Method for producing cocrystals by means of flash evaporation

Abstract

The invention relates to a method for producing a cocrystal of at least two compounds by means of instantaneous evaporation or flash evaporation, for example for the production of cocrystals in the fields of energetic materials, pharmaceutical compounds, phytopharmaceutical compounds, ferroelectric materials, non-linear response materials or bioelectronic materials.

Claims

1. A method for preparing a co-crystal of at least two compounds, comprising: providing at least two organic, mineral, or organometal compounds which may be bound each other by hydrogen bonds, ionic bonds, bonds of the stacking type (- stacking) or Van der Waals bonds; preparing a solution comprising at least one solvent and said at least two compounds to be co-crystalsized, wherein said preparation comprises dissolving said at least two compounds in said at least one solvent; heating the solution, under a pressure ranging from 3 to 300 bars, at a temperature above the boiling point of the solvent or at a temperature above the boiling point of the mixture of solvents; atomizing the solution in an atomization chamber with at least one dispersion device and under an angle ranging from 30 to 150 at a pressure ranging from 0.0001 to 2 bars; separating the solvent or solvents in gaseous form; and obtaining at least a co-crystal of said at least two compounds assembled on a molecular scale.

2. The method according to claim 1 wherein said at least two compounds are selected from the group consisting of: two to ten compounds; two compounds; two compounds in a molar ratio selected from the group consisting of , , , 1/1, 2/1, 3/1, and 4/1; three compounds; three compounds in a molar ratio X/Y/Z wherein X, Y and Z, either identical or different, represent 1, 2, 3 or 4; four compounds; four compounds in a molar ratio W/X/Y/Z wherein W, X, Y and Z, either identical or different, represent 1, 2, 3 or 4; five compounds; and five compounds in a molar ratio V/W/X/Y/Z wherein V, W, X, Y and Z, either identical or different, represent 1, 2, 3 or 4.

3. The method according to claim 1 wherein said co-crystal: is of a micrometric size; or has at least one dimension of less than 500 m; or has at least a dimension of less than 100 m; or is of submicrometric size; or has at least one dimension comprised between 100 nm and 1,000 nm; or is of a nanometric size; or has at least one dimension of less than 100 nm; or is of a size ranging from 2 to 100 nm; or is of a size ranging from 5 to 90 nm; or is of a size ranging from 10 to 80 nm; or is of a size ranging from 50 to 300 nm; or is of a size ranging from 50 to 200 nm; or is of a size ranging from 50 to 120 nm; or is of a size ranging from 10 to 100 nm; or is of a size ranging from 60 to 100 nm.

4. The method according to claim 1, comprising the preparation of one solution comprising said at least two compounds and at least two solvents or at least one solvent and at least one co-solvent or at least one solvent and at least one anti-solvent of one of the compounds.

5. The method according to claim 1, further comprising recovering said co-crystals using one or more devices selected from the group consisting of an electrostatic separator, a cyclone, and a cyclone comprising an electrostatic device.

6. The method according to claim 1 wherein said method is continuous or semi-continuous.

7. The method according to claim 1, wherein the solvent or of the mixture of solvents has a boiling point of less than 80 C. or less than 60 C.

8. The method according to claim 1, wherein heating of the solution is carried out under a pressure ranging from 5 to 150 bars or ranging from 10 to 60 bars.

9. The method according to claim 1, wherein heating of the solution is carried out under the pressure of an inert gas selected from the group consisting of nitrogen, argon, helium, neon, and xenon.

10. The method according to claim 1, wherein atomization of the solution is carried out at a pressure ranging from 0.001 to 2 bars.

11. The method according to claim 1, wherein the dispersion device is selected from the group consisting of a hollow cone nozzle, a solid cone nozzle, a flat jet nozzle, a rectilinear jet nozzle, a pneumatic atomizer, and combinations thereof.

12. The method according to claim 1, wherein the dispersion device is a hollow cone nozzle.

13. The method according to claim 1, wherein the compound is selected from the group consisting of energy compounds, pharmaceutical compounds, phytopharmaceutical compounds, coloring compounds, pigments, inks, paints, and metal oxides.

14. The method according to claim 1, wherein the solvent is selected from the group consisting of alkanes; alcohols; thiols; aldehydes; ketones; ethers; acid esters; amines; and any mixture thereof.

