Gluconic Acid and Its Derivatives FRANCIS J. PRESCOTT, JOHN K. SHAW-, JAMES P. BILELLO, AND GORDOIV 0. CRAGWALL Chas. P'zer
& Co., Inc., Brooklyn 6 , N . Y .
G
LGCONIC acid was first isolated in 1878 by Boutroux (8) during his investigations of lactic acid fermentat,ions. I t was not until the early 1930's, hon-ever, that gluconic acid became available in commercial quantities. This acid and its derivatives have since become important chemicals in the pharmaceutical, food, feed, and general industrial chemical fields. ~-GLUCOSIC ACID,pentahydroxycaproic acid, CH,OH( CHOH)?COOH, occurs as a white, odorless, crystalline powder ha.ving a molecular weight of 196.16, a melting point of 131" C., specific rotation of [ a ] %= -6.7, and a dissociation constant of 2.5 X 10-4. I t is cxt,remely soluble in water, but only slightly soluble in alcohol, and it is insoluble in most ot,her organic solvents. In aqueous solutions an equilibrium exists among gluconic acid and its two lactones, gamma and delt,a, the composition varying w-ith concentrations of the solutions and the temperature. However, the neutralization value of such a solution is as though only gluconic acid was present, As neutralization proceeds upon the addition of alkali, the equilibrium is upset and more lactone is transformed into gluconic acid until complete neutralization is reached. For this reason, in assaying gluconic acid solutions, i t is preferable to back-titrate with dilute hydrochloric acid after a slight excess of caustic has been used. \$-hen phenolphthalein is used as an indicator, a slight excess of dilute sodium hydroxide is added to the solution, so that a pink color will persist. This ensures complete conversion of lactone to gluconic acid, which in turn is neutralized by the caustic. T h e excess sodium hydroxide is neut'ralized with dilute hydrochloric acid, aft,er a 15-minute waiting period, or simply after heating to 70" C. Gluconic acid can be prepared as a solid product ( S Q ) ,but because of the difficulties and resulting high production eo&, the acid of commerce is a 507, aqueous solution. This product is light amber in color, and has a faint acetous odor, and a specific gravity of 1.24 a t 25" C . D-GLUCONO-&LACTONE is also of commercial interest, and may be prepared by cryst,allization from aqueous solutions of gluconic acid ( 6 3 ) . It occurs as a whit'e, odorless, sweet tasting powder, and has a molecular weight of 178.14. This lactone has a melting point of 153" C. and a specific rotation of [CY]'," = +61.7". It is soluble to the extent of 59 grams in 100 ml. of water and 1 gram in 100 ml. of alcohol, and is insoluble in most other organic solvents. Upon addition to water, glucono-&lactone is partially hydrolyzed to gluconic acid, as is shown by the gradual decrease in p H of the solution. The final product is an equilibrium mixture of t,he two lactones and gluconic acid. Figure 1 gives the rate of hydration of glucono-&lactone to form the acid. S A L T S O F GLUCONIC ACID
AMMONITTMGLUCONATE, xH4C6H1107, is prepared as fine, u-hite needlelike crystals. This salt melts at 154' C. with decomposition. Ammonium gluconate is soluble in water to the eutent of 31.6 grams in 100 ml. a t 25" C., slightly soluble in alcohol, but insoluble in other organic solvents. Upon steaming t h e salt decomposes, forming ammonia and gluconic acid, thus indicating that i t may serve as a useful latent acid catalyst. CALCICMGLUCOKATE, Ca(C6Hl10i),, occurs as fine, white crystalline needles, without odor or taste. It crystallizes from strong aqueous solutions of gluconic acid when the acid is neutralized with calcium carbonate. Calcium gluconate is soluble to the extent of 3.5 grams in 100 ml. of water at 25" C. and
338
