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PropofolCAS Registry Number: 2078-54-8 
CAS Name: 2,6-Bis(1-methylethyl)phenolAdditional Names: 2,6-diisopropylphenol; disoprofol 
Manufacturers’ Codes: ICI-35868 
Trademarks: Ansiven (Abbott); Diprivan (AstraZeneca); Disoprivan (AstraZeneca); Rapinovet (Schering-Plough Vet.)Molecular Formula: C12H18OMolecular Weight: 178.27Percent Composition: C 80.85%, H 10.18%, O 8.97% 
Literature References: Prepn: A. J. Kolka et al.,J. Org. Chem.21, 712 (1956); 22, 642 (1957); G. G. Ecke, A. J. Kolka, US2831898 (1958 to Ethyl Corp.); T. J. Kealy, D. D. Coffman, J. Org. Chem.26, 987 (1961); B. E. Firth, T. J. Rosen, US4447657 (1984 to Universal Oil Products). Chromatographic study: J. K. Carlton, W. C. Bradbury, J. Am. Chem. Soc.78, 1069 (1956). Animal studies: J. B. Glen, Br. J. Anaesth.52, 731 (1980).Pharmacokinetics: H. K. Adam et al.,ibid. 743; idem,ibid.55, 97 (1983). Determn in blood: eidem,J. Chromatogr.223, 232 (1981). Comparative studies vs other injectable anesthetics: B. Kay, D. K. Stephenson, Anaesthesia35, 1182 (1980); D. V. Rutter et al.,ibid. 1188. Use in i.v. anesthesia: E. Major et al.,ibid.37, 541 (1982). Cardiovascular effects: D. Al-Khudhairi et al.,ibid. 1007. Pharmacology of emulsion formulation: J. B. Glen, S. C. Hunter, Br. J. Anaesth.56, 617 (1984). Series of articles on pharmacology and clinical experience: Postgrad. Med. J.61, Suppl. 3, 1-169 (1985). 
Properties: bp30 136°. bp17 126°. mp 19°. nD20 1.5134. nD25 1.5111. d20 0.955.Melting point: mp 19°Boiling point: bp30 136°; bp17 126°Index of refraction:nD20 1.5134; nD25 1.5111Density: d20 0.955Therap-Cat: Anesthetic (intravenous).Therap-Cat-Vet: Intravenous anesthetic (dogs and cats).Keywords: Anesthetic (Intravenous).SYN

File:Propofol synthesis.svg

Prepn: A. J. Kolka et al., J. Org. Chem. 21, 712 (1956); 22, 642 (1957); G. G. Ecke, A. J. Kolka, US 2831898 (1958 to Ethyl Corp.); T. J. Kealy, D. D. Coffman, J. Org. Chem. 26, 987 (1961); B. E. Firth, T. J. Rosen, US 4447657 (1984 to Universal Oil Products).SYN


Abstract Image

A commercially viable manufacturing process for propofol (1) is described. The process avoids acid–base neutralization events during isolation of intermediate, 2,6-di-isopropylbenzoic acid (3) and crude propofol, and thus simplifies the synthesis on industrial scale to a considerable extent. Syntheses of five impurities/related substances (USP and EP) are also described. 



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Propofol is used during surgeries for sedation and an injectable grade with purity > 99.90% is desired by the medical community. An embodiment of the present invention provides an economically feasible, industrial process for the manufacture of high purity injectable grade Propofol. An embodiment of the present invention relates to a process and novel strategy for purification of 2,6-diisopropylphenol (Propofol) and similar products.

[0003] Propofol is a sterile injectable drug that appears in the USP, EP and IP Monographs. Drug product is manufactured by using high purity drug substance 2,6-di-isopropylphenol commonly known as Propofol.

[0004] Propofol is used to put patients to sleep and keep them asleep during general anesthesia for surgery or other medical procedures. It is used in adults as well as children 2 months and older. Propofol is frequently used as a sedative, and has a rapid onset of action and a short recovery period. Propofol slows the activity of brain and nervous system. Propofol is also used to sedate a patient who is under critical care and needs a mechanical ventilator (breathing machine). Propofol is a hypnotic alkylphenol derivative. When formulated for intravenous induction of sedation and hypnosis during anaesthesia, Propofol facilitates inhibitory neurotransmission mediated by gamma- Aminobutyric acid (GABA). Propofol is associated with minimal respiratory depression and has a short half-life with a duration of action of 2 to 10 minutes.

