Pharmaceutical Engineering: Production of Aspirin Joseph Kisutcza 2004 - New Jersey Institute of Technology Presented Joe Kisutcza Photographs depict Mark Ladolcetta Animation sequence can be altered to “advance on mouse click” by changing the slide transitions. If animation timings are used, pauses are needed for slides 5,11, 25 and 55. Presentation can be shortened by removing slides 2-3 and/or removing animation sequences. NOTE: This presentation is for demonstration purposes and may not reflect how aspirin is actually synthesized in industry.

Pharmaceutical Synthesis Pharmaceuticals are either synthesized chemically or are extracted from natural sources Pharmaceuticals are usually produced in BATCH as opposed to CONTINUOUS processes Purity in pharmaceuticals is critical – often reaching purity levels in excess of 99.99%

A brief history of Aspirin As early as 1500 B.C. Egyptians recorded a collection of recipes for pain medicines, that included a recipe of an infusion of dried myrtle leaves (which contains salicylic acid).

Around 200 B.C. Hyppocrates of Kos, the father of all doctors proscribed a juice extracted from the bark of the willow tree (salix alba) that alleviated the symptoms of pain and fever.

Around 100 A.D. Dioscoides mentions the use of willow leaves for pain. Pliny the Elder (Roman statesman) and Galen (Greek alchemist) both wrote about using willow leaves to relieve pain. Around 100 A.D. Dioscoides mentions the use of willow leaves for pain. There are signs of natives of North America using salicylate medicines made from birch bark. In 1763 Edward Stone reports the successful use of willow bark to reduce fever in his patients. To reduce stomach irritation, caffeine is also added to most aspirin. Methyl salicylate, the main component in “oil of wintergreen”, is a closely related chemical and is also readily available. Aspirin could be synthesized directly from methyl salicylate by adding a few more steps to the process. 1763 A.D.

Johann Bũchner of Munich isolates salicin from willow bark in 1828. 1828 A.D. Johann Bũchner of Munich isolates salicin from willow bark in 1828. A German chemist Karl Gerhardt in 1853 synthesized a new substance acetylsalicylic acid, but his discovery was overlooked. Another German chemist Hermann Kolbe discovered an effective large scale synthesis for salicylic acid from coal tar in 1859. In Dresden, Germany salicylic acid was made in industrial quantities in 1874. To reduce stomach irritation, caffeine is also added to most aspirin. Methyl salicylate, the main component in “oil of wintergreen”, is a closely related chemical and is also readily available. Aspirin could be synthesized directly from methyl salicylate by adding a few more steps to the process. 1874 A.D.

In 1893 Felix Hoffman an employee of Bayer A. G In 1893 Felix Hoffman an employee of Bayer A.G. reinvestigated the synthesis reported by Gerhardt 40 years earlier and discovered that the “acetylated” form of salicylic acid reduced the unpleasant effects (mouth and stomach irritation) of the “non-acetylated” form without reducing the medical effectiveness.

The chemistry and synthesis of Aspirin Aspirin molecule

The Kolbe Synthesis: Preparation of Salicylic Acid Sodium phenoxide Sodium salicylate Salicylic acid Carbon dioxide @ 125ºC & 100 atm

Preparation of Acetylsalicylic Acid Aspirin

Aspirin manufacturing

Recent US Aspirin production Year. Demand in millions. of pounds 1997 Recent US Aspirin production Year Demand in millions of pounds 1997 23.4 1998 23.5 1999 23.7 2000 23.9 2001 23.8 2002 23.9 2006 24.3 2008 25.1 Recent World Aspirin production Year Demand in millions of kgs 2001 50.0 2002 50.0 2998 52.0

The wholesale value of the 2008 US Aspirin production (based on $4 The wholesale value of the 2008 US Aspirin production (based on $4.00/lb) is over 100 million USD The retail value of the 2008 World Aspirin production (based on $5.00/100 tablets or capsules) is over 25 billion USD

One of the major production step in the manufacturing of Aspirin is crystallization

This step is shown in the following simple animation of the process in a plant environment, together with some photographs of the laboratory process

Aspirin: From Lab to Tab Salicylic acid is first added to the reactor REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2 Although shown as pellets, the salicylic acid is actually in powder form. NOTE: For each slide in the sequence, the photograph shows each step as performed in a laboratory while the graphic depicts the equivalent process in a chemical plant environment. The text box gives a brief description of the process step. In the animation sequence, pipes and pumps are red when they are inactive and green when fluid flows through them. The pipes on both sides of each vessel represent a water jacket, through which hot or cold water can be circulated depending on heating or cooling needs. Hot water is shown in red; cold water is shown in blue.

Aspirin: From Lab to Tab Acetic anhydride and sulfuric acid are added REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2 Sulfuric acid (yellow) is added at the beginning and only sparsely compared to acetic anhydride, the main reactant.

