KR20070058276A - A process for micronized iodopropynyl carbamate using supercritical fluid - Google Patents

Abstract

A method for preparing micronized iodopropynyl carbamate is provided to obtain iodopropynyl carbamate particles having improved skin absorption rate due to increased effective cross-sectional area by changing self-crystallization degree of the iodopropynyl carbamate through temperature and pressure change or flow change of a solution and supercritical CO2. The method comprises the steps of: (a) spray-contacting a mixture solvent prepared by dissolving iodopropynyl carbamate in an organic solvent such as methanol and ethanol with supercritical fluid to generate iodopropynyl carbamate particles, wherein the content of the organic solvent regarding the iodopropynyl carbamate is 0.0001-0.50 wt.%, and preferably 0.001-0.20 wt.%; and (b) introducing supercritical fluid such as supercritical CO2, supercritical N2O, supercritical CHF3, supercritical propane, supercritical ethylene and supercritical xenon, preferably supercritical CO2 into a reactor of the step(a) to remove the organic solvent used for the mixture solvent.

Description

A process for micronized iodopropynyl carbamate using supercritical fluid}

The present invention relates to a micronized urethral propynyl butyl carbamate formulation using a supercritical fluid process, wherein a mixed solution in which urethral propynyl butyl carbamate is dissolved in an organic solvent is sprayed into a supercritical fluid to be contacted with urethral propynyl butyl carbamate particles. Preparing ultrafine iodopropynyl butylcarbamate particles using a supercritical fluid process, comprising the steps of: generating a; and introducing a supercritical fluid into the particles to remove the organic solvent used in the mixed solution. It is about a method.

Despite many treatment requirements for skin diseases caused by microorganisms such as dandruff, acne, and athlete's foot, there are still insufficient satisfactory safe treatments. Many therapeutic agents have been used for the treatment of these diseases, but there are difficulties in treatment due to solubility problems in water or organic solvents and the limited absorbency to the skin and the side effects of residual solvents due to the use of organic solvents.

Supercritical fluids, on the other hand, are incompressible fluids at temperatures and pressures above the critical point, and exhibit unique characteristics not found in conventional organic solvents. That is, supercritical fluids have excellent physical properties such as high density close to liquid, low viscosity close to gas, high diffusion coefficient, and very low surface tension. Supercritical fluids can continuously vary in density from lean to near ideal gas to high density near liquid density, so that the fluid's equilibrium (solubility, entrainer effect) and transfer properties (viscosity, diffusion coefficient, and thermal conductivity). Fig. 2), molecular clustering (clustering) state can be adjusted. Therefore, by utilizing the ease of controlling the physical properties of the supercritical fluid, it is possible to obtain solvent characteristics comparable to various liquid solvents with one solvent. In particular, carbon dioxide has a low critical temperature of 31.1 degrees, making it suitable for thermally denatured substances such as drugs, non-toxic, non-flammable, inexpensive, and easy to recover and reuse. It is ideal for pharmaceutical applications because it has many advantages.

Using these unique properties of supercritical fluids, much research has recently been conducted in the fields of selective extraction of specific substances and analysis of substances through extraction. Also, supercritical fluids are used as solvents or anti-solvents. There is an active research on how to obtain recrystallized or fine particles by using).

Therefore, the present inventors have developed a method for producing urethopynyl butyl carbamate having increased skin absorption rate by increasing the effective area by miniaturizing the particle size of the urethral propynyl butyl carbamate in a supercritical fluid process using supercritical carbon dioxide. The effective urea increases by changing the crystallization of the drug itself through the change of temperature and pressure, which are operating variables of the supercritical fluid process, or the flow rate of the solution and the flow rate of supercritical carbon dioxide. The present invention is completed to obtain finer urethral propynyl butyl carbamate particles having a predicted skin absorption rate.

The present invention is to solve the problems of the prior art as described above, to provide a formulation that increases the skin absorption rate by miniaturizing the large particle size of the urethral propynyl butyl carbamate using a supercritical fluid process.

Hereinafter, the present invention will be described in detail.

The present invention provides a step of producing urethopynyl butyl carbamate particles by spraying and contacting a mixed solution in which urethral propynyl butyl carbamate is dissolved with an organic solvent in a supercritical fluid and introducing a supercritical fluid into the particles to the mixed solution. Provided is a method for preparing micronized iodopropynyl butylcarbamate using a supercritical fluid process comprising the step of removing the organic solvent used.

The basic principle of the manufacturing method is to dissolve the urethral propynyl butyl carbamate in a suitable amount of organic solvent, and then spray it through a nozzle to the reaction port equilibrated with supercritical carbon dioxide to obtain particles, and then flow supercritical carbon dioxide several times. The solvent is extracted and then carbon dioxide is removed to prepare micronized iodopropynyl butyl carbamate.

More specifically, in the present invention, a method for preparing micronized iodopropynyl butyl carbamate using a supercritical fluid process includes the steps of 1) dissolving iodopropynyl butyl carbamate in an organic solvent and preparing a mixture thereof; 2) spraying the mixed solution with a supercritical fluid by contacting the same to produce urethral propynyl butylcarbamate particles; 3) removing the organic solvent by introducing a separate supercritical fluid to the particles; 4) recovering the generated particles. The manufacturing method will be described in detail for each step as follows.

1) Preparation of mixed solution of urethral propynyl butyl carbamate for spraying

The organic solvent used in step 1) is methanol or ethanol, but in the present invention, ethanol having less toxicity to human body is used.

