Naproxen (6-methoxy-a-methyl-2-naphthaleneacetic acid, compound 1a) is one of a growing class of enantiomerically pure drugs (1). Only the (S) isomer is safe to use, because the (R) isomer is reported to be a liver toxin (2). Thus, measurement of the specific optical rotation of commercial naproxen tablets offers students a perceived opportunity to check the integrity of the manufacturer.

Another interesting feature of naproxen is that the free acid (above) is dextrorotatory ([a]_D +66°); merely neutralizing it makes the sodium salt (the material commercially distributed), which is levorotatory ([a]_D-11°) (3). This offers a striking example of the lack of obvious relationship between structure and optical rotation, since both acid and salt have the same configuration about the chiral center.

The experiment also offers an opportunity to introduce elementary concepts of data treatment, by requiring a number of measurements of each rotation and calculating standard deviations of those measurements. The observed rotations are obtained by subtracting the "zero value" of the tube from the solution reading, each of which has a considerable uncertainty. This allows a discussion of propagation of errors in the determination of the uncertainty of the difference. Similarly, assuming that the percentage of error in these measurements is much greater than those in measuring length and concentration, the standard deviation of the specific rotations and optical purities can be obtained without extra repetitions of the latter measurements.

Aleve is the trade name for Proctor-Syntex Health Products' brand of naproxen, distributed by Procter & Gamble. Besides about 220 mg of naproxen sodium salt (1b), each Aleve tablet contains fillers and dye. Fortunately, all the dye and most of the other ingredients are present only in the outer layer, which can easily be separated from the inner tablet by treatment with methanol.

Experimental Procedure

1. Swirl five Aleve tablets in 15 mL of methanol in a small beaker (you want the methanol to completely cover the tablets) until the outer layer begins to peel away from the inner tablet. As soon as this happens, carefully but quickly remove the inner tablets from the liquid with forceps, being sure to leave all the outer coating in the methanol. Place the 5 inner tablets in 20 mL of fresh methanol in a 50-mL Erlenmeyer flask and swirl to dissolve the naproxen sodium salt. Dissolution is rather slow, requiring about 20 minutes at room temperature. While waiting for dissolution, weigh the polarimeter tube you will use and measure the zero reading of the polarimeter. Record these observations on the Data Sheets.¹

2. Filter the resulting solution by gravity into another Erlenmeyer flask to remove residual flaky material and rinse the original flask and filter paper twice with a little fresh methanol, adding the filtered rinsings to the original solution. Evaporate the resulting solution to a volume suitable to use in an available small polarimeter tube (about 8-9 mL).²

3. Transfer all of the solution to the polarimeter tube using a Pasteur pipet. Measure the optical rotation of the solution. Record your observations on the data sheet.

4. Weigh a 25-mL Erlenmeyer flask and record the weight on the data sheet. Measure the length of the solution in the polarimeter tube carefully (to the nearest millimeter) and record it, then pour the solution into the flask. Wash the polarimeter tube with fresh solvent and add the wash liquid to the flask. Evaporate the solvent on a steam bath; then weigh the residue when completely dry. Record this weight.

5. Clean and dry the polarimeter tube. Add distilled water to the level of the solution used for the optical measurement. Weigh the combined tube plus water and record this weight. Then, subtract the previously determined weight of the tube to find the volume of the original solution, since the density of water is 1.00 g/mL at room temperature. The concentration of naproxen in solution can now be calculated as the weight of naproxen divided by the volume of solution. Units are grams per milliliter.

6. Calculate [a] from the relationship [a] = a(obs)/cl, where c = grams residue per milliter of solution and l is the measured path length in decimeters (10 cm = 1 dm).

7. Dissolve the sodium salt from step 3 in water. Treat with aqueous HCl to precipitate the free acid. Dissolve the free acid in chloroform and extract the organic solution from the water. Wash the organic layer with water, dry with MgSO₄, then filter by gravity. Rinse the MgSO₄ and flask with fresh chloroform and add the filtered rinsings to the original filtered solution. Evaporate excess chloroform until the volume of the solution fits into a polarimeter tube.

8. Repeat steps 3 to 6 to obtain the specific rotation of the free acid.

9. Calculate the optical purity of both 1a and 1b.

Results

After the experiment, class data are gathered and distributed for analysis and discussion.

Students generally obtain about 1 g of salt with observed rotations from about {1 to {2°, and about 0.8 g of acid with observed rotations about +5°. Since the observed rotations are fairly low and the polarimeters we use are readable to only about #177;0.5°,³ uncertainties (five measurements of each quantity) amount to an appreciable percentage of the values. Individual uncertainties are sometimes above 50%; taking the class data as a whole lowers the uncertainties to 10-20%. Optical purities obtained to date, however, have been within one or two standard deviations of 100% purity. There have been one or more cases of obvious outliers each time the experiment has been run; this has allowed discussion of the outlier concept with concrete examples.

Notes

1. The data sheet for this laboratory is available (see Supplements link).

2. Polarimeter tubes are 12 x 114-mm flat-bottomed shell vials. They can be obtained as Sample Storage Kit Model CK-3 from R.P. Cargille Laboratories, Inc., Cedar Grove, NM 07009. Tubes are mounted in large 1-hole rubber stoppers to provide stability.

3. Instruments for Research and Industry, Inc., P.O. Box 159X, Cheltenham, PA 19012.

Literature Cited

1. Stinson, S. C. Chem. Eng. News 1995, 73(41), 44-74.

2. Caron, G.; Tseng, G. W.-M.; Kazlauskas, R. J. Tetrahedron: Asymmetry 1994, 5, 83-92.

3. Harrison, I. T.; Lewis, B.; Nelson, P.; Rooks, W.; Rozkowski, A.; Tomolonis, A.; Fried, J. H. J. Med. Chem. 1970, 13, 203-205.