RU2476377C2 - Ordered mesoporous silicon oxide material - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to materials based on silicon oxides. Ordered mesoporous silicon oxide material with uniform in size pores in range from 4 to 30 nm is characterised by ratio Q3 to Q4 for silicon atoms smaller than 0.65. Material is synthesised in weakly acidic or neutral conditions with application of alkali metal silicate, amphiphilic blockcopolymer, buffer with pH within the interval from 5 to 7 and, possibly, compound ammonium tetraalkyl. Material has two-dimensional hexagonal structure of ordered mesoporous silicon oxide materials, designated SOK-12. Size of mezopores is preferably in the range from 4 to 12 nm. Size of pores can be precisely regulated by varying synthesis conditions.

EFFECT: obtained ordered mesoporous silicon oxide materials are efficient in their application as materials-carriers for molecules of poorly soluble drugs and for peroral drug forms with immediate release.

13 cl, 48 dwg, 2 tbl, 24 ex

Description

FIELD OF THE INVENTION

The invention relates to methods of self-organization of ordered mesoporous materials based on silicon dioxide and having a two-dimensional hexagonal structure of ordered mesoporous materials based on silicon dioxide in reaction mixtures at a pH corresponding to slightly acidic or neutral conditions. In addition, the present invention relates to ordered mesoporous materials with a narrow (substantially uniform) size distribution of mesopores obtained by such methods.

State of the art

In the past, some types of ordered mesoporous silica materials were synthesized using strongly acidic (pH <2) or basic (pH> 9) reaction conditions. The use of surfactants and amphiphilic polymers as structure-forming reagents is known in the art. Kresge et al. (Nature 1992, 359, 710-712) reported the synthesis of MCM-41 materials characterized by the hexagonal structure of the arrangement of tubular mesopores. The synthesis of MCM-41 was carried out under basic conditions using cationic surfactants.

Zhao et al. (Science, 1998, 279, 548-552) reported the synthesis of SBA-type materials under strongly acidic conditions. SBA-15 with homogeneous pores from 4.6 to 10 nm was synthesized. Conditions that excluded the formation of silica gel or amorphous silicon dioxide were carefully studied when using various poly (alkylene oxide) triblock copolymers (for example, REO-PPO-PEO and its inverse PPO-PEO-PPO) and TMOS (tetramethylorthosilicate) as a source of silicon dioxide. This article indicates that suitable conditions include (a) the concentration of triblock copolymer in the reaction mixture from 0.5 to 6 wt%, (b) the temperature from 35 to 80 ° C, and (c) the pH below the isoelectric point of silicon dioxide. Zhao et al. (J. Am. Chem. Soc. 1998, 120, 6024-6036) report the use of alkyl-poly (ethylene oxide) oligomeric surfactants and poly (alkylene oxide) triblock copolymers in a strongly acidic medium for the synthesis of mesoporous silica with cubic and a hexagonal structure with a pore size of from 1.6 to 10 nm. Pores ranging in size from 1.6 to 3.1 nm were obtained using alkyl-poly (ethylene oxide) oligomeric surfactants already at room temperature. Ordered mesoporous materials with pores from 3 to 10 nm were obtained using poly (alkylene oxide) triblock copolymers at temperatures from 35 to 80 ° C.

It is known from the prior art that in order to achieve ordering of silicon dioxide at the meso level (from 2 to 50 nm), it is necessary to bring the pH of the mixture in which the synthesis is carried out to values below pH 2, which is the isoelectric point of silicon dioxide. In addition, the ordering quality of the mesoporous materials synthesized at pH 2 was reported by Attard et al. (Nature 1995, 378, 366-368) and Weissenberger et al. (Ner. Bunsenges. Phys. Chem. 1997, 101, 1679- 1692) was lower than that of materials synthesized under more acidic conditions.

S. Su Kim et al. In Journal of Physical Chemistry B, Volume 105, pages 7663-7670, reported the ordering of MSU-H silica using either a one-step or two-step self-organization process in which silicate was used as a source of silica sodium (27% SiO ₂ , 14% NaOH), and as a nonionic structure-forming triblock copolymer surfactant - Pluronic P123. In a one-step process, the mesostructure was formed at a fixed assembly temperature of 308, 318, or 333 K, surfactants and acetic acid in an amount equivalent to the hydroxide content in the sodium silicate solution were mixed at room temperature, then added to the sodium silicate solution to obtain a reactive silicon dioxide in the presence of a structure-forming surfactant. This made it possible to assemble the hexagonal structure under such pH conditions under which both the silicon oxide precursor and surfactant were present predominantly in the nonionic molecular state (pH about 6.5) outside the pH zone, in which the sodium acetate / acetic acid mixture exhibits a buffering effect ( see definition below). To obtain a well-ordered mesoporous material, it was necessary to heat the mixture in which the synthesis was carried out to 308 K. Both the surface area and the pore volume increased with increasing synthesis temperature, which suggests that the material synthesized at the lowest temperature was worse structured and contained areas with lower porosity.

An ordered mesoporous material based on silicon dioxide with increased structural homogeneity is required, synthesized at a pH of more than 2 and less than 9.

SUMMARY OF THE INVENTION

Thanks to the present invention, the problems of the prior art are solved due to the fact that for the production of materials with mesopore sizes from 4 to 30 nm, preferably from 7 to 30 nm, particularly preferably from 11 to 30 nm, even more preferably from 15 to 30 nm without the use or addition of any aromatic hydrocarbon such as 1,2,4-trimethylbenzene during this process, it is necessary to use rigid acid (pH <2) silt in the synthesis through self-organization of the ordered mesoporous silicon oxide material and harsh basic (pH> 9) synthesis conditions and, more specifically, conditions in the reaction mixture.

The present invention also solves the problems of the prior art related to the need to use harsh acidic (pH <2) or harsh basic (pH> 9) conditions in the reaction mixture for the production of materials with substantially uniform mesopores larger than 10 nm without or without the need to add an aromatic hydrocarbon such as 1,2,4-trimethylbenzene to the reaction mixture.

Thus, the ordered mesoporous silica materials of the present invention with substantially uniform pore size, also larger than 10 nm, are obtained in a self-organizing reaction mixture with mild acidity conditions from pH 2 to pH 8 that does not contain an aromatic hydrocarbon such as 1,2,4 trimethylbenzene.

Thus, ordered two-dimensional hexagonal structure ordered mesoporous silica materials of the present invention with substantially uniform pore sizes can be obtained in a self-organizing reaction mixture with mild acidic conditions from pH 2 to pH 8 without an aromatic hydrocarbon such as 1,2,4- trimethylbenzene, by adding to a similar reaction mixture a buffer with a pH of more than 2 and less than 8, even at room temperature, provided that the buffer zone corresponds to the acid component of the buffer.

It was unexpectedly found that when an aqueous solution of a poly (alkylene oxide) tribloxopolymer and an acid with pKa <2, an acid with a pKa in the range of 3 to 9, or a buffer are added to an aqueous solution of alkali metal silicate in order to create soft acidic acid conditions (pH> 2 ) to soft basic (pH <8) and ensuring the passage of the reaction between the components at a buffered pH and temperature in the range from 10 to 100 ° C, the obtained ordered mesoporous silicon oxide materials with substantially uniform pore size after filtering, the ears and the calcination of the reaction product have substantially uniform pore size with a narrow mesopore size distribution near the maximum pore size selected from pore sizes such as 5 nm, 7 nm, 9 nm, 11 nm, 13 nm, 15 nm, 17 nm, 19 nm, 21 nm, 23 nm, 25 nm, 27 nm or 29 nm, even if the reaction was carried out at room temperature. If an aqueous solution of a poly (alkylene oxide) tribloxopolymer with an acid with pKa <2 was used, the additional presence of an alkali or alkaline earth metal hydroxide in the solution before adding alkali metal silicate to the aqueous solution was found to adversely affect the self-organization of the ordered mesoporous silica material. However, the additional presence in the aqueous solution of a poly (alkylene oxide) tribloxopolymer and an acid with pKa <2 organic cationic particles, such as tetraalkylammonium cation, such as tetramethylammonium or tetrapropylammonium, preferably tetrapropylammonium or molecules that form tetrapropylammonium, such as tetrapropylamide does not affect ordered mesoporous silica with substantially uniform pore size and is favorable. The different effect of the presence in the aqueous solution of a poly (alkylene oxide) triblock copolymer and an acid with pKa <2 alkali or alkaline earth metal hydroxides such as calcium hydroxide with pKa 11.43, barium hydroxide with pKa 16.02, sodium hydroxide with pKa 13.8, hydroxide potassium with pKa 13.5 and lithium hydroxide with pKa 14.36, in contrast to the case of the additional presence of tetraalkylammonium cations, for example tetraalkylammonium hydroxide, strong base with pKa 13.8, is unexpected, given the similarity of pKa values.

SOK-10 materials produced in the presence of an acid with pKa <2 and SOK-12 materials produced in the presence of an acid with pKa in the range from 3 to 9 or buffer have several advantages over ordered mesoporous materials known in the art, moreover Some significant benefits can be summarized as follows:

1. During the synthesis, the use of harsh acidic conditions (such as those in the synthesis of SBA materials) or basic conditions (such as those necessary for the synthesis of MCM-41) is excluded. Production is less limited in terms of corrosion resistance of synthesis tanks. Strongly acidic or strongly basic waste streams are not formed.

2. Known in this field of approaches to the implementation of the synthesis usually allow to obtain materials with a mesopore size of from 2 to 10 nm. The synthesis of materials with pores larger than 10 nm is more difficult and requires the use of swelling agents, such as trimethylbenzene. In accordance with the present invention, the use of mild acidic conditions facilitates the formation of mesopores in the range from 4 to 30 nm.

3. SOK-10 materials with their large mesopores are well suited for many applications, for example, for the immediate release of poorly soluble drugs, for the production of HPLC columns, in biotechnology as a substrate for enzymes, proteins, nucleic acids and other types of biomolecules.

In accordance with the purpose of the present invention, formulated and widely described herein, one embodiment of the invention is directed to a broadly outlined new method for the production of new mesoporous materials with a narrow size distribution of mesopores (SOK-10) under such conditions of acidity in a self-organizing reaction medium, in which the pH is selected from mild acidity (pH> 2) to mild basicity (pH <8). Compared to the frame-like mesoporous silica material MSM or SBA, produced in a reaction medium with more stringent acidity conditions (pH> 2 or pH <8), these SOK-10 materials, the pores of which are saturated with poorly water-soluble biologically active preparations, are characterized by an improved rate the release of these poorly water soluble biologically active preparations into the aquatic environment.

Aspects of the present invention are embodied in a method of self-organization of an ordered mesoporous silica material with substantially uniform pore sizes ranging from 4 to 30 nm, preferably from 7 to 30 nm, comprising the following steps:

preparing an aqueous solution 1 containing an aqueous solution of alkali metal silicate;

preparing an aqueous solution 2, in addition to an alkali or alkaline earth metal hydroxide, for example an alkali metal hydroxide such as sodium hydroxide, containing a poly (alkylene oxide) tribloxopolymer and an acid with a pKa of less than 2, preferably less than 1;

adding the specified aqueous solution 1 to the specified aqueous solution 2 to obtain a pH of more than 2 and less than 8 and ensuring the passage of the reaction between the components at a temperature in the range from 10 to 100 ° C, preferably from 20 to 90 ° C, filtering, drying and calcining of the product reactions to produce said ordered mesoporous silica material with substantially uniform pore size.

Aspects of the present invention are also embodied in an ordered mesoporous silica material with substantially uniform pore sizes ranging from 4 to 30 nm, which can be obtained using the above method.

Aspects of the present invention are also embodied in a pharmaceutical composition comprising the aforementioned ordered mesoporous silica material and biologically active preparations.

Aspects of the present invention are also embodied in a method of self-organization with a two-dimensional hexagonal structure of an ordered mesoporous silica material with substantially uniform pore sizes ranging from 4 to 12 nm, comprising the following steps:

preparing an aqueous solution 1 containing an alkali metal silicate solution;

preparing an aqueous solution 3 containing a poly (alkylene oxide) tribloxopolymer and a buffer with a pH of greater than 2 and less than 8, the buffer comprising acidic and basic components;

adding the specified aqueous solution of alkali metal silicate to the specified aqueous solution to obtain a pH of more than 2 and less than 8 and ensuring the passage of the reaction between the components at a temperature in the range from 10 to 100 ° C, preferably from 20 to 90 ° C,

filtering, drying and calcining the reaction product to obtain said ordered two-dimensional hexagonal structured mesoporous silica material with substantially uniform pore sizes.

Aspects of the present invention are also embodied in a method of self-organization with a two-dimensional hexagonal structure of an ordered mesoporous silica material with substantially uniform pore sizes ranging from 4 to 12 nm, comprising the following steps:

preparing an aqueous solution 1 containing an alkali metal silicate solution;

preparing an aqueous solution 4 containing a poly (alkylene oxide) tribloxopolymer and acid with pKa in the range from 3 to 9;

adding said aqueous solution 1 to said aqueous solution 3 and thereby obtaining a pH greater than 2 and less than 8, which corresponds to a range of 1.5 pH units more and 1.5 pH units less than pH with the same numerical value as the pKa of said acids with pKa in the range from 3 to 9, and ensuring the passage of the reaction between the components at a temperature in the range from 10 to 100 ° C;

filtering, drying and calcining the reaction product to obtain said ordered two-dimensional hexagonal structured mesoporous silica material with substantially uniform pore sizes.

Aspects of the present invention are also embodied in a two-dimensional hexagonal structure ordered mesoporous silicon oxide material with substantially uniform pore sizes ranging from 4 to 12 nm, which can be obtained using the above method, obtained using the ²⁹ Si NMR method with rotation of the sample at a magic angle the ratio of silica Q3 to Q4 is preferably less than 0.65, particularly preferably less than 0.60.

Aspects of the present invention are also embodied in a pharmaceutical composition comprising the above ordered two-dimensional hexagonal structure ordered mesoporous silica material and biologically active preparations.

Other applications of the present invention will become apparent from the detailed description given later in this document. However, it should be understood that the detailed description and specific examples, although indicating preferred embodiments of the present invention, are provided for explanation only, as various changes and modifications within the spirit and scope of the present invention will become apparent to those skilled in the art upon reading this detailed description. It should be understood that both the above General description and the following detailed description are exemplary and explanatory and do not limit the present invention defined by the claims.

Brief Description of the Drawings

The present invention can be more fully understood by reading the detailed description given hereinafter and the accompanying drawings, which are given for explanation only and, thus, are not a limitation of the present invention, which depicts:

Figure 1: Diagram of the scattering of x-ray radiation by the material SOK-10 of example 1 in the post-synthesis state, recorded when particles were removed from the storage ring to the BM26B target by the European Synchrotron radiation facility (ESFR) in a transmitting configuration.

Figure 2: Above: Nitrogen adsorption isotherm with calcined SOK-10 material of Example 1. Bottom: Size distribution of mesopores calculated by the BJH method based on the desorption branch.

Figure 3: Obtained using a scanning electron microscope (SEM) image of the calcined material SOK-10 of example 1 at two degrees of magnification.

Figure 4: Diagram of the scattering of x-ray radiation by the material of example 2 in the post-synthesis state, recorded when particles were removed from the storage ring to the BM26B target by the European Synchrotron radiation facility (ESFR) in a transmitting configuration.

Figure 5: Above: Nitrogen adsorption isotherm for the calcined SOK-10 material of Example 2. Bottom: Size distribution of mesopores calculated by the BJH method based on the desorption branch.

FIG. 6: SEM images of the calcined SOK-10 material of Example 2 at two degrees of magnification. Samples were plated with gold. Images taken with Philips (FEI) SEM XL30 FEG.

Fig. 7: X-ray scattering diagram of the material of Example 3 in the post-synthesis state recorded when particles were removed from the storage ring to the BM26B target by the European Synchrotron radiation facility (ESFR) in a transmission configuration.

Fig. 8: SEM images of the calcined material of Example 3 obtained at two degrees of magnification. Samples were plated with gold. Images taken with Philips (FEI) SEM XL30 FEG.

Fig. 9: Above: Nitrogen adsorption isotherm of the material synthesized in Example 3. Bottom: Mesopore size distribution according to the BJH model.

Figure 10: Above: Nitrogen adsorption isotherm of the calcined SBA-15 material of Example 4. Bottom: Mesopore size distribution calculated by the BJH method based on the isotherm branch corresponding to desorption.

