WO2022013243A1

WO2022013243A1 - Soft chemistry method for synthesising micronic silica particles

Info

Publication number: WO2022013243A1
Application number: PCT/EP2021/069508
Authority: WO
Inventors: Karine Fabio; Franck CHUZEL; Marlene SAUVAT; Carole DUBAYLE
Original assignee: Lifescientis
Priority date: 2020-07-16
Filing date: 2021-07-13
Publication date: 2022-01-20
Also published as: FR3112494B1; FR3112494A1

Abstract

The invention relates to a method for the synthesis of micronic silica particles, comprising the following steps: a) preparing silica nuclei by hydrolysis of at least one silica precursor in water in an acidic catalytic medium, the acid content preferably being chosen so as to be less than or equal to an acid equivalent of 0.1, b) forming a matrix phase by mixing at least one condensing agent chosen from at least one basic branched or linear polycationic polymer, and at least one monovalent, divalent or trivalent anion, c) condensing, in a basic medium, the silica nuclei obtained in step a) by stirring to mix the silica nuclei obtained in step a) and the matrix phase obtained in step b) at an alkaline pH of less than or equal to 10. The present invention relates to the field of synthesis and more specifically to the preparation of micronic silica particles, in particular silica particles.

Description

Synthesis process by mild chemistry of micron silica particles

TECHNICAL AREA

The present invention relates to the field of synthesis by soft chemistry and more particularly to the preparation of micron particles, in particular silica particles.

STATE OF THE ART

Microencapsulation is a technology allowing the immobilization of an active ingredient in a microparticle having a size of 1 pm to 1000 pm. The active ingredient is finely dispersed in a continuous matrix (sphere) or coated with a layer of material (capsule or core/shell).

Microencapsulation is used to stabilize an active ingredient, protect it from chemical or physical phenomena of oxidation, humidity, heat, UV radiation and control its release over time or under various external stimuli (heat, friction, pH). Microencapsulation can bring high added value and new functionalities to encapsulated ingredients and thus finds many industrial applications, particularly in the pharmaceutical (human and veterinary), agri-food, cosmetics (human and veterinary), phytosanitary, perfumes and aromas.

Many microencapsulation processes are available and based on mechanical, chemical or physico-chemical methods such as atomization (spray-drying, spray-coating), extrusion, fluidized bed, supercritical fluids, microgels of alginate, coacervation, interfacial polymerization and sol-gel chemistry.

The many advantages of microencapsulation in silica or hybrid particles have been described in particular in document US Pat. No. 10,099, 194 B2 which relates to sol-silica gel microparticles.

These sol-gel silica microparticles are generally obtained by hydrolysis and condensation of a silica precursor in the presence of an organic solvent in an alkaline medium such as concentrated ammonia or in a strong acid medium, hydrophobic solvents or petro-based surfactants. In particular, document US 2012/104639 discloses a process for the synthesis of silica particles from an emulsion obtained by surfactants and a conventional sol-gel condensation requiring an increase in the pH with a strong base.

So-called soft chemistry is increasingly sought after to develop synthetic processes that are more ecological and that integrate more harmoniously into natural processes.

An object of the present invention is therefore to provide a process for the synthesis of silica particles of controlled micron size, which can advantageously allow the carrying of active ingredients, which is more ecological and less energy-consuming than the conventional processes of the state of the art. technical.

The other objects, features and advantages of the present invention will become apparent from a review of the following description and the accompanying drawings. It is understood that other benefits may be incorporated.

ABSTRACT

To achieve this objective, according to one embodiment, a process for the synthesis of micron silica particles is provided, comprising the following steps: a) preparation of silica nuclei by hydrolysis of at least one silica precursor in water in a catalytic medium acid, preferably the amount of acid is chosen so as to be less than or equal to 0.1 equivalent of acid relative to the silica precursor, more preferably between 0.1 and 0.003, more preferably equal to 0.005 eq of acid, preferably the acid is chosen from a weak or strong carboxylic acid, for example formic acid or acetic acid or hydrochloric acid, then b) formation of a matrix phase by mixing at least one condensation agent chosen from at least one branched or linear basic polycationic polymer, advantageously chosen from at least one from among polyethyleneimines, polyamino acids, polyallylamines, derivatives of propylene imines, polylysines, polysaccharide derivatives with galactomannans, fructo-oligosaccharides and oligofructoses or a mixture, and of at least one monovalent, divalent, trivalent anion chosen from at least one from a phosphate salt, a tartrate salt and a citrate salt, a sulphate salt, or a nitrate salt, c) condensation in a basic medium of the silica nuclei obtained in step a) by mixing with stirring the silica nuclei obtained in step a) and of the matrix phase obtained in step b) at alkaline pH less than or equal to 10, conventionally called moderate or low pH, preferably pH less than or equal to 9, preferably pH less than or equal to 8.

The process according to the invention allows the synthesis of particles under mild chemical conditions with in particular a synthesis in water and a condensation at a moderate alkaline pH.

The present method of synthesis is inexpensive, efficient, gentle and rapid.

The process implemented is biomimetic and respects soft chemistry conditions.

Advantageously, the method does not include any organic solvent. Advantageously, the method does not include petroleum-based surfactants. Yields range from good to excellent (min 30%, average 50% up to 90%).

BRIEF DESCRIPTION OF FIGURES

The aims, objects, as well as the characteristics and advantages of the invention will emerge better from the detailed description of an embodiment of the latter which is illustrated by the following accompanying drawings in which:

Figures 1A and 1B are representative images by scanning microscopy (fig 1 A) and optical microscopy (fig. 1B) of silica microcapsules obtained in example 1.

Figures 2A and 2B are representative images by optical microscopy of silica microcapsules containing a linalool/citral mixture obtained in Example 2.

FIG. 3 is a representative image by optical microscopy of microparties of silica containing linalool obtained in Example 3. Figure 4 is a representative image by optical microscopy of silica microcapsules containing a perfumed composition obtained in Example 4.