15. A method for preparing a co-crystal of at least two compounds comprising successively: providing at least two organic, mineral, or organometal compounds which may be bound each other by hydrogen bonds, ionic bonds, bonds of the stacking type (- stacking) or Van der Waals bonds; preparing at least two solutions each comprising at least one solvent and said at least one compound, wherein each preparation comprises dissolving said compound in said solvent; heating the solutions, under a pressure ranging from 3 to 300 bars, at a temperature above the boiling point of the solvent or at a temperature above the boiling point of the mixture of solvents; atomizing the solutions in a same atomization chamber with at least one dispersion device and under an angle ranging from 30 to 150 at a pressure ranging from 0.0001 to 2 bars; separating the solvents in a gaseous form; and obtaining at least a co-crystal of said at least two compounds assembled on a molecular scale.

16. The method according to claim 15 wherein said at least two compounds are selected from the group consisting of: two to ten compounds; two compounds; two compounds in a molar ratio selected from the group consisting of , , , 1/1, 2/1, 3/1, and 4/1; three compounds; three compounds in a molar ratio X/Y/Z wherein X, Y and Z, either identical or different, represent 1, 2, 3 or 4; four compounds; four compounds in a molar ratio W/X/Y/Z wherein W, X, Y and Z, either identical or different, represent 1, 2, 3 or 4; five compounds; and five compounds in a molar ratio V/W/X/Y/Z wherein V, W, X, Y and Z, either identical or different, represent 1, 2, 3 or 4.

17. A method according to claim 15 wherein said co-crystal: is of a micrometric size; or has at least one dimension of less than 500 m; or has at least a dimension of less than 100 m; or is of submicrometric size; or has at least one dimension comprised between 100 nm and 1,000 nm; or is of a nanometric size; or has at least one dimension of less than 100 nm; or is of a size ranging from 2 to 100 nm; or is of a size ranging from 5 to 90 nm; or is of a size ranging from 10 to 80 nm; or is of a size ranging from 50 to 300 nm; or is of a size ranging from 50 to 200 nm; or is of a size ranging from 50 to 120 nm; or is of a size ranging from 10 to 100 nm; or is of a size ranging from 60 to 100 nm.

18. The method according to claim 15, further comprising recovering said co-crystals of compounds using one or several devices selected from the group consisting of an electrostatic separator, a cyclone, and a cyclone comprising an electrostatic device.

19. The method according to claim 15 wherein said method is continuous or semi-continuous.

20. The method according to claim 15, wherein the solvent or of the mixture of solvents has a boiling point of less than 80 C. or less than 60 C.

21. The method according to claim 15, wherein heating of the solutions is carried out under a pressure ranging from 5 to 150 bars or ranging from 10 to 60 bars.

22. The method according to claim 15, wherein heating of the solutions is carried out under the pressure of an inert gas selected from the group consisting of nitrogen, argon, helium, neon, and xenon.

23. The method according to claim 15, wherein atomization of the solutions is carried out at a pressure ranging from 0.001 to 2 bars.

24. The method according to claim 15, wherein the dispersion device is selected from the group consisting of a hollow cone nozzle, a solid cone nozzle, a flat jet nozzle, a rectilinear jet nozzle, a pneumatic atomizer, and combinations thereof.

25. The method according to claim 15, wherein the dispersion device is a hollow cone nozzle.

26. The method according to claim 15, wherein the compound is selected from the group consisting of energy compounds, pharmaceutical compounds, phytopharmaceutical compounds, coloring compounds, pigments, inks, paints, and metal oxides.

27. The method according to claim 15, wherein the solvent is selected from the group consisting of alkanes; alcohols; thiols; aldehydes; ketones; ethers; acid esters; amines; and any mixture thereof.

Description

BRIEF DESCRIPTION OF THE DRAWING FIGURE

(1) FIG. 1 is a schematic view of an exemplary embodiment of a device for preparing co-crystals according to the claimed invention.

(2) An embodiment of a device according to the invention is illustrated by FIG. 1. The device consists of four main portions: a set of two tanks (1 and 1) for storing under a strong pressure, fluids containing the substance(s) to be crystallized, an atomization chamber comprising two integrated heated nozzles (3), two axial cyclones (5) mounted in parallel and allowing a semi-continuous production, a vacuum pump (6).

(3) In the tanks (1 and 1) of 5 L containing the solvent with the solute, an overpressure of compressed nitrogen is applied. In a first phase, this overpressure gives the possibility of displacing the oxygen and prevents evaporation of the solvent. The volume flow rate in this system is induced by the overpressure of compressed nitrogen.

(4) Filters (2 and 2) of 15 m repel all the soluble impurities into the initial solution.