FIG. 11: SEM images of the calcined SBA-15 material of Example 4 at two magnifications. Samples were plated with gold. Images taken on Philips (FEI) SEM XL30 FEG.

12: Above: Nitrogen adsorption isotherm for calcined SOK-10 material of Example 7. Bottom: Size distribution of mesopores calculated by the BJH method based on the desorption branch.

Figure 13: SEM image of the calcined SOK-10 material of Example 7. Sample was coated with gold. Images taken on Philips (FEI) SEM XL30 FEG.

Fig. 14: X-ray scattering diagram of calcined SOK-10 material of Example 7, recorded when particles were removed from the storage ring to the BM26B target by the European Synchrotron radiation facility (ESFR) in a transmission configuration.

Fig: A graphical representation of the laboratory release of itraconazole from a sample of SOK-10 experiment 1. Environment for release: artificial gastric fluid with 0.05% wt. SLS (sodium lauryl sulfate).

Fig: Graphic display of the laboratory release of itraconazole from a sample of mesoporous material not corresponding to the invention synthesized in experiment 3. Release medium: artificial gastric fluid with 0.05% wt. SLS (sodium lauryl sulfate).

Fig: Graphic representation of the laboratory release of itraconazole from SBA-15 synthesized in comparative example 4. Release medium: artificial gastric fluid with 0.05% wt. SLS

Fig. 18: Above: Isotherm of adsorption (right curve) and desorption (left curve) of nitrogen by the calcined SOK-10 material of Example 11. Bottom: Size distribution of mesopores calculated by the BJH method based on the adsorption branch. The measurements were carried out on a Micrometrics Tristar instrument. Before measurement, the sample was pretreated at 300 ° C for 10 h (the rate of temperature change was 5 ° C / min).

Fig. 19: SEM image of the calcined SOK-10 material of Example 11. Sample was plated with gold. Images taken on Philips (FEI) SEM XL30 FEG.

FIG. 20: X-ray scattering diagram of calcined SOK-10 material of Example 11, recorded when particles were removed from the storage ring to the BM26B target by the European Synchrotron radiation facility (ESFR) in a transmission configuration.

21: Above: Isotherm of adsorption (right curve) and desorption (left curve) of nitrogen by the calcined material SOC-10 of Example 12. Bottom: Pore size distribution calculated by the BJH method based on the adsorption branch. The measurements were carried out on a Micrometrics Tristar instrument. Before measurement, the sample was pretreated at 300 ° C for 10 h (the rate of temperature change was 5 ° C / min).

FIG. 22: X-ray scattering diagram of calcined SOK-10 material of Example 12, recorded when particles were removed from the storage ring to the BM26B target by the European Synchrotron radiation facility (ESFR) in a transmission configuration.

Fig. 23: Above: Isotherm of adsorption (right curve) and desorption (left curve) of nitrogen by the calcined SOK-10 material of Example 13. Bottom: Pore size distribution calculated by the BJH method based on the adsorption branch. The measurements were carried out on a Micrometrics Tristar instrument. Before measurement, the sample was pretreated at 300 ° C for 10 h (the rate of temperature change was 5 ° C / min).

24: X-ray scattering diagram of calcined SOK-10 material of Example 13, recorded when particles were removed from the storage ring to the BM26B target by the European Synchrotron radiation facility (ESFR) in a transmission configuration.

Fig: Diagram of scattering of x-ray radiation by the SOK-12 material in the post-synthesis state (thin line) and calcined material (thick line) of Example 14, recorded when particles were removed from the storage ring to the BM26B target by the European Synchrotron radiation facility (ESFR) in the transmission configurations.

FIG. 26: Above: Nitrogen adsorption isotherm for the calcined SOK-12 material of Example 14. Bottom: Size distribution of mesopores calculated by the BJH method based on the desorption branch. The measurements were carried out on a Micrometrics Tristar 3000 instrument. Before measurement, the sample was pretreated at 300 ° C for 10 h (the rate of temperature change was 5 ° C / min).

FIG. 27: SEM images of the calcined SOK-12 material of Example 14 obtained at two degrees of magnification. Samples were plated with gold. Images taken on Philips (FEI) SEM XL30 FEG.

Fig. 28: X-ray scattering diagram of calcined SOK-12 material (thick line) of Example 15, recorded when particles were removed from the storage ring to the BM26B target by the European Synchrotron radiation facility (ESFR) in a transmission configuration.

Fig. 29: Above: Nitrogen adsorption isotherm for the calcined SOK-12 material of Example 15. Bottom: Size distribution of mesopores calculated by the BJH method based on the desorption branch. The measurements were carried out on a Micrometrics Tristar 3000 instrument. Before measurement, the sample was pretreated at 200 ° С for 10 h (the temperature change rate was 5 ° С / min).

FIG. 30: SEM images of the calcined SOK-12 material of Example 15 obtained at two degrees of magnification. Samples were plated with gold. Images taken on Philips (FEI) SEM XL30 FEG.

Fig: Diagram of the scattering of x-ray radiation by the SOK-12 material in the state after synthesis (thin line) and calcined material (thick line) of example 16, recorded when particles were removed from the storage ring to the BM26B target by the European Synchrotron radiation facility (ESFR) in the transmission configurations.

Fig. 32: Above: Nitrogen adsorption isotherm for the calcined SOK-12 material of Example 16. Bottom: Size distribution of mesopores calculated by the BJH method based on the desorption branch. The measurements were carried out on a Micrometrics Tristar 3000 instrument. Before measurement, the sample was pretreated at 300 ° C for 10 h (the rate of temperature change was 5 ° C / min).

Fig: Obtained using SEM images of calcined material SOK-12 of example 16 at two degrees of magnification. Samples were plated with gold. Images taken on Philips (FEI) SEM XL30 FEG.

Fig. 34: X-ray scattering diagram of calcined SOK-12 material (thick line) of Example 17, recorded when particles were removed from the storage ring to the BM26B target by the European Synchrotron radiation facility (ESFR) in a transmission configuration.

Fig. 35: Above: Nitrogen adsorption isotherm for calcined SOK-12 material of Example 17. Bottom: Size distribution of mesopores calculated by the BJH method based on the desorption branch. The measurements were carried out on a Micrometrics Tristar 3000 instrument. Before measurement, the sample was pretreated at 200 ° C for 10 h (the rate of temperature change was 5 ° C / min).

Fig. 36: Above: Nitrogen adsorption isotherm for the calcined SOK-12 material of Example 18. Bottom: Size distribution of mesopores calculated by the BJH method based on the desorption branch. The measurements were carried out on a Micrometrics Tristar 3000 instrument. Before measurement, the sample was pretreated at 200 ° С for 10 h (the temperature change rate was 5 ° С / min).

Fig: Diagram of the scattering of x-ray radiation by the SOK-12 material in the state after synthesis (thin line) and calcined material (thick line) of example 19, recorded when particles were removed from the storage ring to the BM26B target by the European Synchrotron radiation facility (ESFR) in the transmission configurations.

Fig. 38: Above: Nitrogen adsorption isotherm with calcined SOK-12 material of Example 19. Bottom: Size distribution of mesopores calculated by the BJH method based on the desorption branch. The measurements were carried out on a Micrometrics Tristar 3000 instrument. Before measurement, the sample was pretreated at 200 ° C for 10 h (the rate of temperature change was 5 ° C / min).

Fig. 39: X-ray scattering diagram of the SOK-12 material in the post-synthesis state (thin line) and calcined material (thick line) of Example 20, recorded when particles were removed from the storage ring to the BM26B target by the European Synchrotron radiation facility (ESFR) in the transmission configurations.

Fig. 40: Above: Nitrogen adsorption isotherm for the calcined SOK-12 material of Example 20. Bottom: Size distribution of mesopores calculated by the BJH method based on the desorption branch. The measurements were carried out on a Micrometrics Tristar 3000 instrument. Before measurement, the sample was pretreated at 200 ° C for 10 h (the rate of temperature change was 5 ° C / min).

Figure 41: X-ray scattering diagram of the SOK-12 material in the post-synthesis state (thin line) and calcined material (thick line) of Example 21, recorded when particles were removed from the storage ring to the BM26B target by the European Synchrotron radiation facility (ESFR) in the transmission configurations.

Fig. 42: Above: Nitrogen adsorption isotherm for calcined SOK-12 material of Example 21. Bottom: Size distribution of mesopores calculated by the BJH method based on the desorption branch. The measurements were carried out on a Micrometrics Tristar 3000 instrument. Before measurement, the sample was pretreated at 200 ° C for 10 h (the rate of temperature change was 5 ° C / min).

FIG. 43: SEM images of the calcined SOK-12 material of Example 21 obtained at two degrees of magnification. Samples were plated with gold. Images taken on Philips (FEI) SEM XL30 FEG.

Fig. 44: X-ray scattering diagram of the SOK-12 material in the post-synthesis state (thin line) and calcined material (thick line) of Example 22, recorded when particles were removed from the storage ring to the BM26B target by the European Synchrotron radiation facility (ESFR) in the transmission configurations.

Fig. 45: Above: Nitrogen adsorption isotherm for the calcined SOK-12 material of Example 22. Bottom: Size distribution of mesopores calculated by the BJH method based on the desorption branch. The measurements were carried out on a Micrometrics Tristar 3000 instrument. Before measurement, the sample was pretreated at 300 ° C for 10 h (the rate of temperature change was 5 ° C / min).

Fig. 46: SEM images of the calcined SOK-12 material of Example 22 obtained at two degrees of magnification using SEM. Samples were plated with gold. Images taken on Philips (FEI) SEM XL30 FEG.

Fig. 47: Above: Nitrogen adsorption isotherm for the calcined SOK-12 material of Example 23. Bottom: Size distribution of mesopores calculated by the BJH method based on the desorption branch. The measurements were carried out on a Micrometrics Tristar 3000 instrument. Before measurement, the sample was pretreated at 200 ° С for 10 h (the temperature change rate was 5 ° С / min).

Fig. 48: Above: Nitrogen adsorption isotherm for calcined SOK-12 material of Example 24. Bottom: Size distribution of mesopores calculated by the BJH method based on the desorption branch. The measurements were carried out on a Micrometrics Tristar 3000 instrument. Before measurement, the sample was pretreated at 200 ° С for 10 h (the temperature change rate was 5 ° С / min).

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description of the invention relates to the accompanying drawings. The same item numbers in different drawings indicate the same or similar elements. In addition, the following detailed description does not limit the present invention. On the contrary, the scope of the invention is defined by the attached claims and their equivalents.

Some documents are cited in the text of the present description. Each of these documents (including specifications, manufacturer's instructions, etc.) is incorporated herein by reference; however, the recognition that any cited document is indeed prior art in relation to this document is not implied.

The present invention has been described with respect to specific embodiments and with reference to certain drawings, however, the present invention is not limited thereto, but only by the claims. The described drawings are only schematic and are not restrictive. In the drawings, the size of some elements may be exaggerated and not to scale to illustrate. Overall dimensions and relative dimensions do not correspond to the actual bringing of the invention to the extent of practical implementation.

In addition, the terms "first", "second", "third", etc. in the description and in the claims are used to distinguish between similar elements, but not necessarily to indicate a sequence or chronological order. It should be understood that the terms used in this way are interchangeable in appropriate circumstances and that the embodiments described herein allow functioning in a different order than described or illustrated herein.

In addition, the terms “top”, “bottom”, “above”, “under”, etc. in the description and in the claims are used for descriptive purposes, but not necessarily to indicate relative position. It should be understood that the terms used in this way are interchangeable in appropriate circumstances, and that the embodiments described herein allow operation at a different arrangement than described or shown herein.

It should be noted that the term “comprising” used in the claims is not to be construed as limited to what is listed after it; it does not exclude other elements or stages. It should therefore be construed as defining the presence of said distinctive features, numbers, steps or components as mentioned, but not excluding the presence or addition of one or more other distinctive features, numbers, steps or components or groups thereof. Thus, the scope of the expression “device containing components A and B” should not be limited to devices consisting only of components A and B. It means that with respect to the present invention, the only significant components of the device are A and B.

In the present description, a reference to “one embodiment of the invention” or “one of the embodiments of the invention” means that a particular distinguishing feature, structure or characteristic described in connection with this embodiment of the invention is included in at least one embodiment of the present inventions. Therefore, the appearance in various places of the present description of the phrases “in one embodiment of the invention” or “in one embodiment of the invention” does not necessarily mean in all cases a reference to the same embodiment, although this may be. In addition, specific features, structures, or characteristics may be combined in any suitable manner, as will be apparent to those skilled in the art from the present description, in one or more embodiments of the invention.

Similarly, it should be understood that in the description of exemplary embodiments of the present invention, various features of this invention are sometimes grouped together in the same embodiment, in one drawing or in their description in order to simplify the description and facilitate understanding of one or more of the various aspects of the invention. Such a method of presentation, however, should not be construed as reflecting the idea that the claimed invention implies more features than specifically indicated in each claim. More specifically, as reflected in the following claims, aspects of the invention are embodied in less than all features of one of the above-disclosed embodiments. Therefore, the claims following the detailed description are expressly included in this detailed description, with each clause being independent as a separate embodiment of the present invention.

In addition, although some of the described embodiments of the invention include those and not other features included in other embodiments of the invention, combinations of features of various embodiments are considered to be included in the scope of the present invention and form various embodiments, as will be clear to experts in this field . For example, in the following claims, any of the claimed embodiments may be used in any combination.

Numerous specific details are set forth in the description provided herein. However, it is understood that embodiments of the present invention may be practiced without these specific details. In other cases, well-known methods, structures, and techniques have not been shown in detail so as not to obscure the understanding of this description.

The following terms are given only to facilitate understanding of the present invention.

Definitions

The terms “mesoscale”, “mesopore”, “mesoporous” and the like, as used herein, refer to structures with a characteristic size in the range from 5 nm to 100 nm. The term “mesoscale” in the context of this document does not imply any specific spatial organization or mode of production. Therefore, the mesoporous material includes pores that can be ordered or randomly distributed arbitrarily and whose diameter corresponds to a range from 5 nm to 100 nm, while nanoporous material includes pores whose diameter corresponds to a range from 0.5 nm to 1000 nm.

The terms “narrow pore size distribution” and “substantially uniform pore size” in the context of this application mean a pore size distribution curve characterized by such a derivative of pore volume (dV) as a function of pore diameter that at a point on the curve that in the middle of its height, the ratio of the width of the curve (the difference between the maximum pore diameter and the minimum pore diameter at the middle of the height) to the pore diameter at the maximum point of the graph height (as indicated above) is not more than 0.75. The pore size distribution for the materials obtained in accordance with the present invention can be determined by nitrogen adsorption and desorption by plotting the derivative of pore volume as a function of pore diameter based on these data. Data on nitrogen adsorption and desorption can be obtained using instruments known in the art (e.g., Micrometrics ASAP 2010), which instruments are also suitable for plotting the derivative of pore volume as a function of pore diameter. In the micropore range, such a graph can be obtained using the longitudinal pore geometry according to the Horvath-Kawazoe model described in G. Horvath, K. Kawazoe, J. Chem. Eng. Japan, 16 (6), (1983), 470. In the mesopore range, such a graph can be constructed according to the method described in E. P. Barrett, L. S. Joyner, P. P. Halenda, J. Am. Chem. Soc. 73 (1951), 373-380.

The term "practically insoluble" in the context of this document refers to medicines that are essentially completely insoluble in water or at least poorly soluble in water. More specifically, this term refers to any drug characterized by a dose (mg) to water solubility ratio (mg / ml) of more than 100 ml, where the solubility of the drug corresponds to the neutral form (for example, free base or free acid) in unbuffered water . This value includes, but is not limited to, drugs that are substantially water soluble (less than 1.0 mg / ml).

Based on BCS (Biopharmaceutical Classifier), “poorly water-soluble compounds” can be defined as compounds whose highest dose is insoluble in 250 ml or less of an aqueous medium at a pH of 1.2 to 7.5 and 37 ° C. See Cynthia K. Brown et al., “Acceptable Analytical Practices for Dissolution Testing of Poorly Soluble Compounds”, Pharmaceutical Technology (December 2004).

