AU620571B2 - Apparatus and method for making microcapsules - Google Patents

Description

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p AU-AI-25510/88 PCT WORLD INTELLECTUAL PROPERTY ORGANIZATION PCT International Bureau s INTERNATIONAL APPLICATI rPU^IS|E UT "ER hE PtENT COOPERATION TREATY (PCT) (51) International Patent Classification International Pblication Number: WO 89/ 02814 B01J 13/02, B05D 7/00 (43) International I tication Date: 6 April 1989 (06.04.89) (21) International Application Number: PCT/US88/03143 (81) Designated States: AT (European patent), AU, BE (European patent), BJ (OAPI patent), BR, CF (OAPI pa- (22) International Filing Date: 13 September 1988 (13.09.88) tent), CG (OAPI patent), CH (European patent), CM (OAPI patent), DE, DE (European patent), DK, FI, FR (European patent), GA (OAPI patent), GB, GB (31) Priority Application Numbers: 101,802 (European patent), IT (European patent), JP, KR, LU 187,982 (European patent), ML (OAPI patent), MR (OAPI patent), NL (European patent), NO, SE, SE (Euro- (32) Priority Dates: 28 September 1987 (28.09.87) pean patent), SN (OAPI patent), SU, TD (OAPI pa- 29 April 1988 (29.04.88) tent), TG (OAPI patent), US.

(33) Priority Country: US Published With international search report.

Parent Applications or Grants Before the expiration of the time limitfor amending the (63) Related by Continuation claims and to be republished in the event of the receipt US 101,802 (CIP) of amendments.

Filed on 28 September 1987 (28.09.87) US 187,982 (CIP) A. J. 1 J. <8 Filed on 29 April 1988 (29.04.88) J U 8 (71)(72) Applicant and Inventor: REDDING, Bruce, Jr. AUSTRALIAN [US/US]; P.O. Box 66, Darby, PA 19023 18 APR 199 PATENT OFFICE (54) Title: APPARATUS AND METHOD FOR MAKING MICROCAPSULES (57) Abstract This invention is a continu- 31 ous or batchwise process and ap- 2 paratus for the manufacture of COR- S microcapsules having a core which contains a liquid, gaseous, solid or multiple-phase material SHEL DDED which is coated with an imperme- S H E

LL

c RECYCLE able film. The microcapsules are formed by applying high pres- sure, for a short period of time, to OMp PRESSUR a mixture of the core and shell PE-zIXIHO STAGE RIDUCT material, and by gradually reducing the pressure, such as by pass- L..

ing the capsules through a baffled 33 7 chamber. The invention also includes a method for adjusting the size of the microcapsules and the thickness of their shells. The microcal;-ules can be made with several shell layers, to increase their strength, or as multiple cap- CAP sulcs, having two or more cores.CAPsU The apparatus comprises premix- S SD -C P HLARDIWIa -3 ing block compression chamber pressure reduction block optional recycle line and optional capsule hardening block The invention is especially useful in producing time-release capsules and produces micro-capsules in a small fraction of the time required by prior art methods.

Ut WO 89/02814 PCT/US88/03143 1 APPARATUS AND METHOD FOR MAKING MICROCAPSULES BACKGROUND 'OF THE INVENTION This invention relates to the field of making small S capsules, or microcapsules, having a core material encased within a shell or wall material. In this specification, the terms "shell" and "wall" are used with identical meanings.

A microcapsule has a diameter of the order of about 5-5000 microns.

Microcapsules have many applications, such as in the manufacture of pharmaceuticals, pesticides, paints, adhesives, and many other chemical products. Microcapsules are especially useful where it is desired to provide a controlled release of the substance being encapsulated. The product known as "carbonless paper" is made by providing a liquid dye in microcapsules, so that the dye is released when pressure ruptures the capsule walls.

Examples of processes for forming microcapsules are given in Vandegaer, "Microencapsulation Processes and Applications", Plenum Press, New York, 1974, M. Gutcho, "Microcapsules and other Capsules", Chemical Technology Review, No. 135, Noyles Data Service, Park Ridge, N.J. 1979, and the Kirk-Othmer Encyclopedia of Chemical Technology, 3rd Edition (1981), volume S 15. Other references disclosing processes for forming microcapsules include U.S. Patent Nos. 3,943,063, 3,460,972, 4,001,140, and 4,087,376. All of the above-mentioned publications and patents are incorporated by reference herein.

i WO 89/02814 PCT/US88/03143 2 The above-mentioned references describe several liquid-phase methods of encapsulation. These methods include coacervation, thermal coacervation, complex coacervation, interfacial polymerization, and others. In the process of coacervation, the core and shell materials are mixed together in a liquid medium. When the core and shell materials have been agitated for a sufficient period of time, portions of the core material become coated with shell material, thus forming capsules within the liquid medium. The size of these capsules is controlled by the speed and design of the mixing element within the vessel.

The thickness of the shell material is adjusted by a further chemical treatment process.

The coacervation process described above has many disadvantages, It is difficult to achieve precise control of the size of the microcapsules.

Inadequate agitation of the mixture frequently produces capsules which are too large, often beyond the size range suitable for the desired application. In the coacervation process, it is also difficult to adjust the thickness of the shell of the capsules. A thicker shell is often essential to enhance the shear and impact resistance of the capsule, and to enable the capsule to withstand high temperatures.

In addition to the disadvantages discussed above, the coacervation process is very time-consuming. The core and shell materials must be stirred for a long period of time, on the order of several hours, before usable capsules are WO 89/02814 PCT/US88/03143 3 produced. The time required to form the capsules adds significantly to the cost of their manufacture.

Conventional liquid-phase methods of making microcapsules, S such as the coacervation process mentioned above, often produce unsatisfactory quantities of microencapsulated products. Moreover, it often happens that the core material is soluble in the liquid medium, in which case such materials dissolve in the liquid medium long before encapsulation can occur.

There is presently a great demand for microcapsules which can be inexpensively manufactured, and which are suitable for various industrial applications.

Microcapsules used in industry must exhibit the following properties: 1. The capsules must be capable of withstanding large shear forces, or other stressful conditions, when the capsules are added to a host material. Suitable host materials could be paints, plastics, foam products, building materials, paper products and others. Each host material requires varying conditions of heat and stress to produce the final product, and the capsules must have suitable physical properties to enable the capsules to be used during the manufacture of the final S product.

a I I -4- 2. Capsules used in industry must generally be very small. Microcapsules made by conventional liquid-phase methods of encapsulation, and by other methods, usually have an unacceptably wide size distribution, and are often too large for use in industrial processing.

3. Capsules used in industry should be produced in a continuous process, so that the capsules are available in large quantities, and at relatively low cost.

The present invention provides a process and apparatus for making microcapsules which have the properties described above, The process of the present invention can produce microcapsules in a small fraction of the time required by conventional methods. The present invention also permits the accurate adjustment of the size of the capsules and the thickness of their shells.

SUMMARY OF THE INVENTION :According to a first embodiment of the invention there is provided a method of capsules, comprising the steps of mixing a core material and a shell "15 material, applying pressure to the mixture, the pressure being applied in a .o sufficient amount and for a sufficient time to cause capsules to form.

According to a second embodiment of the invention there is provided a method of making capsules, comprising the steps of mixing a shell material with *e a solvent to form the shell material into a film state, combining the shell material with a core material, applying pressure to the mixture, the pressure being applied in a sufficient amount and for a sufficient time to cause capsules to form.

According to a third embodiment of the invention there is provided a method of making capsules, comprising the steps of: mixing a core material and a shell material in a liquid medium, agitating the mixture until capsules begin to form, applying pressure to the mixture, the pressure being applied in a sufficient amount and for a sufficient time to complete the construction of the pre-formed capsules, and optionally gradually reducing the pressure of the capsules.

According to a fourth embodiment of the invention there is provided a method of making capsules, comprising the steps of providing a quantity of preformed capsules, the pre-formed capsules being present in a liquid medium, A E N~ I I -7 applying pressure to the liquid medium, the pressure being applied in a sufficient amount and for a sufficient time to complete the construction of the pre-formed capsules, and optionally gradually reducing the pressure of the capsules.

According to a fifth embodiment of the invention there is provided apparatus for making capsules, comprising: means for storing a mixture of core and shell materials, a compression chamber, fluidly connected to the storing means, the compression chamber also being connected to means for generating pressure within the chamber.

means for conveying the mixture out of the chamber, and means for gradually reducing the pressure of the capsules, the pressure reducing means being connected to the conveying means.

According to a sixth embodiment of the invention there is provided a S method of making microcapsules, comprising the steps of combining a core material and a shell material, applying a first stroke of pressure to the mixture, for a time sufficient to cause capsules to form, and applying a second stroke of pressure to the mixture to adjust the size of the capsules, wherein the pressure of the second stroke is adjusted upward, if smaller capsules are desired, or downward, if larger capsules are desired.

According to a seventh embodiment of the invention there is provided a S method of making capsules, comprising the steps of: mixing a core material and a shell material, subjecting the mixture to pressure, the pressure being applied in a sufficient amount and for a sufficient time so as to form capsules, and hardening the capsules.

