CA2131548A1 - Coacervation processes - Google Patents

Abstract

The invention relates to processes for forming particles which have a core of core material within a shell of polymeric material that has been deposited by coacervation. According to the invention there is provided a dispersion of particles of core material in an aqueous solution of a pH-sensitive polymeric material at a pH
at which the polymeric material is soluble. The polymeric material is deposited as a shell around the core material by insolubilisation of the polymeric material caused by adjusting the pH of the solution to a pH at which the polymeric material is insoluble.
The adjustment of the pH is conducted at a rate that is sufficiently slow and homogeneous throughout the solution so that the polymeric material deposits substantially only as a substantially uniform coacervate around the individual core particles.

Description

~ 93/l8853 ,' 1 3 :~ ~ 4 8 PCT/GBg3/00533 , Coa~rvatio~ Pæoces3es Thi s ~nv~ntion r~lates to proc~sses for forming particles which ha~e a core of core material within a shell of polym~ric material that has been deposited by coacer~ation.
Coacervation processe~ are well known as a class and involve pr~viding a dispersion of particles (liquid or solid) o~ core material in an aqueous medium containing coacervating polymer and causing the polymer to phase-separate and deposit around the par~icles. It i5 common to promote coa ervation by adjusting the conditions in the aqueous medium s~ as to ~ause the polymer to deposit. For instance the concentration of a non-solvent may be increased to bring about deposition or two polymers in the medium may be caused to interact to form a ~polymeric complex as a coacervate~
50me polymeric material5 are pH-sensitive, i.e.i they are soluble'at one pH and ins~luble at another pH. It is known to use pH-sensiti~e p~;lymeric material as a coatin~
or matrix around a pharmac~uti~ally active ingredient to protect that active ingredient from ambient conditi~ns at which the polymeric material is insoluble, and then to : release the active ingredient by exposing the polymeric ma~erial to pH conditions at which it is:soluble. Various technique~ are known for depositing: the pH-sensitive polymeric material around`the active ingredient. Most of them involve forming relatively large particles but coacervation can be used to form small~particles if the active ingredient can be supplied initially as a dispersion of small particles.
It is known to be desirabl~ to encapsulate certain materials, such as the toxin derived ~rom Bacillus thuringiensis (Bt), within a p~-sensitive polymeric material. Proce~ses for doing this are described in U.S.
4,94~,586~ These processes involve the use of organic solvents and achievement of ~ncapsulation depends upon the WO53/18853 ~1~15~ PCI/GB93/lms33 choice of appropria~e solvents, non-solYents, surfactants and temperature conditions.
Coacervation processes of this general type suffer from a number of disadvantages. The use of organic sol~ents in large quantities is undesirable ~ecause it necessitate the provision of suitable solvent handling apparatus and becau5e th~ solvents themselves can exhibit some phytotoxicity. The changes in oncentration or other condition~ necessary to cause coacervation are liable to 0 occur rather æudde~ly (for example at the point of addition of a non-solvent) and it is difficult to obtain uni~orm coacervation under these conditions.
. It might be thou~ht that ~t would be possible to achieve satisfactory coacervation of a pH-sensitive polymer by dispersing particles of core material in an aqueous solution of the polymeric material at a pH at which the polymeric material is soluble, and causing insolubilisation of the polymeric material and deposition of the insolubilised polym:eric material as a shell around the core material by adding acid~:or alkali and thereby adjusting the pH of the solution to a pH at which the polymeric material : is insolubl~0 Un~ortunately, little~or no deposition of insolubilis~d material occurs as a shell around individual core particles, as would occur in proper coacervation.
: 25 Instead, a ~igni~icant amount, and generally most or all, of the polymeric material deposits as ag~lomerates. A
:~ substant~al proportion: of the particles o~ core material remain substantially uncoated and/or large, but ~ar~iable, - numbers of the particles of core material are also trapped wi~in each agglomerate.
It would be desirable to be a~le to encapsulate par~icles of core material within a shell of pH-~ensi~ive polymeric material by a process that is simpler to operate and that wil1 achie~e more unifo~m coating of the individual particl~s of core material.

