EXPERIMENTS ON EMULSIONS. IV BY
T. R. BRIGGS, F.
R . D U C A S S ~ AND ~ I,.
H. CLARK
PHARMACEUTICAL EMULSIONS Introduction Pharmaceutical emulsions arp prepared on a small scale most satisfactorily by the so-called “Continental” method, which consists in making what is termed an “emulsion nucleus” with more or less definite quantities of oil, water and gum and subsequently diluting this nucleus with water, as desired. The making of a suitable nucleus is looked upon as something of an art in which success follows only upon strict adherence to an arbitrary method of pr0cedure.l The best practice is to place the oil (4 parts) in a dry mortar of sufficient capacity, add acacia ( 2 parts) and triturate until a smooth paste is formed. Water (3 parts) is then added all ut once, with trituration, whereupon a creamy nucleus results almost immediately. This nucleus, of course, is an emulsion of oil in water, containing relatively large quantities of oil and gum, the latter acting as the peptizing or “emulsifying” agent. The nucleus is viscous and very sticky, both of which properties may account for the characteristic “crackling” sound which is emitted whenever the completed nucleus is stirred. Being an emulsion of the oil-in-water type? it is miscible with water and can be diluted without difficulty. Roon and Oesper, in the paper cited, have published some interesting studies on pharmaceutical emulsions. They believe that their results confirm Fischer’s hypothesis, “that their production [i. e., the production of emulsions] is always associated with the discovery of a method whereby the water (or other medium) which is to act as the dispersing agent is Cf. Bancroft: Jour. Phys. Chem., 16, 747 ( 1 9 1 2 ) ; Roon and Oesper: Jour. Ind. Eng. Chem., 9, 156 (1917). Cf Newman: Jour. Phys. Chem., 18, 34 ( 1 9 1 4 ) ; Briggs and Schmidt: Ibid., 19,493 (1915). a “Fats and Fatty Degeneration,” 5 (1917).
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all used in the formation of a colloid hydration (solvation) compound. In other words, when it is said that the addition of soap favors the formation and stabilization of a division of oil in water, it really means that soap is a hydrophilic colloid which, with water, forms a colloid hydrate with certain physical characteristics, and that the oil is divided in this. The resulting mixture cannot, therefore, be looked upon as a subdivision of oil in water, but rather as one of oil in a hydrated colloid.” Roon and Oesper go even farther than Fischer and concludel “ ( I ) that the presence of a hydration compound is necessary for emulsification; ( 2 ) that this hydration compound is most efficiently used if formed a t the moment of dispersion of the internal phase-in other words, the three constituents, the internal phase, emulsifier and water, in critical proportions, must all be mixed a t one time in order to form a properly hydrated nucleus; (3) slight variations from the proper promcedure or from the critical proportions yield either less stable emulsions or none at all ; (4) no emulsion results if the emulsifier is diluted (hydrated) before dispersion of the internal phase.” The most striking part of the hypothesis of Roon and Oesper is that emulsions are formed only when the “hydration compound” is produced a t the moment of trituration or agitation with the oil. Later on, we shall return to review this hypothesis in the light of what our own experiments indicate. Emulsions by the Continental Method Experiment I.-4 grams of powdered gum arabic (acacia) were added to g cc of olive oil contained in a large porcelain mortar (diameter 2 0 cm) and the mixture was thoroughly triturated. Microscopic examination of the product resulting showed that it consisted of a coarse suspension of gum in oil, stabilized more or less by the viscous nature of the oil. Without discontinuing the grinding, 6 cc of water were now added, when in about 2 0 seconds a creamy emulsion (nucleus) resulted ; the latter, owing to its viscous, sticky nature, emitted the characteristic “crackling” sound. The nucleus prepared in 1
Jour. Ind. Eng. Chem., 9, 161 (1917).
