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Investigation of Stability in Emulsions of Varying Viscosities*
Scientific Edition
JOURNAL OF THE AMERICAN PHARMACEUTICAL ASSOCIATION VOLUMEXLVIII
JANUARY I959
NUMBER 1
Investigation of Stability in Emulsions of Varying Viscosities* By EDWIN L. KNOECHELt and DALE E. WURSTER An investigation dealing with the possible effect of viscosity on the stability of oil-inwater emulsions is presented. Interpretation of the size frequency data on the basis of the volume-surface and weight-mean diameters indicated the possible presence of subvisual globules in the formulations. This possibility was not evident when the arithmetic-mean diameter was used. Experimental evidence indicated that viscosity played only a minor role i n the gross stability of the systems studied. tion, flocculation, or coalescence of the discontinuous phase occurs. Since it has been pointed out previously that creaming decreases the interparticle distance, which can then lead to possible changes in the flocculation and coalescence rates, it would appear that the rates of all the above phenomena are interrelated (19). If the change in interparticle distance does cause significant variations in the rate of coalescence, then any existing relationship found between the coalescence and creaming rates would be most useful information. Since the interparticle distances are related to the concentration and the particle size of discontinuous phase and the creaming rate, it is of interest to determine whether or not the rate of coalescence can be altered by changing the viscosity of the continuous phase. Therefore, as a method of study, a series of emulsions of varying viscosities were prepared according to a standard procedure. Every attempt was made to hold all the variables, other than the viscosity of the continuous phase, constant. A size frequency analysis was employed to follow the changes that occurred within the emulsions. Because of the various methods employed in the literature to interpret the internal changes in aged emulsions (7.11-13, 20) all the collected data were analyzed on the basis of the following values, the arithmetic-mean diameter [a& = zn&/Zn;], the interfacial area [So& = 6/dnc], the volume-surface mean diameter [&a = Zn;di'/Znidi*], the specific interfacial area [Sd.. = 6/&*], and the weight-mean diameter [durn = Zn;d;4/Znidia]],where, in all cases, ni = the number of globules having a class diameter of di (12,20-22). Also, the emulsions were followed for a longer period of time than reported by most workers.
HE FACTORS influencing emulsion stability Thave been the subject of many investigations. Thus, the influence of the type of emulsifying agent and its concentration (1-15), the density differential (1-4, 7, 14), and changes in environmental conditions such as those caused by elevated temperature (5, 11, 13) and centrifugation ( i ) have all been studied. The influence of methods of preparation on stability (1-3, 6, 9, 10, 12, 15) and the effect of globule size and distribution (16, 17) and other factors (15, 18) on the rheological flow properties of emulsions have also been investigated. Few if any of the literature references deal specifically with the effect that changing the viscosity of the continuous phase or the viscosity of the emulsion might have on stability. Therefore, a series of emulsions of varying viscosities have been subjected to study.
METHOD OE STUDY A stable emulsion has been described as one in which no sedimentation or creaming and no aggrega-
*
Received April 25, 1958, from the School of Pharmacy, University of Wisconsin, Madison. Presented to the Scientific Section A. PH. A., Los Angeles meeting, April 1958. The paper is based on a dissertation submitted by Edwin L. Knoechel to the Graduate School of the University of Wisconsin in partial fulfillment of the requirements for the degree of Doctor of Philosophy. t Fellow of the American Foundation for Pharmaceutical Education.
1
2
JOURNAL OF THE
XMERICAN
PHARMACEUTICAL .\SSoCIATION
EXPERIMENTAL volumes of Preparation of Emulsions.-Large solutions of the various grades Of methylcellulose, U. P. (10. 25, 50, 100, and 400 C. P. s.) were prepared with boiling distilled water, cooled, and stored at 5' for eight days to allow complete hydration. The solutions were then subjected to pressure filtration (Alsop "Sealed-Disc" filter, No. 51 filter pads) and finally stored a t 25". Microscopic examination of t h e resulting solutions indicated t h a t they were free of particulate m a t t e r t h a t might be confused with oil globules. A solution of sodium lauryl sulfate, U. S. P. (10% w/v). was prepared with hot distilled water and cooled. Filtration through a medium porosity sintered glass funnel removed a brown sediment leaving the resulting solution clear and free of particles. Emulsions (O/W) of varying viscosities containing 25% (v/v) liquid petrolatum, heavy, U. S. P., and 0.375% (w/v) sodium lauryl sulfate were formulated from the above solutions. Pour 1-L. batches of each viscosity were prepared by mixing in a Waring Blendor for five minutes. The individual batches of the same viscosity were then pooled, mixed, and passed twice through a Tri-Homo colloid mill (rotor-stator setting 0.002 in.). Thirty sample bottles of each emulsion, each containing were stored a t constant temperature (250). No samples used in the subsequent analytical procedures were returned to storage for reuse later. the solution comprising the Viscosities of continuous phase and the complete emulsion were followed throughout the entire period of study, All viscosities were calculated from rheograms obtained using an Epprecht Rheometer (Drage Products, Inc.) at 25'. The emulsions are referred to by number according t o the viscosity grade of the methylcellulose used in the preparation of their external phases (i. e., 10, 25, 50, etc.). Method of halYsis--Each stored sample selected for analysis was first uniformly mixed with a specially constructed apparatus. T h e bottle was rotated at the rate of 10 r. p. m. for a total of 400 revolutions in a vertical plane in such a manner t h a t it described a circle having a radius of 10 cm. After each 50 revolutions, t h e bottle was rotated 45" in the holder. With this treatment the discontinuous phase was evenly distributed. Size frequency determinations before and after this procedure indicated t h a t no changes had occurred. Dilution of the emulsion was accomplished by placing 2 to 7 drops into 25 ml. of distilled water in a glass-stoppered cylinder immersed in an ice-water bath. Twenty-five ml. of propylene glycol, U. S. P., was then added. The size frequency analysis used to follow the changes t h a t occurred in the emulsions employed a modified microscopic technique t o classify the globules (23). A portion of the previously diluted emulsion was placed in a Bright Line hemocytometer (Am. Optical Co.) and viewed with a microscope (B. and L. Labrascope) equipped with a 97X Oil immersion Objective, a 2ox ocularl and an Exton Euscope (B. and L.) (24). .4 special grid in which each division 'Orresponded to p was attached to the Euscope screen. A carbon arc lamp fitted
s.
