TW201026674A - Acetazolamide microparticle and its preparation method and use - Google Patents

Abstract

An acetazolamide microparticle and its preparation method and use are provided. The acetazolamide microparticle, having improved pharmaceutical applicability, is obtained by the application of a supercritical fluid.

Description

201026674 VI. Description of the Invention: [Technical Field] The present invention relates to an acetophenazoamine microparticle, a preparation method and use thereof, and particularly to an acetophenone amide prepared by a supercritical antisolvent method Microparticles and their use in medicine. [Prior Art] Φ Ethyl arsenazoamine is a drug that can be used to lower intraocular pressure and treat glaucoma. It can also be used to relieve symptoms such as headache, nausea and dyspnea that are characteristic of mountain sickness, or And edema. In particular, since acetamidine can ''inhibit the formation of aqueous humor, it can be used to lower intraocular pressure and to treat glaucoma. In addition, acetaminophen is a kind of inhibitor of carbonic anhydrase, and its action may be due to the diuretic effect of promoting the elimination of carbonic acid, so it can produce mild metabolic acidemia and stimulate breathing. It also increases the amount of ventilation per minute, and also reduces the production of cerebrospinal fluid and its total amount, so it can treat and prevent mountain sickness. The particle size of the acetaminophen drug currently on the market is about 20 microns (μιη). Table 1 shows the name, molecular formula, IUPAC name, source, purity, melting point and structural formula of acetaminophen. 3 201026674 Table 1 Name IRPAC name face ro tree acetazolattiiide QHet^QSz A^5^amkmJfcn}i)- 13,44riadiaexi-2-)i)- acetamide Sig^ia >99.0% 258 -262 ηΛυυ"3 NN 〇 According to estimates by the National Science and Technology Council, nanotechnology will generate $10 million in production value in 2015. Major projects include nanoparticle, drug delivery systems, microelectromechanical systems n (MEMS), and drugs. Process and nanostructured materials (http://www.ostp.gov/cs/nstc), of which rice medicinal products will account for 0% rj billion billion). In particular, in the field of medical application development, how to increase the efficiency of drug use, reduce the dosage and frequency of drugs, and improve the route of drug use have always been important issues in this field, and nanotechnology (micronization) technology These aspects have a considerable impact, the following examples illustrate the application of micronization technology

The advantage of medicine. Compared to the same amount of the original drug, since the particle size of the micronized drug becomes small, the total surface area thereof is greatly increased, so that a higher dissolution rate can be obtained. On the other hand, after the microparticulation of the drug, the adhesion characteristics due to the fine particle size are advantageous for prolonging the residence time of the drug when the drug is applied locally. For example, micronized drugs can increase the contact time between the drug and the intestinal wall, so that it can be quickly dissolved and effectively absorbed and utilized in the living body, thereby greatly increasing the absorption of the drug by the organism and increasing the biological activity of the drug. The degree of utilization 'relatively reduces the dose of the drug, and can achieve the same medical effect with a dose of less than 4, 2010,674,674. In addition, the nano-medicated drug particles can be swallowed by macrophages in the human body as foreign bodies, so that the drug can be delivered to a large number of reticuloendothelial cells (macrophages), such as the liver. Target area for the action of drugs such as spleen, lung, bone marrow and lymph. For example, Rifampicin antibiotics and poly(lactide-co-glycolide, PLGA) polymers are made into composite particles of 2 to 3 microns for inhalation. In the method of administration, the phagocytic mechanism of alveolar macrophages after inhalation by the nose and mouth can bring the drug to the tuberculosis to achieve therapeutic effect. See Tomoda et al., Preparation and properties of inhalable nanocomposite particles:

Effects of the temperature at a spray-dryer inlet upon the properties of partiele^ Biointerfeees, 64 (20^8) H4-» 43⁄4 >〇; 倂 for reference. Through micronization technology, the dosage form can also be changed to shorten the drug delivery route. In particular, the drug delivery method that directs the drug to the target tissue cells generally requires subcutaneous injection to effectively absorb the drug, but the micronized drug can be converted into an oral drug. The microparticulation of the drug can also process a normally insoluble non-aqueous agent into a stable suspension injection, or even change the drug into a transdermal patch or into a new formulation such as a powder inhaler or an oral spray. For example, in the treatment of pulmonary or tracheal-related diseases, inhaled drug particles can act directly in the affected area instead of indirect or injectable treatment. In addition to increasing the therapeutic effect, microparticulation of the drug can also reduce the side effects caused by oral or injection 201026674, and greatly improve the bioavailability of the drug. Furthermore, the microparticulation of the drug can also be applied to the preparation of biocompatible composite particles constituting the active drug, which can control and regulate the release of the drug. For example, the drug powder or solution may be embedded in the microparticles, and the hydrophilicity and lipophilic properties of the surface of the solid colloidal microparticles may be utilized to improve the hydrophobicity of the original drug, and the like. To delay or increase the rate at which the drug is released, thereby adjusting the rate at which the drug is absorbed by the body and the time it takes to circulate in the body. For example, in order to increase the compliance of chronic drugs and reduce the occurrence of side effects, drugs are often made into special dosage forms, especially cardiovascular drugs, which are generally formulated as extended release to prolong the duration of drug administration and reduce the number of medications. And to maintain the stability of the drug concentration in the blood. A common design utilizes a high molecular polymer to encapsulate the active ingredient in the polymer, allowing the drug to slowly release in the gastrointestinal tract. As mentioned above, the micronization process has a pivotal position in the pharmaceutical industry, and many related technologies have been developed. The conventional physical method for preparing drug microparticles is the most common mechanical method, and the powder to be micronized is gradually miniaturized by pulverization, grinding, and ball milling. However, during the grinding process, the grinding machine may contaminate the drug due to abrasion or peeling, and in the process of pulverizing the drug particles by mechanical force, the original crystal face and crystal form of the drug may be destroyed, thereby affecting the pharmacological effect of the drug or its physical and The stability of chemical properties. Furthermore, the conventional chemical method for preparing drug particles is by evaporation, heating and cooling, or adding a component to the solution to reduce the solubility of the drug solute in the solution, so that the drug solute is deposited by crystallization to form crystals or Amorphous particles. However, the drug particles prepared by the chemical method 201026674 do not have a specific and narrow particle size distribution, and may have problems of solvent residue and are liable to produce different crystal forms. Therefore, a pharmaceutical particle preparation technique capable of effectively controlling the particle size, distribution, and crystallization properties and stabilizing the properties of the drug is quite important. The present invention provides a method for producing yttrium azoamine microparticles in view of the above research and development results, and the obtained acetaminophen azoamine microparticles have advantages in biological application and medical processing.

