EP2144697A2

EP2144697A2 - Process for encapsulating chemically active substances and encapsulated product

Info

Publication number: EP2144697A2
Application number: EP08748062A
Authority: EP
Inventors: Fernando César FERNANDES; Maria Inês RÉ
Original assignee: Instituto de Pesquisa Tecnologicas do Estado Sao Paulo S/A (IPT); Fermavi Eletroquimica Ltda
Current assignee: Instituto de Pesquisa Tecnologicas do Estado Sao Paulo S/A (IPT); Fermavi Eletroquimica Ltda
Priority date: 2007-05-10
Filing date: 2008-05-09
Publication date: 2010-01-20
Also published as: WO2008138085A3; BRPI0701693A2; WO2008138085A2

Abstract

The present invention relates to an encapsulated system which comprises a core containing the active material and a coating layer formed by a water-soluble or hydrophilic material, and to its preparation process (Fig.1 ). According to an embodiment of the invention, the process for preparation of chemically active substances, comprises the steps of partial or total elimination of crystallization water from the active substance (1 ) - (3); preparation of the encapsulating material solution (8) with the equivalent of the crystallization water quantity required to achieve the desired hydration degree for the encapsulated substance; mixing of the active substance partially hydrated, of under anhydrous form, with the coating solution (7); and coating of the active substance (11) by the rehydration of the said substance (14) with the water from the liquid coating composition and simultaneous solidification of the coating material on the active substance.

Description

"PROCESS FOR ENCAPSULATING CHEMICALLY ACTIVE SUBSTANCES

AND ENCAPSULATED PRODUCT"

FIELD OF THE INVENTION

The present invention refers to an encapsulated system that comprises a core containing an active material and a coating layer formed by a water-soluble or hydrophilic material, and to the process for the preparation thereof.

The proposed system can be applied to pharmaceutical, food, veterinary or human products, or other technical applications (pigment industry, accelerating or retarding agents, fillers, crystallization inhibitors, flame retarding substances, etc.).

The coating layer maintains the core isolated under a solid formulation, isolating it from the contact with other components, and protects the core from the action of factors such as humidity, pH, temperature and oxygen presence, and it delays the solubilization of the core when the system is introduced into aqueous medium. The core comprises a chemically active substance, organic or inorganic, under a solid and hydrated form.

The encapsulated system, to which the present invention refers, can be applied for encapsulating or coating active organic or inorganic substances, existing under different hydration forms, which exhibit instability under the action of factors like humidity, temperature, pH, reactivity with other components or ingredients of formulations in which they are introduced.

BACKGROUND OF THE INVENTION

In the technological field, solid, liquids and/or gases substances, said active materials, can be formulated with other materials, said encapsulating materials, for various reasons: to protect additives sensitive to the contact with the surrounding medium and action of external factors like humidity, heat, pH and oxygen presence; to make it compatible and to stabilize sensitive additives in a formulation by limiting their physical contact with other components, to transform easy to handle and able to be incorporated liquids into solid ingredients, to mask taste and flavors, and to modify and control the release profile of the active material to obtain a prolonged or immediate effect of its action.

In the food domain, for instance, substances sensitive to oxygen and/or humidity are incorporated into certain products, among which, vitamins and minerals such as iron for food fortification. If these additives are not protected against the surrounding medium, which is rich in oxygen or humidity, they will be oxidized, thus altering the color, flavor and the nutritive value of the products to which they have been added. The coating or encapsulation of these additives aims at decreasing such reactivity with the surrounding medium and assuring the durability of the product.

A set of techniques allows the preparation of individual particles, constituted by an encapsulating material containing an active substance. The formulated particles present a size ranging from about 1 μm to 1 mm, containing typically between 5 to 90% (in mass) of the active substance. The active substances can be varied: pharmaceutical active principles, cosmetic actives, food additives, phytosanitary products, essential oils, fragrances, microorganisms, cells, chemical catalysts, pigments, etc. The encapsulating materials are natural or synthetic polymers, or lipids. The microparticles present different morphologies: 1) a capsule, i.e., a particle constituted by a core containing the active substance, surrounded by a solid continuous layer of encapsulating material; 2) a matrix, when the particle is constituted by a macromolecular or lipid continuous network wherein the active substance is finely dispersed, or under a molecular state, or in the form of fine solid particles, or also like liquid droplets.

The techniques known in the specialized literature mainly differ for the nature of the process used for the association of the active material with the encapsulating material, which can be either physically (spray drying, coating bed fluidization, extrusion), or physicochemically (coacervation or phase separation, among others), or chemically (molecular inclusion, interfacial or emulsion polymerization). The physicochemical processes are based in the following:

1) The control of solubility variations and precipitation conditions of the encapsulating material. It refers, for instance, to the controlled precipitation of a polymer in solution, due to the addition of a non- solvent (emulsification and evaporation or extraction of the solvent), or of another incompatible polymer (simple coacervation), or also the temperature or pH variation of the solution (complex coacervation).

