United States Patent Office Patented May 8, 1962 2 Until the Effluent Is Reduced in Sodium Content to a Point 3,033,900 METHOD of PREPARING CALCIUM Below 0.4 Mg
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3,033,900 United States Patent Office Patented May 8, 1962 2 until the effluent is reduced in sodium content to a point 3,033,900 METHOD OF PREPARING CALCIUM below 0.4 mg. per milliliter of the effluent, calculated as GLUCOHEPTONATE sodium sulfate. The resulting effluent is treated with Arthur G. Holstein, Lake Bluff, ill, assignor to Pfansfieh sufficient calcium carbonate having a very low sulfate Laboratories, Inc., Waukegan, Ill., a corporation of impurity content, preferably below 0.05%, calculated linois as calcium sulfate to convert the glucoheptolactone and No Drawing. Filled Mar. 25, 1958, Ser. No. 723,671 its equilibrium component, glucoheptonic acid, to cal 8 Claims. (C. 260-535) cium glucoheptonate. During this conversion, the effluent is desirably heated, preferably to a temperature of about This invention relates to methods of preparing gluco O 80 C., in order to facilitate the conversion of the lactone heptonates and more particularly to novel improvements through the equilibrium component, glucoheptonic acid, in the preparation of calcium glucoheptonate. to the calcium salt of the acid. Activated carbon may be The preparation of a high purity calcium glucohepto added to the resulting solution to effect a reduction in nate for use in parenteral solutions has been difficult and the level of any residual color. The solution is then costly. Conventional methods involve the reaction of 15 filtered and evaporated under high vacuum to a specific glucose with hydrocyanic acid and conversion of the gravity of 1.45 or slightly higher. The resulting syrup nitrile thus formed into calcium glucoheptonate with cal is then run in a very fine stream into anhydrous methanol cium or barium hydrate. A pure grade of calcium cy under very active agitation. Amorphous particles of anide for this purpose is not available commercially. The dehydrated calcium glucoheptonate are formed in the high alkalinity developed when calcium or barium hy 20 methanol. Complete dehydration of the particles is drate is employed gives rise to a high level of degradation effected by transferring them to a fresh quantity of an which requires further processing by converting the cal hydrous methanol. The dehydrated solid calcium gluco cium glucoheptonate to glucoheptolactone and its equi heptonate particles are then centrifuged and dried in librium component, glucoheptonic acid by the use of vacuo at a temperature sufficient to remove all traces of sulfuric or oxalic acid. In another process, dextrose is 25 methanol without decomposition of the product. A reacted with sodium cyanide in the presence of calcium temperature of 50° C. has been found to be satisfactory. chloride which produces a double salt. This is then con In place of the methanol dehydration procedure, the verted to the glucoheptolactone and glucoheptonic acid. syrup may be dehydrated to a solid by other suitable Subsequent treatment with calcium hydrate then results methods, for example by drum drying the syrup or spray in a calcium glucoheptonate which is heavily contami 30 drying the syrup. nated with sulfates, oxalates or chlorides, or combina Any resin exchange medium having a high capacity tions thereof. It is extremely difficult to remove such for cation exchange may be employed for removing the impurities once the calcium salt is prepared. Any such sodium from the sodium glucoheptonates. Nuclear sul contaminants in the solution during the preparation of fonic acid polystyrene cation exchange resins are par the salt appear in the final product, since calcium gluco 35 ticularly suitable for this purpose. Resins sold under heptonate is not crystallizable from aqueous solutions the trade names Amberlite IR 120 and Duolite C 25 are and the recovery of amorphous solid material results in representative of this type of resin. The resin bed is occluded impurities. The presence of trace quantities prepared for use in the process of this invention by re of contaminants frequently destroys the stability of par generation with either sulfuric acid or hydrochloric acid enteral solutions prepared from calcium glucoheptonate 40 and is then washed with deionized water until all traces containing impurities such as sulfates and chlorides. of the regenerating acid are removed. Barium chloride One of the objects of the present invention is to pro solution may be used on a sample of the effluent to test vide an improved process of preparing calcium gluco for the presence of sulfates and silver nitrate for the heptonate having a high order of purity, which process presence of chlorides. The effluent from the bed after is characterized by the avoidance of the introduction of passage of sodium glucoheptonate solution therethrough contaminants in the various process steps, thereby avoid is tested to determine the presence of sodium ions there ing their presence in the finished product. in, for