According to an eighth embodiment of the invention there is provided a method of making capsules, comprising the steps of: mixing a first core material and a first shell material, applying pressure to the mixture, the pressure being applied in a sufficient amount, and for a sufficient time, to produce capsules, -6combining the capsules with a mixture of a second core material and a second shell material, and applying pressure to the mixture, the pressure being applied in a sufficient amount, and for a sufficient time, to produce capsules, thereby producing capsules having at least two distinct cores.

According to a ninth embodiment of the invention there is provided a method of making capsules, comprising the steps of: mixing a first core material and a first shell material, agitating the mixture, until capsules begin to form, combining the capsules with a mixture of a second core material and a second shell material, and applying pressure to the mixture, the pressure being applied in an S.amount sufficient, and for a time sufficient, to produce capsules, thereby producing capsules having at least two distinct cores.

0: 15 According to a tenth embodiment of the invention there is provided apparatus for making capsules, comprising: means for storing a mixture of core and shell materials, means for compressing the mixture, the compressing means being S: fluidly connected to the storing means, and means for gradually reducing the pressure of the mixture, the pressure-reducing means being fluidly connected to the compressing means.

According to an eleventh embodiment of the invention there is provided apparatus for making capsules, comprising: means for storing a mixture of core and shell materials, means for compressing the mixture for a period of time sufficient to form capsules, the compressing means being fluidly connected to the storing means, and means for gradually reducing the pressure of the mixture, the pressure-reducing means being fluidly connected to the compressing means, the pressure-reducing means including means for increasing the turbulence of flow of the mixture.

TI'- 7 -7- The core and shell materials are introduced into a chamber, usually in a liquid medium, and the mixture is preferably subjected to high pressure. It is found that the pressure stroke creates microcapsules, almost instantly, in the liquid medium. The microcapsules can be withdrawn from the chamber before thile next batch of core and shell material is introduced. The capsules formed may then be passed through a chamber in which the pressure is gradually reduced. Gradual reduction in pressure tends to prevent the capsules from disintegrating soon after being formed. The chamber can also include means for increasing the turbulence of flow of the capsules; such means may include a plurality of baffles disposed in the chamber. The additional turbulence causes unused shell material to accrete on the capsules already formed, thereby increasing the thickness of the product capsule walls.

The microcapsules can be formed in a continuous, or quasi-continuous i: process. Pressure is applied by the stroke of a pump, and each stroke corresponds, in general, to a new quantity of capsules being formed. The microcapsules can also be produced in a "batch" process, using the same principle.

In a variation of the process described above, pressure is used to complete the encapsulation process begun by a conventional technique.

The core and shell materials are mixed in a liquid medium until capsules begin to form. Then the mixture is subjected to pressure which completes the encapsulation, and which adjusts the size of the capsules and thickens their walls.

Higher pressure produces smaller capsules; lower pressure yields larger capsules.

Pressure can also be used to "repair" the capsules, i.e. to complete the layer of shell material so that the shell has a given minimum thickness.

In another variation of the invention, the capsules are recycled through a pressure chamber at least once, to form additional shell layers around the original Lcapsules, in a minimal amount of time.

In other variations of the invention, the initially-formed capsules are recycled through the pressure chamber one or more times, each time with a different core and/or shell material, and/or a different amount of compression. In this way, it is possible to produce capsules having multiple cores and/or shells, Swith varying sizes.

0.

U- -8- Other advantages of the invention will be apparent to persons skilled in the art, from a reading of the following brief description of the drawings, the detailed description of the invention, and the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a diagram illustrating the process of coacervation, which is one of the methods used, in the prior art, to form microcapsules.

Figure 2 is a graph showing the stages of the coacervation process illustrated, in Figure 1.

Figure 3 is a schematic diagram illustrating the basic concept of the present 1 invention, i.e. the application of pressure to a mixture of core and shell material to form microcapsules.

Figure 4 is a graph showing the time required to form microcapsules, se according to the present invention, as a function of the pressure applied during an interval of about 0.37 seconds.

Figure 5 is a block diagram illustrating the use of the present invention in a continuous process for making microcapsules.

Figure 6 is a block diagram of an alternative process of the present invention, wherein capsules are subjected to repeated applications of pressure, so as to adjust the thickness of the capsule walls.

Figure 7 is a block diagram of an alternative process of the present invention, wherein capsules are recycled through the entire system, to add additional shell layers, or to form capsules with multiple cores.

Figure 8 is a schematic diagram of an apparatus used to practice the method s of the present invention, in a virtually continuous process.

Figure 9 is a schematic diagram showing the baffled chamber which can be used, in the present invention, to reduce gradually the pressure of the newlyformed capsules, in the present invention.

BRIEF DESCRIPTION OF TABLES A TO C Table A is a table showing the size of capsules which can be produced with various methods of the prior art. This table identifies the range of capsule size attainable with each, and indicating the phases of core materials which are feasible.

Coacervation has been described earlier. The other methods listed are described -9in Volume 15 of the Encyclopedia of Chemical Technology (1981), cited above, at pages 472-484.

Table B is a table showing some of the materials which can be encapsulated in microcapsules. This table should not be interpreted as limiting the invention to the encapsulation of these materials only.

Table C is a table showing some of the substances which can be used as shell materials for microcapsules. The substances identified in this table should not be deemed to limit the invention.

O**s 0 *00 0* 0 S ad W *0* 0 @0 0 2I 0 V>

A

WO 89/02814 PCT/US88/03143 DETAILED DESCRIPTION OF THE INVENTION The present invention includes a method for encapsulating liquid, solid, or gaseous compounds within a shell material of a given thickness.

The compound which is encapsulated is known as the "core", The shell material may or may not be permeable to the core material, or to other materials to which the completed capsules may later be added. Capsules provided by the present invention may be capable of slow release of their core materials, or their contents may be released suddenly when the capsules are broken. The capsules can be broken by various external effects, such as change in temperature, change in pH, pressure applied to the capsule, or other stimuli.

Figure 1 shows the process of coacervation, which is a liquid-phase microencapsulation process of the prior art. The details of this method are described in U.S. Patent No.

2,800,457, the disclosure of which is incorporated by reference herein.

In the method shown in Figure 1, an oily substance, which comprises the core of the microcapsule, is dispersed in an aqueous solution of gelable hydrophilic colloid materials, The hydrophilic colloid materials, which become the shell of the capsules, are made to coagulate when the core material 'and the colloid materials are agitated within the aqueous carr.ier.

Eventually, the emulsified droplets of the oily substance, become pw__ -i WO 89/02J14 PCT/US88/03143 11 coated with the colloid material, as the latter forms a solid wall or shell around each droplet, The capsules formed in this manner may be used in the liquid medium, or may be dried to a fine powder form.

Variations in the coacervation process have been developed. For example, polymers have been used as shell materials, and it is possible to adjust the pH of the mixture to crosslink and harden the she'l. However, both the method described above and its variations have disadvantages.

A principal disadvantage of the prior art processes is the amount of time required to form capsules. The time consumed by the coacervation process is illustrated in Figure 2. The figure shows the time required to complete the three major stages in capsule formation. As shown in the figure, it takes about one hour to form "pre-capsules", i.e. newly-formed capsules which have very thin shells, and which need further hardening before they can survive in the outside environment.

Microdispersions are examples of such materials. At this stage, the capsule walls occupy less than 5% of the volume of the capsules.

It may require another two hours or more to reach the second stage, wherein the shell is completely formed. At this point, additional layers of shell material are deposited onto the initial shell. In this second stage, the wall volume may be increased from 5% to above 90% of the total volume of the:.

capsule, depending upon the duration of agitation, the level 12 of turbulence of the agitation, and the concentration of shell material in the mixture.

The third stage of capsule formation, in the coacervation process, may require yet another 1-2 hours. In this stage, the shell is hardened into its final form. The hardening is accomplished by crosslinking the shell material. The crosslinking is often induced chemically, or by adjusting the temperature of the completed capsules.

Thus, as shown in Figure 2, the time required for the entire coacervation process is several hours.

•XI* The present invention, in its most basic form, is illustrated in the schematic diagram of Figure 3. The basic process of the present invention comprises applying a high pressure to a mixture of core and shell materials, for a short time, of the order of one second or less.

too 0 As shown in Figure 3, pressure is applied to a mixture which includes capsular shell material 1 and core material 2, both of which are immersed in a liquid medium 3. The liquid medium is held within container 7. When pressure is applied to the mixture, as indicated schematically by arrows 4, microcapsules are formed in less than about one second.

S The core material 1 may be a liquid droplet, a solid particle, a gas, or a 20Q slurry composed of a solid and liquid mixture. Any of the materials shown in Table B, or any other material which retains its shape and configuration, within the liquid medium, can be used. The core material may be soluble or insoluble within the liquid medium.

The shell material may be any material which can be case into a film within a liquid medium through interaction with solvents. Table C gives examples of such materials. The shell material may be a polymer-based material which dissolves partially into a film, or it may be a gelatinous material which will swell into a manipulatable mass.

The mixture of the shell and core materials is made by providing a microdispersed state through any available means, including tLacch mixers, static mixing devices, motionless mixers, or fluidization equipment.

WO 89/02814 PCT/US88/03143 4-4- The pressure is applied while the shell and core are thus dispersed within the liquid medium or within another solvent.