2) Variations of the physical state (melting and solidification) of the encapsulating materials (thermal gelling of emulsions).

The physical processes rely upon nebulization techniques (spray drying, spray coating), droplets formation and extrusion.

In the physical or physicochemical processes, the formulation of the particles (capsule or matrix) allows the use of a wide range of encapsulating materials. The composition of the encapsulating material, the effect of its association with a given active substance, and the resulting product, or the form under which this association is performed have been the subject of patents.

Thus, for instance, as regards physical encapsulating processes, the specific literature presents several patent documents disclosing encapsulated forms of iron salts widely used for food application, as evidenced through the patent documents mentioned hereafter.

Document US 3,803,292 describes monohydrated iron (II) sulphate, encapsulated with heptahydrated iron sulphate, especially wheat flour, which is obtained by spray drying, i.e., through nebulization of an aqueous iron (II) sulphate solution in a drying chamber with temperature and humidity control during the cooling of the dried product for the formation of a heptahydrated iron sulphate layer surrounding a monohydrated iron (II) sulphate solid core. Documents BR0305871-9 and WO 2005/048995 describe the encapsulation of monohydrate iron (II) sulphate with alginate for the application in dehydrated food products, with the aim of reducing their reactivity and ensuring an adequate durability for aliments like wheat flour, without sensorial organoleptic alterations (color, flavor), wherein solid particles of ferrous sulphate having a granulometry of less than 300 μm are nebulized with a solution of alginate in conventional stirring equipments and solid mixing (fluidized bed, rotating drum, etc.).

Document US6830761 describes the encapsulation or coating of ferrous sulphate (II) granules with a diameter of no more than 850 μm by lipid- based materials (monoglycerides, diglycerides, hydrogenated soy oil and their mixtures) for semi-solid food fortification. This is performed, according to the patent, through conventional physical processes, although they are not detailed in the specification of said document.

In the fertilizers area, inorganic salts are used, which are rather sensitive to humidity, thus leading to caking during storage. Encapsulation of these salts limits this type of problem, as described in patent US 4,659,557, where heptahydrated ferrous (II) sulphate is coated with brown coal dust capable of absorbing a substantial amount of moisture, thus avoiding caking and improving fluidity of the product during handling and storage. The process consists in physically mixing the powders (ferrous sulphate and brown coal) under intense stirring in conventional equipment for solids mixing (rotating drums, centrifugal mixers, etc).

Also in the fertilizers area, document US 2004/0069033 describes a formulation of a water-soluble fertilizer capable of extending their dissolution time by the control of its water permeability and the releasing of encapsulated nutrients, wherein the encapsulation is also made through conventional physical methods like rotating drums, fluidized beds, or Wurster process (which principle is similar to a fluidized bed).

In the field of detergents and cleaning products, document US 2006/0249707 describes a process and a product referring to sodium percarbonate particles coated with at least two layers of encapsulating material, the external layer of the chemical composition being different from the internal one, with the aim of increasing the chemical stability of the substance in the presence of the other detergent components. In the process, the layers are deposited over the particles in a fluidized bed, with drying of the first layer before deposition of the second layer.

Encapsulating physical processes are also widely used in the pharmaceutical field, as described by the patent documents mentioned above.

The document US 2002/0192285 describes a heterogeneous coating for drugs comprising an insoluble polymer presented as a latex dispersion in water, an enteric polymer, which is added to the latex and a water- soluble polymer dissolved in an aqueous medium. This composition of dispersed and dissolved polymers is nebulized over the solid particles (medicine) by conventional nebulizing and drying processes, preferably in a fluidized bed. The polymeric film deposited over the pharmaceutical active principle particles has a controlled porosity with the objective to control the core dissolution rate. Document US 2003/0064108 describes a spray drying process using organic solvent (methylene chloride) and ethylcellulose for encapsulating solid particles with a granulometry below 250 μm, which are dispersed in a polymeric solution. The ethylcellulose layer formed over the particles due to the evaporation of the organic solvent has the property to mask flavor and to promote controlled-release for therapeutic action.

Generally, the known physical process for encapsulating solid particles involves a first step for the preparation of a dispersion of these particles in a solution of the coating encapsulating. Then, the dispersion is dried to eliminate the solvent (generally water), and to form a solid layer of the encapsulating material over the particles.

In the spray drying process, the particles in suspension in the encapsulating material solution are undergo a simultaneous process of drying and coating described in several patents, which innovate for the encapsulating material composition to obtain a programmed effect (controlled-release, flavor masking, etc) as exemplified in the prior art already described herein. However, some of the limitations are the size of the particles to be coated (preferably of no more than 250 μm), the quality of the coating film which tends to be porous due to the rapid solvent evaporation, and the agglomeration tendency of the particles during the process.