example, by treating a portion of the effluent Another object is to provide an improved process of with sulfuric acid and evaporating, ashing the residue preparing calcium glucoheptonate having a high order and weighing the residue. The sodium content should of purity and a high level of stability in aqueous solu 50 be reduced to a point below 0.4 mg. per milliliter. In tion. practice it is not difficult to achieve a much lower level A further object is to provide an improved process of than this. If the bed is of sufficient size, one pass there preparing calcium glucoheptonate of high purity in sub through will accomplish this purpose. If the level of stantially quantitative yields. sodium is too high, another pass is indicated. A further object is to provide an improved process 55 In place of calcium carbonate, calcium hydrate or lime of preparing calcium glucoheptonate having a level of may be employed. It is usually difficult however to ob sulfate impurity below the point at which precipitation tain calcium hydrate or lime of sufficiently low sulfate will occur in stored aqueous solutions of the substance. and iron content for this purpose. It is essential that Further objects will become apparent from the fol the calcium carbonate or lime be very low in sulfate and lowing description and examples. 60 iron. In parenteral solutions containing vitamin C, iron According to the present invention, generally stated, a tends to cause decomposition of this vitamin. Sulfates substantially pure sodium glucoheptonate in the form -cause turbidity on storage in ampoules. Calcium car of crystalline alpha sodium glucoheptonate, or a syrup bonate possesses a further advantage in that the pH con composed of an aqueous solution of alpha and beta trol of the resulting calcium glucoheptonate solution is sodium glucoheptonates, in which the level of sulfate 65 more readily controlled, since calcium carbonate is too impurities is not detectable by the usual quantitative insoluble to materially raise the pH above the neutraliza methods, is dissolved in water and the resulting solution tion point desired. Care has to be taken also to insure is passed through a bed or column of cation exchange that the glucoheptolactone is completely converted into resin from which sulfate impurities have been removed calcium glucoheptonate. By applying heat to the glu by previous washing with deionized water. Sodium ions 70 coheptolactone solution during the formation of calcium are removed from the sodium glucoheptonate solution by glucoheptonate, the conversion is accelerated. Comple this procedure. The operation is repeated if necessary tion of the reaction can be ascertained by measuring the 8,083,900 3. 4. pH at 15 to 20 minute intervals when the pH appears sufficient calcium carbonate (sulfate free) to convert to have become stable at about pH 6.5. This procedure the glucoheptonic values contained therein to calcium is advisable since the lactone is substantially neutral and glucoheptonate. The reaction is complete when the pH calcium carbonate is relatively insoluble in water. Ad of the solution remains constant. In place of calcium justment of the pH of the syrup after evaporation and carbonate, sulfate-free lime may be used but care has to before dehydration may be made by adding a sulfate be taken to avoid adding more than the stoichiometric free lime water to raise the pH or by adding a water quantity of lime and not to exceed the desired pH, which solution of the lactone while the syrup is hot to lower is about 6.5. Thereupon the solution is treated with the pH. w 6 pounds of activated carbon (Norit S.G.2X) with agita The following examples will serve to illustrate the im O tion and filtered. The clear liquor is evaporated under vacuum (27 inches) at 45 C. to a specific gravity of proved process of the present invention. 1.45 or slightly higher. The resulting syrup is then ruri Example I in a very fine stream into anhydrous methanol (approxi Sodium glucoheptonate in crystalline form having a mately 40 gallons) whereupon a finely divided dehydrated very low sulfate content is now available commercially 5 solid calcium glucoheptonate is formed. This material as crystalline alpha sodium glucoheptonate, character is treated with fresh anhydrous methanol to complete ized by a specific rotation of -6.06 (10 percent solution the dehydration. As an alternative procedure, a quan at 20 C.) and a melting point (with decomposition) of tity of methanol may be added to the syrup initially to 16. C. A solution of 450 pounds of crystalline alpha alter the viscosity of the syrup and facilitate the pour sodium glucoheptonate (containing approximately 30 per 20 ing of the syrup into anhydrous methanol for the precipi cent water) in 240 gallons of deionized water is prepared. tation operation. The methanol slurry after dehydration Before use, the deionized water is checked for sulfate, of the calcium glucoheptonate is complete is then ceri iron and chloride content by procedures such as those de trifuged and the solid material is heated in vacuo at scribed hereinabove.