Figure 5 is a representative image by scanning electron microscopy of silica microcapsules containing a perfumed composition obtained in Example 5.

Figures 6A and 6B are representative scanning electron microscopy images of silica microparticles obtained in Example 6.

Figures 7A and 7B are representative transmission (7A) and scanning (7B) electron microscopy images of submicron and micron silica particles obtained in Example 7.

Figure 8 is a representative thermogram of hybrid silica particles obtained in example 7 and reference control.

Figure 9 is a representative scanning electron microscopy image of silica particles obtained in Example 8.

Figure 10 is a representative image by optical microscopy of hybrid silica microparticles containing a perfumed composition obtained in Example 9.

Figure 11 is a representative image by optical microscopy of hybrid silica microcapsules containing a perfumed composition obtained in Example 10.

Figure 12 is a representative image by optical microscopy of hybrid silica microparticles containing linalool obtained in example 11.

Figure 13 is a representative image by optical microscopy of hybrid silica microparticles containing citral obtained in example 12.

Figure 14 is a representative image by optical microscopy of hybrid silica particles containing a perfumed composition obtained in Example 13.

The figure is a representative image by optical microscopy of silica particles containing a perfumed composition obtained in example 14.

The drawings are given by way of examples and do not limit the invention. They constitute schematic representations of principle intended to facilitate understanding of the invention and are not necessarily scaled to practical applications.

DETAILED DESCRIPTION

Before starting a detailed review of embodiments of the invention, optional characteristics are set out below which may possibly be used in combination or alternatively:

According to one example, steps a) to c) are carried out at room temperature, more precisely between 15 and 30°C or even from 5°C to 45°C.

According to one example, the silica precursor or a precursor mixture is chosen from at least one of tetraethyl orthosilicate (TEOS), tetramethyl orthosilicate (TMOS), (3-Aminopropyl)triethoxysilane (APTES), sodium metasilicate, calcium silicate, trimethoxymethylsilane (MTMOS), triethoxymethylsilane (MTEOS), triethoxysilane, trimethoxysilane, triethoxy(ethyl)silane (ETEOS), trimethoxy(ethyl)silane, isobutyl(trimethoxy)silane, propyl(trimethoxy)silane, sodium orthosilicate.

According to one example, the condensing agent is chosen from polyethylene imines, polyamino acids, polyallylamines, derivatives of propylene imines, polylysines, polysaccharide derivatives with galactomannans, fructo-oligosaccharides and oligofructoses or a mixture thereof.

According to one example, the condensing agent is chosen from guar gum or inulin or a mixture thereof.

According to one example, the condensing agent is chosen from guar gum modified with basic amine groups or inulin modified with basic amine groups or a mixture thereof.

According to one example, the condensation agent is added in step b) to be in an amount less than or equal to 100g/L in the matrix phase, preferably less than or equal to 50g/L, preferably less than or equal to 20g/L .

According to one example, the at least one silica precursor is added in step a) in an amount less than or equal to 6000 mM, preferably less than or equal to 5000 mM, preferably less than or equal to 4500 mM.

According to one example, the at least one silica precursor is present in step c) in an amount less than or equal to 1000 mM, preferably less than or equal to 500 mM.

According to one example, the monovalent, divalent or trivalent anion is added in a concentration less than or equal to 300 mM.

According to one example, the monovalent, divalent or trivalent anion is chosen from at least one of a phosphate salt, a tartrate salt and a citrate salt, a sulphate salt, or a nitrate salt.

According to one example, the silica particles are spherical.

According to one example, the method comprises the addition of an active ingredient in step a).

According to one example, the method comprises the addition of an active ingredient in step b).

The active ingredient is chosen for example from a perfuming active ingredient or a perfuming composition or a cosmetic active ingredient, such as for example a sunscreen, a phytosanitary active ingredient, an essential oil, an oily phase or else the active ingredient is silica. According to one example, the method comprises a step of pre-emulsifying the active ingredient in water preceding the addition of the active ingredient in step a) or b).

According to one example, the nuclei obtained in step a) are added to the mixture of step b).

According to one example, the mixture from step b) is added to the nuclei obtained in step a).

According to one example, the method comprises, after step c), a step d) of separating the particles and optionally a step e) of washing the isolated particles and optionally a step f) of drying the particles.

According to one example, the method comprises a step c′) of functionalizing silica particles obtained in step c) by adding a silica precursor, step c′) being simultaneous or successive to step c) and advantageously prior to step d) of separation.

According to one example, step d) of separation is carried out by centrifugation or filtration by tangential route.

According to one example, step e) of purification to eliminate organic residues is carried out by washing, chemical extraction or calcination.

According to one example, the method comprises, after step c), a step f) of drying carried out by atomization.

The term "micron" means a particle size between 1 μm and 1000 μm more precisely between 1 μm and 450 μm.

According to one possibility, the silica produced by the present process is in the form of particles of micron size. By micron is meant that the particles have their largest dimension less than or equal to 1000 μm, more precisely between 1 μm to 1000 μm, more preferably between 1 μm and 450 μm.

The silica particles are advantageously spherical in shape, which represents an advantage for their innocuousness.

The present invention relates to a process for the synthesis of micron silica particles under mild chemical conditions.

Preferably, the method implements a bio-inspired synthesis.

The particles obtained are advantageously biocompatible and/or biodegradable.

The particles obtained by the process according to the invention are particularly suitable for cosmetic, human or veterinary pharmaceutical, phytosanitary, food-processing or perfumery applications. The silica particles obtained according to one of the embodiments have a positive surface charge. This represents an advantage in particular in terms of passive targeting of surfaces, cells and/or tissues/epithelium which have a residual negative surface charge. The positive surface charge is particularly advantageous for deposition on hair fibers for cosmetic applications or on textile fibers for detergent and laundry care applications.

The method advantageously comprises 3 steps.

Preferably, the three steps: step a), step b) and step c) are carried out in an aqueous medium.

According to one embodiment, the method comprises a step a) of preparing the silica nuclei. According to the invention, step a) is a hydrolysis of at least one silica precursor. Step a) is carried out in an aqueous medium and advantageously in an acid-catalyzed aqueous medium.

