Management of metallic ions in food has received considerable attention by the food industry. Metallic ions of iron, copper, and zinc present in some food products, even in minuscule amounts, can cause adverse effects on food flavor and integrity. If those metallic ions are allowed to remain in food products, even in very low concentrations, metallic ions can greatly reduce shelf life of fats, oils, and other foods subject to spoiling and oxidation.

From a food manufacturing perspective, however, metallic chelators serve to stabilize or enhance numerous properties identified with wholesome food, including flavor, color, and texture.(1) Addition of most food chelators does not impair absorption of zinc from foods passing through the intestinal tract because stomach acid dissociates zinc from the ligand. Several efforts were made by companies to find a chelating flavor mask for zinc gluconate.

Citric acid in the Bristol Myers zinc gluconate lozenges (see Chapter 4.C.1) and tartaric acid in the Australian zinc acetate lozenges (see Chapter 4.C.2) are two food acidifiers that have been directly used to chelate zinc lozenges to improve their flavor. Sodium bicarbonate in the Australian lozenges provided a source of carbonic acid in solution to react with zinc gluconate to form nonsoluble, nonionizable zinc carbonate. Chelators, by definition, reduce or eliminate Zn²⁺ ions in solutions at physiologic pH.

Highly chelated compounds of zinc, including zinc orotate (see Chapter 4.B.1) and zinc aspartate (see Chapter 4.B.2), have been shown to be without any effect on the duration of common colds. Zinc aspartate, zinc oxide, and zinc amino acid chelate lozenges -- all highly chelated and ineffective against colds -- are the zinc lozenges most likely to be encountered in health food stores.

Glycine and other sweet amino acids were proposed by Zarembo, Godfrey and co-workers to be effective flavor masks for zinc gluconate and other ionizable zinc compounds (see Chapter 4.C.3). Contrary to claims of 93 percent Zn²⁺ ions being released into saliva from these lozenges, glycine (10 mole) releases no Zn²⁺ ions at pH 7.4 according to Berthon. Hard candy zinc gluconate lozenges compounded with glycine slowly change color from a light tan to bright orangish-brown during ambient summer storage conditions, suggesting a Mailard reaction occurs between sugars and glycine.

Glycine has been rescinded from the FDA list of Generally Regarded As Safe (GRAS) ingredients (21 CFR §170.50) and has been prohibited as an additive to foods including candy lozenges and cough drops since 1971. Glycine is only allowed in prescription drugs under a U.S. Food and Drug Administration New Drug Application.(2) However, glycine is permitted as a food additive to improve the biologic quality of the total protein in a food containing naturally occurring, primarily intact protein but is not to be allowed in excess of 3.5 percent of the total protein.(3) 1998 Addendum: The U.S. Congress passed a law in 1995 decreeing all amino acids safe.

Zinc gluconate lozenges were described in a technical bulletin published by Akzo Chemie Company of The Netherlands dated January 22, 1986.(4) Ten milligrams of zinc (77 mg zinc gluconate) were incorporated in 3.5 gram candy lozenges. The lozenge filler was sorbitol with 2 percent gum arabic (acacia). Zinc gluconate was added at 121 degrees C. to sorbitol and gum arabic. The mixture was batch cooked to 144 degrees C., and cooled to 77 degrees C. to add peppermint oil. The mixture was deposited in molds, and held overnight at 39 degrees C. The resultant product was crystal clear, had no taste of zinc gluconate, and had no astringency. Gum arabic (acacia) has a high molecular weight (240,000 to 580,000), is extremely soluble in water at twice its weight, and is acidic to litmus.(5) Gum arabic consists of (-)-arabinose, (+)-galactose, (-)-rhamnose, (+)-glycuronic acid, tannins and other chemicals. Gum arabic is incompatible with most metallic salts, including salts of zinc, lead, boron, and iron. Combination results in precipitation or jellification.(5)

Zinc gluconate heated in sorbitol without gum arabic rapidly carbonizes and develops a foul, burnt odor producing lozenges having no research or commercial utility. The status of sorbitol as a zinc chelator is stated by Briggs and co-workers(6) to be only 4 times higher than dextrose (K₁ = 0.04), but sorbitol may be a much stronger zinc chelator according to Zarembo and co-workers.(7) Zinc chelated to tight complexes with gum arabic in these lozenges would have no efficacy against common colds.

Encapsulation of zinc gluconate powder, with the first layer being hydrophilic and second layer being hydrophobic, reduces bitterness, astringency, dryness, and roughness of zinc gluconate by about one-third when incorporated into lozenges according to a patent assigned to Warner Lambert Company.(8) Hydrocolloid materials including pectins, alginates, cellulose and its derivatives, gelatin, gums, mucilages, and mixtures are used. Some hydrocolloids are zinc chelators, and they react with zinc gluconate to eliminate Zn²⁺ ions, as well as to reduce and eliminate bitterness and astringency. Incorporation of treated zinc gluconate granules in non-fructose compressed lozenges results in damage to granule membranes with resultant delayed-onset bitterness.