TO\. ~ L ~ I IKO. I ,1
with a mechanical clock feed and a Pyres water cell provided the illumination. X counting field was defined on this grid and the etchings of the hemocytometer were utilized in adapting a standard procedure so t h a t no area was recounted. ;1period of fifteen minutcs was allowed to elapse after charging t h e chambers before readings were taken. Over 100 fields were measured in each sample and three samples from separate bottles were employed for each determination. Over 4,000 globules were therefore counted in each analysis. The size of each observed globule was recorded with a tape recorder and later transcribed onto data sheets. Globules in the visual range which measured up t o one division were classified as having a diameter of 0.5 p , while globules having a size larger than one b u t smaller than two divisions were classified as having a diameter of 1.5 p , and so on. From the sizc frequency data collected the dme, Sdme, dus, SdsS, and dwm values were obtained with the aid of a magnetic-drum-data processing machine (type 650-IBM) . I The emulsions were analyzed a t thirty-day intervals over a period of seven months.
RESULTS AND DISCUSSION In Fig. 1, the per cent of globules of each size class (0.5 to 5.5 is plotted against the aging time for the Least viscous (no. 10) of the emulsions studied. Similar graphs were also obtained for the more viscous emulsions when the data contained in Table I was plotted. This type of plot shows very clearly the changes Occurring in the systems. Thus* the major changes appeared t o occur in the smaller size (0'5 to 2.5 p ) . The arithmetic-mean diameter (dme) increased with time in all emulsions (Fig. 2).2 The decrease in the corresponding interfacial area (sdmc) with time is shown for the various emulsions in Fig. 3. The above effects were of course anticipated, b u t it is interesting to note that these emulsions of widely varying viscosities (34 to 1,800 c. p. s., see Table 11) all behaved in a similar fasIlion, These d a t a Seem to indicate t h a t the apparellt rates of coalescence did
$?
gs bn
50
fi
40
OC7'
k g 30 bO4
&:
"1
20
&Z
war, p
0
0
30
60 90 120 T I M E , DAYS
180
150
Fig. l.-Per Cent Of 0..55.5 p globules emulsion n u d m 1 0 . W . 5 P ; 0 1.5 0 3.5 p ; 0 4.5 p ; A 5.5 p .
Z'S.
M;
210
time for
A 2.5
1:
____ 1 The authors wish to thank the University of Wisconsin Numerical Analysis Laboratory for the use of this equipment and its facilities. 2 Data for emulsion numbers 50 and 400 have not been plotted in Figs, 2 and 3 in order to make it easier to distinguish between the individual graphs of these figures.
.
..
SCIENTIFIC EDITIOK
January 1959
TABLE I.-PER
C E N T O F THE
TOTAL NUMBER
OP G L O B U L E S
3
MEASURED I N EACH SIZE C L A S S I N T H E 1.ARIOC'S
EMULSIONS
-
Emulsion 10 Diameter Microns
__
7---
0.5 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5 11.5 12.5
45
fi0
91
35.21 30.24 17.69 6.69 3.75 2.10 1.32 1.62 0.84 0.36 0.14
26.37 40.53 16.69 6.14 3.78 2.14 1.94 1.26 0.70 0.46 ...
25.73 41.02 17.04 6.57 3.78 1.71 1.45 1.27 0.83 0.44 0.14
21.98 42.10 17.32 8.06 4.21 2.32 1.39 1.39 0.72 0.36 0 . 13 0.02
...
...
0.5 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5
......
Time --,navs----
0
...
...
0
30
40.27 32.48 15.96 6.18 3.15 1.33 0.20 0.03 0.03
38.10 37.04 13.10 6.72 3.79 1.16 0.10
...
...
... ...
120
150
180
210
23.55 29.59 18.73 7.51 3.73 2.58 1.72 1.36 0.7% 0.34 0.09 0.07
22.43 38.54 21.02 7.18 3.60 2.23 1.95 1.66 0.84 0.44 0.07 0.04
16.45 38.45 24.87 8.42 4.31 1.98 2.11 1.83 0.89 0.50 0.11 0.04 0.02
12.89 33.87 27.88 11.01 4.82 2.79 2.36 1.89 1.33 0.84 0.19 0.08 0.04
...
...
Emulsion 25 _____ Time, Days-
...
fiO
90
120
119
180
210
30.90 41.39 15.73 7.35 3.27 1.08 0.21 0. 04
30.80 43.14 16.06 5.96 3.18 0.75
24.51 46.62 18.04 6.74 3.01 0.94 0.14
22.71 41.22 21.41 8.50 4.41 1.54 0.18 0.02 ...
