the invention is further illustrated by the following examples , of which example 1 illustrates a method of preparing sodium p - methyleneaminosalicylate and the remaining examples illustrate the preparation of the composition of the invention . 20 g of sodium p - aminosalicylate were dissolved in a mixture of 75 ml of chemically pure ethanol and 150 ml of chemically pure acetone . the air in the reaction vessel was replaced by nitrogen and the reaction vessel was screened from the light . 10 ml of formalin ( an aqueous solution containing 35 - 40 % formaldehyde ) were then added . the pressure in the reaction vessel was atmospheric and the temperature was ambient ( about 25 ° c .). the materials were allowed to react for about 6 hours , during which time a precipitate formed . at the end of the reaction period , the precipitate was filtered off , washed with small quantities of a 1 : 2 by volume mixture of ethanol and acetone , and then dried in vacuo , until it was substantially free from solvent . in a series of experiments this drying step required periods ranging from 24 to 28 hours . the product consisted of white crystals , which discoloured when exposed to light and air . the yield was substantially 100 % of theory . 12 . 1 g ( 0 . 05 mole ) of thymidine were ground together with 8 . 6 g ( 0 . 05 mole ) of sodium p - methyleneaminosalicylate until a fine powdery mixture was obtained . the mixture was stable , provided that it was kept in a tightly closed dark bottle . i found that i could dissolve 1 g of the mixture in a mere 6 - 7 ml of distilled water ( 0 . 1 g thymidine per ml , 0 . 07 g p - methyleneaminosalicylic acid per ml ). such a solubility will allow the compound to be used in practical therapy , and it was found that the composition had lost substantially none of the thymidine activity . 1 . 00 g ( 4 . 13 mmole ) of thymidine and 0 . 88 g ( 4 . 13 mmole ) of sodium p - methyleneaminosalicylate were dissolved in 10 ml of water . the solution was then freeze - dried to give 1 . 82 g of the desired complex in the form of a light beige , hygroscopic powder . elemental analysis -- calculated for c 18 h 20 na n 3 o 8 : c , 47 . 9 %, h , 5 . 0 %; n , 9 . 3 %. found : c , 48 . 0 %; h , 5 . 4 %; n , 9 . 4 %. the water content of the complex was found to be 5 . 0 % by the karl fischer method . 0 . 24 g of the resulting complex ( containing approximately 0 . 127 g of thymidine ) dissolved immediately in 1 . 1 ml of water and the solution remained homogeneous for 16 hours . the solution had a ph value of 7 . 7 . 1 . 00 g ( 4 . 13 mmole ) of thymidine and 1 . 76 ( 8 . 26 mmole ) of sodium p - methyleneaminosalicylate were dissolved in 10 ml of water and the solution was freeze - dried to give 2 . 63 g of the desired complex in the form of a beige , hygroscopic powder . elemental analysis -- calculated for c 26 h 26 na 2 n 4 o 11 : c , 47 . 1 %; h , 4 . 8 %; n , 8 . 4 %. found : c , 47 . 4 %; h , 4 . 8 %; n , 8 . 5 %. the water content of the resulting complex was 7 . 1 % by weight according to the karl fischer method . 0 . 87 g of the resulting complex ( containing approximately 0 . 32 g of thymidine ) dissolved within 10 minutes in 1 . 1 ml of water and the solution , which had a ph value of 8 . 1 , remained homogeneous for 16 hours . 1 . 00 g ( 4 . 13 mmole ) of thymidine and 0 . 87 g ( 4 . 13 mmole ) of sodium p - aminosalicylate were dissolved in 10 ml of water and the resulting solution was freeze - dried to give 1 . 84 g of the desired complex in the form of a white , hygroscopic powder . elemental analysis -- calculated for c 17 h 20 na n 3 o 8 : c , 46 . 0 %; h , 5 . 3 %; n , 9 . 5 %. found : c , 46 . 1 %; h , 5 . 3 %; n , 9 . 5 %. the water content of the complex , by the karl fischer method , was 6 . 1 % by weight . 0 . 30 g of this complex ( containing approximately 0 . 16 g of thymidine ) dissolved immediately in 1 . 1 ml of water and the solution remained homogeneous for 16 hours . the solution had a ph value of 7 . 2 . 1 . 00 g ( 4 . 13 mmole ) of thymidine and 1 . 74 g ( 8 . 26 mmole ) of sodium p - aminosalicylate were dissolved in 10 ml of water and the solution was freeze - dried to give 2 . 58 g of the desired compound in the form of a white , hygroscopic powder . elemental analysis -- calculated for c 24 h 26 na 2 n 4 o 11 : c , 45 . 4 %; h , 4 . 9 %; n , 8 . 8 %. found : c , 45 . 6 %; h , 4 . 9 %; n , 9 . 0 %. the water content of this complex by the karl fischer method was 6 . 8 % by weight . 1 . 43 g of the complex ( containing about 0 . 55 g of thymidine ) dissolved within 10 minutes in 1 . 1 ml of water and the solution remained homogeneous for 16 hours . the ph of the solution was 7 . 6 . following the procedures described above , a number of complexes of thymidine with different complexing agents were prepared and the results are shown in the following table , which gives the solubility at 22 °- 24 ° c . table______________________________________ complexing agent mole thymidine soluble per mole in 100 ml watercomplexing agent thymidine ( g ) ______________________________________ 0 4 . 8 ± 0 . 5sodium salicylate 1 . 06 20 ± 1sodium p - amino - 1 . 00 17 ± 1salicylate 1 . 15 18 ± 1 1 . 69 45 ± 2 1 . 84 54 ± 2 2 . 49 55 ± 2sodium p - methylene - 1 . 03 12 ± 1aminosalicylate 1 . 36 15 ± 1 2 . 33 33 ± 2sodium p - hydroxyben - 1 . 43 15 ± 1zoatesodium o - amino - 1 . 50 14 ± 1benzoatesodium p - amino - 1 . 60 13 ± 1benzoatesodium benzoate 1 . 63 13 ± 1______________________________________ plotting the solubility of thymidine against the content of the two complexing agents , sodium p - methyleneaminosalicylate and sodium p - aminosalicylate , gave an s - shaped curve with plateaus at 1 and at 2 moles of complexing agent . this is considered to be evidence for the successive formation of 1 : 1 and 1 : 2 complexes with individual solubility properties . at every point in the experiments with aqueous solutions , thymidine and the complexing agent could be identified unchanged . various changes and modifications may be made within the purview of this invention , as will be readily apparent to those skilled in the art , such changes and modifications are within the scope and teachings of this invention as defined by the claims appended hereto .
thymidine may have its solubility in water increased by as much as 10 times or even more by combining the thymidine with a solubilizing agent , such as a salicylate derivative selected from salicylic acid , amino and methyleneamino substituted salicylic acids and salts and esters thereof . the thymidine and solubilizing agent may be combined by grinding in the dry state . the compounds are most conveniently used in approximately equimolar quantities .