[0005] Propofol is commonly used parenteral anesthetic agent in the United States, extensively used for minor and outpatient surgical procedures because of its rapid onset and reversal of action, and in intensive care units (ICUs) for maintaining coma. Propofol has been associated with rare instances of idiosyncratic acute liver injury; in addition, prolonged high dose Propofol therapy can cause the “Propofol infusion syndrome” which is marked by brady arrhythmias, metabolic acidosis, rhabdomyolysis, hyperlipidemia and an enlarged or fatty liver.

[0006] Friedel-Craft’s alkylation of phenol using propylene gas in the presence of Lewis acid (LA) catalysts is a commonly used method for the synthesis of Propofol and is well documented in a number of publications and patents [Ecke, G. G., Kolka, A. J. US 2,831,898 A, 1958. Firth, B. E., Rosen, T. J. US 4,447,657, 1984. Akio, T., Yoshiaki, I., Hidekichi, H., Kiyoji, K., Takashi, K., Masanobu, M. EP 0169359A1, 1986. Ecke, G. G., Kolka, A. J. US 3,271,314, 1966. Napolitano, J. P. US 3,367,981 A, 1968. Goddard L. E. US 3,766,276, 1973. Firth, B. E. US 4,275,248, 1981, etc.]

[0007] A number of patents and published literature describe the manufacture of Propofol. US. Pat. No. 4,275,248; W0200034218; EP169359; US. Pat. No. 3,367,981; US. Pat. No.

3,271,314; US. Pat. No. 3,766,276; US. Pat. No. 2,831,898; US.Pat.No.2,207,753; GB1318100; U.S. Pat. No. 4,391,998; US. Pat. No. 4,774, 368; US. Pat. No. 5,589,598; US. Pat. No. 6,362,234; etc. EP 0511947, discloses purification of Propofol that is obtained by alkylation of phenol and purified by crystallization at -10 to -20°C (melting point of Propofol is 18°C). This patent also describes purification using non-polar solvents such as Petroleum ether or Hexane, where solvent residue is removed by distillation or evaporation and finally Propofol is obtained using fractional distillation under high vacuum.

[0008] Continuous separation of a mixture of Propofol with phenolic impurities and methanol is described in an U.S. Pat. No. 5,264,085. U.S. Pat. No. 5,705,039 describes the purification of impure 2,6-diisopropylphenol first using continuous distillation and then distilling pure Propofol under high vacuum.

[0009] Patent CN103360219A describes purification wherein 2,6-diisopropyl phenol is reacted with benzoyl chloride to generate ‘benzoic acid-2, 6-diisopropyl benzene ester’, which is then purified to yield Propofol. The patent discloses that an adsorbent is added at the rectifying stage, so that impurities with similar chemical structures and boiling points are effectively removed; the content of a single impurity in the product is not higher than 0.01%; the total impurity is not higher than 0.05%.

[0010] CN105601477A describes purification of Propofol wherein crude Propofol is purified with three-stage distillation method; the crude Propofol enters feeding tank protected by nitrogen and is charged into first-stage film distillation system through pump; then the product is fed to second-stage molecular distillation system and low boiling point impurities are removed; finally, the processed product is charged into third-stage molecular distiller through a pump, high-boiling-point impurities are separated, and the colourless or yellowish high-purity Propofol is obtained.