Although not technically chelation, microencapsulation of zinc gluconate with nonsoluble cellulose membranes was demonstrated by Eurand America, Inc., Vandalia, Ohio, in 1985 with the idea of incorporating zinc gluconate into chewing gum. The product effectively flavor-masked zinc gluconate by preventing release of zinc gluconate into saliva, resulting in essentially all zinc being swallowed and thereby rendering products incapable of producing an effect against common colds.

Zinc gluconate in the McNeil Consumer Products lozenges containing sucrose, fructose, mannitol and sorbitol (see Chapter 4.A.3) became very bitter over a month, demonstrating the problem in maintaining a flavor-stable product. Failure of the McNeil lozenges can be directly attributed to poor patient compliance as a result of lozenge bitterness. All sweet carbohydrates except fructose react with zinc gluconate to impart bitterness.

From 1986 to 1992 the present author conducted experiments to mask zinc gluconate flavor. The main thrust of the research was to develop techniques not chelating zinc, while reducing bitterness. Generally, the antidote to bitterness is sweetness. Numerous attempts were made to find sweeteners that would reduce bitterness. Many zinc compounds were tested in many different bases. After over 1000 failures testing various zinc gluconate lozenge compositions, briefly noted below, the author developed two non-chelating methods of flavor-masking zinc lozenges.

Lozenge formulations were tested using zinc gluconate and other zinc compounds in either hard boiled candy or directly compressed lozenges. All zinc gluconate lozenges and nearly all other zinc compounds tested (except zinc acetate), regardless of manufacturing technique, made with bases containing dextrose, sucrose, mannitol, sorbitol, xylitol, maltose, maltodextrins, lactose, other sweet tablet bases, and various combinations became very bitter within a few days to a few months.

The addition of 50 mg sodium, calcium, or acid saccharin to zinc gluconate in lozenges eliminated bitterness and aftertaste from both zinc gluconate and other zinc compounds although saccharin complexes with Zn²⁺ ions. Lozenges became much too sweet resulting in an overly bitter saccharin taste and aftertaste. Efficacy against common colds may have been impaired by incorporation of saccharin. Lozenges were unpredictable in their flavor. Using identical lozenges, some taste testers complained lozenges were too sweet, while others complained of extreme bitterness. Perception of lozenge taste varied too widely with saccharin as a flavor mask to be of value for commercial development. Saccharin may also be objectionable as a potential carcinogen to patients. Therefore, incorporation of saccharin may preclude the fullest utilization of zinc lozenges. Incorporation of saccharin also caused severe headaches in several taste testers. Headaches did not occur in those taste testers when saccharin was not used in lozenges.

Complexation of zinc in 1986 with saccharin by Syntheco Inc., Gastonia, North Carolina, for the present author resulted in an extremely sweet composition using less than 30 mg zinc saccharinate in a 5-gram lozenge. If zinc dosage was increased to therapeutic levels, flavor became extremely bitter. No formal tests against common colds were conducted with zinc saccharinate because of extreme bitterness.

Addition of Magnasweet (mono-ammonium glycyrrhizinate), a flavor enhancer, increased the bitterness and astringency of zinc gluconate lozenges. Again, no tests against common colds were conducted because of extreme bitterness.

Addition of other super-sweeteners including acesulfame K, aspartame, and various licorice extracts did not produce noticeable benefit to sweetness at chemically insignificant doses; and most are strong zinc chelators. Addition of phenyl acetaldehyde diisobutylacetal, a flavor mask used in extremely small amounts, had no beneficial effect and tended to increase the bitterness of zinc gluconate lozenges.

Carbowax 8000 (polyethylene glycol molecular weight 8000), or PEG, coating of zinc gluconate granules using fluid bed agglomeration was performed by I. F. P., Inc. of Hayfield, Minnesota, in 1989 and 1990 for the author. Coatings were in weight-ratios of 10 percent, 50 percent, 100 percent, and 200 percent to zinc gluconate. Directly compressed lozenges of agglomerated sucrose (Sugartab(r) by the Edward Mendell Company in Carmel, New York) incorporating PEG-coated zinc gluconate were tested for flavor stability. After a few weeks, lozenges containing 25 percent and 50 percent coatings became bitter. After 1 to 4 months, lozenges containing higher amounts of coating became bitter. Compression ruptures PEG membranes, allowing chemical reactions between zinc gluconate and other lozenge ingredients. A gummy, solid residue in saliva resulted from oral dissolution of lozenges.