SUMMARY OF THE INVENTION One object of the present invention is to provide an acetamidine azoamine microparticle having an average particle diameter of less than 18 μm. Another object of the present invention is to provide a method for preparing the above-mentioned acesulfonamide particles having a particle diameter of less than 18 μm, which comprises: mixing an acetoin amide solution with a supercritical fluid to precipitate an oxime A nitramide microparticle, wherein the solvent of the acetaminophen solution is miscible with the supercritical fluid. It is still another object of the present invention to provide an agent for diuresis, intraocular pressure reduction, anti-glaucoma, anti-alpine disease, anti-epilepsy and/or anti-edema comprising the above-described ethylene azoamine microparticles. It is still another object of the present invention to provide an application for the manufacture of a medicament using the above-described acetophenone azoamine microparticles for use in diuresis, intraocular pressure reduction, antiglaucoma, anti-alpine, anti-epilepsy, epilepsy and/or Anti-edema. The detailed description of the present invention and the preferred embodiments thereof will be described in the following, and the present invention will be apparent to those of ordinary skill in the art. [Embodiment] The present invention relates to an acetophenazoamine fine particle having an average particle diameter of less than 18 μm, preferably less than 15 μm, more preferably less than 10 μm, particularly preferably less than 5 μm, and most preferably less than 1 μm. Specifically, the particle size of the acetaminophen nitrite particles of the present invention is significantly smaller than that of the acetophenone amide drug substance, which greatly increases the bioavailability of the acetaminophen amide drug. Further, the acetophenone azoamine microparticles of the present invention may have different crystal forms and crystal appearances. For example, the crystalline form of the acetophenone azoamine microparticles of the present invention may be of the second type (form II) and its crystal appearance is a regular rod shape, or the crystal of the acetophenone azoamine microparticles of the present invention. The type may be type 1 (forml) and its crystal appearance is irregular. In the dissolution rate test, it was found that the dissolution rate of the octadecyl azoamine microparticles of the second type is better than that of the acetophenamine fine particles of the first type. Therefore, for the acetaminophen fine particles having a preferable dissolution rate, the acetophenazoamine fine particles having the crystal form of the second type can be used. The substance has three phases of solid, liquid and vapor changes at different temperatures and pressures. When the temperature and pressure of the substance exceed its critical temperature (Tc) and critical pressure (Pc), the fluid phase exists. Supercritical fluid. The physical properties of a supercritical fluid are between a vapor and a liquid. For example, the density of a supercritical fluid is similar to that of a liquid, the diffusion coefficient is between a vapor and a liquid, and the viscosity and compressibility are similar to those of a vapor. In terms of chemical properties, the supercritical fluid 201026674 is also different from the vapor and liquid phases. For example, carbon dioxide does not have the ability to extract in a gaseous state, but after entering a supercritical state, it becomes organophilic and has the ability to dissolve organic matter. Since the solvency varies with temperature and pressure, it is convenient to adjust the required extraction capacity, or to quickly separate the solute from the solvent after the reaction, making the supercritical fluid the best organic and aqueous solvent. Environmentally friendly alternatives. The invention further relates to a method for preparing acetamidine azoamine microparticles by using a supercritical fluid, which comprises mixing an acetoin amide solution with a supercritical fluid to precipitate acetamidine amide particles, wherein The solvent of the acetaminophen solution is miscible with the supercritical fluid. Without being bound by theory, the method of the present invention involves the following stages: the ethyl hydrazide solution reaches a supersaturated state, the nucleation of acetaminophen quinone and crystal growth, that is, by a crystallization process to provide An acetaminophen microparticle having a desired particle size. This crystallization process involves the following two competing effects: supercritical fluid mass transfer to acetamidine amide solution (or supercritical fluid and acetamidine solution), which causes volume expansion of the solution; The effect of nuclear and growth. Among them, when the mass transfer rate of the supercritical fluid is greater than the nucleation and growth rate of the crystal, particles having a smaller particle size and a more uniform distribution can be obtained. In the preparation of the acetophenone azoamine microparticles of the present invention, the solvent of the acesulfonium azoamine solution can be selected, and/or the mixing pressure and mixing temperature of the acetaminophen amide solution and the supercritical fluid can be adjusted. The flow rate of the supercritical fluid, the flow rate of the acetaminophen solution, and/or the mixing mode (for example: batch or continuous, turbulent or countercurrent) to control the quality of the supercritical fluid rate. Each of the above operating parameters will affect the effect of the microparticulation of the drug. By adjusting the various operating parameters and taking into account the interaction between the parameters, an acetonitrile azoamine having the desired particle size, crystal phase and crystal morphology can be obtained. Particles, further explanation will be provided below. Figure 1 is a schematic view showing the operation of the method of the present invention. Briefly, a supercritical body is used as an anti-solvent to precipitate a solution containing a solute having a desired particle size (i.e., acetamidine azoamine particles). Then, the particles are separated from the solvent in the liquid by vaporization. In the method of the present invention, any suitable supercritical organism can be used to act as an anti-solvent. Among them, carbon dioxide in a milder environment, that is, the monthly b reaches a supercritical state (T, 31", Pe = 7.4xl06 Pascal), can be operated under the shirt, and it is non-combustible, non-toxic and inexpensive. The advantage is that the impact on the environment is small', and the dry and solvent-free particles can be obtained at the same time in the operation towel to avoid complicated subsequent treatment. Thus, in a preferred embodiment of the method of the invention, carbon dioxide is made to provide the supercritical fluid. According to the method of the present invention, the arsenazoamine raw material to be micronized is firstly dissolved; the preparation is used to form an acetonitrile azoamine solution, and the solvent is selected according to the condition that the supercritical fluid used is mutually soluble. And acetaminophen is insoluble in the super-immediate fluid. In the method of the present invention, a solvent selected from the group consisting of: methanol, gas, and N-methyl-pyrrolidone (NMP), ethyl acetate, acetone, and The combination thereof is preferably selected from the group consisting of ethyl acetate, acetone and a combination thereof in order to achieve miniaturization as much as possible. 201026674 Since different solvents have different affinities for acetophenamide, it has been found that acesulfonamide particles having different crystal forms and/or particle sizes can be obtained by using different solvents. Wherein, when ethyl acetate or acetone is used as the solvent, the acetamidoamine particles of the second type can be obtained, and when ethanol is used as the solvent, the crystal form of the first type can be obtained.