WO2012110995A1

WO2012110995A1 - Silica core-shell microparticles

Info

Publication number: WO2012110995A1
Application number: PCT/IE2012/000007
Authority: WO
Inventors: Jennifer Mary COAKLEY; John Paul Hanrahan; John Joseph HOGAN; Trevor Richard Spalding; Joseph Michael TOBIN
Original assignee: GLANTREO Ltd
Current assignee: GLANTREO Ltd
Priority date: 2011-02-16
Filing date: 2012-02-16
Publication date: 2012-08-23
Anticipated expiration: 2013-08-16

Abstract

Hybrid silica core - shell microparticles are prepared by growing a porous hybrid silica shell from a mixed silica precursor comprising an alkoxy silica precursor and an organic alkoxy silane precursor onto the surface of non- porous silica particles dispersed in a stabilizing mixed surfactant solution under basic pH conditions, the growth step is repeated a plurality of times. The microparticles are hydrothermally treated in an oil-in-water emulsion system and residual surfactant is removed by calcination or extraction. The final pore diameter of the microparticles is increased by controlled dissolution in an acidic or basic solution.

Description

"Silica core-shell microparticles"

Introduction

The invention relates to a process for preparing core shell silica microparticles and core shell hybrid silica microparticles. The microparticles are especially useful in chromatography, such as liquid chromatography

In the recent development of particle technology targeted for liquid chromatography, the use of core shell (or shell) particles has received considerable attention. The development of core-shell particles is seen to be pivotal to modern liquid chromatography (LC) column technology.

DE-19530031 (Unger et al) describes a process for forming templated core-shell suborn silica particles comprising a porous layer on the surface of a non-porous silica core by sol-gel polycondensation of an alkytrialkoxysilane in an ammonia-water solution in which ammonia acts as a catalyst and alkyltrialkoxysilane functions as porogen. The average particle size produced by this process is less than lOOOnm (1.0 μηι).

JP2006-34789 describes a process for making templated core-shell silica particles that employs alkylammonium halide. The maximum size of the core-shell silica particles described is 1.2 μιη. JP2006-34789A, describes an approach of stacking a single shell layer comprising of silica onto a nonporous silica surface, in the presence of a quaternary ammonium halide as a templating agent to produce the core-shell silica.

In 2006 Advanced Material Technology (AMT) launched the Fused-Core^® particles (Halo™). The 2.7 μη silica particles are described as consisting of 1.7 μηι non-porous particles and 0.5 μηι porous shell. The Halo chromatographic column is described as generating an efficiency of 250,000 N/m equivalent to reduce plate height minimum (/?_mj_n) of 1.5 for small molecules when packed in a 4.6 mm I.D. columns.

In 2009, Phenomenex Inc. offered silica core-shell particles of 2.6 and 1.7 μπι particle diameters. The 2.6 μιη particles were described as consisting of a 1.9 μηι nonporous particles coated with a 0.35 μηι porous layer of aggregated colloidal silica. Similarly, the 1.7 μηι particles were described as consisting of a 1.3 μιη solid-core covered with a 0.25 μηι porous layers of silica. These columns are currently commercialised as inetex™. The 2.6 μιτι particle is described as being capable of producing an efficiency of 320,000 N/m, equivalent to

= 1.2 when packed in a 4.6 mm I.D. columns. It is said that the 2.6 μη particle produces up to 200,000 N/m, equivalent to h_m\n -_^ 1.9 when packed in a narrow bore column, i.e., a 2.1 mm I.D. column.

US2009/0053524A1 (Yamanda-Ashai) describes a process for making core shell silica particles that utilises alkyl ammonium halide surfactant. In particular, dodecyl amine is used as a surfactant template to produce templated core-shell sub^m silica particles. Particles having a shell thickness of 0.15 μιη on the surface of a non-porous silica core having a diameter of 1.0 μηι, are described. The particles have a pore size of 2.5 nm, pore volume of 0.09 mL/g and a maximum particle size of 1.3 μπι. The morphology of these core-shell particles especially pore volume and pore size, are not ideal for use as a chromatographic packing material.

Yoon et. al. (J.Mater.Chem 17 (2007) 1758) describe a process for preparing core-shell nanosized silica using a similar approach to that described in JP2006-34789 but using a different chain length of alkyl ammonium halide. The particles described by Yoon et. al are so small that, they would pose a significant difficulty when packed in a column to be used for conventional or ultra high pressure liquid chromatography separation. The consequences will chiefly be the enormous back pressure encountered, such that no commercial LC or UPLC instrument available today could operate on such a material when packed in a column.

The methods of US2009/0053524, JP2006-34789 and Yoon et al describe single layer stacking of a porous shell silica on a non-porous silica core surface which results in a thin shell that takes between 12 to 24 hours to be deposited.

The physical characteristics of the particles produced by the process of Yoon et al¹' ², US2009/0053524 Al and JP2006-34789 are predicted not to yield enhanced chromatography separation due to the very small pore sizes and thin porous shell to accommodating very small pore volume (0.02 to 0.09 mL/g). There is a need for an improved optimised process for preparing silica and hybrid silica microparticles that can be used as a packing material for chromatography separation.

Statements of Invention

According to the invention there is provided a process for preparing hybrid silica core— shell microparticles comprising the steps of:

a) growing a porous hybrid silica shell from a mixed silica precursor comprising an alkoxy silica precursor and an organo alkoxy silane precursor onto the surface of non- porous silica particles dispersed in a stabilizing mixed surfactant solution under basic pH conditions;

b) hydrothermally treating the microparticles of (a) in an oil-in-water emulsion system;

c) removing residual surfactant by calcination or extraction; and

d) controlled dissolution of the microparticles of (c) in an acidic or basic solution to increase the final pore diameter of the microparticles

wherein step (a) is repeated a plurality of times.

The mixed surfactant may comprise a cationic surfactant and a non-ionic surfactant. The cationic surfactant may be an alkyl ammonium tosylate. The alkyl ammonium tosylate may be selected from the group comprising: hexadecyltrimethylammonium p-tolunensulfonate; 4- chloro-N,N-diethyl-N-heptylbenzenebutanaminium tosylates (Clofilium Tosylate); Ν,Ν,Ν- Trimethyl-4-(6-phenyl- 1 ,3 ,5-hexatrien- 1 -yl)phenylammonium p-toluenesulfonate; and tetrabutylammonium p-toluenesulfonate. The mixed surfactant solution may comprise a tri- block co-polymer. The tri-block co-polymer may be a difunctional pluronic block co-polymer. The tri-block co-polymer may comprise a polyethylene oxide (PEO) and/or a polypropylene oxide (PPO) unit. The tri-block co-polymer may have a terminal HO- group at one or both ends of the PEO group. The triblock co-polymer may comprise the formula:

ΡΕΟχ PPO_yPEO_x

wherein:

x is an integer between 5 and 106; and

y is an integer between 30 and 85. The tri-block co-polymer may be PEO₂₀ PPO₇₀ PEO₂₀ and/or PEO₁₀₆ PPO₇₀ PEOi₀₆ The tri- block co-polymer may act as a steric stabiliser to prevent aggregation of particles during the growth of silica shell.

The alkoxy silica precursor may be one or more of tetrapropyl ortho silicate (TPOS), tetrabutyl ortho silicate (TBOS) tetraethyl ortho silicate (TEOS), and tetramethyl ortho silicate (TMOS).

The organic alkoxy silane precursor may have the general formula

RnX_(3-n)Si-(CH₂)_z-Si- RnX_(3-n)

wherein:

R is an organic radical;

X is a hydrolysable group;

n=l or 2; and

z is an integer from 1 to 30.

The organo alkoxy silane precursor may be selected from triethoxymethylsilane (TEMS) and bis- l,2-(triethoxysilyl) ethane (BTSE).

The molar ratio of alkoxy silica precursor to organo alkoxy silane precursor may be between about 90: 10 to about 40:60. The molar ratio of alkoxy silica precursor to organo alkoxy silane precursor may be between about 90: 10 to about 75:25.

Ammonia may be added to the growth step to form the basic pH conditions.

The oil- in -water emulsion comprises one or more of an aliphatic alkane, a cycloalkane, or aromatic hydrocarbon of the formula:

C_nH₂+_2n> C_nH_2n, C_nH_n-x(CH₃)n;

wherein:

n is an integer between 6 to 12; and

x is an integer between 1 to 3. The oil unit of the oil-in-water emulsion system may comprise one or more of decane, trimethylbenzene, and cyclooctane. The oil-in-water emulsion may comprise ammonium iodide.

Step (a) may be repeated between 2 and 100 times. Step (a) may be performed at a temperature between about 25 °C to about 55 °C. Step (a) may take between about 1 hour and about 24 hours.

The microparticles may be hydrothermally treated at a temperature of from about 60 °C to about 150 °C. The microparticles may be hydrothermally treated from about 1 hour to about 72 hours. The hydrothermally treated microparticles may be dried prior to calcination. The microparticles may be dried under vacuum.

The microparticles may be dried at a temperature of between about 98 °C to about 102 °C. The microparticles may be dried for about 24 hours.

The microparticles may be calcined at a temperature of about 500 °C to about 600 °C to remove surfactant. The microparticles may be calcined at a ramping temperature. The temperature may be ramped at a rate of between about 1 °C and about 10 °C per minute. The microparticles may be calcined for between about 76 hours to about 24 hours.

The surfactant may be extracted from the microparticles using an alcoholiacid mixture.

Controlled dissolution of the microparticles may be performed in an aqueous solution of ammonia and hydrogen peroxide. Controlled dissolution of the microparticles may take place at a temperature of about 75 °C. Controlled dissolution of the microparticles may take place for between about 8 hours to about 16 hours.