insoluble in either ether or alcohol. Aqueous solutions of this material are neutral to litmus. Stabilized calcium gluconate solutions of higher concentrations than the salt itself may be prepared with boric acid ( 1 , 25) or calcium n-saccharate ( 6 4 ) . COPPERGLUCONATE, Cu(C&,O;)~, the cupric salt of gluconic acid, is available as light bluish-green crystals which are odorless and have a slight metallic astringent taste. It is soluble to the extent of 30 grams in 100 ml. of water a t 25' C., but is insoluble in organic solvents. FERROES GLUCOKATE, Fe(CeH,107)2.H20,is the normal iron salt of gluconic acid, and it occurs as a fine yellowish-green crystalline powder with a slight odor resembling burnt sugar. It is stable in air, but solutions of ferrous gluconate are reduced by light owing to a photochemical reaction. The solubility of thiE material is 8.5 grams in 100 ml. of water a t 100" C. It is only slightly soluble in alcohol and insoluble in ether. MAGNESIUM GLUCONATE, Mg(C,Hl10,)2.H,0,is produced as a white cryst,alline powder which is odorless and tasteless. It is stable in air, but decomposes u-hen heated to 200" C. This magnesium salt is soluble in water t o the extent of 16 grams in 100 ml. a t 25" C., but only sparingly soluble in alcohol, and insoluble in most organic solvents. MANGANESEGLUCONATE,Mn( C G H , , O ~ ) ~ . ~ H ,occurs O, as odorless, needlelike crystals, and is stable in air. It is soluble in water to the extent of 10.6 grams in 100 ml. at 25' C., but is insoluble in organic solvents. POTASSITTM GLUCONATE, KC6Hl,0;, is prepared as a fine white crystalline powder. It is anhydrous and st'able in air, and upon being heated decomposes a t 180" C. Potassium gluconate is readily soluble in water, producing solutions with a slightly saline taste. Aqueous solutionR are ~light~ly alkaline, as they have a p H of 7.5 t'o 8.5. SODIUMGLUCONATE, ~ a C 6 H l l o , ,is prepared as irregularly fragmented, odorless, colorless crystals soluble in water to the extent of 59 grams in 100 nil. a t 25" C. but insoluble in organic solvents. Aqueous solut,ions are neutral and are stable even at 100" c. Additional data on the properties of gluconates are given in the publications of May (46)and Hornibrook (38). METHODS O F PRODL'CTIOIV
hlolliard ( 4 8 ) in 1922 showed that gluconic acid was produced of the action of Steriymatocystis nigra on sucrose wastes. Many other methods for the preparation of n-gluconic acid are also described in the literature. For example, i t may be prepared by the chemical oxidation of glucose in alkaline media by the hypobromites ('74)and by the electrolytic oxidat,ion of alkaline solutions of glucose, using an irisoluble anode in the presence of a vater-soluble iodide (33). Biological processes used in the preparation of gluconic acid include the fermentation of aqueous nutrient solutions of glucose with spores from such fungi as P. citrinurn, P. divaricatum, P . l u t e u m pwrpurogenum ( S T ) , Aspergillus niger ( 4 , 82),and P. lzitem (18). Other biological processes make use of bacterial fermentation employing gluconic acidforming bacteria from the awtobacter group such as Bacterium industrium, Bacterium oxydans, and B a c t e r i u m pasteurianum ( l Q , $0). hloger et al. (49, 5 0 ) describe a method in which boron compounds are added during the fermentat.ion of glucose in order to prevent precipitation of calcium gluconate. This use of boron compounds, such as boric acid or horax, with an excess of calcium carbonate permits continuous neutralization of the gluconic acid formed. Gluconic acid is a t present produced in commercial quantities by the fermentative oxidation of the aldehyde group in corn sugar to give t,he characteristic carboxyl group of the acid. as a result
February 1953
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INDUSTRIAL AND ENGINEERING CHEMISTRY
339
TOXICITY
SEQUESTERING ACTION
The nontoxic nature of gluconic acid has been illustrated by Hermann ( 3 5 ) . I n his investigation of methods of solution of phosphate stones in the human kidney, he noted that free gluconic acid is well tolerated in the daily food for years by animal and human organisms without injury and without disturbance of the digestive organs. This low order of toxicity has been further confirmed, as both ammonium gluconate and gluconic acid have been found to be equally effective in lowering the p H of the urine in man without producing any evidence of pathological renal changes ( I I ) , thus indicating the utility oP these compounds as urinary acidifying agents (29).
