'Chewable Multi-Vitamin Tablets

PRODUCT ACCEPTANCE FACTORS IN

'Chewable Multi -Vitamin Tablets By Richard H. Barry and Michael S. Weiss

he market for children's chew-

able vitamins has seen spectacular T growth in the last decade. is estiIt

mated that this market has increased fiyefold since, 1957, reaching approximately 50 million dollars at retail in 1969. Flavo~d chewable tablets, supplying the miniinum daily vitamin requirements for children two to 12 years of age hav~ ' largely displaced multi-vitamin Ijquid products in this age group. It is now common practice to prescribe ftu~ride to the growing child in tbis form . Chewable multivitamin tablets offer the mother an attractive, ,convenient and sanitary way to administer vitamins to her growing family, either as singleflavored or as "multiple-choice" colored and 'flavored tablets in phiin, animal ' or comic book character shapes. Table I (page 603) gives a representative listing of children's chewable vitamin tablets. The minimum daily require,ments for the vitamins are listed in the' labeling. Successful development of chewable multi-vitaniiI). products not only requires knowlepge of the fundamental aspects of the physical and chemical properties of the various vitamins and their techniques of manufacture but particularly an awareness that consumer acceptability depends primarily on visual-organoleptic factors such as appearance, "mouth feel" and general The vitamin tablet flavor profile. should be acceptable ph~rmaceutically, that is, be, of stable composition and have corp pressibili ty characteris tics suitable for high-speed tableting and packaging operations. Since much already has ,been written about the chemical stability of the individual vitamins and their interactions, this paper is concerned primarily with a review of the aforementioned consumer acceptance factors. The principal product acceptance obiectives to be attained in the formulation of rpultiple flayor and color

chewable vitamin tablets can be listed as follows1. Selection of stable flavor profiles which mask the vitamin admixture and ar~ acceptable to children ages two to twelve. 2. Matching of flavor with certified colors stable to ordinary 'lighting exposure. 3. Agreeable "mouth feel"-readily chewable, ptQper "bite size." 4. Avoidance of flavor "carry-over" when multi-flavor tablets are packaged together. 5. Attractive in color and shape to children. Visual-Organolept!c Factors Appearance

To be readily accepted, a food or food supplement should have the expected or correct appearance and color. For vitamin supplements in the form of chewable tablets, colors and shapes which appeal to children are especiaIly desirable. Certified lake dyes are commonly used to color uncoated tablets and it is' to be expected that the choice of color would be made to matc!). the flavor profile; for example, a red for a cherry-flavored tablet, reddish-purple for a grapeflavored one, orange,- yeIlow and green colors for the three citrus flavors. Good color distriblJtion in the tablet granulation is essential ' to a~oid "speckling." This is done by miIling in the colors prior to granulating or slugging. Mouth Feel

Mouth feel 'has been described 1 as the texture factor which involves smoothness, roughness, stickiness and related surface characteristic~ and brittleness. Texture is a subjective factor determined not only by mastication but also by th'e ,ease of cutting or dividing (hardness) before consumption. Multi-vitamin tablets with acceptable mouth feel can be made by

using the natural sugars as excipients. Dextrose and sucrose, for example, can be used if the mesh size chosen avoids grittiness. There is, however, a tendency for natural sugar formulations to harden on aging. Good mouth feel can be achieved using , the polyols mannitol and sorbitol. Mannitol~ in our experience, is the e?,cipient 2 of choice, providing sweetness, smoothness and ready dissolution in the mo.ut~. Introduced in 1958, it has become the preferred' excipient for all types of chewable tablets since it also blends effectiv~ly with sweetening and flavoring agents, is nonre~ctive and non~ygroscopic,. Flavor Flavor, a word derived from "savor," has be'e n defined as "the power to excite the sense of smell or taste; basic power to arouse int~rest or zest.," Flavor and mouth feel are in'terdependent coqtributors to the -overall taste sensation. While commonly accepted as a pleasure-giving property, flavor i~ wholly SUbjective. Ethnic factors, age and sex influence the acceptability of the flavor profile: There can be genuine differences of
Vitamin Bl (thiamine hydrochloride or Vol. NS10, No. 11, November 1970

601

Richard H. Barry is director of research for the Sauter Laboratories division of Hof!mann La Roche. Since receiving his B.S. In pharmacy from Duquesne University and MS and PhD from the University of Maryland, he has held several research and t1;evelopment positio!,-s in industry prior to joining l!ofJmann-La Roche in 1962. Barry has publzshed articles and holds patents on compounds and p r~duct dose forms derived from or~anic medicinal and pharmacy research and development. H e is a member ,of the ACS, APhA, AAAS, Society of Cosmetic Chemists, Rho Chi and Sigma Xi. Barry's present research intel'ests involve the development of proprietary drug and hair care products for the consumer product division of Hoffmr:znnLa Roche.