(5) Two hollow cone nozzles (3), each equipped with an electric heating system, are installed side by side in the atomization chamber. The pressure, temperature and particle grain size parameters are controlled. The type of connection allows a fast change of the nozzles. The temperature of the electric heating is selected by the user and automatically regulated. The nozzles are oriented relatively to each other so that their jets interpenetrate each other.

(6) A tank or pan of solvent (4) is filled with the same solvent as the tank (1) and is used for rinsing the conduit and the nozzle after use. Also, the tank or pan of solvent (4) is filled with the same solvent as the tank (1).

(7) The axial cyclones (5) are installed in parallel. During the operation, only one cyclone is operating; the second cyclone is in a standby situation. By means of the centrifugal force, the solid particles are deposited inside the cyclone, the gas components leave the cyclone through a dip-tube. In order to empty the cyclone, the circuit leading towards the second cyclone is opened first, in order to then close the first circuit leading to the first cyclone.

(8) The vacuum pump (6) ensures a permanent flow in the installation and allows extraction of the solvent vapors of the system.

(9) The different aspects of the invention are illustrated by the following examples.

EXAMPLE 1: PREPARATION OF CO-CRYSTALS FROM A SOLUTION

(10) Co-crystals according to the invention were prepared from caffeine and oxalic acid or glutaric acid. Other co-crystals according to the invention were prepared from 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaiso-wurtzitane (CL-20) and from 2,4,6-trinitrotoluene (TNT) or 1,3,5,7-tetranitro-1,3,5,7-tetrazacyclooctane (HMX).

(11) Comparative examples were prepared from 2,4,6-trinitrotoluene (TNT) and from 1,3,5,7-tetranitro-1,3,5,7-tetrazacyclooctane (HMX).

(12) Co-crystals were prepared in a continuous way by means of the device described in the international patent application WO-2013/117671 according to a method for instantaneous evaporation of a solution of the compounds to be co-crystallized which is overheated and compressed. During the method, the solution undergoes a very strong drop in pressure upon being atomized by means of a hollow cone nozzle.

(13) The compounds to be co-crystallized are dissolved in a solvent for which the boiling point is generally less than 60 C. The compounds and the solvents as well as the reaction parameters applied are shown in table 1.

(14) The solution is compressed (40 to 60 bars) and then atomized in an atomization chamber by means of a heated hollow cone nozzle.

(15) The pressure in the atomization chamber (5 mbars) is obtained by means of a vacuum pump (35 m.sup.3/h).

(16) The sudden pressure drop causes displacement of the thermodynamic equilibrium making the overheated solution unstable. The solvent is instantaneously evaporated and co-crystals form.

(17) The strong drop in pressure is accompanied by a strong drop of the temperature which is lowered to about 200 C. giving the possibility of protecting the co-crystals formed.

(18) The continuous separation of the co-crystals formed is achieved by means of axial cyclones mounted in parallel.

(19) TABLE-US-00001 TABLE 1 Examples according to the invention comparative 1 2 3 4 1 2 Compounds caffeine/oxalic caffeine/glutaric TNT/CL20 HMX/CL20 TNT/HMX TNT/HMX acid acid Molar ratio 2/1 1/1 1/1 1/2 1/1 1/2 Solvent acetone acetone acetone acetone acetone acetone Amount (g) 3.5/0.8 4.8/3.2 2.4/1.2 2.7/8.0 3.4/4.5 2.2/5.7 Concentration of the 1.0 2.0 1.0 2.7 2.0 2.0 solution (% by mass) Volume of the solution 500 500 460 500 500 500 (mL) Temperature of the 160 160 170 170 160 160 nozzle ( C.) Temperature of the 80 80 50 80 80 80 cyclones ( C.) Diameter of the 60 60 60 60 60 60 cyclones (m) Pressure (bars) 40 40 40 50 50 40 Duration (mins) 68 56 60 44 41 62 Amount of co-crystals 2.77 5.13 1.59 4.93 0 0 (g) Amount of composites <LD <LD <LD <LD 5.35 4.85 (g) Yield (%) 64.7 64.1 43.8 46.1 67.8 60.6 <LD: less than the detection limit in XRD

(20) The products were characterized by AFM microscopy (Atomic Force Microscopy) at room temperature and at atmospheric pressure in order not to alter the co-crystals formed.

(21) The average grain size distribution of the particles was evaluated. The average size of the caffeine/glutaric acid co-crystals (1/1) is 111 nm. The average size of the HMX/CL20 co-crystals () is 59 nm.

(22) X-ray diffraction spectra were achieved for characterizing the co-crystals.

(23) The obtained spectra were compared with spectra of the used initial products. The spectra of the co-crystals are different from the spectra of the initial products for the co-crystals formed. They correspond to the spectra of the Cambridge structural data bank or to the spectra available in the literature.

