Process for the Preaparation of Iodine-Polyvinylpyrrolidone by Dry Mixing

United States Patent Office 2,705,701 Patented Apr. 19, 1955 1 2,706,701 PROCESS FOR THE PREPARATION OF IODlNE- POLYVINYLPYRROLIDONE BY DRY MIXING Hans Beller, Cranford, N. J., and William Austin Hosmer, Pittsfield, Mass., assignors to General Aniline & Film Corporation, New York, N. Y., a corporation of Dela- ware No Drawing. Application April 15, 1952, Serial No. 282,458 2 Claims. (Cl. 167-70) This invention relates to an improved process for preparing a dry powdered adduct of iodine and polymeric 1-vinyl-2—pyrrolidone (hereinafter called polyvinylpyr- rolidone) whereby a stable composition is formed which is readily soluble in water and which provides iodine in readily available and germicidally and bactericidally active form which is essentialy non-toxic to warm- blooded animals. In the copending application of Herman A. Shelanski, Serial No. 135,519, filed December 28, 1949, there is disclosed a novel composition of polyvinylpyrrolidone and iodine which has been found to be of substantial value for many applications in which advantage is taken of the bactericidal activity of the iodine but in which the irritating, sensitizing, and toxic properties of the iodine are‘ substantially overcome. As disclosed in this application, this novel iodine-polyvinylpyrrolidone com- position may be prepared by adding a solution of iodine, such as Lugo1’s solution or tincture of iodine to an aqueous solution of polyvinylpyrrolidone. It has now been found that valuable compositions of iodine and polyvinylpyrrolidone can be prepared by thoroughly mixing dry elemental iodine with dry powdered polyvinylpyrrolidone. The iodine and pow- dered polymer may be mixed until a homogenous powder is obtained, the mixing being carried out in materials which are not attacked by iodine so as to avoid the intro- duction of metal ions into the finished composition. This mixing may be effected by grinding the iodine and poly- vinylpyrrolidone in a mortar and pestle or more advan- tageously in a suitable mechanical mixer such as a ball mill. The time of mixing varies only with the efliciency thereof, as the combination of the polyvinylpyrrolidone with iodine on its surface is rapid, in fact, such combina- tion will occur to some extent on dropping iodine crystals on the dry powdered polymer. On completion of the mixing there is obtained a com- pound in a physical state similar to the polymer alone but which contains varying proportions of iodine—available iodine (as distinguished from free iodine), iodide ion, and bound iodine. A distinction between these forms may be made on an analytical basis, available iodine be- ing determined directly by dissolving a sample of the product in water and titrating with 0.1-N sodium thio- sulfate (Na-2S203), solution using starch as an indicator. The amount of iodine present as iodide ion is determined by reducing the iodine compound in solution with 1-N sodium acid sulfite in a NaHSO3, adding enough to make the solution colorless, then adding 0.1-N silver nitrate and enough nitric acid to make the solution acidic and back-titrating with ammonium thiocyanate (NH4SCN). The iodide ion is the difference between this figure and the available iodine as determined above. The total iodine may be determined by combustion methods such as that formulated by Hallett in Scott’s Standard Methods of Chemical Analysis, bound iodine then being deter- mined by substracting the sum of available iodine and iodide ion from the total iodine as determined above. The product obtained on mixing polyvinylpyrrolidone and iodine contains a total amount of iodine equal to the amount employed in making the composition and, as stated, this iodine is present as available iodine, iodide ion and bound iodine. It has been found that with any given sample of polyvinylpyrrolidone the amount of bound iodine is constant but that the iodine present as available iodine and iodide ion may vary somewhat. On 10 I5 20 25 30 35 40 45 50 55 60 70 75 80 2 standing, the amount of available iodine slightly de- creases which the amount of iodide ion increases. It has been found, however, that a stable product in which the ratio of available iodine to iodide ion is substantially 2:1 is readily and rapidly obtained by heating the