[0011] In another prior art disclosure, after completion of the reaction, the final product is isolated and purified by high-vacuum distillation. Alkylation of phenol using propylene gas at high pressure and high temperature is reported. Several impurities like 2,4-diisopropyl and 2,4,6-triisopropyl phenol are the major side products along with the corresponding Isopropyl ether. All these impurities need to be controlled at a limit of NMT 0.05% or less in the final API for it to be pharmaceutically acceptable. In another prior art disclosure, isopropanol was used as the propylating agent instead of direct propylene gas. In this method propylene is generated in situ using IPA and strong acid like sulfuric acid and catalysts like Aluminoslicate [See Baltalksne, A. E.; Zitsmanis, A. H. SU 443019, 1974. Jain, K. P., Edaki, D. U., Minhas H. S., Minhas G. S. WO/2011/ 161687 Al, 2011. Wu, M. US 4,391,998, 1983]

[0012] Another method is to use of protected phenol, where 4-chloro or 4-carboxylic acid substituted phenol is used as starting material along with Isopropanol in sulfuric acid, followed by removal of the 4-substituent to give Propofol [Baltalksne, A. E.; Zitsmanis, A. H. SU 443019, 1974. Jain, K. P., Edaki, D. U., Minhas H. S., Minhas G. S. WO/2011/ 161687 Al, 2011. Wu, M. US 4,391,998, 1983. Tsutsumi, S.; Yoshizawa, T.; Koyama, K. Nippon Kagaku Zasshi 1956, 77, 737-738. Paiocchi, M. US 5,589,598, 1996. Nieminen, K., Essen, P. US 5,175,376, 1992. Keller, S., Schlegel, J. WO/2012/152665 Al, 2012.] The final purification is carried out by high- vacuum distillation to get highly pure Propofol. Since the para position is blocked, related impurities such as 2,4-isopropyl and 2,4,6-triisopropyl derivatives are avoided. In this approach, intermediate is purified before converting to crude Propofol using either de-chlorination by hydrogenation or de-carboxylation before vacuum distillation for final purification.

[0013] It is reported in the literature that 4-hydroxybenzoic acid is used as starting material for alkylation with isopropyl alcohol in sulfuric acid. In that method 2,6-diisopropyl-4-hydroxy benzoic acid gets formed, which is extracted in toluene either in presence of an acid or the impurities are extracted in toluene under alkaline condition. The decarboxylation is carried out using solvents like monoethylene glycol or ethoxyethanol at high temperature. At the end of decarboxylation, crude Propofol is isolated by extracting into toluene. The advantage is Propofol does not form sodium salt under the conditions, but all other acidic impurities form sodium salt and thus do not get extracted in toluene. The toluene containing Crude Propofol is distilled to recover toluene and then vacuum distilled to obtain pure Propofol. [Chen, T; Chen, X.; Bois-Choussy, M.; Zhu, J. J. Am. Chem. Soc. 2006, 128, 87-89. Lau, S.; Keay, B. Can. J. Chem. 2001, 79, 1541-1545]

[0014] In summary, strategies disclosed in prior art for the production of 2,6-diisopropylphenol (Propofol) predominantly involve synthesis starting from phenol or by using protected 4-position of phenol like, 4-hydroxybenzoic acid, 4-chlorophenol (references: Baltalksne, A. E.; Zitsmanis, A. H. SU 443019, 1974. Jain, K. P., Edaki, D. U., Minhas H. S., Minhas G. S. WO/2011/ 161687 Al, 2011. Wu, M. US 4,391,998, 1983. Tsutsumi, S.; Yoshizawa, T.; Koyama, K. Nippon Kagaku Zasshi 1956, 77, 737-738. Paiocchi, M. US 5,589,598, 1996. Nieminen, K., Essen, P. US 5,175,376, 1992. Keller, S., Schlegel, J. WO/2012/152665 Al, 2012). Processes described in the literature generally propose purification of crude 2,6-diisopropylphenol by ‘high vacuum distillation or molecular distillation’.

[0015] The phenols are susceptible to oxidation, formation of polymeric and color impurities. There are processes where repeated vacuum distillation has been carried out to obtain desired purity of product. Sometimes, to reduce the oxidized and colored impurities, reduction of impurities by catalytic hydrogenation is also used.

[0016] Propofol that does not meet Pharmaceutical grade may be manufactured by several processes generally known to persons of skill in the art and described in prior art, but purification of Propofol to consistently achieve high purity required for the injectable drug substance using an economical and industrial process remains a challenge.