~VO93/18853 2 ~ 8 PCT/GB93/00533 A coacervation process for forming particles having a core of core material within a shell of pH-sensitive polymeric material comprises providing a dispersion of particles of core material 5 in an aqueous solution of the polymeric material at a pH at which the pol~meric material is soluble, and depositing the polymeric material as a shell around the core~material, chara~terised in that the poIymeric material is deposited as a shell and is insolubilised by~adjusting the pH of the solution to a pH at which the poly~erlc material - is insoluble, wherein the adj~stment of the pH is conducted at a D~. rate that is sufficiently slow and:homogeneous throughout the solution that the polymeric material deposi~s substantially only as a substantially uniform coacervate around individual particles.
The encapsulating polymer can change from a to~ally water soluble state to a t~tally water insoluble state o~er a relati~ely small pH range.
: 20Th~ polymer is usually one that has a~very sharp ~: change ~rom insolubility to solubility, for instance going . from a wholly ~oluble form to an insoluble form over a p~
chang~ of less than::1 pH unit, often less than 0.5 pH~unit~
and frequently is in the range 0.05 to 0.2 or 0.3:pH units.
-: 25For instance if the viscosity of the composition ~is measured, it~may be found that~this is at a substa~tially constant high Yalue diown to a pH of,:for instance, 6~.8 and that it then drops very fas~ to a value at aro~nd 6.3 and that it then remains substantially constant~ with furthex 3 0 decreases in pH. Alternatively, turbidity can be meas~red in which even~ it may be low at pH values down ~to about 6.8 .
~indicating full solution~ and may then increase rapidly to a substantially constant high vajlue at pH values below 6.3 :~
(indicating an emulsion) . The~ precise pH band over which :~
this rapid change in solubility ~ccurs will vary according ~;
to the particular composition of the polymer but:is usually located within the range 5.5-~.5, most usually 6 to 7~.

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W093/lX853 213 15 ~ PCT/GB93/OQ~33 The rate cf change of pH must be controlled in accordance with the inventlon so as to be slow and homogeneous as it passes through this critical r~nge. The rate of change approaching this range, and passing beyond it, is less ~portant. In practice it is generally necessary for the desired slow rate ~o be controlled over a range of at least 1 pH uni~, and often at least ~ pH
units, because it is difficult to ensure control over the critical range u~less this i~ done. Generally the change lo in 2 pH uni~s ~rom above the insolubili~ation poi~t ~o below it should take at least 5 minutes, often at least lo minutes, but it is usually unnecessary for it to take . longar th~n S0 minutes.
It is necessary that the change in pH through the critical Eange should occur slowly and homogeneously thr~ughout the solution. If it occurs slowly (for instanc~ as indicated by a pH meter in the bulk of the solution) but non-homogeneously then this is unsatisfactory sin~e the slow but non-homogeneous change will necessarily mean that it is occurri~ng fast in: some parts of the solution and slow in others. The parts where it is occurring fast will gi~e unsatisfactory results since significant amounts of th~ polymer will be deposited as particles that ~are free of core material and/or as agglo~erates of variable size and content. Ac~ordingly it is necessary that the pH change should not only be slow but tha~ it should be homogene~us in the sense that it is 510w in all parts of the solution, and not just in some parts of the solution.
For instance conventional pH adjustment by, for example, addition of acid or alkali would cXange the pH
slowly in the bulk of the solution but would create localised rapid pH changes, causing uncontrollable precipitation of the polymer with little or no encapsulat.ion of the core material, at the point of addition of the acid or alkali.