dry blended material to a temperature of the order of 90-100“ C. Higher temperatures are preferably avoided in order to avoid degradation of the polymer. Some slight stirring is advantageous during this heating in order to assure a uniform product. It has been found that the heating should be continued until the ratio of available iodine to iodide ion is substantially 2:1. It has been found that before heating one sample, it had a vapor pressure of 0.06 mm. at 55° C. After heating, the product had sub- stantially no vapor pressure at 55° C. Thus, the heating completed the process of formation of a complex in which the iodine is chemically available but not free. The details of the present invention will be apparent from the following specific examples in which the parts are by weight: By “K value” in these examples is meant Fikentscher K value (1000 k) as defined by H. Fikent- scher—-Cellulosechemie 13, 58-64, 71-4 (1932) and was determined with aqueous solutions of the polymer using an Ubbelohde viscosimeter at 25° C., the concen- tration being 1 gram of polymer (anhydrous basis) per 100 ml. of solution. EXAMPLE I Twelve grams of dry polyvinylpyrrolidone having a K value of 90 (water content about 2 to 3 per cent) was added to 6 grams of solid iodine crystals in a glass bot- tle containing a few pebbles and beads. This was rolled for three days on a roller mill with occasional manual stirring to loosen the material caked on the sides of the bottle. Analysis showed that the thus obtained product contained 35.4 per cent total iodine and 31.91 per cent available iodine; The material was heat—treated at 95° C. for 64 hours in a closed glass bottle with occasional stirring. On completion of this treatment, analysis showed that the material contained 35.3 per cent total iodine, 25.7 per cent available iodine. EXAMPLE II The same procedure was repeated using 12 grams of dry polyvinylpyrrolidone having a K value of 19 in place of 12 grams of polyvinylpyrrolidone a K value of 90. On completion of the mixing, analysis showed that the prod- uct contained 29.0 per cent available iodine. On heat treatment of this material for sixty-four hours, analysis showed that the product contained 31.9 per cent total iodine and 21.3 per cent available iodine. EXAMPLE III An earthenware crock, having a capacity of one gallon, was charged with 832 grams of dry polyvinylpyrrolidone having a K value of 33 and 168 grams of crystalline iodine broken up in the form of small granules. Enough pebbles, approximately 30, were added to assure efficient mixing. The lid was clamped on tightly and the crock rotated on a roller mill for twenty-four hours. After this period, the mixture was homogenous and no iodine crystals were visible. The material was placed in an oven for eighteen hours at 200° F. (93° C.) with oc- casional mixing to assure homogeneity. After this treat- ment, analysis showed 10.2 per cent available iodine, 5.3 iodide ion. About 1.3 per cent thus was in the form of bound iodine, probably mainly combined with unsatu- rated links of the polymer (terminal unsaturation) and a small amount of residual monomer which may have been present therein. This product was stable and series of samples thereof which were maintained at 100° F. and room temperature and tested at Weekly intervals for available iodine and iodide ion over a period of six weeks showed no variation in available iodine and iodide ion. In preparing the novel polyvinylpyrrolidone iodine com- positions of the present invention, it has been found that from 1-35 per cent total iodine can readily be combined with polyvinylpyrrolidone. It has further been found that the amount of iodine which should be mixed with polyvinylpyrrolidone in order to produce a product having any desired percentage of available iodine can readily 2,703,701 3 be determined since it has been found that in order to ob- tain a product which is stable on storage, it is desirable that in the final product the ratio of available iodine to iodine ion be substantially 221. Thus, to produce a prod- uct having any given desired percentage of available iodine, it is necessary to add to the polyvinylpyrrolidone, suflicient iodine so that the available iodine is 65 per cent of the available iodine plus the iodide ion. In addition, enough iodine must be added to take care of the bound iodine. This bound iodine has been found to be uniform for any particular polymer regardless of how much total iodine is added; however, the bound iodine varies some- what with individual batches of polymer. It has been found that the amount of iodine which must be allowed for mixing with any given polymer in order to provide for the bound iodine can readily be determined by simple preliminary tests, i. e., by addition of 0.01-N iodine solu- tion to an aqueous solution of the polymer and back- titrating with 0.1-N sodium thiosulfate solution using starch as an indicator. EXAMPLE IV Three one-hundred-pound batches of polyvinylpyrrol- idone iodine composition containing 10 per cent available iodine, 5 per cent available iodine and 21/2 per cent avail- able iodine, respectively, were prepared. The ratio of iodine to polyvinylpyrrolidone in the charge was deter- mined by adding a total amount of iodine, such that the available iodine would be 65 per cent of the available plus iodide ion and in addition enough iodine was added to take care of bound iodine. In the particular polymer em- ployed, preliminary test showed that 1.3 per cent iodine was necessary and a corresponding allowance was there- fore made. The following is a table of the calculated amounts of iodine added to polyvinylpyrrolidone to prepare the above compositions, a sufficient amount of polyvinylpyrrolidone being used so that the total iodine required plus the amount of polyvinylpyrrolidone equal 100 pounds: Table I Percent Total Distribution of Total Iodine Iodine Charged Required Percent Ava. Iodine for Britt“ P3532“ i8‘£fi%t:‘ Percent Iodine Iodine Ion M°“°m‘“‘ 10 ____________________ . _ 16. 8 10 5. 5 1. 3 5.___. .. 9.0 5 2.7 1.3 21/2 ___________________ __ 5.1 2. 5 1. 34 1.3 ‘Monomer analysis of 0.65 per cent. The iodine, which was crude iodine in the form of soft lumps, Mi" to 1" size, was charged in a 94-gallon ball mill along with 17 pounds of %’’—1’' pebbles. The iodine was ground for one hour at room temperature, at which time it was found that the iodine was approximately 40-80 mesh size. By visual observation no difference could be noticed in the size of the particles in one hour iodine and the 3-4 hour ground samples. The required amount of polyvinylpyrrolidone was then added to the ball mill and blending was continued for six hours at room temperature therein. The ball mill was opened after two hours of mix- ing and any crystals of iodine found around the gasket were scraped back into the mill. The speed of the ball mill for grinding was 16 R. P. M. The thus obtained blended polyvinylpyrrolidone iodine composition was placed in dryer trays, one-half full, and heated for a total time of twenty-two hours at a temperature of 95° C. (200° F.) in a closed tray dryer. After six, twelve, and eighteen hours on temperature, the dryer was opened and the trays were stirred with a glass rod. This was done so as to assure uniform product. The total actual heating time was eighteen hours, a total of four hours being con- sumed in stirring the polyvinylpyrrolidone iodine compo- sition. With each stirring the dryer door was opened slow- ly to permit more rapid cooling and allowed to cool for twenty minutes. The dryer was then closed, the steam turned on. Approximately one-half hour was required to get the dryer back on temperature. The stabilized mate- rial, when discharged from the dryer, was placed in the ball mill with ten pounds of pebbles and mixed for ten hours. Samples of the blended product of the batches l0 l5 20 N) U! 30 40 45 50 55 60 SD 85 4 containing 5% and 21/2 % calculated available iodine were taken before heating and placed in a sealed glass jar. These jars were then heated for eighteen hours at 93° C. The analyses of the thus obtained products are given in the following table: Table 11 Percent Percent Percent Av. Iodine+ Method of Heating Ava. Iodide Total Av. Iodine-l- . Iodine Ion Iodine Iodide Ion Open Tray ............. .. 9. 99 4. 77 14. 77 0. 677 Do ____ __ .... 5.08 2. 58 8.12 0. 663 Closed 32112. . . ...... __ 5. 16 2. 52 S. 14 0. 673 Open Tray ............. _. 2. 86 1. 91 5. 50 0.600 Closed Jar ............. __ 2. 96 2. 04 5. 33 0. 