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Example 1:

[0033] Commercially available concentrated sulfuric acid (30 Kg) was diluted with water (2.26 Kg) at low temperature (0-15°C). Methyl 4-hydroxybenzoate (5 Kg 32.79 mol.) was added to this diluted sulfuric acid at 5 to 10 °C with stirring. After complete addition, isopropyl alcohol (5.9 Kg 98.16 mol.) was gradually added to the reaction content, controlling the temperature at 0-15 °C. The reaction mixture was then heated at 60-70°C and continued to complete di-isopropylation and ester hydrolysis to yield methyl-4-hydroxybenzoate. The conversion was checked on TLC or by HPLC for the complete conversion of methyl-4 hydroxybenzoate to 3, 5 -Diisopropyl 4-hydroxybenzoic acid.

[0034] The reaction contents were cooled at room temperature and carefully charged into a stirred, precooled mixture of water (50 L) and Toluene (40 L) at (0 to 5°C). The mixture was stirred and maintained below 15°C for about 30 to 60 minutes.

[0035] The content was then heated at 25 to 30°C, stirred for 30 min., allowed to settle into two layers. The water layer was extracted again with toluene and discarded. The toluene layers, containing the product 3, 5-Diisopropyl 4-hydroxybenzoic acid, were combined and extracted with about 25 L of 10 % NaOH. The aqueous layer containing the sodium salt of 3, 5 -Di-isopropyl 4-hydroxybenzoic acid was acidified with concentrated HC1 (about 9 Kg) to precipitate 3, 5-Diisopropyl 4-hydroxybenzoic acid, filtered, and washed with water (about 50 L) to yield 3, 5 -diisopropyl 4-hydroxybenzoic acid (about 45-60 %)

[0036] To the mixture of 3, 5-diisopropyl 4-hydroxybenzoic acid (3 Kg, 13.5 mol.) in ethylene glycol (5.0 Kg, 80.55 mol.) was added sodium hydroxide (1.25 Kg, 31.25 mol.) for decarboxylation. The reaction mixture was heated at 145 ± 5°C till completion of

decarboxylation by monitoring using TLC or HPLC (or solubility in bicarbonate of precipitated product). After complete decarboxylation, the reaction mixture was cooled at 40 to 45 °C, under nitrogen environment and diluted with water (about 15 L) and allowed to settle. The oily product layer was separated and washed with water (6L) to isolate crude Propofol (i.e., 2,6-diisopropyl phenol) and stored under nitrogen. The isolated volatile Crude Propofol (along with carry over ppm ethylene glycol and NaOH) was then subjected to steam distillation purification process as described below.

[0037] The Crude Propofol is purified by using one of the steam distillation processes as described below.

[0038] The Crude Propofol layer is added to purified water in a reactor (preferably glass lined reactor), and slowly heated to boiling to co-distil Pure Propofol along with water under normal atmospheric pressure and the high volatile initial fraction is isolated first. The biphasic layers of main distillate, are separated and the liquid layer of Propofol is treated with dehydrating agent to absorb dissolved moisture in Pure Propofol under nitrogen or argon. The transparent Pure Propofol liquid layer is then filtered through ultrafme Micron filter (0.45 and 0.2 micron) under nitrogen (or argon) pressure and isolated in controlled environment to obtain pharmaceutical injectable grade Pure Propofol of more than 99.90% purity.

[0039] The Crude Propofol liquid layer is charged into a reactor with steam distillation arrangement, like steam purging dip tube, column, heat exchanger and receivers. Pure steam is purged in the reactor at controlled pressure to co-distil Pure Propofol with water. The layers are allowed settle and water layer is kept aside for recirculation. The transparent Pure Propofol transparent liquid layer is then filtered through ultrafme Micron filter (0.45 and 0.2 micron) under nitrogen (or argon) pressure and isolated in controlled environment to obtain pharmaceutical injectable grade Pure Propofol of more than 99.90% purity.

[0040] The Crude Propofol layer is added to purified water in a reactor (preferably glass lined or Hastelloy reactor) and slowly heated at boiling to co-distil Pure Propofol along with water under mild vacuum. The biphasic layers are separated and the liquid layer of Propofol is treated with dehydrating agent to absorb dissolved moisture in Pure Propofol under nitrogen (or argon). The transparent Pure Propofol liquid layer is then filtered through ultrafme Micron filter (0.45 and 0.2 micron) under nitrogen (or argon) pressure and isolated in controlled environment to obtain pharmaceutical injectable grade Pure Propofol of more than 99.90% purity.