The coating and encapsulation processes, which involves the nebulization of the encapsulating material over the solid particles maintained under mixing and stirring, are exclusively applied to solid active materials and are very used as evidenced by innumerous patent documents found in the specialized literature. The particles are maintained in suspension in a heated gaseous vehicle (hot air), which can be performed in a fluidized bed, pan coating, or any other equipment of mixing and stirring which maintains the particles in motion, dispersed by a gaseous flux, and able to be aspersed by the coating material solution. The solvent evaporation (generally water) is necessary for the deposition of the solid layer over the particles. These processes allow performing a continuous coating of the particles, leading to the formation of microcapsules, comprising a 3-step cyclic sequence: (1) stirring or fluidization of the particles to be coated; (2) nebulization of the solution or of the dispersion of the encapsulating material over the particles; (3) drying and formation of the coating film.

There are various control parameters and process adjustment in order to assure a uniform coating of the particles. They are linked either to the nebulization step (concentration of the formulation, feed rate and size of the droplets formed), or to the film drying (air temperature, fluidization gas flow or mixing). The concentration and the flow of the solution must be rigorously adjusted to avoid aggregation of the particles when they collide in the mixer; the process requires a rigid control of the nebulization step to have liquid drops smaller than the particles to be encapsulated in order to control the liquid deposition rate over the particles; the particles to be coated must be heated when the liquid layer is deposited on their surface to allow drying and to avoid agglomeration; nebulized drops of the encapsulating solution can dry before making contact with the particles, providing fine particles and reducing the coating process due to the material loss.

Thus, it is verified that the above-mentioned processes present some drawbacks, such as the need for a strict control of the nebulization step so that the liquid drops are smaller than the particles to control the deposition process over the particles; the particles to be coated must be heated when the liquid layer is deposited over their surface. Nebulized drops may dry before touching the particles, generating fine particles and reducing the process efficiency; the control of the liquid deposition rate over the particles ("onion" effect) must be rigid; the coating of the particles surface depends upon the spreadability of the liquid at the particle surface (solid-liquid interaction).

OBJECTIVES OF THE INVENTION

In view of the exposed above, it is an object of the present invention to provide a process, which does not require the strict control of the nebulization conditions.

Another object of the present invention is to provide a new process where the hardening of the coating layer is independent from the simple or complex coacervation steps. SUMMARY OF THE INVENTION

The above-mentioned and others are achieved by the present invention by means of a process comprising the withdrawal of at least part of the crystallization or hydration water from the chemically active substance to be encapsulated, followed by the coating of these particles with an encapsulating material layer in aqueous solution and hardening of said encapsulating material by re-hydrating said active compound, in which such re-hydrating comprises the absorption of the water from said solution.

According to other characteristic of the present invention, said encapsulation occurs by the simple mixing of said solution with the particles of the active compound, at room temperature.

According to another characteristic of the present invention, the process can be carried out in a batch or as a continuous operation.

According to another characteristic of the present invention, the hardening of the encapsulating material occurs due to the water reincorporation of the hydrating or crystallizing water to the active compounds molecules and, thereby, reverts to its original composition.

According to another characteristic of the present invention, the process does not require the heating or drying of the encapsulated particles.

The physical process for coating and encapsulating solid particles described in the present invention, presents several advantages compared to the existing processes conventionally used, which comprises several steps including drying after deposition of the liquid film over the particles for solvent elimination, and solidification of the encapsulating material, namely: - The contact between the encapsulating material solution and the solid particles to be encapsulated occurs through a simple mixture of the encapsulating solution with the active material at room temperature. Differently from the other described processes, there is no need for nebulization under rigid conditions of liquid drops size control of the encapsulation material during its addition to the solid particles, this addition being performed in a batch or as a continuous process.

- The deposition occurs through the re-hydration of the substance with the water of the encapsulating material solution. The solid layer of the encapsulating material is formed over the particles due to the incorporation of water by the substance being hydrated, which means that a later or simultaneous drying of the mixture as occurs in the other physical processes known until then is not necessary.

- The process is adapted to a wide granulometry range (from about 1 μm to 1 mm) and allows the reduction of particles size naturally imposed by their dehydration during the first step of the process. In the case of conventional processes, the particles size distribution of the substance to be encapsulated is adjusted by and additional milling step when starting from a higher granulometry. BRIEF DESCRIPTION OF THE DRAWINGS

Further details, characteristics and advantages of the present invention will be more evident from the description of a preferred embodiment and from the figures to which they refer, and they illustrate, in a general manner, the proposed process, as follows: Figure 1 shows, in a schematic way, the process for producing chemically active substances encapsulated in a hydrated form.

Figure 2 shows optical micrograph images illustrating, after immersion of the samples in water, the effect of gelling during the hydration and swelling of the gelatin layer formed around the iron (II) sulphate encapsulated with 2% gelatin, which is not observed with the non-encapsulated which dissolves in less than 1 minute.

Figure 3 exhibits physical characteristics of the encapsulated and non-encapsulated material after 70 hours of exposure to a load of 1 kg/cm², simulating the loading of a 10 to 15 meters silo.