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this-way wasperfectly miscible with distilled water to form a milky liquid-containing globules of oil whose size varied between z and 4 microns in diameter. No free oil floated to the topof the diluted nucleus on standing in a closed tube, even after several days, nor did the concentrated nucleus separate into layers. This experiment illustrates the standard “Continental” method of making an emulsion. brExperiment 2.-Instead of adding dry gum to the oil and-adding water subsequently, a solution of gum arabic containing 4 grams of gum plus 6 cc of water was added to the oil with grinding. No emulsion nucleus resulted. The oil was only slightly emulsified, much free oil remained undispersed and the oily mixture in the mortar gave no “crackling” sound. Experiment 3.-The procedure of Experiment I was followed except that the water was added a few drops a t a time instead of a t once. No useful nucleus resulted; the emulsion was very incomplete. After the addition of the first few drops of water the gum in suspension throughout the oil coalesced into sticky lumps which adhered to the mortar and prevented proper mixing of the oil and water. Experiment 4 .-No satisfactory nucleus resulted when gum arabic solution was placed in the mortar and oil was added subsequently and all at once, with grinding. These four experiments bring out the importance of the order and manner of mixing the various components of the emulsion nucleus. They confirm the results of Roon and Oesper. Apparently, unless one “hydrates” the gum at the moment of trituration in the presence of oil and unless this hydration is carried out in one step, no satisfactory nucleus results. As a matter of fact, the oil is completely emulsified only under these limiting conditions ; in all those experiments which failed to produce a satisfactory nucleus, some, though little, of the oil was actually emulsified. Unfortunately, the hydration hypothesis of Roon and Oesper cannot be correct for it is easy enough to emulsify olive oil in a solution of gum arabic by shaking oil and solution in a bottle. Such an emulsion can be improved and the globules
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T . R. Briggs, F . R. DuCassd and L. H.Clark
of oil made smaller by subsequent treatment in a homogenizer. One does not “hydrate” the gum in the presence of the oil and yet one gets an emulsion. The experiments which follow will serve to demonstrate that simultaneous hydration is not essential when forming emulsions in a mortar. The Effect of Finely Divided Solids Experiment j.-9 cc of oil were placed in the mortar and rubbed with 3 or 4 grams of sand (finer than IOO mesh). Gum arabic solution (4 grams of gum plus 6 cc of water) was added and, on triturating, there resulted a satisfactory nucleus, very nearly the equal of the nucleus obtained in Experiment I . Time-15 seconds. Oil globules-4 to 12 microns. No emulsion was formed when water instead of gum solution was added to the oil and sand, showing that we were not dealing with sand as the peptizing agent (cf. Pickering’s emulsions). Experiment 6.-Experiment 5 was repeated using 6 grams of cane sugar in place of the sand. On grinding for I O minutes a paste resulted containing irregular fragments of sugar averaging about I O microns in diameter. On adding gum solution and triturating, a perfect nucleus resulted. Time12 to 15 seconds. Oil globules--2 to 4 microns, maximum 8 microns. Experiment 7.-6 grams of sodium chloride were used instead of sand; otherwise same as 5. Perfect nucleus. Time 15 to 2 0 seconds. Oil globules--2 to 4 microns. As control experiment a nucleus was made by the standard “Continental” method (cf. Experiment I ) . Time-20 seconds. Oil globules-2 to 4 microns. Experiments 5, 6 and 7 were checked by performing them in duplicate. This second series of experiments proves that it is possible to prepare a normal nucleus, even by the use of gum arabic solution, i. e., with previously “hydrated” gum, provided a finely divided solid is present in the oil. Powders soluble in water and powders insoluble in water seem more or less equally effective. Complete nucleus emulsions were obtained with sand, ground quartz, pulverized glass and several other finely divided solids, with gum as the peptizing colloid.
