[1]United S-vo--ates Patent 0- ffice 3@043@782 3,043,782 PROCESS FOR PREPARING A MORE EWPE4 RIME. ABLE COATING BY LIQUID-LIQUID PHASE, SEPARATION Erik H. Jensen, IC-alama--oo Township, Kalamazoo County, AUch., assignor to The Unjohn Company, Kalamazoo, Mich., a corporation of Delaviare No Drawing. Filed Dec. 22, 1958, Ser. No. 781,933 3 Cla'uns. (Cl. 252-316) This invention relates to a method for improving liquidliquid phase separation coatiiigs. More particularly, it relates to an improvement in the step of dryili,- the coated material produced by such a procedure. Liquid-liquid phase separation procedures sucli as coacervation @are becoming increasingly important as a means for providing protective coatings Lor particulate materials. Obviously, the relative permeability or impermeability of such coatings is very important. It has now been found that one of the critical conditions for controlling pern. eability involves the pH at which spray drying of paxticles coated by phase separation techniques is carried out. By controlling the pH of spray drying a much more impermeable coating can be obtained. Thus in the process of preparing a more impermeable coating'with a gelable hydrophilic colioid by liquid-liquid phase separation, the present improvement relates to the t step of spraydrying after adjusting the pH of the liquid containing the dispersed coated materials to between about 4 and about 6. Although the reason for the phenomenon is unknown, experimental results unexpectedly indicate optimum results are obtained within the pH range indicated. If the drying step is carried out at a pH substantially above 6, the coating is too permeable for many purposes for which the protection coatings are desired as will be shown hereinafter. The type of spray dryer used or the particular conditiors of spray drying (e.g., air temperature, type of nozzle and air flow) are not particularly critical for present purposes. They are merely adjusted in accordance with the requirements of the materials used in the process. The product produced by the improved process of this invention is valuable as an article ol' manufarture wherever a relatively impermeable coating is desired. Such a coating is especially useftil where either the coated material has penetrating properties or the environment to which the coated material is to be exposed has penetrating properties. For example, the instant produce can be employed in the printing art in the same manner as the products described in U.S. Patents 2,800,457 and 2,800,458 where a pressure sensitive, reproducing film to replace carbon paper is desired @vhenever a more benetrating material (e.g., a dye) is e@capsulated or the finished product must withstand more ri.- orous handling and e: Kt- posure conditions. It can be used to st6re otherwise incompatible mixtures where either the coated or uncoated material involved is a p@-netrating liquid. The -present improvement also finds usefulness in coating oil products 1 such as vitan-iins or edible Vegetable, animal, or mineral fats and oils. Su.ch products are therefore suitable for incorporation int6 dry cereals, margarine, ice cream, butter, milk and other. dairy products, fruit and vegetable juices (e.g., orange juice), bread and other baked goods, jams and other condiments, and for maintaining unstable flavors, the mantle being broken in cooking or mixing. Th.- encapsulated material can thus include medicaments and dietary supplements which must be maintained in fluid form over long periods of time or in more penetrating fluids i'orrelatively short periods of time. The present improvement also provides iinproved coatings for Patented July 10, 1962 orahy ingestible materials which must resist imm,.diate disintegration in certain environmental conditi6ns existing in the @astrointestinal, tract and thereby mask flavors 6r dors o@r provide sustained or controlled release. 5 Liquid-liquid phase separation as employed herein refers to the separation of a colloidal concentrate or col loid-rich phase from an oriinal single-phase solution or sol, leaving behind a colloid-poor phase or equihbrium liquid. Thus, the separating phase is a liquid highly I 0 concentrated with respect to the colloid and dispersed in a liquid medium which is less concentrated with respect to t]@e coue'-,@d. Where the separating phase consists of a sin.-le coll6id, the process is termed simple phase separatio-.i; where inore than one colloid is present, the process 15 is called complex phase separation. In the usual system, the separating phase appears initially as a fine dispersion of microscopic droplets of colloid in the equilibrium liquid. When fornied in a pure cohoidal system, these droplet@ are essentially homo@ ,eneous. However, if for20 eign iiaterials are present in the ori,-inal sol or solution, the separatin-. phase tends to form axound these particles. In order to obtain the maikimum advanta.