[0041] The Crude Propofol layer is added to reactor containing purified water and 0.1 to 1% antioxidant and 0.1 to 0.5% sodium hydroxide and slowly heated to boiling to co-distil Pure Propofol along with water. The biphasic layers are separated and the liquid layer of Propofol is treated or passed through column packed with dehydrating agent to absorb dissolved moisture in Pure Propofol. The transparent Pure Propofol liquid layer is then filtered through ultrafme Micron filter (0.45 and 0.2 micron) under nitrogen (or argon) pressure and isolated in controlled environment to obtain pharmaceutical injectable grade Pure Propofol of more than 99.90% purity.

[0042] The crude Propofol liquid layer is treated with preferably neutral or basic activated carbon (about 2-5%) and filtered under nitrogen. The filtered liquid is collected, under nitrogen, in distillation reactor containing purified water is slowly heated to boiling to co-distil Pure Propofol along with water under normal pressure or mild vacuum. The co-distilled biphasic layers are separated and the liquid layer of Propofol, is treated under nitrogen, with or passed through column packed with dehydrating agent to absorb dissolved moisture trapped in Pure Propofol. The transparent Pure Propofol liquid layer is then filtered through ultrafme Micron filter (0.45 and 0.2 micron) under nitrogen (or argon) pressure and isolated in controlled environment to obtain pharmaceutical injectable grade Pure Propofol of more than 99.90% purity.

Example No. 2:

[0043] Friedel-Crafts reaction was performed as described in Example 1. Decarboxylation was performed by using KOH instead of NaOH by following the same procedure as described in Example 1.

Example No. 3:

[0044] Decarboxylation was performed as per operations described in Example 1. After complete decarboxylation, the reaction mixture was cooled at 40 to 45°C, under nitrogen environment and diluted with water (about 15 L) The biphasic mixture subjected to steam distillation by any of the purification methods described in Example 1.

Example No. 4:

[0045] Friedel-Crafts reaction was performed as described in Example 1. The reaction contents were cooled at room temperature and carefully charged at 0 to 5°C into a sodium hydroxide solution to basic pH at stirred. The aqueous alkaline solution was extracted twice with toluene or hexane. The aqueous layer was acidified with HC1 to precipitate 3, 5-diisopropyl-4-hydroxybenzoic acid. The wet product was washed with water, dried and decarboxylated using sodium hydroxide in ethylene glycol as solvent at 145±5°C. The reaction contents were cooled to room temperature, diluted with water and acidified and then Crude Propofol was extracted twice in toluene. The toluene layer was washed with water, bicarbonate and with water then distilled to obtain crude oily layer of Propofol (>99% pure). This Crude Propofol was then purified by using purification steam distillation by any of the purification methods described in Example 1.

Example 5:

[0046] Continuous steam distillation of crude Propofol by purging pure steam. Continuous steam distillation of Crude Propofol was carried out using a feed pump for feeding liquid Crude Propofol (prepared by one of the processes described in this application or other literature) to the steam distillation system connected to a pure steam generator. Steam at 1-10 kg pressure was purged in the steam distillation system at controlled rate and the co-distilled Pure Propofol with water was cooled using heat exchanger and continuous separator. The residue was discharged from bottom valve at defined time intervals. The water layer was recycled to steam generator and Pure Propofol was dehydrated, filtered and collected in controlled environment as described in Example 1.