(24) For the TNT/HMX composites (1/1 and ), the X-ray diffraction spectra always have the characteristic lines of TNT alone as well as certain lines of HMX. The absence of certain lines of HMX indicates that HMX is present in an amorphous form. The TNT/HMX composites (1/1 and ) are therefore mixtures of TNT crystals and of amorphous HMX.

(25) The heat properties of the co-crystals were studied by Differential Scanning calorimetry (DSC).

(26) The heating (5 C./min) of the TNT/CL20 co-crystals (1/1) shows the absence of the characteristic melting signal of pure TNT at 80 C., the TNT being within the lattice of the co-crystal with CL20. The characteristic melting temperature measured for the TNT/CL20 co-crystal (1/1) is of 135 C.

(27) After the first phase of the DSC analysis, the temperature is reduced and then again increased. During the second heating, the thermal signal of TNT is again present at 80 C. confirming the dissociation of the co-crystal under the action of heat during the first heating followed by crystallization of pure TNT.

(28) The heating of the caffeine/oxalic acid co-crystals (2/1) shows the presence of a thermal signal at 199 C. which is intermediate between the boiling points of both compounds pure caffeine and oxalic acid.

(29) Continuation of the heating leads to the dissociation of the co-crystal. Next, the cooling followed by the second heating shows the presence of the thermal signal of pure caffeine.

(30) For the TNT/HMX composites (1/1 and ) of the comparative examples, the thermal signal of TNT is present as soon as the first heating. Next, this signal is not modified during the second heating. The TNT/HMX composites (1/1 and ) are therefore simple physical mixtures of TNT and HMX particles. The TNT and HMX molecules cannot form intermolecular bonds for giving a co-crystal.

EXAMPLE 2: PREPARING CO-CRYSTALS FROM TWO SOLUTIONS

(31) Co-crystals according to the invention were prepared continuously from HMX and CL20 by means of the device of FIG. 1.

(32) 5 g of CL20 dried beforehand in 250 ml of acetone (CHROMASOLV HPLC quality 99.9% from Sigma Aldrich) are dissolved. Moreover, 1.35 g of HMX dried beforehand in 250 ml of acetone (CHROMASOLV HPLC quality 99.9% from Sigma Aldrich) are dissolved.

(33) Each solution is stirred and then sonicated with ultrasonic waves for 10 seconds. Next, each solution is poured in a tank of 1 L: the acetone solution with CL20 in the tank 1 and the acetone solution with HMX in the tank 1. To each tank 1 and 1 is connected in parallel a tank of technical acetone, indicated by the numbers 2 and 2. All the tanks are closed and pressurized at 40 bars by injecting pressurized nitrogen. The pressure is measured before the the nozzle and controlled all along the reaction.

(34) The vacuum is applied in the whole system by starting the pump. Once the vacuum is stabilized at about 0.1 mbar, one of the two cyclones is isolated from the system.

(35) The valves connecting the tanks 2 and 2 are open and the heating systems are started and regulated for the nozzles to 170 C. and for the cyclones to 80 C. Once the temperatures are stabilized, the cyclone used is isolated and the other isolated cyclone is open. Then the solutions of the tanks 1 and 1 are sprayed.

(36) After 20 minutes, the cyclones are again reversed and then the valves supplying the nozzles are switched onto the tanks 2 and 2 of technical acetone. The heating systems are then stopped.

(37) During the cooling, the co-crystal CL20-HMX is recovered in the cyclone having been used when the solutions 1 and 1 were sprayed. Once the temperatures are below 50 C., the inflows of technical acetone are cut and the vacuum pump is stopped after having allowed the pressure to rise again. Some CL20-HMX 2:1 co-crystal is thereby formed in situ at 2.67% by weight in solution by instantaneous evaporation or flash evaporation with multi-nozzles.

(38) The product was characterized by AFM microscopy (Atomic Force Microscopy) at room temperature and at atmospheric pressure in order not to alter the co-crystal formed.

(39) The average grain size distribution of the particles was evaluated. The average size of the CL20-HMX (2/1) co-crystal is 60 nm. An X-ray diffraction spectrum was produced for characterizing the co-crystal. The obtained spectrum was compared with spectra of the initial products used and with that of the co-crystal obtained in Example 1. The spectrum has all the characteristic lines of the CL20-HMX (2/1) co-crystal whether it is compared with the literature or with the CL20-HMX (2/1) co-crystal obtained in Example 1. The spectrum also has the characteristic lines of the beta phase of CL20.