MXPA01007522A - Sonic impinging jet crystallization apparatus and process - Google Patents

Abstract

A process is provided for the crystallization of pharmaceutical compounds by colliding a liquid jet stream (12) containing a pharmaceutical compound, such as Z-3-[1-(4-chlorophenyl)- 1(4-methylsulfonylphenyl) methylene]- dihydrofuran- 2-one or [R-(R*,R*)]- 4-[2, 4-Difluorophenyl- 2-hydroxy- 1-methyl-3- (1H-1,2,4- triazol- 1-yl)propyl -4-thiazolyl]benzonitrile, and a solvent, such as dimethyl sulfoxide, with another liquid jet stream (14) containing an anti-solvent, such as water, within a crystallizer equipped with a mechanical stirrer (18) and at a velocity sufficient to achieve micromixing of the liquid streams. The micromixing of the liquids is subjected to ultrasonic energy (24) to promote the production of small crystals, 95%of which have a diameter of less than one micron.

Description

APPARATUS AND PROCESS OF CRYSTALLIZATION BY CHOQUE DE CHOQUE SÓNICO FIELD OF THE INVENTION The present invention is directed to an apparatus and crystallization process for producing submicron sized particles.

BACKGROUND OF THE INVENTION The uniform production of very small particles is a challenge in the common processing of pharmaceutical substances. In general, smaller particles provide two very desirable pharmaceutical qualities, especially, greater bioavailability and a higher dissolution rate. In US Patent No. 5,314,506 a method is described that uses two shock jets to achieve uniform particles. However, the particles formed using the process of US Pat. No. 5,314,506 are only as small as 3 microns in size, and most of the crystals formed are in the range of 3-20 microns. The general process by which these small particles of the prior art are produced, comprises REF: 130115 two liquid shock jets placed inside a well-stirred flask to achieve a high-intensity mixing solution. At the point where the two jets hit one another, there is a very high level of supersaturation. As a result of this high supersaturation, crystallization occurs extremely rapidly, within the small mixing volume at the moment of the two liquids colliding. Since the new crystals are constantly nucleating at the moment of shock, a very large number of crystals are produced. As a result of the large number of crystals formed, the average size remains small, although not all crystals formed are small in size. The novel apparatus and process of this invention uses shock jets to achieve a high intensity micromixing in the crystallization process. The background of high intensity micromixing is discussed in detail in U.S. Patent No. 5,314,506, which is incorporated herein by reference.

BRIEF SUMMARY OF THE INVENTION The present invention relates to a novel apparatus and process for the crystallization of submicron sized particles, having an average size of less than 1 miera, and which provides final products in the form of crystals with large surface area, with stability and purity greatly improved. The purity, of particles of large surface area, produced by the process of the present invention, shows a superior crystal structure when compared to particles formed by more slow, standard crystallization grinding methods, known in the art, which use the Same quality and type of feed compounds. These improvements in the crystalline structure result in a decrease in the rate of decomposition and consequently a longer shelf life of the crystallized product or pharmaceutical composition. In addition, the small size of the pharmaceutical crystals formed using the apparatus of the present invention provides crystals that have a higher bioavailability and a higher dissolution rate. More specifically, the novel apparatus and process of this invention relate to the addition of a sonication probe together with the shock jets to achieve a high intensity micromixing of the fluids to achieve a homogeneous composition prior to the start of nucleation in a continuous crystallization process. The novel apparatus and process of the present invention provide direct crystallization of the large surface area of submicron sized particles of superior purity and stability.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic diagram showing a glass production system according to the present invention, which represents two shock jets 12, 14, a stirrer 18, and a sonication probe 22 placed in a flask 16. The figure 2 is an enlarged, sectional view of the region indicated by A in Figure 1, illustrating the substantially diametrically opposite placement of the shock jet tips and the position of the sonicator probe tip within the same plane as the tips of the shock jet.

DETAILED DESCRIPTION OF THE INVENTION The novel process of the present invention comprises the placement of a sonication probe or sonicator in a flask in which the liquid jets are placed to create shock fluid jet streams, to achieve a high intensity micromixing of fluids prior to nucleation in a crystallization process.

