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Reactor Configuration

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Case Study
ASPIRIN PRODUCTION
PHARMACEUTICAL INDUSTRY

Aspirin, also known as acetylsalicylic acid or 2-acetoxybenzoic acid, has been a cornerstone of
modern medicine. The exceptional therapeutic value of aspirin has been extensively
documented in scientific literature, validating its wide-ranging clinical applications. Its
significance lies in its broad therapeutic effects, which include analgesic, anti-inflammatory,
antipyretic, and antiplatelet properties

Aspirin (acetylsalicylic acid) is synthesized via the esterification reaction between salicylic acid
and acetic anhydride in the presence of an acid catalyst (typically sulfuric or phosphoric acid).

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REACTION OF THE PROCESS

A. Domokos, et al. International Journal of Pharmaceutics 581 (2020) 119297

Acetylsalicylic acid (ASA) (>99%)

Aspirin (acetylsalicylic acid) is synthesized via the esterification reaction between salicylic acid and acetic anhydride in the presence of an acid
catalyst (typically sulfuric or phosphoric acid).

Acetylsalicylic acid (Aspirin) synthesis reaction.

Salicylic acid + Acetic anhydride → Aspirin (acetylsalicylic acid) + Acetic acid

Salicylic acid (C₇H₆O₃) reacts with acetic anhydride (C₄H₆O₃) to produce aspirin (C₉H₈O₄) and acetic acid (CH₃COOH).
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PROCESS CONDITION

Catalyst Type: The reaction is catalyzed by a strong acid, sulfuric acid (H₂SO₄) or phosphoric acid (H₃PO₄).

Catalyst Concentration:

• The catalyst is used in small amounts, typically about 0.5% by weight of the salicylic acid

• The catalyst accelerates the esterification reaction by protonating the acetic anhydride, making it more reactive toward salicylic acid.

Process Conditions

• At 85°C to 90°C, the conversion of salicylic acid to aspirin can reach high levels, typically around 90-95% conversion depending on reaction time
and other conditions

• The typical molar ratio of acetic anhydride to salicylic acid is about 1.2:1. An excess of acetic anhydride is used to push the reaction toward
completion, ensuring that most of the salicylic acid is converted to aspirin.

• The reaction is usually carried out at atmospheric pressure. Since no gases are involved in the reaction, special pressure controls
are not typically required.

𝑪𝑺𝑨 = concentration of salicylic acid

𝑪𝑨𝑨 = concentration of acetic anhydride
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SIMPLE BLOCK FLOW DIAGRAM

The aforementioned reaction takes place at mildly elevated

temperatures, approximately 90°C. After the reaction is complete, the
mixture is gradually cooled down to approximately 5-25°C , causing
acetylsalicylic acid to precipitate in the form of white crystals. However,
the size distribution of these crystals is not satisfactory for tablet
formation Therefore, it is necessary to dissolve the crystals in a solvent
mixture and perform recrystallization to obtain crystals suitable for
tablet formation. The addition of an antisolvent, such as water, during
this step facilitates the overall crystallization process. The crystals are
then recovered using a basket centrifuge or a cloth filter, and the
remaining moisture is removed using a dryer. This process yields high-
purity acetylsalicylic acid (>99.5%)

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P1 REACTION (BATCH STIRRED REACTOR)
The stirred batch reactor (BSTR) is USED in the production of aspirin for several important reasons related to the
process requirements and the characteristics of the reaction

• This reactor is ideal for producing aspirin in small to medium quantities, which is common in pharmaceutical
manufacturing. Continuous reactors would be more complex and costly for small-scale production.

The reaction mixture is heated to the desired temperature of around 85°C to 90°C. The heat is supplied through
the jacketed system or internal coils with stirring, ensures uniform heat distribution. Temperature control is
critical because:
• Below 85°C, the reaction rate becomes too slow.
• Above 90°C, there’s a risk of side reactions (such as the degradation of aspirin into salicylic acid and acetic acid).

Since the esterification reaction between salicylic acid and acetic anhydride is time-dependent, the
batch reactor allows the operator to stop the reaction at the optimum time for maximum yield and purity.

The reaction is considered complete when most of the salicylic acid has been converted into aspirin,
typically achieving a conversion rate of 90-95%. This is verified through sampling and analysis.

The batch reactor is a closed vessel, meaning that all the reactants are added at the start of the
process, and no additional materials are introduced during the reaction. This helps in controlling
the reaction conditions and prevents contamination, especially from moisture, which is a major
concern in aspirin production.

•Main Reaction (Esterification):

Salicylic Acid + Acetic Anhydride → Aspirin + Acetic Acid
•Side Reaction (Hydrolysis of Acetic Anhydride):
Acetic Anhydride + Water → Acetic Acid

Acetic anhydride can react with water present in the

system or produced in the reactor to form acetic acid
P2 CRYSTALIZATION (BATCH STIRRED REACTOR)
In the production of aspirin (acetylsalicylic acid), crystallization is used as a separation and purification
step after the main chemical reactions have taken place. It allows the aspirin to separate from the reaction
mixture in a highly pure crystalline form.

• Transfer in. The reaction mixture is received into the reactor.

• Pull In Recycled Solvents. The recycled solvents mixture mainly comprised of ethyl acetate and ethyl alcohol, is
transferred into the reactor.
• Pull in Ethanol. Ethanol is pulled into the reactor. •
• Agitate. The agitator is turned on.
• Aspirin Solubilization. The addition of solvents and agitation triggers the complete dissolution of Aspirin, converting
it into Acetylsalicylic Acid. Two side reactions also occur. Specifically, 30% of acetic anhydride reacts with ethyl alcohol
to produce acetic acid and ethyl acetate (Ethanol Acetylation reaction). In addition, 30% of acetic acid reacts with
ethyl alcohol yielding ethyl acetate and water. The table below displays the stoichiometries of the reactions.

• Pull In Water (Antisolvent). Water is added to the reactor and acts as an antisolvent to
facilitate precipitation
• Cool. The mixture is cooled down from ~45℃ to 35℃ using cooling water.
• Precipitation. The mixture is cooled down to 15℃, using chilled water. The addition of the
antisolvent (water), along with the reduced temperature, gradually decreases the solubility of
the acetylsalicylic acid in the solution, causing crystals to form and precipitate. Alongside, acetic
acid and ethyl acetate are also formed, according to the following stoichiometries and
conversions

Kontovas, Stoilas Stylianos & Misailidis, Nikiforos & Mustafa, Amir & Petrides, Demetri. (2023). Aspirin
Production – Process Modeling and Techno-Economic Assessment (TEA) using SuperPro Designer..
10.13140/RG.2.2.25475.68649.
Thank You

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