醯Aziridine particles. As described above, the acetophenone amide particles of the second type exhibit a better dissolution rate, so if an acetamidoamine fine particle having a preferred dissolution rate is to be produced, ethyl acetate or acetone can be used. Reference as a solvent. The acetaminophen solution and the supercritical fluid can be mixed in any convenient manner. In one embodiment of the method of the invention, the mixing step is carried out by feeding the acetaminophen solution to a vessel containing the supercritical fluid. Specifically, the supercritical fluid is first introduced from above the container, the container is filled with supercritical fluid and the supercritical fluid is maintained in a continuous flow at a fixed flow rate, and the prepared acetaminophen amide is further prepared. The solution is passed through the top of the vessel @ (ie a continuous mixing method). That is, in this embodiment, the acetamidine amide solution and the supercritical fluid system are delivered to the vessel in a cocurrent manner. Further, in the method of the present invention, if the batch mixing method is adopted, that is, the supercritical fluid is introduced into the static solution, the disturbance caused by the process is limited, and it is difficult to achieve uniform mixing, so There is a high mass transfer resistance between the critical fluid and the solution, so that only a small portion of the mixed solution in the container is saturated, and the number of crystal nuclei formed is insufficient, resulting in most of the solute attached to the finite nuclei for proceeding. Since the crystal grows, it is impossible to obtain particles having a small particle size. However, 11 201026674 If the above continuous mixing method is adopted, since a small amount of solution is sprayed into a large amount and continuously flowing supercritical fluid from, for example, a nozzle, the solution and the supercritical fluid are easily uniformly mixed, and the solution is at the nozzle outlet. The pressure is the pressure of the container (less than the pressure before the solution is ejected), and the solution spray nozzle is mixed with the supercritical fluid, and then the density of the solution phase is decreased due to the volume expansion, and the acetaminophen is dissolved in the mixed solution. The equilibrium solubility is low (the acetaminophen is insoluble in the supercritical fluid), thereby achieving a high degree of supersaturation and producing a large number of crystal nuclei, and only a small part of the solute causes the crystal to grow, that is, the mass transfer rate of the supercritical fluid. Greater than the nucleation and growth rate of the crystal. Therefore, the continuous mixing method is advantageous for producing a mixing method of particles having a small particle size and a narrow particle diameter distribution. In addition, without being bound by theory, the concentration of the sulphur oxime solution is higher (for example, greater than 70% of the saturation concentration), and when mixed with the supercritical fluid, the acesulfonium azoamine solute The chance of collision between the two increases the volumetric expansion rate to achieve the desired supersaturation and precipitates the acetaminophen azoamine particles; however, at high solution concentrations, the acetyl azoamine solute crystal The rate of nuclear growth is greater than the rate of nucleation, resulting in a larger particle size of the resulting acetaminophen. Therefore, the effect of solution concentration on the micronization is a competing effect. Further consider the effect of the flow rate of the acetaminophen solution and its concentration on the particle size of the obtained particles. Without being bound by theory, the letter is in a cocurrent mode of transporting the acetaminophen solution and the supercritical fluid into the vessel (ie, continuous turbulent mixing) due to the supercritical fluid. The flow rate is greater than the flow rate of the acetaminophen solution. Therefore, under the condition of low solution flow rate, the relative velocity between the solution and the fluid of the super-protocol 12 201026674 is large; in this case, because of supercritical The mass transfer rate of the fluid is faster, so when the solution is mixed with the supercritical fluid and the solution precipitates particles due to volume expansion, the nucleation step consumes most of the solute, thereby greatly reducing the solute required for the subsequent crystal growth step. Therefore, it is easy to obtain a smaller particle size. At this time, if the concentration of the solution is increased, in addition to the solute consumed during nucleation, there is a solute for crystal growth, so the average particle size becomes large. Therefore, at low solution flow rates, the average particle size increases as the concentration of the solution increases. In the continuous turbulent mixing method, the relative velocity between the solution and the supercritical fluid is small at high solution flow rate, and the mixing of the two is not as good as the low flow rate. Therefore, the solute with higher supersaturation The nucleus will be nucleated first, and the solute with low supersaturation will not be nucleated and will move to the surface of the nucleus for crystal growth due to insufficient driving force. At this time, if the concentration of the solution is increased, the solute is precipitated in a supersaturated state, so that the gradient of the supersaturation is small, and a small particle size is easily obtained. Conversely, if the solution concentration is lowered and the gradient of supersaturation is large, a larger particle size is easily obtained. Therefore, under high solution flow rate conditions, the average particle size decreases as the concentration of the solution increases. From the above, it is known that the effect of the flow rate of the acetaminophen solution on the atomization is also affected by the solution concentration conditions. In general, when carbon dioxide is used as the supercritical fluid, the concentration of the acetaminophen solution is usually at least 10% of the saturation concentration, preferably at least 25% of the saturation concentration, more preferably at least 50% of the saturation concentration. Preferably, the saturation concentration is at least 75%; in addition, when the flow rate of the supercritical carbon dioxide fluid is from 2 liters/min to 4 liters/min, the flow rate of the acetaminophen solution is generally 0.1 ml/2010. Minutes to 5 ml/min, preferably from 0.8 ml/min to 1.5 ml/min. For example, when a supercritical carbon dioxide fluid and an ethyl acetate solvent are used, and the following operating conditions are utilized: the flow rate of the acetaminophen solution is 1 ml/min, the mixing temperature is 35 ° C, and the mixing pressure is 1 Torr. 〇巴, the concentration of the acetaminophen solution is 30% of the saturated concentration, and the average particle diameter of the prepared acetaminophen azoamine particles is 0.73 ± 0.34 μm; and when the same conditions as described above are utilized, When the concentration of the acesulfonic acid amide solution was adjusted to 90% of the saturated concentration, the average particle diameter of the prepared acrylamide fine particles was 0.36 ± 0.12 μm. It can be seen that under the above operating conditions, the high concentration of the acetaminophen solution has a better micronization effect. In terms of the effect of mixing pressure and temperature, when the pressure is not limited by the theory, when the pressure is increased, the supercritical fluid is diffused to the solvent, the volume of the solution is uniformly expanded, and the nucleation rate is accelerated, so that it is easy to obtain Smaller particle size and evenly distributed particles; on the other hand, when the pressure is increased, the density of the solution increases, which slows down the rate at which the supercritical fluid diffuses into the solvent, thus making it easier to obtain larger particle sizes and not Uniformly distributed particles. Therefore, the pressure effect is a competitive effect. Temperature also has the same effect on particle size and distribution. Without being bound by theory, when the temperature is increased, the density of the supercritical fluid is lowered, the solubility of the supercritical fluid in the solvent is decreased, and the degree of volume expansion of the solution is also decreased, thereby reducing the supersaturation of the solution. It helps to grow solute crystals, so it is easy to obtain particles with larger particle size and uneven distribution. On the other hand, increasing the temperature will increase the vaporization degree of the solvent and increase the mass transfer effect, which is conducive to the criticality of the solution and super-201026674. The mixing and mass transfer between the fluids makes it easy to obtain smaller particle sizes and uniform particles. Therefore, the temperature effect is also a competitive effect. If both pressure and temperature effects are considered for the size and distribution of the particles, the pressure and temperature can determine whether the solvent and the supercritical fluid are in a uniform phase, or a is in a vapor-liquid coexisting phase, so a mixture of solvent and supercritical fluid can be used. Judging the critical point (Mixture Critical Point). When the temperature and pressure are in six