The invention also provides a hybrid silica core-shell microparticle comprising a non-porous core with an average diameter of at least 1.4μηι and a porous hybrid silica shell. The invention further provides a hybrid silica core-shell microparticle comprising a non-porous core with an average diameter of about 1.4μπι and a porous hybrid silica shell with an average thickness of about 0.15 μιη.

The invention further provides a hybrid silica core-shell microparticle comprising a non-porous core with an average diameter of about 1.8μπι and a porous hybrid silica shell with an average thickness of about 0.4 μηι.

The invention also provides a hybrid silica core-shell microparticle comprising a non-porous core with an average diameter of about 2.5μπι and a porous hybrid silica shell with an average thickness of about 0.5 μιη.

The core may be solid. The core may be formed from silica.

The porous hybrid silica shell may contain up to about 60% carbon by weight within the silica framework. The porous hybrid silica shell may contain up to about 50% carbon by weight within the silica framework. The porous hybrid silica shell may contain up to about 25% carbon by weight within the silica framework. The porous hybrid silica shell may contain up to about 15% carbon by weight within the silica framework. The porous hybrid silica shell may contain up to about 10% carbon by weight within the silica framework.

The porous hybrid silica shell may have a thickness of between about 0.1 μιη and about Ι Ομηι. The porous hybrid silica shell may have a thickness of between about 0.1 μιη and about Ι μηι. The porous hybrid silica shell may comprise multiple layers of hybrid silica. The microparticle may have a substantially smooth surface. The pores may have an average size of between about 20A and about 300A. The pores may have an average size of between about 60A and about 300A. The pores may have an average size of about 80 A.

The microparticle may have a specific surface area from about 50m²/g to about 1000m²/g.

The microparticle may comprise a functional ligand attached to the shell. The functional ligand may be chemically attached to the shell. The functional ligand may be C8 or CI 8. The invention also provides a silica core-shell microparticle with an average diameter of about 2.6μηι comprising a non-porous silica core with an average diameter of about 1.8μπι and a porous silica shell with an average thickness of about 0.4μηι wherein the pores have an average size of about 80 A. The microparticle may have a specific surface area of about 174 m²/g.

The invention further provides a silica core-shell microparticle with an average diameter of about 3.5μηι comprising a non-porous silica core with an average diameter of about 2.5μιη and a porous silica shell with an average thickness of about 0.5μη wherein the pores have an average size of about 80 A. The microparticle may have a specific surface area of about 230 m²/g.

Also provided is a chromatography packing material comprising hybrid silica core-shell microparticle or silica core-shell microparticles described herein.

The invention also provides for the use of hybrid silica core-shell microparticles produced by the process of liquid chromatography separation.

The invention further provides for the use of hybrid silica core-shell microparticle or silica core- shell microparticles described herein.

Also described is a process for preparing silica and hybrid silica core— shell microparticles comprising the steps of: a) growing a porous silica shell from a silica precursor onto the surface of non- porous silica particles dispersed in a stabilizing mixed surfactant solution under basic pH conditions;

b) hydrothermally treating the particles of (a) in an oil-in-water emulsion system; c) removing residual surfactant by calcination or extraction; and

d) controlled dissolution of the particles via acidic or basic solutions of (c) to increase the final pore diameter of the particles.

The mixed surfactant may comprise a cationic surfactant and a non-ionic surfactant. In one case the cationic surfactant is an alkyl ammonium tosylate. The alkyl ammonium tosylate may be selected from the group comprising: hexadecyltrimethylammonium p-tolunensulfonate;

4-chloro-N,N-diethyl-N-heptylbenzenebutanaminium tosylates (Clofilium Tosylate);

N,N,N-Trimethyl-4-(6-phenyl-l ,3,5-hexatrien-l-yl)phenylammonium p- toluenesulfonate; and tetrabutylammonium p-toluenesulfonate.

The mixed surfactant solution may comprise a tri-block co-polymer. The tri-block co-polymer may be a difunctional pluronic block co-polymer. The tri-block co-polymer may comprise a polyethylene oxide (PEO) and/or a polypropylene oxide (PPO) unit. The tri-block co-polymer may have a terminal HO- group at one or both ends of the PEO group.

In one case the triblock co-polymer comprises the formula:

PEO_x PPO_yPEO_x wherein: x is an integer between 5 and 106; and y is an integer between 30 and 85.

The tri-block co-polymer may be PEO₂₀ PPO₇₀ PEO₂₀ and/or PEOi₀₆ PPO₇₀ PEO,o₆

The tri-block co-polymer may act as a steric stabiliser to prevent aggregation of particles during the growth of silica shell.

The silica precursor may be an alkoxy silica precursor. The silica precursor may be one or more of tetrapropyl ortho silicate (TPOS), tetrabutyl ortho silicate (TBOS) tetraeThyl ortho sfficate^{^} (TEOS), and tetramethyl ortho silicate (TMOS).

In one case the silica precursor is an organic alkoxy silane precursor having the general formula RnX_(3-n)Si-(CH₂)z-Si- RnX₍3-n) wherein R is an organic radical X is a hydrolysable group, n=l or 2, and z is an integer from 1 to 30

In one case ammonia is added to the growth step to form the basic pH conditions.

The oil- in -water emulsion may comprise one or more of an aliphatic alkane, a cycloalkane, or aromatic hydrocarbon of the formula:

C_nH_2+2n> C_nH_2n, C_nH_n-x(CH3)_n; wherein: n is an integer between 6 to 12; and x is an integer between 1 to 3.

The oil unit of the oil-in-water emulsion system may comprise one or more of decane, trimethylbenzene, and cyclooctane.

The oil-in-water emulsion may comprise ammonium iodide.

Step (a) may be repeated at least more than once. Step (a) may be repeated between 2 and 100 times.

In one case step (a) is performed at a temperature between about 25 °C to about 55 °C. Step (a) may take between about 1 hour and about 24 hours.

In one case the particles are hydrothermally treated at a temperature of from about ^~60^~°C to abouT 150 °C.

The particles may be hydrothermally treated from about 1 hour to about 72 hours. The hydrothermally treated particles may be dried prior to calcination. The particles may be dried under vacuum. The particles may be dried at a temperature of between about 98 °C to about 102 °C. The particles may be dried for about 24 hours.

In one case the particles are calcined at a temperature of about 500 °C to about 600 °C to remove surfactant. The particles may be calcined at a ramping temperature. The temperature may be ramped at a rate of between about 1 °C and about 10 °C per minute. The particles may be calcined for between about 76 hours to about 24 hours.

In one case the surfactant is extracted from the particles using an alcohohacid mixture

The particles may be base etched in an aqueous solution of ammonia and hydrogen peroxide.

The particles may be base etched at a temperature of about 75 °C. The particles may be base etched for between about 8 hours to about 16 hours.

Also described is a silica core-shell particle when made by a process wherein the particle has an average diameter of between about 0.9 μιη and about 4.0 μηι. The core may have an average diameter of between about 0.6μπι and about 2.6μιη. The particle may have an average diameter of about 1.7μηι comprising a core with an average diameter of about 1.4μηι and a shell thickness of 150nm.

In one case the core is non-porous. The core may be solid.

The shell may have an average thickness of between about 0.1 μπι and about ΙΟμπι. In one case the shell is porous.

The pores may have an average size of between about 2nm and about 30nm. The pores may have an average pore volume of between about O. lcc/g and about 2.0cc/g. The particle may have a specific surface area of from about 50m²/g to about 1000m²/g. The shell may comprise multiple layers of silica. The surface hydroxyl groups of the particle may be more thermally stable than the surface hydroxyl groups of particles synthesized using alkyl ammonium halides. Complete dehydroxylation of the surface silanol groups may occur at temperatures in excess of 1200°C.

The particle may comprise a functional ligand attached to the shell. The functional ligand may be chemically attached to the shell. The functional ligand may be C8 or CI 8.

Also described is a silica core-shell particle wherein the surface hydroxyl groups of the particle are more thermally stable than the surface hydroxyl groups of particles synthesized using alkyl ammonium halides.

Also described is a silica core-shell particle wherein complete dehydroxylation of the surface silanol groups occurs at temperatures in excess of 1200°C.

In another aspect the invention provides a hybrid silica core-shell particle.

Also described is a hybrid silica core-shell particle having an average diameter of between about 0.9 μηι and about 4.0 μηι.

The porous shell of the hybrid particle may contain up to 50% carbon by weight within the silica framework.

Also described is a chromatography packing material comprising silica core-shell or hybrid silica core shell particles of the invention.

The particles of the invention may be used in liquid chromatography separation.

Particle sizes of 2.0μηι or less are more suited to UPLC instrumentation whereas particle sizes of greater than 2.0μπι are more suited to 'traditional' HPLC instrumentation.

In one aspect the invention provides a process for preparing silica and hybrid silica core shell microparticles for use in chromatography, such as liquid chromatography (LC). The hybrid particles have a percentage of carbon 'in built' into the silica framework. These hybrid silica particles are seen to have several advantageous over 'pure silica' particles such as increased resistance to acidic and basic solutions. In particular, the invention provides a process for producing sub - 4μηι microparticles for use in LC. The core-shell spherical silica and hybrid silica microparticles have a thin to thick porous shell with diameters from 100 nm to 500 nm, perpendicularly grown around the surface of non-porous silica core with an average diameter of about 1.0 μπι to about 5.0 μηι such as about 1.4 μιη to about 2.5 μηι or about 600 nm (0.6 μιτι) to about 1500 nm (1.5 μιη). The core-shell microparticles may be used as packing material in chromatography such as liquid chromatography.