According to one embodiment, the at least one silica precursor is chosen from precursors:

• of the siloxy type corresponding to the formula (R)xSi(0-R1) _4.x with R1= (C1-C4) alkyl or hydroxyl group, and

• R= group of the alkoxy, hydrogen, linear or branched alkyl type or an alkene, which may have a functional group of the amine, carboxyl, thiol, hydroxyl or epoxy type.

• of the silicate type corresponding to the formula SiO M=metal such as Ca, Na for example, (M20) _x (Si02) _y x=1 or 2, y = 1 or 2.

Preferably, the at least one silica precursor is advantageously chosen from at least one of tetraethyl orthosilicate (TEOS), tetramethyl orthosilicate (TMOS), (3-Aminopropyl)triethoxysilane (APTES), sodium metasilicate, calcium silicate, trimethoxymethylsilane (MTMOS), triethoxymethylsilane (MTEOS), triethoxysilane, trimethoxysilane, triethoxy(ethyl)silane (ETEOS), trimethoxy(ethyl)silane (ETMOS), isobutyl(trimethoxy)silane, propyl(trimethoxy)silane, sodium orthosilicate.

According to one possibility, the silica precursor is an extract of biogenic silica such as, for example, from residues of rice or diatoms, sodium silicate or a natural source of ortho silicic acid.

Preferably, the amount of silica precursor added during step a) is less than or equal to 6000 mM, preferably less than or equal to 5000 mM, more preferably less than 4500 mM.

Preferably, the amount of silica precursor during step c) is lower or equal to 1000 mM, more preferably less than 500 mM.

According to one embodiment, the amount of acid added is advantageously less than or equal to 0.1 acid equivalent. More specifically, the amount of acid is between 0.003 and 0.1 acid equivalent. As a preferred example, the amount of acid is equal to 0.005 acid equivalent. The amounts of acid are given in acid equivalent with respect to the silica precursor.

According to one possibility, the acid is chosen from a weak carboxylic acid or a strong acid. Preferably, the acid is chosen from formic acid, acetic acid or hydrochloric acid.

Advantageously, the pH of the aqueous medium in which the nuclei are prepared is at pH less than or equal to 5, preferably less than or equal to 4, preferably less than or equal to 3. Advantageously, the pH is less than or equal to 3 with a concentration of minimal acid so as to place it in an acid-catalyzed medium making it possible to ensure mild chemical conditions for the process.

By way of example, the nuclei are formed of a maximum of a few tens of atoms, for example, a silica nuclei has a size of the order of a few nm in diameter and preferably less than 20 nm

Without being bound to a particular theory, it has been observed that the concentration of silica precursor and of acid allow the formation of nuclei capable of stabilizing an emulsion comprising microdroplets of at least one water-insoluble active ingredient and of advantageously obtaining microparticles.

According to one embodiment, the method comprises a step b) of forming a matrix phase. The matrix phase is understood as the phase intended to allow the formation of silica. The matrix is formed by mixing at least one condensing agent and at least one monovalent, divalent, or trivalent anion or a mixture of monovalent, divalent, or trivalent anions.

The condensation agent is advantageously a branched or linear basic polycationic polymer. This represents an advantage compared to the more traditional use of a strong ammonia-type base. The choice of a basic polycationic polymer eliminates the need to adjust the pH by adding a strong ammonia-type base to control the condensation. This makes it possible to have a more ecological process of soft chemistry type. The method does not include a step intended solely for adjusting the pH.

Preferably, the polymer is chosen to have a weight less than or equal to 800 KDa. According to one aspect, said polymer comprises polyamino acids, in particular basic ones, such as polyarginines, polylysines and polyhistidines, but also polyallylamines, polyethylene imines (PEI), polypropylene imines, derivatives of polysaccharides of galactomannan type, fructo-oligosaccharides, of oligofructoses or mixtures thereof.

The condensation agent can result from the chemical modification of one of the polymers mentioned above in order to modulate its physico-chemical properties.

According to one aspect, the condensation agent is more precisely a polymer rich in primary, secondary or tertiary amine functions, that is to say comprising a number of amine residues greater than or equal to 4.

In the case of branched or linear polyethylene imines (PEI), they consist of the repetitive unit ethylene imine type (C2H5N)n with a molar mass of 43.04 g/mol. By way of example, a polymer can be diethylenetriamine or any of its higher homologs.

The condensation agent can also be a branched PEI of the following formula: H(NHCH ₂ CH2)nNH ₂ )n with a molecular weight of between 10,000 and 750,000, in particular between 25,000 and 750,000, or a mixture of PEI such as, for example, mixtures of PEI at 10kDa and 25kDa.

According to one aspect, the condensing agent is a - a polyamine dendrimer of generation greater than 1 containing [-CH ₂ CH ₂ N(CH ₂ CH ₂ CH ₂ NH ₂ ) ₂ ] _{2 type units} , by way of example DAB-Am-4, Polypropyleneimine tetramine dendrimer, generation 1.

In the case of derivatives of galactomannan polysaccharides, guar gum, modified or not, is preferred. Guar gum can be modified with a synthetic or non-synthetic basic amine group, for example a quaternary ammonium group.

In the case of oligofructose derivatives, inulin is preferred. Inulin can be modified with a synthetic or non-synthetic basic amine group, for example a quaternary ammonium group.

According to one possibility, the condensing agent is a mixture of PEI and guar and/or inulin.

Preferably, the condensing agent is added during step b) to reach a final mass concentration in step b) less than or equal to 100 g/L, more precisely less than or equal to 50 g/L, preferably less than or equal at 20g/L. The method according to the invention makes it possible to use a small quantity of condensation agent and therefore to obtain a basic condensation pH closest to physiological conditions, preferably of the order of a pH of 9, more preferably of order of 8. The condensation agent is advantageously selected to have chemical groups favorable to the formation of non-covalent interactions such as, for example, electrostatic bonds and/or hydrogen bonds. In this way, the condensing agent assists in a controlled manner the polymerization of the silica monomers.