When ❹ is above the critical point of the mixture with the supercritical fluid, it is operated in a single phase, ie, / in a homogeneous phase for nucleation and growth of the crystal. Conversely, if the temperature and = force are below the critical point, then the two phases operate. The particle size obtained during the operation in the single-phase region is relatively uniform, and when operating in the two-phase region, the age-incorporated + & xa < block-like particles are obtained and the particle size distribution is relatively uneven, because the two phases are During the operation of the zone, the vapor-liquid interface still exists, which increases the mass transfer resistance between the solvent and the supercritical fluid, so that the/grain cannot be quickly supersaturated and uniformly precipitated. In the case where carbon dioxide is used as the supercritical fluid, the method of the present invention is generally carried out at a pressure of 8 Torr to 16 Torr and a temperature of (10) to 7 Torr. It is preferably carried out under conditions of a pressure of 90 bar to 110 bar and a temperature of 3 (rc to 邾 ° C. If higher pressure or temperature is used, the overall process cost is increased on the one hand] On the other hand, the risk of operating the device is relatively increased; on the contrary, the appropriate process yield may not be achieved. For example, when a supercritical carbon dioxide fluid and an ethyl acetate solvent are used, and the following operating conditions are utilized: acetonitrile The flow rate of the guanamine solution is 1 ml/min, the mixing temperature is 35 〇c, the concentration of the acetaminophen amide solution is 15 201026674 30% of the saturated concentration, and the mixing pressure is 100 bar. The particle size of the guanamine particles was 0.73 ± 0.34 μm; and when the same conditions as described above were used, but the mixing pressure was adjusted to 140 bar, the particle diameter of the prepared acetaminophen azoamine particles was 1.04 ± 0.49 μm. Under the above operating conditions, the lower mixing pressure has better micronization effect. In addition, when supercritical carbon dioxide fluid and ethyl acetate solvent are also used, the following operating conditions are utilized: acetaminophen The flow rate is 1 ml/min, the concentration of the acetaminophen solution is 30% of the saturation concentration, the mixing pressure is 100 bar, but the mixing temperature is 55 ° C, and the prepared acetonitrile azoamine particles are prepared. The particle size is 0.88±0.33 μm. Compared with the above embodiment, the lower mixing temperature has better micronization effect under the above operating conditions. From the above description, the atomization effect of acetonitrile azoamine It is closely related to the various process conditions involved in the process, and the acetamidoamine particles having the desired properties can be obtained by controlling the respective process conditions. According to a preferred embodiment of the method of the present invention, a purification may be included. a step of removing the solvent remaining in the precipitated acetonitrile azoamine microparticles to improve the quality of the obtained acetamidoamine microparticles. Generally, it can be continued in the precipitated acetaminophen particles. The supercritical fluid is introduced to remove the solvent by evaporation. By this purification step, residual and contamination of the organic solvent can be avoided, thereby obtaining solvent-free residual acetamidine azoamine microparticles. The present invention also relates to the use of the present invention. B The use of a guanamine microparticle in the manufacture of a medicament for use in the treatment of diuresis, hypotensive hypotension, antiglaucoma, anti-alpine, anti-epileptic and/or anti-edema. The particles have a smaller particle size, so they have advantages in the application of the medicine. The following is a description of the equipment and the operation steps which can be used in the present invention by taking the supercritical carbon dioxide fluid as an example, but the illustration is used for illustration, not for use. The invention is shown in Fig. 2. The schematic diagram of the apparatus for preparing the acetophenazoamine microparticles of the invention is shown in Fig. 2. The whole apparatus is divided into three parts: the first part is a high pressure of precipitation of acetaminophen particles. The section mainly comprises a carbon dioxide cylinder 1, a supercritical carbon dioxide transportation pipeline composed of a plurality of adapters and a plurality of stainless steel pipelines of different sizes, and a precipitation tank 7; the second part is an acetaminophen solution. The high-pressure pump 13 continuously delivers the solution feed section to the precipitation tank 7; the third part is used to separate the solvent and the supercritical carbon dioxide rear end line, that is, the solvent recovery section. The carbon dioxide sent from the carbon dioxide cylinder 1 is passed through a filter having a pore size of 7 μm and an adsorption cylinder filled with molecular sieve to purify carbon dioxide (estimated purity is greater than 99.8%). The carbon dioxide is completely cooled to a liquid through a recirculation tank 2 at about 0 ° C, and then pressurized with a high pressure pump 3 (maximum flow rate at 3,000 psi (99.9 cc / min), via a check valve B2 enters the sedimentation tank 7, and the pressure of the sedimentation tank 7 is regulated by the back pressure valve C. A pressure gauge is arranged at the outlet end of the high pressure pump 3 to monitor the outlet pressure of the high pressure pump 3, and a safe blasting 17 201026674 piece is set. The carbon dioxide is output from the high pressure pump 3 and then preheated by the preheater 5, and then enters the sedimentation tank 7 from the three-way ball valve D above the sedimentation tank 7, and the pressure transmitter 8 and the thermocouple temperature measuring element 9 are used to measure the sedimentation tank. 7 pressure and temperature. The Shendian trough 7 is composed of a high-pressure steel pipe, a plurality of adapters and a filter 10. The pore size of the filter 10 is 0.5 micrometer, which has two functions, one is when the acetaminophen particles are generated. Disperse the supercritical fluid, and the other is to block the acetaminophen particles and sample when drying and depressurizing with a supercritical fluid. The temperature of the sinking tank 7 is controlled by the constant temperature water bath 4. The arsenic amine solution is placed in the vial 6, pressurized by a high pressure pump 13 (maximum flow rate at 6,000 psi), and a capillary nozzle via a check valve B3. Sprayed into the sedimentation tank 7. The capillary nozzle is a double-casing structure in which the inner tube is a 1/16 inch capillary (the inner diameter is 127 μm), which is used to transport the acetonitrile azo-amine solution; the outer tube is connected to the sink chamber 7 It is used to transport carbon dioxide. The acetaminophen solution is mixed with supercritical carbon dioxide at the outlet of the nozzle to form acetamidine azoamine microparticles, and is immersed in the ruthenium sheet 10 at the bottom of the sedimentation tank 7 or on the wall of the sinking tank 7 Precipitate. The micro-metering valve E in the pipeline is used to regulate the flow of supercritical carbon dioxide leaving the sinking chamber 7. In the back-end pipeline, the supercritical carbon dioxide is separated from the supercritical carbon dioxide by the pressure and temperature dip of the supercritical carbon monoxide leaving the precipitation tank 7, and the supercritical carbon dioxide is also depressurized into gaseous carbon dioxide, and finally enters the conical flask 11 Inside. The conical flask 11 contains five points of water for recovery of the solvent. The flow rate of carbon dioxide is measured by the float flow meter 12. 201026674 Procedure [Test for Solubility of Ethylamine] Before the continuous supercritical antisolvent operation, it is necessary to find the appropriate combination of acetamidine amide and solvent. The saturation solubility of the arsenylamine solution was measured by continuously adding the acetaminophen amide starting drug to a flask containing a solvent at a constant temperature until it could not be dissolved again. Next, an appropriate amount of a clear liquid was dropped into the flask, and the solvent was removed by heating, and the saturated solubility of acetaminophen in the solvent was obtained by changing the weight of the flask before and after the heating. [Operation Procedure of Continuous Supercritical Antisolvent Method] The operation steps of the continuous supercritical antisolvent method are mainly divided into five steps. Step 1 is the assembly, pre-cleaning and leak detection of the experimental equipment. First, close the two-way needle valve A, A2, A3, A4, and A5, the back pressure valve C, and the three-way ball valve D, and 0 to check whether the functions of the check valves B1, B2, and B3 are normal. Next, the washed and dried precipitation tank 7 is assembled, and then carbon dioxide is introduced, and the equipment is pre-cleaned by degassing to remove impurities in the apparatus. After the pre-cleaning is completed, pass carbon dioxide to the desired pressure, let stand for about 丨 hours, and observe whether the pressure in the equipment has changed. If there is no change, it means that the equipment has no gas leakage. Step 2 is the feeding of supercritical carbon dioxide. Set the temperature of the constant temperature water bath 4 to the desired mixing temperature. When the temperature reaches the desired temperature, the constant temperature water bath 4 is raised by a hydraulic lifting platform 19 201026674 until the precipitation tank 7 is completely immersed in the constant temperature water bath 4. Next, the carbon dioxide in the carbon dioxide cylinder 1 is pressurized by the high pressure pump 3, and the pressure of the apparatus is regulated by the back pressure valve C to a desired mixing pressure to bring the carbon dioxide into a supercritical state. After passing through the high pressure pump 3, the carbon dioxide enters from the top of the sedimentation tank 7 via the preheater 5. When the settling tank 7 reaches the set pressure, the supercritical carbon dioxide is removed from the bottom of the sedimentation tank 7 by opening the needle valve A5. The flow rate of the supercritical carbon dioxide is finely adjusted by the micro-metering valve E and is read by the float flow meter 12. Step 3 is the feeding of the acetaminophen solution. When the temperature and pressure of the equipment reach the set conditions and the flow rate of the supercritical carbon dioxide is stabilized, the feed of the acetaminophen solution is carried out. The residual solvent and air in the feed line of the acetaminophen amide solution are removed prior to delivery of the acetaminophen solution to the precipitation tank 7. The acetaminophen solution is transported by the high pressure pump 13, and then adjusted by the three-way ball valve D, so that the residual solvent, air and the acetaminophen solution in the pipeline are discharged by bypass. To ensure that the line is filled with acetaminophen solution. The flow rate of the acetaminophen solution is set, and then the three-way ball valve D is adjusted to the direction of the feed, and the acetonitrile azoamine solution is sprayed into the precipitation tank 7 through the capillary nozzle to precipitate B.醯Aziridine particles. Step 4 is the purification of acetaminophen microparticles. After all of the prepared acetaminophen amine solution has entered the precipitation tank 7, the delivery of the acetaminophen solution is stopped. In order to obtain the solvent-free residual acetamidine azoamine microparticles, supercritical carbon dioxide is continuously supplied to the precipitated acetaminophen azoamine microparticles to remove the solvent remaining in the acetamidine 201026674 amidamine microparticles, and dried. The time is about 30 minutes to 60 minutes. The residual solvent in the acetaminophen granules volatilizes into supercritical carbon dioxide and is then carried out of the precipitation tank 7 by supercritical carbon dioxide. The resulting arsenylamine microparticles were collected on a filter 10 having a pore size of 0.5 μm. Step 5 is decompression and post-cleaning. After the residual solvent is completely removed from the precipitation tank 7 by the supercritical carbon dioxide, the carbon dioxide is stopped and the equipment is depressurized, and the time required for the pressure to be reduced from the operating pressure to the normal pressure is about 1 hour. It should be noted that the decompression should not be too fast, otherwise the particles will be aggregated due to the extrusion of the acetophenamide particles. After the pressure is released to normal pressure, the sedimentation tank 7 is removed, and the acetaminophen particles are taken out from the sedimentation tank 7. Finally, the sink tank 7 and the piping are cleaned and dried for the next operation. Analytical method (A) Particle form and size <1> Scanning Electron Microscopy (SEM) analysis The appearance change of the acetaminophen amide starting material before and after the SAS treatment was observed by SEM. First, an appropriate amount of the acetaminophen steroid raw material or the acetaminophen amide fine particles of the present invention is adhered to a sample disk with a carbon tape, and after gold plating in a vacuum, the appearance is photographed by SEM. The SEM analysis was performed using a scanning electron microscope (JEOL JSM-5600) of the Insect Department of the Taiwan University and a scanning electron microscope (JOEL JSM-6700F) of the Institute of Polymer Science and Engineering, National Taiwan University. 21 201026674 <2> Particle Size Distribution (PSD) analysis using image analysis software Image J (refer to Abramoff et al. Image processing with Image J, Biophotonics Inter., 11 (2004) 36-42), In the SEM spectrum, more than 200 intact crystal particles were selected, and the particle size was measured, and the average particle size and particle size distribution were determined by statistical methods. (B) Analysis of crystallization characteristics <1> X-ray Diffraction (XRD) analysis Using an X-ray Diffractometer to observe the acetonitrile azo-amine reagent before and after SAS treatment Crystalline nature. First, an appropriate amount of an acetamidine azoamine bulk drug or the acetaminophen amide amide particles of the present invention is filled onto a sample tank and subjected to X-ray diffraction. The X-ray diffraction angle is scanned from 5 degrees to 4 degrees and the scanning rate is 3 degrees per minute. This analysis was performed using an X-ray diffractometer (PANalytical, X'pert) in the Common Instrument Room of the Department of Chemical Engineering, National Taiwan University. <2> Differential Scanning Calorimetry (DSC) analysis The Differential Scanning Calorimeter was used to observe whether the crystal form of the acetaminophen arylamine drug substance before and after the SAS treatment was changed. The differential sweep cat card has a scan rate of 5 〇c per minute. This analysis was performed using a differential scanning calorimeter from the Common Instrument Room of the Department of Chemical Engineering, National Taiwan University (DuPont > ΤΑ 2010) 0 22 201026674 <3> Fourier transform infrared spectroscopy (F〇urier Transf〇rm