DETAILED DESCRIPTION OF THE INVENTION

The process for preparing chemically active substances, in hydrated form and coated with an encapsulating material, which is the object of this invention, is performed through the steps described hereafter. 1) Dehydration of the chemically active substance The chemically active substance containing crystallization water must firstly be partially or totally dehydrated. By "crystallization water" is meant the water present in crystalline compounds, within determined proportions. Many crystalline salts forms hydrated compounds containing 1, 2, 3, or more water molecules for each molecule of compound, and the water can be trapped within the crystal under various forms. Thus, the water molecules can simply occupy positions in the crystal network, or to form links with the anions or cations.

The complete or partial removal of the crystallization water from the chemically active substance can be performed through any drying or precipitation process that allows its removal.

In the present exemplificative embodiment, this operation can be done by evaporation through conventional drying processes. Convective methods are indicated for this operation, such as rotating dryers equipped or not with agitating pallets, pneumatic transport or fluidized bed with temperature control, wherein the particles are maintained in ascending-descending movement through an air stream that permeates the particle bed. In these processes, the important factor is the control of the process temperature for controlling the dehydration (kinetic of the process and amount of removed water), and the composition of the drying gas (control of the oxygen content) to avoid the oxidation of the active substance if it is easily oxidize.

The removal of crystallization water can be equally done, by an alternative step, by precipitation of the substance under anhydrous form by varying the temperature of a saturated solution (precipitation by temperature increase or decrease, depending upon the effect of this parameter on the substance solubility).

Whatever the technique used, it is recommended to remove an amount of water equivalent to at least to 30% of the crystallization water of the hydrated substance to be encapsulated, preferably between 40 and 70% in mass.

2) Preparation of the coating material solution

In this step of the process, the amount of the water used for the preparation of the aqueous solution of the encapsulating material must be equivalent to the amount of the hydration water removed from the chemically active substance in the previous step of the process, or equivalent to the amount of the hydrated substance in the encapsulated form. In such volume of water, it is dissolved the specified amount of the encapsulating material preferably under controlled temperature between 15 and 60⁰C, and more preferably between 40 and 50⁰C.

The encapsulating material can be any water-soluble or hydrophilic substance, with film formation properties like proteins, raw materials derived from the collagen hydrolysis such as food gelatin, technical gelatin, animal glue, polyvinyl alcohol, polyvinylpirrolidone, alginate, chitosan, cellulose derivatives such as hydroxypropylmethylcellulose or sodium carboxymethylcellulose, acrylic acids and similar compounds. Water absorbing compounds but not soluble in water at the temperature between 15 to 25°C, and, which can be treated by crosslinking or hardening agents to decrease the coating solubility are particularly desired to increase the applicability of the product in aqueous media.

In the present embodiment, it was used a protein, more specifically a gelatin, which is a protein derived from the partial hydrolysis of the collagen, which is the main constituent of animal skins, bones, tendons and connective tissues. Gelatin is obtained from the collagen purification, which is separated and processed, being converted in the final product. This process can be carried out under acid conditions, resulting in type A gelatin, or in alkaline conditions, resulting in type B gelatin. The production encompasses as basic steps the treatment of the collagen tissue, extraction, purification, concentration, sterilization, cooling, drying, milling and packaging.

The technical gelatin produced from raw bovine leather or bones through alkaline process, known as animal source glue, also can be used; it can also be used vegetal source proteins, such as the ones disclosed in US 2002/0187185, which has good physical property in place of the animal gelatin, in a great range of applications, especially in the manufacture of gelatin capsules.

The gelatin is sold in several classifications corresponding to these specific properties. Commercially, gelatin is classified in function of the mechanical resistance to gel (Bloom value) measured under standard test conditions. Usually, gelatin having gel strength of 80 to 520 g bloom can be selected, preferably between 200 and 380 g bloom.

The present invention is not limited to the use of some gelatin with specific properties. It can be used, for example, gelatins extracted from raw material of bovine, swine, poultry, fish origin and the like, and which has the property of changing the sol-gel condition in function of the temperature.

The process of the present invention allows the use of conventional gelatins used in the manufacture of capsules, such as acid, alkali and amphoterically-treated gelatins, or chemically modified gelatins, pure or in combination, food grade gelatins, pharmaceutical grade, technical gelatin or animal glue, besides vegetal source gelatins. In the described process, it can be used gelatins with gel strength between 80 and 520 g bloom and, preferably, between 200 and 38Og bloom. It is recommended that the amount of the encapsulating material

(such as, gelatin) is between 0.05 and 20% (in mass) of the active substance in its hydrated form to be encapsulated, preferably between 0.2 and 4%.

3) Mixing of the chemically active substance (partially hydrated or in anhydrous form) with the encapsulating material solution This step can be easily performed by using any stirring and mixing equipment with the aqueous solution of the encapsulating material prepared in the previous step (2).

The encapsulating material solution can be added to the active substance that will be encapsulated (partially hydrated or in anhydrous form) in one single step (batch) or gradually (continuous process), in the desired proportion of the encapsulating material to the substance to be encapsulated.

