(T0930-01-04) Sublimation Loss of Drugs from Topical Products at the Site of Application

Purpose: The primary objective was to investigate the potential loss of API from topical products at the site of application and its impact on the mass balance studies of in vitro permeation testing of topical products. The second major objective was to investigate the potential loss of other topically administered drugs from the site of application by sublimation mechanism.

Methods: Salicylic acid ointments (6%) were subjected to In vitro permeation testing across human cadaver skin using Franz diffusion cells. A finite dose of 5 mg/cm² of formulation was applied on the skin. PBS was used as a buffer in the receiver compartment. The samples were withdrawn at 4 hours’ time intervals and drug from the skin was extracted using three solvent system methods reported in the literature and validated in our laboratory. Therefore, the potential for sublimation of salicylic acid from the Franz diffusion cells during IVPT was investigated by occluding the donor compartment and recovering the drug in the lid used to close the donor. Further, topical formulations with different APIs were subjected to a sublimation screening test to investigate the potential for other drugs to undergo sublimation losses at the site of application.

Results: The mass balance calculations revealed that recovery of the drug in all the methods was not more than 70% of the applied dose. The salicylic acid recovery form mass balance studies were 72±3.8 %. This recovery is corroborating with the recoveries reported in the literature (about 75-58% by Banga et al., and about 80% by Lane et al) by eminent dermal drug delivery research scientists. The closed donor chamber experiments clearly demonstrated the fact that salicylic acid does undergo sublimation significantly from the site of application which is the reason for the poor mass balance of salicylic acid during IVPT studies. Sublimation is a process of direct conversion of solids into vapor. The temperature was found to impact the rate of sublimation directly. At 32^oC the extent of sublimation of salicylic acid forms the topical ointment with 6% salicylic acid at 5mg/cm² dose was about 11%. The sublimation screening test showed that ketoprofen underwent sublimation up to 7%. The extent of sublimation from lidocaine and clobetasol ointment was also < 1%. A few other most common topically administered APIs were also found to undergo significant sublimation from the topical products (figure 1). The formulation components were found to cause an impact on the extent of sublimation of clobetasol.

Conclusion: The potential loss of drugs from the site of the application is a knowledge gap in the field of topical products. A significant loss of drugs by sublimation could lead to variability in bioavailability and bioequivalence testing of drugs.

References: 1. Hiep X. Nguyen, Ashana Puri, Ajay K. Banga, Methods to simulate rubbing of topical formulation for in vitro skin permeation studies, International Journal of Pharmaceutics, 519 (1-2), 22-23.
2. Rita Mateus, David J. Moore, Jonathan Hadgraft, Majella E. Lane, Percutaneous absorption of salicylic acid – in vitro and in vivo studies, International Journal of Pharmaceutics, 475 (1-2), 471-74.

Acknowledgements:We thank Topical Products Testing LLC, OXford, MS for the funding support for this project.