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1.51
The Surface Factor Experiment ti’. Varying the Size of Mortar and Pestle.Three mortars and three pestles were used in making standard “Continental” emulsions as in Experiment I . Large mortar -20 cm in diameter; 7.3 cm deep. Medium mortar-g cm in diameter; 4.2 cm deep. Small mortar-6.5 cm in diameter; 3.5 cm deep. Width of pestles at base-large, 5.8 cm; medium, 3.2 cm; small, 3.0 cm. Mortar and pestles of porcelain. ( a ) Large mortar, large pestle. Time-25-30 seconds. Oil globules-1 to 2 microns. Exceedingly uniform emulsion. (b) Medium mortar, medium pestle. Time-25-30 seconds. Globules-2 to 6 microns. Fairly uniform. (c) Small mortar, small pestle. Time-35 seconds. Globules--q to I O microns. Non-uniform (many large drops of oil). This experiment shows that the best results are obtained when the largest rubbing surface is made available. A mortar with a slightly roughened surface seems better than a smooth one. Experiment 9 . Varying the Fivteness of Sand .-Pollowing the‘ procedure of Experiment 5, one gram samples of sand (SiOz) were ground gently with g cc of oil and gum solution was added. The data follow: Fineness of Sand
60-100mesh 100-zoo mesh
zoo-350 mesh Through 350 mesh
Remarks
Unsatisfactory nucleus; incomplete emulsion Satisfactory nucleus ; complete emulsion; 5 t o I O microns Satisfactory nucleus ; complete emulsion; 3 to I O microns Excellent nucleus; complete emulsion; z t o 5 microns
In each of these individual experiments the nucleus was diluted by adding 25 cc of distilled water and set aside in order that the permanence of the emulsion might be tested. The emulsions made with sand finer than IOO mesh were fully as permanent as similar emulsions made by the standard “Con-
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T . R. Briggs, F . R. DuCassb and L. H.Clark
tinental” method. It is evident that the finer the sand, i. e., the greater the specific surface-the better the nucleus emulsion. The sand employed in this work was a pure white material used in the manufacture of high grade carborundum. Control Experiment.-Oil, 350 mesh sand and water (without gum arabic) did not give a satisfactory nucleus. The results of Experiment g cannot therefore be due, save possibly very slightly, to the sand as peptizing agent. Experiment IO. Varying the Quantity of Sand.-These tests were carried out according to the procedure of Experiment 9, using sand of IOO to 2 0 0 mesh and varying the quantity of sand added. The results follow : Weight of Sand f Grams)
Remarks
Poor nucleus; some unemulsified (free) oil Good nucleus; no free oil; 5 to IO microns Good nucleus; no free oil; 3 to I O microns Very good nucleus; no free oil; 4 microns Excellent nucleus; no free oil; less than 4 microns
Sand-Si02 Chalk-C aC0 3 Galena-PbS Zinc blende-ZnS Aluminum
2.5 2.2
7. j 4.o 2.7
Good nucleus, uniform; 2-4 microns Good nucleus, uniform; 3-6 microns Poor nucleus, non-uniform; 3-2 j microns Poor nucleus, non-uniform; 3-20 microns Poor nucleus, non-uniform; 3-30 microns
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To realize the latter condition experimentally, weights in grams were taken equal to the density of the solid. Care was taken not to grind unduly the powdered solid when suspending it in the oil. These experiments indicate that there are distinct and specific effects due to the nature of the finely powdered solid. Apparently solids easily wetted by water (sand and chalk) are more satisfactory than solids less readily wetted by water1 (galena, blende, and aluminum) so far as the production of small globules and uniform emulsions is concerned. The influence of the wetting factor will be brought out clearly in later experiments. Emulsions with Sodium Oleate Experiwent 12 .-4 grams of powdered sodium oleate were ground in the mortar with 9 cc of olive oil. On adding 6 cc of water and grinding, a perfect nucleus resulted. Other experiments, similar to Nos. 2, 3 and 4 showed that all the results’’obtained with gum arabic could be duplicated with sodium oleate. The diluted nucleus made by the standard “Continental” method contained globules avera&ng 2 to 3 microns in diameter. Experiment 13.-2.6 grams of sand (350 mesh) were added to 9 cc of oil, whereupon a solution of sodium oleate (4 grams soap plus 6 cc of water) was added with grinding. Although the soap solution was in the form of a paste the nucleus emulsion was obtained after sufficient grinding. Globules-2 microns. This nucleus was even more perfect than the one made by the standard method. This group of experiments shows that sodium oleate and gum arabic behave in essentially the same way. The effect of finely divided solid is the same in both cases. Emulsions with Other Oils Experiments with different oils and gum arabic carried out according to the standard “Continental” method, showed Cf. Hofmann: Zeit. phys. Chem., 83, 385 (1913);Bancroft: Jour‘. Phys. Chem., 19,294 (1915).