The condensation agent is advantageously a bio-inspired or natural or bio-sourced polymer.

The condensation agent is advantageously recycled at the end of the process according to the invention. Recycling of the condensation agent is carried out by methods known to those skilled in the art such as filtration techniques on exclusion gel and/or ion exchange resins, ultrafiltration on membranes of nominal molecular weight appropriate limits. Recycling the condensation agent is an undeniable advantage.

The condensation agent, such as in particular PEI or modified or unmodified guar gum, acts both as a catalyst accelerating the condensation reaction and as a matrix which controls the reaction and the formation of the particles for the enlargement of the nuclei from nucleation points provided by the polymer-anion association such as phosphate.

According to one embodiment, the at least one monovalent, divalent, trivalent anion is an anionic salt. Preferably, the monovalent, divalent, trivalent anion is chosen from at least one of a phosphate salt, a citrate salt, or a tartrate salt, a sulfate salt, or a nitrate salt.

By way of example, the phosphate salt is chosen from sodium phosphate, magnesium phosphate, potassium phosphate, calcium phosphate.

By way of example, the citrate salt is chosen from sodium citrate, potassium citrate, calcium citrate, magnesium citrate.

By way of example, the tartrate salt is chosen from sodium tartrate, potassium tartrate, calcium tartrate, sodium and potassium tartrate, choline tartrate, ammonium tartrate.

Preferably, the monovalent, bivalent or trivalent anion is added during step b) to reach a final concentration less than or equal to 300 mM, more precisely 200 mM, for example 130 mM. The addition of at least one anion or a mixture of anions according to this concentration selection makes it possible to obtain the effect of the anion while limiting the impact on the pH of the condensation medium.

The at least one anion, or mixture of anions, monovalent, divalent or trivalent is added to the condensation agent in particular to ensure interactions electrostatics with the condensing agent and allow the formation of the matrix, in particular to control the formation of spherical particles.

According to one possibility, the nuclei obtained in step a), also called hydrolysis phase, are added to the matrix obtained in step b) is also called matrix phase.

According to another possibility, the matrix phase obtained in step b) is added to the nuclei obtained in step a).

According to one embodiment, the hydrolysis phase is added in a single portion to the matrix phase. According to one possibility, the addition is done with a controlled flow or without control directly at once.

According to one embodiment, the method comprises a step c) of condensation in a basic medium. The condensation step ensures the condensation of the silica nuclei (allowing the silica particles to grow in size) obtained in step a) in a controlled manner thanks to the matrix obtained in step b). The condensation step allows the nuclei obtained in step a) to grow in size to obtain particles.

Step c) advantageously comprises mixing the silica nuclei and the matrix, preferably with stirring.

Advantageously, step c) of condensation is carried out at basic pH, said to be moderate, that is to say less than or equal to 10. Preferably, at pH less than or equal to 9, even more preferably less than or equal to 8 and greater at 7.

According to an advantageous embodiment of the present invention, the synthesis process is carried out at ambient temperature. Advantageously, the various steps a), b) and c) are carried out at ambient temperature, which advantageously does not require any heating or cooling. Advantageously, at least steps a), b) and c) of the synthesis process are carried out without heating or cooling. These arrangements ensure a process which consumes little energy and which allows synthesis under so-called mild conditions. The ambient temperature preferably means between 18°C and 30°C, or even from 5°C to 45°C, more preferably between 20°C and 25°C.

According to one embodiment, the process according to the invention ensuring the synthesis of micron particles of silica advantageously comprises a stage c'), subsequent to or simultaneous with stage c) of condensation, comprising a stage of functionalization of the particles. In the case where step c′) is subsequent to step c), it is advantageously directly subsequent, that is to say that step c) and step c′) are successive, preferably without step intermediate. The functionalization step makes it possible to modify the surface of the silica particles to lead to a targeted surface functionalization and to attribute new properties to the particles. The functionalization step advantageously comprising the addition of a silica precursor. According to one example, the silica precursor is chosen from at least one of TEOS (tetraethyl orthosilicate), TMOS (tetramethyl orthosilicate), MTMOS (methyltrimethoxysilane), MTEOS (methyltriethoxysilane), ETEOS (ethyltriethoxysilane), ETMOS (ethyltrimethoxysilane) , APTES ((3-Aminopropyl)triethoxysilane), sodium orthosilicate or sodium metasilicate. The silica precursor from the functionalization step can be identical to or different from the silica precursor used in step a).

According to one embodiment, the method of the invention ensuring the synthesis of micron particles of silica advantageously comprises a step d), subsequent to step c) of condensation, preferably subsequent to step c′) if present, comprising a particle separation step. The separation step makes it possible to dissociate the microparties from any non-condensed nuclei, matrix phase and/or residual active ingredients. The particle separation step can be carried out, for example, by centrifugation or tangential cross-flow filtration.

According to one embodiment, the method according to the invention ensuring the synthesis of micrometric particles of silica comprises a step e), subsequent to step c), preferably subsequent to step c′) if present, and optionally to the separation step d) which allows purification of the silica microparticles by washing or chemical extraction. The purification step is intended to allow the removal of organic residues from the process. However, due to the synthesis process of the invention, carried out under mild chemical conditions, in particular bio-inspired, in particular advantageously without organic solvent, any organic residues are not harmful and do not impact the properties of the particles, therefore they do not do not necessarily have to be removed from the micro-parties and can bring new properties to the particles such as deposition. For example, cationic polymers do not have to be removed from microparticles to promote deposition on charged surfaces. By way of example, the purification step can be carried out by cycles of washing and/or centrifugation or calcination.

According to one embodiment, the method according to the invention ensuring the synthesis of micrometric particles of silica comprises a step of drying the microparties had the f) after step c) of condensation preferably after step c ') if present, and optionally steps d) of separation and e) of purification. The drying step makes it possible to obtain microparticles in the dry form, which can be a advantage in terms of storage, for example. The drying step can be carried out by atomization or spray drying. Advantageously, this step of drying by atomization or spray-drying can lead to a step of mechanical shaping of the microparticles of silica and of active agents.