The liquid medium can be water, or it can be another liquid. The micro-dispersion is, on a macroscopic level, generally homogeneous, though not perfectly so. The shell material, which is illustrated only symbolically in Figure:-, is believed to entrap particles of core material, when the pressure is applied.

If the mixture is made in a solvent, the completed mixture may then be directly subjected to pressure. Alternatively, the solvent-based mix-ture may be added to another liquid which then acts as the liquid medium during the encapsulation process. The liquid medium is also known as the "carrier". The mixture of core and shell materials, before pressure has been applied, is called the "pre-mixture".

The compressive forces indicated by arrows 4, in Figure are generated by compacting the fluid during a short time interval, producing a pressure shock wave 5. This shock wave is believed to cause the partially dissolved shell material to assume a globular shape. While assuming a globular shape, the shell material begins to surround and encapsulate any particle, or gas or liquid droplet, which is present within the liquid medium.

The amount of pressure required, in the present invention, depends on the time interval during which the pressure ",is LA applied. The required pressure varies inversely with tha: time terval. In the preferred embodiment, a high pressure is I 1 l 1 y block optional recycle line S(37), and optional capsule hardening block The invention is especially useful in producing time-release capsules and produces micro-capsules in a small fraction of the time required by prior art methods.

m i In m i i a m ,II I Im WO 89/02814 PCT/US88/03143 114 i applied for a short time period. The advantage of this embodiment is that the capsules are produced more rapidly. But it is also possible to reduce the level of pressure, by lengthening the time interval of i ts application.- Both alternatives yield similar results, and both are within the scope of the present invention.

There are several means of generating the pressure shock wave 5. The preferred device is a simple piston-plunger system which compresses the pre-mixture 6. The motion of the pistonplunger system may be controlled by hydraulic, pneumatic, or electric motors.

The viscosity of the shell material, in a film state in the pre-mixture, determines whether the capsules will form under the influence of pressure. If too much of the shell material has been dissolved in the liquid medium, the film will not respond to the pressure shock wave and cannot be manipulated into a globular shape.

The core material 2 may be either a solid, liquid, gas or slurry.

SIf the core material 2 is a solid, the shell material 1, when in a film state, will generally coat the particle easily, as the pressure shock wave 5 surrounds the particle with loose shell- material. Eventually, under pressure, the shell material forms a complete enclosure of the solid particle, and i,4olidifies, thereby forming an encapsulated solid.

WO 89/028144 PCT/US88/03143 The coating process continues as long as the pressure is maintained on the pre-mixture, but the coating is most effective when the pressure is applied for a very short period of time.

Figure shows -the time required to form capsules, as a function of the pressure applied, for a particular combination of core and shell materials. The time indicated is for initial encapsulation; the capsules thus formed may need some further treatment, as will be discussed below. Note that the times shown are of the order of one second or less.

If the core material is a liquid droplet, the liquid core material must have a viscosity which differs from that of the liquid medium in which it is immersed. If the viscosity of the liquid core is teo close to that of the liquid medium, the shell material, when compressed, tends to displace the liquid droplet and forms globular spheres composed solely of the shell material. The liquid droplet then dissolves and disperses within the liquid medium, and tends not to become encapsulated.

the such take If the core material is soluble within the liquid nedium, application of pressure may cause formation of a capsule in a short period of time as to enable the encapsulation to place before the core disperses or is dissolved.

If the core is a gas bubble within the pre-mixture, then the pressure shock wave will "recognize" the bubble as a solid i form and will enclose the bubble with the shell material, i Sthereby forming a gas-filled'microcapsule. f^ J .U 0hj WO 89/02814 PCT/US88/03143 The core material may be a liquid droplet which is not soluble in the liquid medium. If this is so, the pressure shock wave will tend to form the shell material into an encapsulating coating around the liquid core droplet. The shell material then solidifies and seals the droplet, forming an encapsulated liquid.

As stated above, the amount of pressure applied depends on the interval during which the pressure is maintained. The function of pressure versus time is different for different shell materials in a film-formed state. Colloid materials generally require higher pressure to form complete capsules than do polymeric materials. Through the variation of pressure levels and the regulation of the time of application, many materials may be induced to form capsules, provided that they can first be cast into a film state within the liquid medium.

The process described so far involves the use of pressure alone, to form microcapsules. This process is the essential element of the present invention. However, in some cases, the shell material may not respond as desired to the pressure shock wave, and will not properly encapsulate the core material within the pre-mixture. In such cases, a conventional liquid-phase encapsulation technique is combined with the application of pressure, as described above. In this method, the encapsulation begins with a liquid-phase technique, such as coacervation, except that the liquid-phase process is not carried to ,ompletion. Instead, the pre-formed capsules are subjected to WO 89/02814 PCT/US88/03143 -tpressure treatment to complete the encapsulation, This process is therefore known as a "combination technique".

"Pre-formed" capsules are defined as capsules having a very thin shell, wherein the shell occupies less than about of the total volume of the capsule. Such pre-formed capsules are very malleable. They are unstable, and will fall apart if their shells are not thickened and hardened quickly, The preformed capsules may be made by a process such as coacervation or interfacial polymerization, or by any other methods which permit the formation of a capsule whose shell is neither thick nor hardened.

The combination technique thus includes two steps,, namely a liquid-phase stage, wherein pre-formed capsules are made by a conventional method, and a pressurization stage, which completes the encapsulation process. The core and shell materials need to remain in the liquid medium only until such time as the capsules begin to form. After that, the encapsulation process is completed with pressure. Thus, the time spent in the liquid-phase step is typically one-fourth of the time that would be spent if the encapsulation were done by a purely conventional process.

Any conventional process for making the pre-formed capsules may be used as the first stage of the -combination technique, In the combination technique, the pre-formed capsule made according to the conventional process becomes the new core terial which is encapsulated by application of pressure. Thus, if 0 WO 89/02814 PCT/US88/03143 the pressure shock wave places an 'additional layer of shell material onto the capsule, increasing the thickness of the shell. If the pressure is maintained for a sufficient period of time, and if the mixture is agitated during the pressurization stage, the walls of the pre-capsules can be coated with several layers of shell material, approximating the second stage of a conventional coacervation process, as described above. However the use of pressure to complete the encapsulation reduces the process time dramatically. With pressure, it is possible to complete the process in seconds instead of hours.

The pressure may be applied over a relatively long period of. time, or it can be applied with aquick compressive stroke of a piston acting upon the mixture.

The combination technique described above is especially useful in cases where the core or shell materials do not readily form capsules under pressure. For reasons which are not fully understood, certain core materials tend to disperse when pressure is applied, and do not form neat cores. Other materials cannot be used as shell materials, for similar reasons. In these cases, one can overcome the problem by Smaking pre-formed capsules with a conventional technique, and by completing the capsules with pressure, The conventional liquid-phase technique is thus used as a "starter" in cases where direct application of pressure on the liquid mixture would not work.

K* 'V 7-E N63 i WO 89/02814 PCT/US88/03143 In the combination technique, if the pressure is maintained for a additional period of time which is relatively long, of the order of 3-4 seconds, the shell becomes hardened.

Additional application of pressure oan drive reeid.al solvent out of the shell, further solidifying the material. This part of the process approximates Stage 3 of -the liquid-phase encapsulation processes described above. The capsule is sufficiently hardened to enable it to survive in the outside environment, and to release its contents only in the desired manner. As before, this stage of the process is significantly speedier than conventional processes, since the application of pressure requires only a few additional seconds. Also, heat treatment and/or crosslinking chemicals may be used to produce a hardened shell at this final stage of pressurization.

The level of pressure used in the invention may vary significantly from one formulation to another. The factors determining whether the pressurization stage will be effective are: 1. The viscosity differences between the core materials, the shell materials, and the liquid medium. Distinct differences in viscosity will yield more complete encapsulation due to pressure. If the viscosity levels are too similar, encapsulation may not occur. 2. The time interval during which pressure is applied to i -the system. This time interval determines the features and i size, of the final capsules.

WO89/02814 PCT/US88/03143 3. The level of pressure employed. Low pressure tends to lengthen the time required to complete the shell layering stage.

High pressure tends to decrease the size of the completed capsules. This decrease in size occurs because the pressure wave compresses the pre-capsule into a smaller volume or fractures the pre-capsule into smaller particles. In the latter case, the shell material will coat each smaller component of the original pre-capsule, thereby producing a batch of capsules of lower average size.

4. The pressure responsiveness of the shell and core materials.

Materials which are not easily manipulated under pressure may require longer pre-capsule formation periods and longer pressurization times.

In general, any material which may be cast into a film state within a liquid medium is suitable for use as a capsular shell material in this invention. Such materials include those which are used in conventional liquid-phase encapsulation techniques, Sas well as other, more exotic materials which appear to function only under pressurization processing.

Examples of the latter substances are the synthetic elastomers listed in as well as certain ceramic materials and ethylene vinyl acetate copolymers.

V c ;1 zs^ *0 WO 89/02814 PCT/US88/03143 3-\ The shell material occurs as a film when the material is dissolved within a solvent to the point where a thin, viscous membrane is formed within that solvent. The material is not totally dissolved within the solvent. With colloid materials such as gelatin, the material is "bloomed" to the point where the materials pick up moisture or soak up the solvent and expand into a gelatinous film. In this case, the film may not be a single distinct form but a gelled mass.