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fairly conclusively that the more viscous oils, such as olive oil, linseed oil and pine oil, are much more readily emulsified than are the less viscous oils, such as benzene, toluene, chloroform, and aniline. Discussion of Results In view of the foregoing experiments, it is evident t h a t “hydration” of the emulsifying agent-gum arabic or soapneed not be carried out at the moment of disintegrating t h e oil. It is possible to prepare a perfect emulsion of oil in water with previously “hydrated” gum or soap by using a solution instead of the dry material, provided one follows a suitable procedure. One way to succeed is to use a fairly viscous oil, mix the latter with finely divided solid, such as sand or sugar, and finally to add the solution of acacia or soap with energetic trituration. It is known that the “Continental” method of the pharmacist gives emulsions of olive oil whose globules are much smaller on the average than they are when oil and previously hydrated gum are mixed and shaken by hand in a bottle. One might argue from this that simultaneous “hydration” produces a far better emulsion. Opposed to such a point of view, however, are the experiments with sand and sugar, in which previously hydrated colloids (solutions of gum and soap) afforded emulsions fully equal to the “Continental” ones. Of course, one might say that sand or sugar are “hydrated” by gum solutions, but this is certainly stietching the theory beyond its elastic limit, a t least so far as sand is concerned. It seems better to abandon the hypothesis suggested by Roon and Oesper, and to substitute a new one. Our own experiments indicate that the presence of finely divided solid in the oil is the sine qua non of the “Continental” method. Finely divided solid was present in every experiment which resulted in a satisfactory nucleus emulsion. In the standard “Continental” method powdered gum or soap play the part that sand or sugar do in the subsequent experiments. Finely divided solids serve to increase the area of the interface between oil and water or between oil and solution.
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Anything which increases the interface between oil and water, assists in the production of an emulsion. We may consider the mechanism of the “Continental” method to be somewhat as follows: Gum arabic is suspended in a viscous oil by grinding. Water is added and the grinding is continued. Gum being soluble in water (it is really peptized by water) it is probably much more readily wetted by water than i t is by oil. Water, therefore, tends t o displace the oil from the gum so that each particle becomes coated with an aqueous film. The interface between oil and water is thus enormously increased. The gum soon dissolves, leaving drops of solution scattered momentarily throughout the oil. The triturating action flattens out these drops and in the process oil is disintegrated and emulsified in the solution. The drops of gum solution, as they are stirred around in the mixture, exert an interfacial tearing effect upon the oil and aid in its dispersion. The large drops of gum solution, each drop bearing its load of emulsified oil, soon coalesce to a uniform mass of emulsion (the nucleus). In the standard “Continental” method the powdered gum plays a double r81e (I) that of finely divided solid, (2) that of emulsifying and stabilizing colloid. The part played by finely divided solids needs no further elucidation. The solid relieves the gum of one of its functions in the standard method so that the gum solution may now be used. The experiments with soluble powders, such as sugar and sodium chloride, show that insolubility is not a necessary requirement. There are, however, some other interesting possibilities. One might suggest, for example, that when water is added to sodium oleate suspended in oil, the sudden change (decrease) in the surface tension, produced by soap dissolving, might account for the disintegration of oil, much as changes of surface tension at the interface are said to account for Gad’s so-called spontaneous emulsions.1 That the change of surCf. Bancroft: Jour. Phys. Chem., 16,348
(1912).