According to the invention, the method makes it possible to produce particles having a capsular or matrix morphology. By capsular is meant that the microparticle comprises at least one hollow vesicle. According to one possibility, the microparticle is a hollow vesicle or according to another possibility, the microparticle is a hollow vesicle itself containing hollow vesicles. By matrix is meant that the microparticle is a solid sphere.

According to the invention, the method is advantageously configured to encapsulate an active ingredient in the microparticles. The active is also called active substance. The asset can be of various nature depending on the application. The active ingredient comprises at least one active molecule or a mixture of active molecules. The active ingredient is chosen, for example, from a perfuming active ingredient or a perfuming composition, or a cosmetic active ingredient, such as for example a sunscreen, a phytosanitary active ingredient, an essential oil or an oily phase, or else the active ingredient is silica.

The method according to the invention is advantageously configured to encapsulate the active ingredient either in a micro-capsule, the active ingredient is in the core of the capsule, or in a microsphere, the active ingredient is dispersed in the encapsulation material.

According to one possibility, the active ingredient comprises at least one perfuming substance. The active ingredient is a perfume or a perfuming composition.

According to one possibility, the active comprises at least one water-insoluble substance. The active ingredient is an oily phase or an essential oil.

According to one possibility, the active comprises at least one water-soluble substance. The active is a polar molecule.

According to one possibility, the active ingredient is silica, allowing the microparticles formed to carry silica.

The method according to the invention advantageously comprises a step of adding an active ingredient. According to a first embodiment, the step of adding an active ingredient is advantageously carried out before step c) of condensation.

Advantageously, the method does not include the addition of a surfactant, also called surfactant in English, to stabilize the active ingredient.

According to a first possibility, the step of adding an active ingredient comprises adding the active ingredient to the hydrolysis phase. The active ingredient is added to the nuclei obtained in step a). The asset is advantageously added to the nuclei obtained in step a) before mixing with the matrix phase obtained in step b). Advantageously, the active ingredient is added at the end of step a), when the nuclei are formed so as to limit the disturbances on the formation of the nuclei during step a). This process advantageously leads to the production of particles of capsular morphology.

According to a second possibility, the step of adding an asset comprises adding the asset to the matrix phase. The active ingredient is added to the mixture of the condensing agent and the monovalent, divalent or trivalent anion or the mixture of monovalent, divalent or trivalent anions. Preferably, the addition of the active is carried out after mixing the condensation agent and the anion, or the mixture of anions, monovalent, divalent or trivalent. This process advantageously leads to the production of microparticles of capsular or matrix morphology in the form of a microsphere.

Advantageously, the active ingredient is stabilized by the silica nuclei obtained in step a) by controlled acid conditions and reaction conditions. Then, the controlled condensation of the silica nuclei with the condensation agent makes it possible to condense the silica nuclei without destabilizing the active ingredient, present for example in the form of droplets and without adding surfactant.

According to an advantageous embodiment, the step of adding an active ingredient comprises a pre-homogenization step in water before adding the active ingredient to the hydrolysis phase or to the matrix phase. The pre-homogenization step in water is also called pre-emulsion. This pre-homogenization or pre-emulsion step includes mixing the active ingredient in water so as to form and stabilize droplets of active ingredients. Preferably, this step does not include the addition of a surfactant. The mixing of the active ingredient in the water is done with stirring. For example, the active-water mixture is stirred for a minimum of 30 seconds and up to 5 minutes. For example, the mixture is stirred at a minimum speed of 2000 rpm and up to 10000 rpm. For example, the mixture has a mass concentration of active ingredients in water of the order of 10% by weight. According to this embodiment, it is the active ingredient pre-homogenized or pre-emulsified in water which is added to the matrix phase or to the hydrolysis phase.

According to a second embodiment, the step of adding an active ingredient is carried out during the drying step, in particular by atomization. Drying the particles in the presence of an active promotes stabilization and adsorption.

The invention is not limited to the embodiments previously described and extends to all the embodiments covered by the claims. Example 1: embodiment for the formation of silica microcapsules

2.7 g of MTMOS are hydrolyzed in 1.1 g of water in an acid catalytic medium (pH£2, HCl) for 10 minutes at room temperature with stirring (300 rpm). The mixture is then added at a flow rate of 1mL/min to a mixture containing 10.4mL of sodium phosphate buffer (pH7, 500mM), 0.4g of polyethylene imine (25KDa) in 25.5g of water. The medium is stirred at 250 rpm at room temperature for 45 minutes. The microcapsules are isolated by centrifugation (1000g) and purified by washing with water (2 times). The microparties were obtained with a yield of 50% and an average diameter of 24.5 pm +/- 11 pm (standard deviation, s) measured from observations by scanning electron microscopy (SEM) and reprocessed by the ImageJ software. The capsule-like spherical morphology of the microparticles is confirmed by optical and electron microscopy (Figures 1A & B).

Example 2: embodiment for the formation of silica microcapsules in the presence of a linalool/citral mixture

2.7 g of MTMOS are hydrolyzed in 1.1 g of water in an acid catalytic medium (pH£2, HCl) containing 0.5 g of a linalool/citral mixture (1/1) for 10 minutes at room temperature with stirring (300 rpm). The mixture is then added at a flow rate of 1mL/min to a mixture containing 10.4mL of sodium phosphate buffer (pH7, 500mM), 0.4g of polyethylene imine (25KDa) in 25.0g of water. The medium is stirred (at 2000 rpm) at room temperature for 45 minutes. The microcapsules are isolated by centrifugation (1000g) and purified by washing with water (twice at 1000g). The mean particle diameter measured from optical microscopy observations and reprocessed by ImageJ software of 36.5 µm +/- 19 µm (o) (Figures 2A and 2B). The theoretical encapsulation rate is approximately 25.6% by weight. The encapsulation rate was determined to be 13.7% by GC-MS analyzes after extraction of the volatile compounds in ethyl acetate, which means an encapsulation yield of at least 58%.