Aspirin: From Lab to Tab Acetic anhydride and sulfuric acid are added REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab Acetic anhydride and sulfuric acid are added REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab Acetic anhydride and sulfuric acid are added REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab Acetic anhydride and sulfuric acid are added REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The reactor is heated to complete the reaction REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2 The picture shows a hot water bath

Aspirin: From Lab to Tab The reactor is heated to complete the reaction REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The reactor is heated to complete the reaction REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The reactor is heated to complete the reaction REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The solution is transferred to recrystallizer #1 REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2 The pump starts and transfers the solution from the reactor to recrystallizer #1

Aspirin: From Lab to Tab The solution is transferred to recrystallizer #1 REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The solution is transferred to recrystallizer #1 REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The solution is transferred to recrystallizer #1 REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The solution is transferred to recrystallizer #1 REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The solution is transferred to recrystallizer #1 REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The solution is cooled to promote crystal growth REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2 Converse to heating promoting dissolution of a solute, cooling promotes recrystallization of a solute from a solution. The picture shows immersion of the recrystallizer in an ice bath.

Aspirin: From Lab to Tab The solution is cooled to promote crystal growth REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The solution is cooled to promote crystal growth REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The solution is cooled to promote crystal growth REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab Ice and water are added to the aspirin solution REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2 The ice and water aid in cooling the solution and dissolve any unwanted water soluble contaminants.

Aspirin: From Lab to Tab Ice and water are added to the aspirin solution REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The original solution (mother liquor) is drained REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2 The pump transfers the mother liquor out to drain (or potentially to be recycled). The picture shows the crystals being separated from the mother liquor with a Buchner funnel connected to a vacuum.

Aspirin: From Lab to Tab The original solution (mother liquor) is drained REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The original solution (mother liquor) is drained REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The original solution (mother liquor) is drained REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The original solution (mother liquor) is drained REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The original solution (mother liquor) is drained REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab Ethanol is added to dissolve the crystals REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2 The ethanol solubilizes some remaining contaminants along with the aspirin crystals for pumping to recrystallizer #1.

Aspirin: From Lab to Tab Ethanol is added to dissolve the crystals REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab Ethanol is added to dissolve the crystals REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab Ethanol is added to dissolve the crystals REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab Ethanol is added to dissolve the crystals REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab Ethanol is added to dissolve the crystals REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The solution is transferred to recrystallizer #2 REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2 The picture shows another Buchner funnel used to filter out any insolubles that may have come from the ethanol solution.

Aspirin: From Lab to Tab The solution is transferred to recrystallizer #2 REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The solution is transferred to recrystallizer #2 REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The solution is transferred to recrystallizer #2 REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The solution is transferred to recrystallizer #2 REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The solution is transferred to recrystallizer #2 REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab Warm water is added to the aspirin solution REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2 The water is added to aid in the dissolution of the aspirin crystals and contaminants.

Aspirin: From Lab to Tab The solution is cooled to promote crystal growth REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2 The final product will recrystallize out of solution. The picture shows the recrystallizer in an ice bath covered with a watch glass to slow evaporation.

Aspirin: From Lab to Tab The solution is cooled to promote crystal growth REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The solution is cooled to promote crystal growth REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The solution is cooled to promote crystal growth REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The remaining mother liquor is drained REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2 Another Buchner funnel is used to drain off and dry the final product crystals.

Aspirin: From Lab to Tab The remaining mother liquor is drained REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The remaining mother liquor is drained REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The remaining mother liquor is drained REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The remaining mother liquor is drained REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The remaining mother liquor is drained REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2

Aspirin: From Lab to Tab The pure aspirin can now be dried and tabletized REACTOR RECRYSTAL-LIZER #1 RECRYSTAL-LIZER #2 Industrially, drying is usually done with a rotary kiln dryer or, more recently, a microwave dryer. Tablets are usually press-formed.

Recent developments

In 1971 John Vane found that aspirin inhabits the production of prostaglandin. Later he receives the Nobel Prize for Medicine and was given a knighthood for his work. A study in 1977 proves that aspirin prevents stroke In 1995 it was discovered that aspirin reduces the risk of colon cancer FDA in 1998 approves the use of aspirin for preventing heart attacks

Pharmaceuticals are our first line of defense against deadly diseases We just examined Aspirin process – the metamorphosis of a laboratory discovery into a mass-marketable product Aspirin is particularly important because it was one of our first analgesics and because it has properties we are still discovering. Pharmaceuticals are our first line of defense against deadly diseases Aspirin’s anti-coagulant properties make it ideal for preventing blood clot stoppages in heart attack victims. Many pharmaceutical companies, large and small, are headquartered in New Jersey. Fully 60% of the engineers working in New Jersey have graduated from NJIT.

JUST IMAGINE – You could be the first engineer to bring an important cure to market – perhaps for AIDS, cancer, or another serious disease that plagues mankind . . .