RU2580279C2 - Method of producing nano-sized powders of medicinal substances and device therefor - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: conversion of initial substance in gaseous phase and arrangement of directed flow of molecules of compounds is carried out in dynamic mode due to capture of substance vapours by heated inert carrier gas at molar ratio of carrier gas in range from 0.01 to 2.0 mol/(m²*s), degree of expansion of carrier gas flow (K) from values K_min=10 to K_max=3,060, distance between nozzle and flow condenser surface molecular generator in the range of 0.005-1.0 m. At that heating of carrier gas is performed in step-by-step first, to initial temperature corresponding to pressure of saturated vapour of the initial substance in the range of 10^-2-10⁴ Pa (T_n), then at output of carrier gas flow from container containing initial substance, to working temperature higher than initial on 5-300 °C (T_k), and condensation is carried out on surface with temperature in the range from -269 °C to T_max, where T_max is determined by nature of connection and corresponds to pressure of deposited connection saturated vapors not higher than 10^-4 Pa.

EFFECT: disclosed is a method of producing nano-sized powders of medicinal substances, which includes conversion of initial substance in gaseous phase, arrangement of directed flow of molecules of compounds and subsequent condensation substance in form of nano-particles on cooled surface, and device for its implementation.

6 cl, 103 ex, 2 tbl, 10 dwg

Description

Technical field

The invention relates to the field of nanomedicine, in particular, to a technology for producing highly dispersed powders of organic drug compounds with a given average particle size and small dispersion of particle size distribution, and can be used in the manufacture of highly effective dosage forms, cosmetics and the production of biologically active additives (BAA).

In recent years, the development of nanotechnology from materials science and electronics has shifted towards biology and medicine. Nanoparticles in medicine are used in several directions. One of them is the early diagnosis of diseases [U.H.F. Bunz, V.M. Rotello, "Gold nanoparticle - Fluorophor Complexes: Sensitive and Discerning" Noses "for Byosystems Sensing", Angev. Chem. Int. Ed., 2010, V. 49, Is. 19, pp. 3268-3279]. Other actively developing applications of nanoparticles in medicine are targeted drug delivery to diseased organs [E. Ruoslahti, S.N. Bhatia, M.J. Sailor, "Targeting of drugs and nanoparticles to tumors", J. Cell Biol., 2010, V. 188, No. 6, pp. 759-768], regenerative [S. Rannarda, A. Owenb, "Nanomedicine: Not case One size fits all", Nano Today, 2009, V. 4, pp. 382-384] and personal [K.K. Jain, Textbook of Personalized medicine, 2009, New York, Springer] medicine.

The development of nanomedicine has shown that the effectiveness of the action of drugs to a large extent depends on the particle size of the drug.

Many modern drugs are poorly soluble in water [C. Lipinski, Poor aqueous solubilty - an industry wide problem in drug discovery, Am. Pharm. Rev., 2002, v. 5, pp. 82-85], although one of the main properties that determine the effectiveness of the use of organic compounds as drugs is their solubility and dissolution rate, which greatly depends on the particle size. Therefore, the synthesis of nanoparticles of drugs is one of the main directions in the creation of new highly effective drugs. In addition, the transfer to the nanoscale state makes it possible to create dosage forms suitable for new routes of administration into the body: aerosol, transdermal, intravenous, intramuscular, etc. Nanoparticles, due to the specific interaction with some tissues, can enhance the selectivity of the drug, increase adsorption and bioavailability.

The use of nanoparticles in medicine is associated with a number of problems. First of all, this is the stabilization problem. Currently, stabilizers of various nature are used for these purposes, and the side effects associated with stabilizers are often ignored [L. Wu, J. Chang, W. Watanabe, "Physical and chemical stability of drug nanoparticles", Adv. Drug Del. Rev. 2011, V. 63, pp. 456-469]. He solved the problems of increasing the productivity of methods, reducing material costs and reducing the cost of nanoscale active pharmaceutical ingredients. None of the methods used makes it possible to obtain a final product with a broadly defined average particle size and small dispersion of their size distribution.

State of the art

Most of the methods developed in detail for the production of inorganic nanoparticles, for example, chemical reduction in solution, are not applicable for the production of nanoparticles of organic compounds, which are the basis of new drugs.

The most common technology for producing nanoparticles of organic compounds is dry and wet mechanical grinding [G.H. Ward, Pharm. Res., 1995, V. 12, p. 773] [M.T.H. Nutan, I.K. Reddy, "Pharmaceutical suspensions: from formulation development to Manufacturing", Springer, 2009, pp. 39-66]. This technology has been brought to industrial implementation and is actively used by companies for the preparation of micro suspensions of drug compounds. This technology, however, has a number of significant drawbacks:

- partial dissolution of the drug substance and its uncontrolled recrystallization upon drying are possible,

- the inevitable ingress of the material of the grinding device into the final product,

- the destruction of thermally unstable substances is possible due to heat generation during grinding,

- a wide dispersion of the distribution of particle sizes and the presence of a relatively large number of particles with sizes> 5 μm,

- substances with additional side effects are used to stabilize the suspensions.

To obtain nanoparticles of drug compounds also apply: methods of replacing the solvent and the controlled evaporation of drops [N-K. Chan, P.C.L. Kwok, "Production methods for nanodrug particles using the bottom-up approach", Advanced Drug Delivery Reviews, 2011, V. 63, pp. 406-416], laser ablation [Y. Tamaki, T. Asahi, H. Masuhara, App. Surf Sci, 2000, V. 168, p. 85], water-in-oil emulsions [E. Kwon, H. Oikawa, H. Kasai, H. Nakanishi, Cryst. Growth Des., 2007, V. 7, p. 600].

More and more actively, supercritical fluids are used to obtain nanoforms of medicinal substances [E. Reverchon, R. Adami, "Nanomaterials and supercritical fluids", J. of supercrit. fluids, 2006, V. 37, pp. 1-22]. However, since the range of organic substances readily soluble in supercritical carbon dioxide and other non-polar fluids is very limited, the use of the direct RESS (Rapid Expansion of Supercritical Solution) method for the preparation of nanoparticles of most drug compounds is impossible. The use of fluids based on polar compounds, for example water, for these purposes is impossible due to the high critical temperature (373 ° C for water), at which chemical decomposition of organic compounds is inevitable.

To obtain nanoparticles of sparingly soluble substances, variants are used in which the supercritical fluid acts as an anti-solvent - the SAS method (Supercritical Anti-Solvent). The starting drug compound is dissolved in an organic solvent that is fully or partially mixed with the supercritical fluid. The resulting solution is injected under controlled conditions through a spray nozzle into a container with supercritical fluid. As a result of a sharp decrease in solubility, the compound crystallizes with the formation of micro- and nanoparticles. A significant drawback of the method is the contamination of the final product with residual amounts of organic solvents used, and to reduce the size of the resulting nanoparticles, it is necessary to increase the concentration of the starting material in the organic solvent [I. De Marco, E. Reverchon, "Influence of pressure, temperature and concentration on the mechanism of particle precipitation in supercritical antisolvent micronization", J. of Supercrit. fluids, 2011, V. 58, pp. 295-302], which leads to an increase in the degree of contamination of the final product, a decrease in its output and an increase in the cost of producing a unit of production.

Known methods for producing micronized and nanoscale forms of organic drug compounds using the translation of the starting compound into the gas phase and its deposition on a cold surface. For example, from the patent [BC Komarov, “Method for the micronization of an organic drug substance,” RF Patent No. 2301058 of 07/19/2006], a method for micronization of an organic drug substance is known, according to which the initial substance is vaporized in a gaseous medium with a vacuum of 133-1.3 Pa and its deposition at a rate of 10 ¹⁴ -5 * 10 ¹⁷ molecules / (cm ² * s) on the deposition surface having a stable temperature of 175-100 ° C at an angle of 5-90 degrees relative to the direction of the deposition vector. The method provides a one-stage production of powders of organic medicinal substances with a narrow range of particle sizes in the micron and submicron size ranges. The fundamental limitation of the method is the impossibility of obtaining nanosized powders of drug substances — the average particle size, as follows from the description of the invention, exceeds 1 μm.

The closest in its technical essence to the proposed method for producing nanosized powders of drugs is known from the patent [G. B. Sergeev, BC Komarov, V.P. Shabatin, “A Method for the Preparation of Pharmaceutical Powders”, RF Patent No. 2195264 of July 5, 2001] a method according to which the initial pharmaceutical preparations are evaporated at a temperature of 160-220 ° C in a vacuum of 7 * 10 ^-4 ... 10 ^-5 Torr (10 ^-1 -1.33 * 10 ^-3 Pa) and condense on a surface cooled to -180 ... -196 ° C. The invention allows to obtain powders of drugs with a particle diameter of 0.008-0.010 microns. The disadvantage of the above method is that the particles of the obtained powder of the drug compound with a size of 0.008-0.018 μm are in a fused state and additional efforts are required to translate them into a free-dispersed state.

Disclosure of invention

The aim of the present invention is to obtain stable nanodispersed powders of organic drug compounds with a given average particle size in the range of 10-2000 nm and a small dispersion of the particle size distribution.

The goal is achieved by the proposed method, which includes the transfer of the starting substance into the gas phase, the organization of the directed flow of the compound molecules and the subsequent condensation of the substance in the form of nanoscale particles on the cooled surface, while the translation of the starting material into the gas phase and the organization of the directed flow of the compound molecules are carried out in dynamic mode the capture of vapor of the substance by the flow of a heated inert carrier gas at a given molar flow rate of the carrier gas in the range from 0.01 to 2.0 mol / (m ² * s), the degree of expansion of the carrier gas stream (K) from the values of K _min = 10 to K _max = 3060, the distance between the nozzle of the molecular flow generator and the surface of the condenser in the range of 0.005-1.0 m moreover, heating of the carrier gas is carried out stepwise - first to the initial temperature corresponding to the pressure of saturated vapors of the starting material in the range of 10 ^-2 -10 ⁴ Pa (T _n ), then after the flow of the carrier gas from the container containing the starting material to the operating temperature exceeding the initial by 5-300 ° C (T _to ), and the condensation is carried out on the surface temperature with a temperature in the range from -269 ° C to T _max , where T _max is determined by the nature of the compound and corresponds to the saturated vapor pressure of the precipitated compound not higher than 10 ^-4 Pa.

It is additionally possible to use a mixture of two or more gases, which differ in thermophysical and adsorption characteristics, as a carrier gas.

In addition, it is possible to use individual substances or mixtures of substances that, under the used experimental parameters, condense on a cooled surface, including those under standard conditions (temperature 25 ° C and atmospheric pressure 1.013 * 10 ⁵ Pa), in liquid or solid states, and to obtain the target product, additionally carry out the removal of condensed carriers by sublimation.

It is additionally possible to use a mixture of two or more substances as a carrier gas, including substances, one part of which condenses on the surface to be cooled under the used experimental parameters, and the other part does not condense, and to obtain the target product, the condensed carriers are additionally removed by sublimation.