In accordance with this guide, the solubility of pharmaceuticals (M. E. Aulton) in any solvent is defined as the amount of solvent (g) required to dissolve 1 g of these compounds, using the following solubility classification: 10-30 g (“soluble”); 30-100 g ("sparingly soluble"); 100-1000 g ("sparingly soluble"); 1000-10000 g ("very sparingly soluble" or "poorly soluble"); more than 10,000 g (practically insoluble).

The terms “drug” or “biologically active compound” are broadly understood and mean a compound with favorable prophylactic and / or therapeutic properties when taken, for example, by humans. In addition, the term “drug in itself” is used in the present description for the purpose of comparison and means a drug in an aqueous solution / suspension without adding any auxiliary substance.

The term “antibody” refers to intact molecules, as well as fragments thereof, that are capable of binding the antigenic determinant of the corresponding factor or domain of that factor. The Fv fragment is the smallest fragment of the antibody and contains the complete antigen recognition site and the binding site. This region is a dimer (VH-VL dimer) in which the various variable regions of both the heavy chain and light chain are firmly bonded by a non-covalent bond. Three CDRs (complementary determining region) of each of the variable regions interact with each other to form an antigen binding site on the surface of the VH-VL dimer. In other words, all six CDRs of the heavy and light chains together function as an antigen binding site. However, it is known that the variable region (or half of the Fv, containing only three antigen-specific CDRs) by itself is also capable of recognizing and binding the antigen, although its affinity is weaker than the affinity of the entire binding site. Thus, a preferred antibody fragment of the present invention is an Fv fragment, but is not limited to it. Such an antibody fragment may be a polypeptide that contains a conserved antibody fragment with a heavy or light chain CDR and which can recognize and bind an antigen. The Fab fragment (also referred to as F (ab)) also contains the constant region of the light chain and the constant region of the heavy chain (CH1). For example, as a result of papain cleavage of an antibody, two types of fragments are formed: an antigen-binding fragment called a Fab fragment and containing variable regions of the heavy chain and light chain, which serves as a single antigen-binding domain; and the rest, which is called "Fc", because it crystallizes easily. The Fab'-fragment differs from the Fab-fragment in that the Fab'-fragment also contains some groups remaining from the carboxyl end of the CH1 heavy chain region, which contain one or more cysteine residues of the hinge region of the antibody. However, the Fab'fragment is structurally equivalent to Fab in that both are antigen binding fragments containing various regions of the heavy chain and light chain that serve as a single antigen binding domain. As used herein, an antigen binding fragment containing various regions of a heavy chain and a light chain that functions as a single antigen binding domain that is equivalent to that obtained by papain cleavage is referred to as a “Fab-like antibody” even if it is not identical to the fragment of the antibody resulting from proteolytic cleavage. Fab'-SH is a Fab 'with one or more cysteine residues containing free thiol groups in the constant region.

Used in the description of the present invention, the term "biologically active drug" means drugs and antibodies.

The term "solid dispersion" means a system in the solid state (as opposed to a liquid or gaseous state) containing at least two components, where one component is more or less evenly dispersed in the other component or components. When said dispersion of the components is such that the system is chemically and physically homogeneous, or completely homogeneous, or formed by a single phase in terms of thermodynamics, such a solid dispersion is referred to herein as a “solid solution”. Solid solutions are preferred physical systems because their components are usually readily bioavailable by the organisms to which they are administered. This advantage can perhaps be explained by the simplicity with which these solid solutions can form liquid solutions in contact with a liquid medium such as gastric juice. This simplicity, at least in part, can be attributed to the fact that the energy required to dissolve the components of the solid solution is less than to dissolve the components of the crystalline or microcrystalline solid phase.

The term “solid dispersion” also encompasses dispersions that are less homogeneous than solid solutions. Such dispersions are chemically and physically heterogeneous throughout or contain more than one phase. For example, the term “solid dispersion” also refers to particles with zones or small areas where amorphous, microcrystalline or crystalline structures (a), or amorphous, microcrystalline or crystalline structures (b), or both are dispersed more or less evenly in another phase containing (b) or (a), or a solid solution containing (a) and (b). Such zones are areas within the particles that are definitely different in some physical parameter, small in size compared to the size of the particle as a whole, and uniformly or randomly distributed throughout the particle.

As used herein, the term "room temperature" means a temperature of from 12 to 30 ° C, preferably from 18 to 28 ° C, more preferably from 19 to 27 ° C, most preferably from 20 to 26 ° C.

As used herein, the term “low temperature” means a temperature of from 15 to 40 ° C., preferably from 18 to 23 ° C., more preferably from 20 to 30 ° C., most preferably tentatively taken as a temperature from 22 to 28 ° C. .

The term "buffer zone buffer", used to describe the present invention, means a zone with a pH in the range from about 1.5 pH units above to about 1.5 pH units below a pH numerically equal to the pKa of the acid component of this buffer.

Method for self-organization of ordered mesoporous silica material with substantially uniform pore size

Aspects of the present invention are embodied in a method of self-organization of an ordered mesoporous silica material with substantially uniform pore sizes ranging from 4 to 30 nm, preferably from 7 to 30 nm, comprising the following steps: preparing an aqueous solution 1 containing an aqueous solution of alkali metal silicate; preparing an aqueous solution 2, in addition to an alkali or alkaline earth metal hydroxide, for example an alkali metal hydroxide such as sodium hydroxide, containing a poly (alkylene oxide) tribloxopolymer and an acid with a pKa of less than 2, preferably less than 1; adding said aqueous solution 1 to said aqueous solution 2 to obtain a pH of greater than 2 and less than 8, i.e. isoelectric point of silicon dioxide equal to 2, and ensuring the passage of the reaction between the components at a temperature in the range from 10 to 100 ° C, filtering, drying and calcining the reaction product to obtain the specified ordered mesoporous silicon oxide material with substantially uniform pore size.

According to a preferred embodiment of the method of self-organization of an ordered mesoporous silica material with substantially uniform pore size according to the present invention, the aqueous solution 2 further comprises a tetraalkylammonium surfactant, preferably tetrapropylammonium hydroxide forming a tetrapropylammonium cation or tetramethylammonium hydroxide forming a tetramethylammonium cation. The presence of tetraalkylammonium surfactant causes changes in the resulting ordered mesoporous silica.

The acid is substantially removed during the washing process associated with the filtering process, with any remaining amount of acid being removed during the calcination process.

A change in the pH of the reaction mixture within the ranges of the present invention, along with a change in the reaction time and temperature, can be used as a parameter for precisely controlling the pore size of the finished ordered mesoporous silicon oxide material. Pore size slowly increases with increasing pH. A stronger pore size increases depending on the reaction temperature, but does not significantly affect the total pore volume. The pH at which the reaction is carried out preferably corresponds to a range of 2.2 to 7.8, particularly preferably a range of 2.4 to 7.6, extremely preferably a range of 2.6 to 7.4.

In another embodiment of the method, the pH at which the reaction is carried out is preferably in the range from 2.8 to 7.2, particularly preferably in the range from 3 to 7.2, extremely preferably in the range from 4 to 7, in a particular way extremely preferred in the range of 5 to 6.5.

In a method for self-organizing an ordered mesoporous silica material with substantially uniform pore size in accordance with the present invention, the mixing speed is preferably in the range of 100 to 700 rpm.

In addition, it was shown that the materials SOK-10 can be obtained in reaction mixtures with a pH of more than 2 and less than 8 at room temperature (26 ° C in example 11) or at low temperatures.

The process conditions can be adjusted so as to obtain ordered mesoporous silica materials with pore sizes selected from the range from 4 to 30 nm, preferably selected from the range from 7 to 30 nm, particularly preferably selected from the range from 10 to 30 nm, from which range of 10 to 30 nm is most preferred.

The aqueous solution 1 is preferably an aqueous solution of sodium silicate containing at least 10% wt. sodium hydroxide and at least 27% wt. silica.

It will be apparent to those skilled in the art that various modifications and changes can be made to the amount of reagents or intermediates, such as amphiphilic polymers, where Pluronic P123 is used, or such as tetraalkylammonium cation, in particular tatrapropylammonium hydroxide, or to temperature conditions, mixing speeds or reaction times of the method of the present invention and to the scheme of the system or method, not beyond the scope or essence of the present invention. Such differences can be precisely adjusted to produce the mesoporous materials of the present invention with a narrow pore size distribution with a predetermined maximum pore size in the range of 7 to 30 nm.

Poly (alkylene oxide) triblock copolymer

Poly (alkylene oxide) triblock copolymer is preferably a triblock copolymer of poly (ethylene oxide) poly (alkylene oxide) poly (ethylene oxide), in which the alkylene oxide component contains at least 3 carbon atoms, for example, propylene oxide or butylene oxide, more preferably such tribloxopolymers in which the number of ethylene oxide components in each block is at least 5 and / or in which the number of alkylene oxide components in the central block is at least 30.

Poly (alkylene oxide) Pluronic P123 triblock copolymer of the composition EO ₂₀ PO ₇₀ EO ₂₀ (where EO means ethylene oxide, PO means propylene oxide) is particularly preferred.

Acids

Acids with pKa less than 2 suitable for increasing the acidity of reaction mixtures include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, cyclic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.

pKa pKa Trifluoromethanesulfonic Acid - 13 Trifluoroacetic acid 0,0 Hydroiodic Acid <1 Trichloroacetic acid 0.77 Hydrobromic acid <1 Chromic acid 0.74 Perchloric acid - 7 Iodic acid 0.80 Hydrochloric acid - four Oxalic acid 1.23 Chloric acid <1 Dichloroacetic acid 1.25 Sulphuric acid - 3 Sulphurous acid 1.81 Benzenesulfonic acid - 2.5 Maleic acid 1.83 Methanesulfonic acid - 2 Cyclamic acid 1.90 Toluenesulfonic acid - 1.76 Chlorous acid 1.96 Nitric acid - one

Hydrochloric acid is the preferred acid to increase the acidity of the reaction mixtures.

Silica

The source of silicon dioxide for the synthesis of ordered mesoporous material may be a monomer source, such as silicon alkoxides. Typical examples of silicon alkoxides are TEOS (tetraethylorthosilicate) and TMOS (tetramethylorthosilicate). Alternatively, alkali metal silicate solutions such as soluble glass can be used as the source of silicon. Kosuge et al. Have demonstrated the use of water-soluble sodium silicate for the synthesis of SBA-15 type material [Kosuge et al. Chemistry of Materials, (2004), 16, 899-905]. In materials called zeolites, silicon dioxide is preliminarily organized into zeolite-like nanoplates, which are mesoscale organized into three-dimensional mosaic structures [Kermer et al. Adv. Mater. 20 (2003) 1705].

Ordered Mesoporous Silicon Oxide Materials (SOK-10)

The present invention also relates to an ordered mesoporous silica material obtained by a synthesis method with moderate acidity from pH 2 to pH 8 (pH of the final reaction mixture), whereby the reaction mixture ultimately does not contain aromatic hydrocarbons, such as 1,2,4- trimethylbenzene. Self-organization of such materials can be achieved after adding tetraalkylammonium cation to the reaction mixture, preferably tetrapropylammonium or tetramethylammonium in the form of tetrapropylammonium hydroxide or tetramethylammonium hydroxide at moderate acidity, for example, moderate acidity from pH 2 to pH 8, or moderate acidity from pH 2.2 to pH 7.8, or moderate acidity from pH 2.4 to pH 7.6, or moderate acidity from pH 2.6 to pH 7.4, or moderate acidity from pH 2.8 to pH 7.2, or moderate acidity from pH 3 to pH 7.2, or Eren acidity of pH 4 to pH 7, or moderate acidity of pH 5 to pH 6.5.

The present invention also relates to an ordered mesoporous material with a narrow pore size distribution around a maximum pore size selected from the range from 7 to 30 nm, from 10 to 30 nm, from 12 to 30 nm, from 14 to 30 nm, from 16 to 30 nm, from 16 to 25 nm or from 15 to 20 nm, obtained by the synthesis method with moderate acidity, i.e. from pH 2 to pH 8 in the final reaction mixture, wherein the reaction mixture does not contain aromatic hydrocarbons such as 1,2,4-trimethylbenzene. Such ordered mesoporous materials obtained by this method are characterized in that they have a narrow mesopore size distribution around the maximum pore size selected from pore sizes such as 6 nm, 8 nm, 10 nm, 12 nm, 14 nm, 16 nm, 18 nm, 20 nm, 22 nm, 24 nm, 26 nm, 28 nm or 30 nm.

The method of self-organization with a two-dimensional hexagonal structure of an ordered mesoporous silicon oxide material with essentially uniform pores in size

Aspects of the present invention are also embodied in a method of self-organization with a two-dimensional hexagonal structure of an ordered mesoporous silica material with substantially uniform pore sizes ranging from 4 to 12 nm, comprising the steps of: preparing an aqueous solution 1 containing an alkali metal silicate solution; preparing an aqueous solution 3 containing a poly (alkylene oxide) tribloxopolymer and a buffer with a pH of greater than 2 and less than 8, the buffer comprising acidic and basic components; adding the specified aqueous solution of alkali metal silicate to the specified aqueous solution to obtain a pH of more than 2 and less than 8 and ensuring the passage of the reaction between the components at a temperature in the range from 10 to 100 ° C, filtering, drying and calcining the reaction product to obtain the specified having a two-dimensional hexagonal structure ordered mesoporous silica material with substantially uniform pore size.

A change in the pH of the reaction mixture in the ranges according to the present invention, along with a change in the reaction time and temperature, can be used as a parameter for precisely controlling the pore size of the finished ordered mesoporous silicon oxide material. Pore size slowly increases with increasing pH. The pH at which the reaction is carried out preferably corresponds to a range from 2.2 to 7.8, particularly preferably a range from 2.4 to 7.6, extremely preferably a range from 2.6 to 7.4.

In another embodiment of the method, the pH at which the reaction is carried out is preferably in the range from 2.8 to 7.2, particularly preferably in the range from 3 to 7.2, extremely preferably in the range from 4 to 7, in a particular way extremely preferred in the range of 5 to 6.5.

In a method of self-organizing an ordered mesoporous silica material having a two-dimensional hexagonal structure with substantially uniform pore size in accordance with the present invention, the mixing speed is preferably in the range of 100 to 700 rpm.

The poly (alkylene oxide) tribloxopolymer is preferably Pluronic P123.

The aqueous solution 1 is preferably an aqueous solution of sodium silicate containing at least 10% wt. sodium hydroxide and at least 27% wt. silica.

It will be apparent to those skilled in the art that various modifications and changes can be made in the amount of reagents, pH, temperature, mixing speed, or reaction time of the method of the present invention and in the scheme of the system or method that do not go beyond the scope or essence of the present invention. Such changes can be precisely adjusted to produce materials of the present invention with a narrow pore size distribution with a predetermined maximum pore size in the range from 4 to 12 nm.

Acids with a pKa value in the range of 3 to 9

Suitable acids with a pKa value in the range of about 3 to about 9 include those shown in the following table.

ON pKa ON pKa Lemon acid H ₃ C ₆ H ₅ O ₇ 3.14 Wine acid ^- OOSN (OH) -CH (OH) COOH 4.8 Vitamin C H ₂ C ₆ H ₆ O ₆ 4.10 Propionic acid C ₂ H ₅ COOH 4.87 succinic acid (-CH ₂ COOH) ₂ 4.16 succinic acid NOOSSN ₂ CH ₂ -COO ^- 5.61 Benzoic acid C ₆ H ₅ COOH 4.19 Malonic acid ^- OSOOS ₂ COOH 5.69 Glutaric acid NOOS (CH ₂ ) ₃ -COOH 4.31 Carbonic acid H ₂ CO ₃ 6.35 p-Hydroxybenzoic acid 4.48 Lemon acid HC ₆ H ₅ O ₇ ^2- 6.39 Acetic acid CH ₃ COOH 4.75 Phosphoric acid H ₂ PO ₄ ^2- 7.21 Lemon acid H ₂ C ₆ H ₅ O ₇ ^- 4.77 Boric acid H ₃ IN ₃ 9.27

In a preferred embodiment of the method of self-organization of an ordered mesoporous silica material having a two-dimensional hexagonal structure with substantially uniform pore sizes of the present invention, the acid has a pKa value in the range of 4 to 7. Adding an aqueous solution of 1 to an aqueous solution of 4 results in a pH of more 2 and less than 8, which corresponds to a range of 1.5 pH units greater and 1.5 pH units less than pH with the same numerical value as the pKa of the acid with pKa in d in the range from 3 to 9, i.e. Due to the alkali mixing effect, the alkali metal silicate solution and the acid with pKa in the range of 3 to 9 form a buffer solution. Citric acid, acetic acid, succinic acid and phosphoric acid are particularly preferred; when mixing aqueous solutions 1 and 4, they give a buffer citrate / citric acid, a buffer acetate / acetic acid, a buffer succinate / succinic acid or buffer N ₂ PO ₄ / NRA ₄ ^- , respectively.