20.72 40.88 24.73 7.57 3.92 1.74 0.45
18.10 39.19 25.63 9.74 4.66 1.91 0.71 0.06
150
180
210
24.62 41.75 21.58 9.28 2.69 0.09
24.01 40.93 23.78 8.39 2.75 0.14
23.31 39.37 23.89 10.07 3 . 13 0.22
0.14
... ...
t . .
... ...
...
...
Emulsion 50
0.5 1.5 2.5 3.5 4.5 5.5
0.5 1.5 2.5 3.5 4.5 5.5
-Time, 90
Days---119
- ___
-
0
30
41.45 35.29 15.61 6.27 1.34 0.03
41.17 34.31 15.53 7.09 1.79 0.11
0
30
GO
90
120
150
181
210
46. 26 28. 05 15. 59 9.05 0.75
41.45 31.93 17.11 8.61 0.89
36.89 34.72 16.83 10.58 1.00
29.02 40.08 20.09 9.60 1.21
30.23 42.54 17.88 8.46 0.88
25.53 41.16 19.09 11.80 2.43
...
24.84 37.58 25.51 9.90 2.17 0.02
20.75 37.22 26.15 12.57 3.24 0. 06
150
180
210
24.32 37.38 26.28 10.89 1.12
...
24.24 36.35 26.69 11.35 1.30 0.07
19.50 37.41 26.65 13.92 2.41 0.14
...
...
60
30.73 26.52 42.76 43.23 17.51 19 51 7.25 8.64 1.73 2.05 ... 0.02 0.07 Emulsion 100 ______ -Time, Day------------34.40 43.36 14.06 6.50 1.60
...
...
...
Emulsion 200 7 -
0.5 1.5 2.5 3.5 4.5 5.5
...
0
30
GO
91
39.22 31.59 21.42 7.43 0.32
36.56 35.32 21.49 6.24 0.39
34.69 39.47 19.82 5.78 0.24
28.56 41.17 22.25 7.68 0.34
...
Time, Days-119
...
...
22.02 44.89 23.73 8.78 0.60
...
-
-
--
Emulsion 400
0.5 1.5 2.5 3.5 4.5 5.5
not differ greatly.
0
31
60
39.70 31.16 25.20 3.56 0.37
34.13 37.81 24.16 3.56 0.34
30.92 40.47 24.18 4.16 0.27
...
...
...
--Time, Days-----
1
90
120
150
181
210
28.23 42.53 25.31 3.67 0.26
25.84 42.13 26.41 5.36 0.27
24.84 37.97 28.42 8.33 0.39 0.07
19.50 37.62 32.37 9.60 0.83 0.09
14.76 37.56 34.16 12.23 1.16 0.12
In fact the terminal value of the
kewas approximately 1.3 times larger than the initial value in all cases. From the plots of the volume-surface mean dianleter (dBS)and the related specific interfacial area
...
...
(S&) versus time (Figs. 4 and 5) it appears this diameter decreased and the S&S increased during the first ninety to one hundred twenty days. After this time period the specific interfacial area decreased in nearly a linear manner with time (2, 3, 6, 13, 25).
4
JOURNAL OF +HE
AMERICAN PHARMACEUTICAL
ASSOCIATION
vl)l. S L V I I I , NO. 1
TABLE II.--VISCOSITY OF THE AGED EMULSIONS A N D METHYLCELLULOSE SOLUTIONS AT 25O Fluid Number
10 Tea WPh
25 qe WP 50 oe WP 100 ve WP 200 qe WP 400 ve WP
l i m e , Days90 120
0
30
GO
34 9.5 95 20 205 35 460 80 830 130 1,800 270
34 9.0 94 20 204 36 450 80 830 130 1,790 270
33 9.0 92 20 202 35 445 79 828 130 1,775 260
32 9.0 9% 20 205 35 440 79 844 129 1,770 262
32 9.0 90 20 203 35 436 79 836 128 1,765 262
-
150
180
32 9.0 91 20 202 34 432 78 820 125 1,755 262
32 9.0 91 20 198 34 430 79 812 122 1,740 260
210
31 9.0 89 19 198 34 428 78 812 120 1,740 260
(‘qe = Viscosity (c. p. s.) of the emulsion. 6qcp = Viscosity (c. p. s.) of the continuous phase (methylcellulose solution).
I
t? 0
30
60 90 120 T I M E , DAYS
150
180
210
Fig. 2.-Arithnietic mean diameter, d,,, vs. time for emulsions of varying viscosities. Emulsion 100; 200. number: 0 10; 0 25;
0
30
60-&90 120 T I M E , DAYS
150
180
210
Fig. 4.-Volume-surface mean diameter, dv8, vs. time for emulsions of varying viscosities. Emulsion number: 0 10; 0 25; G 50; 0 100; 200; A 400.
4.4 4.2 4.0 3.8 & - 3.6 4 x 3.4
2
4;;
4 -.
2 a 3.2
V f 3 . 0 4 -. ~ ra , 2.8 2.B @ 2.4 2 2
$
5
I
0
.
30
60 90 120 TIME, Days
150
180
I 210
Fig. 3.-Interfacial area, Sd,,,, vs. time for emulsions of varying viscosities, Emulsion number: 0 10; 025; 100; 200.