Example 3: embodiment for the formation of silica microparticles in the presence of linalool

2.7 g of MTMOS are hydrolyzed in 1.1 g of water in an acid catalytic medium (pH£2, HCl) containing 0.5 g of linalool for 10 minutes at room temperature with stirring (300 rpm). A mixture containing 10.4mL of sodium phosphate buffer (pH7, 500mM), 0.4g of polyethylene imine (25KDa) in 25.0g of water is then added at a flow rate of 1mL/min to the hydrolyzed precursor. The medium is stirred (at 250 rpm) at ambient temperature for 45 minutes. The microcapsules are isolated by centrifugation (1000g) and purified by washing with water (twice at 1000g). The microparticles were obtained with a yield of 69%. The average diameter of the particles is 39.9 μm +/- 21 μm (o) measured from observations by optical microscopy and reprocessed by the ImageJ software (Figure 3). The theoretical encapsulation rate of linalool is approximately 23% by weight. After extraction of the compounds in ethyl acetate, the degree of encapsulation is 19.6% by GC-MS analyses, which means that the encapsulation yield is at least 85.4%.

Example 4: embodiment for the formation of silica microcapsules in the presence of a perfumed composition

9.2 g of MTMOS are hydrolyzed in 3.7 g of water in an acid catalytic medium (pH£2, HCl) containing 6.3 g of a perfumed composition containing at least 30% DPG for 10 minutes at room temperature with stirring (300 rpm). The mixture is then added at a flow rate of 3.5ml_/min to a mixture containing 39.1mL of sodium phosphate buffer (pH7, 500mM), 1.7g of polyethylene imine (25KDa) in 89.5g of water. The medium is stirred at 250 rpm at room temperature for 45 minutes. The microcapsules are isolated by centrifugation (1000g) and purified by washing with water (2 times). The mean diameter of the microcapsules is 141.8 pm +/- 132 pm (o, 24 pm min diameter, 639 pm max diameter) measured from observations by optical microscopy and reprocessed by the ImageJ software. (Figure 4). The theoretical encapsulation rate of the perfumed composition is approximately 50% by weight. The encapsulation rate was evaluated by thermogravimetric analysis from the dry residue (powder dried for at least 2 hours at 70°C in a convection oven). The mass loss measured between 25° and 250° C. is 48%. This means that the encapsulation rate is at least 48%.

Example 5: embodiment for the formation of silica microcapsules in the presence of a perfumed composition

3.4 g of MTEOS are hydrolyzed in 1.2 g of water in an acid catalytic medium (pH£2, HCl) containing 0.85 g of a perfumed composition containing at least 30% of DPG for 30 minutes at room temperature with stirring (600 rpm). The mixture is then added with a flow rate of 1 ml_/min to a mixture containing 10.4 ml of sodium phosphate buffer (pH7, 500 mM), 0.4 g of polyethylene imine (25 KDa) in 23.5 g of water. The medium is stirred at 3000 rpm at room temperature for 45 minutes. The microcapsules are isolated by centrifugation (1000g) and purified by washing with water (twice). The average diameter of the microcapsules is 35.1 μm +/- 21.0 μm (o) measured from observations by optical microscopy and reprocessed by the ImageJ software. The Spherical microcapsule-like morphology is observed by scanning microscopy (Figure 5).

Example 6: embodiment for the formation of microparties of hybrid silica

5.0 g of MTMOS are hydrolyzed in 2.0 g of water in an acid catalytic medium (pH<3, HCl) for 15 minutes at room temperature with stirring (300 rpm). A solution containing 0.3 g cationic modified guar gum (N-Hance3215™ Ashland - Guar hydroxypropyltrimonium chloride), 20.3 g sodium tartrate buffer (pH 6.2, 500 mM), 0.08 g citrate buffer (pH 4.5, 0.78M ), 0.1g with sodium hydroxide (6.25M) is added dropwise with a flow rate of 2ml_/min to the hydrolyzed precursor. The medium is stirred (at 250 rpm) at room temperature for 45 minutes. The microparticles are isolated by centrifugation (15000g) and purified by washing with water (3 times). The microparticles were obtained with a minimum yield of 40%. The mean particle diameter is 5.3 ± 2.5 pm measured from observations by scanning electron microscopy (SEM) and reprocessed by ImageJ software (Figure 6). The size distribution d50 equal to 16.7 μm was measured by laser granulometry (Master sizer S 2000 Malvern). The particles have a matrix spherical morphology observed by SEM (Figure 6A). The presence of residual polymer favorable to surface deposition is observed by SEM (FIG. 6B). The zeta potential was determined at +11.7 mV.

Example 7: embodiment for the formation of hybrid silica particles (submicron and micron)

A solution containing 2.6 g of hydrolyzed MTMOS in 4.5 g of water in an acid catalytic medium (pH<3, HCl) for 10 minutes at room temperature with stirring (300 rpm) is added to a mixture containing 0.3 g of modified guar gum (N - Hance3215™ Ashland - Guar hydroxypropyltrimonium chloride), 10.1 g of sodium tartrate buffer (pH 6.2, 500 mM), 0.09g of citrate buffer (pH 4.5, 0.78M), 0.05g with sodium hydroxide ( 6.25M). The medium is stirred (at 250 rpm) at room temperature for 45 minutes. The particles are isolated by centrifugation (15000g) and purified by washing with water (3 times). The particles were obtained with a yield of 50%. The mean diameter of the particles is 0.75 μm ± 0.20 μm measured from observations by transmission electron microscopy and reprocessed by the ImageJ software (FIG. 7A). The particles have a matrix spherical morphology observed by SEM (Figure 7B). The presence of residual polymer favorable to surface deposition is observed by SEM (FIG. 7B). A thermogravimetric analysis carried out from 25 to 800°C with a 10°C/min ramp made it possible to measure a quantity of residual polymer contained in the solid dry of at least 4.6% by measuring the loss of mass between 220°C and 300°C (Figure 8).