Michael S. Weiss is a senior pharmaceutic"al chemist at Sauter Laboratories, division of Hoffmann-La Roche. APhA member We~ss earned his BS fron:z The College of The Cl,ty New York in 1944 and his MS from New York U niyersity in 1947. After several years of research in the field of enzyme chemistry and physiology at Columbi.a U niversity and New York University, Weiss joined Roche in, 1948. He is the author of ~umerous papers on enzyme, analytical and pharmaceutical chemistry as well as the holder of several pharmaceutical patents. A specialist in the flavoring of pharmaceutical products, many commercially successful oral dosage forms, both ethical and proprietary, are the result of his efforts.

of

nitrate)-"yeasty," bitter Vitamin Bo (pyridoxine HCl)-slightly bitter, slightly salty Vitamin B12 (cyanocobalamin)-t~steless Ni'a cinamide-very bitter Ascorbic acid-sour Sodium ascorbate-salty, somewhat "soapy" Calcium pantothenate-bitter Biotin-tasteless Folic acid-nearly tasteless Minerals (e.g., iron salts)-ffi,etallic

There are certain taste relationships which are encountered in the evaluation of each magnitude. Souniess in general can be depre~sed by providing sweetness ~m4 by sodium chloride. Saltiness can be reduced by sweetness but can be enhanced by acid. Ascorbic acid, a normal constituent of chewable vitamins, serves to confer a degree ' of acidity. The "sourness" (or acidity) of ascorbic acid can be d'epressed by providing this vitamin wholly or partially in the form of its sodium $alt. The level of tartness selected by adjusting the ratio of acid to its salt depend~ on the flavor impression to be imparted, e.g., citrus flavors require a more acid taste. 602

Bitterness is characteristic of many and it is th~ most difficult parameter to deal with. The sensatiqn of bitterness usually follows that of sweetness since the sweet buds are located ~n the surface and tip of the tongue and the bitter in grooves tow~rd the rear. There is no universal bitternessri1aski~g agent. To overcorrie th~ objectionable taste of the multi-vitamin sweetening agents, saltiness and tartness are used with flavor enhancers to "blend out" the taste of the vitamin mixture., This is accomplished by a c,a reful balance of all these factors so that the vitamin taste becqmes part of the flavor impression. Natural ' complementary flavors include anise (gly<;yrrhiza), ' coffee, citrus, mint, maple, ~pficot, cherry, peach, strawberry, raspberry, wintergreen, cinnamon, pineapple, and certain wine and plant extractives, e.g., eriodi~tyon. Cherry is a popular flavor for both plain and iron-containing chewable vitami~s. Th~ Medimetric Institute Physicians' Survey of 1957 found cherry 'to be the most popular flavor in children's pediCherry and grape atric products.

of the vitamins

Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION

flavors rank high in children's beverage products. ,F lavors in the form of dry powders, wherein the flavor oils are emulsified in a gum base, then spraydried (the so-called encapsulated flavors) , are especially suitable 'for chewa~le vitamins. When these dry, staple powders ~re used, chewi~g releases the flavors almost immediately and there is minimal "carry-over" from one flavored tablet to a~other wh~n ~he multiflavored tablets are packaged tqgether. . Unpl~asant tastes of the B-corriplex vttamins in chewable vitamins can be reduced by using coated vitamin powders. 3 These are made by spray c~ol­ ing edible fat-vitamin mixtures. Such coated powders are uniform, have good flow characteristics and are readily compressible. Their use also tends to reduce vitamin interactions and odor development. Moreover, the coaj ed vitamins are readily avaitable in vivo. Accordingly, coated niacinamide, thiamine, ribofl~vin and py:ridoxiri~ are commonly used. Additi
Let us consider non-nutritive sweeteners as flavori~g aqjuncts. ~accharin and the cyclamates have been widely used with flavorjng agent~ in both liquid and solid dosage forms to provide good flavor profiles of pharmaceutical products which are riormally disagreeable in taste. It has' been stated that 10 mg of saccharil1 is equivalent ' in sweetening power to approximately 5.'5 gms 'sucrose. 5 Other references state that it is 200 to 700 time~ sucrose in sweetness but these rel~tive sweetness values must take into account the concentration of the two sqbstances being compareq. When the concentr~tion of the syn~hetic $weet-