Hybrid silica particles are a member of a class of materials known as organic/inorganic hybrids. These materials contain both inorganic (such as silica) and organic (such as organosiloxane) elements and thus share the advantages of both. One route to creating hybrid particles is to use a mixture of two high-purity monomers: one that forms Si0₂ units during the particle formation process and another that forms RSiOl .5 (organosiloxane) units. The resulting particles contain organosiloxane groups incorporated throughout their internal and surface structure. Waters Technology (Milford, MA) have pioneered the use of fully porous hybrid silica particles for applications as stationary phases in HPLC and UPLC, so called X'bridge particles.

Hybrid particles offer a number of advantages (in HPLC) over pure silanous particles such as

1. Basic Compound performance; The peak shapes obtained for strongly-basic compounds in reversed-phase HPLC are dependent upon both the concentration and acidity of the residual silanol groups that are present after bonding. Steric hindrance limits the extent of derivatisation for traditional surface-bonded packings. However, because the hybrid particles contain methylsiloxane groups in place of a third of the Si0₂ units, they yield bonded phases with reduced concentrations of residual silanols. As a consequence, bonded phases based on hybrid particles deliver exceptional peak shape for basic compounds.

2. Improved high-pH stability; The high-pH stability of silica-based reversed columns is determined by the rate of dissolution of the underlying silica particle. After dissolution has proceeded to a critical point, the packed bed abruptly collapses, causing voids which result in catastrophic loss of efficiency. Because dissolution requires access of hydroxyl ions to the silica surface, the rate of dissolution depends on the amount of underivitased silica surface. Bonded phases based on hybrid particles have an extremely low area of underivitised silica surface because of the methylsiloxane units incorporated throughout their structure. Accordingly, columns containing these particles show exceptional lifetimes in high pH mobile phases.

Chromatographers have an on going need to increase productivity and decrease costs. This can be accomplished by leveraging higher efficiency HPLC columns to increase analysis speed. Significant improvements have been made in the preparation of fully porous sub-2 μιη HPLC packing materials. These materials which provide high-efficiency separations in less time when packed in shorter columns. Unfortunately, columns packed fully porous with sub-2 μηι particles typically generate pressures that exceed the limits of standard HPLC instruments and require the use of ultra-high pressure HPLC systems, which can be cost-prohibitive. Core shell particles allow chromatographers to get performance comparable to sub-2-micron columns without investing in UPLC systems.

With the above in consideration the optimum particle size for silica core shell for hybrid silica core shell particles is greater than about 1.7 μπι as this allows for columns to be utilised on traditional HPLC systems. If the core size of the hybrid silica particle is less than 1.4 μηι a thicker porous shell (for example thickness greater than 500nm) would have to be grown on the core particles to yield a particle with an average diameter of greater than 1.7μπι. A thick porous shell (greater than 500nm) would inhibit the mass transfer properties during chromatographic separations and will lead to higher back pressure during separation, [i.e the particle will start to behave as if it were a fully porous particle.

In the process of the invention an alkyl ammonium tosylate surfactant is utilised in conjunction with a triblock copolymer in order to create layered porous shell structure on a solid silica particle. The use of alkyl ammonium tosylate surfactants is advantageous over alkyl ammonium halides for one or more of the following reasons:

(a) Smoother layering of the porous silica or hybrid silica shell;

(b) larger pore sizes obtained using this templating approach;

(c) alkyl ammonium tosylate surfactants have lower melting points than corresponding halide versions and are therefore easier to remove during the calcination process (d) the process produces a silica or hybrid silica material in which the hydroxyl groups on the silica or hybrid silica surface are more thermally stable than analogous silicas synthesised using alkyl ammonium halide precursors.

Without wishing to be bound by theory, it is thought that the presence of a larger counter ion in alkyl ammonium tosylates assists in significantly controlling the organic-inorganic interface and leads to greater long range ordering and more silica or hybrid silica wherein the surface hydroxyl groups are more thermally stable. It is thought that the use of an organic counter ion leads to a more thermally stable silica or hybrid silica as a more hydrophobic interface between the surfactant and the silicate is formed during polycondensation.

We have found that in order to achieve a thick layer of porous silica or hybrid silica shell (for example up to about 0.5 μιη (500nm)), the energetic interaction known as "steric effect" involved between particles adsorbed with surfactant in aqueous dispersion need to be systematically controlled. Growing thicker shell layers of silica or hybrid silica surrounding surfactant adsorbed nonporous spherical materials in aqueous dispersion, requires a systematic method to prevent agglomeration during the growth process. The use of co-surfactants, such as a block co-polyether with a terminal difunctional OH group to promote sterically stabilised particle system, was found to be useful in growing a thicker shell (for example up to about 0.5 μηι (500nm)) under the conditions described herein. Employing a temperature above ambient conditions (for example about 45 C) minimizes the changes in free energy associated with the "mixing effect" of adsorbed surfactant on silica surface, and prevents agglomeration during the growth of shell particles.

In the process described herein, the shell is grown on the core layer by layer. A layer by layer approach allows for the controlled growth of the porous shell structure without the generation of fines (small sub lOOnm particles). This is advantageous because if a continuous process was used to form the shell, for example the continuous addition of an alkoxysilane mixture to a basic solution of core particles, a significant number of fines (small sub lOOnm particles) will be generated and the fines would have to be separated from the reaction mixture which would add several extra processing steps to the continuous process. In the process described herein for producing hybrid silica core-shell particles, a surfactant (such as alkyl ammonium tosylate) is utilised as a porogen, and a mixture of silane and alkoxysilane (for example BTSE, TEMS) is utilised as the silica source. The alkoxysilane contains the carbon groups that will form the hybrid portion of the hybrid silica. The porogen is a surfactant and is not chemically bound into the matrix of the silica and can therefore be removed (by extraction) at very low temperature to introduce porosity into the hybrid silica shell of the particle. The use of a surfactant based approach as described herein allows the porogen (for example alkyl ammonium tosylate) to be extracted using very mild conditions such as by soxlet extraction in an alcohol :acid mixture at 60°C. The use of the alkyl ammonium surfactant with an organic counter ion (such as tosylate) also allows for the facile extraction of the surfactant molecule from the hybrid silica material. The low temperature used in the extraction process will not degrade any of the carbon content of the hybrid silica shell. Furthermore, as the porogen is a surfactant rather than for example an organofunctional silane, the process described herein allows for the simple tailoring of the final content of carbon in the hybrid silica shell as the ratio of alkoxysilane to silane in the reaction mixture can be adjusted to produce the desired content of carbon in the shell (for example up to about 60% by weight) without effecting the porosity of the shell.

The mixed surfactant system used in the process described herein drives templated layer on layer growth of the shell such that a particle with a smooth surface is formed.

Brief Description of the Drawings -

The invention will be more clearly understood from the following description thereof given by way of example only with reference to the accompanying figures in which:-

Fig. 1 is a scanning electron micrograph image of core shell particle prepared in accordance with Example 1 ;

Fig. 2 is transmission electron micrograph images of a core shell particles prepared in accordance with Example 1 after (a) 1 round of silica shell growth and (b) after 7 rounds of silica shell growth; Fig. 3 illustrates a particle size measurement of a core shell particles prepared in accordance with Example 1 ;

Fig. 4 is a graph showing the BJH adsorption and desorption isotherms of core shell particles prepared in accordance with Example 1 ;

Fig. 5 is a graph showing the BJH pore size measurement of core shell particles prepared in accordance with Example 1 ;

Fig. 6 illustrates a cross section microscopy analysis of core shell particles prepared in accordance with Example 1 ;

Fig. 7 illustrates particle size measurements of core shell particles prepared in accordance with Example 1 (squares), Example 4 (circles) and Example 6 (triangles);

Fig. 8 is a graph showing the BJH adsorption and desorption isotherms of core shell particles prepared in accordance with Example 1 (squares), Example 4 (circles) and Example 6 (triangles);

Fig. 9 is a graph showing the BJH pore size measurement of core shell particles prepared in accordance with Example 1 (squares), Example 4 (circles) and Example 6 (triangles);

Fig. 10 is a scanning electron micrograph image and its associated EDX spectrum of hybrid silica core-shell particles prepared in accordance with Example5;

Fig. 1 1 is a scanning electron micrograph image and its associated EDX spectrum of hybrid silica core-shell particles prepared in accordance with Example7; and

Fig. 12 is a scanning electron micrograph image and its associated EDX spectrum of hybrid silica core-shell particles prepared in accordance with Example 8. Detailed Description

We describe processes for preparing monodisperse silica or hybrid silica cores-shell particles (spheres) having a diameter between about 1.5 μιη and about 4.0 μπι such as about 1.7 μηι or 2.6 μιη or 3.5 μηι, comprising a thick (for example up to 0.5 μηι (500nm) porous silica or hybrid silica layer (shell) with pore sizes up to about 120 angstrom. The processes described herein involve the use of a template, such as a cationic surfactant with a tosylate organic counter ion and a non-ionic surfactant (to act as a steric stabiliser) under basic pH, conditioned to tailor the formation of pores in a silica or hybrid silica shell layer. A porous silica or hybrid silica shell is grown on a non-porous silica spheres (core) via polycondensation of an alkoxysilicate or mixed silica precursor.

We have devised a simple and reproducible method for synthesising size-monodisperse micrometer core-shell particles in the range of 1 to 4μιτι. The process provides for the preparation of uniform particles, with tunable mesoporous and macroscopic morphologies, in particular porous silica or hybrid silica core-shell particles in the form of spheres.

By careful control of the reaction conditions, such as the concentration and type of surfactants, additional rates, temperature, agitation speed, hydrothermal treatment and base etching (controlled dissolution) steps, the pore size and structure of core shell particles can be predetermined.

Using the process described herein we are able to prepare macroscopic mesoporous materials of regular, predictable and controlled shape. Previously the control of both the macroscopic and mesoporous properties of such materials has been difficult to achieve on a consistent basis.