Infrared

Spectrometry, FTIR) analysis using Fourier transform infrared light sputum (F〇urier Transf〇rm

Infrared

Spectrometer) Qualitative analysis of the arsenyl amide raw material drug and the acetaminophen azoamine microparticles of the present invention. When a compound molecule absorbs infrared rays, it causes vibration and rotation between atoms, and the energy absorbed by it is discontinuous (quantization). Different ❹ 胄 energy bases have different vibration and rotational energy, so they absorb infrared and lines of specific frequencies. Therefore, the base of the compound molecule and its ruthenium can be identified by not collecting the position. First, 'put the appropriate acetaminophen azoamine bulk drug or the acetaminophen azoamine microparticle of the present invention on the sleeved single crystal, and set the scanning wave number range from 4000 to 700 cnfl 'the number of scans is 8 times. The resolution is 4 cm-1. This analysis is based on the Fourier transform infrared spectrometer (PerkinElmer, Spectrum 1〇〇 FTIR-ATR) of the Thermal and Supercritical Technology Laboratory of the Institute of X. ® (C) Dissolution Rate Analysis To understand the effectiveness of the acetaminophen carbamide drug after SAS treatment, the dissolution rate was analyzed. This analysis was performed using the Dissolution Tester (Shin Kwang Machinery, DT3) of the Department of Chemical Engineering of the University of Taiwan, and the dissolution test machine (Diss〇iuti〇I1 Tester, Shin Kwang Machinery, DT3). The dissolving medium used in this analysis was a buffer having a pH of 6.8. Add 6.8 g of p〇tassjurn Phosphate Monobasic 23 201026674 and 0.2 equivalent of (N) sodium hydroxide to distilled water and adjust the volume to 1,000 ml with distilled water to prepare a pH of 6.8. Buffer, which is a simulated intestinal fluid. The above methods were formulated according to the United States Pharmacopeia (2008). A standard curve must be made prior to the dissolution rate analysis. First, the acetaminophen amide is dissolved in the buffer, and then the solution is scanned at full wavelength by an ultraviolet-visible spectrometer to obtain the maximum absorption wavelength (λπ^χ) of the arsenylamine. Next, different concentrations of acetaminophen amide solution were prepared in the buffer, and the absorbance was measured at the maximum absorption wavelength to prepare the standard curve of the concentration of acetamidine amide to absorbance. The method used for this analysis was a paddle with a set speed of 50 rpm, 900 ml of the buffer in the dissolution medium, and a set temperature of 37 ± 0.5 °C. About 20 mg of the acetaminophen phthalamide raw material or the acetaminophen azoamine microparticles of the present invention was directly introduced into the buffer in the dissolution tester. A 2.5 ml sample was taken at fixed time intervals and the sample was removed by a Syringe Filter with a pore size of 0.45 microns to remove the undissolved acetamidine. After appropriately filtering the filtered sample, the concentration was measured by an ultraviolet-visible spectrometer. In this analysis, an empirical Weibull model commonly used to describe the dissolution behavior was used to describe the dissolution behavior of acetamidine amide. The mode is in the form of 201026674 where m is the dissolved fraction of acetaminophen at a particular sampling time t, and a and b are two empirical parameters which can be obtained by regression of the dissolution curve. Based on this model, when the drug dissolution ratio is 63.2%, the reciprocal of the required time is defined as the dissolution rate coefficient (kw), and the rate of drug dissolution rate is compared, as defined below. : (Propers and dissolution of drugs micronized by crystallization from supercritical gases, Int. J. Pharm., 32 (1986) 265-267) by Loth and Hemgesberg. According to the data obtained from the calculation and regression elution rate analysis, the dissolution rate coefficient of acetaminophen amide is h/mirf1, and after continuous SAS treatment, the dissolution rate coefficient of acetaminophen is increased to A^min·1. By calculating the ratio of A:w2/A:w/, the increase in the elution rate of the acetaminophen microparticles of the present invention can be determined. [Examples 1 to 3] Solvent effects Examples 1 to 3 were carried out in the above apparatus, operation steps and analysis methods. First, fix the pressure, temperature, solution concentration, and solution flow rate and select different solvents to observe the solvent effect. The operating parameters of Examples 1 to 3 are shown in Table 2 below, wherein the solvents used were respectively ethyl lactate (Example 1), acetone (Example 2), and B 25 201026674 acid ethyl ester (Example 3). Table 2 Example solvent solution flow rate (ml/min) Concentration (saturated concentration, %) Temperature (°C) Pressure (bar) Average particle size (micron) Standard deviation (micron) Recovery (%) 1 Ethanol 1 30 35 100 4.95 2.97 10.78 2 Propionate 1 30 35 100 0.86 0.45 84.49 3 Ethyl acetate 1 30 35 100 0.73 0.34 60.81 Note: The average particle size of the acetaminophen amide is 19.64 microns with a standard deviation of 13.2 microns. The saturated solubility of acetaminophen amide is: 1.5 mg/ml (in ethanol), 8.3 mg/ml (in acetone), 0.6 mg/ml (in ethyl acetate). In the presence of ethanol, the solubility of acetamidine azoamine in supercritical carbon dioxide is 5.7 乂 10-6 mg / ml (d = 40 ° (: and ? = 150 bar). As shown in Figure 3 (a) As shown, the crystalline form of the acetaminophen carbamide is irregularly shaped and has a particle size of about 19.64 micrometers. Figure 3 (b) shows the acetaminophen obtained in Example 1. The fine particles have an irregular crystal shape and a particle diameter of about 4.95 μm. The third (c) is the acetaminophen azoamine microparticles prepared in Example 2, which has a crystal grain shape and a particle diameter. It is about 0.86 μm. The third (d) is the acetaminophen azoamine microparticles prepared in Example 3, which has a rod shape and a particle diameter of about 0.73 μm. Fig. 4 is a comparative example 1 The particle size and distribution of the acetophenone azoamine microparticles obtained in Example 3. As can be seen from Fig. 4, when acetone and ethyl acetate were used as the solvent, a better micronization effect was obtained, wherein Ethyl acetate is preferred. Figures 5(a) to 5(d) are DSC analysis of acetaminophen amide derivatives and acetonitrile azoamine particles prepared in Examples 1 to 3. the result of. As shown in Fig. 5(a), the melting point of the acetoinamide (Form II) has a melting point of 258 ° C to 262 ° C. As shown in Figure 5 (b), When ethanol 201026674 is used as the solvent (Example), 1971 to 199t; and the crystal form is the first, the melting point of the azo arsenic amine particles is added, and the crystal form is changed by the first type · F〇rm ...the temperature increases by 25 (TC to 252t. For example, the fifth (type 2, type 2 and the melting point of the fine particles is changed to > the melting point of the amine fine particles is 256 ° Γ S mq ' and the crystal form is the second type. As shown in Fig. 5(4), when the solvent is used (Example 3), the prepared bismuth acetate is prepared.