Propofol, marketed as Diprivan, among other names, is a short-acting medication that results in a decreased level of consciousness and a lack of memory for events.[4] Its uses include the starting and maintenance of general anesthesia, sedation for mechanically ventilated adults, and procedural sedation.[4] It is also used for status epilepticus if other medications have not worked.[4] It is given by injection into a vein, and the maximum effect takes about two minutes to occur and typically lasts five to ten minutes.[4] Propofol is also used for medical assistance in dying in Canada.[5]

Common side effects of propofol include an irregular heart ratelow blood pressure, a burning sensation at the site of injection and the cessation of breathing.[4] Other serious side effects may include seizures, infections due to improper use, addiction, and propofol infusion syndrome with long-term use.[4] The medication appears to be safe for use during pregnancy but has not been well studied for use in this case.[4] It is not recommended for use during a cesarean section.[4] It is not a pain medication, so opioids such as morphine may also be used,[6] however whether or not they are always needed is not clear.[7] Propofol is believed to work at least partly via a receptor for GABA.[4]

Propofol was discovered in 1977 and approved for use in the United States in 1989.[4][8] It is on the World Health Organization’s List of Essential Medicines[9] and is available as a generic medication.[4] It has been referred to as milk of amnesia (a play on “milk of magnesia“), because of the milk-like appearance of the intravenous preparation, and because of its tendency to suppress memory recall.[10][11] Propofol is also used in veterinary medicine for anesthesia.[12][13]

Medical uses


To induce general anesthesia, propofol is the drug used almost always, having largely replaced sodium thiopental.[14][6] It can also be administered as part of an anesthesia maintenance technique called total intravenous anesthesia, using either manually programmed infusion pumps or computer-controlled infusion pumps in a process called target controlled infusion (TCI). Propofol is also used to sedate individuals who are receiving mechanical ventilation but not undergoing surgery, such as patients in the intensive care unit.[15][16] In critically ill patients, propofol is superior to lorazepam both in effectiveness and overall cost.[17] Propofol is relatively inexpensive compared to medications of similar use due to shorter ICU stay length.[17] One of the reasons propofol is thought to be more effective (although it has a longer half-life than lorazepam) is because studies have found that benzodiazepines like midazolam and lorazepam tend to accumulate in critically ill patients, prolonging sedation.[17] Propofol has also been suggested as a sleep aid in critically ill adults in the ICU, however, the effectiveness of this medicine at replicating the mental and physical aspects of sleep for people in the ICU are not clear.[16]

Propofol is often used instead of sodium thiopental for starting anesthesia because recovery from propofol is more rapid and “clear”.[citation needed]

Propofol can be run through a peripheral IV or central line. Propofol is frequently paired with fentanyl (for pain relief) in intubated and sedated people.[18] Both are compatible in IV form.[18]

Procedural sedation

Propofol is also used for procedural sedation. Its use in these settings results in a faster recovery compared to midazolam.[19] It can also be combined with opioids or benzodiazepines.[20][21][22] Because of its rapid induction and recovery time, propofol is also widely used for sedation of infants and children undergoing MRI.[23] It is also often used in combination with ketamine with minimal side effects.[24]


In March 2021, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for Propofol‐Lipuro 1% to maintain sedation via continuous infusion in people greater than age sixteen with suspected or confirmed COVID‑19 who require mechanical ventilation in an intensive care unit ICU setting.[25][26][27][28] In the circumstances of this public health emergency, it would not be feasible to require healthcare providers to seek to limit Fresenius Propoven 2% Emulsion or Propofol-Lipuro 1% only to be used for patients with suspected or confirmed COVID‑19; therefore, this authorization does not limit use to such patients.[28]

Other uses


The US state of Missouri added propofol to its execution protocol in April 2012. However, Governor Jay Nixon halted the first execution by the administration of a lethal dose of propofol in October 2013 following threats from the European Union to limit the drug’s export if it were used for that purpose.[29][30] The United Kingdom had already banned the export of medicines or veterinary medicines containing propofol to the United States.[31]

Recreational use

Recreational use of the drug via self-administration has been reported[32][33] but is relatively rare due to its potency and the level of monitoring required for safe use.[citation needed] Critically, a steep dose-response curve makes recreational use of propofol very dangerous, and deaths from self-administration continue to be reported.[34][35] The short-term effects sought via recreational use include mild euphoria, hallucinations, and disinhibition.[36][37]

Recreational use of the drug has been described among medical staff, such as anesthetists who have access to the drug.[38][39] It is reportedly more common among anesthetists on rotations with short rest periods, as usage generally produces a well-rested feeling.[40] Long-term use has been reported to result in addiction.[38][41]