In a preferred embodiment of the method of self-organization of an ordered two-dimensional hexagonal structure ordered mesoporous silica material with substantially uniform pore size in accordance with the present invention, the acids have a pKa value in the range of 4 to 7.

Buffers with pH greater than 2 and less than 8

In the pH zone of the acid component of the buffer, a pH value of greater than 2 and less than 8, i.e. corresponding to a range of 1.5 pH units greater and 1.5 pH units less than pH with the same numerical value as the pKa of the acid component of the buffer, while the pH range is 1.2 pH units larger and 1.2 pH units less than a pH with the same numerical value as the pKa of the acidic component is particularly preferred, and a pH range of 1.0 unit of pH is greater and 1.0 pH unit is less than a pH with the same numerical value as the pKa of acidic component is extremely preferred.

Buffers are mixtures of weak acids and salts of these weak acids or mixtures of salts of weak acids. Preferred buffers are those based on polyacids / polyacid salts having a plurality of pKa ranging from 2 to 8, such as citric acid / citrate buffers with overlapping buffer zones around each pKa covering the entire range from 2.0 to 7.9: 3, 14 ± 1.5, 4.77 ± 1.5 and 6.39 ± 1.5, respectively; and succinic acid / succinic acid salt with overlapping buffer zones around each pKa, covering the entire range from 2.66 to 7.1: 4.16 ± 1.5 and 5.61 ± 1.5, respectively.

Preferred buffers with a pH of more than 2 and less than 8 are sodium citrate / citric acid buffers with a pH in the range of 2.5 to 7.9, sodium acetate / acetic acid buffers with a pH in the range of 3.2 to 8.0, Na buffers ₂ HPO ₄ / citric acid with a pH in the range from 3.0 to 8.0, HCl buffers / sodium citrate with a pH in the range from 1 to 5 and Na ₂ HPO ₄ / NaH ₂ PO ₄ buffers with a pH in the range from 6 to 9.

The sodium citrate / citric acid buffer is preferably characterized by a weight ratio of sodium citrate: citric acid in the range from 0.1: 1 to 3.3: 1.

Medicines

The Biopharmaceutical Classifier (BCS) is the basis for the classification of drugs by their solubility in water and intestinal permeability (Amidon, GL, Lennernäs H., Shah VP, Crison JR, “A theoretical Basis for a Biopharmaceutics Drug Classification: The correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability ”(Theoretical Framework for the Classification of Biopharmaceutical Medicines: In Vitro Pharmaceutical Product Solubility to In Vivo Bioavailability), Pharmaceutical Research, 12: 413-420 (1995), and Adkin, DA, Davis, SS, Sparrow, RA, Huckle, PD, Wilding, IR, 1995. The effect of mannitol on the oral bioavailability of cimetidine bioavailability by oral administration of cimetidine). J. Pharm. Sci. 84, pp. 1405-1409).

In the biopharmaceutical classifier (BCS), originally developed by G. Amidon, pharmaceutical preparations for oral administration are divided into four classes depending on their solubility in water and their permeability through the intestinal cell layer. According to BCS, drugs are classified as follows:

class I - high permeability, high solubility;

class II - high permeability, low solubility;

class III - low permeability, high solubility;

Class IV - low permeability, low solubility.

The interest in this classification system is mainly due to its use in the first period of drug development and then when changes are made throughout the product life cycle. In the initial stages of drug development, knowledge of the class of a particular drug is an important factor influencing the decision to continue or stop its development. Due to the described delivery form and the suitable method of the present invention, which provides greater bioavailability of BCS class 2 drugs, this decision-making process may change.

The class boundary for solubility is based on the effectiveness of the maximum dose of the immediate release dosage form (IR) and the pH curve — the solubility of the test drug in an aqueous medium with a pH in the range from 1 to 7.5. Solubility can be measured by shaking or titration, or by examining the results of an approved stability-assay assay. A drug substance is considered highly soluble if its maximum effective dose is soluble in 250 ml or less of an aqueous medium at a pH in the range of 1-7.5. A volume of 250 ml was taken from conventional bioequivalence test protocols (BE), which prescribe the administration of a dosage form to fasting volunteers with a glass (about 8 ounces or 227 g) of water. The permeability class boundary is based directly on measurements of the rate of mass transfer through the intestinal membrane of a person and indirectly on the degree of absorption (absorbed portion of the dose, unsystematic bioavailability) of a drug substance in humans. The degree of absorption in humans is measured using pharmacokinetic studies of material balance; studies of absolute bioavailability; methods for studying intestinal permeability; in vivo human intestinal perfusion studies ; studies of intestinal perfusion in vivo or in situ in animals. An in vitro permeability study can be carried out using the operatively removed intestinal tissues of a human or animal; in vitro permeability studies can be carried out with monolayers of epithelial cells. Alternatively, non-human systems can be used to predict the extent of drug absorption in humans (e.g., in vitro epithelial culture methods ). In the absence of signs of instability in the gastrointestinal tract, the drug is considered highly soluble when 90% or more of the administered dose is dissolved based on the determination of mass or compared with the intravenous standard dose. The FDA (Food and Drug Administration, USA) has a pH of 7.5, and the ICH / EU (International Harmonization Conference, EU) has a pH of 6.8. An immediate release dosage form is considered to be rapidly dissolving if at least 85% of the labeled drug is dissolved in 30 minutes when using USP Device I (USP) at 100 rpm (or Device II at 50 rpm) in a volume of 900 ml or less in each of the following environments: (1) 0.1 N. HCl or artificial gastric fluid according to USP without enzymes; (2) pH 4.5 buffer; (3) a pH 6.8 buffer or artificial gastric fluid according to USP without enzymes. Based on BCS, sparingly soluble compounds are compounds whose maximum dose is insoluble in 250 ml or less of an aqueous medium with a pH of 1.2 to 7.5 at 37 ° C. See Cynthia K. Brown et al., “Acceptable Analytical Practices for Dissolution Testing of Poorly Soluble Compounds,” Pharmaceutical Technology (December 2004). An immediate release (IR) dosage form is considered to be rapidly dissolving if at least 85% of the labeled drug dissolves in 30 minutes when using USP Device I (USP) at 100 rpm (or Device II at 50 rpm) in volume 900 ml or less in each of the following media: (1) 0.1 N HCl or artificial gastric fluid according to USP without enzymes; (2) pH 4.5 buffer; (3) a pH 6.8 buffer or artificial gastric fluid according to USP without enzymes.

A medicinal substance is considered highly penetrating if the established degree of absorption in humans exceeds 90% of the administered dose based on the material balance or compared with the intravenous standard dose. The permeability class boundary is based directly on measurements of the rate of mass transfer through the intestinal membrane of a person and indirectly on the degree of absorption (absorbed portion of the dose, unsystematic bioavailability) of a drug substance in humans. The degree of absorption in humans is measured using pharmacokinetic studies of material balance; studies of absolute bioavailability; methods for studying intestinal permeability; in vivo human intestinal perfusion studies ; studies of intestinal perfusion in vivo or in situ in animals. An in vitro permeability study can be carried out using the operatively removed intestinal tissues of a human or animal; in vitro permeability studies can be carried out with monolayers of epithelial cells. Alternatively, non-human systems can be used to predict the degree of absorption of a class I drug in humans (e.g., in vitro epithelial culture methods ). A drug substance is considered highly penetrating if the established degree of absorption in humans exceeds 90% of the administered dose I on the basis of material balance or compared with the intravenous standard dose. A medicinal substance is considered to have low permeability if the established degree of absorption in humans is less than 90% of the administered dose based on the material balance or in comparison with the intravenous standard dose. An immediate release dosage form is considered to rapidly dissolve if at least 85% of the labeled amount of the drug dissolves in 30 minutes when using Device I USP (US Pharmacopeia) at 100 rpm (or Device II at 50 rpm) in a volume of 900 ml or less in each of the following environments: (1) 0.1 n. HCl or artificial gastric fluid according to USP without enzymes; (2) pH 4.5 buffer; (3) a pH 6.8 buffer or artificial gastric fluid according to USP without enzymes.

BCS Class II drugs are drugs that are practically insoluble or dissolve slowly but are readily absorbed from the solution by the lining of the stomach and / or intestines. Therefore, to achieve absorption, prolonged interaction with the lining in the gastrointestinal tract is necessary. Such drugs may belong to many pharmacotherapeutic groups. Of particular interest is the class of antifungal drugs such as itraconazole. Many of the known class II drugs are hydrophobic, so they have proven difficult to administer. In addition, due to hydrophobicity, they tend to significant variations in absorption, depending on whether the patient is taking this drug on an empty stomach or eating. This, in turn, can adversely affect the maximum serum concentration, complicating the calculation of doses and the mode of administration. Many of these drugs are also relatively inexpensive, so simple drug preparation technologies are required, and some yield inefficiencies are acceptable.

In a preferred embodiment of the present invention, the drug is itraconazole or a related drug, such as fluoconazole, terconazole, ketoconazole and saperconazole.

Itraconazole is a class II drug used to treat mycosis and is effective against a wide range of fungi, including dermatophytes (shingles), candidiasis, malaysia and chromoblastomycosis. The action of itraconazole is based on the destruction of the cell wall and the critical enzymes of yeast and other fungal pathogens. Itraconazole can also increase testosterone levels, which makes it applicable in the treatment of prostate cancer, and can reduce the production of excess corticosteroid hormones, which makes it useful in terms of Itsenko-Cushing's syndrome. Itraconazole is available in the form of capsules and solution I for oral administration. For the treatment of fungal infections, the recommended dose of capsules for oral administration is 200-400 mg once a day.

Itraconazole has been produced in capsule form since 1992, in the form of oral solution I since 1997, in the form of an intravenous solution since 1999. Since itraconazole is a highly lipophilic compound, its high concentrations in fatty tissues are achievable. and purulent exudates. However, its penetration into aquatic environments is very limited. Gastric acidity and food strongly influence the absorption of oral formulations (Bailey, et al., Pharmacotherapy, 10: 146-153 (1990)). The oral absorption of itraconazole capsules is variable and unpredictable despite the bioavailability of 55%.

Other suitable drugs include class II anti-infective drugs, such as griseofulvin and related compounds, such as griseoverdin; certain antimalarial drugs (e.g., atovaquone); immune system modulators (e.g., cyclosporine); cardiovascular drugs (e.g., digoxin and spironolactone) and ibuprofen. In addition, sterols and steroids can be used. Drugs such as danazol, carbamazopine and acyclovir can also be applied to the mesoporous materials of the present invention, and then converted into a pharmaceutical composition.

Danazole derived from etisterone is an artificial steroid. Danazole, referred to as 17a-pregna-2,4-dien-20-ino [2,3-d] isoxazol-17-ol, has the formula C ₂₂ H ₂₇ NO ₂ and a molecular weight of 337.46. Danazole is an artificial steroid hormone similar to the group of natural hormones (androgens) found in the body. Danazole is used to treat endometriosis. It is also applicable for the treatment of cystic fibrous mastopathy and hereditary angioedema. The action of danazol is based on lowering estrogen levels by inhibiting the production of pituitary hormones called gonadotropins. Under normal conditions, gonadotropins stimulate the production of sex hormones such as estrogen and progestogen, which are responsible for processes such as menstruation and ovulation in the body. Danazole, administered orally, has a bioavailability that does not clearly correlate with the dose and a half-life of 4-5 hours. An increase in the dose of danazol is not proportional to an increase in its concentration in plasma. It was shown that doubling the dose can lead to an increase in the concentration of I in plasma by only 30-40%. The maximum concentration of danazole occurs after 2 hours, but the therapeutic effect is usually invisible for about 6-8 weeks after daily intake of the appropriate doses.

Acyclovir is an artificial analog of a nucleoside that has an antiviral effect. Acyclovir is available in capsules for oral administration, tablets and in suspension. It is a white crystalline powder, designated as 2-amino-1,9-dihydro-9 - [(2-hydroxyethoxy) methyl] -6H-purin-6-one, has the empirical formula C ₈ H ₁₁ N ₅ O _3, and molecular weight 225. Acyclovir can also be applied to the mesoporous materials of the present invention, and then converted into a pharmaceutical composition.

Acyclovir has an absolute bioavailability of 20% at a dose of 200 mg administered every 4 hours, with a half-life of 2.5 to 3.3 hours. In addition, its bioavailability decreases with increasing dose. Despite the low bioavailability, acyclovir has a highly selective inhibitory activity against viruses due to its high affinity for thymidine kinase (TK) (encoded by this virus). TC converts acyclovir into a nucleotide analog that prevents viral DNA replication by inhibiting and / or inactivating viral DNA polymerase and by terminating the growth of the viral DNA chain.

Carbamazepine is used to treat psychomotor epilepsy and as an adjuvant in the treatment of partial epilepsy. It can also soothe or ease pain associated with trigeminal neuralgia. It was also found that carbamazepine, administered as monotherapy or in combination with lithium or antipsychotics, is suitable for the treatment of acute manic syndrome and the prevention of bipolar disorders. Carbamazepine can also be applied to the mesoporous materials of the present invention, and then converted into a pharmaceutical composition.

Carbamazepine is a white to off-white powder, designated as 5H-dibenz [b, f] azepine-5-carboxamide, and has a molecular weight of 236.77. It is practically insoluble in water, soluble in alcohol and acetone. The absorption of carbamazepine is relatively slow, despite the fact that its bioavailability in the form of tablets is 89%. With oral administration of a single dose of carbamazepine tablets and chewable tablets, the maximum plasma concentration of unchanged carbamazepine is reached after 4-24 hours. The therapeutic range for achieving a stable plasma carbamazepine concentration is usually in the range of 4 to 10 μg / ml.

Other class II compounds are antibiotics that kill Helicobacter pylory, including amoxicillin, tetracycline and metronidazole, or therapeutic agents containing acid suppressants (H2 blockers, including cimetidine, ranitidine, famotidine and nizatidine; proton pump inhibitors, including including omeprazole, lansoprazole, rabeprazole, esomeprazole and pantoprozole), agents that improve the protective properties of mucous membranes (bismuth salts; basic salicylic acid bismuth salt) and / or mucolytic agents (mega ldrat). The above preparations can also be applied to the mesoporous materials of the present invention, and then converted into a pharmaceutical composition.

Many of the known class II drugs are hydrophobic and historically difficult to administer. In addition, due to hydrophobicity, they tend to significant variations in absorption, depending on whether the patient is taking this drug on an empty stomach or eating. This, in turn, can adversely affect the maximum serum concentration, complicating the calculation of doses and the mode of administration. Many of these drugs are also relatively inexpensive, so simple drug preparation technologies are required and some yield inefficiencies are acceptable.

In a preferred embodiment of the present invention, the drug is itraconazole or a related drug, such as fluoconazole, terconazole, ketoconazole and saperconazole, and the drugs can be applied to the mesoporous materials of the present invention, and then converted into a pharmaceutical composition.

Itraconazole is a class II drug used to treat mycosis and is effective against a wide range of fungi, including dermatophytes (shingles), candidiasis, malaysia and chromoblastomycosis. The action of itraconazole is based on the destruction of the cell wall and the critical enzymes of yeast and other fungal pathogens. Itraconazole can also increase testosterone levels, which makes it applicable in the treatment of prostate cancer, and can reduce the production of excess corticosteroid hormones, which makes it useful in terms of Itsenko-Cushing's syndrome. Itraconazole is available in capsule form and oral solution. For the treatment of fungal infections, the recommended dose of capsules for oral administration is 200-400 mg once a day. In the form of capsules, itraconazole has been produced since 1992, in the form of an oral solution since 1997, in the form of an intravenous solution since 1999. Since itraconazole is a highly lipophilic compound, its high concentrations in fatty tissues are achievable and purulent exudates. However, its penetration into aquatic environments is very limited. Gastric acidity and food strongly influence the absorption of oral formulations (Bailey, et al., Pharmacotherapy, 10: 146-153 (1990)). The oral absorption of itraconazole capsules is variable and unpredictable despite the bioavailability of 55%.