A plot of the weight-mean diameter (dwm) versus time (Fig. 6) shows a similar effect. From these data i t would appear that the emulsions were becoming more instead of less stable during the first few time periods. This effect could be explained if it were assumed that subvisual globules coalesce in time to form visible globules. Other workers (11, 12) have indicated subvisual globules may be present; however, no reference was found in the literature where the possible effects of these particles are treated. If the above interpretation is valid the initial values of dnC,As,and dwm would be smaller and the interfacial areas larger. This serves to emphasize
0
30
60 90 120 T I M E . DAYS
150
180
210
1;ig. 5.-Specific interfacial area, Sd,,s, us. time for emulsions of varying viscosities. Emulsion number: 0 10; 0 25; A 50; 0 100; 200; A 400. one of the recognized limitations of the microscopic method of analysis. Thus, when this analytical method is employed with relatively stable emulsions, it is well not to rely upon a single value for interpretation of the data. Furthermore, the studies should be carried on for an adequate period of time. For example, if the investigation of these emulsions had been conducted for only three months the dos value would have shown just a decrease, and the d m value would have indicated almost no change, whereas the ACvalue shows an increase throughout. The drae value is predominantly a number distribution value
January 1959
0
5
SCIENTIFIC EDITION
30
60
90
120
150
180
210
TIME (DAYS)
Fig. 6.-Weight-mean diameter, am, vs. time for emulsions of varying viscosities. Emulsion number: 0 10; 0 2 5 ; A 50; 0 100; M200; A400. which is not appreciably affected by a small change in the number of large size globules, while the & and durn, factors are essentially area and volume distributions and are more influenced by the loss or gain of a few large globules (12). These inherent differences are more obvious when all the values are calculated. The voluminous amount of collected data could not have been processed in the various ways without the aid of the electronic computing equipment. Table I1 shows that there was no appreciable variation in the viscosities of the emulsions or the methylcellulose solutions which constituted the continuous phase. As mentioned previously, there appeared to be no marked differences in the rate of coalescence within the viscosity range of the tested emulsions for the duration of the study. Thus although interparticle distances may be assumed to decrease when creaming occurs, an increase in viscosity appeared to play only a minor role in the gross stability. Indeed, even the emulsion with the lowest viscosity appeared to be very stable. Other workers (4, 18) have suggested that viscosity is not of major importance. Whether changes in the interfacial film, the increased viscosity of the creamed layer, or other factors played a part were not determined in this study.
SUMMARY
A modified microscopic method was employed in a size frequency analysis study to follow the
stability of a series of emulsions preparcd hy varying the viscosity of the continuous phase. A niunrrical analysis method which made possible the interpretation of the data on the basis of the arithmetic, volume-surface, and weight-mean diameters was employed. Experimental evidence indicating the presence of subvisual particles which can lead to unreliable diameters and interfacial area values during the early period of aging was obtained. Only a slight variation in the apparent stability of the emulsions studied for a period of seven months was observed. Changing the viscosity did not seem to yield corresponding changes in the rates of coalescence. Thus, viscosity appeared to play only a minor role in the overall stability of these systems. REFERENCES (1) Harkins, W. D., and Beeman, N.. J . A m . Chem. SOL., 51, 1674(1929). (2) King, A.. and Mukherjee, L. N., J . Soc. Chem. I n d . , 58, 243(1939). (3) King, A., and Mukherjee, L. N., ibid., 59. 185(1940). (4) King A. Trans. Faraday Soc. 37 168(1941). (5) Jelli~ek.’H.H. G.,and Ansod, 6. A., J . Soc. Chem. Ind. 68 108(1949). (6 jellinel, H.H.G., and Anson, H. A,, ibid., 69, 229 (19501. (7) Cockton. J. R.,and Wynn. J. B.. J . Pharm. and Pharmacol., 4. 959(1952). - - .-(8) - - -.Jowdy, A. N., and Brecht, E. A., THISJOURNAL, 46, 88(1W57).
(9) Beal, H. M., and Skauen, D. M., ibid., 44, 487(1955). (10 Beal H M ,and Skauen. D. M., ibid., 44, 490(1955). (111 LeviLs,’H. P., and Drommond, F. G.. J . Pharm. and Pharmacol., 5 , 743(1953). (12) Cooper. F. A,, J . Soc. Chem. Ind., 56, 447(1937). (13) Mullins. T. D.. and Becker. C. H., THISJWRNAL.45. 105(1956). (14) Mullins, J. D., and Becker, C. H . , ibid., 45. llO(1956). (15) Axon, A., J . Pharm. and Pharmacol., 8 , 762(1956). (16) Richardson. E.G., J . Colloid Sci., 5 , 404(1950). (17) Richardson, E. G.,ibid., 8, 367(1953). (18) Neogy. R. K.,and Ghosh, B. N., J . Indian Chem. Soc., 30, 113(1953). (19) Greenwald, H.L.. J . Soc. Cosmetic Chemists, 6, 104 (‘~%]’JelIiinek,
H.H.G., and Anson, H. A,, ibid., 69, 225
“?”2]. Fisher, E. K., “Colloidal Dispersions,” John Wiley and Sons, New York, 1950,pp. 7-13. (22) Cadle, R. D.,“Particle Size Determinations,” Manual No. 7, Interscience Publishers, Inc., New York, 1955,pp. 27-40. (23) Campbell, Vermont Uniu. Agri. Ex$. Sfa. BULL, 34, 24(1932). (24) Exton, W.G., J . A m . Mcd. Assoc., 82, 1838(1924). (25) Lawrenct, A. S . C., and Mills, 0. S . , Discussions Faraday Soc., 18. 102(1954).