In its film state, the shell material is very responsive to the pressure shock wave applied to the liquid mixture. The shock wave tends to force films within the liquid medium into a spherical shape. While assuming a spherical shape, the shell surrounds and seals whatever particle is present within the liquid medium. Normally, the liquid medium which is present during the pressurization step is the same as the solvent in which the shell material is initially partially dissolved to form a film.

Examples of liquids which can be used as the liquid -medium/solvent are water, hexane, toluene, cyclohexane, and alcohols. Water is often used for colloid materials.

Figure is a block diagram illustrating the use of- the present invention in a continuous process for capsule manufacture. In Figure o, core material 12'and shell material 11 are first mixed together, within a liquid medium. As* entioned above, the shell material may be formed into a film i -9 him'-- WO 89/02814 PCT/US88/03143 -9 cfQ, through the use of solvents which are distinct from the liquid medium to be used during pressurization, or the same liquid medium can be used throughout the process.

The core material may be added to the pre-mixture at the time the shell material is made into a film state, or the core material may be present as the shell material is processed into a film, from the start of processing. In most cases, the shell material requires separate preparation. In certain capsules, multiple core materials may be used.

The next stage in the process is represented by block 13, and is known as the pre-mixture processing stage. In this stage, the core and shell materials are mixed further, Any appropriate mixing device may be used, such as batch load stirring devices, motionless mixers, or fluidizing equipment.

The mixture may or may not be heated during this stage, depending upon the materials employed and their chemical properties.

The agitation of the mixture is intended to produce a homogeneous mixture containing discrete particles of core material within a partially dissolved or bloomed shell material, all well-dispersed within the liquid medium. At this stage, the mixture is what has been called the "pre-mixture", and' may be formed in a time as short as a few seconds, or as long as several hours, depending on the materials used. In the preferred' embodiment, one uses a motionless mixer oi static mixer device SJwhich draws the pre-mixture ingredients through a long tube. W2 I O.-i __i WO 89/02814 PCT/US88/03143 Within the tube, a series of inserts iroduces turbulence which helps to mix the ingredients.

The ingredients are drawn through the tube by a pump attached to one end of the tube. This method yields a very complete mixture, and uses less energy and much less time than other methods.

The process stage represented in block.-13 can also be modified by using a partial liquid-phase encapsulation technique (such as coacervation) to produce pre-formed capsules, which may then be perfected through the later stages of the invention.

The next stage in the process is shown in block 17. Block 17 represents a compression chamber, in which the mixture is subjected to pressure by the action of a piston or equivalent device. Quantities of the pre-mixture are drawn periodically into the chamber. The mixture is compressed, and the resulting capsules ejected. The next batch of pre-mixture is then drawn Sinto the chamber. In the preferred embodiment, the pressurizing means is a hydraulic pump having a plunger attached to the piston assembly.

In some cases, the burst of pressure from the piston is all ,I that is required to form usable microcapsules. But, in other cases, the capsules which emerge from block 17 are unstable, and

.J

1 rsemble the pre-formed capsules which result after the initial a t=UU= carr =uer Eventually, the emulsified droplets of the oily substance, become 1 I; WO 89/02814 PCT/US38/03143 etage of coacervation. In these cases, additional processing is needed to thicken and harden the capsular wall to form a complete capsule.

The pump and piston used to pressurize the mixture is also used to move the mixture through the system. The pump draws the pre-mixture continuously through the system, applies the pressure shock wave, and then pushes the pressure-treated mixture (called the "post-mixture") through the remainder of the system.

If the pressure of the compressive stroke of the piston/plunger assembly is increased, the system tends to form smaller capsules. If the pressure is decreased, the system tends to produce larger capsules.

The next stage, in the process of Figure 4, provides gradual reduction in the pressure. Capsules formed rapidly under high pressure may dissolve quickly if they are exposed to atmospheric pressure soon after formation. The internal pressure within the capsules may be sufficient to expand and unravel the thin shell layer, causing the capsule to return to its original mixture state. To avoid this problem, the pressure is maintained, within the system, for a longer period of time.

Capsules which are made within the compression chamber 17 are delivered to a pressure reducing area, symbolized by block 19.

Block 19 includes a set of channels or tubes, or a single ube, for reducing the pressure on the capsules gradually. The WO 89/02814 PCT/US88/03143 gradual reduction of pressure enables the shell material to harden fully before the capsule is returned to atmospheric pressure.

The preferred means of reducing the pressure is a Bernoulli tube, connected to the exit port of compression chamber 17. The diameter of the Bernoulli tube decreases immediately following the point at which the tube is connected to the exit port, so that the mixture leaving the compression chamber immediately encounters a channel of reduced diameter.

This smaller diameter creates a back pressure on the highvelocity mixture, and thus prevents the mixture from rushing too quickly through the channel.

After initially encountering the tube of reduced diameter, the mixture is preferably conveyed through a tube of either a constant diameter, or a tube having a gradually increasing diameter, depending on *the time interval during which it is desired to reduce the pressure, If the tube increases in diameter, the pressure of the mixture will decrease more

A

rapidly than if the tube has a constant diameter. A gradual reduction of pressure enables the shells of the capsules to harden slowly.

In the preferred embodiment, the tube is constructed so that the pressure is reduced to atmospheric pressure in about 3 LL s ,seconds. However, the optimum period of time over which the ressure should be reduced varies with the formulation used.

WO 89/02814 PCT/US88/03143 For some formulations, the time period might be 5-6 seconds, or, if a longer tube is used, as much as 20 seconds. In most cases, the time period will be in the range of about 1-10 seconds.

In the preferred embodiment, the tube also includes means for providing turbulent flow, so that loose shell material within the mixture will agglomerate onto the capsules and thicken the capsule wall. Latent pressure within the tube causes this additional shell material to become attached to the capsules and to harden as a new shell layer. The turbulence can be induced by baffles, or equivalent structures, inserted in the tube, in the path of the flow of the fluid.

The mixture which exits from block 19 is known as the stabilized capsule slurry.

The capsules exiting the tube in block 19 are allowed to harden into a final fornm, in block 20. The hardening may be effected by allowing the mixture to rest for a time, or by subjecting the capsules to additional chemical treatments, depending upon the nature of the materials used. Such treatments include temperature hardening, crosslink hardening through pH adjustments, or the use of chemical stabilizers.

The completed capsules leave the hardening treatment area in the form of a slurry containing the liquid medium and the apsules This slurry is known as the final post-mixture.

c WO89/02814 PCT/US88/03143 Depending upon the application of the capsules, it may be desirable to provide the final product as a dry powder. In the latter case, dry powder separation and drying techniques are required.

It should be observed from the above description that the process of the present invention uses pressure in the following ways: I. Pressure is used to create a shock wave, which initially forms the capsules.

2. Pressure is used to draw the pre-mixture and to move the slurry containing the initially-formed capsules through the later stages of the system.

3. Pressure is used to stabilize the capsules by channeling the latent pressure in the system so as to harden and thicken the capsular walls.

An extended hardening stage, not shown in Figure may be used to solidify the wall material into a final capsule. This stage would follow the hardening stage of block The system shown in Figure -6 thus allows virtually continuous manufacture of capsules, at a very high speed.

As stated above, high pressure tends to form smaller capsules and low pressure tends to form larger capsules.

Capsules having a diameter less than one micron may be produced by adjusting the pressure level at the co=pression stage (block 4 WO 89/02814 PCT/US88/03143 17 in Figure More specifically, when capsules are formed in the initial compression step, their size is determined by the following factors: 1. The initial size of the pre-formed capsules made in the mixing step or by a conventional liquid-phase encapsulation technique.

2. The initial size of the core material.

3. The amount of pressure applied in the compression chamber.

4. The duration of the application of pressure.

4

A

4 Figure shows an alternative version of the process of Figure wherein capsules are passed through the system more than once. The method of Figure-4-is used where the initial compression stroke produces capsules having undue variation in the size of the capsules, or where the capsules cannot be sufficiently stabilized by the methods described above.

In the so-called recycling method of Figure 9, shell material 31 and core material 32 are mixed as before, and premixed in block 33. The capsules are initially formed by passing the mixture through compression chamber 34. The mixture is then stabilized, as before, in block 36. If the capsules, at this stage, are found to be too large, or if their shells are imperfect, the mixture is conveyed back to block 33, as I. 41 14 14 -r -s r- i__ T~is ~1 a- l :I i i: I: WO089/02814 PCT/US88/03143 indi-cated by arrow 37, and the process is repeated. After leaving block 36 the second time, the capsules are conveyed to block 38, where they are hardened as before. The pressure treatment on the second pass through block 34 will generally reduce the size of the capsules, as the initially-formed capsules are not yet hardened and are still malleable.

There are several physical mechanisms for reducing the size of the capsules. First, the compression of the nearly completed capsule will drive out moisture present within the shell of the capsule, compacting the shell into a smaller thickness around the core, and reducing the total volume of the capsule. Secondly, if the core is a solid, the pressure can fragment the material into small pieces. The residual shell material, though also broken during the fragmentation, may be still malleable enough to form another layer around the smaller particles. Thirdly, if the core material is a liquid, the combined effect of the pressure and the turbulence in the tube, described above, produces smaller disperse:d droplets from the j original capsule core. The shell material will tend to form a layer around the new droplets.