Carbowax treatment of fructose produced lozenges containing zinc gluconate that did not become bitter upon aging, at least for the first 6 months.

Carbowax 8000 coating of ground crystalline fructose (Krystar 300 by A. E. Staley Manufacturing Company, Decatur, Illinois) was possible only at low temperature and only when PEG was diluted with water. The resultant agglomerated fructose product contained 9 to 12 percent PEG. Five gram, 7/8 inch diameter lozenges were produced with direct compression. Lozenge quality was high with a hardness of over 15 kg and 20 to 30 minute dissolution. Additionally, un ground Krystar 300 crystals were coated with PEG 8000, and ground Krystar 300 crystals were agglomerated with PEG 8000 for use as tablet bases. Lozenges had a break strength of 12 to 25 kg, respectively, when compressed to 9 tons applied pressure. Lozenges dissolved in 20 to 25 minutes and produced 30 ml of saliva.

Zinc gluconate in PEG-treated fructose was superior in taste to other zinc gluconate products. The mild taste and aftertaste of pure zinc gluconate remained, requiring modest flavor-masking. Several zinc gluconate, fructose, and PEG compositions became tan to light brown in severe aging and thermal tests, suggesting slow degradation of lozenges.

RBS Pharma zinc gluconate lozenges tested by the Medical Research Council (see Chapter 4.A.2) were outstanding examples of flavor-stable zinc gluconate lozenges. RBS Pharma lozenges had a 44 ZIA value, nearly the highest ZIA value possible for flavor-masked zinc gluconate. The one-gram lozenges were made of fructose, zinc gluconate, and Methocel(r) and were sweetly flavored. Even after storage for five years, no extra bitterness occurred, even though the flavor oil was then absent. However, the generally objectionable bland, chalky zinc gluconate taste and 24-hour aftertaste remained. There is a 1-to-3 order of magnitude reduction in bitterness between zinc gluconate lozenges made with fructose and zinc gluconate lozenges made with any other sweet tablet base after equivalent lozenge aging.

As only moderate amounts (about 30 percent) of zinc gluconate are available as Zn²⁺ ions at pH 7.4, a daily ZIA of 100 using 23 mg zinc as zinc gluconate 9 times per day is possible only from lozenges producing little saliva and remaining in the mouth for an extended time (see Chapter 4.A.1).

The maximum ZIA value for 23-mg zinc flavor-masked zinc gluconate lozenges having a wet granulated fructose and Methocel(r) base is about ZIA 50 when used each 2 hours. Consequently, to obtain a ZIA 100 response with flavor-masked zinc gluconate lozenges, patients would necessarily treat themselves once every hour while awake. Alternately, lozenges with higher zinc gluconate dosages can be developed. Unfortunately, addition of Methocel(r) causes an unpleasant slimy feeling in the mouth because of the high viscosity of the Methocel(r)-saliva mix, resulting in a product of questionable commercial value. Lozenges containing zinc gluconate in a base of crystalline fructose with Methocel(r) binder do not become bitter regardless of time. However, addition of as little as 1 percent sucrose or other sweet carbohydrate is sufficient to cause onset of delayed bitterness.

Clearly, the only suitable tablet base for zinc gluconate is fructose, which is non-compressible in crystalline form. However, zinc gluconate lozenges could be manufactured using micro-powdered fructose (powdered Krystar(r)). Powdered Krystar(r) contains 2% silica gel as a moisture absorbent and flow enhancer. Powdered Krystar(r) was easily compressed on a hand press to form extremely hard lozenges having a very slow dissolution rate without increased bitterness over time. Lozenges were very hygroscopic. Direct compression of lozenges using powdered fructose is not commercially possible, because of the extreme lightness and fluffiness of the composition, and the extreme amount of dust generated by the process.

Slugging (precompression of powder, followed with milling to obtain compressible granules) the powdered fructose, re grinding the pellets, and using the ground composition to mix with zinc gluconate and other tablet ingredients appears feasible and perhaps desirable. Addition of nonsoluble wax to fructose may produce a viable tablet base for zinc gluconate lozenges.

When the lozenge base is fructose, zinc gluconate lozenges can be effectively flavor-masked with anethole to eliminate unpalatable taste and aftertaste. Anethole, a highly stable but aromatic flavor oil, is the main constituent of the essential oils of anise, star-anise, and fennel. Anethole is almost totally insoluble in water and cannot chelate Zn²⁺ ions.