Example 8: embodiment for the formation of micro particles of hybrid silica

5.0 g of MTMOS are hydrolyzed in 2.0 g of water in an acid catalytic medium (pH<3, HCl) for 10 minutes at room temperature with stirring (300 rpm). The mixture is added drop by drop with a flow rate of 2 mL/min to a solution containing 0.3 g non-cationic modified guar gum (N-Hance HP40™ Ashland), 20.3 g of a sodium tartrate buffer (pH 6.2, 500 mM), 0.08g citrate buffer (pH 4.5, 0.78M), 0.1g with sodium hydroxide (6.25M). The medium is stirred (at 250 rpm) at room temperature for 45 minutes. The microcapsules are isolated by centrifugation (15000g) and purified by washing with water (3 times). The average diameter of the microparticles is 3.7 ± 1.7 pm measured from observations by scanning electron microscopy and reprocessed by the ImageJ software (Figure 9). The microparties were obtained with a minimum yield of 40%. The size distribution d50 equal to 23.6 μm was measured by laser granulometry (Master sizer S 2000 Malvern). The particles have a matrix spherical morphology (Figure 9). The presence of residual polymer favorable to surface deposition is observed by SEM (Figure 9).

Example 9: embodiment for the formation of microparties of hybrid silica in the presence of a perfumed composition

2.6 g of MTMOS are hydrolyzed in 1.4 g of water in an acid catalytic medium (pH<3, HCl) containing 0.84 g of a perfumed composition containing at least 30% DPG for 10 minutes at room temperature with stirring (300 rpm). The mixture is added drop by drop with a flow rate of 1 ml_/min to a solution containing 0.3 g of cationic modified guar gum (N-Hance3215™ Ashland - Guar hydroxypropyltrimonium chloride), 10.4 g of a sodium tartrate buffer (pH 6.2, 500 mM), 0.1g citrate buffer (pH 4.5, 0.78M), 0.1g with sodium hydroxide (6.25M). The medium is stirred (at 250 rpm) at ambient temperature for 45 minutes. The microparticles are isolated by centrifugation (15000g) and purified by washing with water (3 times). The particles are obtained with a minimum yield of 50%. The diameter of the microparticles is between 2.5 μm and 55 μm. The average diameter of the microparticles is 19.4 pm ± 12.8 pm (o) measured from observations by optical microscopy and reprocessed by the ImageJ software (Figure 10).

Example 10: embodiment for the formation of hybrid silica microcapsules in the presence of a perfumed composition 2.7 g of MTMOS are hydrolyzed in 1.1 g of water in an acid catalytic medium (pH£2, HCl) containing 0.84 g of a perfumed composition containing at least 30% of DPG for 10 minutes at room temperature with stirring (300 rpm). The mixture is then added at a flow rate of 1 ml_/min to a mixture containing 0.3 g guar gum (N-HanceHP40™ Ashland), 10.4 g of a sodium phosphate buffer (pH 7, 500 mM), 0.1 g of buffer citrate (pH 4, 0.78M) and 0.4g of polyethylene imine (25KDa) in 24.4g of water. The medium is stirred (at 250 rpm) at room temperature for 45 minutes. The microcapsules are isolated by centrifugation (1000g) and purified by washing with water (3 times). The particles are obtained with a minimum yield of 50%. The average diameter of the microparticles is 22.8 μm ± 13 μm (o) measured from observations by optical microscopy and reprocessed by the ImageJ software (FIG. 11).

Example 11: embodiment for the formation of microparties of hybrid silica in the presence of linalool

5.0 g of MTMOS are hydrolyzed in 2.0 g of water in an acid catalytic medium (pH<3, HCl) for 10 minutes at room temperature with stirring (300 rpm). A solution containing 0.3 g cationic modified guar gum (N-Hance3215™ Ashland - Guar hydroxylpropyl trimonium chloride), 20.3 g sodium tartrate buffer (pH 6.2, 500 mM), 0.1 g citrate buffer (pH 4.5, 0.78 M), 0.1g with sodium hydroxide (6.25M) and 0.98g of natural linalool is added dropwise with a flow rate of 2mL/min to the hydrolyzed precursor. The medium is stirred (at 250 rpm) at ambient temperature for 45 minutes. The microparties are isolated by centrifugation (15000g) and purified by washing with water (3 times). The microparticles were obtained with a yield of 67%. The diameter of the microparticles is between 8 μm and 80 μm. The average diameter of the microparticles is 56.6 pm ± 17.4 pm (o) measured from observations by optical microscopy and reprocessed by the ImageJ software (Figure 12). The theoretical encapsulation rate of linalool is approximately 20.3% by weight. After extraction of the compounds in ethyl acetate, the encapsulation rate is 17.0% by GC-MS analyses, which means that the encapsulation yield is at least 83.6%.

Example 12: embodiment for the formation of microparties of hybrid silica in the presence of citral

5.0 g of MTMOS are hydrolyzed in 2.0 g of water in an acid catalytic medium (pH<3, HCl) for 10 minutes at room temperature with stirring (300 rpm). A solution containing 0.3 g cationic modified guar gum (N-Hance3215™ Ashland - Guar hydroxylpropyltrimonium chloride), 20.3 g sodium tartrate buffer (pH 6.2, 500 mM), 0.1 g citrate buffer (pH 4.5, 0.78M ), 0.1g with sodium hydroxide (6.25M), 0.98g of citral is added drop by drop with a flow rate of 2ml_/min to the hydrolyzed precursor. The medium is stirred (at 250 rpm) at ambient temperature for 45 minutes. The microparties are isolated by centrifugation (15000 g) and purified by washing with water (3 times). The microparties were obtained with a yield of 79%. The diameter of the microparties is between 10 μm and 70 μm. The average diameter of the microparticles is 39.5 μm ± 8.0 μm (o) measured from observations by optical microscopy and reprocessed by the ImageJ software (Figure 13). The theoretical encapsulation rate of linalool is approximately 20.9% by weight. After extraction of the compounds in ethyl acetate, the degree of encapsulation is 15.9% by GC-MS analyses, which means that the encapsulation yield is at least 76.34%.