By repeatedly passing the capsules through the system, the capsules can be reduced to any desired size. Application of pressure during the second and subsequent passes can significantly reduce the size of capsules made during the first pass. The pressure level of subsequent passes may be increased, decreased, or maintained constant, depending upon the amount of size reduction desired. W'en the capsules have reached the r .i WO 89/02814 PCT/US88/03143 desired size, they are passed through the hardening stage, as described above.

Another use of a recycling process enables one to correct problems with the capsular wall material. Weak spots in the shell may undesirably reduce the strength of the capsule. The recycling process illustrated in Figure 49 solves this problem also, because repeated applications of pressure place additional layers of shell material onto the capsule, Additional material for these layers is derived from the shell material contained in the pre-mixture in block 33. The various layers bind together due to the effects of surface tension or adhesion. The finished, multi-walled capsule is then hardened as before.

Different shell materials can be used for each layer in the multi-wall construction, or the same material may be used more than once. The use of differing materials may alter the release rates of time-release capsules, and may also increase the overall strength of the capsule.

In short, the recycling procedure provides at 'least three major benefits. First, it corrects defects in the walls of the initially formed capsules. Secondly, it increases the shell thickness by providing multiple wall layers. Thirdly, it adjusts the time-release characteristics of the capsules, by adjusting i the overall permeability of the shell, The recycling technique, described above, can also be used to produce capsules within capsules. Small capsules are made -tO 8 4 PCT/US88/03143 Li in a first pass through the system. On the second pass, lower pressure is used, together with the same or a different core material. In this manner, the smaller capsules can become encapsulated within another core material, and within another, final shell material. This technique is especially useful in producing time-release capsules, and also in providing unique microencapsulated products.

Figure 40\ shows another variation of a recycling technique. Core material 40 and shell material 41 are mixed in block 42. The pre-mixture is compressed in block 43, and the pressure is reduced in block 44. The capsules are hardened in block 45. The capsules are then returned to block 42, as shown by arrow 46. Unlike the recycling process of Figure /J9, -7 Figure 4-Q repeats essentially all of the process steps. This variation is useful in making capsules within capsules, and in adding additional layers of shells. It can also be used to "tag" already-hardened shells with additional compounds.

Figure -4*+is a schematic diagram of an apparatus which can be used to produce capsules according to the present invention, R in a continuous process. Pre-mixture 50 is stored in reservoir 51. The contents of the reservoir are conveyed into compression chamber 52, through check valve 53. Check valve 54 seals the compression chamber during the compression stroke.

The pressure is applied by piston and plunger assembly 55, which is mounted within housing 56. After the pressure has been applied, check valve 54 opens, and the mixture containing the i microcapsules leaves the compression chamber and enters output S WO 89/02814 PCT/US88/03143 1 _4 chamber 57. Figure -4also illustrates pre-formed capsules and more completely formed capsules 66. It is understood that the representation of capsules is symbolic only; in practice, as explained above, it is usually necessary to pass the preformed capsules through a longer channel before the capsules can be considered complete.

q Figure -a4 is a schematic diagram of a pressure reduction apparatus, such as is represented in block 19 of Figure Figure -a~shows output chamber 57, which is the same as shown in Figure The output chamber includes a section 58 of gradually decreasing diameter. There follows a chamber 59 having baffles 60 which interrupt and delay the flow of the mixture as it is pumped through the tube, and increase the turbulence of the flow, Exhaust area 62 is connected to chamber 59 by a section 61 of gradually increasing diameter. As explained above, the turbulence created by the baffles tends to cause additional shell material, present in the mixture, to form around the capsules, thereby increasing the total thickness of the capsule walls.

9 The tube shown in Figure -b is sometimes called the !I "stabilization tube", because it is there that the capsules are Sstabilized. Pressure from the pump is maintained in the I' stabilization tube, due to its reduced diameter, relative to 'i the diameter of the pressure chamber, as can be calculated from the Bernoulli equations of mass fluid flow dynamics. As the pump forces the capsule mixture through the stabilization tube,

H,

WO 89/02814 PCT/US88/03143 t the fluid encounters a reduced, diameter channel which increases the velocity of the fluid. As described above, the baffles in the tube cause turbulence which helps to cause unused shell material, which is floating freely within the mixture, after the pressure treatment, to agglomerate around the pre-capsules formed within the compression chamber. This has the effect of thickening the shell layer of the capsules by placing a second layer onto the initial shell layer.

The advantage of this two-layer construction is evident when the capsules were subjected to industrial stress, such as the pressure experienced in high-shear or high-speed pumps. The second shell layer tends to cover and correct the imperfections of the first shell layer. This layered shell structure has significant advantages over capsules made under prior art coacervation techniques, which produce only one shell layer.

Single-layered capsules tend to have lesions, crevasses, and holes in the shell, and may be too weak to withstand the stress or shear experienced in many industrial processes, The baffled tube also allows for the slow release of pressure, which is generated within the compression chamber of the pump. This slow release of pressure across the length of the baffled tube provides additional time for the wall layers to become hardened. By the time the capsules exit the baffled tube, the shell raterial has hardened sufficiently to enable the capsules to retain their shape and size.

7

A

814 PCT/US88/03143 34- Regardless of which variation of the present invention is used, the results are obtained much more rapidly than with any of the methods of the prior art. The speed of the process of the present invention makes it possible to encapsulate many compounds which cannot be encapsulated by regular liquid-phase methods. In conventional liquid-phase techniques, core materials which are soluble in the liquid medium often dissolve long before encapsulation can occur. But with the -method of the present invention, many such soluble core materials can be encapsulated, because the encapsulation takes place before the materials have an opportunity to dissolve.

Example 1 Combination of Partial Coacervation and Pressurization Processing This example shows the encapsulation of a flame retardant.

The materials used in this experiment were: a) 40 grams of Type 300 Bloom gelatin supplied by Kind and Knox Corp.

b) 40 grams of gum Arabic supplied by Tic Gums c) 20 grams of Ethylcellulose supplied by Berol Industries d) 3.7 liters of tap water e) 360 grams of a bromochlorinated parrafin known as DD- 8307, supplied by Dover Chemical WO 89/02814 PCT/US88/03143 In this example, the pressure applicator v.'as an air-powered hydraulic pump supplied by SC Hydraulic Engineering Corp., Los Angeles, California, the pump being designated as Model No. SC- 10-600-8. The latter pump, with its associated check valves, essentially corresponds to the apparatus illustrated schematically in Figure i-.

The above-described pump is sold with inlet and outlet check valves, corresponding to check valves 53 and 54, respectively, in Figure These valves are also sold separately by the same company, under Model Nos. 10-450-24-SS and 10-450-23-SS, the latter valve having somewhat lesser stiffness it opens at a somewhat lower pressure) than the former. The pump has a rating of from 1,100 to 15,750 psi 7,584.50 to 108,596.25 KPa The compressive pressure resulting from an inlet air pressure of 60 psi 413.70 KPa is rated, by the manufacturer, to be 8,500 psi 58,607.50 KPa on the assumption that the medium being compressed has a viscosity equivalent to that of water. Thus, the pressure is multiplied by the pump by, a factor of 141.67. The ratio of the maximum pressure in the chamber to the inlet pressure is called the pressure amplification factor. If the viscosity of the mixture being compressed is greater than that of water, the pressure amplification factor will be lower.

It was found that, in order to confine the mixture within j the pressure chamber for a sufficient time to produce capsules by pressure, it was necessary to increase the spring tension -I ::i.iu r~n-*ll WO 89/02814 PCT/US88/03143 in the output check valve.

The necessary increase in spring tension was achieved by replacing the check valve, which was originally sold with the hydraulic pump, with a check valve designed to open at a greater pressure level. The replacement check valve was also obtained from SC Hydraulic Engineering, and was sold under Model No. 10-450-30-SS. The latter valve is one which is normally sold with another pump model, namely SC10-600-15, which is a similar pump having a higher pressure rating, namely from 1,900 to 26,000 psi 13,100.50 to 179,270 KPa and having a nominal multiplier of over 233. Thus, outlet check valve 54 of Figure was taken from a higher-pressure pump, and installed on the cutlet end of the lower-pressure pump which was actually being used to produce capsules.

Because the replacement check valve was designed to withstand more pressure, before opening, than the valve which was originally supplied with the pump, the replacement valve tended to remain closed longer than the original valve. The delay in opening of the outlet valve thus caused the pre-capsule material to be confined somewhat longer within the compression chamber. Eventually, the pressure in the chamber becomes sufficiently great to force the valve open, allowing the fluid to leave the chamber. Thus, it is believed that this j modification of the pump insures that the pressure developed by the pump will actually form capsules, and will not simply propel the fluids from the chamber. i W 14 PCT/US88/03143 It is also believed that the same results can be obtained by simply increasing the tension on the spring of the original check valve, without replacing the entire valve. A stiffer spring was found to approximate the action of the higher-pressure valve.