Two or more jets can be used to micromix two or more fluids, although it is preferable to use two jets to micromix the fluids. A liquid jet is generally a solvent saturated with product, and the other liquid jet usually contains an anti-solvent. Maximum micromixing is effected when the two shock jets are positioned substantially diametrically opposite each other, for example, at or about 180 ° from each other, and advantageously located at a distance of 10.16 mm (0.4 inches) apart from one another. As illustrated in Figure 1, the shock jet apparatus comprises a first jet 12 and a second jet 14 disposed substantially diametrically opposite each other in a flask 16, preferably a 1,000 ml flask, which is agitated by a 18 upper agitator. The flask 16 contains filler or liquid 13, which is advantageously the same material as that coming through the second jet 14 (anti-solvent). The first jet 12 and the second jet 14 are provided with jet orifices 12a and 14a respectively, which are substantially positioned 180 ° from each other at a distance of 10.16 mm (0.4 inches) from one another. As illustrated in Figure 1 and more clearly in Figure 2, the space 20 defined between the first and second jet orifices 12a and 14a defines a point of collision where the fluid of the first jet 12 and the fluid of the second jet 14 collide and are micromixed inside the flask 16. The liquids that are pumped through the first and second jets 12, 14 may be of different solvent composition. A fluid may be a solution of the pharmaceutical compound to be crystallized or a combination of solvents (generally referred to as * > feed solution ") and the other fluid may be a solvent or a combination of solvents capable of initiating the precipitation of the compound of the solution (generally referred to as "anti-solvent"), chosen for its relatively low solvation property with respect to that compound.Such solvents and anti-solvents may include but are not limited to water, methanol, ethanol, DMSO (sulfoxide dimethyl), IPA (isopropyl alcohol), DMF (dimethylformamide) or acetone Alternatively, the two fluids used in the process of the present invention can both be the solution of the pharmaceutical compound to be crystallized in the same suitable solvent or combination of solvents but each one at different temperature, and nucleation / precipitation can be initiated by instantaneous temperature reduction A small amount of suitable surfactant can be added to the fluids used in the process in order to decrease the agglomeration that can occur during the crystallization process by micromixing. Suitable surfactants that can be used include, but are not limited to, Tween 80, Cremophor A25, Cremophor EL, Pluronic F68, Pluronic F127, Brij 78, Klucel, Plasdone K90, Methocel E5, and PEG (molecular weight 20,000) and the like . , A sonication probe or sonicator 22, preferably a 20 kHz sonication probe having a probe tip 24 at one end, is placed in a flask 16. Advantageously, the probe tip 24 of a sonication probe 22 is submerin the crystallization suspension throughout the crystallization process. For maximum efficiency, the probe tip 24 of the sonicator 22 is advantageously located as close as possible to the shock point 20, as illustrated in Figure 2. Depending on various parameters of the process, such as temperature, viscosity of the liquid and percentage of solids, among others, the probe 24 can provide up to 500 volts of energy within the crystallization suspension. The addition of ultrasonic energy in the immediate vicinity of the shock jets 12, 14 produces a particle of average size of less than 1 miera. In accordance with the present invention, the liquid is pumped through the first and second jets 12, 14 at a minimum linear velocity of 12 meters / second. The liquid is comprised of one or more solvents which may include a combination of the pharmaceutical compound and a solvent and an anti-solvent, or simply a combination of solvents and an anti-solvent. When the two jet streams emerge and are between the tips 12a, 14a, of the orifice, a high intensity micromixing occurs and a crystallization suspension disk is formed. Depending on the solvents and compound or pharmaceutical compounds that are used, each jet stream is advantageously independently maintained at a temperature in the range of 0 to 100 ° C. To ensure good mixing in the fill 13, a stirring speed is maintained >300 RPM throughout the crystallization process using a mixer or agitator 18, such as a Rushton turbine or other high shear propeller, although the invention is not limited in the type of mixer or agitator used. As illustrated in Figure 1, the agitator 18 is placed inside the flask 16 with the first and second jets 12, 14 and a sonicator 22. The agitator 18 is advantageously placed close to the first and second jets 12, 14, but should not interfere with micromixing at point 20 of shock. Proper positioning of the probe tip 24 of the sonicizer 22 within the shock point 22 is essential. A comparison of two placed probe tips 24 has shown that placing the probe tip 24 lower than the jet holes 12a, 14a and therefore outside the shock point 20, produces slightly larger crystals than if the tip 24 The probe is placed at the same level as the impact holes 12a, 14, and therefore within the impact point 20. For example, in Experiments 44032-007-12 and 44032-006-18, referred to hereinafter in the Examples, the probe tip 24 was placed approximately 2.54 cm (1 inch) below the level of the holes 12a , 14th of jet. The resulting crystals of these batches have average sizes of 0.5164 and 0.5178 micras with 97.499% and 97.092% respectively, of the crystals less than 0.500 micras. In contrast, in Experiment 44032-006-27, where the probe tip 24 was placed at the same level as the jet holes 12a, 14a and within the shock point 20, crystals having an average diameter of 0.5129 were formed. microns, with 99.987% less than 0.5000 microns. Despite the number of jets used, the jet holes must be placed so that the emitted fluid currents will strike a high intensity. The shock of the fluids is essential to that immediate impact of high turbulence that is created. Thus, it is crucial that when the two jets are used, they should be positioned such that their holes are substantially diametrically opposed to one another to facilitate an adequate fluid shock. The following examples are provided for the purpose of illustrating the present invention and should not be construed as limiting the spirit and scope of the present invention. It should be understood that there may be other modalities that fall within the spirit and scope of the invention as defined by the claims appended hereto.