Gluconic acid and its derivatives, particularly the alkali salts, are capable of forming water-soluble complexes with certain metallic ions. This conversion of divalent and trivalent ions, such as calcium and iron, to a deionized but water-soluble form has been defined as sequestering (84). The effectiveness of sodium gluconate as a sequestrant has been studied and compared with such materials as sodium citrate, sodium tetraphosphate, and the tetrasodium salt of ethylenediaminetetraacetic acid. I n the case of calcium, the test used was such as to prevent the precipitation of calcium oxalate by including the sequestering agent in the solution. For iron, cobalt, aluminum, manganese, and zinc, the prevention of the precipitation of the hydroxide of these metals was used as a measure of the sequestering ability of the various products listed. CALCIUM. The sequestering action of the gluconate in regard to calcium was studied over a wide p H range (Figure 2 ) . In the range of p H 1 to 14 sodium gluconate or neutralized gluconic acid is relatively ineffective as a sequestrant for calcium. On the other hand, the gluconate is an outstanding sequestrant for calcium in the presence of sodium hydroxide. T h e optimum sequestering action is obtained in a 9% caustic solution where 31 p.p.m. of calcium is sequestered by 100 p.p.m. of sodium gluconate. I n strongly alkaline solutions, only sodium citrate most closely approximates the gluconate; the phosphate, and ethylenediaminetetraacetic acid derivative, though exhibiting sequestering ability, were far less effective.
3.5
I, 3.0
P.5
~
~~~
1 TIME, HOURS
P
1- SODIUM TETRAPHOSPHATE PDERIVATIVES OF ETHYLENE DIAMINE TETRAACETIC ACID 3-SODIUM GLUCONATE 4-SODIUM CITRATE
40[ 35
30
Figure 1. Rate of Hydration of Glucono-S-lactone 1 gram per 100 ml. of water at 2 5 O C.
20 15
8
Other investigations reported the nontoxic nature of gluconic acid, as evidenced by the fact t h a t no gastric irritation was noted with either the lactone or acid (64). Though gastric upset was noted in one or two cases when dosages t o animals exceeded 6 grams a t 2-hour intervals, it was concluded t h a t glucono-blactone was well tolerated (73). Rabbits which were treated daily with 10 ml. of a 10% gluconic acid solution, subcutaneously and intravenously, showed no ill effects after 1 week ( 7 ) . On the basis of studies conducted with 0.25 M acid solutions given intravenously, it was also found that gluconic acid was the least toxic of the following acids, which are listed in decreasing order of toxicity: oxalic, malonic, phosphoric, tartaric, pyromucic, hydrochloric, lactic, formic, propionic, succinic, acetic, and gluconic ($4). Patch tests carried out on humans have also indicated t h a t gluconic acid is nonirritating. Toxicity studies of a number of the salts of gluconic acid showed t h a t magnesium gluconate is well tolerated by animals and man when administered orally or parenterally (24). Small dosages of sodium gluconate administered to rabbits were without toxic effect (2%). Potassium gluconate is less irritating than potassium chloride, when given orally (55)and parenterally ( 3 ) . Extensive clinical studies have been made with ferrous gluconate because of its usefulness in iron therapy, especially because of its nonirritating properties (SO). It has been found to be the best tolerated iron salt when used with patients who are ordinarily not capable of being treated with other forms of iron (SO). Ferrous phosphogluconate has been reported as being well tolerated, and its action on the intestine is less irritating than other forms of iron ( 4 2 ) . Further indications of the nontoxic nature of gluconic acid and its derivatives are illustrated by the acceptance by the Committee on Foods of the American Medical Association of glucono-&lactone for use in foods (40).
IO
Figure 2.