The speed of the stroke of the modified hydraulic pump is important in controlling the pressure in the chamber. To control the speed of the pump, a quarter-turn air valve was inserted in the air-flow line leading from the air inlet source to the pump.

The air valve controls the speed of each stroke of the pump by "borrowing" part of the air flow from the line, and venting this air to the outside. However, this air valve is not believed to affect the pressure of the air which enters the pump.

A dial was placed adjacent the quarter-turn valve, and the di@ was marked with nine gradations representing increments of accounting for a total arc of 90*, The gradations were numbered from 1 to 9, and these settings are designated herein as "Level "Level etc. Level 9 corresponds to the point at which the quarter-turn valve is fully opened, and thus represents the maximum pump speed. The "level zero" position is the position for which the valve is fully closed.

The speed of the pump, for each setting of the dial, was ii measured by direct observation, i.e. by cointing the strokes of the pump for a measured period of time. The relationship between th f dial settings and the number of strokes per minute was found to be as follows: W O89/02814 PCT/US88/03143 Dial Setting 3 4 6 7 8 Number of Strokes Per Minute 162 168 252 264 324 342 348 For all of the above settings, the inlet pressure was psig, 586.075 KPa and, after taking into account the pressure drop in the valve, the line pressure was reduced to about 75 psig 517.125 KPa No entries are shown for Levels 1 and 2 because the pump does not work satisfactorily at these levels.

Thus, in the following description, a speed setting of "Level 3" means that the pump was set to operate at 162 strokes per minute.

In performing the procedure, the shell material was first treated to allow it to be used to form the capsular shell. The first four of the above-listed ingredients were mixed at room WO 89/02814 PCT/US88/03143 temperature under mild agitation, with a mixer operating at 100 R.P.M for 60 minutes. The result was a pre-condensate cblloid wall material which is partially dissolved. A flame retardant known as DD-8307, which is a bromochlorinated paraffin in liquid form, in the amount of 360 grams, was added to the vessel containing the shell material pre-condensate under vigorous agitation. The mixture was heated to a temperature of 55* C and then held at that temperature for 60 minutes. The mixture was then allowed to cool to 28* C while agitation was continued, for about 10 minutes. Observation at this point revealed the presence of pre-capsules with an average particle size of 30-75 microns and containing a 5% shell material volume in relation to the fill material volume.

Then the mixture was introduced into the apparatus of Figure The apparatus was set for an inlet pressure of 80 psi. 606.76 KPa Unless otherwise noted, all pressure readings mentioned herein are gauge pressure (psig). Because the viscosity of the mixture being compressed was greater than that of water, it was estimated that the pressure amplification factor was reduced to about 100, That is, the pressure in the compression chamber was estimated to be about 100 times the inlet pressure. Thus, it is bel'ieved that the pressure applied to the mixture containing the pre-capsules was about 8,800 psi. 60.676 KPa). Since the pump speed was set at Level 3 (162 strokes per minute), the pressure, of each

-I^

WO 8 34 PCT/US88/03143 stroke, was applied for an estimated period of 0.37 seconds.

Examination of the capsules at this point, immediately after application of the pressure, revealed capsules similar to those which would have been produced by ordinary coacervation techniques. The capsules ranged in size from 5-15 microns, and now had an average shell volume of 12%. The capsules formed were observed to be spherical and complete, but the capsule shells were still malleable. Moreover, some loose shell material was observed within the mixture.

To help harden and solidify the walls of the capsules, the mixture containing the pre-capsules was directed, from the outlet of the apparatus of Figure/@-, into the structure shown in 9 Figure and described above. The capsules were observed to have a two-layer shell construction, when they exited the tube. The tube shown in Figure i was, in this example, about six inches 15 cm long. The length wis found not to be critical, for the materials used in this experiment.

In this example, the capsules were hardened chemically after leaving the machine, by using formaldehyde to help cross-link the gelatin into a solidified form. Five grams of formaldehyde was used to accomplish this additional hardening.

The capsules finally exiting the apparatus were found to have a size range of 5-15 microns, with a wall material total s NW89/02814 PCT/US88/03,43- 1k4 volume of 25%. The efficiency of encapsulation, as measured by the percentage of fill material which was encapsulated at the conclusion of the process, was 98%.

The time required to obtain the completed capsules, using the starting materials listed above, was 2 hours and 10 minutes, to form the pre-capsules under the partial coacervation stage, with just 4 seconds of pressurization processing, excluding the extra hardening step. However, when the experiment was repeated using coacervation alone, the time required to produce capsules of similar wall thickness was 7 hours and 35 minutes.

The following table compares the conventional coacervation process with the combination technique used in Example 1: Partial Coacervation With Pressure Coacervation d Capsule Size: Process Time: Wall Thickness: Melt Temperature: Efficiency Permeability in water (in 5 days) 10 60 u 7 hours, 35 min.

27% 265* C 85% 100% 5 15 u 2 hours, 10 min.

275* C 98% 12% The above table shows that the present invention vastly increased the speed of encapsulation, and produced capsules

I

(block j c~ siz r- ri; I 1:: WO 89 fS88/0t143 W4) 89/02814 7' E tA PCT/US88/03143 /2

IC.

aasured by i at the s, using minutes, .on stage, .uding the ient was 1o produce linutes, cervation having a marked decrease in permeability. The walls of the capsule. produced according to the present invention were more dense, which partly explains why the capsules have a higher melting temperature. Also, the encapsulation efficiency was greatly increased.

In the following example, Example 1 was repeated, with the goal of reducing the capsule size even further. The procedure of Example 2 could therefore be used where the completed capsules are too large for the desired industrial application, and where it is necessary to reduce their size.

exce 3-10 into mate Example 2 agai to stil beli the whic occu size re ma cervation re Size Reduction Through Recycling min.

The procedure of Example 1 was repeated, producing capsules which were of the order of 5-15 microns in diameter, on the first pass through the system. But instead of the extra hardening stage involving additional pressure or chemical treatments, the capsules were returned to the original compression chamber. On this second pass through the compression chamber, the inlet pres. as increased to 100 psi 689.50 K~a corresponding to 10,000 psi 68,950 KPa in the compression chamber, using the same speed setting of the pump. As explained in Example 1, it is believed that the time of confinement of the capsule material, in the compression chamber, was about 0.37 seconds.

Firs Seco Thir vastly capsules t I -56facture has process, in TABLE C i i WO 89/02814 PCT/US88/03143 4a -6- The results were the same as those obtained in Example 1, except that the size of the microcapsules was reduced to about 3-10 microns. The higher pressure had compacted the capsules into a small volume by compressing the void between the core material and the shell.

The capsules were then returned to the compression chamber again. On this pass, the capsules were further reduced in size to about 1-5 microns. The pressure on the latter pass was still 10,000 psi 68,950 KPa and the confinement time was believed to be the same. Although the pressure was unchanged, the capsules were nevertheless fractured into smaller particles, which were then re-coated by the wall material. The volume occupied by the capsule wall remained nearly unchanged for each size reduction, and the permeability of the capsule wall also remained constant.

The following table summarizes the results of Example 2: First Pass: Second Pass: 8,800 psi 60,676 KPa 5 15 Microns 10,000 psi 68,950 KPa 3 10 Microns Third Pass: 10,000 psi 68,950 KPa 1 5 Microns r I i~r~ii .1 WO 89/02814 PCT/US88/03143 LfL Example 3 Size Reduction by Recycling, with Constant Pressure The goal of this experiment was to observe the effects of a static pressure, i.e. pressure which is unchanged from pass to pass, on the capsule, after each cycle.

Example 2 was repeated, using 3 passes through the compression chamber. However, the pressure, on each pass, was maintained at the original level of 8800 psi 60,676 KPa applied for an estimated time of 0.37 seconds, using the same speed setting for the hydraulic pump. The same chemical formulation was used.

The results of the experiment are indicated in the table below. In each re-cycle pass, capsules were reduced in size, even at a constant pressure setting.

First Pass: (8,800 psi) (60,676 KPa) 5 15 microns Second Pass: (8,800 psi) (60,676 KPa) 5 12 microns Third Pass: (8,800 psi' (60,676 KPa) 3 -8 microns WO 89/02814 PCT/US88/03143 Example 4 Size Reduction Caused by High Initial Pressure In this Example, Example 1 was repeated, except that the initial compaction pressure was increased to 15,000 psi (103,425 KPa), applied for an estimated period of 0.37 seconds, using the same speed setting (Level 3) on the modified hydraulic pump system. The properties of the capsules were un-changed, except .for their size and permeability. The process initially produced capsules having a diameter of about 1 5 microns, with a permeability of only 8% in water, during 5 days of exposure.

Thus, where the pressure was higher than in Example 1, and applied over the same period of time, the result was a smaller I capsule having a shell which was more dense.

A Small capsules tend to release their contents more rapidly than large capsules, due to their higher permeability.

But, in this Example, the permeability of the small capsules was reduced by making their shells more dense. Thus, the present invention enables one to produce small capsules which release their contents more slowly.

c WQ.89/02814 PCT/US88/9314

J

-44 -Iti6 Example Production of Capsules Without a Liquid-Phase Process In this Example, Example 1, was repeated, except that the initial partial coacervation stage was omitted. The mixture was not agitated or heated. Instead, a motionless mixer was used to form microdispersions of the shell material, and this material was then mixed with the core material in another motionless mixer. A motionless mixer, also known as a static mixer, is characterized by a long tube with a helical element within.