EXAMPLE 1 Crystallization of (Z-3- [1- (4-chlorophenyl) -1- (4-methylsulfonylphenyl) methylene] -dihydrofuran-2-one Experiment No. 422216-195 (1) 152.5 grams of the pharmaceutical compound were dissolved in 300 ml of DMSO at 65-75 ° C. It was cooled to 2 ° C, 1200 ml of water (RO quality, filtered). The rich solution and water were loaded into lined containers, with agitation. The respective temperatures of the contents were maintained by heating or cooling the liners. The process fluids were circulated through the feed lines to reach the temperatures and flow rates at rest. (2) 300 ml of water (RO quality, filtered) was charged to the shock vessel. The liner temperature was maintained at 2 ° C throughout the crystallization. (3) With the mechanical agitator and peak level sonication energy, the solution and water jets were shocked at a mass flow ratio of 1: 4. The flow rate of the rich solution was 0.18 kg / min through a 0.5 mm (0.020 inch) nozzle and the water flow rate was 0.72 kg / min through a 0.5 mm (0.40 inch) nozzle ). (4) After completing the crystallization, the product was filtered and then washed with approximately 100 ml of water (RO quality, filtered). The filter press cake was dried under vacuum at 70 ° C until dry. The yield is 89.4% excluding 24.19 grams recovered from the solution container and circulating lines. (5) The dried product was deagglomerated by passing it through an 80 mesh screen.

The API-sized aerocalibrator assays produce an average particle size of 0.54 microns with 95% of particles below 0.94 mica.

Summary of Experiments with BMS-225969 Experiment Size% < 0.5000 μm Percentile 95 Average No. 42216-157-20 0.5090 micras 99.011 0.5086 micras 42216-158 0.5124 98.097 0.5087 42216-195 0.5376 92.224 0.9373 44032-006-12 0.5164 97.499 0.5087 44032-006-18 0.5178 97.092 0.5088 44032-006-27 0.5129 97.987 0.5087 EXAMPLE 2 Crystallization of [R- (R *, R *)] -4- [2- (2,4-difluorophenyl) -2- hydroxy-l-methyl-3- (1H-1,2, -triazol-1-yl) ) propyl-4-thiazolyl] benzonitrile Experiment No. 42216-027 . (1) 50 grams of the pharmaceutical compound was dissolved in 150 ml of DMSO at 70 ° C and the solution was filtered well. 1000 ml of water (RO quality, filtered) was tempered at 20 ° C. The rich solution and water were loaded into lined containers, with agitation. The respective temperatures of the contents were maintained by heating or cooling the liners. The process fluids were circulated through the feed lines to reach the temperatures and flow rates at rest. (2) 300 ml of water (RO quality, filtered) were charged to the shock vessel. The liner temperature was maintained at 20 ° C throughout the crystallization. (3) With the mechanical stirrer and sonication energy at maximum level the solution and water jets were shocked at a mass flow ratio of 1: 4. The flow velocity of the solution is 0.18 kg / min through a 0.5 mm (0.020 inch) nozzle and the water flow rate is 0.72 kg / min through a 10.16 mm (0.40 inch) nozzle . (4) After completing the crystallization, the product was filtered and washed with 2 liters of water (quality RO, filtered). The filter press cake was dried under vacuum at 70 ° C until dry. (5) The dried product was deagglomerated by passing it through an 80 mesh screen. The API sized aerocalibrator tests produced an average particle size of 0.5324 micras with 95% particles below 0.8321 micras. Experiment Size % < 0.5000 μm Percentile 95 Average No. 42216-028-10 0.5324 microns 91.563 0.8321 microns It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (17)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A process for the crystallization of a pharmaceutical compound, characterized in that it comprises placing a tip of a sonication probe within an empty space defined between two or more jets of fluid placed such that the fluid jet streams, which emerge from said jets of fluid collide with an empty space creating a point of high turbulence at the point of impact of said fluid currents, each of the fluid currents has sufficient linear velocity to achieve high intensity micromixing of the solutions prior to nucleation, the sonication probe provides ultrasonic energy in the immediate vicinity of the shock fluid streams to effect nucleation and the direct production of small crystals, at least 95% of the crystals have a diameter of less than 1 miera.