-
Sequestering Efficiency of Calcium
IRON. Sodium gluconate has been found t o possess outstanding sequestering action for iron over a wide range of pH. I n Figure 3 the results of a recent study conducted by the Technical Service Department of Chas. Pfizer & Co., Inc., illustrate the effectiveness of these materials. Even in the presence of free caustic the gluconate exhibits a high degree of sequestering ability for the ferric ion. Over the entire p H range studied, the gluconate is superior t o sodium citrate, tetrasodium ethylenediaminetetraacetate, and sodium tetraphosphate. Sodium gluconate has also been found effective as an iron sequestrant in caustic soda solutions of up to 3.5% concentration. ALUMINUM, COBALT,MANGANESE, AND ZINC. Although a detailed study of the sequestering ability of the gluconate for aluminum, cobalt, manganese, and zinc a t various pH’s was not undertaken, a limited investigation indicated that these products are effective to some extent as sequestrants for these ions. I n Figure 4 the results of this study are compared, and the p H a t which the test was conducted is noted. I n general, the gluconate is not as effective as the other sequestering agents tested. MILDNESS AND NONCORROSIVENESS
A particularly important property of gluconic acid is its extremely low corrosive action on metals. Early studies had shown that gluconic acid, of a group of mild acids, had the least deleterious effect on tin-plate surfaces (66). Recent laboratory in-
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340 I- SODIUM T E T R A P H O S P H A T E P'OERIVATIVES O F ETHYLENE TETRAACETIC ACID
Vol. 45, No. 2
alcohol and the lactone when slightly heated. However, gluconic acid will undergo most of the reactions attributed t o sugar acids. Phosphorylation of this material may be carried out, resulting in stable phosphoric acid esters of gluconic acid ( 7 2 ) . Acetvlation of gluconic acid results in several interesting derivatives, including pentaacetyl gluconic acid, ethyl pentaacetyl gluconate, pentaacetyl gluconic phenyl hydroxide, and pentaacetyl D-gluconamide (44). Unsaturated alkyline amides and ureides of gluconic acid, such as B-monoallylamide, monomethylallylamide, and monoallylureide of gluconic acid, have been prepared (79). Stable aromatic amides of gluconic acid have also been successfully prepared (60). Tertiary aliphatic amines ( 2 7 ) , ephedrine ( 7 8 ) ,and naphthylamine (15) react readily with gluconic acid.
DIAM NE
PH
Figure 3.
Sequestering Action of Sodium Gluconate for Iron
vestigations have further demonstrated the low order of corrosiveness of gluconic acid. Strips of aluminum, brass, copper, mild steel, Monel metal, 316 stainless steel, and zinc, 4 inches long and 0.5 inch wide, were thoroughly cleaned, their total exposed area was determined, and they were accurately weighed. These metal strips were immersed in 1 N solutions in individual flasks containing acetic, formic, gluconic, glycollic, lactic, and phosphoric acids, for 4 hours a t 212" F., under reflux conditions. T h e losses in weight were determined and reported as milligrams lost per square centimeter of exposed metal surface. The results are given in Figure 5 . Examination of these data reveal that gluconic acid is the least corrosive acid of the group tested. Ieo
c
In an investigation conducted by Contardi and coworkers ( 1 6 ) , it was reported that a glossy resin could be prepared by reaction of sodium gluconate with formaldehyde. A number of salts of gluconic acid which include calcium. antimony, iron, aluminum, chromium, copper, arsenic, nickel, lead, vanadium, and titanium gluconates (10, 13, 41, 51, 62, 69-71) have been prepared and are commercially available. Several of these have been found valuable as pharmaceutical chemicals, and others hold promise for use in industrial applications, particularlp in view of their comparatively high water solubility.
100
USES O F GLUCONIC ACID
80
PHARMACEUTICAL USES. Gluconic acid and its deiivatives are useful pharmaceutical chemicals. Stone (76) stated that the salts of gluconic acid serve as an efficient mwns of introducing the so-called "trace" elements into diets. Ferrous gluconate, because of its nonirritating properties, is an excellent source of iron in the treatment of nutritional anemia and for iron therapy (2,30,80). Ferrous phosphogluconate has been prepared (62) and has also been found effective in the treatment of secondary anemia (42). Stone has reviewed the various methods for the preparation of ferrous gluconate for use in pharniaceutical applications ( 7 7 ) . Calcium gluconate has been shown to be an excellent therapeutic agent for the treatment of diseases caused or aggravated by a deficiency of calcium in the body (68). This salt has also been found t o be useful as an ingredient in an intramuscular injection material which consists of a water-soluble salt of d-tubocurarine which is used in the treatment of spastic children (9). Calcium gluconate and magnesium gluconate have also been reported to be useful dentifrice ingredients (69). Rawlings has reported that magnesium gluconate is very effective in dysmenorrhea (67). Recently, it was shown that potassium gluconate is useful in the treatment of hypopotassemia (3). Ephedrine gluconate has been prepared, and has been reported to be less irritating than ephedrine sulfate, which is more commonly used (78). A preservative for human and animal blood used for transfusions is made from gluconic acid and tertiary aliphatic amines (66). Monoallyl ureide of gluconic acid is a useful diuretic (79). FOODA X D FEEDUSES. The inclusion of small amounts of gluconic acid in shortenings based on fats and oils such as lard, beef fat, hydrogenated cottonseed oil, and other vegetable and animal fats and oils results in more stable products which are less likely t o become rancid (31, 3 6 ) . Glucono-&lactone is an effective leavening agent, as its use CBLISF a more gradual liberation of
60
40
PO 0
ABCD Cobalt pH 10
ABCD Aluminum PH 7
ABCD Manganese PH 10
A B C D Zinc PH 7
Figure 4. Sequestering Action of Sodium Gluconate for Aluminum, Cobalt, Manganese, and Zinc A . Sodium tetraphosphate B . Derivatives of ethylenediamioetetraacetic acid C. Sodium aitrate D.