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~vo 93/18853 ~131~ 4 ~ PCI`/CB93/00533 .` `
If the pH adjustment is suf f iciently slow and homogeneous throughout the solution, the encapsulating p~lymer will deposit predominantly around the individual particles of core material, resulting in efficient encapsulation. If the rate in any part of the sol~tion or throughout the soluti~n is too fast there will be an increasin~ tendency for polymer to be deposited in forms other than as a coacervate coating (with the result that ~:
core material remains uncoated) and~or as agglomerates of variable n~mbers of core particles.
One way of determining whether the process has been conducted satisfactorily is to subject the end product to centrifugation ~inee thi~ can be u~ed to determine whether the great majority of particles are of the desired similar particle size and s~,ape or whether the particles vary considerably in size, for instance between random agglomerat~s of polymer and small particles of rore material.
Another good indication of the product can be obtained by scanning electron microscopy. By this technique it is easily possibly to differentia~e between coated materials of approximately uniform size and random agglomerates and o~her parti~ulate materials. . .
Preferably the ~ajority of the polymeric material, for instance at least 75%, preferably at least 90% and most preferably at least 95% by weight is present as particles of substantially uniform size and that enclose core material, and the majority of core particles, generally at least 75~, preferably at least 90% and most preferably at least 95% by weight, are enclosed within a shell of polymeric material. :;
In some instances the process can be conducted in such a manner that coacervation occurs first and the coacervated particles may then aggregate to some extent and t~is can be 3~ satisfactory since the polymer is deposited as a :~
substantially uniform coacervate around individual particles. This type of produc~ is in contrast with a WO93/18853 21~ 8 PCT/~B93/00-~3 product in which the polymer deposits too fast and in an irregular manner leavin~ significant numbers of particles uncoated.
The pr~f~rred products of the invention have at leas~
S 90% by weight nf the core material microencapsulated within the polymeric material and at least 90% by weight of the polymeric ~aterial present as coac~rvate coating around the core ~aterial.
In order to achieve the desired slow homogeneous lo change in p~ it is preEerred to dissolve a latent pH~
adjusting material in the aqueous solution and cause this to reac~ in the solution to. liberate acid or base . throughout the 501ut~0n and thereby cause the adjust~ent in pH. Since the pH-adjusting material is dissolved in the solution, the pH change is homogeneous, and the desired slow rate can be achieved mere}y by controlling the rate of reaction, ~or instance by adjusting the temperature or the dilution of the solution. ~
When the polymer is so:Luble in acld~and insoluble in alkali t~e pH-adjusting material should be one that will liberate alkali. Pref2rably the polymeric material is material t~at is soluble in alkali and insoluble in acid in which event the latent pH-adjusting material should be one : that will react in the solution to liberate acid in the solution.
The polymer itself may serve as the latent pH~
adjusting material if it is included initially as a salt with ammonia or a YoIatile amine, since heating of the solution will drive off the ammonia and convert the polymer from its soluble, salt, form to an insoluble, acidic, form.
Alternatively, the solution may include an added heat decomposable salt of a volatile base ~ammonia or a volatile amine) with an acid, so that when the solution is heat~d the ~alt decomposes, the base volatilises and the acid that is formed reduces ~he pH. It is necessary to ensure that the salt does not cause a signi~icant change of pH before , .

