The preparation of menthol (1 per cent w/w) in aqueous cream BP

Home > Pharmacy Information Pointers > The preparation of menthol (1 per cent w/w) in aqueous cream BP

The preparation of menthol (1 per cent w/w) in aqueous cream BP

Recently, the Royal Pharmaceutical Society’s fellow in pharmaceutics, Colin Cable, has dealt with several enquiries from members regarding the preparation of menthol in aqueous cream. Outlined below are methods of preparing this product and information concerning its stability. Further information on this and other pharmaceutics topics can be obtained from Dr Cable (tel 020 7572 2302; e-mail colin.cable@rpsgb.org).

The topical application of menthol in aqueous cream soothes and cools the skin. It is thought that, when applied to the skin, menthol dilates blood vessels and selectively stimulates sensory nerve endings for cold, to produce a sensation of coldness, which is followed by an analgesic effect. It has been used to treat patients with HIV infections or patients in palliative care situations to relieve irritation or pruritis, often side effects associated with concomitant drug therapy. As no commercially available product is available, menthol in aqueous cream must either be prepared extemporaneously or obtained from a specials manufacturer.

Traditional methods of preparation

Traditionally, menthol was included in ointment formulations. Being soluble in paraffin, it was generally incorporated into soft paraffin, which was then mixed with other ointment ingredients.

If menthol creams were to be prepared, the entire product was prepared extemporaneously. The menthol was incorporated into liquid paraffin or soft paraffin, before the cream was extemporaneously prepared.¹

The adoption of this method may be related to the fact that, in the past, it was well recognised, if not formally documented, that the direct addition of menthol crystals to a previously prepared aqueous cream was associated with a high risk of cream instability, especially cracking of the cream, where the oily phase separates out.

Alternative preparation methods

With time, there has been a move away from the complete extemporaneous preparation of menthol creams using the individual ingredients towards the addition of method to a cream base, usually aqueous cream BP.

Three different approaches have been adopted when incorporating menthol into aqueous cream BP. In spite of traditionally held concerns about stability, one method involves incorporating menthol crystals into the cream. From enquiries received from pharmacists, and information available in the pharmaceutical literature, it appears that two alternative methods of treating menthol crystals before incorporation into the cream have been used. In one method, the menthol is wetted and partially dissolved by a solvent; in the other, the crystals are ground to a fine powder in a mortar and pestle. The reasoning behind modifying the menthol crystals before incorporation into the cream is probably to minimise the risk of the cream cracking.

Incorporation of menthol crystals In 1991, a formula for menthol 1 per cent in aqueous cream BP appeared in a booklet of specials formulations prepared in Birmingham hospital pharmacies.² In spite of the traditionally held concerns surrounding the direct addition of menthol crystals to creams, this cream was prepared by gradually mixing the aqueous cream BP into the menthol crystals until the crystals dissolved. The label for the cream stated that the product was not to be applied to broken skin, and a shelf-life of two weeks was recommended for the product.

Inclusion of a solvent Although there are no published reports citing the use of a solvent, from enquiries received from pharmacists, there is anecdotal evidence that this method has been used in pharmacy practice. From discussions with pharmacists, it appears that solvents such as glycerol, ethanol, water and olive oil have been proposed.

Menthol is described as being very slightly soluble both in water (0.1 per cent to 0.01 per cent) and in glycerol,³ although solubility in glycerol is likely to be higher than in water.⁴ Although it is also soluble in ethanol and in four parts of olive oil, incorporating an ethanolic or an oily solution of menthol into aqueous cream BP could induce cracking.

A small quantity of water, or up to 5 per cent glycerol,⁵ can be incorporated into aqueous cream without inducing physical instability. Given menthol’s greater solubility in glycerol, glycerol would be the solvent of choice for wetting and dissolving the menthol crystals before addition to the cream. The small volume of glycerol used would not be sufficient to dissolve all the menthol. However, there may be health and safety benefits in this approach as the amount of menthol dust released into the atmosphere during preparation would be reduced.

Preparation of a menthol powder The most comprehensive report of the preparation, storage and stability of menthol 1 per cent in aqueous cream BP was published by Gallagher and Jones in 1997.⁶ To prepare the cream, the menthol crystals were ground to a fine powder using a mortar and pestle and aqueous cream BP was gradually added. No significant chemical degradation of menthol was observed when the cream was stored at room temperature for 18 months.

Conclusion

The available evidence indicates that menthol 1 per cent can be added to aqueous cream BP to prepare a chemically and physically stable product. To minimise the risk of the cream cracking, the menthol crystals should be ground to a fine powder in a mortar and pestle. If necessary, a small quantity of glycerol may be added to minimise the creation of airborne menthol dust. The aqueous cream BP is then added to the menthol by trituration and mixed until smooth; the final product should be smooth and free from particles or grittiness, with all the menthol dissolved in the cream.

Although it has been shown that there is no significant chemical degradation of menthol in the cream following long-term storage, from a microbiological viewpoint, a shelf life of the order of one month should be considered when the cream is supplied to a patient.

References

1. Pharmaceutical formulas. Volume 1. 12th edition. London: Chemist & Druggist, 1953.
2. Birmingham Health Authorities. Specials formulary. 3rd edition. Wirral: Bristol-Myers Squibb Pharmaceuticals, 1991:14.
3. The pharmaceutical codex. 11th edition. London: Pharmaceutical Press, 1979:525.
4. Rowe RC, Sheskey PJ, Weller PJ, editors. Handbook of pharmaceutical excipients. 4th ed. London: Pharmaceutical Press, 2003:383-5.
5. Australian pharmaceutical formulary and handbook. 16th edition. Canberra: Pharmaceutical Society of Australia, 1997:468.
6. Gallagher P, Jones S. A stability and validation study of 1% w/w menthol in aqueous cream. International Journal of Pharmacy Practice 1997;5(2):101–4.