Table I Representative 0-T -C Chewable Multi-Vitamin Tablets Representative Children's Chewable Vitamins

Manufaeturer

Animates** Chocks Chocks plus Iron Cluvisol*** Deca-Vi-Sol w/Iron Dura-Chews Engran Flintstones Flintstones with Iron Livitamin*** Mulvidren Nectavite Nectavite-M*** Novacebrin

Hudson Miles Labs Miles Labs Ayerst . Mead Johnson Drug Guild Squibb Miles Labs Miles Labs Massengill Stuart Hudson Hudson Lilly

Paladac Pals** Pals with Iron** Poly-Vi-Sol St. Joseph's Tri-Vi-Sol Unicap • Vi-Daylin Vigran Viterra Zestabs Zestabs with Iron

A USP Units 3500 5000 5000 4000 4000 5000 4500· 5000 5000 5000 5000 5000 4000

D USP Units 400 400 400 400 400 500 400 400 400 1000 400 400 400

Parke-Davis 4000 400 Mead Johnson 3500 400 Mead Johnson 3500 400 Mead Johnson 4000 400 Plough 5000 500 Mead Johnson 4000 400 Upjohn . 1.2mg 10mcg Ross 4000 400 Squibb 5000 500 Roerig 5000 500 Sauter 5000 400 Sauter 5000 400

B6

Niacinamide mg

C* mg

Bl mg

B2 mg

mg

60 50 50 40 75 50 80 50

0.8 2.0 2.0 2.0 1.2 3.0 1.3 2.0 2.0 3.0 2.0 2.5 2.5 1.5

1.3 2.5 2.5 2.0 1.5 2.5 1.8 2.5 2.5 3.0 2.0 2.0 2.0 2.0

1.0 1.0 1.0 1.0 1.2 1.0 2.0 1.0 1.0 3.0' 1.2 2.0 2.0 1.0

14 20 20 10 15 20 17 20 20 10 10 15 15 12

3.0 0.8 0.8 1.2 2.4

3.0 1.3 1.3 1.5 2.5

1.0 1.0 i .0 1.0

20 14 14 15 20

2.0 1.5 3.0 1.0 1.2 1.2

2.0 1.2 3.0 1.5 1.5 1.5

1.0 1.0 1.0 1.0 1.2 1.2

18 10 12.5 10 10 10

~O

100 75 75 75 60 50 60 60 75 50 75 75 75 50 50 60 60

Pantothenate mg 5.0 5.0 5.0 10.0 2.0 3.0 5.0 5.0 2.5 (panthenol) 5.0 5.0 5.0

B12 mcg 2.5 1.0 1.0 3.0 -3.0 1.0 5.0 1.0 1.0 5.0 3.0 5.0 5.0 3.0 5 2.5 2.5

E IU

Biotin meg

Iron mg

40

10.0 3.0 12.0

10 10.0 16.4 30 30

1.0

10 12.0

2.0 5.0 5.0 2.0 10.0 _1 0.0

2.0 3.0 2.0 2.0 3.0 3.0

2.0 2.0

40 40

10.0

o as ascorbic acid and/ or sodium ascorbate 00 contains folic acid 0.05 mg ' 000 contains other trace minerals

Table II A Typical Stabiiity Pattern for a Chewable Multi-Vitamin Tablet at 25°C. 6

12

24

36

Initial

months months months months - - - -. - normal-------no change-----. - - - - -eJCpressed as percent label claim-

Appearance Assay Vitamin A (acetate) Vitamin D Vitamin C Vitamin Bl \;itamin B2 Vitamin B6 Vitamin B12 d-Biotin Niacinamide Vitamin E Calcium pantothenate

5 ,000 VSP units 400 tJSP units 60 . 0 mg 1.2 mg 1.5 mg 1.2 mg 0 . 003 mg 0.040 mg 10 . 0 mg 2.0 IV 10.0 mg

ener is increased, the relative sweetness compared to sucrose falls off rapidly. Compared to a two and one-half percent sucrose solution wt/wt, saccharin is about 550 times sweeter but only 90 to 110 times sweeter if the saccharin concentration is increased to be about equal to four percent sucrose. 6 About one-fourth to one-third of the population find saccharin to have an off-taste described as metallic and bitter. On the other hand, cyclamate is approximately 31 times as sweet as sucrose when tasted at low concentrations, i.e., at a level equal to 2.5 percent sucrose. It is only 15 times as sweet as sucrose at levels equivalent to