As the organic solvent to be used, it is preferable to use 0.0001 to 0.50 parts by weight of urido propynyl butyl carbamate, and more preferably 0.001 to 0.20 parts by weight. Below 0.0001 parts by weight, the amount of particles obtainable is too small, and above 0.50 parts by weight of urine propynyl butyl carbamate does not dissolve in the organic solvent.

2) Generation of particles through the portion of the mixed solution in the supercritical fluid

Supercritical fluids that can be used in step 2) include supercritical carbon dioxide, supercritical dinitrogen monoxide, supercritical methane trifluoride, supercritical propane, supercritical ethylene or supercritical xenon, and the like in the present invention. Supercritical carbon dioxide was used.

The carbon dioxide is injected into the reaction port so that the temperature and pressure of the reaction port made of stainless steel are above the critical point of carbon dioxide of 31.1 degrees and 73.8 bar, and are pressurized and warmed to maintain the supercritical state. Wait for equilibrium. It is preferable to use a syringe pump to maintain a constant pressure and pressurize the carbon dioxide to know the precise injection amount, and to use a circulating thermostat or a thermostat to maintain a constant temperature. When the reaction port is equilibrated to the supercritical state, a mixed solution of the urethral propynyl butyl carbamate and the additive prepared in Step 1) is injected into the reaction port at a constant speed using a small liquid pump capable of precise speed control. . At this time, in order to prevent clogging of the nozzle, it is preferable to inject a small amount of empty solvent, for example, 3-4 ml, into the mixed solution.The higher the amount of the cosolvent to be injected, the more supercritical thereafter. The cleaning time by the fluid will be longer. The injected mixed solution is sprayed through the nozzle, and the organic solvent in the injected mixed solution is rapidly mixed into the supercritical carbon dioxide to generate particles. A separate supercritical fluid may be injected to prevent the mixture from being saturated at the same time as the injection of the mixed solution.

3) Removal of organic solvent using supercritical fluid

After spraying the mixed solution, a particle washing process is required to introduce a supercritical fluid to remove the organic solvent in the resulting particles. In the above process, the supercritical fluid is injected into the reactor at a constant rate while being discharged through the outlet at the same rate as the injection rate to induce the reaction port state at a constant pressure. At this time, the back pressure regulator is connected to the outlet to maintain the constant pressure in the reaction port by adjusting the discharge rate. A double membrane filter with an aperture size of 0.45 μm is used to prevent particles from escaping. When the solvent remains, the solvent is reprecipitated when the temperature and pressure are lowered to collect the particles, so that the particles are re-dissolved to form agglomerates. Therefore, the washing process should be sufficiently performed until all solvents are removed. The amount of supercritical fluid for washing depends on the amount of solvent used and the size of the reaction port, preferably about 2,000-3,000 ml.

4) recovery of particles

At the end of the cleaning process, the supercritical fluid supply to the reactor is stopped and the supercritical fluid is discharged. At this time, if the discharge is made too fast, the produced particles may be damaged, so it is preferable to discharge slowly. After removing all of the supercritical fluid in the reactor, the particles are collected from the base wall or bottom of the reactor.

Hereinafter, the present invention will be described in detail with reference to comparative examples and examples.

First, Comparative Example shows the urethral propynyl butyl carbamate before the treatment of the particle size of 50-100 microns, the Example was measured the particle size by the particle size analyzer for the iodopropynyl butyl carbamate particles produced under the following conditions, As a result, a microparticle size of 255 to 318 nm was obtained. The content of the mixed solution used to prepare the small surface area of urethral propynyl butyl carbamate by using a supercritical fluid process is 0.12 g of urido propynyl butyl carbamate, 23.67 g of ethanol, and the height of the precipitation tank where precipitation occurs is 200 mm and volume Is 100 ml.

As shown in Table 1, the operating variables in this embodiment are the temperature and pressure, the carbon dioxide flow rate, the solution flow rate, Example 1-2 is to change the temperature of 313, 333K by adjusting the temperature, the pressure in Example 3-4 130-170 bar, in Example 5-6 it is possible to obtain a refined urethral propynyl butyl carbamate while changing the carbon dioxide flow rate 2.5-3.5kg / hr, Example 7-8 solution flow rate 0.5-1.5ml / min there was.

Table 1 Working conditions and particle size by four operating variables in Example 1-8

Example Temperature (K) Pressure (bar) Carbon Dioxide Flow Rate (kg / hr) Solution flow rate (ml / min) Particle size (nm) Example 1 313 150 2.5 0.5 230 Example 2 333 150 2.5 0.5 310 Example 3 313 130 2.5 0.5 270 Example 4 313 170 2.5 0.5 245 Example 5 313 150 2.5 0.5 264 Example 6 313 150 3.5 0.5 260 Example 7 313 150 2.5 0.5 318 Example 8 313 150 2.5 1.5 255

As described above, the urethral propynyl butyl carbamate (Example 1-8) obtained by using the supercritical fluid process of the present invention can obtain ultrafine particles as compared to the existing urethral propynyl butyl carbamate (comparative example). In addition, the preparation process of the ultrafine urethral propynyl butyl carbamate formulation, which is expected to enhance the skin effect due to the increase of effective area, has been completed.

Claims (1)

Contacting by spraying a mixed solvent in which the iodopropynyl butyl carbamate is dissolved in an organic solvent by spraying the supercritical fluid to produce the urethopynyl butyl carbamate particles, and introducing the supercritical fluid to provide the organic solvent used in the mixed solution. A process for preparing micronized iodopropynyl butyl carbamate using a supercritical fluid process, comprising the step of removing, wherein the organic solvent used is 0.0001 to 0.50 parts by weight of iodopropynyl butyl carbamate. Preferably, more preferably 0.001 to 0.20 weight fraction.