Anethole is found in beverages, foods, candy, and pharmaceuticals as a flavor- and odor-masking agent. Anethole is also used as a sedative, stimulant, and expectorant in cough mixtures and lozenges. The taste-masking effect of anethole on zinc compounds is strong, long-lasting, and unique. Such parameters allow sustained application of zinc gluconate in the form of a lozenge to the oral and oropharyngeal mucosa with no bitter taste or aftertaste. With the amount of high-quality anethole properly balanced with zinc gluconate in a fructose lozenge, anethole can mask taste and aftertaste of zinc gluconate for over 24 hours. Anethole cannot, however, mask the bitter taste occurring when zinc gluconate is combined with sucrose, dextrose, mannitol, sorbitol, lactose, maltose, xylitol, or various combinations.

Flavor-masked zinc gluconate lozenges can be prepared by adding 12-16 mg of high purity anethole (Arizole Anethole Extra, by Arizona Chemical Company, Panama City, Florida) plated onto silica gel (Siloid 244FP, by Davidson Chemical, Baltimore, Maryland), with 175 mg zinc gluconate (23 mg zinc) to a 5-gram tablet of pure fructose incorporating PEG 8000 or Methocel(r) as a binder.

Stability of anethole flavor-mask in fructose was acceptable over a 4-month test period, unless lozenge container remained unsealed. If left unsealed, anethole quickly evaporates, and the lozenge taste eventually becomes bland and chalky but not offensive or bitter in taste. Spray dried flavors or flavor oil incorporated within beta-cyclodextrins were not flavor-stable, as dextrose within those compositions reacted with zinc gluconate causing bitterness.

The main disadvantages of anethole as a zinc gluconate flavor mask are extreme aromaticity and a distinctive, anesthetic-like taste in the amounts used. Evaporative loss of only 2 or 3 mg anethole is sufficient for loss of flavor mask. Although other flavors can be added, such as eucalyptol and menthol, the primary taste is anethole and is disliked by many taste-testers.

The most alarming finding about anethole flavor-masked zinc gluconate lozenges is their low ZIA value. Five-gram fructose and PEG lozenges containing 23 mg zinc from zinc gluconate compressed to 9 tons, dissolve in the mouth in 21 minutes, and produce 30 ml saliva, resulting in a daily ZIA 34 value when a lozenge is used every 2 hours while awake (9 t/d). A pleasant taste could be obtained with anethole flavor-masked, 5-gram fructose-based lozenges, or efficacy could be obtained with a slow-dissolving, unflavored, nonsoluble tablet (see chapter 4.A.1). A zinc gluconate lozenge with both high efficacy and flavor appears impossible using direct compression techniques.

Many other zinc compounds were examined for utility in zinc lozenges. Modest amounts of zinc sulfate, zinc oxide, zinc picolinate, zinc ascorbate, and zinc amino acid chelates showed little or no utility against the duration or severity of common colds.

Several interesting lipophilic compounds were found to be highly cytotoxic by Merluzzi and colleagues,(10) and were not tested by the author. Chelated zinc compounds releasing neutral zinc complexes, including zinc gluconate (releases mainly zinc gluconate-hydroxide at physiologic pH 7.4; see Figure 1), may produce mild cytotoxicity. The objectionable 24-hour aftertaste of zinc gluconate may be evidence of mild cytotoxicity through intra cellular absorption of zinc gluconate-hydroxide.

Only zinc compounds releasing 100 percent of their zinc as Zn²⁺ ions at salivary pH through physiologic pH 7.4 are currently viewed as having adequate safety potential for use in zinc lozenges. Of generally regarded as safe (GRAS) compounds, only zinc chloride and zinc acetate have such properties.

Evaluation of many zinc compounds having a first stability constant of less than or equal to log K₁ = 2.0, and particularly zinc compounds having a first stability constant less than or equal to log K₁ = 1.0 (zinc chloride, propionate, butyrate, benzoate, formate, acetate and others),(1) were considered, and numerous other experiments were conducted over several years.

Perhaps the zinc compound most likely viewed by zinc researchers to be beneficial in zinc lozenges is zinc chloride. Zinc chloride has a very low first stability constant (log K₁ = 0),(1) but zinc chloride immediately complexes with carbohydrates such as dextrose and sucrose in situ to form brown discolorations on white lozenges. Zinc chloride and all lozenges made with it are extremely hygroscopic. Zinc chloride also has an objectionable, caustic taste, rendering it less than desirable for incorporation in zinc lozenges.

Although many formulations using these highly unstable zinc compounds appeared useful to shorten common colds, the search ultimately led to zinc acetate, an extremely pungent, sharply flavored, stable, non-hygroscopic zinc compound which in concentrated solutions tastes like vinegar. Patently surprising and unique, when zinc acetate is compounded into sweet, carbohydrate-based lozenges of almost any composition, lozenges have pleasant tastes to the normal palate and are flavor-stable for years.