2. The process according to claim 1, characterized in that two fluid streams are used, the first fluid jet is provided to carry a first fluid stream, the first fluid stream comprises a combination of DMSO and the pharmaceutical compound, the second fluid jet is provided to carry a second fluid stream, the second fluid stream comprises water.

3. The process according to claim 2, characterized in that the first and second fluid jets are substantially diametrically opposed from one another, such that the first and second fluid streams collide to achieve a high intensity impact. .

The process according to claim 1, characterized in that at least one of the fluid streams comprises a surfactant.

5. The process according to claim 1, characterized in that the pharmaceutical compound is selected from (Z-3- [1- (4-chlorophenyl) -1- (4-methylsulfonylphenyl) methylene] -dihydrofuran-2-one, and [R- (R *, R *)] -4- [2- [2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl-4-thiazolyl] benzonitrile.

The process according to claim 1, characterized in that each jet stream is independently at a temperature in a range of about 0 ° C to 100 ° C.

7. The process according to claim 1, characterized in that substantially all the crystals have a diameter equal to or less than 1 miera.

8. The process according to claim 1, characterized in that the empty space defined between the fluid jets is 10.16 mm (0.4 inches).

The process according to claim 1, characterized in that the tip of the sonication probe is placed in the empty space in the same plane with the fluid jets and at the same point where the fluid streams of the fluid jets established collide with one another.

The process according to claim 9, characterized in that the sonication probe provides energy in the range of between 30 and 150 volts.

11. A crystallization apparatus for producing submicron sized particles, characterized in that it comprises: a crystallizing flask two or more shock fluid jets, a stirrer, and a sonication probe having a probe tip, where the jets collide , the agitator and the sonication probe are placed inside the crystallization flask, the shock jets are placed substantially diametrically opposite each other, and the sonication probe placed next to the shock jets in such a way that the tip of the probe it is positioned in such a way that it is at the same level as the shock jets.

12. The crystallization apparatus according to claim 11, characterized in that the apparatus comprises two jets of shock fluid, the first fluid jet is provided to carry a first fluid stream., said first fluid stream comprises a combination of DMSO and a pharmaceutical compound, the second fluid jet is provided to carry a second fluid stream, said second fluid stream comprises water.

The crystallization apparatus according to claim 12, characterized in that the first and second fluid jets are substantially diametrically opposed to each other, so that the first and second fluid streams collide to achieve a high intensity impact.

14. The crystallization apparatus according to claim 11, characterized in that the agitator provides a stirring speed of more than 300 rpm, which is maintained through the crystallization process.

15. The crystallization apparatus according to claim 11, characterized in that the sonication probe is a 20 kHz probe. The crystallization apparatus according to claim 15, characterized in that the sonication probe provides energy to the first and second fluid streams within a flask in the range of 30 to 50 volts. The process according to claim 11, characterized in that the pharmaceutical compound is selected from (Z-3- [1- (4-chlorophenyl) -1- (4-methylsulfonylphenyl) methylene] -dihydrofuran-2-one, and [R- (R *, R *)] -4- [2- [2,4-difluorophenyl) -2-hydroxy-l-methyl-3- (1H-1, 2,4-triazol-1-yl) propyl-4-thiazolyl] benzonitrile.