140 130 118 111 118 114 132 115 111 113 120

126 135 115 115 120 109 130 110 113 118 112

112 132 110 101 115 112 128 120 112 i02 118

104 128 108 t04 118 106 132 117 109 107 111

102 124 108 108 112 103 130 108 107 105 109

about six percent sucrose. 6 Again, some of the population report off-taste from cyclamate sodium at high sweetness levels. In our initial chewable vitamin formulations (made prior to 1969) a combination of cyclamate sodium and sodium saccharin was :used in approximately 12: 1 ratio. Published work1> suggested that a 10: 1 ratio gave a combination which was satisfactorily sweet with little or no aftertaste. The 12: 1 ratio, combined with salt and a suitable tartness level gave a satisfactory organoleptic balance; This combination when used with five flavors-cherry, grape, lemon, orange and lime in a mannitol base-gave

chewable vitamin products * which when submitted to children"s taste panels showed that an acceptable formulation was achieved. Most, if not all, children's chewable vitamins contain a non-nutritive sweetener. The commercial products listed in Table I were obtained locally and were found to contain cyclamate when analyzed in October 1969 by the method of the Association of Official Agricultural Chemists. 7 Many contained saccharin in addition to cyclamate. 8 Since the Food and Drug Administration removed. cyclamates from the list of substances Generally Recognized as Safe (GRAS), a reformulation of chewable vitamins containing cyclamates has become necessary.9 Of the non-nutritive sweeteners which are still GRAS, saccharin remains the logical replacement for cyclamate despite its propensity to elicit an after-taste. Glycyrrhizin (also GRAS), while imparting a sweet taste (approximately 50 times as sweet as sucrose), has a licorice flavor which can be quite foreign if used at high concentrations to the flavor profiles of the five fruit flavors mentioned earlier. Glycine (GRAS) is 0.7 the sweetness of sqcrose and provides a cool, smooth taste but it is costly and reactive and has caused darkening in some vitamin ad°ZEST ABS, brand of chewable multiflavored vitamins, Sauter Laboratories Inc., marketed in 1960.

Vol. NSI0, No. 11, November 1970

603

mixtures. The natural sugars such as d-glucose (0.7 sweetness of sucro.se) and the more costly d-fructose (1.1 the sweetness of sucrose) ate chemically reactive sugars and, like sucrose, do not provide enough sweetness per se unless tablets are made to a size and weight many times that of the conventional size tablet. Moreover, there is a tendency of tablets made with certain of the natural sugars to harden and discolor with time. The polyols, mannitol and sorbitol (0.7 and 0.5 the sweetness of sucrose, respectively) do not proyide enough sweetness per se; the latter is hygroscopic ::tnd may necessitate the use of a drying agent (e.g., silica gel bag or capsule) to accompany the packaged tablets. Saccharin in conjunction with mannitol provides a sufficient level of sweetness and good "mouth feel." When used with other GRAS ingredients selected to minimize the saccharin "offtaste" and using proper levels of flavorings and tartness to provide a new organoleptic balance, noncyclamate chewable tablets in many flavors ' can be made which are acceptable to children. The currentiy marketed ZESTAB brand does not contain cyclamates. . Newer synthetic sweetenets, such as dihydrocha1cones derived from flavone glycosides, e.g., neohesperedin dihydrocha1cone (2,000 times sweeter than sucrose) and certain poiypeptides, e.g., l-aspartyl-l-phenylalanine (250 times as sweet as sucrose) have not yet achieved GRAS status. 10 Product Acceptance As mentioned earlier, consumer acceptance by children is the criterion for market success of a chewable multivjtamin product. Children are less sophisticated in taste testing and are prone to summarily accept or reject a product for reasons which might be obscure to adults. Taste testing should be individualized and not as a group and should reflect the age and sex of the eventual consumer. No more than two samples should be given for .comparison and the order of submission shouid De randomized. Questions as to the reason for acceptance or rejection should be asked .after the subjects have made their selection. Unsolicited comments should be recorded and often provide a valuable guide for the formulator. The number of children in the panel should meet the requirements for a statistically significant study. A panel of 100 children is minimal for final decision; smaller sized panets (10 to 20) are useful in comparing interim formulations. . In our experience, the final panel should consist of children who have had no previous exposure to the product. 60~