JOURNAL OF THE AMERICAN PHARMACEUTICAL ASSOCIATION VOLUMEXLVIII
JANUARY I959
NUMBER 1
Investigation of Stability in Emulsions of Varying Viscosities* By EDWIN L. KNOECHELt and DALE E. WURSTER An investigation dealing with the possible effect of viscosity on the stability of oil-inwater emulsions is presented. Interpretation of the size frequency data on the basis of the volume-surface and weight-mean diameters indicated the possible presence of subvisual globules in the formulations. This possibility was not evident when the arithmetic-mean diameter was used. Experimental evidence indicated that viscosity played only a minor role i n the gross stability of the systems studied. tion, flocculation, or coalescence of the discontinuous phase occurs. Since it has been pointed out previously that creaming decreases the interparticle distance, which can then lead to possible changes in the flocculation and coalescence rates, it would appear that the rates of all the above phenomena are interrelated (19). If the change in interparticle distance does cause significant variations in the rate of coalescence, then any existing relationship found between the coalescence and creaming rates would be most useful information. Since the interparticle distances are related to the concentration and the particle size of discontinuous phase and the creaming rate, it is of interest to determine whether or not the rate of coalescence can be altered by changing the viscosity of the continuous phase. Therefore, as a method of study, a series of emulsions of varying viscosities were prepared according to a standard procedure. Every attempt was made to hold all the variables, other than the viscosity of the continuous phase, constant. A size frequency analysis was employed to follow the changes that occurred within the emulsions. Because of the various methods employed in the literature to interpret the internal changes in aged emulsions (7.11-13, 20) all the collected data were analyzed on the basis of the following values, the arithmetic-mean diameter [a& = zn&/Zn;], the interfacial area [So& = 6/dnc], the volume-surface mean diameter [&a = Zn;di'/Znidi*], the specific interfacial area [Sd.. = 6/&*], and the weight-mean diameter [durn = Zn;d;4/Znidia]],where, in all cases, ni = the number of globules having a class diameter of di (12,20-22). Also, the emulsions were followed for a longer period of time than reported by most workers.
HE FACTORS influencing emulsion stability Thave been the subject of many investigations. Thus, the influence of the type of emulsifying agent and its concentration (1-15), the density differential (1-4, 7, 14), and changes in environmental conditions such as those caused by elevated temperature (5, 11, 13) and centrifugation ( i ) have all been studied. The influence of methods of preparation on stability (1-3, 6, 9, 10, 12, 15) and the effect of globule size and distribution (16, 17) and other factors (15, 18) on the rheological flow properties of emulsions have also been investigated. Few if any of the literature references deal specifically with the effect that changing the viscosity of the continuous phase or the viscosity of the emulsion might have on stability. Therefore, a series of emulsions of varying viscosities have been subjected to study.
METHOD OE STUDY A stable emulsion has been described as one in which no sedimentation or creaming and no aggrega-
*
Received April 25, 1958, from the School of Pharmacy, University of Wisconsin, Madison. Presented to the Scientific Section A. PH. A., Los Angeles meeting, April 1958. The paper is based on a dissertation submitted by Edwin L. Knoechel to the Graduate School of the University of Wisconsin in partial fulfillment of the requirements for the degree of Doctor of Philosophy. t Fellow of the American Foundation for Pharmaceutical Education.
1
2
JOURNAL OF THE
XMERICAN
PHARMACEUTICAL .\SSoCIATION
EXPERIMENTAL volumes of Preparation of Emulsions.-Large solutions of the various grades Of methylcellulose, U. P. (10. 25, 50, 100, and 400 C. P. s.) were prepared with boiling distilled water, cooled, and stored at 5' for eight days to allow complete hydration. The solutions were then subjected to pressure filtration (Alsop "Sealed-Disc" filter, No. 51 filter pads) and finally stored a t 25". Microscopic examination of t h e resulting solutions indicated t h a t they were free of particulate m a t t e r t h a t might be confused with oil globules. A solution of sodium lauryl sulfate, U. S. P. (10% w/v). was prepared with hot distilled water and cooled. Filtration through a medium porosity sintered glass funnel removed a brown sediment leaving the resulting solution clear and free of particles. Emulsions (O/W) of varying viscosities containing 25% (v/v) liquid petrolatum, heavy, U. S. P., and 0.375% (w/v) sodium lauryl sulfate were formulated from the above solutions. Pour 1-L. batches of each viscosity were prepared by mixing in a Waring Blendor for five minutes. The individual batches of the same viscosity were then pooled, mixed, and passed twice through a Tri-Homo colloid mill (rotor-stator setting 0.002 in.). Thirty sample bottles of each emulsion, each containing were stored a t constant temperature (250). No samples used in the subsequent analytical procedures were returned to storage for reuse later. the solution comprising the Viscosities of continuous phase and the complete emulsion were followed throughout the entire period of study, All viscosities were calculated from rheograms obtained using an Epprecht Rheometer (Drage Products, Inc.) at 25'. The emulsions are referred to by number according t o the viscosity grade of the methylcellulose used in the preparation of their external phases (i. e., 10, 25, 50, etc.). Method of halYsis--Each stored sample selected for analysis was first uniformly mixed with a specially constructed apparatus. T h e bottle was rotated at the rate of 10 r. p. m. for a total of 400 revolutions in a vertical plane in such a manner t h a t it described a circle having a radius of 10 cm. After each 50 revolutions, t h e bottle was rotated 45" in the holder. With this treatment the discontinuous phase was evenly distributed. Size frequency determinations before and after this procedure indicated t h a t no changes had occurred. Dilution of the emulsion was accomplished by placing 2 to 7 drops into 25 ml. of distilled water in a glass-stoppered cylinder immersed in an ice-water bath. Twenty-five ml. of propylene glycol, U. S. P., was then added. The size frequency analysis used to follow the changes t h a t occurred in the emulsions employed a modified microscopic technique t o classify the globules (23). A portion of the previously diluted emulsion was placed in a Bright Line hemocytometer (Am. Optical Co.) and viewed with a microscope (B. and L. Labrascope) equipped with a 97X Oil immersion Objective, a 2ox ocularl and an Exton Euscope (B. and L.) (24). .4 special grid in which each division 'Orresponded to p was attached to the Euscope screen. A carbon arc lamp fitted
s.