Example 13: embodiment for the formation of hybrid silica microparticles in the presence of a perfumed composition

2.6 g of MTMOS are hydrolyzed in 1.4 g of water in an acid catalytic medium (pH<3, HCl) containing 0.84 g of a perfumed composition containing at least 30% DPG for 10 minutes at room temperature with stirring (300 rpm). A solution containing 11.1 g of cationic modified inulin (Quatin™1280, Cosun), 10.4 g of a phosphate buffer (pH 7, 500 mM) and 0.55 g with sodium hydroxide (6.25 M) is added drop by drop. drop with a flow rate of 1mL/min to the hydrolyzed precursor. The medium is stirred (at 250 rpm) at ambient temperature for 45 minutes. The microparticles are isolated by centrifugation (1500g) and purified by washing with water (3 times). The particles were obtained with a yield of 46%. The diameter of the microparticles is between 10 μm and 160 μm, the average diameter is 15.5 μm ± 7.6 μm (o) measured from observations by optical microscopy and reprocessed by the ImageJ software (Figure 14A). The matrix spherical morphology is checked by scanning electron microscopy (FIG. 14B).

Example 14: embodiment for the formation of silica microcapsules in the presence of a perfumed composition

2.7 g of MTMOS are hydrolyzed in 1.1 g of water in an acid catalytic medium (pH£2, HCl) for 10 minutes at room temperature with stirring (300 rpm). The mixture is then added at a flow rate of 1ml_/min to a mixture containing 10.4mL of sodium phosphate buffer (pH7, 500mM), 0.4g of polyethylene imine (25KDa) in 23.9g of water and 1.7g of a composition scented containing at least 70% DPG. The medium is stirred at 250 rpm at room temperature for 45 minutes. The microcapsules are isolated by centrifugation (1000g) and purified by washing with water (twice). The average diameter of the microcapsules is 16.7 pm +/- 6.0 pm (o) measured from observations by optical microscopy and reprocessed by ImageJ software. The microcapsule-like spherical morphology is observed by optical microscopy (Figure 15).

Claims

1. Process for the synthesis of micron silica particles comprising the following steps: a. preparation of silica nuclei by hydrolysis of at least one silica precursor in water in an acid catalytic medium, preferably the quantity of acid is chosen so as to be less than or equal to 0.1 equivalent of acid relative to the silica precursor, b. formation of a matrix phase by mixing at least one condensation agent chosen from at least one branched or linear basic polycationic polymer chosen from at least one from polyethyleneimines, polyamino acids, polyallylamines, derivatives of propyleneimines , polylysines, polysaccharide derivatives with galactomannans, fructo-oligosaccharides and oligofructoses or a mixture, and of at least one monovalent, divalent or trivalent anion chosen from at least one of a phosphate salt, a tartrate salt and a citrate salt, sulfate salt, or nitrate salt, c. condensation in a basic medium of the silica nuclei obtained in step a) by mixing, with stirring, the silica nuclei obtained in step a) and the matrix phase obtained in step b) at an alkaline pH less than or equal to 10 .

2. Method according to the preceding claim, in which the condensation agent is chosen from guar gum or inulin, preferably modified with basic amine groups.

3. Method according to any one of the preceding claims, in which the condensation agent is added in step b) to be in an amount less than or equal to 100 g/L in the matrix phase, preferably less than or equal to 50 g/L , preferably less than or equal to 20 g/L.

4. Process according to any one of the preceding claims, in which steps a) to c) are carried out at ambient temperature of between 18°C and 30°C.

5. Method according to any one of claims 1 to 3 wherein steps a) to c) are carried out without heating and without cooling.

6. Method according to any one of the preceding claims, in which the silica precursor or a mixture of precursors is chosen from at least one of tetraethyl orthosilicate (TEOS), tetramethyl orthosilicate (TMOS), (3-Aminopropyl)triethoxysilane (APTES), sodium metasilicate, calcium silicate, trimethoxymethylsilane (MTMOS), triethoxymethylsilane (MTEOS), triethoxysilane, trimethoxysilane, triethoxy(ethyl)silane (ETEOS), trimethoxy(ethyl)silane (ETEOS), isobutyl (trimethoxy)silane, propyl(trimethoxy)silane, sodium orthosilicate.

7. Process according to any one of claims 1 to 5, in which the silica precursor is chosen from at least one of a biogenic silica extract, sodium silicate or a natural source of ortho silicic acid.

8. Process according to any one of the preceding claims, in which the at least one silica precursor is added in step a) in an amount less than or equal to 6000 mM, preferably the at least one silica precursor is present in step c) in an amount less than or equal to 1000 mM.

9. Method according to any one of the preceding claims, in which the monovalent, divalent or trivalent anion is added in a concentration less than or equal to 300 mM.

10. Process according to any one of the preceding claims, comprising the addition of an active ingredient in step a).

11. Method according to any one of claims 1 to 9 comprising the addition of an active ingredient in step b).

12. Method according to any one of claims 10 or 11 comprising a step of pre-emulsifying the active ingredient in water preceding the addition of the active ingredient in step a) or b).

13. Method according to any one of the preceding claims, in which the nuclei obtained in step a) are added to the mixture of step b).

14. Process according to any one of claims 1 to 12, in which the mixture of step b) is added to the nuclei obtained in step a).

15. Process according to any one of the preceding claims, comprising a step c′) of functionalizing the silica particles obtained in step c) by adding a silica precursor, step c′) being simultaneous or successive to step c).

16. Process according to any one of the preceding claims, comprising, after step c), a step d) of separating the particles and optionally a step e) of washing the isolated particles and optionally a step f) of drying the particles.

17. Process according to the preceding claim, in which step d) of separation is carried out by centrifugation or filtration by tangential route.

18. Process according to any one of the two preceding claims, in which step e) of purification to eliminate organic residues is carried out by washing, chemical extraction or calcination.