. (: to the boot, and the crystal form is the second type (4) The melting point of the azo-amine granules is the addition of the 6th (a) to the 6th (d) squaring ± ± ) pattern before the continuous SAS treatment XRD pattern of azlactone. For example, 灸 moxibustion 6 shoulder medicine 夕 四 四 四 四 第 第 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 As shown in Figure 6(b), when ethanol is used as the solvent (in the example, the amine microparticles produced at 2 (4).9 are not present in the scale, so the crystal form is 丨i. As shown in "c) and Fig. 6(d), when acetone and ethyl acetate were used as solvents (Examples 2 and 3), the obtained azo azoamine microparticles were found at 2 (four) 9 The characteristic peaks are present, so the crystal forms are of the second type. The 7th (a) to 7th (4) diagrams are the FHR patterns of the acetamidine-terminated amines before and after the continuous SAS treatment. Among them, the 7th (a) The figure is the spectroscopy of the acetaminophen amide drug, and the 7th (1)th to 7th (4th) diagrams are ethanol (Example 1), acetone (Example 2) and acetic acid (Example 3) as solvents. The FTIR spectrum. In these figures, the simple 2 and s〇2 functional groups of the arsenic amine are shown and no signal due to solvent residue is detected. 27 201026674 Examples 1 to 3 It was confirmed that by selecting a different solvent, after the treatment of the arsenylamine raw material by the continuous SAS method, in addition to being able to effectively reduce the particle size, different crystal forms can be produced without leaving a solvent. Ethyl acetate was selected as a solvent to observe the effects of pressure, temperature, solution concentration, and solution flow rate. [Examples 4 to 9] Pressure and temperature effects Examples 4 to 9 were carried out in the above apparatus, operation steps, and analysis methods. Examples 4 to 9 are operated at 100 bar, 120 bar, and 140 bar, respectively, under the conditions of a solvent of ethyl acetate, a solution concentration of 30% of a saturated concentration, and a solution flow rate of 1 ml/min. The operating temperature was observed at 35 ° C and 55 ° C to observe the effects of pressure and temperature. The operating parameters of Examples 4 to 9 are shown in Table 3 below. Table 3 Example Solvent solution flow rate (ml / min) Concentration (saturated concentration, %) Temperature (°C) Pressure (bar) Average particle size (micron) Standard deviation (micron) Recovery (%) 4 Ethyl acetate 1 30 35 100 0.73 0.34 60.81 5 Ethyl acetate 1 30 35 120 0.82 0.32 83.63 6 ethyl acetate 1 30 35 140 1.04 0.49 84.66 7 ethyl acetate 1 30 55 100 0.88 0.33 63.96 8 ethyl acetate 1 30 55 120 0.90 0.37 59.37 9 ethyl acetate 1 30 55 140 1.18 0.54 47.81 Note: B醯 醯 醯 原料 原料The average particle size was 19.64 μm, the standard deviation was 13.2 μm, and the saturated threshed skin in acetic acid was 0.6 mg/ml. In Comparative Examples 4 to 6, the pressure effect at a fixed temperature of 35 ° C was observed. Figure 8 (a) shows the acetonitrile azo hydrazide 201026674 amine microparticles prepared in Example 4 (pressure 100 bar) having a rod shape and a particle size of about 微米73 μm. Fig. 8(b) is a graph of Example 5 (pressure is i2 〇巴) prepared by B_& ray particles having a crystal appearance of a rod shape of about G 82 μm. Fig. 8(1) is a graph of Example 6 (pressure: 140 bar) of styrene azoamine fine particles having a crystal morphology of a rod shape and having a particle diameter of about 1, 〇 4 μm. Fig. 9 is a graph showing the particle size and distribution of the acetophenazoamine fine particles obtained in Comparative Examples 4 to 6. As can be seen from the figure, the particle size increases with increasing pressure at a fixed temperature of 35 〇c. Comparing Examples 7 to 9, the pressure effect at a fixed temperature of 55 ° C was observed. The (a) figure is an acetonitrile azoamine fine particle obtained by the example 7 (pressure: 1 bar), which has a crystal appearance of a rod shape and a particle diameter of about 〇·88 μm. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 8 is an example of an acetaminophen azoamine fine particle obtained by a pressure of 120 bar, which has a crystal grain shape and a particle diameter of about 〇 9 μm. The first 〇 (c) is the acetamidamine fine particle obtained in Example 9 (pressure: 140 bar), which has a rod shape and a particle diameter of about 1.18 μm. Fig. 11 is a graph showing the particle size and distribution of the acetoxiranamine fine particles obtained in Comparative Examples 7 to 9. As can be seen from the figure, the particle size increases with increasing pressure at a fixed temperature of 55 ° C. For the temperature effect, Comparative Example 4 (temperature 35 ° C) and 7 (temperature 55: (:) prepared acetonitrile azoamine microparticles] under the conditions of a pressure of 1 Torr. The average particle diameter was 0.73 μm and 0.88 μm, respectively. Under the conditions of a pressure of 120 29 201026674 bar, Comparative Example 5 (temperature 35 ° C) and Example 8 (temperature 55 ° C) were prepared. The 醯 醯 醯 微粒 微粒 微粒 , , , , 微粒 微粒 微粒 0.8 0.8 0.8 0.8 0.8 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯The particle diameters were 1.04 μm and 1.18 μm, respectively. Therefore, it can be seen from the above comparison that the particle size and distribution of the acesulfonamide particles increase with increasing temperature. From Examples 4 to 9, Under the conditions of a pressure of 100 bar and a temperature of 35 ° C (Example 4), the minimum particle size (0.73 ± 0.34 μm) of acetamidine azoamine microparticles can be obtained. Therefore, the pressure is 100 bar and the temperature is Observation of the effects of the following solution concentrations and solution flow rates was carried out under operating conditions of 35 ° C. [Examples 10 to 13] Effect of concentration and flow rate of ruthenium amide solution Examples 10 to 13 were carried out in the above apparatus, operation steps and analysis methods. Examples 10 to 13 were in which the solvent was ethyl acetate, the temperature was 35 ° C, and the pressure was Under 100 bar conditions, 30% and 90% of the saturated concentration were used as the solution concentration, and 1 ml/min and 2 ml/min were used as the solution flow rate to observe the concentration of the acetaminophen solution and the solution flow rate. The operating parameters of Examples 10 to 13 are shown in Table 4 below. 30 201026674 Table 4 Example solvent solution flow rate (ml/min) Concentration (saturated concentration, %) Temperature (°c) Pressure (bar) Average particle size (micron) Standard deviation (micron) Recovery (%) 10 Ethyl acetate 1 30 35 100 0.73 0.34 60.81 11 Ethyl acetate 1 90 35 100 0.36 0.12 36.17 12 Ethyl acetate 2 30 35 100 2.96 1.90 28.84 13 Ethyl acetate 2 90 35 100 2.83 2.07 70.74 Note: The average particle size of the acetaminophen amide is 19.64 μm and the standard deviation is 13.2 μm. The saturated solubility of acetamidine in ethyl acetate is 0.6. Mg/ml. Comparative implementation 10 and 11, the effect of the solution concentration at a fixed solution flow rate of 1 ml/min can be observed. Figure 12 (a) is an example of the acetonitrile azo prepared in Example 10 (solution concentration is 30% of the saturated concentration). The guanamine granules have a crystal appearance of a rod shape and a particle diameter of about 0.73 μm. The 12th (b) is an acetonitrile azoamine granule prepared in Example 11 (solution concentration is 90% of a saturated concentration). The crystal grain is a regular rod shape and has a particle diameter of about 0.36 μm. Comparing Examples 12 and 13, the effect of the solution concentration at a fixed solution flow rate of 2 ml/min was observed. Fig. 13 (a) is an acetaminophen azoamine fine particle obtained in Example 12 (solution concentration is 30% of a saturated concentration), which has an irregular crystal appearance and a particle diameter of about 2.96 μm. Fig. 13 (b) is a graph of acetonitrile azoamine fine particles prepared in Example 13 (solution concentration of 90% of a saturated concentration) having a crystal grain shape and a particle diameter of about 2.83 μm. From the above comparison, the particle size and distribution of the acetaminophen azoamine microparticles decreased as the concentration of the solution increased. For the effect of the flow rate of the acetaminophen solution, the comparative example 10 (solution flow rate of 1 ml/min) and 12 (solution flow rate of 2) were carried out under the condition that the solution concentration was 30% of the saturated concentration.