The process provides particles with a narrow size distribution. Such materials have large surface areas and are very effective for use in chromatographic, absorbent and separation applications.

The process utilises a difunctional block-co-polymer such as PI 23 or F127 that will aid stabilization, which can effectively promote the seeded growth model of growing larger shell thickness. Silica and hybrid silica core-shell particles produced by the process described herein have a solid, non-porous core. Mesopores are only present in the exterior layer (shell) of the particles. The porous layer (shell) has a thickness of between about 20 nm to about 500 nm and the pore sizes and pore volume of the porous layer (shell) range from about 20 A to about 300 A and about 0.1 cc/g to about 2.0 cc/g respectively.

The process comprises three stages:

Firstly, continuous growth of polycondensation silicate species on the surface of non-porous core silica particles in the presence of a mixed surfactant solution containing both an alkyl ammonium tosylate (such as CTATos) and a difunctional non-ionic alkyl poly (oxyalkylene) tri-block copolymer (such as pluronic PI 23 or pluronic F-127) as templating agents under basic pH conditions.

Secondly, the as synthesised silica or hybrid silica particles having a porous shell surrounding the non-porous core are hydrothermally treated in an oil-in-water emulsion system to expand the size of the pores in the shell. After drying and calcination, the silica or hybrid silica particles may be used as a packing material for liquid chromatography (LC).

Thirdly, the hydrothermally treated particles are subjected to a controlled dissolution step to increase the pore diameter core shell material.

The mesoporous shell silica particles made by the process described herein may be functionalised with a functional group such as a mono-, di- or tri-organosilane.

Core shell silica and hybrid silica particles in the 0.1 to 4μηι range offer a number of advantages over current commercially available porous silica spheres which include:

1) Monodispersed particle sizes

2) Tunable pore size

3) No need for hydrogen fluoride (HF) etching to increase pore size

4) No subsequent separation steps i.e. sieving/classification 5) No Bimodal Pore size distributions

6) High yield

7) Relatively Short Preparation Time (2 week)

The invention will be more clearly understood from the following Examples. Examples

Materials and Methods Reagents and Chemicals

Tetraethyl orthosilicate (TEOS) > 99%, triethoxymethylsilane (TEMS) 99%, bis-1 , 2- (triethoxysilyl) ethane (BTSE) 96%, hexadecyltrimethylammonium p-tolunensulfonate (CTATos), 4-chloro-N,N-diethyl-N-heptylbenzenebutanaminium tosylate (Clofilium) > 97%, N,N,N-Trimethyl-4-(6-phenyl-l,3,5-hexatrien-l-yl)phenylammonium p-toluenesulfonate (TMA- DPH) > 96%, ammonia hydroxide (NH₄OH) solution 33 wt %, dimethyldecylamine (DMDA) 98%, hydrogen peroxide (H₂0₂) 30 wt % were all purchased from Sigma-Aldrich Ireland Ltd. Ethanol (EtOH) 100 grade, was purchased from Reagacon Ireland Ltd. and was distilled over Mg/I. Water (H₂0) was deionised water from Millipore Q water purifier (18.0 Qm). Difunctional block-co-polymer surfactants E0₂oP0₇₀E0₂o (PI 23) average molecular weight 5800 and E0₂₀P0₇oE0₂o (P123) average molecular weight 12600 were obtained from BASF.

Equipment

PTFE bottles (1L) (Sigma Aldrich), magnetic stirrer and hot plate with temperature control sensor (VWR International, UK), Micromeritics Tristar II BET surface area analyser (Particle and Surface science (UK) Ltd), Philips Xpert MPD diffractometer with Cu Ka radiation, Jeol 2000 FXII transmission electron microscopy (JEOL (UK) Ltd), Inspect F scanning electron microscopy (FEI (Europe) Ltd). Micromeritics Elzone Particle Sizer II. Jeol 5510 scanning electron microscope with an Oxford Instruments Energy Dispersive X-Ray Spectroscopy detector. Example 1 - Synthesis of a 1.7 urn core-shell particle with a superficially porous silica shell of 150 nm on a spherical, non-porous silica surface using CTATog as a surfactant.

Prior to the synthesis of the silica mesoporous shell, solid core non-porous silica seeds of 1.4 microns in diameter were synthesised according to methods described in literature³.

Step 1: Shell Growth

lOg of as synthesized 1.4 μιτι, non-porous silica spheres (seeds) was dispersed in a solution of 100 mis dry ethanol and 200 mis of deionised water. After 20 mins sonication, the silica sol was transferred to a 1L PTFE bottle and allowed to stir at 45 °C for 20 mins. A surfactant solution containing 0.297g CTATos and 1.3 g of PI 23 in 30mls dry ethanol and 53.7 mis deionised water was prepared and added to the silica sol under stirring. After 20 min of stirring, 12.3 mis of 32.5% of ammonia was added and allowed to mix for 20 mins with 3.6 mis of TEOS then being added and allowed to react for 1 hour.

After a 1 hour reaction, the silica particles formed were collected from the solution by centrifugation. A small portion (about 5 mg) of silica particles were removed after each reaction round and analysed for particle size increase and corresponding size distribution using dynamic light scattering (DLS) techniques. The remainder of the as produced particles were resuspended in 102 mis dry ethanol and 204 mis deionised water following the sequence in Table 1 below, the growth process was repeated 9 times. As shown below in Table 1, the total volume of each addition is increased by 6 mis.

A growth scheme for the formation of core-shell particles having a shell thickness

Growth Silica Surfactant P123: NH₄OH Vol of DLS

Round Shell Solution CTATos (mis) TEOS (μιη)

Dispersion EtOH:H₂0 (g) Added

EtOH:H₂0 (mis) (mis)

(mis)

1 100:200 30:53.7 1.3:0.297 12.3 3.6 1.46 2 102:204 30:53.5 1.3:0.297 12.5 3.6 1.52

3 104:208 30:53.3 1.3:0.297 12.7 3.6 1.57

4 106:212 30:53.1 1.3:0.297 12.9 3.7 1.63

5 108:214 30:52.9 1.3:0.297 13.1 3.7 1.70

6 1 10:220 30:52.7 1.3:0.297 13.3 3.8 1.75

7 1 12:224 30:52.5 1.3:0.297 13.5 3.9 1.81

8 1 14:228 30:52.3 1.3:0.297 13.7 3.9 1.86

9 1 16:232 30:52.1 1.3:0.297 13.9 4.0 1.91

Following the 9 round of the growth process, the silica particles formed were collected from the solution by centrifugation and a pore expansion protocol was performed to expand the pores as follows:

Step 2: Hydrothermal pore treatment

4.21 g of PI 23 was dissolved in a 100 mL beaker with 62 mL of 2-propanol under stirring. 5.2 mis of cyclooctane was added and stirred for 15 min. In a different 250 mis beaker, 52 mg of NH₄I was dissolved with 126 mis of deionised water. The surfactant and cyclooctane solutions were transferred to the beaker containing deionised water under stirring and allowed to emulsify for 1 h until a clear solution was formed. The emulsion solution was used to disperse the as synthesized particles generated in step 1 and transferred to a 250 mis PTFE bottle and stirred for 1 h at 35 °C and finally transferred to a pre-heated oven at 100 °C for 72 hours. After the hydrothermal treatment was complete, the silica precipitate is separated by filtration (vacuum filtration through a Whatman 1 10 mm diameter filter paper), washed with deionised water several times and transferred to a crucible and dried for 24 h at 1 10 °C.

Step 3: Calcination

The dried silica particles generated in step 2 was calcined at 66θ^~°€ to bum off the tcmplatcd surfactant to generate pores. The calcination was performed in a furnace by ramping up the temperature at 5 °C /min to 600 °C and the particles were held at this temperature for 18 h. Finally the furnace was turned off and the temperature allowed to cool down to room temperature. Step 4: Chemical pore etching

To achieve the desired pore size that will enhance rapid separation when the particles are used as a packing material for liquid chromatography, the pore size of the porous shell must be expanded above 60 A and to a maximum of 300 A, typically 90 A pore size was suitable for most separation application.

6.75g silica particles generated in step 3 were dispersed in a solution of 75.6 mis deionised water and placed in a heating oil to bring the temperature to 75 °C under stirring, then a mixture of 14.4 mL (5.0 wt %) aqueous ammonia and 0.56 mis (0.2 wt%) of hydrogen peroxide (H₂0₂) was added via a glass syringe under stirring. The slurry was allowed to etch for 8 hours; followed by series of washing with de-ionized water and finally with methanol. The etched silica particles were dried in an oven at 150 °C for 24 hours.

Fig. 1 is a scanning electron micrograph image of core shell particles prepared by a method of example 1. The average particle size was measured to be approx 1.7 μιτι [composed of a 1.4 μπι core and a 150nm shell]. The SEM images confirm that the silica particles have a smooth surface free from major defects. The SEM also confirms that the particles are monodispersed in nature suggesting that the process provides very tight control over particle size distribution. Little or no aggregates of particles were noted in the SEM images.

Fig. 2(a) is transmission electron micrograph image of a core shell particles prepared by the process of Example 1 after a single round of layer growth. The average layer thickness is approx 30nm. The layer thickness can be seen to be relatively uniform around the particles. Figure 2(b) is a TEM image of a core shell particle prepared by the process of Example 1 after 7 rounds of silica shell growth. The shell thickness was noted to be approx. 150nm. Again, the shell layer thickness can be seen to be relatively uniform around the particles.