Sodium gluconate
The mildness of gluconic acid has been further illustrated by the fact that i t does not "tender" fabric which has been immersed in it and not given an afterwash (66). blammut Eisen Black Special and Bottich coatings are unaffected by 5% gluconic acid solutions even after immersion in these solutions for 60 days (66). After 60 days' immersion in technical 50$&gluconic acid, lithcote No. 321, a resinous coating ( 6 6 ) , was unaffected. Rubber hose compounds used in breweries (Goodyear Tire and Rubber Co. Nos. 6732 and 15025) discolored slightly, but retained their initial flexibilities after 60 days' immersion in 50 and 5% gluconic acid solutions (66). There was no evidence of swelling or crazing. REACTIONS O F GLUCONIC ACID
I n spite of its multifunctionality, gluconic acid has found only limited application in the field of organic chemical synthesis. Its use as a chemical intermediate is minimized by the unstable derivatives which it forms. For example, ethyl gluconate has been prepared a t low temperature, but decomposes very readily t o ethyl
INDUSTRIAL AND ENGINEERING CHEMISTRY
February 1953
carbon dioxide than is possible with tartaric acid and its salts ( 4 7 ) . Therefore, a more even leavening activity is possible, resulting in products of greater uniformity. The use of calcium salts in the prevention of excessive browning of potato products (65) in deep fat frying indicates another possible use for calcium gluconate.
341
The textile industry (6, 75) has employed gluconic acid, glucono-8-lactone, and ammonium gluconate t o a considerable extent as acid catalysts or acid-forming catalysts because they are nontoxic and nontendering, and have a relatively low order of corrosiveness. I n printing with vat-soluble ester dyestuffs, both gluconic acid
-
1A-316 STAINLESS STEEL
1B MONEL METAL*
0.12+
a
1
1 -1 U 0
L.
0
4 -
-
1C COPPER
1D ALUMINUM 16.q
0.2o-c
-
-
1F MILD STEEL
1E ZINC
Figure 5 .
Effect of 1 N Acid Solutions on Metals
A calf feeding supplement which includes calcium gluconate has been found effective in preventing scours or curing scouring calves of the disease ( 1 7 ) . Calcium gluconate has been shown t o be a satisfactory source of calcium for young and mature poultry; the quality of egg shells is improved when it is included in the ration (36). GENERALINDUSTRIAL USES. Gluconic acid and its derivatives serve as effective pharmaceutical, food, and feed chemicals. The versatility of these products is further indicated by the use of many of these compounds as general industrial chemicals.
and ammonium gluconate have been used t o obtain the necessary acid medium for the development of these dyestuffs. The need for an odorless, nontoxic acid catalyst for acid colloid resins used in the textile industry has led t o the wide acceptance of glucono-blactone or gluconic acid for this purpose. The sequestering action of sodium gluconate has also been of interest to the textile industry. Of particular value is the sequestering ability of this material for iron in free caustic. This property indicates the possible use of sodium gluconate in the prevention of iron contamination in mercerizing processes.
