Synthesis and transdermal properties of acetylsalicylic acid derivates

Thesis (M.Sc. (Pharm.))--North-West University, Potchefstroom Campus, 2004.The skin is an amazing elastic and relatively impermeable barrier that provides protective, perceptive and communication functions to the body. The stratum corneum is widely accepted as the barrier of the skin - limiting the transport of molecules into and across the skin. It is evident that the transdermal permeation of drugs depend on a number of factors of which the physicochemical properties play the most prevalent role. The potential of using intact skin as the site of administration for dermatological preparations to elicit pharmacological action in the skin tissue has been well recognised. Transdermal drug delivery offers several advantages over oral and parenteral dosing. They include avoiding hepatic first pass metabolism, maintaining constant blood levels for longer periods of time, improving bioavailabiliv, decreasing the administered dose, adverse effects and gastrointestinal side effects, easy discontinuation in case of toxic effects and improved patient compliance. Optimal transport through the skin requires a drug to possess lipophilic as well as hydrophilic properties. Research has indicated that the ideal log P value for optimal transdermal permeation is between 1 and 2. Acetylsalicylic acid (aspirin) possesses anti-inflammatory, analgesic and antipyretic activity, and as an anti-inflammatory analgesic agent it is used in the treatment of musculoskeletal disorders, such as rheumatoid arthritis. Its use is limited to the relief of pain and inflammation, as it does not halt the progression of the pathological injury caused to the tissue. Acetylsalicylic acid is also used in the treatment of fever, prevention of thromboembolic disorders, reducing the incidence of colon cancer and it delays the onset of Alzheimer's disease. The most common adverse effect of acetylsalicylic acid occurring with therapeutic doses is gastro-intestinal disturbances. The primary aim of this study was to determine the transderrnal penetration of acetylsalicylic acid and some of its derivatives and to establish a correlation, if any, with selected physicochemical properties. The ten derivatives of acetylsalicylic acid were prepared by esterification of acetylsalicyloyl chloride with ten different alcohols. The structures of the products were confirmed by mass spectroscopy (MS), nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR) and differential scanning calorimetry (DSC) for methyl acetylsalicylate. Experimental aqueous solubility and partition coefficients were determined for acetylsalicylic acid and its different derivatives at a pH of 4,5. In vitro penetration was measured through excised female human abdominal skin in diffusion cells. The prediction software Interactive Analysis (IA) was used to predict aqueous solubility, while prediction software IA, &,Win and ACD Labs were used to predict the log P values for each derivative. None of the predicted values correlated with the experimental values. The experimental aqueous solubilily, partition coefficient and transdermal flux values were determined for acetylsalicylic acid and its derivatives. The experimental aqueous solubilily of acetylsalicylic acid (6,56 mg/ml) was higher than that of the synthesised acetylsalicylate derivatives (ranging from 1,76 x lo3 to 3,32 mg/ml), and the partition coefficient of acetylsalicylic acid (-0,85) was lower than that of its derivatives (ranging from -0,25 to 1,954. There was thus a direct correlation between the aqueous solubility data and the partition coefficients. The experimental transdermal flux of acetylsalicylic acid (4733 pg/cm2/h) was much higher than that of its derivatives (ranging from 0,03 to 28,32 pg/cm2/h). With the ethyl derivative (28,32 pg/cm2/h) and the methyl derivative (10,06 pg/cm2/h) being the only derivatives with appreciable flux. Pentyl acetylsalicylate (0,03 pg/cm2/h) had the lowest flux. The higher flux values of acetylsalicylic acid and its methyl and ethyl derivatives might be due to the fact that it is more hydrophilic and had better aqueous solubilily, thus permeating through the proteins of the skin. Pentyl acetylsalicylate had a log P value of 1,95, but had the lowest flux (0,03 pg/cm2/h), just proving once again that to cross the stratum corneum a drug should posses both hydrophilic and lipophilic properties. Tert-butyl acetylsalicylate had a flux (7,30 &cm2/h) lower than that of methyl and ethyl acetylsalicylate, but a higher flux than the other synthesised derivatives which could be due to its log P value being slightly greater than 1 and having an average aqueous solubility. The low transdermal permeation may also be attributed to the fact that at the pH (45) chosen for transdermal studies, acetylsalicylate was only 9,09 % unionised. A higher degree of unionised species results in higher flux values. This study has confirmed that transdermal flux is dependent on several factors including optimum solubility, partitioning, diffusion and the degree of ionisation in the stratum corneum in addition to a suitable partition coefficient and high aqueous solubilily. The solution to the increased transdermal delivery of lipophilc drugs does not simply lie in producing a derivative with a higher aqueous solubilily and more ideal partition coefficient. Other means of increasing the transdermal permeation of lipophilic acetylsalicylic acid derivatives will have to be investigated in further studies.Master