Other class II drugs include anti-infective drugs, such as sulfazalazine, griseofulvin and related compounds, such as griseoverdin; certain antimalarial drugs (e.g., atovaquone); immune system modulators (e.g., cyclosporine); cardiovascular drugs (e.g., digoxin and spironolactone) and ibuprofen (analgesic); ritonavir, nevirapine, lopinavir (antiviral); clofazinin (leprostatic); Diloxanide furoate (anti-amoebic); glibenclamide (antidiabetic); nephidipine (antianginal); spironolactone (diuretic); steroid drugs such as danazol; carbamazepine and antiviral agents such as acyclovir. These preparations can be applied to the mesoporous materials of the present invention, and then converted into a pharmaceutical composition.

Danazole derived from etisterone is an artificial steroid. Danazole, referred to as 17a-pregna-2,4-dien-20-ino [2,3-d] isoxazol-17-ol, has the formula C ₂₂ H ₂₇ NO ₂ and a molecular weight of 337.46. Danazole is used to treat endometriosis, cystic fibrous mastopathy and hereditary angioedema. Danazole, administered orally, has a bioavailability that does not clearly correlate with the dose and a half-life of 4-5 hours. An increase in the dose of danazol is not proportional to an increase in its concentration in plasma. It has been shown that doubling the dose can lead to an increase in plasma concentration by only 30-40%. The maximum concentration of danazole occurs after 2 hours, but the therapeutic effect is usually invisible for about 6-8 weeks after daily intake of the appropriate doses.

Acyclovir is an artificial analog of a nucleoside that has an antiviral effect. Acyclovir is available in the form of capsules, tablets, and oral suspension. It is a white crystalline powder, designated as 2-amino-1,9-dihydro-9 - [(2-hydroxyethoxy) methyl] -6H-purin-6-one, has the empirical formula C ₈ H ₁₁ N ₅ O _3, and molecular weight 225. Acyclovir has an absolute bioavailability of 20% at a dose of 200 mg administered every 4 hours, with a half-life of 2.5 to 3.3 hours. Its bioavailability decreases with increasing dose. Despite the low bioavailability, acyclovir has a highly selective inhibitory activity against viruses due to its high affinity for thymidine kinase (TK) (encoded by this virus). TC converts acyclovir into a nucleotide analog that prevents viral DNA replication by inhibiting and / or inactivating viral DNA polymerase and by terminating the growth of the viral DNA chain. Acyclovir can also be applied to the mesoporous materials of the present invention, and then converted into a pharmaceutical composition.

Carbamazepine is used to treat psychomotor epilepsy and as an adjuvant in the treatment of partial epilepsy. It can also soothe or ease pain associated with trigeminal neuralgia. It was also found that carbamazepine, administered as monotherapy or in combination with lithium or antipsychotics, is suitable for the treatment of acute manic syndrome and the prevention of bipolar disorders. Carbamazepine is a white to off-white powder, designated as 5H-dibenz [b, f] azepine-5-carboxamide, and has a molecular weight of 236.77. It is practically insoluble in water, soluble in alcohol and acetone. The absorption of carbamazepine is relatively slow, despite the fact that its bioavailability in the form of tablets is 89%. With oral administration of a single dose of carbamazepine tablets and chewable tablets, the maximum plasma concentration of unchanged carbamazepine is reached after 4-24 hours. The therapeutic range for achieving a stable plasma carbamazepine concentration is usually in the range of 4 to 10 μg / ml. Carbamazepine can also be applied to the mesoporous materials of the present invention, and then converted into a pharmaceutical composition.

BCS Class IV drugs (low permeability, low solubility) are drugs that are practically insoluble or slowly soluble in water and have poor gastrointestinal permeability.

Most class IV drugs are lipophilic drugs, so they have poor gastrointestinal permeability. Examples include acetazolamide, furosemide, tobramycin, cefuroxmin, allopurinol, dapsone, doxycycline, paracetamol, nalidixic acid, chlortiazide, tobramycin, cyclosporine, tacrolimus and paclitaxel. Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsucubaensis. Tacrolimus prolongs the lifetime of the recipient and transplant in experimental models of transplantation on animals of the liver, kidneys, heart, bone marrow, small intestine and pancreas, lungs and trachea, skin, cornea of the eye and limbs. The immunosuppressive effect of tacrolimus is based on the inhibition of T-lymphocyte activation by an unknown mechanism. Tacrolimus has the empirical formula C ₄₄ H ₄₉ NO ₁₂ H ₂ O and a molecular weight of 822.05. Externally, tacrolimus is a white crystal or crystalline powder. It is practically insoluble in water, readily soluble in ethanol and highly soluble in methanol and chloroform. Tacrolimus is released for oral administration in the form of capsules or a sterile solution for injection. Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability of tacrolimus is approximately 17% at a dose of 5 mg taken twice a day. Paclitaxel is a chemotherapeutic agent with cytotoxic and antitumor activity. Paclitaxel is a natural product obtained in a semi-synthetic way from Taxus baccata. Although it has a clear reputation for tremendous therapeutic potential, paclitaxel has some patient-dependent deficiencies as a therapeutic agent. In part, this can be attributed to the extremely poor solubility in water, which makes it difficult to provide a suitable dosage form. Due to the poor solubility of paclitaxel in water, the currently approved FDA clinical formulation consists of a 6 mg / ml solution of paclitaxel in 50% polyoxyethylated castor oil (CREMOPHOR EL®) and 50% dehydrated alcohol. Am. J. Hosp. Pharm., 48: 1520-24 (1991). In some cases, serious reactions, including hypersensitivity, arise on CREMOPHOR®, administered in combination with paclitaxel to compensate for its poor solubility in water. Due to cases of hypersensitivity reactions to paclitaxel commercially available drugs and the potential for precipitation of paclitaxel in the blood, the drug must be infused for several hours. In addition, previously, before infusion, patients need to take a course of steroids and antihistamines. Paclitaxel is a white to off-white powder intended for infusion in the form of a non-aqueous solution. Paclitaxel is highly lipophilic and insoluble in water. Such lipophilic drugs can also be applied to the mesoporous materials of the present invention, and then converted into a pharmaceutical composition.

Examples of compounds that are poorly soluble in water include poorly soluble drugs that can be found in the group of prostaglandins, for example prostaglandin E2, prostaglandin F2 and prostaglandin E1, proteinase inhibitors, for example indinavir, nelfinavir, ritonavir, sahinavir, cytotoxic drugs, for example paclitaxel, doxorubicin, daunorubicin, epirubicin, idarubicin, zorubicin, mitoxantrone, amsacrine, vinblastine, vincristine, vindesine, dactiomycin, bleomycin, metallocenes, for example titanium metallocene dichloride, and conjugato fat - a medicine, for example, diminazole stearate and diminazole oleate, and, as a rule, poorly soluble anti-infective agents, such as griseofulvin, ketoconazole, fluconazole, itraconazole, clindamycin, especially antiparasitics, for example chloroquine, mefloquinquinamine, princine, , metronidazole, nimorazole, tinidazole, atovaquone, buparvachone, nifurtimox, and anti-inflammatory drugs, for example cyclosporine, methotrexate, azathioprine. These biologically active compounds can also be applied to the mesoporous materials of the present invention, and then converted into a pharmaceutical composition.

Pharmaceutical composition

The ordered mesoporous silica materials of the present invention, saturated with biologically active drugs, such as drugs that are poorly soluble in water or drugs that are practically insoluble in water, or an antibody fragment or nucleotide fragment, can be converted into pharmaceutical compositions and administered to a mammal, such as a sick person or a pet, in a variety of forms, corresponding to the chosen method of administration of the drug, for example orally, orally, topically, h cut mouth, parenterally, rectally or by other means.

The ordered mesoporous silica materials of the present invention can also be saturated with small oligonucleic acids or peptide molecules, for example, binding to a specific target molecule, such as aptamers (DNA aptamers, RNA aptamers or peptide aptamers). Mesoporous materials of the present invention saturated with small oligonucleic acids or intended to be saturated with such can be used to hybridize such oligonucleic acids.

The ordered mesoporous materials of the present invention are particularly suitable for carrying and immediately releasing poorly water soluble drugs, class II drugs according to BCS, drugs class IV according to BCS or compounds which are practically insoluble in water in aqueous media. For example, the ordered mesoporous silica materials of the present invention may be saturated with itraconazole.

The pharmaceutical composition (preparation) of the present invention can be produced by a method optionally selected from, for example, “Guide Book of Japanese Pharmacopoeia”, Ed. of Editorial Committee of Japanese Pharmacopoeia, Version # 13, published July 10, 1996 Hirokawa publishing company. The new mesoporous materials of the present invention can be used to carry small fragments of antibodies. Examples of small antibody fragments include an Fv ’fragment, a single chain Fv antibody (scFv), Fab antibody fragments, Fab ′ antibody fragments, a heavy and light chain CDR antibody fragment, or an antibody.

The washed, dried and calcined SOK-10 materials, in the pores of which biologically active drugs are poorly soluble in water, are characterized by an increased rate of release of these biologically active drugs poorly soluble in water into the aquatic environment.

Saturation of ordered mesoporous silica materials

Solution in solvent: 50/50 v / v dichloroethane / ethanol can be prepared for biologically active preparations such as 1) intraconazole, 2) a derivative of itraconazole, 3) a triazole compound in which the polar surface area (PSA) ranges from 60 Å ² to 200 Å ² , preferably from 70 Å ² to 160 Å ² , more preferably 80 Å ² to 140 Å ² , even more preferably 90 Å ² to 120 Å ² , most preferably 95 Å ² to 110 Å ² , 4) a triazole compound with distribution coefficient (XlogP) in the range of 4 to 9, more preferably in the range of 5 to 8, most preferably in di a range from 6 to 7, 5) a triazole compound with more than 10 freely rotating bonds, 6) a triazole compound with a polar surface area (PSA) in the range from 80 to 200, a distribution coefficient in the range from 3 to 8, and from 8-16 freely by rotating bonds or 7) the connection of triazole with PSA more than 80 Å ² . To speed up the dissolution of itraconazole, sonication can be used. Such solutions, in which 50 mg of the biologically active preparation are freely soluble per ml of solvent mixture, are suitable for impregnating the mesoporous materials of the present invention in order to saturate the pores with the biologically active preparations and to disperse them at the molecular level in the specified mesoporous material.

Another solvent generally suitable for dissolving compounds that are practically insoluble in water or poorly soluble in water is dichloroethane (CH ₂ Cl ₂ ). A solution containing 50 mg of a biologically active preparation dissolved in 1 ml can be used to impregnate the mesoporous materials of the present invention in order to saturate their pores with biologically active preparations. However, dichloroethane can be replaced by another organic (carbon-containing) solvent, such as chemically inert solvents 1,4-dioxane, tetrahydrofuran, 2-propanol, n-methylpyrrolidone, chloroform, hexafluoroisopropanol and the like. Polar aprotic solvents selected from the group consisting of 1,4-dioxane (/ -CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -O \), tetrahydrofuran (/ -CH ₂ -CH) are especially suitable for such a replacement _2- O-CH ₂ -CH ₂ - \), acetone (CH ₃ -С (= О) -СН ₃ ), acetonitrile (СН ₃ -С≡N), dimethylformamide (Н-С (= О) N (СН ₃ ) ₂ ) or dimethyl sulfoxide (CH ₃ -S (= O) -CH ₃ ), or from the group consisting of non-polar solvents such as hexane (CH ₃ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₃ ), benzene (C ₆ H ₆ ), toluene (C ₆ H ₅ -CH ₃ ), diethyl ether (CH ₃ -CH ₂ -O-CH ₂ -CH ₃ ), chloroform (CHCl ₃ ), ethyl acetate (CH ₃ -C (= O) -O-CH ₂ -CH ₃ ). In addition, a suitable organic (carbon-containing) solvent in the context of the present invention is a solvent in which biologically active drugs or drugs are poorly soluble in water, or which is an organic solvent in which the solubility of poorly water-soluble drugs is high. For example, an organic compound such as fluorinated alcohol, for example hexafluoroisopropanol (HFIP - (CF ₃ ) ₂ CHOH), which forms strong hydrogen bonds, can be used to dissolve substances that act as a hydrogen bond acceptor, such as amides and ethers, which are poorly soluble in water. Biologically active preparations or medicinal compounds belonging to the amide group contain dipole groups of carbonyl (C = O) and ether (NC), which are the result of covalent binding of electronegative oxygen and nitrogen atoms and electroneutral carbon atoms, while primary and secondary amides also contain two and one dipole N-H, respectively. The presence of a C = O dipole and, to a lesser extent, an NC dipole allows amides to act as hydrogen bond acceptors; therefore, HFIP is a suitable solvent. Another group of organic solvents is, for example, non-polar solvents such as halogenated hydrocarbons (e.g. dichloromethane, chloroform, chloroethane, trichloroethane, carbon tetrachloride, etc.), of which dichloromethane (DCM) or methylene chloride, which suitable as a solvent for biologically active preparations or drugs such as diazepam, alpha-methyl-p-tyrosine, phencyclidine, quinolinic acid, simvastatin, lovastatin; paclitaxel, alkaloids, cannabinoids. To select a solvent suitable for saturating ordered mesoporous oxides with well-known poorly soluble biologically active preparations, specialists in this field can use card indexes and databases available for well-known solvents and drug compounds (such as Cosmologic Gmbh & Co, GOS COSMOfiles (trademark)) . For newly created drugs, the solubility in any solvent can be calculated using thermodynamic criteria that reflect the basic physical properties and phase equilibrium conditions, for example, using expert systems in computational chemistry and hydrodynamics (T. Bieker, KN Simmrock, Comput. Chem. Eng. 18 (Suppl. 1) (1993) S25-S29; KG Joback, G. Stephanopoulos, Adv. Chem. Eng. 21 (1995) 257-311; L. Constantinou, K. Bagherpour, R. Gani, JA Klein , DT Wu, Comput. Chem. Eng. 20 (1996) 685-702; J. Gmehling, C. Moellmann, Ind. Eng. Chem. Res. 37 (1998) 3112-3123; M. Hostrup, PM Harper, R Gani, Comput. Chem. Eng. 23 (1999) 1395-1414: R. Zhao, H. Cabezas, SR Nishtala, Green Chemical Syn theses and Processes, ACS Symposium Series 767, American Chemical Society, Washington, DC, 2000, pp. 230-243), such as COSMOfrag / COSMOtherm (trademark) of Cosmologic Gmbh & Co, GK, which interact with a variety of databases described molecules. Another possibility is the use of automated solubility measuring instruments available to those skilled in the art, such as Millipore’s Biomek® FX, designed to test the solubility in water of a particular compound without undue cost.

EXAMPLES

The following are examples of the synthesis of SOK-10 and SOK 12, illustrating the synthesis conditions that are most favorable for obtaining a narrow size distribution of mesopores.

Example 1

Synthesis of SOK-10 using TRAON (SiO ₂ / TRAON = 25/1) at a pH of the reaction mixture equal to 5.8

Pluronic P123 surfactant (BASF) in an amount of 4.181 g was mixed with 107.554 g of water, 12.64 g of a solution (2.4 M) of HCl and 1.4 ml of a 1 M solution of tetrapropylammonium hydroxide (TPAOH) (from Alpha) in a polypropylene (PP) vessel ( 500 ml). This vessel was placed in an oil bath at 35 ° C and its contents were stirred with a magnetic stirrer (400 rpm) overnight. In a second PP reservoir, 10.411 g of a sodium silicate solution (Riedel de Haen, pure at least 10 wt.% NaOH and at least 27 wt.% SiO ₂ ) was mixed with 30.029 g of water. This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature for 5 minutes. This second solution was added to the PP vessel in an oil bath. The resulting solution was stirred (400 rpm) for 5 minutes at 35 ° C. At this stage, the pH measured using a Mettler Toledo, InLab® Expert Pro pH electrode was 5.8. The resulting reaction mixture was placed in a preheated oven at 35 ° C for 24 hours without stirring. After 24 hours, the temperature in the furnace was raised to 90 ° C and kept unchanged for 24 hours. The resulting reaction mixture was cooled to room temperature and subjected to vacuum filtration (filter holding capacity of 20-25 μm). The powder on the filter was washed using 300 ml of water. The resulting powder was dried in a glass tank for 24 hours at 60 ° C. The x-ray scattering diagram of this material in the post-synthesis state is shown in FIG. 1. The presence of diffraction peaks indicates that this material is ordered at the meso level. After synthesis, the powder was transferred to porcelain dishes and calcined in an oven in air at 550 ° С for 8 h with a heating rate of 1 ° С / min. The nitrogen adsorption isotherm of the calcined SOK-10 material is shown in FIG. 2. The measurements were carried out on a Micrometrics Tristar 3000 instrument. Before measurement, the sample was pretreated at 300 ° C for 10 h (the rate of temperature change was 5 ° C / min). Type IV isotherm is characteristic of mesoporous material. Strongly inclined parallel branches of the hysteresis loop indicate that the pore size is exactly the same. The size distribution of mesopores was determined based on the nitrogen adsorption isotherm using the BJH method (Figure 2, below). The pore size was about 11 nm. The results for nitrogen adsorption (FIG. 2) in combination with the X-ray scattering diagram (FIG. 1) show that this SOK-10 sample is an ordered mesoporous material. The morphology of this sample was investigated using a scanning electron microscope (SEM) (Figure 3). This material is formed by interweaving fused particles.