93/18853 ~1~ 5 ~ ~ PCT/GB93/00533 heat decomposition occurs, for instance as a result of being sufficiently acidic before decomposition.
The use of a salt of a weak acid with a volatile base (for instance a salt of acetic acid or other organic weak acid with ammonia or a volatile amine) can therefore be convenient. However salts with stronger acids can be used, especially if the r~action temperature is sufficiently low that they decompose slowly.
It can also be useful to include a buffer in the sQlution so as to pre~ent unacceptab}e pH adjustment when .. the salt is first added to the solution.
~he need to;heat the solution to decompose the salt .
,~. ca~ be undesirable, e~pecially when the core material comprises Bt toxin or other heat sensitive material and so preferably the latent pH-adjusting material is one that undergoes hydrolysis in the agueous polymer solution to cause the desired liberation of acid (or alkali).: The preferred~ materials are lactones that hydrolyse~ in the polymer solution to form a carboxylic acid. The pre}erred lactone is gluconola~ton~. Again, it can be useful to incorpora~e a buffer.
Provided sufficient care is taken, including especially ~he applica~ion~of sufficient agitation, other ways of achieving the pH change may be `possible. For instance a dispersion o~ pH-adjustlng material may be distributed through the solution. For instanc the beads may be of ion exchange material tgenerally a weak base or weak acid ion exchange materialj or they may be beads comprising a po}ymeric matrix enclosing acid or:alkali that can permeate slowly through the matrix. For instance beads of polyacrylic acid scale inhibitor or the other weak acid~
in a polymeric matrix can be used to liberate acid. ~t is essential to~apply vigorous stirring so as to prevent the c~ncentration of acid or alkali at the surface of the beads increasing su~ficiently to cause local precipitation.
Similarly, dialysis could be used to generate hydrogen or hydroxyl ions within ~he solution on a molecular scale, for W093/18853 PCT/~B93/OQ~3 ~13~4& 8 instance using one or more dialysis sheets, tubes or particles with acid or base on one side of the membrane and the polymer solution on the other. ~gain, however, very vigorous agitation will be needed to prevent the pH
5 changing too fast l~c:ally, thus leading to unwanted polymer deposition.
Similarly, ~ome other material may be adde~ ~o the sc~lution from outside, but again very vigs:~rous agitation and careful addition will be required to prevent the pH
o changing too rapidly locally. Normal techniques of adding, for instance, acid dropwise to a solution that is being stirred at a conventional rate of stirring will not be satisfactory. .
The pH^ sensitive polymeric material is normalIy a 15 copolymer of a blend of ionic and non-ionic ethylenically unsaturated monomers where both the blend and t~e polymer are insolubIe at one pH and soluble at a different pH.
When the ionic monomer is all amino or amido monomer, for instance a dialkylaminoalkyl (meth) acrylate or acrylamide as acid addition or quaternary ammonium salt, the po}ymer can be ~nsolublised by raising the pH. More - .
usually, however, the enteric polymer is an anionic polymer, generally a copolymer of ethylenically unsaturated carboxylic acid monomer with water insoluble ethylenically unsaturated non-ionic monomer. Su~table carboxylic monomers include acrylic acid, methacrylic acid, malPic acid or anhydride, crotonic acid and itaconic acid.
Suitable non-ionic monomer (for incorporation in anionic or cationic polymers) include aromatic 30 ethylenically unsaturated monomers such as styrenes, vir:yl halides, acrylonitrile, and alkyl esters of carboxylic monomers, for instance alkyl (meth3 acxylates.
Preferred copolymers are formed from (meth) acrylic acid with styrene andtor alkyl (meth) acrylate, The 35 amount o~ ionic monomer is generally in the range 5 to 40%, usually 15 to 3096, by weight, with the balance being insoluble non~ )nic monomer. Copolymers of acrylic acid ~l~i5g8 `'10~3/18853 PCT/GB93100533 or other water ~olubl~ ionic monomer with a hydrocarbon monomer such as ~tyr~ne are preferred. By appropriate selection of the comonomer blend and the polymerisation conditions, it is possible to produce polymer having the desired pH ~ensitivity.
The polymer can be formed by polymerisation at a pH at which ~t is ~oluble or by polymerisation in an organic solv~nt or in an aqueous organic solve~t mixture, for instance at a pH at which it would be insoluble in the a~sence of the organic solv~nt. Preferably, howev~r, it is formed by oil-in-water emulsion polymerisation at a pH
at which it is in~oluble.
. Instead of using copolymers of et~ylenically unsaturated monomers, it is also possibl to use natural pol~mer~ ~r synthetic homopolymers, for instance sodium alginate or poiymethacrylic acid, provided they have th~
requ~red solubility propertie~.
Although the polymer ~solution i5 usually free of organic solvent, in some instances it may include solvent 20 (for instance from the initial polymerisation) or solven~
may be ~ncluded in a s~all ~mount (generally less than 50%
and usually less than 10% by weight of the solution3 in order to modify the polymerisation or coa`ceryation process.