To implement a method for producing nanosized powders of medicinal substances, a device is proposed that includes a carrier gas flow setting unit, a molecular flow generator unit with temperature programmers, a low-temperature condenser unit, a vacuum unit, wherein:

- the molecular flow generator block is made in a stepwise manner and includes a preliminary adjustable carrier gas flow heater, a container for containing the starting material, a final adjustable carrier gas heater, an output nozzle whose geometric shape ensures parallelism of the carrier gas stream,

- the design of the block of low-temperature condenser provides the ability to smoothly adjust the temperature of its surface,

- block setting the flow of carrier gas consists of two or more parallel lines for independently adjusting the flow rate of each component of the gas mixture used as carrier gas,

- a vacuum unit, which consists of vacuum pumps, vacuum valves, vacuum communications, vacuum sensors and a vacuum gauge, with the ability to measure vacuum and control the degree of expansion of the carrier gas stream (K).

It is additionally possible to use mesh sublimators in the molecular flow generator to place the starting material, in which a layer of the starting material is applied to a grid of conductive material - metal and mechanically press the resulting layer to the grid, and to transfer the substance into the gas phase, the grid is heated to a certain temperature by transmitting through a grid of adjustable electric current.

The prototype of the device is described in [Yu.N. Morozov, A.Yu. Utekhina, V.P. Shabatin, V.V. Chernyshev, G. B. Sergeev, "Cryosynthesis of nanoscale medicinal compounds", ZhRHO them. DI. Mendeleev, 2012, vol. LVI, No. 5-6, ss. 43-51] and in the patent: [B.C. Komarov, S.P. Mikhalev, Yu.N. Morozov, G.B. Sergeev, “Method for the sublimation of hardly volatile organic compounds”, RF Patent No. 2295511 from 12.30.2005]. The essence of their work is that a layer of organic material is applied to the grid of conductive material and mechanically presses the resulting layer to the grid. The layer is heated by passing electric current through the grid. As an electrically conductive material, a metal with a sufficiently high electrical resistance was used. Prevention of thermal decomposition of the organic drug compound is achieved by heating only a thin surface layer of the substance from which sublimation takes place.

The essence of the proposed method is that when approaching the surface to be cooled, the carrier gas stream with the vapor of the substance quickly cools, the gas phase is many times supersaturated with respect to the equilibrium vapor pressure of the compound and the system creates conditions for rapid gas-phase nucleation, and these conditions are due to high temperature gradient are constantly being recreated. In turn, the high nucleation rate depletes the vapor phase of the gas phase, which limits the further growth of crystallites. The resulting nuclei of a new phase grow due to the flow of molecules or clusters of matter from the gas phase. Growing particles can collide in the gas phase and aggregate. Further, the nanoparticles formed in the gas phase are captured by the cold surface and stabilized.

As the output parameters characterizing the efficiency of the process, we will use the following:

- the average particle size of the obtained substance (1), and the dispersion of the particle size distribution,

- the yield of the final product is the ratio of the mass of the obtained nanosized powder to the mass of the starting compound,

- reduced rate of removal mole substance in the gas phase, which characterizes the efficiency of the process ^{- (S -1 * dn / dt} , mol / s).

To ensure reproducibly high characteristics of the final product, the experimental modes of the process should, to the maximum extent, prevent heterogeneous nucleation and growth of particles on the surface of the condenser, for which the concentration of the substance in the carrier gas stream reaching the surface should be negligible. For this, in the initial stages of the process, conditions must be created that ensure a high nucleation rate, and the formed nuclei must have sufficient time for their growth.

The main experimental parameters, the change of which allows you to adjust the average size of the resulting particles and the maintenance of which provides a small dispersion of the particle size distribution, are:

- the initial temperature of the container containing the starting substance,

- operating the carrier gas stream temperature discharged from the nozzle molecular flow generator (T ₀₎ and the initial concentration of the substance in the gaseous phase (C ₀₎

- condenser temperature (T _c ),

- reduced molar flow rate of the carrier gas (S ^-1 * dN / dt),

- the distance between the nozzle of the molecular flow generator and the surface of the condenser (d),

- the degree of rarefaction of the carrier gas stream (K).

The heating of the starting material placed in the container is carried out by a stream of heated carrier gas passing through the container, the temperature of the carrier gas should ensure the transfer of the starting substance into the gas phase, the pressure of saturated vapor of the compound should be in the range 10 ^-2 -10 ⁴ Pa. Lowering the pressure of saturated vapors below 10 ^-2 Pa is impractical, since the rate of removal of the substance, and therefore, the productivity of the process will be unacceptably low. An increase in the pressure of saturated vapors above 10 ⁴ Pa is impractical, since the rate of removal of the substance will be too high and in practice this leads to the fact that all the starting substance will fly out of the container until the desired temperature is reached.

Saturated vapor pressure is an unambiguous function of temperature, this dependence is individual for each substance. For the vast majority of drugs, data on the experimental determination of these parameters are not available. The ACD / Labs program was used to evaluate the saturated vapor pressure and its temperature dependence for the used drug compounds. In this program, a theoretical estimate of the boiling point (T _k ) and the enthalpy of evaporation (ΔH _isp ) of a substance is performed. When calculating the pressure of saturated vapors at a certain temperature, the Kliperon-Clausewitz equation was used:

Here, P ₀ (T ₁ ), P ₀ (T ₂ ) is the saturated vapor pressure of the compound at temperatures T ₁ and T ₂ , ΔH _gas is the enthalpy of transition of the substance into the gas phase. When calculating the saturated vapor pressure in the range from the boiling point (according to the calculation data according to the ACD / Lab program) to the melting temperature, the vaporization enthalpy was used as ΔH _gas (according to the calculation data according to the ACD / Lab program): ΔH _gas = ΔH _isp . When calculating the saturated vapor pressure below the melting temperature, the sum of the enthalpies of evaporation and melting was used as ΔH _gas : ΔH _gas = ΔH _isp + ΔH _pl . The melting temperature and enthalpy were determined experimentally by differential scanning calorimetry. Calculated according to the ACD / Lab program and experimentally determined physicochemical data on the medicinal compounds used in the work are given in Table. one.

For experimental estimation of saturated vapor pressure, we used data on the rate of removal of the substance from the cartridge and its temperature dependence, obtained at installation No. 1 (Fig. 1), under the assumption that the carrier gas stream at the outlet of the container is saturated relative to the vapor of the starting compound, what can be shown using the Hertz-Knudsen equation [M. Knudsen, Die Gesetze der Molekularströmung und der inneren Reibungsströmung der Gase durch Röhren, Ann. Phys., 1909, V. 333, pp. 75-130], describing the sublimation-sublimation processes:

Here, P ₀ is the elastic vapor pressure of the substance at temperature T, P is the real vapor pressure of the substance in the gas phase, μ is the molecular weight of the substance, β is the sublimation-condensation coefficient (0≤β≤1), r _eff is the sublimation rate. Dimension r _eff - mol per square meter per second.

Considering the container with the starting material as a perfect mixing reactor, assuming that its temperature at all points is constant and equal to T, we can obtain the ratio:

Here, P ₀ - saturated vapor pressure material at a temperature T, P - elasticity substance vapor stream at the outlet of the molecular flow generator container, S _eff - total effective surface area sublimed substance, dV / dt = K * dv / dt - volume gas- carrier passing through the container per unit time, dv / dt is the carrier gas flow specified by the carrier gas flow setting unit, K is the degree of expansion of the carrier gas flow.

For example, for 5-androsten-3β, 17β-diol monohydrate (μ = 308.4 g / mol) at a temperature of 403 K, a container with the starting material of 0.1 g is loaded, the average particle size of the sublimated substance is 100 μm (S / m = 5.2 * 10 ^-2 m ² / g), β = 0.1, K = 1000, dV / dt = 0.9 / 3600 * 1000 * 403/293 = 0.34 l / s = 0.34 * 10 ^-3 m ³ / s. Here, 0.9 l / h is the volumetric flow rate of the carrier gas specified by the gas line (the flow rate corresponds to a temperature of 293 K and a pressure of 1.013 * 10 ⁵ Pa), 1000 is the degree of expansion of the flow of carrier gas, 403/293 is the temperature correction. Substituting the values in equation 2, we obtain:

Thus, the composition of the carrier gas stream leaving the nozzle of the molecular flow generator should be close to saturated with respect to the temperature of the container containing the starting material. To calculate the saturated vapor pressure, the equation was used:

откуда следует

whence follows

Here, dn / dt is the molar rate of transfer of the substance into the gas phase, С ₀ is the initial concentration of the substance in the gas phase.

The reheating of the carrier gas stream at the outlet of the container is necessary to prevent deposition of the substance from the gas phase at the outlet nozzle of the molecular flow generator facing the cold surface, as well as for transferring small particles or droplets of the initial compound captured by the carrier gas stream into the gas phase. In addition, an increase in the initial temperature of the carrier gas stream escaping from the nozzle leads to a shift of the effective nucleation zone closer to the cold surface to a region of higher temperature gradient, which serves as an additional factor in controlling the processes of gas-phase nucleation and nanoparticle growth. The temperature difference between the pre and reheated carrier gas stream must be between 5-300 ° C. Lowering the temperature difference below 5 ° C can lead to partial deposition of the substance from the gas phase at the output nozzle of the molecular flow generator and a decrease in the yield of the final product. Raising it above 300 ° C can lead to a suppression of nucleation processes in the gas phase and, as a result, to a change in the mechanism of nucleation and particle growth from gas-phase homogeneous to surface heterogeneous, which leads to irreproducibility of the experimental results. In addition, for a number of drugs, a significant increase in temperature can lead to partial decomposition of the compound.

To minimize the dispersion of the distribution of the final product by size, it is necessary to ensure the maximum possible identity of the physical conditions over the cross section of the carrier gas stream perpendicular to the direction of its movement. This is achieved due to the formation of a practically non-diverging jet of a carrier gas of a given geometry under vacuum conditions by the nozzle of a molecular flow generator. The small divergence of the carrier gas jet when moving from the nozzle of the molecular flow generator to the cooled surface is confirmed by the fact that, while maintaining the optimal experimental parameters, more than 95% of the substance deposited on the condenser was in the region of the molecular flow generator opposite the nozzle and strictly repeating its geometric configuration.

Provided that the carrier gas flow is non-divergent and the physical parameters are identical over the carrier gas cross section perpendicular to the direction of its movement, to calculate the stationary thermal field of the carrier gas flow in the working area, we can apply the one-dimensional differential heat equation that takes into account mass transfer:

- линейная скорость фронта газа-носителя, Cv, µ, ρ, λ - теплоемкость при постоянном объеме, молекулярная масса, плотность и теплопроводность газа-носителя, соответственно. Координата x направлена от сопла генератора молекулярного потока (x=0) к поверхности низкотемпературного конденсора (x=d).Here $$\overrightarrow{\nu }$$

is the linear velocity of the front of the carrier gas, Cv, µ, ρ, λ is the specific heat at constant volume, molecular weight, density and thermal conductivity of the carrier gas, respectively. The x coordinate is directed from the nozzle of the molecular flow generator (x = 0) to the surface of the low-temperature condenser (x = d).

It is assumed that the thermal conductivity of the carrier gas is a function of temperature only (λ ~ T ^0.5 ) and does not depend on its density.

поэтому:In stationary mode -

so:

(здесь dN/dt - мольный расход газа-носителя, задаваемый газовой магистралью, S - площадь сопла генератора молекулярного потока), дифференциальное уравнение теплопроводности можно записать в виде:Taking into account that the molar flow rate of the carrier gas can be written as:

(here dN / dt is the molar flow rate of the carrier gas specified by the gas line, S is the nozzle area of the molecular flow generator), the differential heat equation can be written in the form:

Here S ^-1 * dN / dt - given (a unit area of the nozzle generator molecular flow) the molar flow rate of the carrier gas. It follows from the form of the equation that it is this parameter that determines the stationary thermal field in the region between the nozzle of the molecular flow generator and the surface of the low-temperature condenser.

The given differential heat equation can be solved by imposing the following boundary conditions: T (0) = T ₀ , T (d) = T _C , where T ₀ is the initial temperature of the carrier gas at the outlet of the molecular flow generator nozzle, T (d) is the temperature surface of a low temperature condenser.

From the above it follows that the form of the solution of this differential heat equation is given by a set of the following parameters:

- reduced to the unit area of the nozzle of the molecular flow generator, the molar flow rate of the carrier gas (S ^-1 * dN / dt),

- the initial temperature of the carrier gas flying out of the nozzle of the molecular flow generator (T ₀ ),

- the temperature of the condenser (T _C ),

- the distance between the nozzle of the molecular flow generator and the condenser (d),

- thermophysical characteristics of the carrier gas (λ, Cv).

в сформированном стационарном температурном поле.The process of gas-phase nucleation and growth of nanoparticles in a jet of a carrier gas can be described as a result of a change in temperature when the front of the carrier gas moves with a certain linear velocity $$(\overrightarrow{\nu })$$

in the formed stationary temperature field.

The reduced molar flow rate of the carrier gas (S ^-1 * dN / dt) should be in the range from 0.01 to 2 mol / (m ² * s). Using the parameter S ^-1 * dN / dt below 0.01 mol / (m ² * s) is impractical due to the following reasons:

- the speed of departure of the substance from the molecular flow generator is proportional to S ^-1 * dN / dt and, therefore, the performance of the process falls below acceptable limits,

, приблизительно пропорциональной S^-1*dN/dt, приводит к понижению скорости зародышеобразования, вследствие уменьшения скорости снижения температуры, при одновременном увеличении времени эффективного роста частиц, что приводит к росту размеров частиц выше наноразмерного диапазона,- drop in the linear velocity of the front of the carrier gas, $$(\overrightarrow{\nu })$$

, approximately proportional to S ^-1 * dN / dt, leads to a decrease in the rate of nucleation, due to a decrease in the rate of decrease in temperature, while increasing the time of effective growth of particles, which leads to an increase in particle size above the nanoscale range,

- with a decrease in the parameter S ^-1 * dN / dt, the divergence of the carrier gas flow increases, which leads to an increase in the dispersion of the size distribution of the final product.

Using the parameter S ^-1 * dN / dt above 2 mol / (m ² * s) is impractical due to the following reasons:

- the yield of the final product falls below reasonable limits due to the fact that the linear velocity of the front of the carrier gas becomes so large that the formed particles acquire large kinetic energy and cannot be held on the surface of the condenser during the first collision. Visually, it looks like that a smaller part of the substance as a result of repeated collisions is deposited with a thin layer on all surfaces of the reactor, including not cooled, and the majority part flies into the vacuum system,

- an increase in the parameter S ^-1 * dN / dt leads to an increase in the linear velocity of the carrier gas stream, a decrease in the effective nucleation time, a decrease in the residence time of the growing particles in the gas phase, and, consequently, an increase in the concentration of compound molecules in the carrier gas stream reaching the condenser surface , which leads to additional heterogeneous surface nucleation and uncontrolled growth of particles fixed on the surface, which, in turn, leads to a deterioration in the output characteristics of the final product and an increase in their non-reproducibility.

The carrier gas stream is cooled by transferring heat from it to the cold surface of the condenser by the heat conduction mechanism, therefore, a decrease in the temperature of the condenser surface leads to a uniform increase in the temperature gradient in the region between the nozzle of the molecular flow generator and the surface of the condenser, and, consequently, to an increase in the effective speed nucleation and a decrease in the average particle size of the final product, an increase in the surface temperature of the condenser, respectively, leads to the opposite th result.

The minimum condenser temperature at which the experiments were carried out is 269 ° C, which corresponds to the boiling point of helium. Carrying out experiments at a lower temperature is practically not feasible due to technological difficulties. The upper limit of the condenser temperature is determined by the fundamental possibility of deposition of a substance on its surface. Experience shows that the maximum surface temperature should correspond to the saturated vapor pressure of the deposited compound not higher than 10 ^-4 Pa.

The time taken for the nucleation and growth of nanoparticles, the distribution of the temperature gradient over the stationary temperature field, and the divergence of the carrier gas flow, the carrier molecule and the nanoparticle of the drug compound depend on the distance between the nozzle of the molecular flow generator and the condenser (d). A decrease in the parameter d of less than 0.005 m is impractical due to the fact that the time of motion of the carrier gas flow front from the nozzle of the molecular flow generator to the condenser surface is insufficient for effective nucleation and particle growth, and therefore the carrier gas flow reaching the condenser surface is enriched molecules of the compound, which leads, firstly, to the rapid uncontrolled growth of particles on the surface and, secondly, to a decrease in the yield of the final product below acceptable limits.

An increase in the parameter d of more than 1.0 m is impractical due to the fact that on most of the path of the front of the carrier gas the temperature gradient is too small to ensure effective nucleation, and the long residence time of the formed particles in the path leads to the fact that the particle sizes reaching the surface of the condenser is out of the nanometer range. In addition, with an increase in the parameter d, the divergence of the carrier gas flow increases, which leads to an increase in the dispersion of the particle size distribution, as well as to a decrease in the yield of the final product.

внутри реактора является сложной экспериментальной задачей, которая, как показывает анализ доступной литературы, до сих пор не решена. Для косвенного определения $$(\overrightarrow{\nu })$$

проводили оценку степени расширения газа-носителя - K. Действительно, выражение для приведенного мольного расход газа-носителя можно представить в виде:Direct remote determination of the linear velocity of the front of the carrier gas $$(\overrightarrow{\nu })$$

inside the reactor is a complex experimental task, which, as analysis of the available literature shows, has not yet been solved. For an indirect definition $$(\overrightarrow{\nu })$$

we evaluated the degree of expansion of the carrier gas — K. Indeed, the expression for the reduced molar consumption of the carrier gas can be represented as:

здесь ρ - плотность потока газа-носителя, выходящего из сопла генератора молекулярного потока, ρ₀ - начальная плотность газа-носителя (приблизительно равная плотности при комнатной температуре 298 К и стандартном давлении 1,01325*10⁵ Па),

и

- соответствующие мольные объемы газа-носителя.whence follows:

here ρ is the density of the carrier gas flow leaving the nozzle of the molecular flow generator, ρ ₀ is the initial density of the carrier gas (approximately equal to the density at room temperature 298 K and standard pressure 1.01325 * 10 ⁵ Pa),

and

- the corresponding molar volumes of the carrier gas.

The carrier gas, when moving through the internal cavity of the molecular flow generator, overcomes a certain gas-dynamic resistance, heats up, as a result of which its expansion degree - K is constantly changing. To assess the effective value of K used the ratio:

K = T _n / 293 * P _at / P _eff , P _eff = 0.5 * (P _beg + P _con ),

here P _at - atmospheric pressure (1,013 * 10 ⁵ Pa), P _beginning and P _con - pressure at the inlet to the reactor and at the outlet from it into the vacuum system, respectively, T _n - temperature of the container with the starting material. The temperature of the carrier gas at the inlet and outlet of the reactor is close to room temperature.

The degree of expansion of the carrier gas flow is determined by the ratio of the carrier gas flow (dN / dt) specified by the gas line, the productivity of the used vacuum pump and the total gas-dynamic resistance of the internal cavity of the molecular flow generator and vacuum communications. In plants of the first type (Fig. 1), the carrier gas flow passes directly through the container, therefore, as the starting material leaves it, the gas-dynamic resistance of the molecular flow generator decreases, which leads to an increase in K during the experiment. In plants of the second type (Fig. 2), the carrier gas flow passes parallel to the surface of the grid sublimators containing the initial substance, therefore, the change in gas-dynamic resistance and K does not occur during the experiment.

For a mounted stationary vacuum system, with completely open communications, it is possible to achieve a certain maximum value of K - K _max . The use of controlled vacuum valves allows you to adjust the gas-dynamic resistance of the vacuum system and thereby change the value of K in the range from 1 to K _max . In this capacity, for example, multi-turn Teflon vacuum taps can be used.

When conducting experiments with non-condensable carrier gases, to create a vacuum, we used only fore-vacuum pumps (2НВР-5ДМ, 2НВР-60ДМ). During experiments with carrier gases condensing under experimental conditions, the overwhelming majority of them are deposited on the surface of a low-temperature condenser. Under these conditions, the value of K _max for open vacuum communications is almost completely determined by the flow rate of the carrier gas (dN / dt) and the gas-dynamic resistance of the contents of the molecular flow generator. The value of K _max thus little depends on the type and performance of the used vacuum pumps. The use of other types of vacuum pumps, in addition to the forevacuum, is advisable to ensure effective thermal insulation, for example, in experiments using a helium flow cryostat.

Conducting experiments with completely open vacuum communications in all cases led to the efficient synthesis of nanoforms of drugs with a high yield.

и, как следствие, к росту размеров получаемых частиц, поскольку эффективная скорость зародышеобразования падает, а предоставляемое для роста частиц время растет. Таким образом, изменение параметра К позволяет регулировать размер частиц. Уменьшение значения К в определенных пределах приводит также к росту выхода конечного продукта. Дальнейшее уменьшение К приводит к снижению выхода, поскольку растет степень рассеивания потока газа-носителя и вещество начинает осаждаться тонким слоем на всех поверхностях, включая и неохлаждаемые. Уменьшение параметра К ниже 10 нецелесообразно, поскольку выход конечного продукта падает до недопустимо малых значений.A decrease in K leads to a decrease in the linear velocity of the front of the carrier gas $$(\overrightarrow{\nu })$$

and, as a consequence, to an increase in the size of the resulting particles, since the effective nucleation rate decreases, and the time provided for particle growth increases. Thus, a change in the parameter K allows you to adjust the particle size. A decrease in the value of K within certain limits also leads to an increase in the yield of the final product. A further decrease in K leads to a decrease in the yield, since the degree of dispersion of the carrier gas flow increases and the substance begins to deposit a thin layer on all surfaces, including uncooled ones. A decrease in the parameter K below 10 is impractical, since the yield of the final product drops to unacceptably small values.

As carrier gases, it is possible to use any gases that are inert with respect to the drug compound transferred to the gas phase. The use of carrier gases with various thermophysical properties provides additional opportunities for the formation of an optimal stationary thermal field. An increase in the thermal conductivity of the carrier gas provides a more uniform distribution of the temperature gradient over the stationary temperature field of the carrier gas stream and thereby an increase in the temperature gradient in the initial sections of the motion of the carrier gas front, which leads to the expansion of the effective nucleation zone and its displacement to this region of its beginning. This, in turn, ceteris paribus, should lead to a decrease in the average size of the resulting nanoparticles.

A characteristic feature of the gaseous state is the practical independence of the thermal conductivity of gases on density in the pressure range, provided that the mean free path of the molecules is much less than the characteristic size of the system. From the molecular-kinetic theory, the following dependence of the mean free path on density follows:

here µ is the molecular mass, d is the effective gas kinetic diameter of the gas molecules, N _a is the Avogadro number, ρ is the density. The nitrogen density under standard conditions used in the work of gas pipelines (T = 293 K and P = 1.01325 * 10 ⁵ Pa) is:

The density of the carrier gas under the experimental conditions is: ρ = ρ ₀ / K. The typical value of K in experiments is of the order of 10 ³ ; therefore, the typical value of ρ is 1.165 * 10 ^-3 kg / mol. Substituting this value in formula 10, using for nitrogen the known value of the effective gas-kinetic diameter of the molecules 3 * 10 ^-9 m, we obtain:

This value significantly exceeds the characteristic size of the system ~ 10 ^-2 m.

The thermal conductivity of light gases - hydrogen and helium - significantly exceeds the thermal conductivity of heavier gases. For example, at 0 ° C at normal pressure, the thermal conductivities of hydrogen, helium, nitrogen, and argon are 0.1655, 0.1411, 0.0237, and 0.0165 W / (m * K), respectively. The temperature dependence of the thermal conductivity of these gases obeys the root law:

here: Cv is the specific heat at constant pressure, µ is the molar mass, T is the absolute temperature, d is the effective gas kinetic diameter of the molecules, R is the universal gas constant.

A comparison of the results obtained when using nitrogen and argon as a carrier gas qualitatively confirms this conclusion, but the results obtained using pure helium contradict it - the average particle sizes obtained under comparable conditions when using pure helium are several times higher than those when using nitrogen or argon. Apparently, the fact is that the carrier gas influences the nucleation processes. This fact is well known [M.P. Anisimov, S.D. Shandakov, I.N. Shaimordanov, A.S. Berezina, Yu.I. Polygalov, S.A. Tymoshenko “Determination of the surface energy of critical nuclei from nucleation experiments”, DI I.R. Mendeleev, 2001, t. XLV, No. 3, ss. 38-44]. Gases such as nitrogen or argon, unlike helium, are capable of adsorbing on the surface of the formed nuclei, thereby facilitating nucleation processes. It is known that the nucleation rate depends extremely strongly on the surface energy of the crystals formed. For example, in the book [V.M. Portnov, E.V. Chuprunov, “The Appearance and Growth of Crystals”, M., “Fizmatlit”, 2006, 328 pp.], The following formula is given for calculating the nucleation rate of cubic crystals:

Here I is the nucleation rate (units / (m ³ * s)), σ is the surface energy (J / m ² ), k is the Boltzmann constant, R is the universal gas constant, ρ is the density of the substance (kg / m ³ ), µ is the molecular weight of the substance (kg / mol), V _m = µ / ρ is the molar volume (m ³ / mol), P ₀ (T) is the saturated vapor pressure corresponding to the temperature T, P is the pressure, P / P ₀ ( T) is the supersaturation, d _k is the size (cube length) of the critical nucleus.

Therefore, even a slight decrease in surface energy can lead to a significant increase in the rate of nucleation and, consequently, to a decrease in the average size of the resulting nanoparticles.

Design features of the installation, designed and manufactured for the implementation of the method, allow the use of a mixture of two or more gases as a carrier. In view of the foregoing, the use of such mixtures opens up new possibilities for controlling the processes of nucleation and growth of nanoparticles. Indeed, taking light gas with high thermal conductivity, such as helium, as one component of the gas mixture, and gas with the desired adsorption characteristics, such as nitrogen, as the other, it is possible to widely regulate the size of the resulting particles. The thermal conductivity of the gas mixture is not an additive function of the composition and depends on temperature in a complex way, however, the monotonicity of these dependences makes it possible to easily control it.

The use of a mixture of helium and nitrogen as a carrier gas allows one to significantly reduce the average size of the formed nanoparticles and increase the yield of the final product in comparison with experiments in which pure nitrogen, and especially pure helium, was used for these purposes. Thus, the dependence of the average particle size on the composition of the helium-nitrogen gas mixture is extreme. Similar dependences should be observed for other gas mixtures, some components of which provide high thermal conductivity, while others have the necessary adsorption characteristics, for example, helium - argon, hydrogen - nitrogen, hydrogen - argon, etc.

In a certain range of experimental conditions used carrier gases can be deposited on the surface of the condenser. The possibility of deposition is determined primarily by the surface temperature of the condenser and the nature of the carrier gas. When using liquid nitrogen as a refrigerant, this ability is possessed, for example, by CO ₂ , N ₂ O, Xe, C ₃ H ₈ , C ₄ H ₁₀ and many other gases. Gases such as N ₂ , Ar, condense only when using liquid helium as a refrigerant. Condensed carriers can be removed by sublimation to obtain the desired product.

The use of condensable gases in the process is advisable due to the following circumstances:

- there is no reverse flow of the carrier gas, since it is almost completely deposited on the surface of the condenser, therefore, under these conditions, diffusion, turbomolecular and other pumps can be used to achieve a deep vacuum in the main part of the reactor. All this provides a greater degree of identity of physical conditions along the cross-section of the carrier gas stream perpendicular to the direction of its movement and thereby reducing the dispersion of the distribution of the final product by size,

- the nanoparticles falling on the surface of the condenser enter a “cell” formed by molecules of a frozen carrier gas, which ensures effective dissipation of their kinetic energy, and therefore the yield of the final product increases,

- nanoparticles fixed on the surface are quickly isolated by a layer of condensate from the residual molecular flow incident on the surface, which prevents the possibility of additional surface growth of particles,

- the molecular force field of the molecules of the carrier gas, which provides the possibility of condensation, can facilitate the nucleation processes and affect the processes of growth of nanoparticles,

- it becomes possible to implement a higher degree of expansion of the carrier gas stream (K).

Since at high values of the degree of expansion of the carrier gas stream (K), the pressure at the inlet of the reactor (P _beg ) in all experiments did not exceed 1000 Pa, and the operating temperatures, as a rule, exceed 100 ° C, substances can be used as the carrier gas which under normal conditions (temperature 25 ° C and pressure 1.013 * 10 ⁵ Pa) are liquids and solids, but possessing a fairly high saturated vapor pressure not only at room temperature, but also at temperatures corresponding to the solid phase of the compound.

These substances must be medically harmless. The high saturated vapor pressure over the solid phase of the compound at relatively low temperatures allows it to be completely separated from the drug compound by sublimation in vacuum. An example of a compound satisfying these requirements is water. The pressure of saturated water vapor is at 25, 0, -25 ° C, respectively 3167, 611 and 63 Pa.

The use of water as a carrier gas allows one to reduce the size of the resulting particles by almost an order of magnitude in comparison with experiments where nitrogen is used as a carrier gas. Among other things, the proposed method allows you to directly obtain aqueous dispersions of medicinal compounds suitable for medical use.

Water is a polar compound. As a non-polar compound, 2,2,3,3-tetramethylbutane or hexamethylethane (C ₈ H ₁₈ ) was used as a carrier gas. This compound is a branched, highly symmetric hydrocarbon having an abnormally high melting point (~ 100 ° C) and good volatility from the solid state (at 25, 0, -25 ° C) the saturated vapor pressure of the compound determined by the ACD / Labs program is 5800, 1700 , 390 Pa, respectively). The use of 2,2,3,3-tetramethylbutane as the carrier gas also makes it possible to reduce the size of the resulting particles, but to a lesser extent than water.

Other substances can also be used as carrier gases, which under normal conditions are liquids and solids, as well as mixtures thereof. By selecting such compounds, taking into account the specificity of a particular drug compound, it is possible to obtain nanosized powders with a given average particle size for specific medical applications.

In order to obtain even smaller particles, as well as to fine-tune their size, it is advisable to use as a carrier gas a mixture of two or more substances, including substances, one part of which condenses on the cooled surface under the experimental parameters used, and the other part does not condense. To obtain the desired product, the condensed portion of the carrier gas can be removed by sublimation. The condensing and non-condensing parts of the carrier gas can perform different functions, the directed combination of which is an effective tool to achieve the goals.

For example, in the He + H ₂ O mixture, the role of helium is to form a temperature field with a high gradient in the initial sections of the motion of the carrier gas flow front, and the role of water is to ensure effective nucleation in the gas phase, as well as the fixation and isolation of the formed nanoparticles on condenser surface. The use of a He + H ₂ O mixture as a carrier gas allows one to achieve the same results in terms of particle size reduction as the use of ultra-low temperatures.

In the N ₂ + H ₂ O system, the role of nitrogen is to dilute the gas mixture and reduce the effectiveness of the action of water. The use of this mixture with an equimolar ratio of the components made it possible to obtain the target product with an intermediate (compared with the case of pure components) average particle size. This gives reason to believe that the task of a certain composition of the gas mixture will allow you to smoothly control the average particle size of the target product. This is important for specific medical applications.

The use of systems containing large quantities of both condensing and non-condensing components as a carrier gas will make it possible to achieve even finer control over the properties of the final product.

As medicinal compounds, for the implementation of the method used: phenazepam, 5-androsten-3β-ol-17-one (DHEA), 5-androsten-3β, 17β-diol (A-diol), 5-androsten-3β monohydrate, 17β -diol (A-diol * H ₂ O), fluticasone propionate, piroxicam, gabapentin, d-camphor and metronidazole. Their structural formulas are given below. The medical purpose and properties of the used medicinal substances are given in Table. one.

Medicinal compounds form, as a rule, several solid-phase polymorphic modifications that differ in physicochemical properties. Therefore, the initial drug compounds and nanoforms obtained as a result of the application of the method were investigated by thermal analysis, IR spectroscopy, XRD, and chemical purity was determined by chromatographic methods.

It was recorded that in all cases the phase state of the starting drug compounds corresponded to the most thermodynamically stable crystalline modification. The resulting nanoforms of drug compounds resulting from the application of the method are crystalline substances with a crystallographic structure modified relative to the starting compounds. It was also recorded that the chemical purity of the obtained nanoscale forms is not worse, and in some cases better, in comparison with the starting materials.

To determine the particle sizes of the obtained nanoforms of medicinal compounds, we used: transmission electron microscopy (TEM), scanning electron microscopy (SEM), measurement of the effective surface by the amount of adsorbed argon (S-I (Ar)).

The invention is illustrated by the examples given in Table. 2.

Brief Description of the Drawings

Figure 1. Installation diagram for obtaining nanosized powders of drug compounds:

1 - sources of carrier gases (metal cylinders with gears),

2 - gas pipelines based on commercially available gas flow controllers (RRG-10),

3 - vacuum inputs of electric wires and thermocouples of the primary and final heaters of the carrier gas stream,

4 - seal

5 - primary heater flow of carrier gas,

6 - container with the starting substance,

7 - insulating insert,

8 - the final heater of the carrier gas stream,

9 - multi-channel PID temperature controller,

10 - nozzle of the molecular flow generator,

11 - layer of precipitated substance,

12 - removable part of the reactor,

13 is a flat vacuum section for joining removable and fixed parts of the reactor,

14 - refrigerant

15 - fixed part of the reactor,

16 - rotating part of the reactor,

17 - exit to the vacuum system,

18 - vacuum sensors (PMT-6-3M-1),

19 is a flat vacuum section for connecting the movable and stationary parts of the reactor,

20 - output teflon vacuum valve.

Figure 2. Installation diagram for producing nanosized powders of drug compounds using mesh sublimators:

1 - sources of carrier gases (metal cylinders with gears),

2 - gas pipelines based on commercially available gas flow controllers (RRG-10),

3 - vacuum inputs of electric wires and thermocouples of the primary and final heaters of the carrier gas stream,

4 - seal

5 - primary heater flow of carrier gas,

7 - insulating insert,

8 - the final heater of the carrier gas stream,

9 - multi-channel PID temperature controller,

10 - nozzle of the molecular flow generator,

11 - layer of precipitated substance,

12 - removable part of the reactor,

13 is a flat vacuum section for joining removable and fixed parts of the reactor,

14 - refrigerant

15 - fixed part of the reactor,

16 - the rotating part of the reactor is a low temperature condenser,

17 - exit to the vacuum system,

18 - vacuum sensors (PMT-6-3M-1),

19 is a flat vacuum section for connecting the movable and stationary parts of the reactor,

20 - output teflon vacuum valve.

21 - metal mesh

22 - layer of the parent drug compound,

23 - the lower rod of the mesh sublimator,

24 - spring

25 - the upper rod of the mesh sublimator,

26 - spring retainers mesh sublimator,

27 - latches mesh sublimator,

28 is a flat vacuum section for mounting the mesh sublimator compartment,

29 is a flat vacuum section for connecting the built-in and removable parts of the mesh sublimator compartment,

30 - vacuum inputs of electrical wires and thermocouples of a mesh sublimator,

31 - integrated part of the mesh sublimator compartment,

32 - removable part of the mesh sublimator compartment

Figure 3. A micrograph of a sample of 5-androsten-3β, 17β-diol monohydrate obtained using a scanning electron microscope.

Figure 4. A micrograph of a sample of 5-androsten-3β, 17β-diol monohydrate obtained by scanning electron microscope.

Figure 5. A histogram of the particle size distribution of 5-androsten-3β, 17β-diol monohydrate according to scanning electron microscope.

Figure 6. Micrograph of a sample of 5-androsten-3β, 17β-diol obtained by transmission electron microscope.

Figure 7. A histogram of the particle size distribution of 5-androsten-3β, 17β-diol monohydrate according to a transmission electron microscope.

Figure 8. A micrograph of a sample of the anhydrous form of 5-androsten-3β, 17β-diol obtained using a transmission electron microscope.

Figure 9. A micrograph of a sample of the anhydrous form of 5-androsten-3β, 17β-diol obtained using a transmission electron microscope.

Figure 10. A histogram of the particle size distribution of the anhydrous form of 5-androsten-3β, 17β-diol in size according to a transmission electron microscope.

The implementation of the invention in statics.

For the implementation of the invention designed device of two types. Their circuits are shown in FIG. 1 and FIG. 2. Devices differ in the method of placement of the starting substance and in the organization of the removal of its vapor.

The implementation of the invention in statics in devices of the first type.

In devices of the first type (Fig. 1), the carrier gas flows from the source (1) to the gas line (2). As a source of carrier gas, gas cylinders with the corresponding gas (N ₂ , CO ₂ , Ar, He, etc.) and vessels containing the corresponding liquid (H ₂ O) or solid (2,2,3,3-tetramethylbutane) are used ) The gas line serves to precisely control the flow of carrier gas. To implement the invention, serial gas pipelines manufactured by Eltochpribor (Zelenograd, Russia) are used. The gas main includes a pressure regulator, gas flow regulator (RRG-10), and an outlet valve. If gas mixtures are used as the carrier gas, an independent gas line is used for each component of the gas mixture. The source (sources) of carrier gas and the gas line (s) comprise a block for setting the carrier gas stream.

Upon exit from the gas line (s), the carrier gas stream enters the molecular flow generator block, which includes in series and hermetically connected to each other: the primary heater (5), the container with the starting substance (6), the heat insulating insert (7), the final heater (8) and nozzle (10).

The primary (5) and final (8) heaters, the container with the starting material (6) are cylindrical copper tubes, and heating elements made of nichrome wire are mounted on the outside of the heaters. The temperature of the heaters is controlled and maintained using thermocouples. Part of the copper tube of the primary heater (5) remains free and serves to rigidly fix the molecular flow generator to the removable part of the reactor. To this end, the space between the free outer wall of the copper tube and the inner wall of the removable part of the reactor is clogged with a sealant (4), which uses asbestos fiber. The function of the sealant is to ensure that the generated carrier gas stream completely passes only through the molecular flow generator. Thermocouple and power wires are drawn through the seal and then through the vacuum inlets (3) are brought out and connected to the corresponding inputs of the multi-channel PID temperature controller (9), which is used as a serial device TPM-148 manufactured by Aries, Russia. The removable part of the reactor (12) with the molecular flow generator connected to it is joined to the fixed part of the reactor (15) using a flat vacuum section (13). To adjust the distance between the nozzle of the molecular flow generator (10) and the surface of the condenser (16) - d, an insert of the desired length is installed between the removable and fixed parts of the reactor.

The carrier gas stream, heated to the initial temperature in the primary heater (5), passes through the container (6) directly through the layer of the starting compound, heats it, captures the vapors of the substance and carries them through the insulating insert (7) to the final heater and then through nozzle (10) into the working space. In order to prevent the starting material from being carried out of the container during the experiment, its entrance and exit are closed with a mesh of conductive material (metal), for example, stainless steel with openings of 40 μm.

The heat insulating insert (7) is a fluoroplastic or ceramic tube of cylindrical shape. Its role is to prevent overheating of the starting material. The length of the insulating insert depends on the temperature difference between the primary and final heaters. For example, with a difference of 300 ° C, the insert must be at least 5 cm long.

The nozzle of the molecular flow generator (10) is a copper cylindrical piece of complex configuration. The inner part of the nozzle, facing the low-temperature condenser (16), has a parabolic shape, which provides parallelism and the divergence of the carrier gas stream carrying the molecules of the starting material. A nichrome wire heating element was mounted on the outer surface of the nozzle.

When the carrier gas stream moves from the nozzle of the molecular flow generator (10) to the surface of the low-temperature condenser (16), it suddenly cools, leading to rapid homogeneous nucleation, the new-phase nuclei that grow due to the flow of molecules or clusters of matter from the gas phase. Growing particles can collide in the gas phase and aggregate. Then, nanoparticles formed in the gas phase are captured by the cold surface of the condenser and stabilized on it (11).

The low-temperature condenser (16) is a cylindrical vessel closed from below. In the upper part, the vessel is connected to a flat vacuum section (19). Due to this thin section, the low-temperature condenser (16) can rotate relative to the stationary part of the reactor (15). Due to the rotation of the low-temperature condenser (16), the deposited substance layer (11) is evenly distributed over its surface.

The required temperature of the condenser (16) is achieved due to the refrigerant poured inside it (14), which was used as liquid nitrogen in most experiments (Т _к = -196 ° C). To ensure the surface temperature of the condenser above -196 ° C, cooled liquids with low melting points are used - isopentane (T _PL = -160 ° C), methylcyclohexane (T _PL = -126.7 ° C). To maintain the stability of the surface temperature of the condenser during the experiment, cold nitrogen vapors are blown through the volume of the refrigerant liquid.

To ensure temperatures in the range of -269 ÷ -196 ° C, the molecular flow generator is connected to the inlet of a submersible helium cryostat, which was designed and manufactured at the OKTB of the Physical and Technical Institute of Low Temperatures, Kharkov.

To ensure rarefaction of the carrier gas stream, the reactor is connected to a vacuum system (17). To determine the level of vacuum in the system, vacuum sensors are used (18). To measure a vacuum level from 0.133 to 10 ⁴ Pa, a Meradat-VIT16T1 vacuum gauge is used with a PMT-6-3M-1 thermometer resistive pressure gauge and a PMT-2 gauge thermocouple converter, and a VIT-3 vacuum gauge with a converter for measuring higher vacuum manometric ionization PMI-2.

The degree of rarefaction of the carrier gas stream (K) is regulated by a Teflon vacuum valve (20) installed at the outlet of the reactor. To provide a more accurate determination of the degree of rarefaction of the carrier gas stream, vacuum sensors are placed both at the inlet and at the outlet of the reactor.

The implementation of the invention in statics in devices of the second type.

In devices of the second type (Fig. 2), the carrier gas flows from the source (1) to the gas line (2). As a source of carrier gas, gas cylinders with the corresponding gas (N ₂ , CO ₂ , Ar, He, etc.) and vessels containing the corresponding liquid (H ₂ O) or solid (2,2,3,3-tetramethylbutane) are used ) The gas line serves to precisely control the flow of carrier gas. To implement the invention, serial gas pipelines manufactured by Eltochpribor (Zelenograd, Russia) are used. The gas main includes an inlet valve, a pressure regulator, a gas flow regulator (RRG-10), and an outlet valve. If gas mixtures are used as the carrier gas, an independent gas line is used for each component of the gas mixture. The source (sources) of carrier gas and the gas line (s) comprise a block for setting the carrier gas stream.

Upon exit from the gas line (s), the carrier gas stream enters the molecular flow generator block, which includes in series and hermetically connected together: a primary heater (5), a mesh sublimator compartment, which consists of an integrated (31) and removable (32) parts , insulating insert (7), end heater (8) and nozzle (10).

The mesh sublimator is a cylindrical tube made of heat-resistant and non-conductive material (Teflon, glass or ceramic). At one end of the tube, a grid (21) is made of conductive material (metal), for example stainless steel, to which electric buses are connected. The grid is heated by passing an electric current through it. The use of busbars provides a uniform distribution of electric current density and thereby a uniform temperature distribution over the grid surface.

The starting material is placed in a uniform layer (22) between the metal mesh and the lower rod (23). The diameter of the rod and the inner diameter of the cylinder are exactly the same. A layer of the starting material (22) is compressed between the metal mesh (21) and the lower rod by means of a spring (24). The opposite edge of the spring rests on the upper rod (25), which is fixed in a cylindrical tube by means of special clamps (26). The design of the clips (26) allows you to adjust the compression force of the spring (24). The upper rod (25) is connected to the removable part of the mesh sublimator compartment (32) by means of clamps (27), which is rigidly fixed to it.

The removable (32) and integrated (31) parts of the mesh sublimator compartment are connected by means of a vacuum section (28). To isolate the removable part of the reactor from the external space, an insert with a flat vacuum section (29) is used, on which the vacuum inlets of power and thermocouple wires (30) are mounted. To adjust the temperature of the grid of the grid sublimator, these wires are connected to the inputs of the multi-channel temperature controller (9).

Mesh sublimators are designed to transfer thermally unstable substances into the gas phase. The essence of their action is that only a thin layer of the substance directly adjacent to the grid is exposed to heating in them. This layer is constantly updated due to the removal of substances from the surface layer into the gas phase.

The primary (5) and final (8) heaters are cylindrical copper tubes, and heating elements made of nichrome wire are mounted on the outside of the heaters. The temperature of the heaters is controlled and maintained using thermocouples. Part of the copper tube of the primary heater (5) remains free and serves to rigidly fix the molecular flow generator to the removable part of the reactor. To this end, the space between the free outer wall of the copper tube and the inner wall of the removable part of the reactor is clogged with a sealant (4), which uses asbestos fiber. The function of the sealant is to ensure that the generated carrier gas stream completely passes only through the molecular flow generator. Thermocouple and power wires are drawn through the seal and then through the vacuum inlets (3) are brought out and connected to the corresponding inputs of the multi-channel PID temperature controller (9), which is used as a serial device TPM-148 manufactured by Aries, Russia. The removable part of the reactor (12) with the molecular flow generator connected to it is joined to the fixed part of the reactor (15) using a flat vacuum section (13). To adjust the distance between the nozzle of the molecular flow generator (10) and the surface of the condenser (16) - d, an insert of the desired length is installed between the removable and fixed parts of the reactor.

The carrier gas stream heated to the initial temperature in the primary heater (5) passes through the space above the grid sublimator (31) and blows off vapor from the surface. The temperature of the carrier gas stream exiting the primary heater (5) is maintained equal to the grid temperature of the grid sublimator (21).

The heat insulating insert (7) is a fluoroplastic or ceramic tube of cylindrical shape. Its role is to prevent overheating of the starting material. The length of the insulating insert depends on the temperature difference between the primary and final heaters.

The nozzle of the molecular flow generator (10) is a copper cylindrical piece of complex configuration. The inner part of the nozzle, facing the low-temperature condenser (16), has a parabolic shape, which provides parallelism and the divergence of the carrier gas stream carrying the molecules of the starting material. A nichrome wire heating element was mounted on the outer surface of the nozzle.

When the carrier gas stream moves from the nozzle of the molecular flow generator (10) to the surface of the low-temperature condenser (16), it suddenly cools, leading to rapid homogeneous nucleation, the new-phase nuclei that grow due to the flow of molecules or clusters of matter from the gas phase. Growing particles can collide in the gas phase and aggregate. Then, nanoparticles formed in the gas phase are captured by the cold surface of the condenser and stabilized on it (11).

The low-temperature condenser (16) is a cylindrical vessel closed from below. In the upper part, the vessel is connected to a flat vacuum section (19). Due to this thin section, the low-temperature condenser (16) can rotate relative to the stationary part of the reactor (15). Due to the rotation of the low-temperature condenser (16), the deposited substance layer (11) is evenly distributed over its surface.

The required temperature of the condenser (16) is achieved due to the refrigerant (14) poured inside it, which is used in most experiments with liquid nitrogen (T _{k =} -196 ° C). To ensure the surface temperature of the condenser (16) above -196 ° C, cooled liquids with low melting points and relatively high boiling points are used, for example, isopentane (T _PL = -160.0 ° C), methylcyclohexane (T _PL = -126.7 ° C) and other substances. To maintain the stability of the surface temperature of the condenser during the experiment, cold nitrogen vapors are blown through the volume of the refrigerant liquid.

To ensure rarefaction of the carrier gas stream, the reactor is connected to a vacuum system (17). To determine the level of vacuum in the system, vacuum sensors are used (18). To measure the vacuum level from 0.3 to 10 ⁴ Pa, the PMT-6-3M-1 thermometer resistive pressure gauge is used, and the PMT-2 gauge thermocouple gauge and the PMI-2 gauge ionization gauge are used to measure a higher vacuum.

The degree of rarefaction of the carrier gas stream is regulated by a Teflon vacuum valve (20) installed at the outlet of the reactor. To provide a more accurate determination of the degree of rarefaction of the carrier gas stream, vacuum sensors are placed both at the inlet and at the outlet of the reactor.

The implementation of the invention in dynamics.

The implementation of the invention in dynamics in devices of the first type.

Example 1

Powder of 5-androsten-3β, 17β-diol monohydrate (A-diol * H ₂ O) was added to an empty container (6), weighing 15.4365 g, closed on one side with a metal mesh. The mass of the container with the substance was 15.9369 g. The mass of the added substance was 0.5004 g. The container was closed on the open side with a metal mesh and connected to the primary heater of the carrier gas stream (5), which was previously connected to the removable part of the reactor by means of a sealant (four). Next, a heat insulating insert (7) and a final carrier gas heater (8) with a nozzle (10) connected to it were connected in series to the container (6).

Power and thermocouple wires of the initial (5) and (8) final heaters were connected to the free ends emerging from the seal (4). The removable part of the reactor (12) with the mounted molecular flow generator connected to it was connected to the fixed part of the reactor (15) by means of a flat vacuum section (13). The length of the molecular flow generator section protruding from the removable part of the reactor was selected so that the distance between the nozzle of the molecular flow generator (10) and the low-temperature condenser (16) was 0.02 m.The removable part of the reactor was connected to the gas line (2), and it, in turn, with a metal cylinder containing nitrogen (1).

External power and thermocouple wires of the initial (5) and (8) final heaters were connected to the inputs of the multi-channel PID temperature controller TRM-148 (9). The assembled reactor was connected to the vacuum system (17) through a vacuum Teflon valve (20), it was completely opened, the reactor was pumped out to a vacuum of 2 Pa by a sensor (18) located at the outlet of the reactor (17). The gas flow regulator (RRG-10) of the gas line (2) was turned on, the carrier gas zero flow rate was installed on it, the outlet valve of the gas line was opened, and the reactor was again pumped out to a vacuum of 2 Pa.

The valves of the gas cylinder with nitrogen (1) and the inlet valve of the gas line (2) were opened, an overpressure of 0.5 atm was installed on the gas line pressure regulator. Gradually, with the help of RRG-10, the carrier gas flow rate was set at 900 ml per hour. The pressure, according to the vacuum sensor (18) located at the outlet of the reactor (17), was 144 Pa.

According to the passport data of the RRG-10 device, the gas flow rate, expressed in volume units, refers to a temperature of 293 K (20 ° C) and a pressure of 1.01325 * 10 ⁵ Pa. Translated to molar values, this is:

900 · 10 ^-6 * 1.01325 * 10 ⁵ * (8.31 * 293) ^-1 * (3600) ^-1 = 1.040 * 10 ^-5 mol / s.

The nozzle diameter of the molecular flow generator (10) is 1 cm. Thus, the molar flow rate of the carrier gas (nitrogen) reduced to the unit area of the nozzle was:

1.040 * 10 ^-5 * (3.1416 · 0.5 ² ) ^-1 * 10 ⁴ = 0.1325 mol / (m ² * s).

The carrier gas stream was passed through the reactor for 30 minutes in order to remove residual atmospheric gases. After that, liquid nitrogen (14) was poured into the low-temperature condenser (16). The pressure, according to the vacuum sensor (18) located at the outlet of the reactor (17), remained unchanged - 144 Pa.

Next, we turned on the multi-channel PID temperature controller TRM-148 (9), with it gradually gradually increased the temperature of the initial heater (5) to 110 ° C and the final heater (8) to 130 ° C, after which they were maintained at this level for four hours. During the experiment, liquid nitrogen was constantly poured into the low-temperature condenser (16), for uniform deposition of the substance (11), it was rotated through the angle π / 4 every thirty minutes. The pressure in the reactor was recorded using vacuum sensors (18) in two places - at the inlet to the removable part of the reactor (12) and at the outlet of the reactor (17). The pressure at the outlet of the reactor during the experiment remained unchanged at 144 Pa. The pressure at the inlet to the reactor during the experiment varied from 255 Pa at the beginning of the experiment to 190 Pa at its end. The decrease in pressure at the inlet to the reactor is associated with a decrease in gas-dynamic resistance during the motion of the carrier gas through the molecular flow generator as the initial substance is consumed.

According to the testimony of vacuum sensors, the degree of rarefaction of the carrier gas stream (K) was estimated. At the beginning of the experiment, it amounted to: 101325 * 2 / (144 + 255) * 383/293 = 664, and at the end: 101325 * 2 / (144 + 190) * 383/293 = 794. The average value of the degree of expansion was: (664 + 794) ≈730.

After four hours, the carrier gas heaters were turned off. When the temperature of the heaters reaches below 50 ° C, the carrier gas flow was reduced to zero, the reactor was disconnected from the gas line, the gas flow regulator RRG-10 was turned off, the gas line inlet cock and the valves of the metal cylinder with nitrogen were closed.

After that, the reactor was pumped out to 2 Pa according to the testimony of the vacuum sensor (18) located at the outlet of the reactor (17), the residual liquid nitrogen was removed from the low-temperature condenser, brought to room temperature, the reactor was disconnected from the vacuum system, it was opened and the precipitate collected surface of the condenser (16) substance (11). The mass of the collected substance was 0.2673 g.

The removable part of the reactor was disconnected (12), the molecular flow generator was disassembled, the container with the remaining material was taken out and weighed. The mass of the container was 15.5805 g. The container flew out: 15.9369-15.5805 = 0.3564 g. The yield of the cryochemically modified substance was 0.2673 / 0.3564 = 0.75 (75%). The performance of the process was:

(0.3564 / 308.45) * (3600 * 4) ^-1 * (π * 0.005 ² ) ^-1 = 1.02 * 10 ^-3 mol / (m ² * s).

According to IR Fourier spectroscopy, combined thermal analysis, x-ray phase analysis, the cryochemically modified substance is 5-androsten-3β, 17β-diol monohydrate.

Particle sizes of the preparation obtained as a result of the experiment were determined by transmission electron microscopy - TEM (Fig. 3, 4, 5) and scanning electron microscopy - SEM (Fig. 6, 7), the average particle size was also determined by measuring the effective surface by the amount of adsorbed nitrogen - SI (Ar).

Experiments No. 2-4, 22-25, 27, 40-45, 69-74, 83-89 were done similarly to experiment No. 1.

In experiments No. 26, 28-32, the reduced molar flow rate of the carrier gas was changed using the gas flow regulator of the gas line. All other actions were carried out similarly to experiment 1.

In experiment No. 55, helium was used as a carrier gas, which was supplied from a gas metal cylinder. To fine-tune the flow of carrier gas by the gas flow regulator of the gas line and to adjust the readings of the vacuum gauge, corrections for gas - He were introduced. All other actions were carried out similarly to experiment 1.

In experiment No. 56, argon was used as a carrier gas, which was supplied from a gas metal cylinder. To fine-tune the flow of carrier gas by the gas flow regulator of the gas line and to adjust the gauge readings, gas corrections, Ar, were introduced. All other actions were carried out similarly to experiment 1.