Formulation A typical chewable multi-vitamin tablet guide .formulation is shown below. The labeled vitamin content provides from 100 to 300 percent the Minimum Daily Requirement for children two to twelve years of age.

cent) is essential for good vitamin stability. A typical stability pattern i,s shown in Table II (page 603). While expiration dates are not mandatory at this writing it is exp~cted that a multi-vitamin tablet should contain the labeled amounts for at least three years . •

Chewable Multi-Vitamin Tablet Guide Formulation Label claim Vitamin A (acetate) 5000 USP units as dry vitamin A acetate-Type 500 Roche Vitamin (ergocalciferol) 400 USP units as dry vitamin D2-Type 850 Roche Vitamin C (ascorbic acid) 60.0 mg as ascorbic acid-sodium ascorbate mixture 1 : 11 Vitamin Bl (thiamine mononitrate) 1.2 mg as Rocoat thiamine mononitrate 33 1/3 percent Roche Vitamin B2 (riboflavin) ' 1.5 mg as Rocoat riboflavin 33 1/ 3 percent 1.2 mg Vitamin B6 (pyridoxine hydrochloride) as Rocoat pyridoxine hydrochloride 33 1/3 percent Niacinamide 10.0 mg as Rocoat niacinamide 33 1/3 percent 10.0 ing Calcium pantothenate Vitamin B12 (cyanocobalamin) 0.003 mg as Merck 0.1 percent in gelatin or Pfizer Stablets 1 percent Vitamin E (dl-~lpha tocopheryl acetate) 2IU as dry vitamin E acetate 33 1/3 percent Roche d-Biotin 0.040 mg Certified lake color2 Flavor-e.g., Permaseal orange F-5531 (Givaudan) 3 Sweetener-sodium saccharin 4 Lubricants (e.g., magnesium stearate)5 Excipients (e.g., mannitol) q. s. to make

n

1

2

3 4 5

Mfg. excess (%)

Gms/l000 ta~lets

35

6,750,000 u. . 13.5 500,000 u. . 0.6 70 :b

25 10 10

4.0 10 5.0 10 4.0 10 33.0 11.5 3.5

-15 15 10

6.6 0.044 ca. 5.0

10

ca. 8.0 ca. 1.0 10.0 500.0

Ratio depends on tartness level desired. . Amount depends on color and intensity of shade desired; jet-milled lakes are preferable. Level of flavor depends on type and intensity desired. The addition of a small amount of sodium chloride may be helpful. Alternately, saccharin-sodium-saccharin combinations can be used. A mixture of talc and magnesium stearate can also be used.

Directions

References 1. Harmann, E., and Gunther, E., "Spices and

In a suitable powder blender, mix all ingredients except vitamins A and D, mill to homogeneity. Slug with flat-faced .punches, grind slugs to 14 mesh, add and mix vitamin A and 1) beadlets. Compress using flat-faced or shallow concave punches at 0.500 gram each. The hardness of the tablets is generally in the range of seven to nine Strong Cobb units.

3.

Commentary

7.

The vitamin overages should be ample to account for losses on storage, tabiet-to-tablet variation and analyticai variance. The maintenance of low moisture con~ent (less than one per-

Flavors" in Kir!<:-Othriler, Encyclopedia of Chemical Technology, 2nd ed., J. WlIey & Sons, ~ (1966) . Bulletin LM26, Atlas Chemical Industries, Inc., (1969) Koff; A., U.S. 3,080,292-3 3,279,994 to Hoffmann-La Roche; Stoyle; L., U.S .. 3,037,911 to Merck & Co. Raymond, J., U.S. 3,458,623 to HoffmannLa Roche . V.S. Pharmacopeia XVII; 573 _ Helgren, F.J., U.S. 2,803,551 to Abbott Laboratories Ofjicial Methods oi Analysis of the A.O.A.C., 10th ed., Association of Official Agricultural Chemists, Washington, D.C.; ' 452 (1962) Stahl, E., Diinnschicht Chromato8raphie, Springer-Verlag, Berlin, 377 (1962) Federal Register, 34 F.R. 17063 (Oct. 21, 1969) . . Anon., Chem. and Eng. News, 36 (Jan. 5, 1970) <

2.

4.

5. 6.

8;

9. 10.

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Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION