April, 19.

55 SCIENTIFIC
EDITION 341

SUMMARY 5 . Differences in water-retentive capacities

are more clearly defined when determined at
1. A modified osmometric procedure has been 38O.
used to compare the water-retentive properties 6. Measurement of water retention against a
of some proprietary preparations containing solution of increased hypertonicity (50% Carbo-
psyllium seed, karaya gum, and several grades of wax@4000 W) at body temperature ( 3 8 O ) con-
methylcellulose. The results confirm the work of stitutes, we believe, a closer approach of the test
previous investigators (1). method, to physiological conditions. The great
2. Products containing the synthetic hydro- dehydrating capacity of the colon is best simu-
philic colloid, methylcellulose, were superior in lated by a solution possessing a high degree of
water-retentive properties to products containing hypertonicity.
natural hydrophilic colloids. Dispersions of
methylcellulose of relatively low viscosity showed REFERENCES
greater water-retentive capacity than equally 1) Blythe, R. H Tars JOURNAL, 38, 59(1949).
concentrated, natural gum dispersions of greater {2) Walker, W. "J.. Hahncmannian Monfhly. 83, 445
(1948).
viscosity. The latter behavior may be clinically (3) Lesser, M. A,, Drug and Cosmefic Inn. 68, 592(1951).

significant in minimizing the probability of in-

testinal blockage or impaction.
I 4) Gray, H., Tainter, M. L., A m . J . Digesf. Diseases, 8,
130 1941).
6) Tainter, M. L., Prac. Sac. E x f i l l . Biol. Med., 54, 77
(1943).
(6) Schweig. K.,N . Y . Sfale J . Med., 48, 1822(19487.
3. Liquid preparations of low viscosity, bulk (7) Marks, M. M., A m . J . Digesf. Diseases, 16, 215
( 1949).
laxative, and high gel grades of methylcellulose (8) Bargen J . A. Gaslroenfcrology. 13,275(1949).
were compared. High gel grade methylcellulose (9) Blake, 'A. D:, Jr.. A m . J . Digesf. Diseases, 15, 330
(1948).
was found to possess superior water-retention (10) Bauer R. O., Federalion Proc., 3, 65(1944).
(11) Hodge, H. C . . J . Pharm. E x p f l . Thcra9.. 99. 112
capacity, in all tests performed. (1950).
(12) Editorial J . A m . Men. Assoc.. 127,992(1945).
4. A modified osmometric apparatus is de- (13) Bauer, R: O., Lehman, A. J., THISJOURNAL. 40, 257
(1951).
scribed. (14) Knight, H. F., Jr.. ibid.. 41.427(1952).

The Stability of Ascorbic Acid in Various Liquid

Media*
By F. J. BANDELIN and J. V. TUSCHHOPP
The stability of ascorbic acid at several concentrations in various liquid media in-
cluding aqueous solutions of cellulose gums, pectin, sucrose, dextrose, corn syrup,
and in glycerin and ropylene glycol was studied. The effect ofpH in aqueous solu-
tions of ascorbic aci8 was also studied. Viscosity alone as produced by g u m s did not
prevent decomposition of ascorbic acid. Sugar and sorbitol solutions exerted a
marked stabilizing effect. Ascorbic acid was relatively stable in glycerin and propy-
lene glycol and in sugar and sorbitol solutions. Data are presented on the rates of
decomposition of ascorbic acid in these media after storage at room temperature
and at 40° C. The stability of ascorbic acid in syrups containing conjointly vita-
mins of the B-complex is not materially affected.

to decompose Bartilucci and Foss (16)touched upon the subject

T HE TENDENCY OF ASCORBIC ACID
in solution has been a distinct deterrent to its
use in liquid pharmaceutical preparations. Al-
of ascorbic acid stability in various mixtures of
liquid media incidental to a study of the stability
though methods of stabilizing aqueous solutions of vitamin BIZsolutions containing ascorbic acid.
of ascorbic acid, usually as the sodium salt for To our knowledge, no comprehensive, sys-
parented use, have been discussed in the litera- tematic, or integrated study of the stability of
ture (1-14) little has been published concerning ascorbic acid, in usual therapeutic concentrations,
its stability in liquid preparations for oral ad- in various liquid media, has appeared. We
ministration. Giral (15), in 1947 published a therefore undertook to study the effects of PH,
study of factors affecting the destruction of oxidation, dilution, and various compounds
ascorbic acid solutions. While the work of the commonly encountered in pharmaceutical liquids
present paper was in progress, a paper by such as ethanol, sugars, certain polyhydric
alcohols, and natural and synthetic gums. It is
the purpose of this paper to present the scope,
* Received August 28. 1954. from the Research 1,abora-
details, and observations, of this study.
tories of Flint, Eaton & Co.. Decatur, Ill.
 242 JOURNAL OF THE AMERICANPHARMACEUTICAL
ASSOCIATION Vol. XLIV, N o . 4

TABLE I N SOLUTIONS
ACIDREMAINING
I.-PER CENTASCORBIC AT VARIOUSPH LEVELSAFTER AERATION
AT 25°C.
-

Hrs.
7--

fiH 3.0
Ascorbic Acid, 1 mg. per mi.-
PH 4.0 PH 5.0 BH 6.0
--PH 3.0
Ascorbic Acid, 5 mg. per ml.-
PH 4.0 pH 5.0 pH 6.0
0 100 100 100 100 100 100 100 100
1 96.0 90.4 86.2 82.4 97.7 93.2 90.8 88.2
2 88.4 80.6 70.4 68.7 90.6 84.0 77.6 74.3
3 84.5 75.6 61.4 56.3 88.7 78.2 66.4 62.5
4 82.2 68.8 50.3 45.2
~~ ~ 87.1 72.9
~. 56.4 54 2
5 80.2 61.4 39.2 32.9 83.7 68.5 47.7 46.4
6 77.5 56.2 30.4 23.4 80.5 65.5 42.0 37.4
7 72.2 51.7 24.4 16.3 76.8 61.7 32.6 30.2
24 62.0 39.9 12.0 0 71.1 48.7 23.8 6.0

TABLE ACID REMAINING

II.-PER CENTASCORBIC IN VARIOUS
SOLUTIONS AT 25" C.
AFTER AERATION

Ascorbic Acid, 5 mg./ml. in:

25%
Eth-
25 %
Propy-
lene
25%
Glyc-
25%-
Suc-
223- 25%
Corn
50%
Eth-
50%
R O P Y - 50%
lene Glyc-
50%
SUC-
50%
Sorbi-
50%
Corn
Hrs. anol Glycol erm rose tol' Syrup' anol Glycol erin rose" tol' Syrup'
' 0 100 100 100 100 100 100 100 100 100 100 100 100
2 96.5 99.5 100 93.5 100 94.7 100 99.5 99.5 99.5 99.5 99.4
4 9 6 . 5 99.5 99.6 92.5 96.5 94.3 99.3 99.2 9 9 . 5 99.5 97.8 95.0
7 95.0 94.2 95.0 89.4 95.4 94.4 97.4 96.5 99.5 98.6 9 7 . 8 95.0
24 80.0 91.0 9 0 . 5 79.5 89.7 88.4 92.2 96.0 97.1 96.5 97.0 93.7
a w/v solutions based on solids content; others, all liquids, prepared on v/v basis.

EXPERIMENTAL pared in 25 and 500/, aqueous solutions each of

ethanol, propylene glycol, glycerin, sucrose, sorbi-
Solutions of ascorbic acid of various selected con- tol, and corn syrup. These solutions have a PH
centrations and a t definite pH levels were prepared of approximately 3.0.
in distilled water and in various liquid media as Two hundred milliliters of each solution was
hereinafter described. Syrups were also prepared aerated as previously described in a 250-ml. cylindri-
with synthetic vitamins of the B-complex. Solutions cal graduate and analyses carried out after two,
were observed after aging at room temperature and four, seven and twenty-four hours. Results are
a t 40" and some after aeration for varying periods given in Table 11.
of time. Analyses were carried out at definite All compounds in both concentrations exerted a
intervals using the official dichlorophenol-indo- noticeable stabilizing effect on ascorbic acid. The
phenol method after appropriate dilution. In all protective action of sucrose was considerably better
cases, the quantity of ascorbic acid found on analysis at the higher concentration. Propylene glycol,
immediately after preparation of the solution was glycerin, sucrose, and sorbitol all seemed t o afford
considered as 100~o. about the same amount of protection in 50% con-
Effects of pH and Aeration.-Solutions containing centration.
1 and 5 mg. per ml., respectively, of ascorbic acid Effect of Aging at 40".-1n addition t o the alco-
were prepared and buffered to PH 3.0, 4.0, 5.0, and hol and sugar vehicles already investigated, addi-
6.0 using 0.5 N acetic acid and 0.5 N sodium acetate. tional ascorbic acid solutions were prepared with
Two hundred milliliters of solution was placed in synthetic and natural gums. These included methyl-
each of four 250-ml. cylindrical graduates and air cellulose, carboxymethylcellulose, pectin and traga-
passed through them at a constant rate of 120 canth. These gums were used t o impart viscosity
bubbles per minute. Residual ascorbic acid in the to the solutions with the thought that viscid solu-
solutions was determined after one, two, three, tions might hinder oxygen exchange, thereby pro-
four, five, six, seven, and twenty-four hours. Re- ducing a stabilizing effect upon the dissolved ascorbic
sults are given in Table I. These results indicate acid. Solutions containing 5 mg. and 20 mg. of
that the oxidative destruction of ascorbic acid is ascorbic acid per ml. were prepared and kept a t
accelerated as the acidity of the solution decreases. 40" for twelve weeks. Analyses were carried out a t
The solution containing 5 mg. of ascorbic acid per two-week intervals. Results are given in Table 111.
ml. showed a smaller percentage loss than did the The gums investigated offered no protection to
weaker solution. After seven hours, loss was ac- the decomposition of ascorbic acid and, in fact,
celerated. The solutions having a PH of 6 acquired seemed t o accelerate its decomposition when com-
a yellow color after two hours of aeration while pared against control solutions of ascorbic acid in
those having a PH of 5 acquired a yellow color after distilled water.
three t o four hours of aeration. Solutions with PH 3 I n this series, sugars and polyhydric alcohols again
and p H 4 remained clear and water-white over the exhibited a marked stabilizing effect upon ascorbic
entire twenty-four hour period. acid solutions of both concentrations. Glycerin,
Effect of Aeration on Solutions Containing Eth- swbitol, U. S. P. Syrup, and propylene glycol ap-
anol, Polyhydric Alcohols, and Sugars.-Solutions pear to possess the greater stabilizing effect on
containing 5 mg. per ml. of ascorbic acid were pre- ascorbic acid in solution.
April, 1955 SCIENTIFIC
EDITION 243
TABLE ACIDIN VARIOUS LIQUIDMEDIAAT 40" C.
TII.-STABILITY OF ASCORBIC
-Ascorbic Acid, 5 mg. per m1.- -Ascorbic Acid, 20 mg. per ml.-
Weeks-- Weeks
Solvent 2 4 6 8 1 0 12 2 4 6 8 10 12
1. Corn syrup" 96.5 93.5 91.0 86.5 83.5 82.0 97.5 94.0 93.0 88.0 84.5 83.0
2. Sorbitolb 99.5 99.5 98.5 94.0 91.5 90.0 99.5 99.5 99.5 95.0 92.5 90.0
3. 4%!CMC
Med. vis.= 79.5 72.0 56.0 36.0 14.0 86.0 74.5 63.0 53.5 47.5 44.5
4. Glycerin 98.0 96.0 96.0 93.0 90.5 s7:o 100 100 99.5 98.5 95.0 93.0
5. Propylene glycol 95.5 92.0 87.0 82.0 72.0 63.0 100 100 98.0 93.5 90.0 84.0
6. 3y0 Methylcel-
lose 1500
C.P.S. 78.0 69.0 50.5 33.0 15.0 . . 95.0 88.5 77.0 70.5 58.5 55.0
7. 4T0 Pectin 76.0 53.0 39.0 13.0 94.0 86.0 79.5 77.5 55.0 48.0
8. Syrup U. S. P. 99.5 97.5 94.5 90.0 90:o 88:O 99.0 98.5 94.5 92.5 91.5 90.0
9. Syrup 425
Gm./L. 97.0 91.0 80.0 72.5 53.0 44.0 99.0 98.0 90.0 81.0 77.5 73.0
10. Syrup 2i2
Gm./L. 92.0 74.0 70.5 63.5 41.0 33.0 93.5 92.0 86.5 72.0 67,5 65.0
11. Corn syrup 50%
in water 95.5 86.0 77.5 68.0 63.0 59.5 97.0 93.0 80.0 75.5 68.0 62.0
12. 2.5% Tragacanth
solution 72.0 41.0 27.0 10.0 .. 88.0 70.0 59.5 52.0 41.5 37.0
13. Sat. soh.
dextrose 94.5 89.0 87.5 84.0 81.0 77.0 95.5 92.0 90.0 87.5 86.0 83.5
14. Distilled water 78.0 68.0 56.0 39.0 28.0 . . 94.0 86.0 75.0 68.0 59.0 53.0
Corn Syrup used marketed as Sweetose by the A. E. Staley C o . , Decatur, Ill.
b Arlex is a solution containing approximately 83% sorbitol. obtainable from Atlas Powder Co., Wilmington, Del.
Carboxymethyl cellulose, sodium salt, medium viscosity.

TABLE
IV.-PER ACID REMAINING
CENTASCORBIC IN SOLUTIONS
ON STORAGE
AT ROOMTEMPERATURE
(5MG. PER ML.ASCORBIC
ACID)
-
c Day------- F

Solvent 30 60 90 120 180 240 360

1. Corn syrup 96.5 92.5 92.0 92.0 9D.O 86.0 76.0
2. Sorbitol 99.0 99.0 99.0 97.0 96.0 92.5 89.0
3. 4y0 CMC Med. vis. 84.0 68.0 56.5 38.0
4. Glycerin 100 100 99.0 99.0 97:o 93:5 92:o
5. Propylene glycol 99.5 99.0 98.0 94.5 92.0 90.0 90.0
6. 3% Methylcellulose 1500c.p.s. 76.0 60.0 39.5 15.0 ..
7. 4% Pectin 80.5 78.0 64.5 .56.0 4610 26:O
8. Syrup U. S.P. 100 100 98.0 98.0 93.0 90.0 8S:O
9. Syrup 425 Gm./L. 98.0 96.0 94.5 94.0 86.5 79.0 69.0
10. Syrup 212 Gm./L. 88.0 81.0 77.5 74.5 64.5 59.0 '44.0
11. Corn syrup 50% in water 96.0 88.0 87.0 76.5 75.0 68.0 56.0
12. 2.5y0 Tragacanth solution 78.5 62.0 51.0 32.0
13. Sat. soh. dextrose 99.0 93.5 87.5 80.0 6i:o 58:o 5i:o
14. Distilled water 90.0 81.5 74.5 67.5 40.5 18.5 ..

TABLE
V.-~TABILITYOF VARIOUSCONCENTRATIONS ACIDIN WATER,PROPYLENE
OR ASCORBIC GLYCOL,
AND U. S. P. SYRUP
AT ROOM PERCENTASCORBICACIDREMAINING
TEMPERATURE, IN SOLUTION