593 It has also been found that, if desired, a polyvinyl- pyrrolidone iodine composition having a desired percent- age of available iodine may be obtained by first preparing a composition having a higher percentage of available iodine than that desired in the final product and diluting the thus obtained material by the addition of further quan- tities of polyvinylpyrrolidone so as to obtain a final prod- uct having the desired percentage of available iodine. This method of preparation is illustrated by the following examples: EXAMPLE V 832 parts of polyvinylpyrrolidone having a K value of 36 was charged to a ball mill along with 168 parts of iodine crystals and the mixture blended for six hours, the ball mill being opened after two hours of mixing, at which time any crystals of iodine found around the gasket were scraped back in the mill. On completion of this mixing, 636 parts of the thus ob- tained ten per cent available iodine unstabilized polyvinyl- pyrrolidone iodine composition was diluted with 566 parts of polyvinylpyrrolidone and the mixture blended for six hours in the ball mill. The ratio of the ten per cent mix- ture of polyvinylpyrrolidone iodine composition to poly- vinylpyrrolidone is 1:1.13 on a dry basis. This ratio of polyvinylpyrrolidone, before dilution, was used in order to obtain the normal nine per cent total iodine necessary in the preparation of a polyvinylpyrrolidone iodine compo- sition having a final five per cent available iodine after stabilization. 430 parts of the unstabilized five per cent available iodine-polyvinylpyrrolidone composition, obtained as de- scribed immediately above, was subsequently diluted to produce a two and one-half per cent available iodine- polyvinylpyrrolidone composition. The same method was used as in diluting ten per cent available iodine- polyvinylpyrrolidone composition to prepare the five per cent available iodine-polyvinylpyrrolidone composition. By calculation, it was found that in order to obtain two and one-half per cent available iodine in the composition after stabilization, 5.1 per cent iodine should be present. Therefore, 320 parts of polyvinylpyrrolidone was charged along with the 330 parts of five per cent available iodine- polyvinylpyrrolidone composition and the materials were blended for six hours in the ball mill. The ratio of five per cent unstabilized mixture to polyvinylpyrrolidone, on the dry basis, is l:l.39. Samples of all three batches were heated at 93° C. for twenty hours in glass jars. On completion of this heat- ing, each of the products was a brown powder which was readily soluble in water. On analysis for available iodine, iodide ion and total iodine the following analytical results were obtained. Table III « - . Percent Percent Percent Ava-. Iodine—'.- Deslredllgggflgnt AW Ava. Iodide Total Ava. Iodine+ Iodine Ion Iodine Iodide Ion 12.1 4. 35 16.45 0. 735 5. 71 2. 87 8. 58 0. 666 3.01 1. 75 4. 76 0. 633 EXAMPLE VI Six pounds of dry polyvinyl pyrrolidone having a K value of 36 and three pounds of solid iodine crystals were placed in a ceramic ball mill containing three pounds of pebbles. The mill was closed and rolled for a total of 2,708,701 5 30 hours in an oven maintained at 200° F. The mill was removed from the oven three times during the course of the mixing and, after cooling to room temperature, the contents manually stirred to loosen material caked on the sides and top thereof. On completion of this treat- ment, analysis showed that the material contained 32.5 per cent total iodine, 20 per cent available iodine and 11 per cent iodide ion. The product was a homogeneous brown powder, soluble in water. We claim: 1. The method of producing a stable polyvinylpyrroli- done-iodine composition which comprises thoroughly mixing elemental iodine and powdered polymeric 1 vinyl 2 pyrrolidone and heating said mixture until the ratio of available iodine to iodide ion in said composition is 15 No. 8, pp. substantially 2: 1. 10 6 2. The method as defined in claim 1 wherein a tem- perature of 90—100° C. is employed in the heating step specified. ' References Cited in the file of this patent UNITED STATES PATENTS 2,077,298 Zelger ______________ __ Apr. 13, 1937 2,121,029 Goedrich ____________ -_ June 21, 1938 2,329,445 Turner ______________ __ Sept. 14, 1943 2,495,918 Bolton ______________ __ Jan. 31, 1950 OTHER REFERENCES Murat: Produits Pharmaceutiques, August 1949, vol. 4, 350-356.