Attention to the risks of off-label use of propofol increased in August 2009 due to the Los Angeles County coroner’s conclusion that music icon Michael Jackson died from a mixture of propofol and the benzodiazepine drugs lorazepammidazolam, and diazepam on June 25, 2009.[42][43][44][45] According to a July 22, 2009 search warrant affidavit unsealed by the district court of Harris County, Texas, Jackson’s physician, Conrad Murray, administered 25 milligrams of propofol diluted with lidocaine shortly before Jackson’s death.[43][44][46] Even so, as of 2016, propofol was not on a US Drug Enforcement Administration schedule.[40][47]

Side effects

One of propofol’s most common side effects is pain on injection, especially in smaller veins. This pain arises from activation of the pain receptor, TRPA1,[48] found on sensory nerves and can be mitigated by pretreatment with lidocaine.[49] Less pain is experienced when infused at a slower rate in a large vein (antecubital fossa). Patients show considerable variability in their response to propofol, at times showing profound sedation with small doses.

Additional side effects include low blood pressure related to vasodilation, transient apnea following induction doses, and cerebrovascular effects. Propofol has more pronounced hemodynamic effects relative to many intravenous anesthetic agents.[50] Reports of blood pressure drops of 30% or more are thought to be at least partially due to inhibition of sympathetic nerve activity.[51] This effect is related to the dose and rate of propofol administration. It may also be potentiated by opioid analgesics.[52] Propofol can also cause decreased systemic vascular resistance, myocardial blood flow, and oxygen consumption, possibly through direct vasodilation.[53] There are also reports that it may cause green discolouration of the urine.[54]

Although propofol is heavily used in the adult ICU setting, the side effects associated with propofol seem to be of greater concern in children. In the 1990s, multiple reported deaths of children in ICUs associated with propofol sedation prompted the FDA to issue a warning.[55]

As a respiratory depressant, propofol frequently produces apnea. The persistence of apnea can depend on factors such as premedication, dose administered, and rate of administration, and may sometimes persist for longer than 60 seconds.[56] Possibly as the result of depression of the central inspiratory drive, propofol may produce significant decreases in respiratory rateminute volumetidal volume, mean inspiratory flow rate, and functional residual capacity.[50]

Diminishing cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure are also characteristics of propofol administration.[57] In addition, propofol may decrease intraocular pressure by as much as 50% in patients with normal intraocular pressure.[58]

A more serious but rare side effect is dystonia.[59] Mild myoclonic movements are common, as with other intravenous hypnotic agents. Propofol appears to be safe for use in porphyria, and has not been known to trigger malignant hyperpyrexia.[citation needed]

Propofol is also reported to induce priapism in some individuals,[60][61] and has been observed to suppress REM sleep stage and to worsen the poor sleep quality in some patients.[62]

As with any other general anesthetic agent, propofol should be administered only where appropriately trained staff and facilities for monitoring are available, as well as proper airway management, a supply of supplemental oxygen, artificial ventilation, and cardiovascular resuscitation.[63]

Because of its lipid base, some hospital facilities require the IV tubing (of continuous propofol infusions) to be changed after 12 hours. This is a preventive measure against microbial growth and infection.[64]

Propofol infusion syndrome

Main article: Propofol infusion syndrome

A rare, but serious, side effect is propofol infusion syndrome. This potentially lethal metabolic derangement has been reported in critically ill patients after a prolonged infusion of high-dose propofol, sometimes in combination with catecholamines and/or corticosteroids.[65]


The respiratory effects of propofol are increased if given with other respiratory depressants, including benzodiazepines.[66]



Propofol has been proposed to have several mechanisms of action,[67][68][69] both through potentiation of GABAA receptor activity and therefore acting as a GABAA receptor positive allosteric modulator, thereby slowing the channel-closing time. At high doses, propofol may be able to activate GABAA receptors in the absence of GABA, behaving as a GABAA receptor agonist as well.[70][71][72] Propofol analogs have been shown to also act as sodium channel blockers.[73][74] Some research has also suggested that the endocannabinoid system may contribute significantly to propofol’s anesthetic action and to its unique properties.[75] EEG research upon those undergoing general anesthesia with propofol finds that it causes a prominent reduction in the brain’s information integration capacity.[76]


Large vial filled with milky white fluid

A 20 ml ampoule of 1% propofol emulsion, as sold in Australia by Sandoz

Propofol is highly protein-bound in vivo and is metabolised by conjugation in the liver.[77] The half-life of elimination of propofol has been estimated to be between 2 and 24 hours. However, its duration of clinical effect is much shorter, because propofol is rapidly distributed into peripheral tissues. When used for IV sedation, a single dose of propofol typically wears off within minutes. Propofol is versatile; the drug can be given for short or prolonged sedation, as well as for general anesthesia. Its use is not associated with nausea as is often seen with opioid medications. These characteristics of rapid onset and recovery along with its amnestic effects[78] have led to its widespread use for sedation and anesthesia.


John B. Glen, a veterinarian and researcher at Imperial Chemical Industries (ICI) spent 13 years developing propofol, an effort which led to the awarding to him of the prestigious 2018 Lasker Award for clinical research. Propofol was originally developed as ICI 35868. It was chosen for development after extensive evaluation and structure–activity relationship studies of the anesthetic potencies and pharmacokinetic profiles of a series of ortho-alkylated phenols.[79]

First identified as a drug candidate in 1973, clinical trials followed in 1977, using a form solubilised in cremophor EL.[80] However, due to anaphylactic reactions to cremophor, this formulation was withdrawn from the market and subsequently reformulated as an emulsion of a soya oil/propofol mixture in water. The emulsified formulation was relaunched in 1986 by ICI (now AstraZeneca) under the brand name Diprivan. The currently available preparation is 1% propofol, 10% soybean oil, and 1.2% purified egg phospholipid as an emulsifier, with 2.25% glycerol as a tonicity-adjusting agent, and sodium hydroxide to adjust the pH. Diprivan contains EDTA, a common chelation agent, that also acts alone (bacteriostatically against some bacteria) and synergistically with some other antimicrobial agents. Newer generic formulations contain sodium metabisulfite or benzyl alcohol as antimicrobial agents. Propofol emulsion is a highly opaque white fluid due to the scattering of light from the tiny (about 150-nm) oil droplets it contains: Tyndall Effect.


A water-soluble prodrug form, fospropofol, has been developed and tested with positive results. Fospropofol is rapidly broken down by the enzyme alkaline phosphatase to form propofol. Marketed as Lusedra, this formulation may not produce the pain at injection site that often occurs with the conventional form of the drug. The U.S. Food and Drug Administration (FDA) approved the product in 2008.[81] However fospropofol is a Schedule IV controlled substance with the DEA ACSCN of 2138 in the United States unlike propofol.[82]

By incorporation of an azobenzene unit, a photoswitchable version of propofol (AP2) was developed in 2012, that allows for optical control of GABAA receptors with light.[83] In 2013, a propofol binding site on mammalian GABAA receptors has been identified by photolabeling using a diazirine derivative.[84] Additionally, it was shown that the hyaluronan polymer present in the synovia can be protected from free-radical depolymerization by propofol.[85]






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External links

Wikimedia Commons has media related to Propofol.
  • “Propofol”Drug Information Portal. U.S. National Library of Medicine.
  • GB patent 1472793, John B Glen & Roger James, “Pharmaceutical Compositions”, published 1977-05-04, assigned to Imperial Chemical Industries Ltd
Clinical data
Trade namesDiprivan, others[1]
License dataUS DailyMedPropofol
Physical: very low (seizures)
Psychological: no data
Routes of
ATC codeN01AX10 (WHO)
Legal status
Legal statusAU: S4 (Prescription only)CA℞-onlyUK: POM (Prescription only)US: ℞-only [3]In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding95–99%
MetabolismLiver glucuronidation
Onset of action15–30 seconds[4]
Elimination half-life1.5–31 hours[4]
Duration of action~5–10 minutes[4]
showIUPAC name
CAS Number2078-54-8 
PubChem CID4943
CompTox Dashboard (EPA)DTXSID6023523 
ECHA InfoCard100.016.551 
Chemical and physical data
Molar mass178.275 g·mol−1
3D model (JSmol)Interactive image


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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, CLEANCHEM LABS as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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