Fig. 3 illustrates a particle size measurement of a core shell particles prepared by the process of Example 1 via the Electrical Zone Sensing (EZS) Technique. The average particle size is noted to be 1.7 μηι [composed of a 1.4 μιτι core and a 150 nm shell] which is in very good agreement with the SEM images in Figure 1. The d90/dl0 (measure of monodispersivity) value was calculated to be 1.2 again confirming the monodispersed nature of the sample. Fig. 4 is a graph showing the BJH adsorption and desorption isotherms of core shell particles prepared by the process of Example 1. The isotherm is noted to be Type IV by IUPAC classification.

Fig.5 is a graph showing the BJH pore size measurement of core shell particles prepared by a process of Example 1. The mean pore diameter (MPD) was calculated to be 100 A. The pore size distribution profile is relatively monomodal.

Fig. 6 is a cross section microscopy image of core shell silica particles prepared by a process of Example 1. The solid silica core of the particle can be seen quite clearly. The layered porous silica shell structure is also very visible. The shell thickness was noted to be approx. 150 nm, which is in agreement with the TEM data of Figure 2.

Fig. 7 illustrates a particle size measurement of core shell particles prepared by the process of Example 1 (squares), Example 4 (circles) and Example 6 (triangles) via the Electrical Zone Sensing (EZS) Technique. The average particle size is noted to be 1.7 μπι [composed of a 1.4 μηι core and a 150 nm shell] for Example 1 , 2.6 μπι [composed of a 1.8 μπι core and a 400 nm shell] for Example 4 and 3.5 μιη [composed of a 2.5 μηι core and a 500 nm shell].

Fig. 8 is a graph showing the BJH adsorption and desorption isotherms of core shell particles prepared by the process of Example 1 (squares), Example 4 (circles) and Example 6 (triangles). The isotherms for Examples 1 , 4 and 5 are noted to be Type IV by IUPAC classification.

Fig.9 is a graph showing the BJH pore size measurement of core shell particles prepared by a process the process of Example 1 (squares), Example 4 (circles) and Example 6 (triangles). The mean pore diameter (MPD) was calculated toJ e 100 A for Example 1, . The pore size distribution profile is relatively monomodal.

Example 2 - Synthesis of a 1.7 um core-shell particle with a superficially porous hybrid silica shell of 150 nm on a spherical, non-porous silica surface using Clofilium as a surfactant. Prior to the synthesis of the hybrid silica mesoporous shell, solid non-porous silica seeds of 1.4 μηι diameter were synthesised according to methods described in the literature .

10 g of as synthesized 1.4 μιη, non-porous silica spheres (seeds) was dispersed in a solution of 100 mis dry ethanol and 200 mis of deionised water. After 20 mins sonication, the silica sol was transferred to a 1L PTFE bottle and allowed to stir at 45 °C for 20 mins. A surfactant solution containing 0.333 g Clofilium and 1.3 g of P123 in 30mls dry ethanol and 53.7 mis deionised water was prepared and added to the silica sol under stirring. After 20 min of stirring, 12.3 mis of 32.5% of ammonia was added and allowed to mix for 20 mins with 3.2 mis of TEOS and 0.4 mis TEMS then being added and allowed to react for 1 hour.

After a 1 hour reaction, the hybrid silica particles formed were collected from the solution by centrifugation. A small portion (about 5 mg) of hybrid silica particles were removed after each reaction round and analysed for particle size increase and corresponding size distribution using dynamic light scattering (DLS) techniques. The remainder of the as produced hybrid silica particles were resuspended in 102 mis dry ethanol and 204 mis deionised water following the sequence in Table 2 below, the growth process was repeated 9 times. As shown below in Table 2, the total volume of each addition is increased by 6 mis.

Table 2. A growth scheme for the formation of hybrid silica core-shell particles having a shell thickness of 150 nm.

Growth Silica Surfactant P123:Clofilium NH₄OH TEOS:TEMS DLS

Round Shell Solution (g) (mis) (mis) ( ^ηι)

Dispersion EtOH:H₂0

EtOH:H₂0 (mis)

(mis)

1 100:200 30:53.7 1.3:0.333 12.3 3.2:0.4 1.46

2 102:204 30:53.5 1.3:0.333 12.5 3.2:0.4 1.52

3 104:208 30:53.3 1.3:0.333 12.7 3.2:0.4 1.57

4 106:212 30:53.1 1.3:0.333 12.9 3.25:0.45 1.63 5 108:214 30:52.9 1.3:0.333 13.1 3.25:0.45 1.70

6 1 10:220 30:52.7 1.3:0.333 13.3 3.25:0.45 1.75

7 112:224 30:52.5 1.3:0.333 13.5 3.3:0.5 1.81

8 1 14:228 30:52.3 1.3:0.333 13.7 3.3:0.5 1.86

9 1 16:232 30:52.1 1.3:0.333 13.9 3.35:0.55 1.91

Following the 9 round of the growth process, the hybrid silica particles formed were collected from the solution by centrifugation and a pore expansion protocol was performed to expand the pores as described in Step 2 of Example 1.

Removal of the surfactant template was performed by use of soxhlet irradiation in an alcohohacid mixture (90% Ethanol: 10% Cone. Nitric Acid). The chemical pore etching protocol was performed as described in Step 4 of Example 1.

Example 3 - Synthesis of a 1.7 urn core-shell particle with a superficially porous (bridged) hybrid silica shell of 150 nm on a spherical, non-porous silica surface using TMA-DPH as a surfactant.

Prior to the synthesis of the hybrid silica mesoporous shell, solid core non-porous silica seeds of 1.4μηι diameter were synthesised according to methods described in literature³.

10 g of as synthesized 1.4 μιη, non-porous silica spheres (seeds) was dispersed in a solution of 100 mis dry ethanol and 200 mis of deionised water. After 20 mins sonication, the silica sol was transferred to a 1L PTFE bottle and allowed to stir at 45 °C for 20 mins. A surfactant solution containing 0.301g TMA-DPH and 1.3 g of P123 in 30mls dry ethanol and 53.7 mis deionised water was prepared and added to the silica sol under stirring. After 20 min of stirring, 12.3 mis of 32.5% of ammonia was added and allowed to mix for 20 mins with 3.2 mis of TEOS and 0.4 mis BTSE then being added and allowed to react for 1 houtr

After a 1 hour reaction, the hybrid silica particles formed were collected from the solution by centrifugation. A small portion (about 5 mg) of hybrid silica particles were removed after each reaction round and analysed for particle size increase and corresponding size distribution using dynamic light scattering (DLS) techniques. The remainder of the as produced hybrid silica particles were resuspended in 102 mis dry ethanol and 204 mis deionised water following the sequence in Table 3 below, the growth process was repeated 9 times. As shown below in Table 3, the total volume of each addition is increased by 6 mis.

Table 3. A growth scheme for the formation of hybrid silica core-shell particles having a shell thickness of 150 nm.

Removal of the surfactant template was perfonhecTby use^{^}of soxhlet extraction. The chemical pore etching protocol was performed as described in Step 4 of Example 1.

Example 4 - Synthesis of a 2.6 nm core-shell particle with a superficially porous silica shell of 400 nm on a spherical, non-porous silica surface using CTATos as a surfactant. Prior to the synthesis of the silica mesoporous shell, solid core non-porous silica seeds of 1.8 microns in diameter were synthesised according to methods described in literature .

Step 1: Shell Growth

lOg of as synthesized 1.8 μη , non-porous silica spheres (seeds) was dispersed in a solution of 100 mis dry ethanol and 200 mis of deionised water. After 20 mins sonication, the silica sol was transferred to a 1L PTFE bottle and allowed to stir at 45 °C for 20 mins. A surfactant solution containing 0.297g CTATos and 1.3 g of P123 in 30mls dry ethanol and 53.7 mis deionised water was prepared and added to the silica sol under stirring. After 20 min of stirring, 12.3 mis of 32.5% of ammonia was added and allowed to mix for 20 mins with 2.1 mis of TEOS then being added and allowed to react for 1 hour.

After a 1 hour reaction, the silica particles formed were collected from the solution by centrifugation. A small portion (about 5 mg) of silica particles were removed after each reaction round and analysed for particle size increase and corresponding size distribution using dynamic light scattering (DLS) techniques. The remainder of the as produced silica's were resuspended in 102 mis dry ethanol and 204 mis deionised water following the sequence in Table 4 below, the growth process was repeated 14 times. As shown below in Table 4, the total volume of each addition is increased by 6 mis.

Growth Silica Surfactant P123: NH₄OH Vol of DLS

Round Shell Solution CTA-Tes-- (mis) TEO (urn)

Dispersion EtOH:H20 (g) Added

EtOH:H20 (mis) (mis)

(mis)

1 100:200 30:53.7 1.3:0.297 12.3 2.1 1.88 2 102:204 30:53.5 1.3:0.297 12.5 2.2 1.95

3 104:208 30:53.3 1.3:0.297 12.7 2.1 2.02

4 106:212 30:53.1 1.3:0.297 12.9 2.2 2.09

5 108:214 30:52.9 1.3:0.297 13.1 2.3 2.17

6 1 10:220 30:52.7 1.3:0.297 13.3 2.4 2.22

7 1 12:224 30:52.5 1.3:0.297 13.5 2.3 2.29

8 1 14:228 30:52.3 1.3:0.297 13.7 2.4 2.37

9 1 16:232 30:52.1 1.3:0.297 13.9 2.5 2.45

10 1 18:236 30:51.9 1.3:0.297 14.1 2.4 2.53

1 1 120:240 30:51.7 1.3:0.297 14.3 2.6 2.60

12 122:244 30:51.5 1.3:0.297 14.5 2.7 2.66

13 124:248 30:51.3 1.3:0.297 14.7 2.8 2.72

14 126:252 30:51.5 1.3:0.297 14.9 2.5 2.77

Following the 14 round of the growth process, the silica particles formed were collected from the solution by centrifugation and a pore expansion protocol was performed to expand the pores as described in step 2 of Example 1.