毫升 分钟 分钟 所 所 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 The acetonitrile azoamine microparticles prepared by a solution flow rate of 1 ml/min and 13 (solution flow rate of 2 ml/min) had an average particle diameter of 0.36 μm and 2.83 μm, respectively. From the above comparison, it can be observed that the particle size and distribution of the acesulfonamide particles increase with the increase of the solution flow rate. It can be seen from Examples 1 to 13 that the optimum conditions for preparing the acetoinamide particles of the present invention by the continuous SAS method are ethyl acetate, a pressure of 1 bar, a temperature of 35 ° C, and acetamidine. The concentration of the azoamine solution was 90% of the saturated concentration, and the flow rate of the acetaminophen solution was 1 ml/min. Under the optimum conditions, acesulfonium azoamine fine particles having an average particle diameter of 0.36 ± 0.12 μm can be obtained. [Dissolution rate analysis] From the above examples, it was found that the solvent was ethyl acetate, the pressure was 100 bar, the temperature was 35 ° C, the solution concentration was 90% of the saturated concentration, and the solution flow rate was 1 ml/min. The acetonitrile azoamine microparticles having a minimum average particle diameter of 〇.36 ± 0.12 μm and a crystal form of the second type were obtained (Example 11). The average particle size is 4.95 ± 2.97 μm and the crystal is obtained under the conditions of a solvent of ethanol, a pressure of 100 bar, a temperature of 35 ° C, a solution concentration of 30% of a saturated concentration, and a solution flow rate of 1 ml/min. The type is acetaminophen microparticles of the first type (Example 1). The following is an analysis of the dissolution rate of the acetaminophen azoamine particles prepared by the above two operating conditions to compare the dissolution rates of acetophenone amide before and after the continuous SAS treatment. 32 201026674 Figure 14 is an absorption spectrum obtained by scanning the acetaminophen at full wavelength of the ultraviolet-visible spectrometer in the simulated intestinal fluid. As can be seen from the figure, the maximum absorption wavelength of acetamidine is 266.8 nm. Figure 15 is a graph showing the absorbance versus concentration of UV-visible acetonitrile. Figure 16 is a comparison of a ruthenium amide derivative having a crystal form of a second type, an acetaminophen microparticle having a crystal form of the second type (Example 11, optimum operating conditions), and a crystal form. A graph showing the dissolution rate of the acetaminophen microparticles of the first type (Example 1, solvent is ethyl alcohol). It can be seen from Fig. 16 that the acetaminophen azoamine microparticles prepared under the optimal operating conditions have a significantly improved dissolution rate compared to the acetaminophen amide derivative, and the solvent is ethanol. The crystal form prepared under the operating conditions is the first type of acetamidine azoamine microparticles, which has a slower dissolution rate. If the Weibull mode is used to describe the dissolution behavior of acetaminophen amide, the dissolution rate coefficient of the acetaminophen amide is 0.0626 min·1; the acetonitrile obtained under the optimal operating conditions The elution rate coefficient of the nitrogen amide microparticles was 0.2745 min·1; the dissolution rate coefficient of the acetaminophen azoamine microparticles of the first type prepared under the operating conditions of the solvent was ethanol was 0.0399 mirT1. Therefore, the dissolution rate of the acetaminophen azoamine microparticles produced under the optimum operating conditions is increased by about 4.4 times compared to the acetaminophen amide starting material, and is produced under the operating conditions of the solvent being ethanol. The dissolution rate of the acetaminophen microparticles was reduced by about 0.64 times. Since the crystal form is the type I acetaminophen nitrite particles, the density is larger than that of the crystal form 33 201026674 is the second type of arsenazo amide particles, and the crystal form is the first type of acetamidine amide. The kinetic stabiuty of the particles is extremely high at temperatures, so the dissolution rate is slower. As described above, 'the present invention is a continuous supercritical antisolvent process for preparing acetamidine azoamine microparticles' by different operating conditions (solvent, operating pressure and temperature, and concentration and flow of the azo arsenic amine solution). Rate) Acetyl azo amide particles with smaller particle size and more uniform distribution, and different crystal morphology and crystal form, can be used for production _ type. In addition, the present invention also analyzes the elution rate of & ® azo arsenamide particles having different crystal diameters to compare the dissolution rates of acetaminophen before and after supercritical antisolvent treatment. The optimum operating conditions for the preparation of acetaminophen azoamine microparticles by a continuous supercritical antisolvent method are: ethyl acetate, pressure bar, temperature 35. 〇, the solution concentration is 9G% of the saturated concentration, and the solution flow rate is 丨ml/min. Under the optimal operating conditions, the acetonitrile azoamine particles with a minimum average particle size of 0 36 ± 0 12 μm can be obtained, and the crystal appearance thereof is changed from the irregular block Φ of the acetaminophen amide compound to The rule is rod-shaped, and its dissolution rate is about 4.4 times higher than that of the arsenylamine bulk drug. Further, when ethanol is used as the solvent, the crystal form of the produced acetaminophen amide fine particles is converted from the second plastic to the first type of the acetaminozoamine raw material drug. The guanamine microparticles have a smaller particle size and a higher dissolution rate, so for pharmaceutical applications such as diuretic, hypotensive, anti-glaucoma, anti-alpine, anti-epileptic, anti-edema, or for Manufacturing pharmaceuticals are more advantageous. 34. The above embodiments are merely illustrative of the principles and functions of the present invention and are not intended to limit the invention. Modifications and variations of the above-described embodiments can be made by those skilled in the art without departing from the spirit and scope of the invention. Therefore, the scope of the invention should be as set forth in the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic diagram showing the operation principle of the supercritical antisolvent (SAS) method; Fig. 2 is a schematic diagram showing the production equipment of acetaminophen azoamine microparticles; Fig. 3 (a) is a diagram Electron micrograph of the azoamine drug substance; Figure 3 (b) is an electron micrograph of the acesulfonamide microparticle of Example 1; and Figure 3 (c) is the arsenazo of Example 2. Electron micrograph of the amine microparticles; Fig. 3(d) is an electron micrograph of the acesulfonium azoamine microparticles of Example 3; and Fig. 4 is the acetaminophen microparticles of Examples 1, 2 and 3. Comparison of particle size and distribution; Figure 5 (a) is an analysis chart of differential scanning card method (DSC) of acetaminophen amide drug substance; Figure 5 (b) is an example of Analysis chart of DSC of azoamine microparticles; Figure 5(c) is an analysis chart of DSC of acetaminophen microparticles of Example 2; Figure 5(d) is an acetonitrile of Example 3 An analysis chart of DSC of guanamine microparticles; Fig. 6 (a) is an X-ray diffraction pattern of an acetaminophen acetonide drug substance; and Figure 6 (b) is an acetaminophen azoamine particle of Example 1. X-ray diffraction pattern; Figure 6 (c) X-ray diffraction pattern of the acetoinamide particles of Example 2; Figure 6(d) is an X-ray diffraction pattern of the acetophenazoamine particles of Example 3; 35 201026674 Section 7(a) Figure is the Fourier transform infrared (FTIR) spectrum of the acetamidoamine drug substance; Figure 7 (b) is an example! FTIR spectrum of acetaminophen microparticles; Figure 7 (c) is an FTIR spectrum of the acetaminophen microparticles of Example 2; and Figure 7 (d) is a diagram of Example 3 FTIR spectrum of guanamine microparticles; Fig. 8(a) is an electron micrograph of acesulfonium azoamine microparticles of Example 4; and Fig. 8(b) is an acetonitrile azoamine granule of Example 5. Electron micrograph of Fig. 8(c) is an electron micrograph of the acetaminophen microparticles of Example 6; Fig. 9 is the particle size of the acetophenamide microparticles of Examples 4, 5 and 6. Comparison of size and distribution; Fig. 10(a) is an electron micrograph of the acetaminophen microparticles of Example 7; and Fig. 10(b) is an electron of the acetonitrile azoamine microparticles of Example 8. Micrograph; Figure 10(c) is an electron micrograph of the acetaminophen microparticles of Example 9; Figure 11 is the particle size and size of the acetonitrile azoamine microparticles of Examples 7, 8 and 9. Comparison of the distribution; Figure 12 (a) is an electron micrograph of the acetaminophen microparticles of Example 1; and Figure 12 (b) is an electron microscope of the acetaminophen particles of Example 11. Figure; 13 (a) is an electron micrograph of the acetaminophen microparticles of Example 12; and Figure 13 (b) is an electron microscope of the acetaminophen microparticles of Example 13 201026674. Absorption spectrum of full-wavelength ultraviolet-visible light of azoinamide; Figure 15 is a standard curve of absorbance versus concentration of ultraviolet-visible light of acetamidine; and Figure 16 compares acetaminophen with acetonitrile A graph of the dissolution rate of the drug substance, the acetoin azoamine microparticles of Example 1, and the arsenyl amide microparticles of Example 11. [Main component symbol description]