Example 2

Synthesis of SOK-10 using TRAON (SiO ₂ / TRAON = 25/1) at a reaction mixture pH of 2.4

Pluronic P123 surfactant in an amount of 4.162 g was mixed with 107.093 g of water, 13.039 g of a solution (2.4 M) of HCl and 1.8 ml of a 1 M solution of TRAON (from Alpha) in a PP vessel (500 ml). This vessel was placed in an oil bath at 35 ° C and its contents were stirred with a magnetic stirrer (400 rpm) overnight. In a second PP reservoir, 10.441 g of a sodium silicate solution (Riedel de Haen, pure at least 10 wt.% NaOH and at least 27 wt.% SiO ₂ ) was mixed with 30.027 g of water. This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature for 5 minutes. This second solution was added to the PP vessel in an oil bath. The resulting solution was stirred (400 rpm) for 5 minutes at 35 ° C. At this stage, the pH measured with a Mettler Toledo InLab® Expert Pro pH electrode was 2.4. The resulting reaction mixture was placed in a preheated oven at 35 ° C for 24 hours without stirring. After 24 hours, the temperature in the furnace was raised to 90 ° C and kept unchanged for 24 hours. The resulting reaction mixture was cooled to room temperature and subjected to vacuum filtration (filter holding capacity of 20-25 μm). The powder on the filter was washed using 300 ml of water. The resulting powder was dried in a glass tank for 24 hours at 60 ° C. Finally, the powder was transferred to porcelain dishes and calcined in an oven in an air atmosphere at 550 ° C for 8 hours at a heating rate of 1 ° C / min.

The presence of diffraction peaks in the region of low q values in the X-ray scattering diagram of this material SOK-10 (Figure 4) indicates that this material is ordered at the meso level. The nitrogen adsorption isotherm of this sample was obtained using a Micrometrics Tristar instrument. Before measurement, the sample was pretreated at 300 ° С for 10 h (the rate of temperature change was 5 ° С / min). The nitrogen adsorption isotherm (Figure 5) was a type IV adsorption isotherm with a hysteresis loop. The branches of the hysteresis loop are strongly inclined, which indicates a narrow size distribution of the mesopores. The mesopore size was estimated using the BJH method (Figure 5). The pore size was about 9 nm.

The morphology of this sample was investigated using SEM (Fig.6).

Example 3

Synthesis of mesoporous material at a pH of 6.4 of the reaction mixture without TPAOH (comparative example)

Pluronic P123 surfactant in an amount of 4.212 g was mixed with 107.592 g of water, 12.630 g of a solution (2.4 M) of HCl and 0.066 g of NaOH in a PP vessel (500 ml). This vessel was placed in an oil bath at 35 ° C and its contents were stirred with a magnetic stirrer (400 rpm) overnight. In a second PP tank, 10.413 g of a sodium silicate solution (Riedel de Haen, pure at least 10 wt.% NaOH and at least 27 wt.% SiO ₂ ) was mixed with 30.020 g of water. This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature for 5 minutes. This second solution was added to the PP vessel in an oil bath. The resulting solution was stirred (400 rpm) for 5 minutes at 35 ° C. At this stage, the pH measured with a Mettler Toledo, InLab® Expert Pro pH electrode was 6.4. The resulting reaction mixture was placed in a preheated oven at 35 ° C for 24 hours without stirring. After 24 hours, the temperature in the furnace was raised to 90 ° C and kept unchanged for 24 hours. The resulting reaction mixture was cooled to room temperature and subjected to vacuum filtration (filter holding capacity of 20-25 μm). The powder on the filter was washed using 300 ml of water. The resulting powder was dried in a glass tank for 24 hours at 60 ° C. Finally, the powder was transferred to porcelain dishes and calcined in an oven in an air atmosphere at 550 ° C for 8 hours at a heating rate of 1 ° C / min. On the x-ray scattering diagram in the region of small angles (Fig. 7), there are several diffraction peaks. This indicates that this material is ordered at the meso level. The SEM image of the SOK-10 material shown in FIG. 8, detected by SEM, detects the presence of grouped particles. The nitrogen adsorption isotherm of this sample was obtained using a Micrometrics Tristar instrument (Fig. 9). Before measurement, the sample was pretreated at 300 ° С for 10 h (the rate of temperature change was 5 ° С / min). There is a hysteresis loop on the nitrogen adsorption isotherm of this material, which indicates the presence of mesopores. The branches of the hysteresis loop are not parallel. An analysis of the size distribution of mesopores indicates that this sample contains mesopores with a very wide range of diameters in the range from about 5 to 40 nm with a maximum of 11 nm. From this example, we can conclude that without an organic cation, such as tetrapropylammonium, it is difficult to achieve ordering at the meso level.

Example 4

Synthesis of SBA-15 (comparative example)

In this example, a strongly acidic reaction mixture was used. High acidity was obtained using a large amount of 2M HCl solution. Pluronic P123 surfactant (BASF) in an amount of 4.1 g was mixed with 120.1 g of a solution of (2M) HCl in a PP vessel (500 ml). This vessel was placed in an oil bath at 35 ° C and its contents were stirred with a magnetic stirrer (400 rpm) overnight. In a second PP reservoir, 10.4 g of a sodium silicate solution (Riedel de Haen, pure at least 10 wt.% NaOH and at least 27 wt.% SiO ₂ ) was mixed with 30.0 g of water. This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature for 5 minutes. This second solution was added to the PP vessel in an oil bath. The resulting solution was stirred (400 rpm) for 5 minutes at 35 ° C. The resulting reaction mixture was placed in a preheated oven at 35 ° C for 24 hours without stirring. After 24 hours, the temperature in the furnace was raised to 90 ° C and kept unchanged for 24 hours. The resulting reaction mixture was cooled to room temperature and subjected to vacuum filtration (filter holding capacity of 20-25 μm). The powder on the filter was washed using 300 ml of water. The resulting powder was dried in a glass tank for 24 hours at 60 ° C. After synthesis, the powder was transferred to porcelain dishes and calcined in an oven in air at 550 ° С for 8 h with a heating rate of 1 ° С / min. The nitrogen adsorption isotherm of SBA-15 is shown in FIG. 10. The pore size of the obtained SBA-15 material was about 8 nm. The measurements were carried out on a Micrometrics Tristar 3000 instrument. Before measurement, the sample was pretreated at 300 ° C for 10 h (the rate of temperature change was 5 ° C / min). An SEM image of the obtained SBA-15 material is shown in FIG. 11. This material looks like micron-sized grouped particles.

Example 5

Synthesis Experiment Using TRAON (SiO ₂ / TRAON = 25/1) at a pH of the reaction mixture equal to 11.12 (comparative example)

Pluronic P123 surfactants in an amount of 4.043 g were mixed with 140.335 g of water, 2.6 g of a solution of (2M) HCl and 1.8 ml of a 1M solution of TPAH in a PP vessel (500 ml). The contents of this vessel were mixed with a magnetic stirrer (400 rpm) at room temperature. In a second PP reservoir, 10.428 g of sodium silicate solution was mixed with 5.510 g of water. This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature for 5 minutes. This second solution was added to the mixture containing surfactant. The resulting solution was stirred (400 rpm) for 5 minutes at room temperature. At this stage, the pH measured with a Mettler Toledo, InLab® Expert Pro pH electrode was 11.12. The reaction mixture remained in a clear gel state. The formation of particles of silicon dioxide did not occur. The pH value of 11.12 is outside the range preferred for the synthesis of the material SOK-10.

Example 6

Synthesis Experiment Using TRAON (SiO ₂ / TRAON = 25/1) at a pH of the reaction mixture equal to 8.9 (comparative example)

Pluronic P123 surfactant in an amount of 0.811 g was mixed with 22.1 g of water, 2.01 g of a solution (2.4 M) of HCl and 1.8 ml of a 1 M solution of TPAH in a PP vessel (60 ml). The mixture was stirred using a magnetic stirrer (400 rpm) at room temperature. In a second PP reservoir, 2.090 g of sodium silicate solution was mixed with 6.261 g of water. This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature for 5 minutes. This second solution was added to the surfactant mixture. The resulting reaction mixture was stirred (400 rpm) for 5 minutes at room temperature. At this stage, the pH measured with a Mettler Toledo, InLab® Expert Pro pH electrode was 8.9. During this synthesis, the reaction mixture remained in a state of a transparent gel. The formation of particles of silicon dioxide did not occur. The pH value of 8.9 is outside the range preferred for the synthesis of the material SOK-10.

Example 7

Synthesis of SOK-10 using TRAON (SiO ₂ / TRAON = 25/1) at a pH of the reaction mixture equal to 5.8

Pluronic P123 surfactant in an amount of 4.140 g was mixed with 107.55 g of water, 12.779 g of a solution (2.4 M) of HCl and 1.8 ml of a 1 M solution of TPAH in a PP vessel (500 ml). The mixture was stirred using a magnetic stirrer (400 rpm) at room temperature. In a second PP reservoir, 10.448 g of sodium silicate solution was mixed with 30.324 g of water. This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature. This second solution was added to the surfactant mixture. The resulting reaction mixture was stirred using an electric mixer with direct drive (400 rpm) for 5 minutes. At the end of this step, the pH measured with a Mettler Toledo InLab® Expert Pro pH electrode was 5.8. The resulting reaction mixture was placed in a preheated oven at 35 ° C for 24 hours without stirring. After 24 hours, the temperature in the furnace was raised to 90 ° C and kept unchanged for 24 hours. The resulting reaction mixture was cooled to room temperature and subjected to vacuum filtration (filter holding capacity of 20-25 μm). The powder on the filter was washed using 100 ml of water. The resulting powder was dried in a glass tank for 24 hours at 60 ° C. Finally, the powder was transferred to porcelain dishes and calcined in an oven in an air atmosphere at 550 ° C for 8 hours at a heating rate of 1 ° C / min. The nitrogen adsorption isotherm of this sample was obtained using a Micrometrics Tristar instrument. Before measurement, the sample was pretreated at 300 ° С for 10 h (the rate of temperature change was 5 ° С / min). On the nitrogen adsorption isotherm (FIG. 12) there is a hysteresis loop with strongly inclined parallel branches typical of a mesoporous material. This SOK-10 material is characterized by a narrow size distribution of mesopores with a maximum of about 9 nm (Fig. 12).

This SOK-10 material consists of spherical particles with a size of about 1 μm, measured using SEM (Fig.13). The X-ray scattering diagram of the calcined SOK-10 material is shown in Fig. 14. The presence of diffraction peaks on it indicates that this material is ordered at the meso level.

Example 8

In vitro experiment on the release of itraconazole from the material SOK-10 of example 1

Itraconazole is a poorly soluble drug compound. 50.00 mg of itraconazole was dissolved in 1 ml of dichloromethane. SOK-10 in an amount of 150.03 mg was impregnated with a solution of itraconazole three times in 250 μl. The impregnated SOK-10 sample was dried in a vacuum oven at 40 ° C.

The release medium was an artificial gastric fluid (SGF) to which sodium lauryl sulfate (SLS) (0.05% by weight) was added. Saturated with itraconazole, SOK-10 was suspended in 20 ml of dissolution medium. The suspension was stirred at 730 rpm. The saturation of the silicon oxide materials was 18% wt. The concentration of itraconazole in the solution was determined using HPLC. On Fig presents a graph of the dependence of the release of itraconazole on time. A rapid release of a significant amount of itraconazole from SOK-10 into the dissolution medium was noted. After 5 minutes, 20% of itraconazole contained on the SOK-10 carrier was released. After 30 minutes, the amount released was close to 30%.

Example 9

In vitro experiment on the release of itraconazole from a mesoporous material synthesized not in accordance with the present invention (obtained in comparative example 3)

49.98 mg of itraconazole was dissolved in 1 ml of dichloromethane. The mesoporous material of Example 3 in an amount of 150.03 mg was impregnated with a solution of itraconazole twice in 375 μl each. An impregnated sample of mesoporous silica was dried in a vacuum oven at 40 ° C.

The release medium was an artificial gastric fluid (SGF) to which sodium lauryl sulfate (0.05% wt.) Was added. Saturated itraconazole mesoporous silica was suspended in 15 ml of dissolution medium. The suspension was stirred at 730 rpm. The saturation of the silica carrier with itraconazole was 15.65% wt. The concentration of itraconazole in the solution was determined using HPLC. On Fig presents a graph of the dependence of the release of itraconazole on time. A significantly lower amount of itraconazole is released from this material into the dissolution medium than from the SOK-10 sample (cf. FIG. 15). After 5 minutes, only about 7% of itraconazole was released into the dissolution medium. After 60 minutes, this amount increased only to 15%.

Example 10

In vitro experiment on the release of itraconazole from SBA-15 material (obtained in comparative example 4)

50.05 mg of itraconazole was dissolved in 1 ml of dichloromethane. A sample of SBA-15, prepared as described in Example 4, in an amount of 150.02 mg was impregnated with a solution of itraconazole three times in 250 μl. The impregnated SBA-15 sample was dried in a vacuum oven at 40 ° C.

The release medium was an artificial gastric fluid (SGF) to which sodium lauryl sulfate (0.05% wt.) Was added. Saturated itraconazole mesoporous silica was suspended in 20 ml of dissolution medium. The saturation of the silicon oxide material SBA-15 with itraconazole was 18% wt. The suspension was stirred at 1100 rpm. The concentration of itraconazole in the solution was determined using HPLC. On Fig presents a graph of the dependence of the release of itraconazole on time. A significantly lower amount of itraconazole is released from this material into the dissolution medium than from the SOK-10 sample (cf. FIG. 15). After 5 minutes only about 5% of itraconazole was released into the dissolution medium from SBA-15. After 60 minutes, this amount increased only to about 18%.

Example 11

Synthesis of SOK-10 using TRAON (SiO ₂ / TRAON = 25/1) at room temperature at a pH of the reaction mixture equal to 6.06

Pluronic P123 surfactant in an amount of 4.116 g was mixed with 107.506 g of water, 12.78 g of a solution (2.4 M) of HCl and 1.8 ml of a 1 M solution of TPAH in a PP vessel (500 ml). This mixture (mixture 1) was stirred using a magnetic stirrer (400 rpm) at room temperature. In a second PP reservoir, 10.45 g of sodium silicate solution was mixed with 30.04 g of water (mixture 2). This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature. This second solution was added to a mixture containing a surfactant (mixture 1). The resulting reaction mixture was stirred using an electric mixer with direct drive (200 rpm) for 5 minutes. At the end of this step, the pH measured with Mettler Toledo, the pH electrode of InLab® Expert Pro, at a temperature of 24 ° C., was 6.06. The reaction mixture was left at room temperature for 24 hours without stirring. The resulting reaction mixture was subjected to vacuum filtration (filter retention 20-25 μm). In this case, there was no next stage of increasing the temperature to 90 ° C and isothermal aging for 24 hours, as in examples 1, 2, 3, 4, and 7. The powder on the filter was washed using 300 ml of water. The resulting powder was dried in a glass tank for 24 hours at 60 ° C. Finally, the powder was transferred to porcelain dishes and calcined in an oven in an air atmosphere at 550 ° C for 8 hours at a heating rate of 1 ° C / min. The nitrogen adsorption isotherm of this sample is shown in Fig. 18 (above). On this isotherm there is a hysteresis loop with parallel branches of adsorption and desorption, characteristic of the presence of homogeneous pores. The pore diameter is estimated to be approximately equal to 8 nm (Fig. 18, below). The size and shape of the particles was investigated using SEM (Fig.19). The particle size was about 1 μm. Particles are combined into larger groups (Fig.19). The X-ray scattering diagram of the calcined material is shown in FIG. The presence of diffraction peaks on it indicates that this material is ordered at the meso level. The characteristics of this mesoporous silica SOK-10 as a carrier for drugs with poor solubility were evaluated during an in vitro experiment on the release of itraconazole. This mesoporous carrier was saturated with 21.38% wt. itraconazole. In a short time, a significant amount of itraconazole was released from SOK-10 into the dissolution medium.