In experiments No. 60-62, the nitrogen – helium binary system was used as a carrier gas. An independent gas line equipped with a gas flow regulator was used to supply each carrier gas. For each gas in the corresponding gas flow controller, the desired coefficient was entered. As a source of gases used metal gas cylinders.

Helium and nitrogen have significantly different thermophysical characteristics. Since in this case the thermophysical characteristics of gas mixtures are complex nonadditive compositional properties, accurate calibration of the PMT-6-3M-1 gauge thermistor converter is practically impossible. Therefore, in experiments by analogy, we evaluated the degree of expansion of the carrier gas K. All other actions were carried out similarly to experiment 1.

In experiments No. 7-9, 32-34, 57-59, carbon dioxide was used as a carrier gas, which was supplied from a gas metal cylinder. To fine-tune the flow of carrier gas by the gas flow regulator of the gas main and to adjust the gauge readings, corrections for gas, СО _2, were introduced.

At a temperature of -196 ° C, carbon dioxide almost completely condenses on the surface of a low-temperature condenser together with the drug substance. When the condenser is heated under vacuum, carbon dioxide completely sublimates, releasing a pure drug substance. All other actions were carried out similarly to experiment 1.

In experiments No. 63-65, the double nitrogen system — carbon dioxide — was used as a carrier gas. An independent gas line equipped with a gas flow regulator was used to supply each carrier gas. For each gas in the corresponding gas flow controller, the desired coefficient was entered. As a source of gases used metal gas cylinders.

Nitrogen and carbon dioxide have various thermophysical characteristics. Since in this case the thermophysical characteristics of gas mixtures are complex nonadditive compositional properties, accurate calibration of the PMT-6-3M-1 gauge thermistor converter is practically impossible. Therefore, in experiments by analogy, we evaluated the degree of expansion of the carrier gas K.

At a temperature of -196 ° C, carbon dioxide condenses for the most part on the surface of a low-temperature condenser together with a drug substance. When the condenser is heated under vacuum, carbon dioxide completely sublimates, releasing a pure drug substance. All other actions were carried out similarly to experiment 1.

In experiments No. 66-68, a double helium – carbon dioxide system was used as a carrier gas. An independent gas line equipped with a gas flow regulator was used to supply each carrier gas. For each gas in the corresponding gas flow controller, the desired coefficient was entered. As a source of gases used metal gas cylinders.

Helium and carbon dioxide have significantly different thermophysical characteristics. Since in this case the thermophysical characteristics of gas mixtures are complex nonadditive compositional properties, accurate calibration of the PMT-6-3M-1 gauge thermistor converter is practically impossible. Therefore, in experiments by analogy, we evaluated the degree of expansion of the carrier gas K.

At a temperature of -196 ° C, carbon dioxide condenses for the most part on the surface of a low-temperature condenser together with a drug substance. When the condenser is heated under vacuum, carbon dioxide completely sublimates, releasing a pure drug substance. All other actions were carried out similarly to experiment 1.

In experiments No. 10-12, 36, water was used as a carrier gas, which was supplied from a round-bottom flask equipped with a vacuum valve. Before the experiment, the vessel with water was freed from the gases dissolved in it by a three-fold repetition of the cycle: freezing in liquid nitrogen - pumping out in vacuum - heating with melting - re-freezing. When working with water, an additional vacuum trap cooled with liquid nitrogen was installed between the reactor and the vacuum unit. The flow of water as a carrier gas was adjusted using the gas flow regulator of the gas line, which allows you to enter the "gas coefficient" based on the chemical formula of the substance. To more accurately set the water flow as a carrier gas, a preliminary calibration of the gas flow regulator was performed according to the weight loss of the vessel with water. Since the accurate calibration of the ПМТ-6-3М-1 gauge thermistor transducer in water is practically impossible, the degree of expansion of the carrier gas K was estimated by analogy.

At a temperature of -196 ° C, water almost completely condenses on the surface of a low-temperature condenser together with a drug substance. When the condenser is heated under vacuum, the water completely sublimates, releasing the pure drug substance. All other actions were carried out similarly to experiment 1.

In experiments No. 13-15, 37, the nitrogen-water binary system was used as a carrier gas. When working with a gas mixture containing water, an additional vacuum trap cooled with liquid nitrogen was installed between the reactor and the vacuum unit. An independent gas line equipped with a gas flow regulator was used to supply each carrier gas. For each gas in the corresponding gas flow controller, the desired coefficient was entered. For water, a coefficient previously determined in experiments with an individual substance was used.

As a source of nitrogen, a metal gas cylinder was used. A round bottom flask equipped with a vacuum valve was used as a water source. Water preparation and calibration of the gas flow regulator of the corresponding gas line was carried out in the same way as in experiments No. 10-12, 36.

Nitrogen and water have significantly different thermophysical characteristics. Since in this case the thermophysical characteristics of gas mixtures are complex nonadditive compositional properties, accurate calibration of the PMT-6-3M-1 gauge thermistor converter is practically impossible. Therefore, in experiments by analogy, we evaluated the degree of expansion of the carrier gas K.

At a temperature of -196 ° C, water almost completely condenses on the surface of a low-temperature condenser together with a drug substance. When the condenser is heated under vacuum, the water completely sublimates, releasing the pure drug substance. All other actions were carried out similarly to experiment 1.

In experiments No. 16-18, 38, a double helium-water system was used as a carrier gas. When working with a gas mixture containing water, an additional vacuum trap cooled with liquid nitrogen was installed between the reactor and the vacuum unit. An independent gas line equipped with a gas flow regulator was used to supply each carrier gas. For each gas in the corresponding gas flow controller, the desired coefficient was entered. For water, a coefficient previously determined in experiments with an individual substance was used. A metal gas cylinder was used as a source of helium. A round bottom flask equipped with a vacuum valve was used as a water source. Water preparation and calibration of the gas flow regulator of the corresponding gas line was carried out in the same way as in experiments No. 10-12, 36.

Helium and water have significantly different thermophysical characteristics. Since in this case the thermophysical characteristics of gas mixtures are complex nonadditive compositional properties, accurate calibration of the PMT-6-3M-1 gauge thermistor converter is practically impossible. Therefore, in experiments by analogy, we evaluated the degree of expansion of the carrier gas K.

At a temperature of -196 ° C, water almost completely condenses on the surface of a low-temperature condenser together with a drug substance. When the condenser is heated under vacuum, the water completely sublimates, releasing the pure drug substance. All other actions were carried out similarly to experiment 1.

In experiments No. 19-21, 39, 2,2,3,3-tetramethylbutane was used as the carrier gas. When working with this substance, an additional vacuum trap cooled with liquid nitrogen was installed between the reactor and the vacuum unit. A round bottom flask equipped with a vacuum valve was used as a substance source. Before the experiments, the vessel with 2,2,3,3-tetramethylbutane was released from the air by vacuum pumping of a substance previously frozen in liquid nitrogen.

The flow control of 2,2,3,3-tetramethylbutane as the carrier gas was carried out using the gas flow regulator of the gas line, which allows you to enter the "gas coefficient" based on the chemical formula of the substance. To more accurately set the flow of 2,2,3,3-tetramethylbutane as the carrier gas, a preliminary calibration of the gas flow regulator was performed based on the loss of mass of the vessel with the substance. Since the exact calibration of the PMT-6-3M-1 gauge thermistor converter with 2,2,3,3-tetramethylbutane is practically impossible, the degree of expansion of carrier gas K was estimated by analogy.

At a temperature of -196 ° C, 2,2,3,3-tetramethylbutane partially condenses on the surface of a low-temperature condenser together with the drug substance. When the condenser is heated under vacuum, 2,2,3,3-tetramethylbutane completely sublimates, releasing the pure drug substance. An additional nitrogen trap located between the reactor and the vacuum system was used to collect the freeze-dried 2,2,3,3-tetramethylbutane. All other actions were carried out similarly to experiment 1.

In experiments No. 5, 6, 53, 54 — a cooled plate of an immersion helium cryostat (OKTB FTINT, Kharkov) was used as a low-temperature condenser, to which a molecular flow generator was connected during the experiments. The design of the cryostat makes it possible to achieve temperatures in the range of -269 ÷ -196 ° C, which requires effective thermal insulation, which can be achieved only with almost complete condensation of the carrier gas on the cooled surface, which is achieved using nitrogen. Helium and other low boiling gases cannot be used under these conditions.

The procedure for operations with a helium cryostat was different from that described in Example 1. After connecting the molecular flow generator to the cryostat and installing electrical connections, the system was connected to a vacuum unit. Previously, to release from air, a carrier gas, nitrogen, was passed through the system for 30 minutes. After that, using a gas line, the carrier gas flow was set to zero, the reactor was pumped out until a stationary pressure was established (0.8 Pa). Liquid nitrogen was poured into the external cavity of the helium cryostat, after 60 minutes, using the overflow system, liquid helium was poured into the internal cavity. The temperature of the cryostat plate was set to the chosen value (-269 and -240 ° C), the carrier gas flow rate was raised to the required value, after which the heating of the initial and final heaters of the molecular flow generator was turned on. The time to maintain the operating temperature of the heaters was 60 minutes. Subsequently, the sequence of operations was the same as in the experiment described in example 1.

In experiments No. 46-49, the distance between the nozzle of the molecular flow generator (20) and the surface of the condenser (26) —d was changed, for which an insert of the required length was installed between the removable and fixed parts of the reactor. All other actions were carried out similarly to experiment 1.

Experiments No. 50-52, 90-92 were carried out at surface temperatures of the condenser above -196 ° C. To do this, methylcyclohexane (Т _mp = -126.7 ° C), previously cooled to the required temperature, was poured into a low-temperature condenser. The condenser temperature was maintained using thermocouples. To maintain the stability of the surface temperature of the condenser during the experiment, cold nitrogen vapors were blown through the volume of the refrigerant liquid and mixed. All other actions were carried out similarly to the experiment described in example 1.

Experiments No. 75-82 were performed with d-camphor. This substance has high volatility even at a temperature of 0 ° C; therefore, when pumping the reactor, an additional vacuum trap cooled with liquid nitrogen was installed between it and the vacuum system.

The preparation of the system for operation began with passing cold nitrogen through a container with the starting material under vacuum pumping conditions. To cool, the nitrogen stream from the gas line was passed through a tube cooled with liquid nitrogen. The temperature of the cartridge was reduced to -30 - -35 ° C, after which the carrier gas was turned off and the reactor was deeply pumped out, then the carrier gas - nitrogen was again turned on, and communications were freed from air residues. After that, the temperature of the heaters was raised to the set values and an experiment was conducted. The temperature of the condenser was increased to room temperature by maintaining the pressure in the reactor above 10 ⁴ Pa with the help of an outlet Teflon valve (20).

When determining the particle size of a substance by measuring the effective surface by the amount of adsorbed argon, special precautions were taken in the case of d-camphor, preventing the sample from heating above -30 ° C.