Ascorbic Acid
c
30 60 90
Days-
120 180 240
-
360
10 mg./ml. water 93.0 84.0 82.0 67.0 51.5 41.0
50 mg./ml. water 94.0 92.0 88.0 79.5 60.5 59.0 3010
100 mg./ml. water 97.0 93.0 91 .o 83.5 70.5 68.0 59.0
10 mg./ml. P. G. 100 98.5 98.0 97.5 96.0 92.0 86.0
50 mg./ml. P. G. 100 97.0 98.0 98.0 98.0 96.5 93.5
100 mg./ml. P. G. 100 ' 100 100 100 99.0 100 92.5
10 mg./ml. Syrup 100 100 98.0 99.0 97.0 96.0 84.0
50 mg./ml. Syrup 100 100 100 100 99.0 100 96.0
100 mg./ml. Syrup 100 100 100 100 100 100 99.5

Effect of Aging at Room Temperature.Solutions of the sugar content of the vehicle was accompanied
listed in Table I11 were aged at room temperature at by a corresponding increase of ascorbic acid de-
the 5 mg. per ml. level. Results of aging over a struction. Also in group 4, gums, both natural and
period of three hundred and sixty days are given in synthetic, accelerated the rate of destruction of
Table IV. In this series as in the previous one aged ascorbic acid compared to an aqueous solution under
at 40°, glycerin, propylene glycol, sorbitol, and the same conditions.
U. S. P. Syrup again appeared superior t o the other Effect of Concentration.-Since ascorbic acid ap-
media. I n both series, it was noted that reduction peared to be relatively stable at room temperature
244 JOURNAL OF THE AMERICANPHARMACEUTICAL
ASSOCIATION Vol. XLIV, NO.4

in propylene glycol and in U. S. P. Syrup, solutions compounds in the solutions produces increased sta-
were prepared containing 10.50 and 100 mg. per ml., bility of the ascorbic acid. That the viscosity of the
respectively, in each of these and in water. Propyl- solution is probably not a factor in so far as ascorbic
ene glycol may be considered to represent an an- acid stability is concerned is indicated by the fact
hydrous solvent while syrup is an aqueous solution. that various gums in solution, producing increased
Control solutions of each of these concentrations viscosity, did not seem to retard the decomposition
were made up in diqtilled water and all were allowed of ascorbic acid but, in fact, seemed t o accelerate it.
to age at room temperature for three hundred and Syrups of ascorbic acid containing 1 and 5 mg. of
sixty days with analyses for ascorbic acid being ascorbic acid per ml. (which may be considered
carried out at regular intervals. Results are given within the usual therapeutic range for pharmaceuti-
in Table V. cal preparations) are relatively stable for short
In all cases higher concentrations of ascorbic! acid periods of time or even up to one year. U. S. P.
showed less relative destruction based on the per Syrup, sorbitol, glycerin, and propylene glycol were
cent of residual ascorbic acid. all of approximately equal efficacy in retarding the
Stability of Ascorbic Acid in Syrups Containing destruction of ascorbic acid solutions on aging.
&Complex Vitamins.-Syrups containing ascorbic The inclusion of vitamins of the B-cornplex to
acid with synthetic vitamins of the B-complex were syrups of ascorbic acid seemed t o produce a stabi-
prepared in a base of U. S. P. Syrup and in sorbitol lizing effect. Whether or not this is an artifact or
(Arlex). Results of aging at room temperature and due t o reaction of some of the ascorbic acid with
a t 40" are given in Table VI. These preparations some of the vitamin bases such as the reaction of
had a PH ranging from 3.1t o 3.4. Under conditions ascorbic acid with niacinamide described by Fox
of the test, ascorbic acid in conjunction with vita- and Paterson (17) is, as yet, a matter of conjecture.
mins of the Bcomplex seemed t o be more stable At this point, most evidence suggests that ascorbate
than in syrups containing no other vitamins. Loss ion is more prone t o decomposition than is the
of ascorbic acid, even after two years, was less than undissociated acid.
15% in all cases.
SUMMARY
VI.-ASCORBrC ACID I N VITAMIN B-COMPLEX
TABLE
SYRUPSAT ROOMTEMPERATURE 0' C.
A N D AT 4
1. The rate of oxidative decomposition of
-Ascorbic Acid Remaining in Solution, %- ascorbic acid solutions increases as the pH value
-Days- -Years-
90 180 270 360 2 3 increases. Destruction of the acid is markedly
Sucrosebasea R T 100 100 98 98 88 80 accelerated above PH 4.0.
40" 98 94 84 76 .. 2. Addition of ethanol, polyhydric alcohols
Sorbitolbas@RT 100 98 98 94 86 78
40" 97 92 84 72 .. such as glycerin, propylene glycol, and sorbitol,
Sucrosebasee R T 100 99 94 92 89 82 and sugars such as sucrose, corn sugar, a n d
40' 95 92 80 68 .. dextrose, all tend to produce a stabilizing effect
SorbitolbasedRT 100 98 95 91 87 70
40" 96 92 84 62 .. .. on ascorbic acid. Sucrose, sorbitol, glycerin,
(I
~

