Kinetics and Thermodynamics of Drug Permeation Through Silicone Elastomers (II) Effect of Penetrant Lipophilicity

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Abstract
The permeation of testosterone analogs through silicone membranes was studied. The variation in the lipophilicity of testosterone molecules was accomplished by the addition or elimination of methyl group and the formation of ester. Furthermore, the effects of replacing one of the CH3 groups on the dimethylsiloxane unit in the silicone polymer chains by a polar CH2CH2CF3 group, which ranges polymer characteristics and thus affects the membrane permeability, was investigated as well. It was found that either variation in the number of methyl groups on the steroidal skeleton or esterification at 17 position has profoundly affected the magnitude of permeation across the lipophilic silicone membrane. In general, higher permeation rate was achieved when testosterone derivative became more lipophilic. However, as the ester side chain became too bulky in chain length, the permeation rate decreased. The presence of the polar, bulkier CH2CH2CF3 group in the silicone polymer chains was found to reduce the rate of permeation. The thermodynamics of membrane permeation was also determined and the results suggested that the presence of polar trifluoropropyl group in the silicone polymer markedly increased the energy of activation for permeation; on the other hand, filler has little effect on the magnitude of activation energy for permeation. The addition of 17-CH3 group and the elmination of 19-CH3 group from testosterone molecule reduced the energy required for membrane permeation. The presence of a saturated or an unsaturated ring structure in the ester chain was found to affect the lipophilicity and the kinetics and thermodynamics of membrane permeation of testosterone analogs.