Removal of the surfactant template was performed by use of calcination. The chemical pore etching protocol was performed as described in Step 4 of Example 1.

Fig. 7 illustrates a particle size measurement of core shell particles prepared by the process of Example 4 (circles) via the ElectricalSensing Zone (ESZ) Technique compared to Example 1 (squares). The average particle size for Example 4 is noted to be 2.6μη [composed of a 1.8 μπι core and a 400nm shell]. The d90/dl0 (measure of monodispersivity) value was calculated to be 1.7. A secondary peak at approx 3μηι was also noted in this sample. This is thought to be doublets of the existing core particle.

Fig. 8 is a graph which displays the BJH adsorption and desorption isotherms of the core shell particles prepared by the method of Example 4 (circles) compared to Example 1 (squares). The isotherms are noted to be Type IV by IUPAC classification. Fig. 9 is a graph which displays the BJH pore size measurement of core-shell particles prepared by the process of Example 4 (circles) compared to example 1 (squares). The mean pore diameter was calculated to be 80 A. The pore size distribution profile is relatively monomodal.

Example 5 - Synthesis of a 2.6 um core-shell particle with a superficially porous hybrid silica shell of 400 nm on a spherical, non-porous silica surface using CTATps as a surfactant.

Prior to the synthesis of the hybrid silica mesoporous shell, solid core non-porous silica seeds of 1.8 microns in diameter were synthesised according to methods described in literature³.

Step 1: Shell Growth

lOg of as synthesized 1.8 μιτι, non-porous silica spheres (seeds) was dispersed in a solution of 100 mis dry ethanol and 200 mis of deionised water. After 20 mins sonication, the silica sol was transferred to a 1L PTFE bottle and allowed to stir at 45 °C for 20 mins. A surfactant solution containing 0.297g CTATos and 1.3 g of P123 in 30mls dry ethanol and 53.7 mis deionised water was prepared and added to the silica sol under stirring. After 20 min of stirring, 12.3 mis of 32.5% of ammonia was added and allowed to mix for 20 mins with 1.89 mis of TEOS and 0.21 mis of TEMS then being added and allowed to react for 1 hour.

After a 1 hour reaction, the silica particles formed were collected from the solution by centrifugation. A small portion (about 5 mg) of hybrid silica particles were removed after each reaction round and analysed for particle size increase and corresponding size distribution using dynamic light scattering (DLS) techniques. The remainder of the as produced hybrid silica particles were resuspended in 102 mis dry ethanol and 204 mis deionised water following the sequence in Table 5 below, the growth process was repeated 14 times. As shown below in Table 5, the total volume of each addition is increased by 6 mis.

Table 5. A growth scheme for the formation of hybrid silica core-shell particles having a shell thickness of 400 nm. Growth Silica Surfactant P123: NH₄OH Vol of DLS

Round Shell Solution CTATos (mis) TEOS:TEMS (μηι)

Dispersion EtOH:H20 (g) Added

EtOH:H20 (mis) (mis)

(mis)

1 100:200 30:53.7 1.3:0.297 12.3 1 .89:0.21 1.88

2 102:204 30:53.5 1.3:0.297 12.5 1.98:0.22 1.95

3 104:208 30:53.3 1.3:0.297 12.7 1.89:0.21 2.02

4 106:212 30:53.1 1.3:0.297 12.9 1.98:0.22 2.09

5 108:214 30:52.9 1.3:0.297 13.1 2.07:0.23 2.17

6 1 10:220 30:52.7 1.3:0.297 13.3 2.16:0.24 2.22

7 1 12:224 30:52.5 1.3:0.297 13.5 2.07:0.23 2.29

8 1 14:228 30:52.3 1.3:0.297 13.7 2.16:0.24 2.37

9 1 16:232 30:52.1 1.3:0.297 13.9 2.25:0.25 2.45

10 1 18:236 30:51.9 1.3:0.297 14.1 2.16:0.24 2.53

1 1 120:240 30:51.7 1.3:0.297 14.3 2.34:0.26 2.60

12 122:244 30:51.5 1.3:0.297 14.5 2.43:0.27 2.66

13 124:248 30:51.3 1.3:0.297 14.7 2.52:0.28 2.72

14 126:252 30:51.5 1.3:0.297 14.9 2.25:0.25 2.77

Following the 14 round of the growth process, the hybrid silica particles formed were collected from the solution by centrifugation and a pore expansion protocol was performed to expand the pores as described in step 2 of Example 1.

Removal of the surfactant template was performed by use of microwave irradiation. The chemical pore etching protocol was performed as described in Step 4 of Example 1.

Fig. 10 is a scanning electron micrograph image and its associated EDX spectrum of core-shell particles prepared in accordance with this Example. Example 6 - Synthesis of a 3.5 um core-shell particle with a superficially porous silica shell of 500 nm on a spherical, non-porous silica surface using CTATns as a surfactant.

Prior to the synthesis of the silica mesoporous shell, solid core non-porous silica seeds of 2.5 microns in diameter were synthesised according to methods described in literature³.

Step 1: Shell Growth

lOg of as synthesized 2.5 μηι, non-porous silica spheres (seeds) was dispersed in a solution of 100 mis dry ethanol and 200 mis of deionised water. After 20 mins sonication, the silica sol was transferred to a 1L PTFE bottle and allowed to stir at 45 °C for 20 mins. A surfactant solution containing 0.297g CTATos and 1.3 g of PI 23 in 30mls dry ethanol and 53.7 mis deionised water was prepared and added to the silica sol under stirring. After 20 min of stirring, 12.3 mis of 32.5% of ammonia was added and allowed to mix for 20 mins with 1.9 mis of TEOS then being added and allowed to react for 1 hour.

After a 1 hour reaction, the silica particles formed were collected from the solution by centrifugation. A small portion (about 5 mg) of silica particles were removed after each reaction round and analysed for particle size increase and corresponding size distribution using dynamic light scattering (DLS) techniques. The remainder of the as produced silica particles were resuspended in 102 mis dry ethanol and 204 mis deionised water following the sequence in Table 6 below, the growth process was repeated 19 times. As shown below in Table 6, the total volume of each addition is increased by 6 mis.

Table 6. A growth scheme for the formation of core-shell particles having a shell thickness of 500 nm.

Growth Silica Surfactant P123: NH40H Vol of DLS

Round Shell Solution CTATOS (mis) TEOS (μ^ηι)

Dispersion EtOH:H20 (g) Added

EtOH:H20 (mis) (mis)

(mis)

1 100:200 30:53.7 1.3:0.297 12.3 1.9 2.57 2 102:204 30:53.5 1.3:0.297 12.5 2.0 2.63

3 104:208 30:53.3 1.3:0.297 12.7 1.9 2.69

4 106:212 30:53.1 1.3:0.297 12.9 2.0 2.75

5 108:214 30:52.9 1.3:0.297 13.1 2.1 2.81

6 1 10:220 30:52.7 1.3:0.297 13.3 2.2 2.87

7 1 12:224 30:52.5 1.3:0.297 13.5 2.3 2.93

8 1 14:228 30:52.3 1.3:0.297 13.7 2.2 3.00

9 1 16:232 30:52.1 1.3:0.297 13.9 2.3 3.06

10 1 18:236 30:51.9 1.3:0.297 14.1 2.4 3.13

1 1 120:240 30:51.7 1.3:0.297 14.3 2.5 3.19

12 122:244 30:51.5 1.3:0.297 14.5 2.4 3.25

13 124:248 30:51.3 1.3:0.297 14.7 2.6 3.31

14 126:252 30:51.5 1.3:0.297 14.9 2.7 3.36

15 128:256 30:51.7 1.3:0.297 15.1 2.8 3.42

16 130:260 30:51.9 1.3:0.297 15.3 2.5 3.48

17 132:264 30:52.1 1.3:0.297 15.5 2.6 3.55

18 134:268 30:52.3 1.3:0.297 15.7 2.8 3.62

19 136:272 30:52.5 1.3:0.297 15.9 2.9 3.69

Following the 19 round of the growth process, the silica particles formed were collected from the solution by centrifugation and a pore expansion protocol was performed to expand the pores as described in step 2 of Example 1.

Fig. 7 illustrates a particle size measurement of core shell particles prepared by the process of Example 6 (triangles) via the Electrical Sensing Zone (ESZ) Technique compared to Example 1 (squares) and Example 4 (circles). The average particle size for Example 6 is noted to be 3.5 μιη [composed of a 2.5 μηι core and a 500 nm shell]. The d90/dl0 (measure of monodispersivity) value was calculated to be 1.7. A secondary peak at approx 4.5 μιη was also noted in this sample. This is thought to be doublets of the existing core particle.

Fig. 8 is a graph which displays the BJH adsorption and desorption isotherms of the core shell particles prepared by the process of Example 6 (triangles) compared to Example 1 (squares) and Example 4 (circles). The isotherms are noted to be Type IV by IUPAC classification.

Fig. 9 is a graph which displays the BJH pore size measurement of core-shell particles prepared by the process of Example 6 compared to Example 1 (squares) and Example 4 (circles). The mean pore diameter was calculated to be 80 A. The pore size distribution profile is relatively monomodal.

Example 7 - Synthesis of a 3.5 um core-shell particle with a superficially porous bridged hybrid silica shell of 500 nm on a spherical, non-porous silica surface using CTATps as a surfactant.

Prior to the synthesis of the hybrid silica mesoporous shell, solid core non-porous silica seeds of 2.5 microns in diameter were synthesised according to methods described in literature³.