In experiments 93-95, a change was made in the degree of expansion of the carrier gas — K. For this, after carrying out preliminary operations, including mounting a molecular flow generator, attaching it to the fixed part of the reactor, preliminary pumping with a fully open Teflon vacuum tap (20), releasing paths of the system from air, liquid nitrogen was poured into a low-temperature condenser. Next, using a multi-turn outlet Teflon tap (20), using the readings of vacuum sensors (18) located at the inlet and outlet of the reactor, the selected value of the degree of expansion of the carrier gas K was established taking into account the temperature correction. After that, the temperature of the initial and final heaters of the molecular flow generator was raised to the required values. If necessary, adjustments were made to the degree of expansion of the carrier gas - K.

It should be noted that with a decrease in the degree of expansion of the carrier gas - K, the difference in the readings of the vacuum sensors (18) located at the inlet and outlet of the reactor decreases. The drift also decreases during the experiments, the testimony of the vacuum sensor (18) located at the inlet to the reactor. After the molecular flow heaters were turned off, the subsequent operations were carried out with the exhaust valve (20) fully open, similar to the experiment described in Example 1.

The implementation of the invention in dynamics in devices of the second type.

Example 96

A molecular flow generator was mounted, for which the initial heater (5), the integrated part of the mesh sublimator compartment (31), and the final heater (8) were connected in series. Power and thermocouple wires of the initial (5) and final (8) heaters were connected to the free ends emerging from the seal (4). The removable part of the reactor (12) with the molecular flow generator connected to it was connected to the fixed part of the reactor (15) by means of a flat vacuum section (13). The removable part of the reactor (12) was connected to the gas line (2), and it, in turn, with a metal cylinder containing nitrogen (1).

A metal grid (21) with bus wires connected to it was mounted on a cylindrical glass tube with an inner diameter of 20 mm. The mesh cell size was 40 μm, the living section was 32.7%. 0.5003 g of 5-androsten-3β, 17β-diol monohydrate powder (A-diol * H ₂ O) was added to the open part of the cylindrical tube. The substance was distributed evenly over the surface of the metal mesh in a uniform layer (22). The lower rod (23) was placed on top of the substance layer. A glass cylinder with a metal mesh (21), a layer of the starting substance (22) and the lower rod (23) was weighed on an analytical balance. Its mass was 23.7572 g.

A mesh sublimator was assembled, for which a spring (24) and an upper rod (25) were inserted into the open part of the cylindrical tube. The spring was squeezed by the upper rod and secured it inside the tube using clamps (26). The mesh sublimator was connected to the removable part of the compartment of the mesh sublimator (32) by fixing the rod of the upper rod (25) using latches (27). The removable part of the mesh sublimator compartment was connected to the built-in part by a flat vacuum section (28). The inner space of the removable part of the reactor (12) was isolated from the outer space by an insert connecting to the removable part of the reactor with a flat vacuum section (29). Before connecting, the wires of the grid sublimator were connected to the internal wires of the vacuum input of the power and thermocouple wires mounted on the insert (30).

External power and thermocouple wires of the grid sublimator, the initial (5) and final (8) carriers of the carrier gas flow were connected to the inputs of the multichannel PID temperature controller TRM-148 (9). The assembled reactor was connected to the vacuum system (17) through a vacuum Teflon valve (20), it was completely opened and the reactor was pumped out to a vacuum of 2 Pa using a sensor (18) located at the outlet of the reactor (17).

The gas flow regulator (RRG-10) of the gas line (2) was turned on, the carrier gas zero flow rate was installed on it, the outlet valve of the gas line was opened and the reactor was pumped out to a vacuum of 2 Pa again.

The valves of the gas cylinder with nitrogen (1) and the inlet valve of the gas line (2) were opened, an overpressure of 0.5 atm was installed on the gas line pressure regulator. Gradually, with the help of RRG-10, the carrier gas flow rate was set at 900 ml per hour. The pressure, according to the vacuum sensor (18) located at the outlet of the reactor (17), was 144 Pa.

According to the passport data of the RRG-10 device, the gas flow rate, expressed in volume units, refers to a temperature of 293 K (20 ° C) and a pressure of 1.01325 · 10 ⁵ Pa. Translated to molar values, this is:

900 · 10 ^-6 * 1.01325 * 10 ⁵ * (8.31 * 293) ^-1 * (3600) ^-1 = 1.040 * 10 ^-5 mol / s.

The nozzle diameter of the molecular flow generator (10) is 1 cm. Thus, the molar flow rate of the carrier gas (nitrogen) reduced to the unit area of the nozzle was:

1.040 * 10 ^-5 * (3.1416 · 0.5 ² ) ^-1 * 10 ⁴ = 0.1325 mol / (m ² * s).

The carrier gas stream was passed through the reactor for 30 minutes in order to remove residual atmospheric gases. After that, liquid nitrogen (14) was poured into the low-temperature condenser (16). The pressure, according to the vacuum sensor (18) located at the outlet of the reactor (17), remained unchanged - 144 Pa.

Then we turned on the multichannel PID temperature controller TRM-148, with it gradually gradually increased the temperature of the initial heater (5) to 120 ° C, the final heater (8) to 140 ° C, and then set the grid temperature of the grid sublimator (21) to 120 ° C. These temperatures were maintained for four hours. During the experiment, liquid nitrogen (14) was constantly poured into the low-temperature condenser (16), for uniform deposition of the substance, it was rotated through the angle π / 4 every thirty minutes. The pressure in the reactor was recorded using vacuum sensors (18) in two places - at the inlet to the removable part of the reactor (12) and at the outlet of the reactor (17). The pressure at the outlet of the reactor during the experiment remained unchanged at 144 Pa. The pressure at the inlet to the reactor during the experiment also did not change and amounted to 172 Pa.

According to the testimony of vacuum sensors, the degree of rarefaction of the carrier gas stream (K) was estimated. It amounted to: 101325 * 2 / (144 + 172) * 393/293 = 860.

After four hours, the carrier gas heaters were turned off. When the temperature of the heaters reaches below 50 ° C, the carrier gas flow was reduced to zero, the reactor was disconnected from the gas line (2), the gas flow regulator RRG-10 was turned off, the inlet valve of the gas line and the valves of the metal cylinder with nitrogen were closed (1).

After that, the reactor was pumped out to 2 Pa according to the testimony of the vacuum sensor (18) located at the outlet of the reactor (17), the residual liquid nitrogen was removed from the low-temperature condenser, brought to room temperature, the reactor was disconnected from the vacuum system using a vacuum valve (20), opened it and collected the substance deposited on the surface of the condenser (11). The mass of the collected substance was 0.3280 g.

The removable part of the reactor was disconnected (12), the molecular flow generator was disassembled, the mesh sublimator with the residues of the initial substance was removed, disassembled and weighed on an analytical balance. The mass of the glass cylinder with a metal mesh (21), a layer of the remaining substance (22) and the lower stem (23) was 23.3187 g.

From the container flew: 23.7572-23.3187 = 0.4315 g. The yield of cryochemically modified substance was: 0.3280 / 0.4315 = 0.76 (76%). The productivity of the process was: (0.4315 / 308.45) * (3600 * 4) ^-1 * (π * 0.005 ² ) ^-1 = 1.24 * 10 ^-3 mol / (m ² * s).

According to IR Fourier spectroscopy, combined thermal analysis, x-ray phase analysis, the cryochemically modified substance is 5-androsten-3β, 17β-diol monohydrate.

Particle sizes of the preparation obtained as a result of the experiment were determined by transmission and scanning electron microscopy, the average particle size was also determined by measuring the effective surface by the amount of adsorbed nitrogen.

Experiments No. 97, 100, 101 were carried out similarly to experiment No. 96.

In experiments No. 98, 99, 102, 103, carbon dioxide was used as a carrier gas, which was supplied from a metal gas cylinder. To fine-tune the flow of carrier gas by the gas flow regulator of the gas main and to adjust the gauge readings, corrections for gas, СО _2, were introduced.

At a temperature of -196 ° C, carbon dioxide almost completely condenses on the surface of a low-temperature condenser together with the drug substance. When the condenser is heated under vacuum, carbon dioxide completely sublimates, releasing a pure drug substance. All other actions were carried out similarly to experiment 96.

Claims (6)

1. The method of obtaining nanosized powders of medicinal substances, including the transfer of the starting substance into the gas phase, the organization of the directed flow of the molecules of the compound and the subsequent condensation of the substance in the form of nanosized particles on the cooled surface, characterized in that the conversion of the starting substance into the gas phase and the organization of the directed flow of the molecules of the compound carried out in a dynamic mode due to the capture of vapor by a stream of heated inert carrier gas at a given molar flow rate of the carrier gas ranging from 0.01 to 2.0 mol / (m ² * s), the expansion ratio of the carrier gas flow (C) from the values K _min = 10 and K _max = 3060, the distance between the nozzle and a flow generator molecular surface of the condenser in the range 0.005-1.0 m, and heating of the carrier gas is carried out stepwise - first to the initial temperature, corresponding to the saturated vapor pressure of the starting material in the range of 10 ^-2 -10 ⁴ Pa (T _n ), then after the carrier gas stream leaves the container, containing the starting substance, to a working temperature exceeding the initial by 5-300 ° C (T _to ), and condensation carried out on a surface with a temperature in the range from -269 ° C to T _max , where T _max is determined by the nature of the compound and corresponds to the saturated vapor pressure of the precipitated compound not higher than 10 ^-4 Pa. 2. The method according to claim 1, characterized in that as the carrier gas, a mixture of two or more gases is used, differing in thermal and adsorption characteristics. 3. The method according to claim 1 or 2, characterized in that as the carrier gas, individual substances or mixtures of substances are used that condense on the cooled surface under the experimental parameters used, including those under standard conditions (temperature 25 ° C and atmospheric pressure 1.013 * 10 ⁵ Pa), are in a liquid or solid state, and to obtain the target product, additionally remove the condensed carriers by sublimation. 4. The method of claim 1 or 2, characterized in that the carrier gas is a mixture of two or more substances, including substances, one part of which condenses on the surface to be cooled under the experimental parameters used, and the other part does not condense, and to obtain the target the product is additionally carried out the removal of condensed carriers by sublimation. 5. A device for implementing a method for producing nanosized powders of medicinal substances, including a unit for setting a carrier gas stream, a molecular flow generator unit with temperature programmers, a low-temperature condenser unit, a vacuum unit, characterized in that:
- the molecular flow generator block is made in a stepwise manner and includes a preliminary adjustable carrier gas flow heater, a container for containing the starting material, a final adjustable carrier gas heater, an output nozzle whose geometric shape ensures parallelism of the carrier gas stream,
- the design of the block of low-temperature condenser provides the ability to smoothly adjust the temperature of its surface,
- block setting the flow of carrier gas consists of two or more parallel lines for independently adjusting the flow rate of each component of the gas mixture used as carrier gas,
- a vacuum unit, which consists of vacuum pumps, vacuum valves, vacuum communications, vacuum sensors and a vacuum gauge, with the ability to measure vacuum and control the degree of expansion of the carrier gas stream (K). 6. A device for implementing the method for producing nanosized powders of medicinal substances according to claim 5, characterized in that in the molecular flow generator for placement of the starting substance, mesh sublimators are used, in which a layer of the starting substance is applied to the grid of a conductive material - metal - and mechanically presses the resulting layer to the grid, and to transfer the substance into the gas phase, the grid is heated to a certain temperature by passing an adjustable electric current through the grid.

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