Oil Carriers and Solvents: Benzyl Benzoate and Benzyl Alcohol
Many long-acting injectable medicines are oil-based solutions. Alongside the active drug and the carrier oil, they often contain benzyl benzoate as a co-solvent and benzyl alcohol as a preservative. These excipients are well studied in licensed products but become a source of risk when the same chemistry is used in unregulated preparations. Our editorial team explains their role and safety.
Why oil-based injections need excipients
Oil-based depot injections allow a lipophilic drug to be released slowly from muscle tissue. Examples among licensed medicines include certain antipsychotics, hormone preparations and vitamin products. The oil, commonly sesame, castor, cottonseed or medium-chain triglycerides, acts as the carrier.
Many drugs do not dissolve sufficiently in oil alone at the required concentration. Co-solvents increase solubility and keep the drug from crystallising, which would make the injection unusable or unsafe.
Multi-dose vials also need a preservative to limit microbial growth after the stopper has been pierced. Benzyl alcohol is one of the most commonly used preservatives in injectable medicines.
Larsen and Larsen reviewed the factors that determine how drugs are released from oily solutions, including the oil type, drug solubility and the presence of co-solvents. Formulation choices therefore affect not only stability but also how the medicine behaves after injection.
Benzyl benzoate
Benzyl benzoate is an ester of benzyl alcohol and benzoic acid. It is a colourless liquid that dissolves many steroid-like molecules well, which is why it appears in several licensed oil-based injections as a co-solvent.
It also has a long history as a topical treatment for scabies and lice and is used in fragrances. These different uses involve different concentrations and routes of exposure.
When injected, benzyl benzoate is metabolised to benzoic acid and then to hippuric acid, which is excreted in urine. In licensed products, the amount is controlled and declared in the summary of product characteristics.
Known risks include local irritation and pain at the injection site and hypersensitivity reactions. Pulmonary oil microembolism, in which oil droplets reach the lungs and cause coughing and breathlessness shortly after injection, has been described with some long-acting oily injections; regulators require warnings about this reaction for affected products.
| Excipient | Main function | Key safety concerns |
|---|---|---|
| Benzyl benzoate | Co-solvent improving solubility | Injection-site irritation, hypersensitivity |
| Benzyl alcohol | Preservative; local anaesthetic effect | Toxicity in neonates, allergy, accumulation |
| Carrier oil | Depot formation and slow release | Allergy (e.g. sesame), oil microembolism |
Benzyl alcohol
Benzyl alcohol is an aromatic alcohol with antimicrobial activity. It is used as a preservative in many injectable medicines and also has a mild local anaesthetic effect, which can reduce injection pain.
The most serious historical safety issue involves newborns. In the early 1980s, Gershanik and colleagues described the "gasping syndrome" in premature infants exposed to benzyl alcohol in flushing solutions. Immature metabolism led to accumulation of benzoic acid, causing metabolic acidosis, breathing difficulties and deaths.
As a result, products containing benzyl alcohol must not be used in neonates unless specifically justified. The European Medicines Agency has issued guidance on labelling benzyl alcohol as an excipient, including warnings about use in young children and in pregnancy, and about accumulation in people with liver or kidney impairment.
Allergic reactions to benzyl alcohol are uncommon but well recognised. People with a known sensitivity should check the excipient list of any medicine.
Risks in unregulated products
Licensed medicines are made under Good Manufacturing Practice, with controlled excipient concentrations, sterility testing and endotoxin limits. Illicit "underground" injectable products, including those sold for performance enhancement, offer none of these guarantees.
- Excessive concentrations of benzyl benzoate or benzyl alcohol can cause severe local pain, inflammation and tissue damage.
- Non-sterile manufacture can lead to abscesses and serious infections, as described in reports of complications from self-administered steroid injections such as that by Evans.
- Contents may differ from the label, including wrong substances, particles or toxic contaminants.
- Repeated injections of irritating solutions can cause lasting tissue changes.
In the UK, anabolic steroids are Class C controlled drugs, and illicit injectables are not quality-controlled medicines. The editorial team does not provide guidance on preparing or using such products and strongly advises against their use.
Anyone who experiences swelling, redness, heat, fever or severe pain at an injection site should seek medical care promptly. Infections can progress rapidly and may require surgery.
How to read excipient information
For licensed medicines, excipients are listed in the patient information leaflet and the summary of product characteristics. Benzyl alcohol and benzyl benzoate must be declared with relevant warnings.
The Handbook of Pharmaceutical Excipients is a standard reference describing properties, uses and safety data of these substances, and it is widely used by pharmacists and formulators.
If you are prescribed an oil-based injection and have experienced reactions before, tell your prescriber or pharmacist. Alternatives with different excipients sometimes exist.
Pregnant women, parents of young children and people with liver or kidney disease should be especially attentive to benzyl alcohol content and discuss it with a healthcare professional.
The editorial team's conclusions
Benzyl benzoate and benzyl alcohol are established excipients that make oil-based injections possible and stable.
In licensed medicines their amounts are controlled and their risks are documented, including serious toxicity in newborns and rare allergic reactions.
In unregulated products, the same substances can cause pain, tissue damage and infection, compounded by uncertain sterility and content.
See also our articles on injection-site infections, quality control of pharmaceutical products, and how to read a medicine’s package leaflet.
References
- Gershanik J, Boecler B, Ensley H, McCloskey S, George W. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med. 1982;307(22):1384–1388.
- European Medicines Agency. Questions and answers on benzyl alcohol used as an excipient in medicinal products for human use. Amsterdam: EMA; 2017.
- Rowe RC, Sheskey PJ, Quinn ME, editors. Handbook of Pharmaceutical Excipients. 6th ed. London: Pharmaceutical Press; 2009.
- Larsen SW, Larsen C. Critical factors influencing the in vivo performance of long-acting lipophilic solutions—impact on in vitro release method design. AAPS J. 2009;11(4):762–770.
- Evans NA. Local complications of self administered anabolic steroid injections. Br J Sports Med. 1997;31(4):349–350.