This step can be performed in conventional stirring and mixing equipments such as intense stirring mechanical mixers, for example, those having pallets or stirring pins. Due to the possibility of the presence of fine particles of the active substance and, consequently, powder formation in the materials mixture, it is recommended to perform this operation in closed equipments.

4) Coating of the chemically active substance

At the end of the mixing step (3), the obtained material (generally under paste form) is maintained at rest to cool at room temperature, preferably in the form of a small thickness layer, for a period sufficient for the active substance re-hydration by the water of the encapsulating material solution. This operation results in an increase of the temperature of the material, due to the hydration heat of the active substance. The water is then incorporated to the active substance as crystallization water and the encapsulating material solidifies at its surface.

After the re-hydration and cooling until the desired room temperature, the obtained material can be submitted to a mechanical disintegration process of the aggregated particles of the coated and hydrated active substance. The disintegration of this material does not require milling and is easily obtained by any process that promotes the contact and mechanical stirring of these aggregates, like contact mills (roll), fluidized bed, or even pneumatic transport. The disaggregated product can be submitted to a final granulometric classification, if necessary.

A variation of the process of the present invention consists in a fifth optional step for the reinforcement of the resistance of the encapsulating material deposited over the surface of solid re-hydrated particles by means of stable reactions of ionic complexation chemical crosslinking or by the action of hardening agents.

In particular, gelling hydrophilic compounds, especially hydrophilic compounds able to expand in water but not soluble in water in the application temperature, that is, between 15 and 25⁰C, such as proteins, polyvinyl alcohol and similar compounds, which can be treated by crosslinking and hardening agents to avoid dissolution of the coating, are particularly adequate as coating forming substances for use in aqueous medium. Proteins like gelatin are preferred, this being a material able to form gel and to form stable complexes of the polyelectrolyte source (polycation-polyanion) or chemical reticulation with aldehydes, tannic acid and others.

Polyelectric complexes are formed by the interaction of a polyanion with polycations. As polyanion, it is advantageous to use water- soluble cellulose derivatives such as, for instance, carboxymethylcellulose, cellulose sulphate, or also pectins, alginates, Arabic gum, but also synthetic polymers such as polyacrylic or polymetacrylic acids, etc. As polycations, it can be applied mainly natural substances, such as chitosan, gelatin, etc.

The reinforcement can be performed through the deposition of an additional layer of a cross-linking material solution (e.g. glutaraldehyde solution) or of a complexing agent (polyanion such as sodium alginate or sodium carboxymethylcellulose). The process involves the deposition of the complexing or crosslinking solution over the already formed layer on the re-hydrated particles, followed by drying of the chemically modified layer. The variation of the process is done by the aspersion of a crosslinking solution layer over layer already deposited in the particle surfaces. After the deposition, a subsequent drying step is carried out by any known technique reported in the specialized literature (fluidized bed, liophylization, rotating drum, etc).

A suggestive schematic description of application of the process object of this invention and its steps (1) to (4) is presented in Figure 1.

The solid material to be re-hydrated and coated by the encapsulating material is fed through a screw conveyor (1) into a vertical fluidized bed (2). The drier is fed by a hot gas stream (3) that maintains the solid mass under stirring and mixing. The material is dehydrated during its permanence time in the drying chamber due to its contact with the hot gas (3). The fluidization speed control is done so that the dehydrated particles are transported to a cyclone (4), from which a fine fraction is recovered from a filter (5), and the thicker fraction, through a screw conveyor (6), feeds the mixer/encapsulator (7). The encapsulating material solution (8) is added to the mixer (7) where the encapsulating process as schematized in (11) occurs. After a period of mixture for re-hydration of the water present in the system by the solid particles, the product is discharged in the conveying belt.

As illustrated, the encapsulating material (12) is contacted with the active substance granules (13), recovering their surface. As a consequence of the contact between these materials, the compound absorbs water from the encapsulating solution, as indicated by the arrows. As a result, the encapsulating material contained in the solution solidifies by forming a film wall (15), which coats the re-hydrated compound (14).

Below are presented some tests of procedures for the obtainment of solid particles encapsulated by the process of the present invention.

EXAMPLE 1

PROCESS FOR THE PRODUCTION OF HEPTAHYDRATED FESO* PARTICLES COATED WITH 1% GELATIN TO OBTAIN A PRODUCT WITH GRANULOMETRY OF LESS THAN 200 ΜILI

The process described in this invention can be applied to the production of heptahydrated FeSO₄ encapsulated with gelatin.

The iron sulphate (II) can be in different hydrated forms (heptahydrate, tetrahydrate, and monohydrate). The most common type is the heptahydrate one (FeSO₄ ^* 7 H₂O), which is not thermally stable. At 60-70⁰C, it dehydrates to tetrahydrate (FeSO₄ ^* 4 H₂O), and at 115⁰C to monohydrate (FeSO₄ ^* 1 H₂O). Heptahydrated FeSO₄ particles have been used in this process, as an example of its applicability.