Example 12

Synthesis of SOK-10 using TMAON (SiO ₂ / TRAON = 25/1) at room temperature at a pH of the reaction mixture equal to 5.75

Pluronic P123 surfactant in an amount of 4.154 g was mixed with 107.606 g of water, 12.762 g of a solution of (2.4 M) HCl and 1.8 ml of a 1 M solution of TMAOH in a PP vessel (500 ml). This mixture (mixture 1) was stirred using a magnetic stirrer (400 rpm) at room temperature. In a second PP reservoir, 10.463 g of sodium silicate solution was mixed with 30.03 g of water (mixture 2). This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature. This second solution was added to a mixture containing a surfactant (mixture 1). The resulting reaction mixture was stirred using an electric mixer with direct drive (200 rpm) for 5 minutes. At the end of this step, the pH measured with Mettler Toledo, the pH electrode of InLab® Expert Pro, at a temperature of 22 ° C., was 5.75. The reaction mixture was left at room temperature for 24 hours without stirring. After 24 hours, the reaction mixture was placed in an oven with a temperature of 90 ° C for 24 hours. The resulting reaction mixture was subjected to vacuum filtration (filter retention capacity 20-25 μm). The powder on the filter was washed using 300 ml of water. The resulting powder was dried in a glass tank for 24 hours at 60 ° C. Finally, the powder was transferred to porcelain dishes and calcined in an oven in an air atmosphere at 550 ° C for 8 hours at a heating rate of 1 ° C / min. The nitrogen adsorption isotherm of this sample is shown in Fig. 21 (above). On this isotherm there is a hysteresis loop with parallel branches of adsorption and desorption, characteristic of the presence of homogeneous pores. The pore diameter is estimated to be approximately 12 nm (FIG. 21, bottom). The X-ray scattering diagram of the calcined SOK-10 material is shown in FIG. The presence of diffraction peaks on it indicates that this material is ordered at the meso level.

Example 13

Synthesis of SOK-10 at pH 6.5 of the reaction mixture

Pluronic P123 surfactant in an amount of 4.090 g was mixed with 107.544 g of water, 12.017 g of a solution of (2.4 M) HCl in a PP vessel (500 ml). This mixture (mixture 1) was stirred using a magnetic stirrer (400 rpm) at room temperature. In a second PP reservoir, 10.43 g of sodium silicate solution was mixed with 31.0 g of water (mixture 2). This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature. This second solution was added to a mixture containing a surfactant (mixture 1). The resulting reaction mixture was stirred using an electric mixer with direct drive (200 rpm) for 5 minutes. At the end of this step, the pH measured with Mettler Toledo, the pH electrode of InLab® Expert Pro, at a temperature of 22 ° C., was 6.5. The reaction mixture was left at room temperature for 24 hours without stirring. In this case, there was no next stage of increasing the temperature to 90 ° C and isothermal aging for 24 hours. The resulting reaction mixture was subjected to vacuum filtration (filter holding capacity of 20-25 μm). The powder on the filter was washed using 300 ml of water. The resulting powder was dried in a glass tank for 24 hours at 60 ° C. Finally, the powder was transferred to porcelain dishes and calcined in an oven in an air atmosphere at 550 ° C for 8 hours at a heating rate of 1 ° C / min. The nitrogen adsorption isotherm of this sample is shown in Fig. 23 (above). On this isotherm there is a hysteresis loop with parallel branches of adsorption and desorption, characteristic of the presence of homogeneous pores. The pore diameter is estimated to be approximately 8 nm (FIG. 23, bottom). The X-ray scattering diagram of the calcined SOK-10 material is shown in FIG. 24. The presence of diffraction peaks on it indicates that this material is ordered at the meso level.

Example 14

Synthesis of SOK-12 (ordered mesoporous material) using a buffer at room temperature with a pH of 5.2

Pluronic P123 surfactants in an amount of 4.060 g were mixed with 107.672 g of water, 2.87 g of sodium citrate and 3.41 g of citric acid in a PP vessel (500 ml). This solution was stirred with a magnetic stirrer (400 rpm) overnight. The pH of the solution, measured using Mettler Toledo, the pH electrode of InLab® Expert Pro, at a temperature of 22 ° C, was 3.8.

In a PP beaker (50 ml), 10.420 g of sodium silicate solution (Riedel de Haen, pure, ≥10% NaOH and ≥27% SiO ₂ ) was mixed with 30.012 g of water. This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature for 5 minutes. This second solution was added to a PP vessel with a surfactant-containing mixture with mechanical stirring (200 rpm). The resulting solution was stirred (200 rpm) for 5 minutes at room temperature. After 3 minutes, the pH stabilized at 5.2. The vessel was kept at room temperature for 24 hours. The resulting reaction mixture was subjected to vacuum filtration (filter retention 20-25 μm). The powder on the filter was washed using 300 ml of water. The resulting powder was dried in a glass tank for 24 hours at 60 ° C. After synthesis, the powder was transferred to porcelain dishes and calcined in an oven in air at 550 ° С for 8 h with a heating rate of 1 ° С / min.

The X-ray scattering diagram of the material in the post-synthesis state and the calcined material is shown in FIG. 25. This material is ordered at the meso level and has a two-dimensional hexagonal structure (space group p6m ). The unit cell parameter a is 9.872 nm.

The nitrogen adsorption isotherm of the calcined SOK-12 material is shown in Fig. 26 (above). Type IV isotherm is characteristic of mesoporous material. The strongly inclined parallel branches of the hysteresis loop indicate that the pore size is completely uniform. The size distribution of mesopores was determined based on the nitrogen adsorption isotherm using the BJH method (Fig. 26, below). The pore size was about 5 nm. The results for nitrogen adsorption (FIG. 26) in combination with the X-ray scattering diagram (FIG. 25) show that this sample is an ordered mesoporous material. The morphology of this sample was investigated using SEM (Fig.27). This material is formed by interweaving fused particles.

Example 15

Synthesis of SOK-12 using a buffer at room temperature with a pH of 4.9

Pluronic P123 surfactants in an amount of 4.109 g were mixed with 107.573 g of water, 2.540 g of sodium citrate and 3.684 g of citric acid in a PP vessel (500 ml). This solution was stirred with a magnetic stirrer (400 rpm) overnight. The pH of the solution, measured using Mettler Toledo, the pH electrode of InLab®Expert Pro, at a temperature of 22 ° C, was 3.6.

In a PP glass (50 ml), 10.424 g of sodium silicate solution (Riedel de Haen, pure, ≥10% NaOH, ≥27% SiO ₂ ) was mixed with 30.091 g of water. This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature for 5 minutes. This second solution was added to a PP vessel with a surfactant-containing mixture with mechanical stirring (200 rpm). The resulting solution was stirred (200 rpm) for 5 minutes at room temperature. After 3 minutes, the pH stabilized at 4.9. The vessel was kept at room temperature for 24 hours. The resulting reaction mixture was subjected to vacuum filtration (filter retention 20-25 μm). The powder on the filter was washed using 300 ml of water. The resulting powder was dried in a glass tank for 24 hours at 60 ° C. After synthesis, the powder was transferred to porcelain dishes and calcined in an oven in air at 550 ° С for 8 h with a heating rate of 1 ° С / min.

The X-ray scattering diagram of the SOK-12 material in the post-synthesis state is shown in FIG. This material is ordered at the meso level and has a two-dimensional hexagonal structure (space group p6m ). The unit cell parameter a is 10.091 nm.

The ²⁹ Si NMR spectrum with rotation of the sample at the magic angle of the material after synthesis was obtained on a Bruker AMX300 (7.0T) spectrometer. 4000 scans were made with a repeat delay of 60 s. The sample was embedded in a rotor made of zirconium oxide. The rotor speed was 5000 Hz. Tetramethylsilane was used as a shift standard. Silica particles Q3 and Q4 are visible as wide peaks at -99 and -109 ppm, respectively, with a Q3 / Q4 ratio of 0.59, which is considered to indicate that the walls of silicon dioxide are in the SOK-12 material are highly dense. This value can be compared with the Q3 / Q4 ratio (0.78) of SBA-15 samples (Zhao et al., J. Am. Chem. Soc., 1998, Vol. 120, No. 24, p. 6024). The nitrogen adsorption isotherm of the calcined SOK-12 material is shown in Fig. 29 (above). Type IV isotherm is characteristic of mesoporous material. The strongly inclined parallel branches of the hysteresis loop indicate that the pore size is completely uniform. The size distribution of mesopores was determined based on the nitrogen adsorption isotherm using the BJH method (Fig. 29, below). The pore size was about 5 nm. The results for nitrogen adsorption (FIG. 29) in combination with the X-ray scattering diagram (FIG. 28) show that this sample is an ordered mesoporous material. The morphology of this sample was investigated using SEM (Fig.30). This material is formed by interweaving fused particles.

Example 16

Synthesis of SOK-12 using a buffer at 90 ° C at a pH of the reaction mixture equal to 4.6

Pluronic P123 surfactant in an amount of 4.116 g was mixed with 107.495 g of water, 5.104 g of sodium citrate and 4.335 g of citric acid in a PP vessel (500 ml). This solution was stirred with a magnetic stirrer (400 rpm) overnight. The pH of the solution, measured using Mettler Toledo, the pH electrode of InLab®Expert Pro, at a temperature of 22 ° C, was 3.8.

In a PP glass (50 ml), 10.434 g of a sodium silicate solution (Riedel de Haen, pure, ≥10% NaOH, ≥27% SiO ₂ ) was mixed with 30.586 g of water. This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature for 5 minutes. This second solution was added to a PP vessel with a surfactant-containing mixture with mechanical stirring (200 rpm). The resulting solution was stirred (200 rpm) for 5 minutes at room temperature. After 3 minutes, the pH stabilized at a value of 4.6. The vessel was kept at room temperature for 24 hours and in an oven at 90 ° C for 24 hours. The resulting reaction mixture was cooled to room temperature and subjected to vacuum filtration (filter holding capacity of 20-25 μm). The powder on the filter was washed using 300 ml of water. The resulting powder was dried in a glass tank for 24 hours at 60 ° C. After synthesis, the powder was transferred to porcelain dishes and calcined in an oven in air at 550 ° С for 8 h with a heating rate of 1 ° С / min.

The X-ray scattering diagram of the SOK-12 material in the post-synthesis state and the calcined material is shown in FIG. This material is ordered at the meso level and has a two-dimensional hexagonal structure (space group p6m ). The unit cell parameter a is 11.874 nm.

The nitrogen adsorption isotherm of the calcined SOK-12 material is shown in Fig. 32 (above). Type IV isotherm is characteristic of mesoporous material. The strongly inclined parallel branches of the hysteresis loop indicate that the pore size is completely uniform. The size distribution of mesopores was determined based on the nitrogen adsorption isotherm using the BJH method (Fig. 32B, bottom). The pore size was about 10 nm. The results for nitrogen adsorption (Fig. 32) in combination with the X-ray scattering diagram (Fig. 31) show that this sample is an ordered mesoporous material. The morphology of this sample was investigated using SEM (Fig.33). This material is formed by interweaving fused particles.

Example 17

Synthesis of SOK-12 using a buffer at 90 ° C at a pH of the reaction mixture equal to 5.6

Pluronic P123 surfactant in an amount of 4.140 g was mixed with 107.574 g of water, 7.340 g of sodium citrate and 3.005 g of citric acid in a PP vessel (500 ml). This solution was stirred with a magnetic stirrer (400 rpm) overnight. The pH of the solution, measured using Mettler Toledo, the pH electrode of InLab®Expert Pro, at a temperature of 22 ° C, was 4.7.

In a PP beaker (50 ml), 10.405 g of sodium silicate solution (Riedel de Haen, pure, ≥10% NaOH, ≥27% SiO ₂ ) was mixed with 30.578 g of water. This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature for 5 minutes. This second solution was added to a PP vessel with a surfactant-containing mixture with mechanical stirring (200 rpm). The resulting solution was stirred (200 rpm) for 5 minutes at room temperature. After 3 minutes, the pH stabilized at a value of 5.6. The vessel was kept at room temperature for 24 hours. The resulting reaction mixture was subjected to vacuum filtration (filter retention 20-25 μm). The powder on the filter was washed using 300 ml of water. The resulting powder was dried in a glass tank for 24 hours at 60 ° C. After synthesis, the powder was transferred to porcelain dishes and calcined in an oven in air at 550 ° С for 8 h with a heating rate of 1 ° С / min.

The X-ray scattering diagram of the SOK-12 material in the post-synthesis state and the calcined material is shown in FIG. This material is ordered at the meso level and has a two-dimensional hexagonal structure (space group p6m ). The unit cell parameter a is 11.721 nm.

The nitrogen adsorption isotherm of the calcined SOK-12 material is shown in Fig. 35 (above). Type IV isotherm is characteristic of mesoporous material. The strongly inclined parallel branches of the hysteresis loop indicate that the pore size is completely uniform. The size distribution of mesopores was determined based on the nitrogen adsorption isotherm using the BJH method (Fig. 35, bottom). The pore size was about 11 nm. The results for nitrogen adsorption (Fig. 35) in combination with the X-ray scattering diagram (Fig. 34) show that this sample is an ordered mesoporous material.

Example 18

Synthesis of SOK-12 using a buffer at room temperature with a pH of 6.0 in the reaction mixture

Pluronic P123 surfactants in an amount of 4.069 g were mixed with 107.524 g of water, 7.993 g of sodium citrate and 2.461 g of citric acid in a PP vessel (500 ml). This solution was stirred with a magnetic stirrer (400 rpm) overnight. The pH of the solution, measured using Mettler Toledo, the pH electrode of InLab®Expert Pro, at a temperature of 22 ° C, was 4.9.

In a PP beaker (50 ml), 10.400 g of a sodium silicate solution (Riedel de Haen, pure, ≥10% NaOH, ≥27% SiO ₂ ) was mixed with 30,000 g of water. This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature for 5 minutes. This second solution was added to a PP vessel with a surfactant-containing mixture with mechanical stirring (200 rpm). The resulting solution was stirred (200 rpm) for 5 minutes at room temperature. After 3 minutes, the pH stabilized at 6.0. The vessel was kept at room temperature for 24 hours. The resulting reaction mixture was subjected to vacuum filtration (filter retention 20-25 μm). The powder on the filter was washed using 300 ml of water. The resulting powder was dried in a glass tank for 24 hours at 60 ° C. After synthesis, the powder was transferred to porcelain dishes and calcined in an oven in air at 550 ° С for 8 h with a heating rate of 1 ° С / min.

The nitrogen adsorption isotherm of the calcined SOK-12 material is shown in Fig. 36 (above). Type IV isotherm is characteristic of mesoporous material. The strongly inclined parallel branches of the hysteresis loop indicate that the pore size is completely uniform. The size distribution of mesopores was determined based on the nitrogen adsorption isotherm using the BJH method (Fig. 36, bottom). The pore size was about 5 nm.

Example 19

Synthesis of SOK-12 using a buffer at room temperature at a pH of the reaction mixture equal to 5.6

Pluronic P123 surfactant in an amount of 4.087 g was mixed with 107.625 g of water, 7.308 g of sodium citrate and 2.994 g of citric acid in a PP vessel (500 ml). This solution was stirred with a magnetic stirrer (400 rpm) overnight. The pH of the solution, measured using Mettler Toledo, the pH electrode of InLab®Expert Pro, at a temperature of 22 ° C, was 4.7.

