WO1992010282A1 - A method of producing monomeric phases in the form of microspheres dispersed homogeneously and suspended stably in continuous phases constituted by polysaccharide gels, the polymerisation thereof, and use - Google Patents

A method of producing monomeric phases in the form of microspheres dispersed homogeneously and suspended stably in continuous phases constituted by polysaccharide gels, the polymerisation thereof, and use

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Publication number
WO1992010282A1
WO1992010282A1 PCT/EP1991/002276 EP9102276W WO1992010282A1 WO 1992010282 A1 WO1992010282 A1 WO 1992010282A1 EP 9102276 W EP9102276 W EP 9102276W WO 1992010282 A1 WO1992010282 A1 WO 1992010282A1
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Prior art keywords
phase
polymerisation
continuous
monomeric
microspheres
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PCT/EP1991/002276
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French (fr)
Inventor
Paolo Giusti
Marco Mantilli
Maurizio Palla
Giovanna Pizzirani
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S.E.I.P.I. Società Esportazione Importazione Prodotti Industriali S.P.A.
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    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/12Agar or agar-agar, i.e. mixture of agarose and agaropectin; Derivatives thereof
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F2/00Processes of polymerisation
    • C08F2/12Polymerisation in non-solvents
    • C08F2/16Aqueous medium
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F2/00Processes of polymerisation
    • C08F2/12Polymerisation in non-solvents
    • C08F2/16Aqueous medium
    • C08F2/20Aqueous medium with the aid of macromolecular dispersing agents

Abstract

The invention enables polymerisations to be carried out in suspension in order to produce microspheres of polymeric material and is concerned with the following, which is a subject of the claims: the reduction of the monomeric phase into microspheres, involving: a continuous phase (A) constituted by at least one polysaccharide dissolved in hot distilled water, a monomeric phase (B), constituted by at least one monomer and the catalyst, an unstable dispersion (C) produced by the mechanical mixing of the preceding phases, and a stable dispersion (D) produced by reducing the temperature of the unstable dispersion until the continuous phase gels, and stopping the stirring; the production of the polymeric microspheres (E) by discontinuous or continuous processes involving: the raising and control of the temperature of the stable dispersion (D) during the polymerisation, possibly the curing of the polymeric microspheres, their purification by washing with hot water, and the separation of the continuous phase (A); the use of the materials produced in the biomaterials, optics, manufacturing and civil engineering sectors.

Description

A method of producing monomeric phases in the form of microspheres dispersed homogeneously and suspended stably in continuous phases constituted by polysaccharide gels, the polymerisation thereof, and use

The present invention relates to a method of producing monomeric phases in the form of microspheres dispersed homogeneously and suspended stably in continuous phases constituted by polysaccharide gels, the polymerisation thereof, and the use of the materials produced in the biomaterials, optics, manufacturing and civil engineering sectors.

In practice, the physical dimensions and the surface characteristics of particles of material which go to make up complex compositions are parameters of the greatest importance and cases in which these parameters determine the possible uses of the particles, are not sporadic. An associated dimensional uniformity is also sought-after and remains one of the most difficult problems to solve; many resources are expended on industrial research directed towards the perfection of methods of producing elements of very small dimensions.

Examples of materials in the form of microspheres which are used industrially include:

- glasses which are used as fillers in the formulations of composites, as additives in the manufacture of products, as solid-phase elements in chromatographic separation columns, and for other uses, - synthetic polymeric materials, some of which are used, amongst other things, in the following sectors: - 1: the biomaterials sector (cements for bones, composites for dental prostheses, substrates for the controlled release of drugs), 2: the optics sector (components of rear windows and glasses, as well as impact-resistant glasses, lenses, which may be produced by the thermoforming of the materials), 3: manufacturing industry (hot or cold coextrusions, the production of articles by compression moulding or casting), 4: the civil engineering sector (road signs, reflective markings, interior and exterior painting, the colouring of products).

Polymerisation processes produce materials whose physical appearance is:

- undifferentiated or continuous (by polymerisation in bulk, for example, a sheet of Perspex), random (by polymerisation in solution and the precipitation of the polymer in a non-solvent; the physical appearance of the precipitate depends on the nature of the polymer, of the solvent or mixture of solvents and of the non-solvents, on the precipitation times and temperature, and on the quantitative polymer/solvent/non-solvent ratios), or

- predetermined (by polymerisation in suspension; the dimensions of the particles of the polymer are optimised by setting all the variables of the entire mixing and polymerisation process).

Polymeric materials in the form of microspheres can be produced: 1: from the products of polymerisation in bulk or in solution by mechanical crushing and subsequent reduction to spherical proportions by ball grinders, and also by their subjection to certain cutting, compression and abrasion operations by means of friction by rolling, or 2: directly by polymerisation in suspension.

Only polymerisation in suspension is considered, since it supplies the polymeric material directly in the form of microspheres at a low cost and with products of excellent quality; a comparison of the invention with the state of the art thus mainly has to do with the methods used and the problems involved therein.

From a chemical point of view, in order to carry out these processes, the dimensions of the particles must be established beforehand and maintained until polymerisation has taken place and the heat of the reaction, which may vary according to the geometry of the system and the nature of the particular chemical reagents, must be dissipated.

The literature provides ample documentation in connection with the production of microspheres of polymers by polymerisation in suspension. In a polymerisation process, a monomeric phase, which almost always contains the catalyst in solution and is to be polymerised, and a continuous phase, in which the monomeric phase is dispersed, can be distinguished.

In practice, it is known that, in any system including a monomeric phase, a continuous phase, and a catalyst, the polymerisation reaction of a monomeric phase is brought to a conclusion in the desired manner only if certain measures are adopted. These measures form part of the state of the art.

It is clear from bibliographic research carried out by means of Frascati's ESA QUEST data bank (Rome) on the periodicals: Chemical Abstracts (from 1967), Biosis (from 1973), Inspec (from 1969), Pascal (from 1973), CEA (from 1970), and Engineered materials (from 1986), that the production of microspheres of polymethyl methacrylate and its copolymers by polymerisation in suspension in continuous or discontinuous reactors with various catalytic systems has always necessitated suitable dispersants, surfactants, plasticisers and modifiers, even in combination, and the continuous mechanical stirring of the suspension.

Polymerisation in suspension in systems with continuous stirring involves two almost contemporaneous problems which characterise the process and should be considered decisive:

- the formation of the suspension of the monomeric phase, which should have certain dimensional characteristics and a particular, preferably narrow, particle-size distribution which is determined by the geometry of the system and the physical-chemical characteristics of the materials,

- the polymerisation of the monomeric phase in which the dimensional stability of the particles should be maintained until the reaction is complete.

Assuming that the catalytic system is suitable to bring the polymerisation in suspension to a conclusion, the first problem is that of creating the dispersion of the monomeric phase. The dimensional equilibrium of the particles therein depends upon the interaction of chemical-physical, geometrical and operational factors. Some prejudicial factors which must always be taken into account in carrying out industrial and laboratory processes include:

- the fact that the stability of the suspension of two immiscible liquids is adversely affected over a period of time by the absolute affinity of each for its own kind; this means that, in a polyphase liquid mixture there is always a more or less marked tendency for particles of the same kind to coalesce; the regrouping of similar particles sooner or later produces separate continuous phases one above the other, unless their specific weights are identical,

- the fact that two liquids can be mixed, but at least a continuous input of energy, usually in the form of stirring, is necessary to keep one of the two phases dispersed in the other in minute form,

- the fact that the monomer can be split up into small particles to the desired extent only if it is possible to use in a reliable manner data relating to the manner of application of the mechnical force exerted by the dispersion means and to its relationship with the geometrical conditions of the system,

- the fact that the physical and chemical properties of the continuous phase and of the monomeric phase contribute to the achievement of a predetermined final object which, in this case, consists of the production of the desired dimensions and distribution thereof,

- the fact that the dimensions and uniformity of the dispersion also depend on the mixing time; in general, the dimensional equilibrium of the particles is related to the viscosities of the monomeric and continuous phases and is achieved only after a certain period of time. The transitory stage is fortunately of the order of minutes.

During polymerisation in suspension carried out in continuously-stirred reactors, it is unlikely that the dimensions and the particle-size distribution of the dispersed monomeric phase will be maintained when the polymerisation process starts; the diameters of the suspended particles increase with increased viscosity of the dispersed phase and decrease with increased viscosity of the continuous phase. Since the latter remains fixed during the polymerisation, the phenomenon is controlled by the viscosity of the monomeric phase [Hopff H.V. et al. Makromol. Chem. 78, 24, 37, 1964; Makromol. Chem. 82, 184, 1965].

Particularly during the first stage, there is a coalescence effect due to the tackiness of the microspheres, resulting in an increase in their volumes and hence dimensional instability. Aggregates may thus form, and their dimensions may increase considerably until they are too large for the product to be used in practice. There may even be further harm as regards safety problems and the cost of resetting the reactor for operation if the material agglomerates and completely blocks its blades.

It is known for certain that the maintenance of the dimensional stability of the dispersed particles during polymerisation solely by means of the mechanical contribution and the alteration of the geometry of the reactor is always critical. The turbulent action of the mixer and the use of protective colloids ensure equilibrium between the continual breakage of the particles and their coaslescence [Church J.M. et al, Ind. Eng. Chem 53, 479. 1961].

It is therefore preferable to alter the viscosity of the continuous phase and the surface tension of the particles by the addition of additives. These include:

- polyvinyl alcohol or its copolymers; the dimensions of the particles and the quality of the product produced depend on its action as a protective colloid which in turn is determined by the molecular weight, the degree of hydrolysis, the stereochemistry, the distribution of the acetal and hydroxyl groups and, not least, by the preparation method [Garvey M.J. et al, J. Colloid Interface Sci. 49, 57, 1974], electrostatic stabilisers (cationic and anionic soaps) which reduce the interface tension by encapsulating the particles [Mlinek Y et al, AIChE H. 18, 122, 1972], polymeric (steric) stabilisers or electrosteric stabilisers (polyelectrolytes which also have the characteristics of the former) [Napper, D.H. et al, "Polymerisation in emulsion", Comprehensive Polymer Science, Pergamon Press, Vol. 4, part. II, 172, 1989],

- copolymers which act as protective colloids but whose merits and demerits are difficult to compare since they are disclosed as elements of industrial patents [Munzer, M, et al, Polymerisation Processes, and Schildnecht C.E., Wiley-Interscience, New York, Vol. 29, Chap. 5, 1977], and copolymers with hydrophobic and hydrophilic characteristics which fix themselves to the surfaces of the microspheres [Wolf F. et al, Plaste Kaut., 19, 26, 1972].

It is clear from the bibliography that, at the moment, all polymerisations in suspension are carried out to completion in stirred systems even with technically, qualitatively and economicallly valid results. For example, polymers of considerable commercial value such as copolymers (styrene-divinyl benzene) have been produced as 10 micron-diameter pearls by external action on the geometry of the system [Dawkins, J.V. et al, Polymer, 18, 1179, 1977].

An improvement in the state of the art involves, first and foremost, an evaluation of the repeatability of the methods currently used. Clearly, the repeatability of the results should be adversely affected only by environmental conditions and not by assumptions regarding feasibility given out as facts. Environmental conditions mean the geometry of the system and the energy used. It is therefore desirable to show that a known method cannot properly be invalidated by the literature unless it has failed in the same operative conditions.

In order to determine once and for all whether altering the geometry of the system and/or the chemical-physical characteristics of the monomeric components and of the dispersant phase could improve the state of the art, an attempt was made to transfer some industrial formulations reported in the literature to our basic system which consisted of a 1-litre glass reactor with a jacket and vertical walls with a hemispherical base, using various methods and stirring rates.

For this purpose, suitable radical polymerisations of methyl methacrylate (MMA), as well as its copolymerisation with diethylene glycol bis (allyl carbonate) (RAV), which is soluble only in MMA, and with vinyl pyrrolidone (VP), which is soluble both in the monomeric phase and in the continuous phase, were carried out in suspension. Of the additives considered most useful industrially, polyvinyl alcohol, sodium dodecyl sulphate, calcium phosphate, polyacrylic acid and a surfactant for industrial use were selected, singly or mixed.

Various stirring rates and monomer-dispersant phase-catalyst-additive ratios were used but, probably because of the lack of sophisticated dispersion means, we were not successful in producing the polymer in the form of microspheres (see Table No. 1 of the failed tests), rather the blades of the reactor were blocked by the exponential increase in the dimensions of the agglomerations of spheres which were also fused together.

The tests we carried out confirmed that the greatest problem inherent in producing the polymer in the form of microspheres consists of preventing the particles of the polymer, which are tacky because they are dissolved in their own monomer during the first stage of the polymerisation, from coalescing. This effect is inherent in polymerisation in suspension carried out in systems in which the probability of collisions between the particles is proportional to their kinetic energy and to the percentage of the space occupied thereby (reactors which at any rate are stirred) .

The catastrophic agglomeration of the particles is the worst problem. However, it should be remembered that, even if the system does not collapse completely, even though the dimensions of the particles during the mixing of the monomer with the continuous phase may be calculated, intended, and suitable for the predetermined purposes, there will always be a variation in the sense of an increase in their dimensions, which is not always quantifiable. Conversely, the dimensions obtained upon completion of the reaction cannot easily be correlated to the starting dimensions since too many factors are involved which are not always repeatable.

Clearly, in order for the polymerisation of any system including a monomer, a continuous phase, a catalyst, and additives in a stirred reactor to succeed, the geometry of the reactor and the correction of the polymerisation procedure must be optimised. The advantages and disadvantages of the formulations used in the industrial processes may consequently be valid in themselves, but it is difficult to extend them as they are to systems which differ volumetrically and in some physical parameters.

Even if the advantages could be conserved for all the polymeric systems, processes with stirred reactors could at any rate not easily be extended volumetrically and a scale-up would still involve specific studies the cost of which would be very high. Transfer to an industrial scale would probably magnify the problem which is already not easy to interpret.

An evaluation of the state of the art is very difficult because of the very large number of recipes and methods used; sometimes some classes of additives are used for several monometric and catalytic systems.

It is suggested that the addition of the additives is decisive but it involves uncertainties. It is not known whether the improvement of the interface properties of the microspheres introduced by an additive in order to bring a polymerisation method to a conclusion also improves the characteristics of the product produced in comparison with a system without additives. Conversely, it is not always possible to evaluate the damage to the characteristics of polymers due to residual additives or the increased costs of processes for purifying the materials produced.

The practical impossibility of transferring the methods brought to a conclusion with good results elsewhere to our system and evaluating the state of the art caused us to seek new solutions to the problem which might avoid both the mechanical-dynamic optimisation and the previously-patented difficult recipe improvements.

We attempted, with success, to find a new method which is realised by the present invention, and which has eliminated the aforementioned disadvantages and problems which were encountered on a laboratory scale.

The invention, as characterised by the claims, solves the problem of producing a polymeric material in the form of microspheres without the risk of the system collapsing, which is otherwise a certainty. Moreover, the dimensions of the finished product are determined exclusively by the parameters which control the production of the monomeric phase in the form of microspheres and not by the polymerisation itself.

The invention is distinguished from polymerisation in a continuously stirred reactor in that it consists of two independent processes carried out in succession:

- the production of the monomeric phases in the form of microspheres dispersed homogeneously and suspended stably in a continuous phase constituted by a polysaccharide gel,

- the polymerisation of the monomeric phases without stirring, which may be carried out:

- discontinuously in the same environment in which the dispersion was effected, or in another reactor with different geometrical proportions from that in which the dispersion of the monomeric phase was effected, or

- continuously by the transportation of the monomeric phase: through tubular reactors with jackets or with tube nests, or through covered baths in which the temperature is controlled and from which the heat of the reaction is removed by a flow or a contraflow of water, after the surface of the stable suspension (D) has been increased by drawing it through an extrusion head.

The distinguishing characteristic of the invention is the gelling of an unstable dispersion (C) composed of the monomeric phase (B) dispersed in the continuous phase (A) to produce a stable phase (D). This stable dispersion (D) can be polymerised discontinuously or continuously even after a period of time. The stable phase (D) can thus be kept until the time of its polymerisation, according to need, possibly at locations other than that in which it was prepared.

More precisely, the invention concerns: the reduction of the monomeric phase into microspheres involving: a continuous phase (A) constituted by at least one polysaccharide dissolved in hot distilled water, a monomeric phase (B) constituted by at least one monomer and the catalyst, an unstable dispersion (C) produced by the mechanical mixing of the preceding phases, and a stable dispersion (D) produced by reducing the temperature of the unstable dispersion until the continuous phase gels, and stopping the stirring.

- the production of the polymeric microspheres (E) by discontinuous or continuous processes, involving: the raising and control of the temperature of the stable dispersion (D) until polymerisation has taken place, possibly the curing of the polymeric microspheres (E), their purification by washing with hot water and their separation from the continuous phase (A).

Polymerisations carried out on the stable dispersion (D) are defined below as polymerisations in a static system, to distinguish them from those carried out with the stirring of the unstable dispersion (C), which are defined as polymerisations in a dynamic system.

The material which enabled these polymerisations to be carried out for the first time is agarose. This is a colloid whose formula is:

It is produced by the purification of agar which in turn comes from agarophytic algae such as Gelidium, Ahnfeltia, Pterocladia, and Gracilaria, all of the Rodophyta family. Its main use is in the food, pharmaceutical and cosmetics industries and as a bacterial culture medium.

One of the main characteristics of agarose consists of its mechanical-thermal hysteresis. Agarose can be dissolved in hot water to give a clear solution. If the temperature of the solution is reduced both its viscosity and its shear stress gradually increase; as the gel temperature is approached these values rise exponentially. The mechanical-thermal hysteresis lasts for several cycles, a reduction in the aforementioned values being observed only after 4-5 cycles. The data, which we derived with a CONTRAVES Mod. STV rheometer, were compared which those in the literature and confirmed them.

Once formed, the gel, which forms at a temperature which varies with the quantity of sulphur, which is usually kept between 1 and 10 per thousand, has compression strength of the order of 1 kg/sq.cm. and is not broken down by an increase in temperature. In an undisturbed sample and in certain concentrations, the gel state is maintained up to temperatures of almost 90°C.

The thermal stability of the gel actually prevents the mobilistion of the continuous phase and thus also chance contacts between the particles even during the polymerisation stage which usually takes place at temperature of 70° or less. This ensures that the separate spherical particles are kept apart and the kinetic energy induced is practically zero in a dimensionally stable matrix which is stationary within the geometry of the reactor and is inert with respect both to the monomer and to the catalysts used.

The geometry of the system thus affects the dimensions of the particles when the monomeric phase is mixed into the continuous phase but not during its polymerisation.

The invention as characterised in the claims can also be carried out with variations in the values of the physical parameters during the creation of the stable dispersion (D) (the interface tension and the viscosities of the dispersed and dispersant phases, which are related to the temperature and to the concentration of the agarose when the mixing takes place and the geometry of the reactor) and in the operational criteria during the polymerisation stage (the way in which the mass is heated, the temperature is controlled, and the reaction heat is dissipated until the polymerisation is complete).

The curing of the polymer, which may be necessary to remove traces of the monomer, can be effected at a temperature of 85°C even for 10 h, still with the mass in the gel state and hence with the microspheres separated. The gel can then be destroyed by stirring the hot mass. Purification can be carried out simply by washing by decantation with hot distilled water or in a centrifuge with a basket.

During the polymerisations which we carried out on a laboratory scale in a 1 1. glass reactor with a jacket and having a diameter of 10 cm, loaded with 500 g of the stable dispersion (D) including 100 g of the monomeric phase (B), with a polymerisation temperature set externally at 70°C, the temperature profiles detected by thermocouples positioned on the axis at 1/3, 1/2 and 2/3 of the radius and on the wall (r) were recorded.

A temperature front advanced by conduction and convection from the outer layer towards the geometrical centre of the reactor. As it gradually reached successive layers of the gel, successive portions of the stable dispersion (D) polymerised and the temperature rose locally above the temperature set. The effectiveness with which the heat of the reaction was dissipated was determined by the distance from the centre of the reactor; the maximum temperatures thus increased from the periphery towards the centre. The maximum temperature rise found was 14°C. The exothermy of the polymerisation reaction was less than with polymerisation in a dynamic system with stirring, which shows a simultaneous temperature rise of 8°C throughout the mass.

The advantages of an innovative system over any other connected with some characterising aspect thereof. All its aspects may be considered but, sooner or later, they all translate into the possibility of producing a given material which is cheaper than the others and can be produced with fewer operative risks for a product of a given quality.

The advantages achieved by the present invention consist essentially of a reduction in many of the problems involved in polymerisations in suspension carried out with stirred systems and particularly that inherent in the ever-present risk of the microspheres coalescing and possibly eventually blocking the blades of the reactor. The ease with which the polymerisations are effected, the quality of the polymers, and the cleanness of the system follow therefrom.

Although the type of catalytic system used can be left out of consideration since the invention can be used to bring to a conclusion polymerisations initiated by redox systems, by heating, or by U.V. or gamma irradiation, the polymerisations referred to herein are radical polymerisations initiated by peroxides, since these are amongst those which are most used industrially.

One experiment selected at random from those reported in Tables 2, 3 and 4 and illustrating the ways in which the invention can be put into practice is explained in detail. Very high catalytic concentrations were maintained in all the polymerisations carried out because we were also aiming to produce a series of reactive polymers in microsphere form with which to formulate acrylic cements for prosthetic use.

The invention was put into practice by:

1 - dissolving the agarose in distilled water at boiling point,

2 - filling the reactor with 400 ml of water and agarose at a concentration of 10g/litre (1% weight/volume): the creation of the continuous phase

(A),

3 - dissolving benzoyl peroxide catalyst (PBO) separately in the monomer methyl methacrylate (MMA) at a concentration of 5% at ambient temperature so as not to encourage its decomposition which would immediately start the polymerisation-initiating reaction: the creation of the monomeric phase (B),

4 - reducing the temperature in the reactor to 43°C which is slightly above the gel point of the agarose,

5 - introducing the catalyst and the monomer into the reactor over a period of 3 minutes by means of a feeder, stirring at a rate of 1,000 revolutions/min. with a turbine mixer: the creation of the unstable phase (C),

6 - stopping the stirring in the reactor at a temperature just below the gel point of the agarose selected (42°C): the creation of the stable phase (D),

7 - checking that the gel has formed,

8 - raising the temperature in the reactor to 70°C, 9 - polymerising the monomer (E),

10 - heat curing the reaction products at 90°C for 10 h,

11 - discharging the polymeric material from the reactor after breaking down the gel mechanically at 90°C,

12 - sending the polymeric material to the separation processes,

13 - purifying the polymeric material by washing cycles with hot distilled water and centrifuging in a centrifuge with a basket.

Polymerisation in a static system, which is the subject of the invention, is advantageous in that it enabled all the polymerisations and copolymerisations reported in Tables 2, 3 and 4 to be brought successfully to a conclusion.

Table 2 gives the data relating to methyl methacrylate (MMA) polymerisations carried out in a static system on the stable phases (D) produced with stirring rates of 500, 720, 1,000 revolutions/minute and with agarose concentrations of 0.7, 1.0 and 1.3% relative to the water (expt. Nos. 27, 11, 12, 30, 16, 29) and to one MMA polymerisation in a dynamic system (expt. No. 17).

Table 3 relates to polymerisations of methyl methacrylate (MMA) and vinyl pyrrolidone (VP) in:

- a dynamic system with a stirring rate of 1,000 revolutions/minute maintained both during the formation of the unstable phase (C) and during the polymerisation of the monomeric phase contained therein and formulated with monomeric MMA/VP ratios between 1/1 and 100/12.5 and 1% agarose (expt. Nos. 19, 20, 21, 22); experiment No. 19 (formulated with a monomeric MMA/VP ratio of 1/1) showed a division of the monomeric mass into three spheres of the same dimensions;

- a static system (expt. Nos. 23, 24, 25, 26) carried out on stable phases (D) formulated with monomeric MMA/VP ratios between 2/1 and 100/12.5 and 1% agarose, produced with stirring at 1,000 revolutions/minute. It was found that the gel point of the agarose affected coalescence even in the static system (expt. No. 23).

Table 4 shows tests relating to the polymerisation of MMA and bis diethylene glycol (allyl carbonate) (RAV) in:

- a dynamic system with a stirring rate of 720 revolutions/minute maintained both during the formation of the unstable phase (C) and during the polymerisation of the monomeric phase contained therein, which was formulated with a monomeric ratio of 70/30 (esp. No. 13),

- a static system (expt. Nos. 14, 15, 18, 28) carried out on stable phases (D) produced with stirring at 720 and 1,000 revolutions/minute and formulated with monomeric MMA/RAV ratios between 70/30 and 96/4.

During the tests all the predictions were followed both during the production of the continuous phase (D) and during its polymerisation in the static system. Thus :

1 - The monomeric phase (A) was dispersed in the continuous phase (B) in the stable form (D) with particles whose dimensions had changed, upon completion of the polymerisation, only by the shrinkage due to the change in the specific gravity from that of the monomer to that of the polymer .

2 - There was no negative interaction between the monomers and the gelling agent. Elementary analysis carried out on some samples from Tables 2, 3 and 4 and reported in Table 5, shows that the theoretical and experimental values for the polymerisation of the MMA and the copolymerisation of MMA with RAV correspond. The copolymerisations of MMA with VP produced values which differed from the initial formulation when conducted both in a static system and in a dynamic system with a more marked difference in the former. This is quite natural, given that VP is soluble in the continuous phase (A) as well as in the comonomer; because the partition coefficient of VP is more favourable towards water than towards the comonomer, not only is it possible to copolymerise only a portion of the available VP during the formulation, but, because of the movement of the particles in the aqueous phase containing the VP, that portion is greater for polymerisation in a static system than for polymerisation in a dynamic system.

3 - The polymerisation was carried with the absolute certainty that there was no risk of the microspheres agglomerating and blocking the reactor (a situation which always occurred in tests in a static system carried out in a bench reactor). 4 - The presence of contaminants was minimal, given that the suspension medium was simply a polysaccharide which can be removed upon completion of the polymerisation simply by washing with hot water.

5 - The materials had higher molecular weights than those obtained either with the same suspension medium or with other additives (see Table 6).

6 - The distribution of the diameters of the microspheres was narrow and their dimensions were inversely proportional to the rate of revolution of the stirrer and to the concentration of the agarose during the formation of the stable phase (D). The dimensions of the polymethyl methacrylate (PMMA) microspheres for a given agarose concentration (1%) followed a Gaussian distribution centred on dimensions of 250, 180 and 125 microns for values of 500, 720 and 1,000 revolutions/minute respectively. The dimensions of the microspheres with stirring at 1,000 revolutions/minute are apparent dimensions since, when subjected to fracture at -180ºC and analysed by scanning electron microscopy, they were found to be composed of spherical agglomerations of ultramicrospheres with dimensions of less than 1 micron.

7 - There was an almost complete lack of microspheres with superficial or internal imperfections. Although agarose was found to be a good suspension medium, even in polymerisations carried out in dynamic systems, all the microspheres produced with those systems produced considerable percentages of materials with fish-eyes, invaginations, splits, and agglomerations. Those carried out in static systems, however, always produced geometrically spherical materials with uniform and continuous morphology both superficially and internally.

8 - The microspheres were easily separated from the continuous phase.

9 - The difficulties in the purification of the microspheres (E) were eliminated; the agarose was removed by the breaking-down of the continuous phase (A) by mechanical means at a high temperature, followed by normal washing with hot water and the centrifuging or filtration of the microspheres.

10 - The basic materials produced for formulating acrylic cements for biomedical use had mechanical characteristics comparable with those of commercial products in the sector.

Without introducing concepts which lie outside the present explanation, the parameters for scaling up the production capacity from the laboratory scale were evaluated.

A one-litre reactor half filled, for safety, produced 100 grams of polymer/load without running a risk of the microspheres agglomerating.

If the heat of polymerisation is dissipated correctly, for example, by varying the coefficient of the transmission of heat to the exterior, it is easy to envisage the use of reactors with diameters of at least 20cm which, with the same shape coefficient, would have capacities of 8.5 1. Production, still on a laboratory scale, would rise, under conditions of maximum safety, to 8.5 × 0.2 × 0.5 = 0.85 kg of polymeric material/reactor.

Given that the overall polymerisation times are less than 2 h, even with the addition of 1 h for discharging and cleaning the reactor, in an 8 h shift, no less than 8 × 0.85/(2+1) = 2.25 kg of material/reactor/working shift could be produced. The annual production, based on 220 working days would amount to 445 kg/reactor/working shift/year.

For a hypothetical production of 3,000 kg/year of acrylic cements and basic materials for dental prostheses (which is a fairly low proportion of the quantity marketed in Italy) with 50% rejection due to any imperfect particle-size distribution, it would be necessary to have 3,000 × 2/445 = 12 reactors/working shift for single shifts, or 12/3 = 4 reactors/working shift/day.

In order to increase the capacity of the process, if sales were greater and the materials were used for other purposes, the length of the reactor could be increased, so as actually to transform it into a tubular reactor with a shape coefficient even greater than 5/1 compared with those used in the laboratory. In this case the residual safety volume would not be considered and, with the same number of reactors/days, production would rise to 3,000 × 2 × 5 = 30,000 kg/year.

Global industrial production, that is, for all industrial applications could not be achieved solely by multiplying the number of reactors. Although, on the one hand, an increase in the number could make the system more versatile (the reactors could be used for the production of different particle sizes), on the other hand, it would create management problems (if the materials were intended for highly specialised purposes, each production lot would have to be tested before being put on the market).

For consistent industrial production, it would be preferable to transport the stable suspension (D), which can be produced in a container of any dimensions, continuously through a tubular reactor or a reactor with a tube nest at the polymerisation temperature, the entire process being completed during its passage through the reactor, or to transport the unstable suspension (C) through a reactor which is again tubular and has a jacket or a tube nest, but in which the temperature varies, increasing in the direction of travel, and in which the stable phase (D) is both set and polymerised.

A prospect which is more interesting but none the less possible relates to the drawing of the stable suspension (D), by a continuous process, through a container in which the temperature is controlled and from which threads of polymer microspheres (E), gelled in the continuous phase (A), are collected after the necessary time. This solution would enable better control of the temperature than any other system since it enables the greatest increase of the surface for the exchange of heat which, in particular, is excellent.

The increase in production costs due to the use of the agarose can be estimated approximately only by excess (other polysaccharides are not considered herein). Very pure agarose for scientific uses at present costs about 800,000 lire/kilogram but, with a high level of demand, the commercial price could fall below this. Even in the worst case, that is, polymerisations which are carried out with 2.5% agarose with respect to the monomeric phase because that is most suitable for the geometry of the reactor and the stirring rate used, the increase in the cost compared with the polymerisation of a monomer in a system with only monomer/water/catalyst (which, however, is probably impossible to achieve) would be 800,000 × 25/1,000 = 20,000/kg.

Given that the mechanical-thermal hysteresis of agarose lasts for several repeated cycles and that the quantity of 2.5% with respect to the monomer is definitely high, with a mechanically optimised system for producing the stable suspension (D), the additional cost, compared with polymerisation in a suspension without any additive, would therefore certainly fall below 10,000/kg. With three cycles, the increase would be 6,700 lire/kilogram in current conditions.

Still considering materials of very high purity, the current cost of the monomer MMA (18,000/kg) is much less than that of its polymer PMMA (170,000/kg). The polymerisation costs also include the costs of the additives. The cost of agarose appears to be economically comparable with these, again under the conditions given above.

The materials produced are suitable for technical applications. As indicated above, there are many sectors in which polymer microspheres are used and others may gradually be added as knowledge of the materials which can be produced by means of the present invention becomes more widespread. In practice, since they are insoluble in the continuous phase (A), most vinyl monomers like styrene and substituted styrenes, vinylidene chloride, vinyl acetate, and acrylic and methacrylic esters can be polymerised or copolymerised in a system such as that described. Polycarbonate pearls can also be produced by this method.

Reference has been made to the biomaterials, optics, manufacturing, and civil engineering sectors since it is envisaged that the products which can be produced by means of the present invention could be used industrially therein.

A sector of use of particular social relevance is that of biomaterials in which the largest use is in orthopaedics and in dental prosthetic reconstructions. Microspheres of polymeric material are used in the formulations of the acrylic cements used for fixing metal prostheses in femoral bone cavities and anchoring new synthetic acetabuli to hip bones, as well as in the construction of dental prostheses. In these applications, all materials must have at least the following four characteristics: mechanical suitability, physical compatibility with other biological or metallic synthetic components, non-harmful interfacing with biological components, high purity. The present invention provides materials which are certainly comparable with those on the market and probably at a lower cost.

The optics sector appears possible, given the perfect transparency and the high refractive indices of the MMA and RAV copolymers produced according to the present invention. The refractive index increases with the polycarbonate content. Although synthetic glasses for spectacles and heated rear windows are produced by the polymerisation of the monomeric phase in a suitable mould, it is not impossible to envisage a different method if only by hot moulding which would enable them to be produced from these very pure materials.

In the manufacturing sector, the use of fillers and functionalised polymers is widely documented. In the formulation of recipes for products which can be produced by extrusion, moulding, pouring, or casting, hot or cold, reference is always made to the surface characteristics and the dimensions of the constituent particles. The microspheres which can be produced by means of the present invention may represent a reliable element because of their fully-described characteristics.

Uses indicated in the civil engineering sector are for road signs, the production of markings, interior and exterior painting, and the colouring of products. In this sector the vehicles are generally constituted by polymeric matrices (lacquers, paints, bitumen, asphalt etc.) and the reflective element is constituted by microspheres of silanised glass. It is envisaged that, because of their characteristics of hardness, transparency, refractive index, their chemical characteristics (the materials (E) with high catalyst contents, such as reactive polymers), microspheres of a copolymer of MMA and styrene, substituted styrene or polycarbonates, or of polycarbonates themselves could effectively replace glass microspheres.

Claims

1. A method of producing monomeric phases in the form of microspheres, characterised in that it is concerned with the reduction of the monomeric phase into microspheres, involving: a continuous phase (A), constituted by at least one polysaccharide dissolved in hot distilled water, a monomeric phase (B) constituted by at least one monomer and the catalyst, an unstable dispersion (C) produced by the mechanical mixing of the preceding phases, and a stable dispersion (D), produced by reducing the temperature of the unstable dispersion until the continuous phase gels, and stopping the stirring, and the production of the polymeric microspheres (E) by discontinuous or continuous processes involving: the raising and control of the temperature of the stable dispersion (D) during polymerisation, possibly the curing of the polymeric microspheres, their purification by washing with hot water, and the separation of the continuous phase (A).
2. A method according to Claim 1, characterised in that the continuous phase (A) is constituted by a solution containing at least one polysaccharide with mechanical-thermal hysteresis.
3. A method according to Claim 1 and Claim 2, characterised in that, if a copolymerisation between a monomer which is immiscible with the aqueous phase and another which is miscible both with the aqueous phase and with the comonomer with an initiator constituted by a redox pair is involved, in addition to a polysaccharide or a mixture of polysaccharides, the continuous phase (A) may contain, a monomer soluble therein.
4. A method according to one of Claims 1 to 3, characterised in that, of the polysaccharides, agarose was tested but does this not exclude or prejudice the use of agar, alginic acid, Na and K alginates, starch, gelatine, or anything else which has mechanical-thermal hysteresis instead of or in addition to agarose in the composition of the continuous phase.
5. A method according to one of Claims 1 to 4, characterised in that the quantity of agarose in the composition of the phase (A) is between 0.01 and 10% of the quantity of water.
6. A method according to one of Claims 1 to 5, characterised in that the polysaccharide/s is/are normally dissolved in water at the lowest suitable temperature which may vary according to the composition of the continuous phase (A) and according to the percentage of polysaccharides.
7. A method according to Claim 1, characterised in that the monomeric phase (B) consists of at least one vinyl, carboxylic, or diene monomer such as, for example, styrene and substituted styrenes, vinylidene chloride, vinyl acetate, acrylic and methacrylic esters which are immiscible in the continuous phase.
8. A method according to Claim 1 and Claim 7, characterised in that, instead of a single monomer, the monomeric phase (B) may be constituted by two or more monomers which are miscibile with each other but immiscible with the continuous phase, or by one or more monomers which are insoluble in the continuous phase and another monomer which is soluble both in the continuous phase and in the other monomers.
9. A method according to one of Claims 1, 7 and 8, characterised in that the monomeric phase (B) may include one of the radical catalysts in solution, or may not include one, as required in polymerisations which are initiated by redox systems, by heating, or by irradiation with UV or gamma rays.
10. A method according to one of Claims 1 to 9, characterised in that the monomeric phase (B) is mixed with the continuous phase (A) in a container of any size and shape by means of systems and stirring rates suitable to produce microspheres of the desired dimensions and, if necessary, by systems with variable geometry and stirring rates.
11. A method according to one of Claims 1 to 10, characterised in that the monomeric phase (B) is mixed with the continuous phase (A) with a volumetric ratio between the monomeric phase (B) and the continuous phase (A) of between 1:1,000 and 2:1 (between 1 g/litre and 2,000 g/litre of the continuous phase (A)).
12. A method according to Claim 11, characterised in that the mixing takes place at a temperature higher than the gel point of the continuous phase.
13. A method according to one of Claims 10 to 12, characterised in that the unstable dispersion (C) is kept viable by continuous sitrring until it is utilised further.
14. A method according to one of Claims 10 to 13, characterised in that when the temperature of the unstable dispersion (C) is reduced below the gel temperature of the continuous phase (A) and the stirring is stopped, a stable dispersion (D), in which the monomer microspheres are dispersed homogeneously and suspended stably, is generated.
15. A method according to one of Claims 7 to 14, characterised in that the monomer microspheres which form part of the stable dispersion (D) are transformed into polymeric materials (E) in the form of microspheres of the same dimensions as those of the unstable dispersion (C) by a temperature rise and/or irradiation with ultraviolet or gamma rays, which continues at least until the reactions which initiate and propagate polymerisation result.
16. A method according to one of Claims 7 to 15, characterised in that the concentrations of the catalysts which, if they are in the monomeric phase (B), are radical catalysts with peroxide or nitrile bonds and others or, if they are in the continuous phase (A), are redox catalysts and others, are between 0.05 and 10% with respect to the monomeric phase.
17. A method according to one of Claims 7 to 16, characterised in that the polymerisations can be completed with the usual monomeric concentrations (between 0.1 and 1% relative to the monomeric phase (A)).
18. A method according to one of Claims 7 to 17, characterised in that, although they do not appreciably affect the molecular weight of the product, concentrations greater than 1% with respect to the monomer are used when a reactive polymer suitable for initiating and bringing to a conclusion the polymerisation of a new monomer added to the powder of polymeric material (E) is to be produced.
19. A method according to one of Claims 7 to 18, characterised in that the polymerisation reactions may take place in the reactor in which the stable phase (D) is formed, or in other, dimensionally and geometrically different reactors after the dispersion (D) has been transferred from the former to the latter.
20. A method according to one of Claims 7 to 19, characterised in that the polymerisations may take place either discontinuously or continuously.
21. A method according to one of Claims 7 to 20, characterised in that the monomeric phase (B) in the stable dispersion (D) may be polymerised indirectly or directly throughout the mass (D).
22. A method according to one of Claims 7 to 21, characterised in that the stable dispersion (D) is polymerised indirectly and continuously after the unstable dispersion (C) has been transferred into a tubular reactor or a reactor with a tube nest which has a temperature profile with at least two distinct portions, of which the first has a temperature below the gel point of the continuous phase (A) in order to produce the stable dispersion (D) and the other has the temperature selected to polymerise the monomeric phase (B) in the stable dispersion (D), or in which the temperature increases in the direction of flow of the transferred material until it reaches the same temperature.
23. A method according to one of Claims 7 to 22, characterised in that the surface/volume ratio of the stable phase (D) is increased by the direct and continuous polymerisation of the monomeric phase (B) in the stable phase (D), by the continuous transportation of the material through a die in a reactor containing water circulating at the polymerisation temperature.
24. A method according to Claim 23, characterised in that the control of the polymerisation temperature of the monomeric phase (B) in the stable dispersion (D) is facilitated by the very high surface/volume ratio and by the excellent exchange of heat with the circulating water.
25. A method according to one of Claims 1 to 6, and Claims 14 to 24, characterised in that the heat curing of the polymeric material (E) is effected directly in the stable suspension (D) at temperatures up to that at which the continuous phase (A) is almost broken down.
26. A method according to one of Claims 1 to 6 and Claims 14 to 25, characterised in that the polymeric material (E) is purified simply by sufficient washing with hot water to destroy, mechanically or without mechanical intervention, the stable suspension (D) which contains it, decantation or filtration, and successive washings, decantations and filtrations until the residual agarose is eliminated.
27. A use for the polymeric materials produced according to Claims 1 to 6 and Claims 14 to 26, characterised in that at least one of the homopolymers and/or copolymers (E) of the series derived from the monomers MMA, RAV and VP can act as a substrate in compositions for acrylic cements for biomedical use or for prosthetic elements of the masticatory apparatus.
28. A use for the polymeric materials produced according to Claims 1 to 6 and Claims 14 to 26, characterised in that, given that their glass transition temperatures are between 102 and 115 C, at least one of the homopolymers and/or copolymers (E) of the series derived from the monomers MMA, RAV and VP can easily be compressed hot, as it is, to produce a product of certain dimensions.
29. A use for the polymeric materials produced according to Claims 1 to 6 and Claims 14 to 26, characterised in that at least one of the homopolymers and/or copolymers (E) of the series derived from the monomers MMA, RAV, and VP can be used, together with other materials from various sources, in the formulation of recipes for products which can be produced by hot or cold coextrusion, moulding, pouring or casting.
30. A use for the polymeric materials produced according to Claims 1 to 6 and Claims 14 to 26, characterised in that, given the high refractive indices of these materials, at least one of the homopolymers or copolymers (E) of the series derived from the monomers MMA and RAV can be used in the optics sector.
31. A use for the polymeric materials produced according to Claims 1 to 6 and Claims 14 to 26, characterised in that at least one of the homopolymers or copolymers (E) of the series derived from the monomers MMA and RAV may be used to replace silanised glass microspheres in the civil engineering sector, particularly as regards their use for road signs, in the production of markings, for interior and exterior painting and in the colouring of products.
PCT/EP1991/002276 1990-12-05 1991-12-02 A method of producing monomeric phases in the form of microspheres dispersed homogeneously and suspended stably in continuous phases constituted by polysaccharide gels, the polymerisation thereof, and use WO1992010282A1 (en)