-Cs of such a coating as a means for enhancing the usefulness of a wide variety of materials, it is necessary that the said coating 25 or membrane retain its integrity7 except under c6nditions where release of the encapsulated material is desired. Tjais means that the coating must have sufficient integrity to withstand normal usage in formulati6n and packaging. The coating must also remain intact under all contem30 plated environmental conditions unl,il an appropriate physical, chemical or mechanical agency of destruction is opera@ive. In addition to resisting premature destruction, the coating must be highly impermeable to the passage 35 of molecules or ions which riight adversely affect the eneapsulated material. Alternatively, where slow release of materials enclosed within the coating membrane is desired, the coating structure must be of such permeability as to permit the gradtial passage of enviromnental fluids to effect such release. Preparation of the menbrane-by 40 the method of this invention yields a novel coating structure by which the foregoing properties can b.- obtained. It is to be understood Lliat the present method is operative regardless of the method by which the separatin.phase is deposited or precipitated, except that the said 45 separating phase must contain as one of its components a gelable hydrophilic colloid. It is therefore the presence of the said colloid, and not the method by which its separation was effected or the additional presence of other 50 coflo s or polymers in the separating phase, which determines the limits of the applicability of the process described herein. Examples of suitable gelable hydrophilic colloid materials include gp-latin, albimin, fibrinogen, casein, agar-agar, pectin, ichthyocoua, and the like. Qther mat.-rials which can be used in combination with such -clable hydrophilic colloids include partially or completely hydrolyzed styrene maleic anhydride copolymer, gum acacia, sodium carboxymethylcellulose, sodium alignate, cellulose acetate phthalate, starch acetate phthalate, amylose acetate phthalate and other materials vibich are 60 opposite in char.-e to fne gelable hydrophilic coroid used. Since slich hydrophilic colloids are generally soluble in water, the present iniprovement is most advantageously used where the colloid pbase separates from @aqueous 65 rtedia. However, it is also possible to ulilize the present drying irpprovemelit for phase separations from non@queous media. Generally speakin.-, the improvement can be utilized in conjunctio-Ti wilh other recent developments in liquid70 -liqiiid phase separation techniques for coating almost any type ffi particle, whether lipophilic or hydrophilic in its surface characteristics. The particles can be liquid
[2]or solid in phys;cal structurei Tlle liquid particles ca@i be homoge-@icous or can contain dissolved material, dispersed emulsion particles, or other compatible materials. The solid parlicles can be u-.itreated or can be precoated by phase separation techniques or any other suitable method. 111@,istrative of the phase separation (e.g., coacervation) processes which yield coating membranes susceptible of improvement in permeability characteristics are the methods disclosed in U.S. Patent Nos. 2,800,457 and 2 800,458. The said patents describe encapsulation of ;@icroscopic oil droplets which can coitain dissolved or suspended mat@--rials by simple and complex phase separation. In accord with the disclosures of the aforesaid patents phase separation is indliced, for example, by the add@'@tion of a salt in the case of simple phase separation and by the addition of excess solvent (i.e., water) in the case of complex phase separation. In the preferred emb6diment of, the preseit invention the addition of such phase separation indticin- ageiits are spread out over a period of no less tnan about one-half hour or more than two hours. Salts which are suitible for inducing simple phase separat@'.on idelude salts having rnetal, e.g., alkaline earth and alkali-metal, ma.-n-,sium, ammonium, potassium and lithium cations and organic or inorganic aniods, C-9., sulfate, phospi-iate, citrate, acetate, forniate, chloride, bromid.-, nitrate, thiocyanate, and iodid-- anions. 7he ma.-nesium cation is ordinarily more efficacious than the lithiun-i cation and the sulfate anion is ordinarily more efficaciolis than the iodid-. anion. The anion exerts a more profound influence on the efficacy of the salt than does the cation. Sodium sulfate and ammonium sulfate are highly efficaciois for present purposes. The salt shoiild be added in amounts sufilcient to produce a si,-nificant percentage thereof by weight per volume of the resulting mixti-ire, e..