Step 1 - Partial dehydration of heptahydrated iron sulphate The initial step of material dehydration has been performed in a dryer/fluidized bed dehydrator working with 1 ton of FeSO₄.7H₂O feed per hour.

In this type of equipment, the solid material to be dehydrated is placed in contact with a heated drying gas stream, capable of providing the energy necessary for the evaporation of the water incorporated into the product, in this case, FeSO₄JH₂O.

In the example presented herein, it was used LPG combustion gas (Liquefied Petroleum Gas) diluted with atmospheric air, so as to control the oxygen amount within the dryer atmosphere and thus avoid the oxidation of Fe(II) into Fe (III) in the product. The dryer was provided with GLP (Liquefied Gas of Petroleum) combustion gas with a volumetric flow of 7000 m³ per hour at a temperature of 250-300⁰C, and the temperature of the gas at the output of the dryer was maintained at 9O⁰C to control the residence time of the active substance in the dryer (about 6 min., with a mass of 100 kg in permanence in the dryer) and the amount of the hydration water to be eliminated (about 60- 70% of the crystallization water of the heptahydrate form).-

Step 2 - Preparation of the coating material solution Non-edible type B gelatin with 210-230 g bloom and viscosity 30- 41mps is used as the encapsulating material.

In a volume of water equivalent to 60% of the crystallization water of FeSO₄.7H₂O, an amount of type B gelatin equivalent to 1% in mass of the amount of FeSO₄JH₂O was dissolved, at a temperature of 4O⁰C, and an aqueous solution containing 37 g of gelatin per liter of water was thus obtained. Step 3 - Mixture of the iron (II) sulphate partially hydrated with the gelatin solution

The ferrous sulphate previously dehydrated (after lost of 60% of its crystallization water, i.e., 27 kg of water/100kg of initial heptahydrate ferrous

Il sulphate) was added to the gelatin solution in a pin mixing reactor of high stirring potency, and it was mixed until the obtainment of a homogenous mixture, in a semi-solid (paste) state: 9.1 kg of FeSO₄.xH₂O (partially hydrated, a mixture of x=1 and x=4) and 3.6 kg of gelatin solution (37g of gelatin/liter of water) were fed per minute in a continuous mixer, corresponding to a mass relation of gelatin solution to sulphate of 40%. The residence time of the product within the mixer was of 2 minutes.

Step 4 - Encapsulation of the chemically active substance The obtained mixture was discharged and maintained at rest for 30 minutes, which is the period necessary for the absorption of the water of the gelatin solution by the iron (II) sulphate, and for the deposition of the gelatin on the re-hydrated particles. After this period, the material, already under solid form, was disintegrated in a rubber roll mill, in order to obtain the product with the desired granulometry (less than 200 μm). Tables 1 , 2 and 3 show some characteristics of the products at different steps of the process. As can be seen, by comparing the granulometry of the heptahydrated ferrous (II) sulphate introduced in the process (Table 1) and the granulometry of the partially dehydrated product in the end of the first dehydration step (Table 2). The dehydration modifies the physical characteristics of the product, reducing the granulometry to the range specified for the product in this case, which represents an advantage of the process since it eliminates a step that would be necessary with another conventional physical process to adjust the product granulometry. The final coating step and re-hydration led to an increase in the product granulometry, as shown in Table 3, within the granulometry specified for the product (< 200 μm).

TABLE 1 CHARACTERISTICS OF HEPTAHYDRATED FERROUS (II) SULPHATE FED IN THE DRYER/DEHYDRATOR

TABLE 2 CHARACTERISTICS OF THE PARTIALLY HYDRATED FERROUS SULPHATE OBTAINED

AFTER THE DEHYDRATION STEP IN THE FLUlDlZED BED

Fe(II) content 28.2%

Fe total content 28.9%

Water loss at 105⁰C 6.1 %

Particles size:

D(0.5) 13.7 μm

D (0.1) 1.3 μm

D (0.9) 93.1 μm

Fraction < 200 μm 100.0%

Fraction < 100 μm 92.7%

TABLE 3

CHARACTERISTICS OF HEPTAHYDRATED FERROUS SULPHATE ENCAPSULATED WITH A TYPE B GELATIN SOLUTION (1 % IN MASS AS REGARDS THE HYDRATED SULPHATE

MASS)

EXAMPLE 2

PROCESS FOR THE PRODUCTION OF HEPTAHYDRATED FESOA ENCAPSULATED WITH 2% GELATIN, TO OBTAIN THE PRODUCT WITH A GRANULOMETRY OF LESS THAN 200 UM

The above-described process (Example 1) was used to obtain a product with higher type B gelatin content used as encapsulating material. The material used was type B non-edible industrial gelatin with 210-230 g bloom and viscosity of 30-41 mps. An amount of type B gelatin equivalent to 2% in mass of the amount of FeSO₄.7H₂O, was dissolved in a volume of water equivalent to 60% of the crystallization water of FeSO₄JH₂O, at a temperature of 4O⁰C. An aqueous solution containing 74 grams of gelatin per liter of water was obtained.