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156
face tension is actually not an important factor was shown in the following manner. Experiment Iq.-Powdered sodium oleate (4 grams) was suspended in olive oil (9 cc) by triturating in a mortar. Instead of pure water, 6 cc of a two percent solution of sodium oleate were added. An excellent nucleus emulsion made its appearance after a few seconds’ grinding. Globules - 2 to 3 microns. It was found by experiment that the surface tension of a two percent solution of sodium oleate is very slightly changed by further additions of sodium oleate. Thus a 2 percent solution of sodium oleate rose 15 mm in a given capillary tube; an 8 percent solution rose 16 mm and pure water rose 40 mm. It is not at all improbable, however, that the process of wetting the suspended solid with water or solution, entailing as it does a displacement of oil from the surface, may help to disintegrate the oil and form the necessary globules. We should, therefore, expect to find such substances as are easily wetted, by waterLassisting most ably in the emulsion forming process, provided they are suspended in the oil. The experiments which follow were designed to test this point. Experiment ri;.-Part a. 2.6 grams of sand (350 mesh) were suspended in 9 cc of olive oil, whereupon IO cc of gum arabic solution were added. A nucleus emulsion resulted after grinding for 35 seconds. Globules--I to 4 microns. Part b. 7.5 grams of galena (350 mesh) were suspended in 9 cc of olive oil and gum solution ( I O cc) was subsequently added. It required no less than 5 minutes of vigorous trituration to produce a complete emulsion. Globules I to 4 microns. Note that 2.6 grams of sand occupy about the Sam volume as 7.5 grams of galena. Experiment 15 may be regarded as strongly supporting the hypothesis. Oil will be displaced by solution more rapidly from sand than from galena. It should therefore be easier to form the emulsion with sand than with galena, and such proved to be the case. 1
Cf. Hofmann: Zeit. phys. Chem., 83, 385 (1913).
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It follows, as a further necessary consequence of the theory, that sand will be most effective when present originally in the oil and least effective when added with the solution of gum arabic, for under the latter circumstances the displacement of oil does not take place and the solid serves only to increase the interface. Experiment supports this deduction. Experiment IO.-Part a. 2.6 grams of sand (350 mesh) were added to IO cc of gum arabic solution in the mortar. Vigorous grinding for 5 minutes was required to emulsify 9 cc of oil in this mixture. Globules-1 to 4 microns. Compare with Experiment 15, Part a. Part b. 7.5 grams of galena (350 mesh) were added to IO cc of gum solution in the mortar. Vigorous grinding for nearly 8 minutes was needed to complete the emulsion. Globules-1 to 4 microns. Compare with Experiment 15, Part b. Experiment 17.-Part a. 2.6 grams of sand (350 mesh) were added to 9 cc of oil in the mortar and I O cc of gum solution were subsequently added. An emulsion resulted in I minute. Globules-1 to 2 microns. Part b. 2.6 grams of sand were added to I O cc. of gum solution. Nine minutes of grinding were needed to emulsify 9 cc of oil on placing the oil in the mortar and adding the mixture of sand and solution. Globules--a to 4 microns. All of these experiments were checked by tests in duplicate. It is evident that a longer time and more work are needed to make an emulsion when the solid is first wetted by the aqueous solution. It is now quite definitely established that finely divided solids, whether soluble or insoluble in the aqueous phase, serve greatly to facilitate the formation of emulsions in the mortar. The same is also true of finely dividedsolids added in the bottle when emulsions are made by shaking. On grinding sodium oleate in benzene and shaking the mixture with water in a bottle an excellent emulsion resulted. A still better emulsion was obtained when a more perfect suspension of soap was made by adding to benzene a small amount of a fifty percent solution of sodium oleate in ethyl alcohol (Squibb’s soft
