antipyretic and analgesic agent with weak anti- inflammatory effects. • IUPAC name -> N-acetyl-p-aminophenol • It has been around as a drug for more than thirty years. • Paracetamol, being a safe and low priced analgesic, is a quite popular world-wide. • Medical opinion favours Paracetamol, over the established drug ‘Aspirin’, due to its lower side effects. • Paracetamol is the active metabolite of phenacetin which is an analgesic. • Unlike phenacetin and its combinations, paracetamol is not considered carcinogenic at therapeutic doses. • Structure:
• 3-D structure: Physical Properties • Molecular formula- C8H9NO2 • Relative Molecular Mass- 151.17 • Description- White crystalline powder • Melting point- 170o C • Density- 1.293 g/cm3 at 21oC • Solubility-Insoluble in water (17.39 g/kg of water) Soluble in ethanol ( 232.75 g/kg of ethanol) Maximum solubility in diethylamine- 1316.9g/kg solvent
• Specific Heat Capacity-Cp=17.645+0.5226T (for temp up to
70oC)
• Polymorphism- Acetaminophen exists in two meta stable
forms; Orthorhombic and Monoclinic. Orthorhombic is suitable for direct compression tableting and also be slightly more soluble. Monoclinic is the commercially available crystalline form and is thermodynamically more stable.
• Not known to occur naturally.
Chemical Properties • pKa- The pKa of acetaminophen is 9.51 at 25°C. • Stability- Acetaminophen is stable to temperature, light, and moisture. • pH range- Acetaminophen oral solution (ie, elixir, adult liquid) has a pH of 3.8 to 6.1 and the oral suspension (ie, infants' drops, children's suspension) has a pH of 5.4 to 6.9. • Oxidizing nature- • Acetaminophen reacts with CH2CH3I to give Phenacetin-
• Reaction with Nitrous Acid-
• Sulfation And Glucuronidation of Acetaphinomen Applications • It has analgesic properties comparable to those of aspirin, while its anti-inflammatory effects are weaker • Fever- Paracetamol is approved for reducing fever in people of all ages. • Pain- Paracetamol is used for the relief of pains associated with many parts of the body such as :-. o Headaches o Toothaches o Backaches o Osteoarthritis Market Demand and Sales Global Status • There was a 28% growth in acetaminophen market between year 2004 and 2008.
• Over 370 million bottles and packets, or 24.6 billion doses
were sold in year 2008.
• Nearly 80% of entire market is OTC products (nearly $1.15 in
sales).
• Proportion of prescripted acetaminophen market steady at
nearly 20% of overall market(nearly $1.4 billion in sales). Production Total production of paracetamol in india (thousands) 215 210 205 200 195 (packets) 190 185 180 175 170 165 2008 2009 2010 (Years) Indian Status • Indian analgesic and anti-pyretic market is a huge one, growing at 9.5%.
• Acetaminophen comes under the category of OTC drugs.
• India’s Acetaminophen sale has grown around 10%in the last
two years, leaving the U.S. and China, much behind, where the drug sale is estimated at 4% to 5% respectively.
• The share of sales of OTC traditional drugs in India has gone
up to 30%.
• This market actually harbours 62 nationally distributed
analgesics and over hundred local brands. Manufacturing Processes
All the routes primarily lead to the manufacture of Para
Aminophenol (PAP) of which Acetaminophen (APAP) i.e. Paracetamol is a derivative. Why PNCB Route? • Manpower required is less than that of the Phenol route. • It has minimum economic plant size of 20-25TPM as compared to other routes. • It has minimum level of investment for MES Plans of Rs.1 crore. • It has an easy acquisition of technology. • Unit cost of production is less than that of the Phenol route. • Other Advantages- Ease of operation Lower investment Less operational skills required PNCB Route • Currently, almost 100% of paracetamol production in chemical industries is followed by PNCB route. So, this route of production can be considered as the most popular process route.
The entire process is divided intro 4 steps :-
• Neutralization of p-nitrochlorobenzene using NaOH • Nitration to give p-nitro phenol • Reduction of p-nitro phenol to p-amino phenol • Acetylation of p-amino phenol to acetaminophen
Since all the routes lead to the formation of p-amino phenol, the acetylation step gains importance to get the paracetamol of desired pharmaceutical standards. Process Chemistry Process Description • Chlorobenzene with hydrolysis is carried out by the reaction of 9% caustic soda solution with p- nitrochlorobenzene. • The reaction mass is filtered and with suitable process control and proper design of the reactor, the yields could be optimized, resulting into lower requirement of inputs and generation of lower quantities of effluent. • The sodium salt of p-nitrophenol is then treated with concentrated sulphuric acid at 35-45°C. • p-Nitrophenol is filtered. • p-Nitrophenol is reduced with iron at 90-100°C temperature in wooden vat. The reaction temperature is raised by direct injection of steam. • On completion of reduction, water is added to the reaction mass, iron sludge is removed by filtration and the filtrate is cooled to 15°C p-Aminophenol is filtered and the filtrate is collected. • The reaction takes place in an autoclave or suitable hydrogenating equipment.
• This filtrate, containing p-aminophenol could be re-used in the
reduction step 4-5 times before being discharged as effluent.The iron sludge could be used for making iron oxide for red oxide primers.
• Pure p-aminophenol is reported to be prepared by adding more p-
nitrophenol to the reaction mixture (if the reaction has gone to completion), adjusting the pH between 5.0 and 6.5 and separating the p-nitrophenol phase and the p-aminophenol could be purified by giving treatment with carbon in aqueous hydrochloric acid solution and it could be stabilized by the addition of sodium sulphite.
• The acetylation of p-aminophenol to crude paracetamol is carried
out by the addition of acetic anhydride. • The temperature could increase to around 80°C. After cooling, crude paracetamol is filtered. The crude paracetamol is given charcoal treatment and pure paracetamol is recrystallized in water. The wet cake of paracetamol is centrifuged, dried and packed. • A Second Stream arises from the centrifuge.
• The filtrate, after filtration of crude paracetamol, is dilute
acetic acid solution containing unreacted p-aminophenol and paracetamol. Secondary acetylation may ensure that the conversion of p-aminophenol is complete. With solvent extraction, paracetamol could be recovered and dilute acetic acid could find some uses.
• The filtrate obtained after filtration of pure paracetamol could
be re-used in the purification step 3-4 times before being discharged as effluent. • Paracetamol could be recovered from this effluent by lowering its temperature or by solvent extraction or by salting out. This would improve the yields.
• The precipitated paracetamol is separated by filtration through a
centrifuge
• The slurry, still having some paracetamol , is then transferred to a
liquid-liquid extractor where 99% of the acetic acid and over 90 % of the paracetamol is removed in the extract using a suitable solvent like hexane or ethyl acetate
• A vertical packed bed or centrifugal extractor maybe used for the
counter current extraction
• The extract is subjected to distillation for recovery of the solvent
and acetic acid, leaving a residue containing paracetamol • The overhead stream in the distillation column is divided into two parts- one for acetic acid and the other for the solvent
• The residue consists primarily of paracetamol and may be sent to a
second crystallisation unit or recycled back to the primary crystallisation unit
• Where a second crop of crystals is desired, the bottom fraction is
mixed with water to depress paracetamol solubility and then cooled to ambient temperature or somewhat below in order to crystallize it
• If the paracetamol color does not pertain to the standards of
pharmaceutical industry, adsorption by carbon particles may be done in the step before crystallisation to make it completely white Process Flow Sheet