Steps (3) and (4) were similar to the ones used in the preparation process described in Example 1.

Table 4 shows the granulometry and the physical characteristics of the product obtained comparable to the particles coated with 1% gelatin solution presented in Example 1.

TABLE 4

CHARACTERISTICS OF HEPTAHYDRATED FERROUS SULPHATE ENCAPSULATED WITH A TYPE B GELATIN SOLUTION (1% IN MASS AS REGARDS THE HYDRATED SULPHATE MASS)

EXAMPLE 3

PROCESS FOR THE PRODUCTION OF HEPTAHYDRATED FESOΛ ENCAPSULATED WITH 1% ANIMAL GLUE AS THE ENCAPSULATING MATERIAL. TO OBTAIN A PRODUCT WITH A

GRANULOMETRY OF LESS THAN 200 UM

The above-described process (Example 1) was used to obtain a product using, as encapsulating material, gelatin hydrolyzed from collagen, known as animal glue, with 250 g bloom and viscosity of 90 mps). The same proportions used in Example 1 , as well as the same variables, were maintained. An amount of animal glue equivalent to 1 % in mass of the amount of FeSO₄JH₂O, was dissolved in a volume of water equivalent to 60% of the crystallization water of FeSO₄JH₂O₁ at a temperature of 4O⁰C. An aqueous solution containing 37 grams of animal glue per liter of water was obtained.

Steps (3) and (4) were similar to the ones used in the process described in Example 1.

Table 5 shows the granulometry and the physical characteristics of the product obtained comparable to the particles coated with 1 % gelatin solution presented in Example 1.

TABLE 5

CHARACTERISTICS OF HEPTAHYDRATED FERROUS SULPHATE ENCAPSULATED WITH ANIMAL GLUE SOLUTION (1% IN MASS AS REGARDS THE HYDRATED SULPHATE MASS)

EXAMPLE 4

DISSOLUTION RATE OF THE HEPTAHYDRATE FESO4 PARTICLES COATED WITH 1% AND

2% GELATIN

The encapsulated products produced in Examples 1 and 2 were submitted to a dissolution test in water, to verify the presence of a gelatin film covering the surface of the heptahydrated ferrous (II) sulphate crystals.

A given amount of the material (equivalent to 30 mg of iron) was introduced in 22 ml of water, and the amount of iron in aqueous solution was quantified after different exposure times to the dissolution medium. The results obtained are shown in Table 6, evidencing the protective effect of the gelatin layer (1 or 2%), delaying the solubilization of the heptahydrated ferrous (II) sulphate. It is important to remind that this test has a drastic effect of introduction of the product in a very well diluted medium, which favors the immediate solubilization of the ferrous sulphate as seen in the non- encapsulated product. For applications where the contact with water is done in a more concentrated medium the dissolution inhibiting effect demonstrated by the gelatin layer will be more pronounced.

TABLE 6

PERCENTAGE OF IRON (II) DISSOLVED IN WATER AFTER CONTACT WITH THE AQUEOUS

MEDIUM

* Type B gelatin 250 g bloom

A simple and rapid method to observe the gelatin layer deposited over the ferrous (II) sulphate particles is by visual monitoring, by optical microscopy, of the behavior in water of some of these particles. It can be easily visualized the changing in the dissolution through absorption of water by the gelatin layer, as shown in Figure 2, which are micrographs obtained by optical microscopy, with magnification of 40x, illustrating the solubilization of the FeSO₄.7H₂O product encapsulated with 2% gelatin, in water, in comparison to the non-encapsulated FeSO₄JH₂O EXAMPLE 5 EVALUATION OF THE PRODUCT FROM EXAMPLE 2 - HUMIDITY ABSORPTION

The encapsulated product obtained in Example 2 (heptahydrated ferrous (II) sulphate encapsulated with 2% type B non-edible gelatin) and in Example 3 (heptahydrated ferrous (II) sulphate encapsulated with 1% of animal glue) were placed in with 95% of humidity and temperature of 25⁰C for 60 min. The final humidity of the product after drying in halogen light balance for determining the humidity at 105⁰C.

Table 7 shows the obtained results, showing that the coating layer on the surface of the product obtained in Example 2 restricted the absorption of humidity of the medium by the product from 6.3% (heptahydrated product) to

2.8% (encapsulated product with 2% of gelatin) and to 1.4% (encapsulated product with 1% of animal glue).

TABLE 7 WATER INCORPORATION IN THE PRODUCT AFTER EXPOSITION TO A HIGH HUMIDITY

AMBIENT (95% HUMIDITY)

EXAMPLE 6 EVALUATION OF THE PRODUCT FROM EXAMPLE 2 - PHYSICAL CHARACTERISTICS OF

THE PRODUCT AFTER SIMULATION OF STORAGE IN SILO After the determination of the apparent density (mass occupied by a determined volume corresponding to the packaging free of the material, in volumetric measuring glass), the respective samples of heptahydrated ferrous (II) sulphate and encapsulated heptahydrated ferrous (II) sulphate with 2% gelatin (were submitted to a load of 1 kg/cm², corresponding to the load applied by a pile of material in silo corresponding to a height of 10 to 15 meters. The load was maintained for 70 hours, after what the material was removed and re- submitted to a test of density free of packaging.