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soap). Experiment seemed to show that the finer the particles suspended in the oil the more important and beneficial becomes the process of displacing the oil by the aqueous liquid. When the oil contains particles readily peptized in water -such as gum arabic or soap-the act of peptization may be looked upon as an extreme case of wetting by water. Peptization should therefore entail rapid displacement of oil. Rapid displacement produces maximum disintegration, and might if rapid enough, give rise to so-called “spontaneous” emulsions-emulsions formed merely by contact with water and hence with a minimum of mechanical effort. If one were to produce a colloidal solution of sodium oleate in benzene an emulsion should form exceedingly easily on adding water, and might conceivably develop practically spontaneously, wherever water and benzene come in contact. Indeed, certain oily mixtures are known to give spontaneous emulsions in water, for example, lysol and the creosote emulsions. In both these instances, the oil contains the hydrophile1 colloid in some form of suspension and the act of peptization into the water phase gives rise to an extremely perfect emulsion, almost entirely without externally applied mechanical effort. We have surprisingly little information available concerning spontaneous emulsions, though mixtures giving them are common and some are commercially important. An effort was next made to apply the theory to thecase of water-in-oil emulsions. Linseed oil was heated with rosin, some of which dissolved. Six cc of water were placed in a mortar and ground with various powdered solids. The linseed oilrosin mixture was then added, followingthe procedure of Expenment 5. With galena or mercuric iodide emulsions of water in linseed oil were formed in the mortar. These emulsions were analogous to the oil-in-water ones, they could be diluted with linseed oil, but they were very unstable. With water, galena and pure linseed oil no emulsion could be made ; nor could one 1
Cf. Bancroft’s definition: Jour. Phys. Chem., 19,275 (1915). Cf. Briggs and Schmidt: Ibid., 19, 478 (1915).
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be made with water, sand and linseed oil-rosin. The failure with sand might be attributed to the non-wetting of sand by linseed oil and the absence of the displacement factor. White lead plus water in the mortar, with linseed oil-rosin added afterward, gave a water-in-oilnucleus, exactly what one should expect from the behavior of white lead, water and linseed oi1.l The general results of this paper may be summarized as follows : I . The hypothesis of Roon and Oesper that hydration of the emulsifying colloid must take place a t the moment of disintegrating the oil has been shown not to be in accordance with the results of experiment. 2 . Even in a mortar, emulsions may be made with previously “hydrated” colloids, provided one modifies the “Continental’’ procedure. 3. Emulsions are easily produced by the method of trituration in a mortar if the area of the interface between oil and water is made sufficiently large. One way of doing this is to suspend in the oil finely divided solids which are readily wetted by water. 4. The effectiveness of the solid is increased by decreasing the average size of the particles. 5 . Up to a certain limit, the readiness with whicl an emulsion forms increases as the quantity of finely divided solid grows larger. 6 . It is better to suspend the finely divided solid in the liquid to be emulsified, before adding the dispersing solution. 7. The most effective solids are those readily wetted by the dispersion medium. 8. In the “Continental” method, gum arabic (acacia) plays the part both of finely divided solid and emulsifying colloid. 9. The finely divided solid serves to increase the area of the interface between oil and water. Cf. Bancroft: Met. Chem. Eng., 14, 631 (1916).
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T . R. Briggs, F . R.DuCassb and L. H. Clark
IO. Wetting phenomena may also cause the displacement of one liquid by the other and consequently give rise to disintegration of the displaced liquid. It is not known to what ~ upon the emulsifying power extent the action depends p e se of the finely divided solid. 1 1 . Emulsions of water in oil may be made in a mortar in the presence of finely divided solids easily wetted by oil.
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