TO\. ~ L ~ I IKO. I ,1
with a mechanical clock feed and a Pyres water cell provided the illumination. X counting field was defined on this grid and the etchings of the hemocytometer were utilized in adapting a standard procedure so t h a t no area was recounted. ;1period of fifteen minutcs was allowed to elapse after charging t h e chambers before readings were taken. Over 100 fields were measured in each sample and three samples from separate bottles were employed for each determination. Over 4,000 globules were therefore counted in each analysis. The size of each observed globule was recorded with a tape recorder and later transcribed onto data sheets. Globules in the visual range which measured up t o one division were classified as having a diameter of 0.5 p , while globules having a size larger than one b u t smaller than two divisions were classified as having a diameter of 1.5 p , and so on. From the sizc frequency data collected the dme, Sdme, dus, SdsS, and dwm values were obtained with the aid of a magnetic-drum-data processing machine (type 650-IBM) . I The emulsions were analyzed a t thirty-day intervals over a period of seven months.
RESULTS AND DISCUSSION In Fig. 1, the per cent of globules of each size class (0.5 to 5.5 is plotted against the aging time for the Least viscous (no. 10) of the emulsions studied. Similar graphs were also obtained for the more viscous emulsions when the data contained in Table I was plotted. This type of plot shows very clearly the changes Occurring in the systems. Thus* the major changes appeared t o occur in the smaller size (0'5 to 2.5 p ) . The arithmetic-mean diameter (dme) increased with time in all emulsions (Fig. 2).2 The decrease in the corresponding interfacial area (sdmc) with time is shown for the various emulsions in Fig. 3. The above effects were of course anticipated, b u t it is interesting to note that these emulsions of widely varying viscosities (34 to 1,800 c. p. s., see Table 11) all behaved in a similar fasIlion, These d a t a Seem to indicate t h a t the apparellt rates of coalescence did
$?
gs bn
50
fi
40
OC7'
k g 30 bO4
&:
"1
20
&Z
war, p
0
0
30
60 90 120 T I M E , DAYS
180
150
Fig. l.-Per Cent Of 0..55.5 p globules emulsion n u d m 1 0 . W . 5 P ; 0 1.5 0 3.5 p ; 0 4.5 p ; A 5.5 p .
Z'S.
M;
210
time for
A 2.5
1:
____ 1 The authors wish to thank the University of Wisconsin Numerical Analysis Laboratory for the use of this equipment and its facilities. 2 Data for emulsion numbers 50 and 400 have not been plotted in Figs, 2 and 3 in order to make it easier to distinguish between the individual graphs of these figures.
.
..
SCIENTIFIC EDITIOK
January 1959
TABLE I.-PER
C E N T O F THE
TOTAL NUMBER
OP G L O B U L E S
3
MEASURED I N EACH SIZE C L A S S I N T H E 1.ARIOC'S
EMULSIONS
-
Emulsion 10 Diameter Microns
__
7---
0.5 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5 11.5 12.5
45
fi0
91
35.21 30.24 17.69 6.69 3.75 2.10 1.32 1.62 0.84 0.36 0.14
26.37 40.53 16.69 6.14 3.78 2.14 1.94 1.26 0.70 0.46 ...
25.73 41.02 17.04 6.57 3.78 1.71 1.45 1.27 0.83 0.44 0.14
21.98 42.10 17.32 8.06 4.21 2.32 1.39 1.39 0.72 0.36 0 . 13 0.02
...
...
0.5 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5
......
Time --,navs----
0
...
...
0
30
40.27 32.48 15.96 6.18 3.15 1.33 0.20 0.03 0.03
38.10 37.04 13.10 6.72 3.79 1.16 0.10
...
...
... ...
120
150
180
210
23.55 29.59 18.73 7.51 3.73 2.58 1.72 1.36 0.7% 0.34 0.09 0.07
22.43 38.54 21.02 7.18 3.60 2.23 1.95 1.66 0.84 0.44 0.07 0.04
16.45 38.45 24.87 8.42 4.31 1.98 2.11 1.83 0.89 0.50 0.11 0.04 0.02
12.89 33.87 27.88 11.01 4.82 2.79 2.36 1.89 1.33 0.84 0.19 0.08 0.04
...
...
Emulsion 25 _____ Time, Days-
...
fiO
90
120
119
180
210
30.90 41.39 15.73 7.35 3.27 1.08 0.21 0. 04
30.80 43.14 16.06 5.96 3.18 0.75
24.51 46.62 18.04 6.74 3.01 0.94 0.14
22.71 41.22 21.41 8.50 4.41 1.54 0.18 0.02 ...