Composition: Each ml. contains: ascorbic acid 20 mg.,

a n d propylene glycol are superior to the others
thiamine hydrochloride 0.6 mg., riboflavin 0.4 mg., niacin- i n this respect.
amide 6 mg., U. S. P. Syrup q. s
b Same composition as a except Arlex q. s. 3. Vegetable gums added t o produce solutions
C Each ml. contains: ascorbic acid 6.25 mg., thiamine
hydrochloride 0.25 mg., riboflavin 0.25 mg., pyridoxine of greater viscosity seem t o accelerate destruc-
hydrochloride 0.25 mg., calcium pantothenate 0.5 mg..
u.s. P. syrup q. s. tion of the vitamin.
d Same components as c except Arlex q. s.
4. Syrups a n d solutions of ascorbic acid in
varying concentrations indicate that higher con-
DISCUSSION
centrations of ascorbic acid are relatively more
The stability of ascorbic acid in solution is greatly
dependent upon pH. I n the presence of oxygen, stable than are lower concentrations.
ascorbic acid is easily oxidized t o dehydroascorbic 5. Vitamin B-complex factors added to syrups
acid. Although this reaction is reversible, under of ascorbic acid in U. S. P. Syrup and in sorbitol
certain conditions, and the dehydro form exhibits seem to increase the stability of ascorbic acid.
all the activity of the hydro form,the dehydro form
is further decomposed t o soluble, biologically in- REFERENCES
active compounds. This latter reaction is irreversi-
ble and may take place even in the absence of oxy- ( 1 ) Elger P U. S. pat. 2,179,978.
gen if the solution is a t PH 4.0 or higher. The rate (2) Pastemark R. and Regna. P. P U. S. pat. 2,165 184.
(3) Pasternack' R.' and Regna P. P:' U. S. pat. 2 161'651.
of oxidation of ascorbic acid is accelerated with in- (4) Volwiler, E: H:.and Mooie. M. 'B., U. S. pai. 2,i32,-
creasing pH, actual decomposition (caramelbation) Hoffmam-La Roche, Swiss pat. 200,299.
taking place above PH 7.2. Aeration of ascorbic Elger F. U.S. pat. 2 134 246.
acid solutions definitely indicates t h a t the rate of Ruskin 8. L. Canadian ;at. 376 573.
Eisenb;and, i.,and Seinz, M., U:S. pat. 2,140,989.
oxidative decomposition of ascorbic acid increases Warnat K. U. S. pat 2 150 140.
as the pH value increases. The addition of certain Stuart 'E B u s pat 18i 467.
i
i
Rnskd ti L" U:S' pat. 294 937.
alcohols and sugars as described exerts a noticeable Gockel' H. ii.S . pat. 2 267 2i2.
protective action on ascorbic acid by retarding "Ascorbic k=id," Merci Sethce Bulletin, 1941.
Ciminera.. I.
_ T.. and Wilcox, P. W., THIS JOURNAL,
oxidative destruction. This may be due to the re- 35,363(1946).
duced ability of these solutions to carry dissolved (15) Giral F. ibid., 36, 82(1947).
(16) Bartih&i, A,, and Foss, N. E., ibrd.. 43, 159 (1954).
oxygen since increasing concentrations of these (17) Fox. S. H.,and I'aterson, L , U. S. pat. 2,438,688.