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Publication number Priority date Publication date Assignee Title
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US4520178A (en) * 1981-07-15 1985-05-28 Nippon Oil Co. Ltd. Process for producing water-insoluble polymers of uniform shape from gelled salts of alginic acid
EP0213908A2 (en) * 1985-08-26 1987-03-11 Hana Biologics, Inc. Transplantable artificial tissue and process
EP0257412A1 (en) * 1986-08-14 1988-03-02 BASF Aktiengesellschaft Paper-sizing agent based on particulate aqueous dispersions
EP0134449B1 (en) * 1983-07-01 1989-02-01 Wacker-Chemie GmbH Process for preparing aqueous polymer dispersions, and their use

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2875185A (en) * 1954-08-23 1959-02-24 Dow Chemical Co Method of polymerizing a monoethylenically unsaturated vinylidene compound in aqueous suspension
US4520178A (en) * 1981-07-15 1985-05-28 Nippon Oil Co. Ltd. Process for producing water-insoluble polymers of uniform shape from gelled salts of alginic acid
EP0134449B1 (en) * 1983-07-01 1989-02-01 Wacker-Chemie GmbH Process for preparing aqueous polymer dispersions, and their use
EP0213908A2 (en) * 1985-08-26 1987-03-11 Hana Biologics, Inc. Transplantable artificial tissue and process
EP0257412A1 (en) * 1986-08-14 1988-03-02 BASF Aktiengesellschaft Paper-sizing agent based on particulate aqueous dispersions

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Derwent Publications Ltd, London (GB), Database WPIL Acussion no. 91-056158[08], & SU, A, 1551710 (IRKUT UNIV.) 23 March 1990, see abstract *

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