Figure 3 shows pictures that illustrate the material physical state after application of the load for 70 hours. The gelatin encapsulation changes the physical characteristics of the material, preventing the caking observed on Figure 3 (a), which has occurred with the non-encapsulated material (Figure 3b). The results presented in Table 8 show that the particles coating assured a lower alteration of the product during storage (compressibility index of 17% for the encapsulated product compared to 26.7% for the non- encapsulated one), the encapsulated material being able to be stored in silos for a longer time, with less risks for the frequent caking problem encountered with the heptahydrated ferrous (II) sulphate.

TABLE 8 PHYSICAL CHARACTERISTICS OF THE PRODUCT AFTER A SIMULATION OF STORAGE IN

* Compressibility (%)

The examples mentioned above do not limit the possibilities of the process provided by the present invention. Thus, for instance, it is possible to increase the chemical resistance of the protecting layer, by reinforcing the surface of the heptahydrate ferrous (II) sulphate obtained in Example 2, or through a second layer of the gelatin reinforcement layer with an anionic polyelectrolyte by a chemical crosslinking with aldehydes, acids, among other possibilities.

Claims

1. Process for encapsulating chemically active substances in hydrated form comprising the coating of the particles of said substances with a hydrophilic or water-soluble encapsulating material, the process characterized by comprising the steps of:

- partial or total elimination of the crystallization water from the active substance;

- preparation of the encapsulating material solution with the equivalent crystallization water amount required to achieve the desired hydration degree in the encapsulated final product;

- mixing the active substance partially hydrated, or in anhydrous form, with the encapsulating material;

- encapsulation of the active substance by its rehydration with the water from the encapsulating material solution and consequent solidification of an encapsulating material film over the same.

2. Process of claim 1 , characterized in that said active substance can be any substance containing hydration or crystallization water molecules in its chemical structure.

3. Process of claim 2, characterized in that said active substance consists in sulphate, phosphate, nitrate, chloride, chelate, carbonate or lactate salts, existing under different hydration forms.

4. Process of claim 3, characterized in that said active substance consists in a metallic sulphate, in a hydrated salt form or a mixture of different hydrate forms.

5. Process of claim 4, characterized in that said active substance consists in a ferrous sulphate, under its mono-, tetra-, or heptahydrate forms, or a mixture thereof.

6. Process of claim 4, characterized in that said active substance is manganese or tin sulphate.

7. Process of claim 1 , characterized in that said encapsulating material comprises a water-soluble or hydrophilic material capable to form a film or a gel.

8. Process of claim 7, characterized in that said encapsulating material comprises a water-soluble material belonging to the family of proteins.

9. Process of claim 8, characterized in that said encapsulating material comprises a water-soluble material belonging to the family of proteins obtained by the hydrolysis of raw materials rich in collagen.

10. Process of claim 9, characterized in that said encapsulating material comprises gelatin or animal glue.

11. Process of claim 7, characterized in that said encapsulating material comprises a water-soluble cellulose derivative.

12. Process of claim 7, characterized in that said encapsulating material comprises a water-soluble polysaccharide.

13. Process of claims 10, 11 or 12, characterized in that said encapsulating material is ranging from 0.05% to 20%, preferably 0.2% to 4% by weight relative to the active substance to be encapsulated.

14. Process of claims 10 and 13, characterized in that said active substance is iron (II) sulphate.

15. Process of claims 1 to 14, characterized in that it comprises an additional step of reinforcing the material resistance of the encapsulating material deposited on the surface of the re-hydrated solid particles by means of stable reactions of ionic complexation, chemical crosslinking or by the action of hardening agents.

16. Process of claim 15, characterized in that it uses aldehydes such as glutaraldehyde, tannic acid or glyceraldehyde as hardening agents.

17. An encapsulated product obtained by the process of any of claims 1 to 14, characterized in that said product has a granulometry of less than 1 mm, preferably of less than 300 μm.

18. A product obtained by the process of any of claims 1 to 14, characterized in that it comprises a metallic sulphate.

19. The product of claim 18, characterized in that it comprises manganese sulphate.

20. The product of claim 18, characterized in that it comprises tin sulphate.

21. The product of claim 18, characterized in that it comprises heptahydrated iron (II) sulphate.

22. The product of claim 18, characterized in that it comprises iron (II) sulphate x H₂O, wherein x = 1 , or x = 4, or x = 7, or a mixture thereof.

23. The product of claim 19, characterized in that it comprises manganese sulphate encapsulated with gelatin, with a granulometry of less than 1 mm.

24. The product of claim 20, characterized in that it is constituted by tin sulphate encapsulated with gelatin, with a granulometry of less than 1 mm.