The molecu}ar weight of the polymer must not ~e too low since otherwise it may fail to coacervate ou~ of solution adquateIy and/or any coating that is form~d may have inadequa~e properties. Generally therefore the molecular weight is at least 50,000, preferably at least lO0,000 and usually at least 20n,000. If the molecular weight is too high it may be difficult to cause the polymer to co~e out of solution ~ufficiently slowly and so generally the molecular w~ight is below 5 million, and preferably below 2 million and most preferably below l million.
The core material can be a variety of water insoluble liquid or solid materials. If liquid, the material should be broken down into a dispersion of droplets of the WO~3/l8853 PCT/CB93/00~3 21'~ L~ 8 appropriate i~e by conventio~al mechanical homogenisation and/or the use of appropriate oil~in-water emulsifying agent. Preferably the c~re material (irrespective of whether it is liquid or soIid3 has a size of below 30~m and most preferably below lO~m and best results are achieved when the size is below 5~m, for instance 0.1 to 3~m.
However in some instances (~or instance when the c~re material is an ink) it can b~ desirable for the particle size to be much larger, e.g., 30 or 50 to lOO~m or up to 300~m or larger.
A particular advantage of the invention is that it is possible to control the coacervation so acc~rately that, even when the particle size is ve~y small, substantially every particle in the final particulate composition is a monoparticle of the c~re material with a substantially complete coating of the pH-sensitive polymer. Whereas conventional coacervation techniques tend to be unsuitable or difficult to operate if the particle size is to bej for instance, less than lO~m, in the invention it is easily possible to mak~ coated mon~particles having a size of 0.1 to 3~m, typically up to around 1 or 2~m.
Another advantage of the invention is that this very accurate control of coa~ervation can~be achieved without the need to include large amounts of organic solvents.
A further advantage of the invention is that it is pos~ible to synthesise the polymer from a monomer, blend that is selected according to the physical properties that are required of the fi~al polymer coating, provided always sufficient pH-sensitive monomer is included to render the polymer pH sensitive. Thus it is possible to optimise the pol~mer for its ultimate performance qualities. This is in contrast t~ conventional coacervation techniques where the polymer normally had to be selected primarily from the point of view of lts ability to form a coacervate when, for instance, the solvent concentration or temperature changed.
The resultant polymers often gave rather p~or wall W093/18853 ~ i 3 A~ S ~ 8 PCT/GB93/00533 propertie5, and so were often ~urther reacted in an attempt at improving wall strength and other wall properties.
The core material may be a material that relies upon the pH-sensitive nature of the pol~mer coating to protect the material during storaqe or use, or it may be a material - where the pH-~ensitive nature of the pol~mer is merely required for the formation o~ t~e coating. Thus the core material can be, for instance, an ink, a fragrance, ~
sythe~ic pesticide or a biologically produced material such as enzyme (for instance a protease, especially of the type used a5 a detergent enzyme3, a mycelium or insecticidal toxin such as insectiridal virus,: bacteria or fungi, such as are des~ribed in U. S . 4, 948, 586, b~ The invention is of garticular value for ~he encapsulation of c~ystals of the toxin of Bt, Bacillus thuringiensis. This material is preferably present in the form of crystals and/or: spores and conveniently is introduced into the aqueous solution of polymer merely by combinin~ a fermentation~broth of the Bt toxin or other microbiological produc~ with the palymer solution.
Alternatively the b~oth may be~combined with an emulsion o~
the polymer and the pH then adjusted to put the polym r : into solution.
By the invention it is possible to provide a novel 2S product which is a composition of a coating polymer and a particulate biologically produced material wherein at least 50% (of the weight ~f coating polymer and biologically produced material) is present in the form of particles which have a size below 5~m (preferably below 3~m) and 30 which hav~ a core of the biol~gically produced material and a substantially ontinuous coacer~ate shell ~f the polymer, wherein the polymer is a pH-sensitive polymer.
Preferably at least 70%, and most preferably at least or 90%, by weight of the coating polymer and biologically produced material is present in the form of particles having a size of below ~m~ Most preferably the particles have a size of below 2~m, often around l~m. The WO 93/188~3 pcr/c~B93/ons33 213~5 48 12 particle size is generally above 0. l~Lm, frequently above 0.5~m. The particulate core material is preferably solid, e.g., ~t toxin crystals and/or spores. Preferably there is generally only one solid particle in each core. ;:
Thus by the invention it is possible to formulate Bt crystals into a for~ that is particularly suitable for efficient application and u e.
The coated particles of the inve~tion may~be collected and dried as a powder, bu~ usually they are produced and ~o maintained as a suspension in the aqueous medium in which they are formed. ~
In the following examples, polymer ~ :is a polymer ~`
prepared by oil-in-water emulsion polymerisation of 30% by weight ~acrylic acid with 70% by weight styrene, while poly~er B is prepare~ in the same w~y from 15 weight percent me~hacrylic acid, 30 weight percent ethyl acrylate and 55 weight percent methyl methacrylate. ~ :

