Benzene is a highly toxic compound, and long-term exposure to benzene can cause anemia, leukemia, and other medical conditions [1].  The ICH has classified benzene as a Class 1 solvent with a limit of NMT 2 ppm [2], and people in pharma and pharma-related industries are very concerned about controlling and minimizing the levels of benzene in their products.  Benzene and 50 other solvents of the four ICH classes have been screened by headspace GC to detect residual solvents as impurities in APIs [3].

Benzene has been used to make ethyl benzene, styrene, aniline, cyclohexane, cumene, phenol, chlorobenzene, and other simple feedstocks.  So perhaps we shouldn’t be surprised when benzene is found in our APIs, reagents, and solvents.  Although benzene could accidentally contaminate a drum of material, manufacturers catering to the pharma market are probably very alert to sources of benzene contamination in their products.  It is more likely that benzene is present in solvents or reagents, or is formed as an artifact.

Benzene in solvents Toluene is commercially available with less than 0.1 wt% of benzene [4].  Benzene can be separated from toluene by distillation; a high reflux ratio is key [5].

Acetone can contain low levels of benzene.  Acetone is primarily manufactured through alkylation of benzene with propylene to afford cumene, followed by generation of cumyl hydroperoxide, and scission through the Hock reaction to generate phenol and acetone [6].  Hence unreacted benzene could contaminate acetone manufactured from cumene.  A minor route to acetone is that from oxidation of propylene; in principle benzene could be generated as a minor byproduct under these conditions.  (Possible reaction: 2 propylene + 1.5 O₂ produces benzene + 3 H₂O.)  Due to similar volatility of benzene and acetone, separating acetone from benzene is difficult, and azeotropes may be employed [7].

Absolute ethanol can be produced by adding benzene, distilling off the EtOH – benzene – water azeotrope, and then distilling off the benzene – EtOH azeotrope to remove benzene; of course, not all the benzene is guaranteed to be removed [8].  Ethanol can be denatured with many compounds, including benzene.  EtOH denatured with benzene can be labeled as S.D.A. 2-B, S.D.A. 2-C, or S.D.A. 12-A. [9].  Denatured fuel ethanol can contain gasoline, toluene, xylene, and benzene [10].  Hence if denatured EtOH is used in manufacturing it is prudent to confirm that supplies are not contaminated by benzene.

Benzene in reagents Benzene was found in benzenesulfonic acid used to crystallize an NCE [11].

Benzene formed as an artifact Sometimes questioning the method of sample preparation / analysis can be informative.  For instance, benzene was formed from the preservative sodium benzoate when soft drinks containing ascorbic acid were heated at 100 ºC for 30 min [12].  Some control reactions may be needed to ensure that artifacts are not generated during sample preparation and analysis.

Bottom line We are well-advised to look at our reactions to anticipate if benzene could be present or generated in our process streams.  Only a small amount of benzene could derail the development or sale of a drug.  Nature doesn’t care if we think a “good reaction” is needed to generate an impurity.

1. http://www.atsdr.cdc.gov/PHS/PHS.asp?id=37&tid=14#bookmark05
2. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3C/Step4/Q3C_R5_Step4.pdf
3. Li Qin, L.; Chang-qin Hu, C.; Yin, L., “Establishment of a Knowledge Base for Prescreening Residual Solvents in Pharmaceuticals”, Chromatographia 2004, 59(7),
4. http://www.citgo.com/WebOther/CITGOforYourBusiness/Petrochemicals/Toluene.pdf, dated January 2016
5. http://seperationtechnology.com/benzene-distillation
6. Weissermel, K.; Arpe, H.-J. Industrial Organic Chemistry; 3d ed.; VCH: Weinheim; 1997; pp 276-7, 342-3, 353-5.
7. Berg, L., “Separation of Benzene from Acetone by Azeotropic Distillation,” US 4,931,145 (1990).
8. http://cool.conservation-us.org/waac/wn/wn28/wn28-3/wn28-304.pdf. “…smart chemists know to stay away from the lab punch made with absolute ethanol.”
9. https://www.law.cornell.edu/cfr/text/27/21.151
10. http://itecref.com/pdf/MSDS_Fuel_Alcohol_ITEC_Refining.pdf
11. Gross, T. D.; Schaab, K.; Ouellette, M.; Zook, S.; Reddy, J. P.; Shurtleff, A.; Sacaan, A. I.; Alebic-Kolbah, T.; Bozigian, H. Process Res. Dev. 2007, 11, 365.
12. Hileman, B. Chem. Eng. News 2006, 84(17), 10.