-., I to 50% and preferably 3 to 20%. Sir@iilarly, simple phase separatio-@i to enclose small droplets of hydrophilic I-quid-ino:l emulsions can b-@ carri.-d out in conjunction with the ;resent method. The term hydrophilic liqu;d includes water, aqueous solutions orsuspensions, and non-aqueous solutions or suspensions imm@'@scible in the oil phase of the said emulsions. In predaring eiicapsulated droplets of this type, an antii-.iversion agent, such as hydro.- enated castor oil, capable of preventin.- the iiiversion of t'-ne liquid-in-oil emi,,Ision to 'I an o,. -in-hydrophilic liquid emulsion is incorporated iii the oil pliase of the iriitial or primary emulsion. Su-'@table anti-inversion ageits include surface active age-@its, prej'erably thos-, of the nonionic type, and thickening agents such as the natural and synthetic waxes, solid fats, sterols, and other conventional oil-,-elli-.ig or oiltbicke-@iiiig agents. Advantageously, the internal phase of the said emulsions can contain thickening a.-ents, such as methyl cellulose, for increasing the viscosity of the said internal phase and thereby reducing the escaping tendency of ingredients dissolved or suspended therein. Agents employed for this purpose include the -,elable hydrophilic colloids and other viscosity-increasing materials substantially insoluble in the oil pbase. The thus prepared emulsion is dispersed in an aqueous sol of a @elable hydropbilic colloid, such as gelatin, at a temperature above the gel point of the said colloid to form a double emulsion. To this is added an aqueous solution of a separation inducing agent, such as sodium sulfate, to bring about phase separation. In this case, the iiiter-mixture of the emulsion containin-, colloid solution with the salt solution is carried out over a period of between about one-half to about two hotirs. The method of this invention is likewise applicable to the treatment of complex phase separations enclosinhydrophilic liquid-in-oil emulsions as above defined wherein the separating phase includes as a component at least one gelable hydrophilic colloid, such as gelatin, and at least one linear macromolecular synthetic polymer, such as styrenemaleic acid copolymer. In phase separations 04 i this t3,pe, a primai-y hydrophilic liquid-in-oil emulsion containipg an antiinversion agent is prepared as above, and th-, said primary emulsi6n is dispersed in an aqueous sol of the aforesaid colloids to form a double emulsion. The pH of 'the said double emulsion is then adjusted to 'Lhe separation ran.-C of the particular colloids involved, thereby causing a coating to form about the particles of the said secoridary emulsion, as above. Jn this case, pH adjustm-,nt is carried ovit over a period of between about 10 one-half to about tv,,o hours. The py.-sent inethod is equally applicable to the treatir-ent of membranes enclosing oil-in-hydrophilic liquid emulsions by liquid phase separation. Such emulsions are prepared by the techniqiies of simple and complex 15 phase separation alluded to above, except that the hydrophilic liquid phase must be rendered incompatible with aqtiecus media which it encounters in the course of phase s-,paration, i.e., aqueous solutions of separation induci-,ig agents ,tnd aqljeous sols or solutions of the separating 20 cG!Ioids, or otlier materials tendin.- to disturb the inte.-rity o@i- ihe hydrophilic liquid phase of the initial emulsion. Such integrity is obtained by the addition of certain thickening a.-ents, such as methyl cellulose, to th-. hydrophilic liquid phasa. Phase separation is induced 25 essentially as above over the period of time indicated. Phase separation coatings produced by the procedures asgell-,rally outlined above but in which phase separation is ijidticed by d-ilution with a non-solvent in which the colloid is less sGIuble than it is in water a-e also '.improved 30 by the dryi-ii.- tcc'inique of the present inventon. A-ii improved coating is likewise obtainable by the presept process where ,he phase separation coating encloses solid particulate matter to which, if not already l@@pr-,philic in charatcer, a solid lipophilic coating, such as 35 bep-swax, has been applied prior to coating by liquidliquid phase separation. From the foregoing it is to be understood that the present invention is not limited in its applicability to coacervate membranes deposited by any particular method or 40 comprising a-iy particular combination of coacer vatincomponents, with the single limitation before noted, i.e., the use of a -clable hydrophilic colloid. After the separating phase has collected around the dispersed particles, in a liquid form, it can be gelled and/or 4r hard-,ned by conventional techniques as desired. For