Microencapsulatlon of Bt Bioinsectici~de with Pol~er A : ;
A ~esh sample of Bacillus thurinqiensis ~ermentation broth ~100 parts) containing appr~ximately equal amounts of :.
Bt crystals and spores at pH 7 was: vigorously stirred ::
whilst a~solution (25%) of polymer A i~ water at pH 8.~ was added. Stirring was continued whilst a mlxture of 1,5-: 25 glucon~lact~ne (5 parts) in water (lO parts)~was added. .
The pH of this dispersion was monitorsd with time under ;~
constant mechanical agitation. After 30 mi~nutes the pH~had~
dropped ~rom 8.2 ko 6.4. At this time the smooth brown mixture became thixotropic and remained:like that for a:
further 30 ~inutes when the ~H had reached 6Ø
On examina~ion by scanning electron microscopy ~SEM) :~;~
the starting broth was seen to contain roughly equal numbers of diamond shaped Bt crystals and rounded spores in t~e ~-2 micron si~e range. The reaction product by ~on~rast con~aine~ very few diamond shapes and almost all particles had a rounded shape but still in the 1-2 micron region. Thus the alkali-soluble polymer A had ~een '~:

`~093tl8~53 ~ 3 ~ 5 4 ~ PCT/GB93/00533 deposited as a film around the crystals when it was phase separated under acid conditions.
ExAM~LE-2 PreParat ~ Q~ Triflura~lin~ s~apsules An oil phase was prepared consistin~ of the insecticide Trifluralin 70 parts), a solvent (Shellsol A; -:
25 parts~ and an 0IW emulsifier (Tensiofix B7416; 5 parts).
This oil phase (50 parts) was mixed vigorously with water (50 parts) to give a ~mooth orange O/W emulsion.
This em~lsion was next added to a clear ~olution of polymer A in watar ( 6% ) at pH 9~ Glacial acetic acid was added dropwise to reduce the pH to 7. It was n~ted that during this ~ta~ local precipitation of Polymer A occurred an~ :
prolonged stirrin~ at pH 7 was necessary to re-dissolve 15 these polymer clumps. ~.
When a smooth O/W emulsion was finally obtained (60 :~
minutes) a freshly made ~p ~olution of 1,5 gluconolactone (5 parts) in water (95 parts) was added. The pH of this mixture dropped slowly but steadily from 7 to 6 over 120 minutes.
The final product consisted of fin~ly dispersed yellowish orange parti~les in water. On stan~ing for several days these particl~s tended to aggregate at the top of the solution with ab~ut 25% of the volume consisting of a clear colourless lower aqueous phase. With slight :~
agitation tha aggregates easily redispersed. ~:~
EYidence for microencapsulation i5 the fact that after ;~
standing for 1 month ~ery few small orange Trifluralin crystals had been deposited on the sides of the glass container. Also under the visible microscope some capsules }n the regicn 20-30 micron diameter could be s~en with thin surrounding membranes. When pressure was applied to the cover slip the membrane could be seen to rupture and the orange internal phase leaked through the fracture into the 3~ surrounding colourles~ aqueous phase. ~:~