A fluid containing a mixture of chemical compounds is inserted in one end of the tube and pumped through. Interaction of the fluid with the helical elements causes the mixing or dispersion, as the mixture flows through the length of the tube.

IL

In this Example, 40 grams of gelatin were combined with grams of gum arabic, 20 grams of ethylcellulose, and 2.0 liters of tap water, in a mixing tank with mild agitation. The contents of the tank were then drawn, by an impeller pump, through a 2-foot long motionless mixer supplied by Koch Inc., while heat was applied to the mixing tube to raise its 1

I

WO PCT/US88/03143 A -7 temperature to 100* C. This procedure yields a microemulsification of the shell material which is heated. The shell material emulsion was then added to 1.7 liters of tap water containing 360 grams of pre-dispersed DD-8307, which is an oily core material in liquid form. The combined mixture was ,then drawn through a second motionless mixer tube, of the same dimensions, at room temperature, The mixture exiting the second motionless mixer contained pre-capsules suitable for injection into the initial compressive chamber of the hydraulic pump apparatus. The same compression apparatus used in Example 1 was used here. Pressure was applied at 8,800 psi (60,676 KPa), using the same pump speed, producing microcapsules of identical physical parameters as were observed in Example 1, with the exceptior,, of the process time. The process time was reduced from 2 hours and 10 minutes to only 3 minutes and 17 seconds.

In Example 5, a microemulsion was produced with a simple mixing device, and coacervation was not used. The microemulsion stage required most of the process time of 3 minutes and 17 seconds. The actual formation of the capsules occurred during the pressurization step, which required less than one second.

The following table shows the effects of pressure on capsule production, as a function of time within the compression chamber: PCT/US88/03143, WQ 89/02814 Inlet Calculated Speed Pressure Pressure in Setting Setting Compression Level on psi psi Device (KPa) (KPa) 88 (606.76) 8,800 (60,676) 3 150 (1034.25) 15,000 (103,425) 3 Calculated Capsule Time of size Pressure (microns) Treatment (sec) 0.37 0.37 0.23 0.23 5-15 1-15 3-10 0.5-3 88 (606.76) 8,800 (60,676) 150 (1034.25) 15,000 (103,425) 6 The calculated times of pressure treatment simply by dividing 60 seconds by the number of minute. These figures are only estimates; measurements of pressure or time inside the chamber are derived strokes per no direct were made.

The capsule size shown in the table is the initial capsule size after one pass through the compression chamber. The core material was DD-8307 bromochlorinated paraffin liquid, and the shell material was gelatin, gum arabic, and ethylcellulose. The table shows that when the pressure is applied for a shorter time interval, the capsules are generally smaller. Also, the table confirms that when the initial pressure is increased, the W 14 PCT/US88/03143 resulting capsules are also smaller. It has also been found that similar size reductions occur for both liquid and solid core materials.

Example 6 Adding Further Layers of Shell Material to an Existing Capsule This Example demonstrates a process for making capsules wherein there are competing considerations in the choice of the shell material. Suppose, for example, that a fungicide is to be encapsulated, but is found to have a short shelf life, due to the low resistance to permeability of a gelatin-based shell material. A polymeric shell is useful in achieving the desired shelf life, but the polymer has the disadvantage that it repels the bacteria which digest the capsule and cause the release of its contents. The solution is to use a multi-walled capsule. In this case, the first wall is made of the polymeric material, and the second wall is made of gelatin which attracts the bacteria.

The multi-walled capsule was made in two stages. The first stage was the preparation of small capsules. A precondensate of urea-formaldehyde resin was first formed using 'I 120 grams of urea mixed with 325 grams of 37% aqueous S! formaldehyde containing 15% methyl alcohol at room temperature.

.4 ~1~

I.

0o 8S PCT/US88/03143 _5-3- Triethanolamine was added, one drop at a time, to adjust the pH to 8. The mixture was then heated to 70* C, while keeping the pH below 8.5. After 1 hour of agitation, 600 ml of distilled water was added to the mixture, at room temperature. Then, 130.5 grams of the precondensate was further diluted with 200 ml of distilled water, producing a final polymeric solution to be used as the shell material.

Next, 10 grams of the above-described urea-formaldehyde shell solution was mixed with 40 grams of N-96 fungicide supplied by Diamond Shamrock Inc., in 400 ml of water, for minutes, at a temperature of 25* C, under rapid agitation.

Pre-capsules produced in this stage, which is generally referred to as an interfacial polymerization process, were between 10 and 30 microns in diameter. The emulsion was then delivered to the pressure chamber, and 8,250 psi (56,883.75 KPa) of pressure was applied to the emulsion for an estimated time of 0.37 seconds, in one pass, using the Level 3 speed setting on the pump. The pressurization produced capsules having a size between 8 and 20 microns, with an initial wall volume of The second stage was the application of the second capsular wall. A mixture containing 40 grams of Type A, 300 Bloom gelatin was combined with 40 grams of gum arabic, and 20 grams of ethylcellulose, in 3.7 liters of tap water, and mixed at room temperature under mild 'Agitation, for 60 minutes, to form a "bloomed" wall material solution. The capsules manufactured in the first stage were immersed i' this new wall solution, under WO 89/02814 ;i 1 11 i PC/US88/03143 51 -5-2mild agitation, for 60 minutes while heat was applied at 65* C.

The new mixture containing the capsules made in the first stage was then subjected to pressure again. The pressure on the second pass was 6000 psi (41,370 KPa), applied for an estimated 0.37 seconds, at a pump speed of Level 3. The second application of pressure caused a second shell to form around the first wall of the capsules, thereby creating capsules with two distinct wall layers.

The results of the two stages of this Example are summarized in the following tables: Stage 1 (Partial Interfacial Processing) Pre-capsule size 10 30 microns Pressure applied to pre-mix 8,250 psi (56,883.75 KPa) Speed Setting on Device Level 3 Calculated Time of compression 0.37 seconds -r' Wvo PCI/US88/03143 Shell Material, wall layer #1 Volume of Wall in relation to total volume of capsule by weight for wall layer #1 Size of capsules after first pass Urea-Formaldehyde 8 20 microns Stage 2 Shell material mixture Gelatin Gum Arabic Ethylcellulose 6,000 psi (41,370 KPa) Pressure applied in second pass Speed Setting on Device Level 3 Calculated Time of Compression Size of final capsules Total volume of wall in relation to capsule overall volume by weight 0.37 seconds 6 20 microns 18% Volume of second wall layer 8%

M

1K WO 89/02814 P.CT/US88/03143 The above table demonstrates that a second wall was formed around the initial polymeric shell, forming a capsule of two distinct wall layers.

Example 7 Formation of Capsules Within Capsules This and for producing capsules slowly.

Example shows a process for forming small capsules, encapsulating those capsules into larger capsules, what is known as a "multi-fill capsule". Such are unusually strong, and release their contents very The Example was performed in three stages. The first stage was the production of small capsules. Example 6 was repeated through its first stage, except that the pressure was raised from 8,250 psi (56,883.75 KPa) to 10,000 (68,950 KPa), applied for an estimated time of 0.37 seconds, using the pump speed setting of Level 3. The application of pressure produced capsules having a size in the range of 5-12 microns, instead of the 10-30 microns of the first stage of Example 6.

WO 89 2fh PCT/US88/03143 The second stage was the preparation of the mixture for the new capsules. Stage 2 of Example 6 was rrpeated as described, except that a new core material was added to the shell mixture.

This material was 400 grams of mineral oil, The new mixture now contained 100 grams of shell material and 400 grams of the new core material. The materials were immersed in 4 liters of tap water and stirred under mild agitation for 60 minutes.

Heat was applied for the duration of the agitation, to a temperature of 65* C. This stage formed a second pre-mixture.

In the third stage, the capsules produced in the first stage were added to the second pre-mixture and stirred for minutes under mild agitation with no further heat. Next, the new mixture was added to the pressurization device which was set for 6,000 psi (41,370 KPa), at a speed setting of Level 3, thereby applying pressure for an estimated period of 0.37 seconds.

The resulting capsules were found to have several of the original small capsules encased within one large enclosure, The mineral oil was found between the inner shell layer, which was composed of urea-formaldehyde, and the outer shell layer, which was composed of gelatin, gum arabic and ethylcellulose mixture.

The fungicide core material resided at the core center of the* inner capsules. The size of the final multi-fill capsules ranged from 8 to 50 microns.

A ^^v 1 I m Y -I In the above examples, a continuous method of capsule manufacture has been described. The invention may also be practiced with a batch process, in which one large quantity of a pre-mixture is subjected to pressure.

The process of the present invention applies not only to small capsules, i.e.

microcapsules, but also to large capsules, known as macrocapsules.