example, gelling can be brought about by lowering the temperature below the gel point of the gelable component of the coacervate. Illustratively, chemical hardening can be carried out through the use of one or more of several 50 hardening agents including formaldehyde, a dicarbonyl ccmooti,,id (e.g., glyoxal, 2- oxopropionaldehyde, 2,3-,)entane@ione, 3,4-hexanedione, and the like), tannic acid (alone or in combination with ferric chloride), and alum (having the formula M'M ... (S)2'12H20 wherein M' is a 55 monovalent metal, M... is a trivalent rnetal, and S is a radical selected f-rom the group consisting of sulfate and selenate). Subsequent to treatment of the coating as desired, the pH of the equilibrium liquid containing the coated par60 ticles can be adjusted to the desired range before spray drying; or the coated particles can be separated from the e,-,i-iilibrium liquid by conventic-,ial me!@ins and dispersed in water, the pH of the dispersion being adjusted to the desired range before spray drying. After drying, the prod65 uct of the invention generally resembles a dry powder. The following examples are illustrative of the process improvement of the present invention but are not to be construed as limiting. Example I 70 A suspension of 8 gm. of methyl cellulose and 50 gm. of caffeine in 100 ml. of water is heated to 80' C. One hundred milliliters of mineral oil is heated to 80' C. and emulsified into the aqueous suspension.! Seventy-five grams of styrene-maleic acid copolymer is dispersed in 75 1500 ml. of water, heated to 80' C., and sufficient 10%
[3]5 sodium hydroxid6 is added to dissolve the copolymer. The emulsion is then dispersed in the copolymer Sol with agitatioii. Seventy-five grams of gelatin is dispersed in 500 ml. of water, heated to 80' C. and 10% sodium hydroxide is added to raise the pH to 7. The gelatin sol is then added dropwise to the @emulsion-copolymer wixture with c6ntinuous stirring. linmed@iately thereafter is adde,d dropwise over the period of one hour a sufri@ient Amount of 20% acetic acid solution to bring the pH of the mixture down to 3.9. The material is maintained at 80' C. for 15 min., then cooled to 4' C. over a period of 30 min. To harden the separated phase, 75 ml. of 37% formaldehyde solution is added, followed by thd dropwise addition of 10% sodium hydroxide to bring the pH up to 8. The hardened material is then separated by centrifugation, washed with water, dispersed in water adjusfed to a pH of 5 by 20% acetid acid, and spray dried in a Niro spray dryer having centrifugal atomizer rotating at 3 5,000 r.p.m. and a controlled air flow. The inlet air temperature is adjusted to 140' C. and the exhaust air to 90' C. to produce a sustained action oral stimulant. Other thickening agents can be substituted for the methyl cellulose above in equal amounts, such as, for example, acacia, tragacanth, carboxymethylcellulose, magnesium aluminum sihcate, the polyglycols, glycerin, syrups and the like. Similarly, other hydrophihe colloids such as agar-agar, albumin, fibrinogen, and the like, together with other synthetic polymers such as styrene-maleic acid amide, the sulfonated polystyrenes, starch acetate phthalate, cellulose acetate phthalate, amylose acetate phthalate, polymethacryhc acid, and methylvinylether-maleic acid substituted for the styrene-maleic acid above. Example 2 A water-in-oil emwsion is prepared at 40' C. by emulsifying into 37 gm. of lanolin containing 0.25 gm@ of polyoxyethylene sorbitan monostearate 30 ml. of water in which is dissolved 0.01 gm. of sulfanilamide. A sol comprising 15 gm. of fibrinogen in 150 ml. of water is heated to 40' C. and thoroughly mixed with the said eniulsion. To the resulting mixture is introduced slowly 150 ml. of a 20% solution of sodium sulfate over the period of one and one-half hoiirs with vigorous stirrin@. The temperature of the resulting equilibrium liquid containing the @phase-coated emulsion is reduced to 7' C. to gel the fibrinogen. Sufficient 15% sodium carbonate solution is added to bring the ph to 8.5, and 5 ml. of a 10% solution of 2,3-butanedione, previously adjusted to pH 8.5, is added to harden the membrane. A hardening time of 30 minutes is permitted. The pH is adjusted to 4 by the addition of 10% HCI. The resulting coated particles are washed with water and spray dried in a Niro spray dryer as described in Example 1. The coated particles thus prepared can be incorporated in an ointment in the usual manner for topical use. Exam,ple 3 Ten grams 6f glyceryl .1ro-@iostearate is melted by heati-ig to 60' C., and 20 -m. of mercuric oxide is dispersed therein. I A solution of 6 gm. of acacia in 48 ml. of water is prepared and heated to 60' C. The resu g solu on s adjusted to pH 3.9 by the addition of 20% acetic acid solution. A