20.72 40.88 24.73 7.57 3.92 1.74 0.45
18.10 39.19 25.63 9.74 4.66 1.91 0.71 0.06
150
180
210
24.62 41.75 21.58 9.28 2.69 0.09
24.01 40.93 23.78 8.39 2.75 0.14
23.31 39.37 23.89 10.07 3 . 13 0.22
0.14
... ...
t . .
... ...
...
...
Emulsion 50
0.5 1.5 2.5 3.5 4.5 5.5
0.5 1.5 2.5 3.5 4.5 5.5
-Time, 90
Days---119
- ___
-
0
30
41.45 35.29 15.61 6.27 1.34 0.03
41.17 34.31 15.53 7.09 1.79 0.11
0
30
GO
90
120
150
181
210
46. 26 28. 05 15. 59 9.05 0.75
41.45 31.93 17.11 8.61 0.89
36.89 34.72 16.83 10.58 1.00
29.02 40.08 20.09 9.60 1.21
30.23 42.54 17.88 8.46 0.88
25.53 41.16 19.09 11.80 2.43
...
24.84 37.58 25.51 9.90 2.17 0.02
20.75 37.22 26.15 12.57 3.24 0. 06
150
180
210
24.32 37.38 26.28 10.89 1.12
...
24.24 36.35 26.69 11.35 1.30 0.07
19.50 37.41 26.65 13.92 2.41 0.14
...
...
60
30.73 26.52 42.76 43.23 17.51 19 51 7.25 8.64 1.73 2.05 ... 0.02 0.07 Emulsion 100 ______ -Time, Day------------34.40 43.36 14.06 6.50 1.60
...
...
...
Emulsion 200 7 -
0.5 1.5 2.5 3.5 4.5 5.5
...
0
30
GO
91
39.22 31.59 21.42 7.43 0.32
36.56 35.32 21.49 6.24 0.39
34.69 39.47 19.82 5.78 0.24
28.56 41.17 22.25 7.68 0.34
...
Time, Days-119
...
...
22.02 44.89 23.73 8.78 0.60
...
-
-
--
Emulsion 400
0.5 1.5 2.5 3.5 4.5 5.5
not differ greatly.
0
31
60
39.70 31.16 25.20 3.56 0.37
34.13 37.81 24.16 3.56 0.34
30.92 40.47 24.18 4.16 0.27
...
...
...
--Time, Days-----
1
90
120
150
181
210
28.23 42.53 25.31 3.67 0.26
25.84 42.13 26.41 5.36 0.27
24.84 37.97 28.42 8.33 0.39 0.07
19.50 37.62 32.37 9.60 0.83 0.09
14.76 37.56 34.16 12.23 1.16 0.12
In fact the terminal value of the
kewas approximately 1.3 times larger than the initial value in all cases. From the plots of the volume-surface mean dianleter (dBS)and the related specific interfacial area
...
...
(S&) versus time (Figs. 4 and 5) it appears this diameter decreased and the S&S increased during the first ninety to one hundred twenty days. After this time period the specific interfacial area decreased in nearly a linear manner with time (2, 3, 6, 13, 25).
4
JOURNAL OF +HE
AMERICAN PHARMACEUTICAL
ASSOCIATION
vl)l. S L V I I I , NO. 1
TABLE II.--VISCOSITY OF THE AGED EMULSIONS A N D METHYLCELLULOSE SOLUTIONS AT 25O Fluid Number
10 Tea WPh
25 qe WP 50 oe WP 100 ve WP 200 qe WP 400 ve WP
l i m e , Days90 120
0
30
GO
34 9.5 95 20 205 35 460 80 830 130 1,800 270
34 9.0 94 20 204 36 450 80 830 130 1,790 270
33 9.0 92 20 202 35 445 79 828 130 1,775 260
32 9.0 9% 20 205 35 440 79 844 129 1,770 262
32 9.0 90 20 203 35 436 79 836 128 1,765 262
-
150
180
32 9.0 91 20 202 34 432 78 820 125 1,755 262
32 9.0 91 20 198 34 430 79 812 122 1,740 260
210
31 9.0 89 19 198 34 428 78 812 120 1,740 260
(‘qe = Viscosity (c. p. s.) of the emulsion. 6qcp = Viscosity (c. p. s.) of the continuous phase (methylcellulose solution).
I
t? 0
30
60 90 120 T I M E , DAYS
150
180
210
Fig. 2.-Arithnietic mean diameter, d,,, vs. time for emulsions of varying viscosities. Emulsion 100; 200. number: 0 10; 0 25;
0
30
60-&90 120 T I M E , DAYS
150
180
210
Fig. 4.-Volume-surface mean diameter, dv8, vs. time for emulsions of varying viscosities. Emulsion number: 0 10; 0 25; G 50; 0 100; 200; A 400.
4.4 4.2 4.0 3.8 & - 3.6 4 x 3.4
2
4;;
4 -.
2 a 3.2
V f 3 . 0 4 -. ~ ra , 2.8 2.B @ 2.4 2 2
$
5
I
0
.
30
60 90 120 TIME, Days
150
180
I 210
Fig. 3.-Interfacial area, Sd,,,, vs. time for emulsions of varying viscosities, Emulsion number: 0 10; 025; 100; 200.