TABLE A MICROENCAPSULATION: PROCESS LIMITS 0 12i** *000**

S

25 L so PROCESS CORE MATERIAL SIZE (liM) COACERVATION SOLID/LIQUID 10-500 INTERFACIAL ADDITION AND CONDENSATION SOLID/LIQUID 5-2000 AIR SUSPENSION SOLID 50-5000 CENTRIFUGAL EXTRUSION SOLID/LIQUID 250-3000 SPRAY DRYING SOLID/LIQUID 5-500 PAN COATING SOLID 500-5000 TABLE B MATERIALS ENCAPSULATED

A

.1 Activated carbons Adhesives Aminos Amino acids Animal feed ingredients Antibiotics Antiseptics Aqueous solutions Catalysts Chemoluminescents Chlorinated hydrocarbons Corrosion Inhibitors ,-T-D.eodorants Enzymes Flame retardants Flavors Food ingredients Fumigants Inorganic salts Ion-exchange resins Liquid hydrocarbons Oils (vegetable) Organometallic compounds Oxidizers Perfumes Peroxides Pesticides Pharmaceuticals Pigments Reflective Products Resins Resin-curing agents Retinoids Sealants Sterilants Steroids Vitamins Water

SI

56 TABLE C SOME MICROENCAPSULATION MATRIX AND WALL CHEMICALS Natural Polymers Carboxymethylcellulose Cellulose acetate phthalate Ethylcellulose Gelatin Gum arabic Starch Bark Methylcellulose Arabinogalactan Zein Nitrocellulose Propylhydroxycellulose Shellac Succinylaied gelatin Waxes, paraffin Proteins Kraft lignin Natural rubber 0 .00.

0S000S set 0 O. o 00 SO S 00 S 350 5*50 Synthetic Polymers Polyvinyl alcohol Polyethylene Polypropylene Polystyrene Polyacrylamide Polyether Polyester Polyamide Polyurea Epoxy Ethylene-vinyl acetate copolymer Polyvinyl acetate Polyvinylidene chloride Polyvinyl chloride Polyacrylate Polyacrylonitrile Chlorinated polyethylene Acetal copolymer Polyurethane Polyvinylpyrrolidone Poly(p-xylylene) Polymethyl methacrylate Polyhydroxyethyl methacrylate Synthetic Elastomers Polybutadiene Polyisoprene Neoprene Chloroprene Styrene-butadiene rubber Silicone rubber Acrylonitrile Nitrile Butyl rubber Polysiloxane Hydrin rubber Ethylene-propylene-diene terpolymer While the invention has been described with respect to specific embodiments, it is understood that many variations are possible. The examples given are intended to be illustrative, and not limiting. For example, is it possible to use a gas, instead of a liquid, as the carrier for the mixture of core and shell 56a material. It may even be possible to practice the invention without a liquid carrier, by compressing solid, or semi-solid, materials with sufficient force. These and other variations of the invention should be deemed within the spirit and scope of the following claims.

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11

Claims (32)

1. A method of making capsules, comprising the steps of mixing a core material and a shell material, applying pressure to the mixture, the lressurd"being applied in a sufficient amount and for a sufficient time to cause capsules to form.

2. The method of claim 1, wherein the pressure is allowed to dissipate gradually.

3. The method of claim 2, wherein the pressure dissipation step includes the step of inducing turbulence in the mixture.

4. The method of claim 3, wherein the turbulence inducing step comprises the step of directing the mixture through a baffled chamber. The method of any one of claims 1 to 4, wherein the pressure is applied for a period of one second or less.

6. The method of any one of claims 1 to 5, wherein the mixing step includes mixing the core and shell materials with a liquid medium.

7. The method of any one of claims 1 to 6, wherein the pressure is applied in the form of a shock wave. :i 8. A method of making capsules, comprising the steps of mixing a shell material with a solvent to form the shell material into a film state, combining the shell material with a core material, applying pressure to the mixture, the pressure being applied in a sufficient amount and for a sufficient time to cause capsules to form.

9. The method of claim 8, wherein the pressure is allowed to dissipate gradually. The method of claim 9, wherein the pressure dissipation step includes the step of inducing turbulence in the mixture.

11. A method of making capsules, comprising the steps of: mixing a core material and a shell material in a liquid medium, agitating the mixture until capsules begin to form, applying pressure to the mixture, the pressure being applied in a sufficient amount and for a sufficient time to complete the construction of the pre-formed capsules, and optionally gradually reducing the pressure of the capsules. 4, 4 I, I I.r 58

12. The method of claim 11, wherein the pressure reducing step includes the step of inducing turbulence in the mixture.

13. A method of making capsules, comprising the steps of providing a quantity of pre-formed capsules, the pre-formed capsules being present in a liquid medium, applying pressure to the liquid medium, the pressure being applied in a sufficient amount and for a sufficient time to complete the construction of the pre-formed capsules, and optionally gradually reducing the pressure of the capsules.

14. The method of claim 13, wherein the pressure reducing step includes the step of inducing turbulence in the mixture. Apparatus for making capsules, comprising: means for storing a mixture of core and shell materials, a compression chamber, fluidly connected to the storing means, the i compression chamber also being connected to means for generating pressure within the chamber, means for conveying the mixture out of the chamber, and means for gradually reducing the pressure of the capsules, the :.!pressure reducing means being connected to the conveying means.

16. The apparatus of claim 15, wherein the pressure reducing means comprises S: a tube having baffles disposed within the interior of the tube.

17. The apparatus of claim 16, wherein the compression chamber includes inlet and outlet check valves, the check valves having sufficient stiffness to confine the mixture within the chamber while pressure is being applied to the mixture, for a time sufficient to produce capsules. A method of making microcapsules, comprising the steps of combining a core material and a shell material, applying a first stroke of pressure to the mixture, for a time sufficient to cause capsules to form, and applying a second stroke of pressure to the mixture to adjust the size of the capsules, wherein the pressure of the second stroke is adjusted upward, if smaller capsules are desired, or downward, if larger capsules are desired.

19. The method of claim 18, wherein the first pressure-applying step is preceded by the step of agitating the core and shell materials until capsules begin to form. -L c 59 A method of making capsules, comprising the steps of: mixing a core material and a shell material, subjecting the mixture to pressure, the pressure being applied in a sufficient amount and for a sufficient time so as to form capsules, and hardening the capsules.

21. The method of claim 20, wherein the hardening step includes the step of passing the mixture through a baffled chamber, so as to reduce the pressure of the mixture gradually and so as to induce turbulence in the mixture.

22. The method of claim 20, wherein steps and are performed again following step

23. The method of claim 20, wherein the step of subjecting the mixture to pressure is performed at least twice.

24. The method of claim 20, wherein step is followed by the step of adding additional shell material to the mixture, and again subjecting the mixture to pressure.

25. The method of claim 20, wherein the hardening step comprises the step of treating the capsules chemically.

26. The method of claim 20, wherein the hardening step comprises treating the capsules with heat.

27. The method of claim 23 or claim 24, wherein the steps of tt-he S mixture to pressure are performed at different levels of pressure.

28. The method of claim 24, wherein the adding step comprises adding a shell material which is different from the first shell material, whereby the resulting capsitles have shells made of different materials.

29. A method of making capsules, comprising the steps of: mixing a first core material and a first shell material, applying pressure to the mixture, the pressure being applied in a sufficient amount, and for a sufficient time, to produce capsules, combining the capsules with a mixture of a second core material and a second shell material, and applyihg pressure to the mixture, the pressure being applied in a sufficient amount, and for a sufficient time, to produce capsules, thereby producing capsules having at least two distinct cores. The method of claim 29, further comprising the steps of gradually decreasing the pressure of the mixture, and inducing turbulence in the mixture.

31. A method of making capsules, comprising the steps of: mixing a first core material and a first shell material, agitating the mi: ture, until capsules begin to form, combining the capsules with a mixture of a second core material and a second shell material, and applying pressure to the mixture, the pressure being applied in an amount sufficient, and for a time sufficient, to produce capsules, thereby producing capsules having at least two distinct cores.

32. The method of claim 31, further comprising the steps of gradually S decreasing the pressure of the mixture, and inducing turbulence in the mixture.

33. Apparatus for making capsules, comprising: means for storing a mixture of core and shell materials, means for compressing the mixture, the compressing means being fluidly connected to the storing means, and means for gradually reducing the pressure of the mixture, the pressure-reducing means being fluidly connected to the compressing means.

34. The apparatus of claim 33, wherein the pressure-reducing means includes a channel having a gradually decreasing diameter. The apparatus of claim 33, wherein the channel includes means for increasing the turbulence of flow of the mixture.

36. Apparatus for making capsules, comprising: means for storing a mixture of core and shell materials, means for compressing the mixture for a period of time sufficient to form capsules, the compressing means being fluidly connected to the storing means, and I 61 means for gradually reducing the pressure of the mixture, the pressure-reducing means being fluidly connected to the compressing means, the pressure-reducing means including means for increasing the turbulence of flow of the mixture.

37. The apparatus of Claim 36, wherein the turbulence increasing means includes a plurality of baffles positioned within the path of flow of the mixture.

38. A method of making capsules which method is substantially as herein described with reference to any one of the Examples and accompanying drawings 4 to 11.

39. Capsules whenever produced by the method of any one of claims 1 to 14, to 32 or 38.

40. Apparatus for making capsules, substantially as herein described with reference to any one of the accompanying drawings 4 to 11. DATED this 27th day of November 1991. oS BRUCE K. REDDING, JR. By their Patent Attorneys: CALLINAN LAWRIE S