gelatin sol is prepared by dispersing 6 gm. of gelatin in 48 ml. of water. The resulting sol is adjusted to pH 3.9 by addition of 20% acetic acid solution. - Each Of the above three fractions is heated to 60' C. With vigorous stirring, the mercuric oxide-glyceryl monostearate mixture is dispersed in the acacia soluti6n and, stirring being continued, the gelatin sol is slowly added thereto. Approximately 90 ml. of water also heated to 60' C. is added dropwise to the resulting mixture over a period of 30 rainutes to produce a phase coating about the particles of glyceryl monostearate which in tum envelopes the particles of mercuric oxide. When addition of the 90 ml. quantity of water is complete, the temperature is main3,043,782 6 tained at 601 C. for an additional 15 minutes followed by, rapid cooling to 5' C. by the addition of 70 gm. of ice and 500 ml. of water at O' C. The resulting mixture is maintained below 5' C. for two and one-half hours, after which time the pH is adjusted to 4. Thereafter, 300 ml. of a 10% solution of potassium manganic sulfate of pH 4 is added slowly to the above mixture, which is then maintained at 5' C. for 2 hours and then heated to room temperature' The thus treated coated mercuric (jxide par10 ticles are separated by centrifugation and washed with water. The pH is rechecked and adjusted back to 4 if necessary and then the mixture is dried on a Niro spray dryer as described in Example I to produce an orally effective veterinary anthelmintic. 15 Example 4 Chloral hydrate ----------------------- 7 --- gni-- 100 Mineral oil -------------------------------- ml-- 125 Beeswax -------------------------------- gin-- 25 20 -maleic acid copolymer -------------- gm-- 75 --------------------------------- grn-- 75 D-ssol--;e 100 g@-n of chloral hydrate in 50 ml. of I water and heat to 70' C. Dissolve 25 gm. of beeswax in 125 ml. Of mineral oil at 70, C. Emulsify the aqueous so25 lution into &.e oil solution by passing the combined mixture through a hand homogenizer 4 times@ Disperse 75 gm. of styrene-maleic acid copolymer 'm 1500 ml. of water, heat to 70' C. and add sufficient 10% sodium hy&oxide to dissolve the copolymer. (At this point the 30 copolymer solution has a pH between 7 and 8.) Witl-i continuous agitation, disperse the emulsion in the copolymer sol. Dissolve 75 gm. of gelatin in 500 ml. of waterat 70' C. and add 10% sodium hydroxide to raise the pH of the sol to 7. Add -the gelatin sol dropwise to 35 the copoly-mer-emulsion mixture with continuous stirrininimediately theerafter, with the temperature at 70' C. and with continuous stirring, add dropwise over the pe-, rigd of two hours 20% acetic acid solution to bring the pH of the mixture down to 4.5. Maintain the mixture at 40 70' C. with stirring for 30 minutes, and then coo . 1 to 6' C. over a period of 30 minutes. Maintain the material below 10' C. for I hour. Add a solution of 0.8 gm. tannic acid in 1000 ml. of water, with stirting, and after 30 minutes the treated coacervate is washed with 45 water. The pH is checked and readjusted to 4.5 if necessary and dried in a Niro spray dryer as described in Example I to produce a sustained action sedative. Example 5 50 Crystal violet lactone having the formula 3,3-bi s(pdimethylaminophenyl)6- dimethylamino phthalide is dissolved to the extent of 3% by weight in trichlorodiphenyl. One gallon oil-in-water emulsion containing 20 parts by weight of the trichlorodiphenyl and 100 parts @by weight 55 of a sol of 10% by weight of pigskin gelatin having an iso-electric point -at pH 8 in water is prepared. Eniul sification is continued until the drop size of the oil is from 2 to 5 microns. This material is kept at 50, C. to keep the gelatin from gelling. With the temperature 60 kept at 50' C., phase separation is induced by adding slowly and uniformly, fourtenths of a gallon c@,e sodium sulfate in water over the period of one hour with continuous agitation. The gelatin molecules are thus deposited uniformly about each oil droplet as a nucleus. The 65 heated mixture is then poured into 10 gallons of 701o by weight of sodium sil-Ifate in water. at 41 C. with agitation to gel the gelatin. The material is filtered and washed with water while the temperature is kept below the gel point of the gelatin to remove the salt. The fil70 tered material is hardened by combining it under alkaEne conditions with 2 gallons of a 37% solution of formaldehyde in water. This hardened mass is then filtered and washed to remove the residual formaldehyde. The resulting fil@ter cake is adjusted to the proper water con75 tent aDd a pH of 6 by the addition of 5% HCI and dried