In a PP glass (50 ml), 10.410 g of sodium silicate solution (Riedel de Haen, pure, ≥10% NaOH, ≥27% SiO ₂ ) was mixed with 30.040 g of water. This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature for 5 minutes. This second solution was added to a PP vessel with a surfactant-containing mixture with mechanical stirring (200 rpm). The resulting solution was stirred (200 rpm) for 5 minutes at room temperature. After 3 minutes, the pH stabilized at a value of 5.6. The vessel was kept at room temperature for 24 hours. The resulting reaction mixture was subjected to vacuum filtration (filter retention 20-25 μm). The powder on the filter was washed using 300 ml of water. The resulting powder was dried in a glass tank for 24 hours at 60 ° C. After synthesis, the powder was transferred to porcelain dishes and calcined in an oven in air at 550 ° С for 8 h with a heating rate of 1 ° С / min.

The X-ray scattering diagram of the material in the post-synthesis state and the calcined material is shown in Fig. 37. This material is ordered at the meso level and has a two-dimensional hexagonal structure (space group p6m ). The unit cell parameter a is 9.980 nm.

The nitrogen adsorption isotherm of the calcined SOK-12 material is shown in Fig. 38 (above). Type IV isotherm is characteristic of mesoporous material. The strongly inclined parallel branches of the hysteresis loop indicate that the pore size is completely uniform. The size distribution of mesopores was determined based on the nitrogen adsorption isotherm using the BJH method (Fig. 38, bottom). The pore size was about 5 nm. The results for nitrogen adsorption (Fig. 38) in combination with the X-ray scattering diagram (Fig. 37) show that this sample is an ordered mesoporous material.

Example 20

Synthesis of SOK-12 using a buffer at room temperature with a pH of 5.3

Pluronic P123 surfactant in an amount of 4.142 g was mixed with 107.817 g of water, 6.542 g of sodium citrate and 3.674 g of citric acid in a PP vessel (500 ml). This solution was stirred with a magnetic stirrer (400 rpm) overnight. The pH of the solution, measured using Mettler Toledo, the pH electrode of InLab®Expert Pro, at a temperature of 22 ° C, was 4.4.

In a PP glass (50 ml), 10.400 g of sodium silicate solution (Riedel de Haen, pure, ≥10% NaOH, ≥27% SiO ₂ ) was mixed with 30.10 g of water. This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature for 5 minutes. This second solution was added to a PP vessel with a surfactant-containing mixture with mechanical stirring (200 rpm). The resulting solution was stirred (200 rpm) for 5 minutes at room temperature. After 3 minutes, the pH stabilized at 5.3. The vessel was kept at room temperature for 24 hours. The resulting reaction mixture was subjected to vacuum filtration (filter retention 20-25 μm). The powder on the filter was washed using 300 ml of water. The resulting powder was dried in a glass tank for 24 hours at 60 ° C. After synthesis, the powder was transferred to porcelain dishes and calcined in an oven in air at 550 ° С for 8 h with a heating rate of 1 ° С / min.

The X-ray scattering diagram of the material in the post-synthesis state and the calcined material is shown in Fig. 39. This material is ordered at the meso level and has a two-dimensional hexagonal structure (space group p6m ). The unit cell parameter a is 9.871 nm.

The nitrogen adsorption isotherm of the calcined SOK-12 material is shown in Fig. 40 (above). Type IV isotherm is characteristic of mesoporous material. The strongly inclined parallel branches of the hysteresis loop indicate that the pore size is completely uniform. The size distribution of mesopores was determined based on the nitrogen adsorption isotherm using the BJH method (Fig. 40, bottom). The pore size was about 5 nm. The results for nitrogen adsorption (Fig. 40) in combination with the X-ray scattering diagram (Fig. 39) show that this sample is an ordered mesoporous material.

Example 21

Synthesis of SOK-12 using a buffer at room temperature with a pH of 5.1

Pluronic P123 surfactant in an amount of 4.149 g was mixed with 107.523 g of water, 5.771 g of sodium citrate and 4.086 g of citric acid in a PP vessel (500 ml). This solution was stirred with a magnetic stirrer (400 rpm) overnight. The pH of the solution, measured using Mettler Toledo, the pH electrode of InLab®Expert Pro, at a temperature of 22 ° C, was 4.2.

In a PP glass (50 ml), 10.409 g of sodium silicate solution (Riedel de Haen, pure, ≥10% NaOH, ≥27% SiO ₂ ) was mixed with 30.032 g of water. This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature for 5 minutes. This second solution was added to a PP vessel with a surfactant-containing mixture with mechanical stirring (200 rpm). The resulting solution was stirred (200 rpm) for 5 minutes at room temperature. After 3 minutes, the pH stabilized at 5.1. The vessel was kept at room temperature for 24 hours. The resulting reaction mixture was subjected to vacuum filtration (filter retention 20-25 μm). The powder on the filter was washed using 300 ml of water. The resulting powder was dried in a glass tank for 24 hours at 60 ° C. After synthesis, the powder was transferred to porcelain dishes and calcined in an oven in air at 550 ° С for 8 h with a heating rate of 1 ° С / min.

The X-ray scattering diagram of the material in the post-synthesis state and the calcined material is shown in FIG. 41. This material is ordered at the meso level and has a two-dimensional hexagonal structure (space group p6m ). The unit cell parameter a is 9.980 nm.

The nitrogen adsorption isotherm of the calcined SOK-12 material is shown in Fig. 42 (above). Type IV isotherm is characteristic of mesoporous material. The strongly inclined parallel branches of the hysteresis loop indicate that the pore size is completely uniform. The size distribution of mesopores was determined based on the nitrogen adsorption isotherm using the BJH method (Fig. 42, below). The pore size was about 5 nm. The results for nitrogen adsorption (Fig. 42) in combination with the X-ray scattering diagram (Fig. 43) show that this sample is an ordered mesoporous material. The morphology of this sample was investigated using SEM (Fig. 43). This material is formed by interweaving fused particles.

Example 22

Synthesis of SOK-12 using a buffer at room temperature with a pH of 4.6

Pluronic P123 surfactant in an amount of 4.129 g was mixed with 107.520 g of water, 5.771 g of sodium citrate and 4.086 g of citric acid in a PP vessel (500 ml). This solution was stirred with a magnetic stirrer (400 rpm) overnight. The pH of the solution, measured using Mettler Toledo, the pH electrode of InLab®Expert Pro, at a temperature of 22 ° C, was 3.8.

In a PP glass (50 ml), 10.409 g of sodium silicate solution (Riedel de Haen, pure, ≥10% NaOH, ≥27% SiO ₂ ) was mixed with 30.032 g of water. This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature for 5 minutes. This second solution was added to a PP vessel with a surfactant-containing mixture with mechanical stirring (200 rpm). The resulting solution was stirred (200 rpm) for 5 minutes at room temperature. After 3 minutes, the pH stabilized at a value of 4.6. The vessel was kept at room temperature for 24 hours. The resulting reaction mixture was subjected to vacuum filtration (filter retention 20-25 μm). The powder on the filter was washed using 300 ml of water. The resulting powder was dried in a glass tank for 24 hours at 60 ° C. After synthesis, the powder was transferred to porcelain dishes and calcined in an oven in air at 550 ° С for 8 h with a heating rate of 1 ° С / min.

The X-ray scattering diagram of the material in the post-synthesis state and the calcined material is shown in Fig. 44. This material is ordered at the meso level and has a two-dimensional hexagonal structure (space group p6m ). The unit cell parameter a is 9.765 nm.

The nitrogen adsorption isotherm of the calcined SOK-12 material is shown in Fig. 45 (above). Type IV isotherm is characteristic of mesoporous material. The strongly inclined parallel branches of the hysteresis loop indicate that the pore size is completely uniform. The size distribution of mesopores was determined based on the nitrogen adsorption isotherm using the BJH method (Fig. 45, bottom). The pore size was about 5 nm. The results for nitrogen adsorption (Fig. 45) in combination with the X-ray scattering diagram (Fig. 44) show that this sample is an ordered mesoporous material. The morphology of this sample was investigated using SEM (Fig.46). This material is formed by interweaving fused particles.

Example 23

Synthesis of SOK-12 using a buffer at room temperature with a pH of the reaction mixture equal to 3.5

Pluronic P123 surfactants in an amount of 4.074 g were mixed with 108.436 g of water, 0.751 g of sodium citrate and 7.695 g of citric acid in a PP vessel (500 ml). This solution was stirred with a magnetic stirrer (400 rpm) overnight. The pH of the solution, measured using Mettler Toledo, the pH electrode of InLab®Expert Pro, at a temperature of 22 ° C, was 3.5.

In a PP glass (50 ml), 10.414 g of sodium silicate solution (Riedel de Haen, pure, ≥10% NaOH, ≥27% SiO ₂ ) was mixed with 30,059 g of water. This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature for 5 minutes. This second solution was added to a PP vessel with a surfactant-containing mixture with mechanical stirring (200 rpm). The resulting solution was stirred (200 rpm) for 5 minutes at room temperature. After 3 minutes, the pH stabilized at a value of 3.5. The vessel was kept at room temperature for 24 hours. The resulting reaction mixture was subjected to vacuum filtration (filter retention 20-25 μm). The powder on the filter was washed using 300 ml of water. The resulting powder was dried in a glass tank for 24 hours at 60 ° C. After synthesis, the powder was transferred to porcelain dishes and calcined in an oven in air at 550 ° С for 8 h with a heating rate of 1 ° С / min.

The nitrogen adsorption isotherm of the calcined SOK-12 material is shown in Fig. 47 (above). Type IV isotherm is characteristic of mesoporous material. The strongly inclined parallel branches of the hysteresis loop indicate that the pore size is completely uniform. The size distribution of mesopores was determined based on the nitrogen adsorption isotherm using the BJH method (Fig. 47, below). The pore size was about 4.5 nm.

Example 24

Synthesis of SOK-12 with the formation of a buffer during synthesis at room temperature at a pH of the reaction mixture equal to 5.20 (without the addition of sodium citrate)

Pluronic P123 surfactants in an amount of 4.0 g were mixed with 107.50 g of water and 2.79 g of citric acid in a PP vessel (500 ml). This solution was stirred with a magnetic stirrer (400 rpm) overnight. The pH of the solution, measured using Mettler Toledo, the pH electrode of InLab®Expert Pro, at a temperature of 22 ° C, was 1.90.

In a PP glass (50 ml), 10.42 g of a sodium silicate solution (Merck, 8% Na ₂ O, 27% SiO ₂ ) was mixed with 30.01 g of water. This mixture was stirred using a magnetic stirrer (400 rpm) at room temperature for 5 minutes. This second solution was added to a PP vessel with a surfactant-containing mixture with mechanical stirring (200 rpm). The resulting solution was stirred (200 rpm) for 5 minutes at room temperature. After 0.5 min, the pH stabilized at 5.20. The vessel was kept at room temperature for 24 hours. The resulting reaction mixture was subjected to vacuum filtration (filter retention 20-25 μm). The powder on the filter was washed using 300 ml of water. The resulting powder was dried in a glass tank for 24 hours at 60 ° C. After synthesis, the powder was transferred to porcelain dishes and calcined in an oven in air at 550 ° С for 8 h with a heating rate of 1 ° С / min.

The nitrogen adsorption isotherm of the calcined SOK-12 material is shown in Fig. 48 (above). Type IV isotherm is characteristic of mesoporous material. The mesopore size distribution is narrow, with an average diameter of 4.3 nm (see Fig. 48, below).

Other embodiments of the present invention will become apparent to those skilled in the art after reading the present description or practicing the invention disclosed herein. It is understood that the descriptions and examples are for illustrative purposes only, and the scope and spirit of the invention are indicated in the attached claims.

Claims (13)

1. A method of obtaining an ordered mesoporous silicon oxide material having a two-dimensional hexagonal structure with substantially uniform pores of size 4 to 30 nm, in which the ratio of Q3 to Q4 for silicon atoms, obtained by ²⁹ Si NMR with rotation of the sample at a magic angle, is less than 0.65 (where Q3 is a silicon atom in a silicon oxide material bonded to three O-Si bridges and having one free hydroxyl group, and Q4 is a silicon atom in a silicon oxide bonded to four bridges O-Si and not having free hydroxyl groups), comprising the following stages:
preparing an aqueous solution 1 containing an alkali metal silicate solution;
preparing an aqueous solution 3 containing a poly (alkylene oxide) tribloxopolymer and a buffer with a pH of 5 to 7, said buffer comprising acidic and basic components;
adding the specified aqueous solution of alkali metal silicate to the specified aqueous solution 3 to obtain a pH of from 5 to 7 and ensuring the passage of the reaction between the components at a temperature of from 10 to 100 ° C;
filtering, drying and calcining the reaction product to obtain said ordered two-dimensional hexagonal structured mesoporous silica material with substantially uniform pore sizes. 2. The method according to claim 1, wherein said buffer with a pH of 5 to 7 is a sodium citrate / citric acid buffer or a Na ₂ HPO ₄ / NaH ₂ PO ₄ buffer. 3. The method according to claim 2, wherein said buffer sodium citrate / citric acid is characterized by a weight ratio of sodium citrate: citric acid from 0.10: 1 to 3.3: 1. 4. The method according to claim 1, characterized in that it is carried out at a pH of from 5.0 to 6.5. 5. The method according to any one of claims 1 to 4, in which said poly (alkylene oxide) tribloxopolymer is a tribloxopolymer of poly (ethylene oxide) -poly (alkylene oxide) - poly (ethylene oxide), in which the alkylene oxide component is propylene oxide and where the amount of ethylene oxide components in each block is at least 5, and the number of alkylene oxide components in the central block is at least 30. 6. The method according to any one of claims 1 to 4, wherein said poly (alkylene oxide) tribloxopolymer is
HO (CH ₂ CH ₂ O) ₂₀ (CH ₂ CH (CH ₃ ) O) ₇₀ (CH ₂ CH ₂ O) ₂₀ N. 7. The method according to claim 1, in which the ordered mesoporous silicon oxide material has a pore size of from 4 to 12 nm. 8. An ordered mesoporous silica material having a two-dimensional hexagonal structure with substantially uniform pores from 4 to 30 nm in size, in which the ratio of Q3 to Q4 for silicon atoms, obtained by ²⁹ Si NMR with the rotation of the sample at a magic angle, is less than 0 , 65. 9. The ordered mesoporous silicon oxide material of claim 8 having a two-dimensional hexagonal structure, characterized in that the ordered mesoporous silicon oxide material has a pore size of 4 to 12 nm. 10. A pharmaceutical composition comprising an ordered mesoporous silica material having a two-dimensional hexagonal structure with substantially uniform pores of 4 to 30 nm in size, in which the ratio of Q3 to Q4 for silicon atoms is obtained by ²⁹ Si NMR with a magic angle rotation of the sample is less than 0.65, and a biologically active drug. 11. The pharmaceutical composition of claim 10, in which the biologically active drug is a class II or class IV drug in accordance with BCS. 12. The pharmaceutical composition of claim 10, in which the biologically active preparation is selected from itraconazole, griseofulvin, griseoverdin, atovaquone, cyclosporine, digoxin, spironolactone, ibuprofen, danazole, carbamazopine, amoxicillin, tetracycline, metronidazole, cimetidine, nimetidine, ramenidine, nimetidine, rametididine, rametididin omeprazole, lansoprazole, rabeprazole, esomeprazole, pantoprozole, megaldrate, fluconazole, terconazole, ketoconazole, sulfasalazine, ritonavir, nevirapine, lopinavir, clofazinin, diloxanide furoate, glibenclamide, nefid pin, spironolactone and acyclovir. 13. The pharmaceutical composition of claim 10, in which the biologically active preparation is selected from acetazolamide, furosemide, tobramycin, cefuroxmin, allopurinol, dapsone, doxycycline, paracetamol, nalidixic acid, chlortiazide, tobramycin, cyclosporin, tacrolimus, paclaginaglandin, prostilaginandin2, prostilaginlandin2, prostilaglandin2, prostilaginlandin2, prostilaglandin2, prostilaginandin , prostaglandin E1, daunorubicin, epirubicin, idarubicin, zorubicin, mitoxantrone, amsacrine, vinblastine, vincristine, vindesine, dactiomycin, bleomycin, diminazene stearate, diminazene oleate, clindamycin, chlorine on, mefloquine, primaquine, vancomycin, vecuronium, pentamidine, metronidazole, nimorazole, tinidazole, atovaquone, buparvahona, nifurtimox, methotrexate and azathioprine.

Images