342
INDUSTRIAL AND ENGINEERING CHEMISTRY
I n the detergent field, considerable use has been made of gluconic acid and its derivatives, particularly because of their sequestering action in alkaline media. As the main ingredient of many alkaline cleaners, particularly for bottle washing compounds, is sodium hydroxide, there is a tendency for a heavy scale t o form on the washer especially when relatively hard water is used. It has been found that this scale problem can be controlled by the addition of small amounts of gluconic acid or sodium gluconate, thus permitting greater efficiency of operation (96). Gluconic acid is also widely used in the dairy industry to prevent the formation of milkstone, and as an acid constituent in milk can cleaners (57,68). Metal cleaning compounds containing gluconic acid have also been developed (43). Recently, this acid was shown to be effective in the prevention of beerstone, a problem confronting many brewers (6). The leather industry can use gluconic acid or sodium gluconate t o advantage in iron tanning ( 2 1 ) and alum tanning ( 6 1 ) of leather, as the hydroxides of these metals are prevented from precipitating before the isoelectric point of leather is rearhed. Titanium gluconate has been proved t o be very useful in the preparation of white leather ( 5 1 ) . Sodium gluconate and glucono-&lactone have both found use in the photographic industry for preparing conventional chemical mixtures which are stable under varying atmospheric conditions. I n addition, the sequestering ability of the gluconates is of value in the photographic industry for preventing the precipitation of metallic hydroxides in alkaline developing baths (81). Gluconic acid or its lactone has also been employed in the preparation of plates for lithographic printing (8s). Gluconic acid and its derivatives, particularly sodium gluconate, have also found application in water treatment as a means of inhibiting corrosion and tuberculation ( 5 3 ) . Electroplating ( 1 4 ) and electropickling operations ( I d , 2 5 ) have also been developed with gluconic acid. The addition of sodium gluconate to water-soluble paints so as t o prevent “flashing” and color variations has also been recommended ( 5 2 ) . Recently, sulfonated gluconamides resulting from the reaction of glucono-&lactone with fatty acid amines have been described as effective detergents ( 4 6 ) . LITERATURE CITED
(1) Austin, J. A , , U. S. Patent 2,007,786 (1935). (2) Beard, M. F., J. I n d i a n a M e d . Assoc., 39, 331 (1946). (3) Bernhard, A,, Science, 113, 751 (1951). (4) Bernhauer, K., and Schulof, L., U. S. Patent 1,849,053 (1932). (5) Bilello, J. P., Am. Byewer, 85, KO. 5, 30 (1951). (6) Bilello, J. P., Textile W o r l d , 101, 151 (1951). (7) Boden, G., Orvosi Hetilap, 80, 845 (1936). ( 8 ) Boutroux, L., Compt. rend., 91, 236 (1880). (9) Burke, J. C., and Jurist, A. E., U. S. Patent 2,476,082 (1949). (10) Carpmael, A , , Brit. Patent 335,965 (1929). Chenoweth, A. B., et al., J . L a h . Clin. M e d . , 26, 1574 (1941). Chester. A. E.. U. S. Patent 1,995,766 (1935). Chester, A. E., and Reisinger, F. F., Ihid., 2,428,356 (1947). Ibid., 2,486,563 (1949). I h i d . , 2,485,664 (1949). Contardi, A., and Ciocca, B., R e n d . ist. lombardo sei., 69, 1057 (1936). Coyner, J. M., U. S. Patent 2,182,171 (1939). Currie, J. N., et al., Ibid., 1,893,819 (1933). Currie, J. N., and Carter, R. H., Ibid., 1,896,811 (1933). Currie, J. N., and E’inlay, A., Ihid.. 1,908,225 (1933). I
Dawson, W. O., paper presented before American Leather Chemists’ Association, Groton, Conn., June 12, 1951.