[4]7@, in a Niro spray dryer as described in Example 1. The m.aterial is ready for application to a sheet of paper which is then dried to form@ a transfer film. When marking pressures break the capsules and release the oil, it contacts a sensitized undersheet containing attapulgite and transfers the markings to the undersheet as desired. Example 6 A sol is made of 20 grams of gum acacia dissolved in 160 grarns of water. Into this is emulsified 80 grams of trichlorodiphenyl. A second sol of 20 gratns of pork skin gelatin, having its iso-electric point at pH 8, and 160 gm. of water is prepared, and this second sol is mixed with the emulsion. A volume of water is added to the mixture by spray over the period of one hour with constant stirring. All of the foregoing steps are carried out with the ingredients at 50' C. The resulting mi-ture is poured into water at O' C.' enough water bein-, used to bring the total weight of ingredients to 3960 gm. The mixture is agitated and thereafter is allowed tO stand for an hour at not over 6' C. The formation of the capsules is now complete. They can now be separated and washed with water. The pH is adjusted to 4 by adding 20% acetic acid and dried in a Niro spray dryer as described in Example 1. If it is desired tO use the capsules as a coating material for paper, the, dry encapsulated particles can be applied to the paper. Hardening by formaldehyde as in Example, 5 can also be used in conjunction with the present procedure. Example 7 Prepare a sol by dissolving 27.5 gm. of gum acacia into 170 ml. of water at 50' C. 2.75 ml. of 20% acetic acid is added to adjust the pH of the sol to 3.9. 233 milligrams of D. & C. Red No. 18 (1-xylylazO2-naphthol) is dissolved in 46 ' 5 ml. of acidic Piineral oil at 50' C. to produce a 0.5% concentration of dye in the oil. The oil solution is combined with the acacia sol and emulsified four times in a hand homogenizer. A sol is prepared by dissolving 20 gin. of pork spin gelatin in 170 ml. of water at 50' C., and a sufficient amount of 20% acetic acid is added to adjust the pH to 3.9. The gela,tin sol is added to the emulsion over a period of 30 minutes. 700 ml. of water previously heated to 50' C. is added to the emulsion over a period of 45 rninutes. The material is maintained at 50' C. with stirring for 70 minutes. The mixture is cooled to 4' C. over a period of 30 minutes and maintained at this temperature with stirring for two hours. The pH of the mixture is then adjusted to 9.5 by the addition of 10% sodium hydroxide. 20 ml. of 30% glyoxal previously adjusted to pH 9 5 is added dropwise to the inixture. It is then stirred 'at 4' C. for 5 hours. A sufficient amount of 10% hydrochloric acid is added to adjust the pH to 5.0. ne mixture is diluted to 4 liters with water. The sols are separated by centrifugation, washed with water and resuspended in I liter of water. The pH of the dispersion is checked and readjusted to 5 if neces3,043,782 sary. The dispersion is spray dried in a Niro spray dryer as described in Example. 1. . The foregoing procedure was repeated several times, keeping everything constant@ except the pl-I of the material before spray drying to deterrnine its effeot upon the p@-rmeability of the coating membrane of the dried product. In each case, the produce produced was dispersed in chloroform to determine its permeability. Since the gelatin-acacia coating is insoluble in chloroform, the 10 chloroform contacts the oil through the pores of the coat, and the dye from the encapsulated oil diffuses out into the chloroformi Thus, under fixed experimental conditions the rate of diffusion of dye into the chlorofor@m is a quantitative measure of the permeability of -the co15 acervate membrane. In the diffusion assay, 1 gm. of dry product was suspended in 250 ml. of cl@iloroform and stitred at a @'ixed, coiistant rate. The rate of difftision of the dye into the c'alorofe-rm was measured spectrophotometrically on 20 filtered aliqtiots of the chloroform suspension. The results are g;ven in the following table. The diffusion rate is given as the amount of dye (expressed as percent of total amount of encapsulated dye) which is released per mi-.iute. 25 p@@T of niaterial prior Diffusion rate of dye (unit: percent to spray drying dye released per minute 4.00 ----------------------------------- 0.125 5.00 ---- 0.125 0 . 1 2 8 30 7 '25 ----------------------------------- 0.180 8.50 ----------------------------------- 0.302 The data clearly show that adjustment of pH between 4 and 6 before spray drying produces a much more 35 imperrreable coating than that produced at higher pH's. It is to.be understood that the present invention is noL to be limited to the exact compositions or methods shown and described as obvious modifications and equivalents will be apparent to one skilled in the art, and tne inven40 tion is therefore to be limited only by the scope <)f the appended claims. NVhat is