A plot of the weight-mean diameter (dwm) versus time (Fig. 6) shows a similar effect. From these data i t would appear that the emulsions were becoming more instead of less stable during the first few time periods. This effect could be explained if it were assumed that subvisual globules coalesce in time to form visible globules. Other workers (11, 12) have indicated subvisual globules may be present; however, no reference was found in the literature where the possible effects of these particles are treated. If the above interpretation is valid the initial values of dnC,As,and dwm would be smaller and the interfacial areas larger. This serves to emphasize
0
30
60 90 120 T I M E . DAYS
150
180
210
1;ig. 5.-Specific interfacial area, Sd,,s, us. time for emulsions of varying viscosities. Emulsion number: 0 10; 0 25; A 50; 0 100; 200; A 400. one of the recognized limitations of the microscopic method of analysis. Thus, when this analytical method is employed with relatively stable emulsions, it is well not to rely upon a single value for interpretation of the data. Furthermore, the studies should be carried on for an adequate period of time. For example, if the investigation of these emulsions had been conducted for only three months the dos value would have shown just a decrease, and the d m value would have indicated almost no change, whereas the ACvalue shows an increase throughout. The drae value is predominantly a number distribution value
January 1959
0
5
SCIENTIFIC EDITION
30
60
90
120
150
180
210
TIME (DAYS)
Fig. 6.-Weight-mean diameter, am, vs. time for emulsions of varying viscosities. Emulsion number: 0 10; 0 2 5 ; A 50; 0 100; M200; A400. which is not appreciably affected by a small change in the number of large size globules, while the & and durn, factors are essentially area and volume distributions and are more influenced by the loss or gain of a few large globules (12). These inherent differences are more obvious when all the values are calculated. The voluminous amount of collected data could not have been processed in the various ways without the aid of the electronic computing equipment. Table I1 shows that there was no appreciable variation in the viscosities of the emulsions or the methylcellulose solutions which constituted the continuous phase. As mentioned previously, there appeared to be no marked differences in the rate of coalescence within the viscosity range of the tested emulsions for the duration of the study. Thus although interparticle distances may be assumed to decrease when creaming occurs, an increase in viscosity appeared to play only a minor role in the gross stability. Indeed, even the emulsion with the lowest viscosity appeared to be very stable. Other workers (4, 18) have suggested that viscosity is not of major importance. Whether changes in the interfacial film, the increased viscosity of the creamed layer, or other factors played a part were not determined in this study.
SUMMARY
A modified microscopic method was employed in a size frequency analysis study to follow the
stability of a series of emulsions preparcd hy varying the viscosity of the continuous phase. A niunrrical analysis method which made possible the interpretation of the data on the basis of the arithmetic, volume-surface, and weight-mean diameters was employed. Experimental evidence indicating the presence of subvisual particles which can lead to unreliable diameters and interfacial area values during the early period of aging was obtained. Only a slight variation in the apparent stability of the emulsions studied for a period of seven months was observed. Changing the viscosity did not seem to yield corresponding changes in the rates of coalescence. Thus, viscosity appeared to play only a minor role in the overall stability of these systems. REFERENCES (1) Harkins, W. D., and Beeman, N.. J . A m . Chem. SOL., 51, 1674(1929). (2) King, A.. and Mukherjee, L. N., J . Soc. Chem. I n d . , 58, 243(1939). (3) King, A., and Mukherjee, L. N., ibid., 59. 185(1940). (4) King A. Trans. Faraday Soc. 37 168(1941). (5) Jelli~ek.’H.H. G.,and Ansod, 6. A., J . Soc. Chem. Ind. 68 108(1949). (6 jellinel, H.H.G., and Anson, H. A,, ibid., 69, 229 (19501. (7) Cockton. J. R.,and Wynn. J. B.. J . Pharm. and Pharmacol., 4. 959(1952). - - .-(8) - - -.Jowdy, A. N., and Brecht, E. A., THISJOURNAL, 46, 88(1W57).
(9) Beal, H. M., and Skauen, D. M., ibid., 44, 487(1955). (10 Beal H M ,and Skauen. D. M., ibid., 44, 490(1955). (111 LeviLs,’H. P., and Drommond, F. G.. J . Pharm. and Pharmacol., 5 , 743(1953). (12) Cooper. F. A,, J . Soc. Chem. Ind., 56, 447(1937). (13) Mullins. T. D.. and Becker. C. H., THISJWRNAL.45. 105(1956). (14) Mullins, J. D., and Becker, C. H . , ibid., 45. llO(1956). (15) Axon, A., J . Pharm. and Pharmacol., 8 , 762(1956). (16) Richardson. E.G., J . Colloid Sci., 5 , 404(1950). (17) Richardson, E. G.,ibid., 8, 367(1953). (18) Neogy. R. K.,and Ghosh, B. N., J . Indian Chem. Soc., 30, 113(1953). (19) Greenwald, H.L.. J . Soc. Cosmetic Chemists, 6, 104 (‘~%]’JelIiinek,
H.H.G., and Anson, H. A,, ibid., 69, 225
“?”2]. Fisher, E. K., “Colloidal Dispersions,” John Wiley and Sons, New York, 1950,pp. 7-13. (22) Cadle, R. D.,“Particle Size Determinations,” Manual No. 7, Interscience Publishers, Inc., New York, 1955,pp. 27-40. (23) Campbell, Vermont Uniu. Agri. Ex$. Sfa. BULL, 34, 24(1932). (24) Exton, W.G., J . A m . Mcd. Assoc., 82, 1838(1924). (25) Lawrenct, A. S . C., and Mills, 0. S . , Discussions Faraday Soc., 18. 102(1954).