Vol. 45, No. 2
(22) Desnoyer, S., C . 5. Patent 2,265,271 (1942). (23) Di Carli, Ann. chim. applieata, 21, 447 (1931). (24) ’ Di hfattei, P., and Butturini, L., Roll. soc. ital. biol. sper., 7, 104 (1932). (25) Dove, A. B., Enamelist, 15, 21 (1933). (26) Dvorkovita, V., and Hawley, T. G., U. S. Patent 2,584,017 (1952). (27) Fischer, R., Ihid., 2,194,468 (1940). (28) Gajatto, S., A r c h . farmacol. sper., 66,98 (1939). (29) Gold, H., and Civin, H., J . Lab. C l i n . Med., 24, 1139 (1939). (30) Green, M. M . , Bull. Natl. Formularu Comm., 13, 178 (1945). (31) Grettie, D. P., U. 8. Patent 2,236,569 (1941). (32) I h i d . , 2,251,485 (1941). (33) Helwig, E. L., C. S. Patent 1,937,273 (1933). (34) Hermann, S., Arch. E x p t l . P a t h . Ph,armakol., 154, 143 (1930). (35) Hermann, S.,Miinch. M e d . Wochsckr., 82,540 (1935). (36) Herrick, H. T., et al., U. S.Patent 1,767.178 (1930). (37) Herrick, H. T., and May, 0. E.! Ihid., 1,726,067 (1929). (38) Hornibrook, I?. B., “Solubility of Calcium Gluconate,” h1.S. thesis, University of Maryland, 1933. (39) Isbell, H. S.,C. 9. Patent 1,985,255 (1934). (40) J . Am. M e d . Assoc., 100, h-0. 8 , 577 (1933). (41) Kussmaul, N‘., U. S. Patent 1,846,880 (1932). (42) Leger, A , , and Chaput, Y . , J . U n i o n Med. Canada, 70, 1072 (1941). (43) hlcDonald, L., U. S. Patent 2,362,284 (1944). (44) Major, R. T., and Cook, E. IT-., Ihid.. 2,232,712 (1941). (45) May, 0. E., e l al., J . W a s h . A c a d . 9 c i . . 19, 443 (1929). (46) Jlehltretter, C . L., et al., J . Am. Oil Chemists’ Sac., 29,No. 5,202 (1952). (47) Mendelsohn, S., “Baking Powders,” Sew York, Chemical Publishing Co., 1939. (48) Molliard, M., Compt. rend., 174, 881 (1922). (49) Jfoyer, -4. J., C. S. Patent 2,351,500 (1944). (50) Moyer, -4. J., et al., IND. ENG.CHEM.,32, 1379 (1940). (51) Nelson, W.K., French Patent 840,907 (l939), Xewman, B. O., U. S. Patent 2,511.782 (1950). Nieland, W. L., et al., Ihid.. 2,529,178 (1950). Xugent, J., J . Florida M e d . Assoc., 27, 18 (1940). Parker, F. P., Southern M e d . J . , 33, 1301 (1940). Parker, M. E., Food I n d u s . , 12, No. 10, 39 (1940). Parker, 31,E., and Bonewitz, P.TT.., U. S . Patent 2,338,688-9 (1944). Ibid.., ~ 2.424.049 , ~ ~11947) ~~ .,, .. ~ . Pasternack, R., Ibid., 1,861,189 (1932). Pasternack, R., and Ammermari, C. P., I h i d . , 1,901,565 (1933). Pasternack, R., and Cragwall, G . O., Ibid., 1,941,485 (1934). Pasternack, R., and Giles, TT‘. R.. Ibid., 7,900,517 (1933). Ibid., 1,942,660 (1934). (64) I h i d . , 1,965,535 (1934). (65) Patton, A. R., U. S. Patent 2,448,152 (1949). (66) Pfiaer & Co., Inc., Chas., information on file. (67) Rawlings, J., M e d . J . Australia, 1, X o . 3, 61 (1049). (68) Roblin. R. O., U. S. Patent 2,220,992 (1942). ib9) Schmidt, H., Zbzd., 2,066,742 (1937). (70) Schmidt, H., and Jung, H., Ibid., 1,893,872 (1933). 171) Ihid., 2,215,429 (1940). et al., Ibid., 1,907,592 (1933). (72) Schoeller, W., (73) Sisk, I., and Toenhart, O., J . U r d , 39, 699 (1938). (74) Stoll, A , , and Kussmal, IT., U. S. Patent 1,648,368 (1927). (75) Stone, G. B , Am. DuestuJReptr., 37, No. 20 (1948) (76) Stone, G. R.,Drug and Cosmetic I n d . , 67, No. 2 , 192 (1950). (77) Stone, G. B., J . Am. P h a r m Assoc., Sei. E d . , 39, No. 1, 16 ~
~
, ,nrn, ( LYdU).
178) Stuart, E. H., G. S.Patent 2,211,630 (1941). (79) Tabern, D. C., I b i d . , 2,084,626 (1937). (80) Teeter, E. J., J. Am. M e d . Assoc., 127, 973 (1945). L. J., S.Patent 2,214,216 (1940), ( 8 2 ) Williams, A. E., Mfg. Chemist, 16, 239 (1945). (83) Wood, W., C. S. Patent 2,199,865 (1940). (84) Zussman, H. W., paper presented before Detergent Mfgrs. Assoc., Sew York, N. Y . ,.Jan. 2 i . 1948.
u,
RECEIVED f o r review June 3 , 19.52.
Accr:Pcic~September 15, 1952.