Step 1: Shell Growth

10 g of as synthesized 2.5 μπι, non-porous silica spheres (seeds) was dispersed in a solution of 100 mis dry ethanol and 200 mis of deionised water. After 20 mins sonication, the silica sol was transferred to a 1L PTFE bottle and allowed to stir at 45 °C for 20 mins. A surfactant solution containing 0.297g CTATos and 1.3 g of PI 23 in 30mls dry ethanol and 53.7 mis deionised water was prepared and added to the silica sol under stirring. After 20 min of stirring, 12.3 mis of 32.5% of ammonia was added and allowed to mix for 20 mins with 1.71 mis of TEOS and 0.19 mis of BTSE were then being added and allowed to react for 1 hour.

After a 1 hour reaction, the hybrid silica particles formed were collected from the solution by— centrifugation. A small portion (about 5 mg) of hybrid silica particles were removed after each reaction round and analysed for particle size increase and corresponding size distribution using dynamic light scattering (DLS) techniques. The remainder of the as produced hybrid silica particles were resuspended in 102 mis dry ethanol and 204 mis deionised water following the sequence in Table 7 below, the growth process was repeated 19 times. As shown below in Table 7, the total volume of each addition is increased by 6 mis.

Table 7. A growth scheme for the formation of hybrid silica core-shell particles having a shell thickness of 500 nm.

Growth Silica Surfactant P123: NH₄OH Vol of DLS

Round Shell Solution CTATos (mis) TEOS:BTSE (μ^ηι)

Dispersion EtOH:H20 (g) Added

EtOH:H20 (mis) (mis)

(mis)

1 100:200 30:53.7 1.3:0.297 12.3 1.71 :0.19 2.57

2 102:204 30:53.5 1.3:0.297 12.5 1.80:0.20 2.63

3 104:208 30:53.3 1.3:0.297 12.7 1.71 :0.19 2.69

4 106:212 30:53.1 1.3:0.297 12.9 1.80:0.20 2.75

5 108:214 30:52.9 1.3:0.297 13.1 1.89:0.21 2.81

6 1 10:220 30:52.7 1.3:0.297 13.3 1.98:0.22 2.87

7 112:224 30:52.5 1.3:0.297 13.5 2.07:0.23 2.93

8 1 14:228 30:52.3 1.3:0.297 13.7 1.98:0.22 3.00

9 1 16:232 30:52.1 1.3:0.297 13.9 2.07:0.23 3.06

10 1 18:236 30:51.9 1.3:0.297 14.1 2.16:0.24 3.13

1 1 120:240 30:51.7 1.3:0.297 14.3 2.25:0.25 3.19

12 122:244 30:51.5 1.3:0.297 14.5 2.16:0.24 3.25

13 124:248 30:51.3 1.3:0.297 14.7 2.34:0.26 3.31

14 126:252 30:51.5 1.3:0.297 14.9 2.43:0.27 3.36

15 128:256 30:51.7 1.3:0.297 15.1 2.52:0.28 3.42

16 130:260 30:51.9 1.3:0.297 15.3 2.25:0.25 3.48

17 132:264 30:52.1 1.3:0.297 15.5 2.34:0.26 3.55

18 134:268 30:52.3 1.3:0.297 15.7 2.52:0.28 3.62

19 136:272 30:52.5 1.3:0.297 15.9 2.61 :0.29 3.69 Following the 19 round of the growth process, the hybrid silica particles formed were collected from the solution by centrifugation and a pore expansion protocol was performed to expand the pores as described in step 2 of Example 1.

Fig. 1 1 is a scanning electron micrograph image and its associated EDX spectrum of hybrid silica core-shell particles prepared in accordance with this Example. The EDX spectrum confirms the presence of Carbon (ranging from 12.07 to 15.45 weight %) on the surface of the silica spheres in accordance to the expectation for hybrid silica particles.

Table 8 summarises the physio-chemical properties of silica and hybrid silica core-shell particles producedin accordance with Examples 1-7. The silica source used in Examples 2,3, 5 and 7 was a mixture of approx. 90: 10 TEOS/TEMS and TEOS/BTSE. Examples 2,3, 5 and 7 yielded hybrid silica core shell particles and that contained approx 10% by weight Carbon.

Example 8 - Synthesis of a 3.5 urn core-shell particle with a superficially porous bridged hybrid silica shell of 500 nm on a spherical, non-porous silica surface using CTATos as a surfactant. Prior to the synthesis of the hybrid silica mesoporous shell, solid core non-porous silica seeds of 2.5 μπι diameter were synthesised according to methods described in the literature ³.

Step 1: Shell Growth

10 g of as synthesized 2.5 μιη, non-porous silica spheres (seeds) was dispersed in a solution of 100 mis dry ethanol and 200 mis of deionised water. After 20 mins sonication, the silica sol was transferred to a 1L PTFE bottle and allowed to stir at 45 °C for 20 mins. A surfactant solution containing 0.297g CTATos and 1.3 g of P123 in 30mls dry ethanol and 53.7 mis deionised water was prepared and added to the silica sol under stirring. After 20 min of stirring, 12.3 mis of 32.5% of ammonia was added and allowed to mix for 20 mins with 1.43 mis of TEOS and 0.48 mis of BTSE were then being added and allowed to react for 1 hour.

After a 1 hour reaction, the hybrid silica particles formed were collected from the solution by centrifugation. A small portion (about 5 mg) of hybrid silica particles were removed after each reaction round and analysed for particle size increase and corresponding size distribution using dynamic light scattering (DLS) techniques. The remainder of the as produced hybrid silica particles were resuspended in 102 mis dry ethanol and 204 mis deionised water following the sequence in Table 9 below, the growth process was repeated 19 times. As shown below in Table 9, the total volume of each addition is increased by 6 mis.

Table 9. A growth scheme for the formation of hybrid silica core-shell particles having a shell thickness of 500 nm.

Growth Silica Surfactant P123: NH₄OH Vol of DLS

Round Shell Solution CTATos (mis) TEOS:BTSE (μι^η)

Dispersion EtOH:H20 (g) Added

EtOH:H20 (mis) (mls

(mis)

1 100:200 30:53.7 1.3:0.297 12.3 1.43:0.48 2.57

2 102:204 30:53.5 1.3:0.297 12.5 1.5:0.5 2.63

3 104:208 30:53.3 1.3:0.297 12.7 1.43:0.48 2.69 4 106:212 30:53.1 1.3:0.297 12.9 1.5:0.5 2.75

5 108:214 30:52.9 1.3:0.297 13.1 1.58:0.53 2.81

6 1 10:220 30:52.7 1.3:0.297 13.3 1.65:0.55 2.87

7 1 12:224 30:52.5 1.3:0.297 13.5 1.73:0.58 2.93

8 1 14:228 30:52.3 1.3:0.297 13.7 1.65:0.55 3.00

9 1 16:232 30:52.1 1.3:0.297 13.9 1.73:0.58 3.06

10 1 18:236 30:51.9 1.3:0.297 14.1 1.8:0.6 3.13

1 1 120:240 30:51.7 1.3:0.297 14.3 1.88:0.63 3.19

12 122:244 30:51.5 1.3:0.297 14.5 1.8:0.6 3.25

13 124:248 30:51.3 1.3:0.297 14.7 1.95:0.65 3.31

14 126:252 30:51.5 1.3:0.297 14.9 2.03:0.68 3.36

15 128:256 30:51.7 1.3:0.297 15.1 2.1 :0.7 3.42

16 130:260 30:51.9 1.3:0.297 15.3 1.88:0.63 3.48

17 132:264 30:52.1 1.3:0.297 15.5 1.95:0.65 3.55

18 134:268 30:52.3 1.3:0.297 15.7 2.1 :0.7 3.62

19 136:272 30:52.5 1.3:0.297 15.9 2.18:0.73 3.69

Following the 19 round of the growth process, the hybrid silica particles formed were collected from the solution by centrifugation and a pore expansion protocol was performed to expand the pores as described in step 2 of Example 1.

Fig. 12 is a scanning electron micrograph image and its associated EDX spectrum of core-shell particles prepared in accordance with this Example. The EDX spectrum confirms the increase in Carbon content (when compared to Example 7 ranging from 23.19 to 25777 weight %) on the surface of the silica spheres in accordance to the expectation for hybrid silica particles.

The invention is not limited to the embodiments herein before described, with reference to the accompanying drawings which may be varied in construction and detail. References

(1) Yoon, S. B., Kim, J-Y., Kim, J.H., Park, Y. J., Yoon, K. R., Park, S-K., Yu, J-S., Mater. Chem. 2007, 17, 1758-1761.

(2) Kim, J. H., Yoon, S.B., Kim, J-Y., Chae, Y.B., Yu, J.-S., Colloid and surfaces Physicochem. Eng. Aspects 2008, 313-314, 77-81.

Bogush, G. H.; Tracy, M. A.; Zukoski, C. F. J. Non-Cryst. Solids 1988, 104, 95.

Claims

1. A process for preparing hybrid silica core— shell microparticles comprising the steps of:

c) removing residual surfactant by calcination or extraction; and

e) controlled dissolution of the microparticles of (c) in an acidic or basic solution to increase the final pore diameter of the microparticles

wherein step (a) is repeated a plurality of times.

2. A process as claimed in claim 1 wherein the mixed surfactant comprises a cationic surfactant and a non-ionic surfactant.

3. A process as claimed in claim 2 wherein the cationic surfactant is an alkyl ammonium tosylate.

4. A process as claimed in claim 3 wherein the alkyl ammonium tosylate is selected from the group comprising: hexadecyltrimethylammonium p-tolunensulfonate; 4-chloro-N,N- diethyl-N-heptylbenzenebutanaminium tosylates (Clofilium Tosylate); Ν,Ν,Ν-Trimethyl- 4-(6-phenyl- 1 ,3,5-hexatrien- 1 -yl)phenylammonium p-toluenesulfonate; and tetrabutylammonium p-toluenesulfonate.

5. A process as claimed in any one of claims 1 to 4 wherein the mixed surfactant solution comprises a tri-block co-polymer_^

6. A process as claimed in claim 5 wherein the tri-block co-polymer is a difunctional pluronic block co-polymer.

7. A process as claimed in claims 5 or 6 wherein the tri-block co-polymer comprises a polyethylene oxide (PEO) and/or a polypropylene oxide (PPO) unit.

8. A process as claimed in claim 7 wherein the tri-block co-polymer has a terminal HO- group at one or both ends of the PEO group.

9. A process as claimed in claim 7 or 8 wherein the triblock co-polymer comprises the formula:

PEO_x PPO_yPEO_x

wherein:

x is an integer between 5 and 106; and

y is an integer between 30 and 85.

10. A process as claimed in claim 10 wherein the tri-block co-polymer is PEO₂₀ PPO₇₀ PEO₂₀ and/or PEOi₀₆ PPO₇₀ PEOi₀₆

1 1. A process as claimed in any one of claims 6 to 1 1 wherein the tri-block co-polymer acts as a steric stabiliser to prevent aggregation of particles during the growth of silica shell.

12. A process as claimed in any one of claims 1 to 1 1 wherein the alkoxy silica precursor is one or more of tetrapropyl ortho silicate (TPOS), tetrabutyl ortho silicate (TBOS) tetraethyl ortho silicate (TEOS), and tetramethyl ortho silicate (TMOS).

13. A process as claimed in any one of the claims 1 to 12 wherein the organic alkoxy silane precursor has the general formula

RnX_(3-n)Si-(CH₂)_z-Si- RnX_(3-n)

wherein:

R is an organic radical;

X is a hydrolysable group ;

n=l or 2; and

z is an integer from 1 to 30.

14. A process as claimed in claim 13 wherein the organo alkoxy silane precursor is selected from triethoxymethylsilane (TEMS) and bis-l ,2-(triethoxysilyl) ethane (BTSE).

15. A process as claimed in any one of claims 1 to 14 wherein the molar ratio of alkoxy silica precursor to organo alkoxy silane precursor is between about 90: 10 to about 40:60.

16. A process as claimed in any one of claims 1 to 15 wherein the molar ratio of alkoxy silica precursor to organo alkoxy silane precursor is between about 90: 10 to about 75:25.

17. A process as claimed in any one of claims 1 to 16 wherein ammonia is added to the growth step to form the basic pH conditions.

18. A process as claimed in any one of claims 1 to 17 wherein the oil- in -water emulsion comprises one or more of an aliphatic alkane, a cycloalkane, or aromatic hydrocarbon of the formula:

C_nH2+2n> C_nH_2n, C_nH_n-x(CH3)_n;

wherein:

n is an integer between 6 to 12; and

x is an integer between 1 to 3.

19. A process as claimed in any one of claims 1 to 18 wherein the oil unit of the oil-in-water emulsion system comprises one or more of decane, trimethylbenzene, and cyclooctane.

20. A process as claimed in any one of claims 1 to 18 wherein the oil-in-water emulsion comprises ammonium iodide.

21. A process as claimed in any one of claims 1 to 20 wherein step (a) isjepeated between 2 and 100 times.

22. A process as claimed in any one of claims 1 to 21 wherein step (a) is performed at a temperature between about 25 °C to about 55 °C.

23. A process as claimed in any one of claims 1 to 22 wherein step (a) takes between about 1 hour and about 24 hours.

24. A process as claimed in any one of claims 1 to 23 wherein the microparticles are hydrothermally treated at a temperature of from about 60 °C to about 150 °C.

25. A process as claimed in any one of claims 1 to 24 wherein the microparticles are hydrothermally treated from about 1 hour to about 72 hours.

26. A process as claimed in any one of claims 1 to 25 wherein the hydrothermally treated microparticles are dried prior to calcination.

27. A process as claimed in claim 26 wherein the microparticles are dried under vacuum.

28. A process as claimed in claim 26 or 27 wherein the microparticles are dried at a temperature of between about 98 °C to about 102 °C.

29. A process as claimed in any one of claims 26 to 28 wherein the microparticles are dried for about 24 hours.

30. A process as claimed in any one of claims 1 to 29 wherein the microparticles are calcined at a temperature of about 500 °C to about 600 °C to remove surfactant.

31. A process as claimed in claim 30 wherein the microparticles are calcined at a ramping temperature.

32. A process as claimed in claim 31 wherein the temperature is ramped at a rate of b ween about 1 °C and about 10 °C per minute.

33. A process as claimed in any one of claims 1 to 32 wherein the microparticles are calcined for between about 76 hours to about 24 hours.

34. A process as claimed in any one of the claims 1 to 33 wherein the surfactant is extracted from the microparticles using an alcohol:acid mixture.

35. A process as claimed in any one of claims 1 to 34 wherein controlled dissolution of the microparticles is performed in an aqueous solution of ammonia and hydrogen peroxide.

36. A process as claimed in any one of claims 1 to 35 wherein controlled dissolution of the microparticles takes place at a temperature of about 75 °C.

37. A process as claimed in any one of claims 1 to 36 wherein controlled dissolution of the microparticles takes place for between about 8 hours to about 16 hours.

38. A hybrid silica core-shell microparticle comprising a non-porous core with an average diameter of at least 1.4μιη and a porous hybrid silica shell.

39. A hybrid silica core-shell microparticle comprising a non-porous core with an average diameter of about 1.4μηι and a porous hybrid silica shell with an average thickness of about 0.15 μπι.

40. A hybrid silica core-shell microparticle comprising a non-porous core with an average diameter of about 1.8μηι and a porous hybrid silica shell with an average thickness of about 0.4 μπι.

41. A hybrid silica core-shell microparticle comprising a non-porous core with an average diameter of about 2.5μιη and a porous hybrid silica shell with an average thickness of about 0.5 μηι.

42. A hybrid silica core-shell microparticle as claimed in any one of claims 38 to 41 wherein the core is solid.

43. A hybrid silica core-shell microparticle as claimed in any one of claims 38 to 42 wherein the core is formed from silica.

A hybrid silica core-shell microparticle as claimed in any one of claims 38 to 43 wherein the porous hybrid silica shell contains up to about 60% carbon by weight within the silica framework.

A hybrid silica core-shell microparticle as claimed in any one of claims 38 to 44 wherein the porous hybrid silica shell contains up to about 50% carbon by weight within the silica framework.

A hybrid silica core-shell microparticle as claimed in any one of claims 38 to 45 wherein the porous hybrid silica shell contains up to about 25% carbon by weight within the silica framework.

A hybrid silica core-shell microparticle as claimed in any one of claims 38 to 46 wherein the porous hybrid silica shell contains up to about 15% carbon by weight within the silica framework.

A hybrid silica core-shell microparticle as claimed in any one of claims 38 to 47 wherein the porous hybrid silica shell contains up to about 10% carbon by weight within the silica framework.

49. A hybrid silica core-shell microparticle as claimed in any one of claims 38 or 42 to 47 wherein the porous hybrid silica shell has a thickness of between about 0.1 μηι and about ΙΟμηι.

50. A hybrid silica core-shell microparticle as claimed in any one of claims 38 or 42 to 49 wherein the porous hybrid silica shell has a, thickness of between about 0.1 μιη and about Ι μη .

51. A hybrid silica core-shell microparticle as claimed in any one of claims 38 to 50 wherein the porous hybrid silica shell comprises multiple layers of hybrid silica.

52. A hybrid silica core-shell microparticle as claimed in any one of claims 38 to 51 wherein the microparticle has a substantially smooth surface.

53. A hybrid silica core-shell microparticle as claimed in any one of claims 38 to 52 wherein the pores have an average size of between about 20A and about 30θΑ.

54. A hybrid silica core-shell microparticle as claimed in any one of claims 38 to 53 wherein the pores have an average size of between about 60 A and about 300 A.

55. A hybrid silica core-shell microparticle as claimed in any one of claims 38 to 54 wherein the pores have an average size of about 80A.

56. A hybrid silica core-shell microparticle as claimed in any one of claims 38 to 55 wherein the microparticle has a specific surface area from about 50m²/g to about 1000m²/g.

57. A hybrid silica core-shell microparticle as claimed in any one of claims 38 to 56 wherein the microparticle comprises a functional ligand attached to the shell.

58. A hybrid silica core-shell microparticle as claimed in any one of claims 38 to 57 wherein the functional ligand is chemically attached to the shell.

59. A hybrid silica core-shell microparticle as claimed in any one of claims 38 to 58 wherein the functional ligand is C8 or CI 8.

60. A silica core-shell microparticle with an average diameter of about 2.6μιη comprising a non-porous silica core with an average diameter of about 1.8μπι and a porous silica shell with an average thickness of about 0.4μηι wherein the pores have an average size of about 80 A.

61. A silica core-shell microparticle as claimed in claim 60 wherein the microparticle has a specific surface area of about 174 m²/g.

62. A silica core-shell microparticle with an average diameter of about 3.5μη comprising a non-porous silica core with an average diameter of about 2.5μηι and a porous silica shell with an average thickness of about 0.5μη wherein the pores have an average size of about 80 A.

63. A silica core-shell microparticle as claimed in claim 62 wherein the microparticle has a specific surface area of about 230 m²/g.

64. A chromatography packing material comprising hybrid silica core-shell microparticle as claimed in any one of claims 38 to 59 or silica core-shell microparticles as claimed in anyone of claims 60 to 63.

65. Use of hybrid silica core-shell microparticles produced by the process of any one of claims 1 to 37 in liquid chromatography separation.

66. Use of hybrid silica core-shell microparticle as claimed in any one of claims 38 to 59 or silica core-shell microparticles as claimed in any one of claims 60 to 63 in liquid chromatography separation.