WO93/18853 21~ ~ 5 ~ 8 PCT/CB93/00~33 ' Preparat~on of Cap~sules Contai~in~ Leuco-dye for Carbonless Pa~r ~anufacture ~n aqueous phase (100 parts) at pH 7.5 containing 10%
w/w Polymer B was prepared. A ~olution (2~ w/w) of crystal violet lactone in a hydrocarbon solvent (15 parts) was add~d to the a~ueous solution of polymer B t~ form an OIW
emulsion. With continued ~echanical agitation, a ~lurry of ammonium acetate (5 part~) in water (10 parts) was next added. ~h~. pH of thi~ mixture at 20C was 7.3. On warming and stirring the pH dropped steadily to pH 7 (50C) and pH
6.2 ~7~C).
On cooling the mixture remained smooth and well dispersed. The essence of capsules was demonstrated by applying the mixture on to a paper sheet and drying. When this sheet was brought into contact with a second æheet of paper coated with acid clay and pressure applied a blue colour developed where the pressure had caused the capsules to rupture and bring the lactone dye into contact with acid clay.

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Claims (19)

1. A coacervation process for forming particles having a core of core material within a shell of pH-sensitive polymeric material, the process comprising providing a dispersion of particles of core material in an aqueous solution of the polymeric material at a pH at which the polymeric material is soluble, and depositing the polymeric material as a shell around the core material, characterised in that the polymeric material is deposited as a shell and is insolubilised by adjusting the pH of the solution to a pH at which the polymeric material is insoluble, wherein the adjustment of the pH is conducted at a rate that is sufficiently slow and homogeneous throughout the solution that the polymeric material deposits substantially only as a substantially uniform coacarvate around individual particles.

2. A process according to claim 1 wherein the pH of the aqueous solution is adjusted by dissolving a latent pH-adjusting material in the aqueous solution and causing this material to react in the solution to liberate acid or base throughout the solution, thereby causing an adjustment in PH.

3. A process according to claim 2 wherein the latent pH-adjusting material comprises a salt of the polymeric material with ammonia or a volatile amine, whereby heating of the solution will drive off the ammonia and convert the polymeric material from a soluble form to an insoluble form.

4. A process according to claim 2 wherein the pH-adjusting material comprises a heat decomposable salt of a volatile base with an acid, whereby when the solution is heated the salt decomposes, the base volatilises and the acid that is formed reduces the pH.

5. A process according to claim 4 wherein the pH-adjusting material comprises a salt of a weak acid with a volatile base.

6. A process according to any of claims 2 to 5 further comprising a buffer in the aqueous solution.

7. A process according to any of claims 2 to 6 wherein the pH-adjusting material comprises a lactone that hydrolyses in the aqueous solution of polymeric material to form a carboxylic acid.

8. A process according to claim 7 wherein the lactone is gluconolactone.

9. A process according to any of claims 2 to 8 wherein the polymeric material changes from a wholly soluble form to an insoluble form over a pH change of less than 1 pH
unit.

10. A process according to claim 9 wherein the pH change is in the range 0.05 to 0.3 pH units.

11. A process according to any of claims 2 to 10 wherein at least 75% by weight of the polymeric material is deposited as a shell, and at least 75% by weight of core particles are enclosed within a shell of polymeric material.

12. A process according to claim 11 wherein at least 90%
by weight of the polymeric material is deposited as a shell around the core material, and at least 90% by weight of core particles are enclosed within a shell of the polymeric material.

13. A process according to any of claims 2 to 12 wherein the polymeric material is a copolymer of a blend of ionic and non-ionic ethylenically unsaturated monomers, wherein both the blend and the copolymer are insoluble at one pH
and soluble at a different pH.

14. A process according to claim 13 wherein the amount of ionic monomer is in the range 5 to 40%, the balance being non-ionic monomer.

15. A process according to claim 13 or claim 14 wherein the copolymer is formed from (meth) acrylic acid with styrene and/or alkyl (meth) acrylate.

16. A process according to any of claims 2 to 15 wherein the molecular weight of the polymeric material is in the range 50,000 to 1,000,000.

17. A process according to any of claims 2 to 16 wherein the core material has a size below 5µm.

18. A composition of a coating polymer and a particulate biologically produced material wherein at least 50% (of the weight of coating polymer and biologically produced material) is present in the form of particles which have a size below 5µm and which have a core of the biologically produced material and a substantially continuous coacervate shell of the polymer, wherein the polymer is a pH-sensitive polymer.

19. A composition according to claim 18 made by a process according to any of claims 2 to 17.