1 carbon dioxide cylinder 2 cold; east circulation tank 3, 13 high pressure pump 4 constant temperature water bath 5 preheater 6 sample bottle 7 sedimentation tank 8 pressure transmitter 9 thermocouple temperature measuring component

10 filter 11 cone bottle 12 float flowmeter

Al, A2, A3, A4, A5 two-way needle valve Bl, B2, B3 check valve C back pressure valve D three-way ball valve E micro-metering valve 37

Claims (1)

201026674 VII. Patent application scope: 1. An Acetazolamide microparticle with an average particle size of less than 18 microns (μπι). 2. The acetoinamide particles of claim 1 having an average particle size of less than 15 microns. 3. The acetoinamide particles of claim 1 having an average particle size of less than 10 microns. 4. The acetaminophen microparticles of claim 1 having an average particle size of less than 5 microns. 5. The acetoinamide microparticles of claim 1 having an average particle size of less than 1 micron. 6. The acetaminophen microparticles according to any one of claims 1 to 5, wherein the crystalline form is Form I or Form II. 7. The acetoinamide particles according to any one of claims 1 to 5, which are in the form of a regular rod. 8. The acetoinamide microparticles of any one of claims 1 to 7 for use in diuresis, intraocular pressure reduction, antiglaucoma, anti-alpine, anti-epileptic and/or anti-edema. 9. A process for the preparation of the acetoinamide particles according to any one of claims 1 to 8, comprising mixing an acetoin amide solution with a supercritical fluid to precipitate acetamidine amide particles Wherein the solvent of the acetaminophen solution is miscible with the supercritical fluid. 10. The method of claim 9, wherein the solvent is selected from the group consisting of methanol, ethanol, dichlorohydrazine, N-methyl-pyrrolidone (NMP), ethyl acetate , acetone, and combinations thereof. The method of claim 9, wherein the solvent is ethyl acetate. 12. The method of claim 9, wherein the concentration of the arsenylamine solution is at least 10% of the saturation concentration. 13. The method of claim 9, wherein the concentration of the acetaminophen solution is at least 25% of the saturation concentration. 14. The method of claim 9, wherein the concentration of the acetaminophen solution is at least 50% of the saturation concentration. 15. The method of claim 9, wherein the concentration of the acetaminophen solution is at least 75% of the saturation concentration. 16. The method of claim 1, wherein the supercritical fluid system carbon dioxide. The method of any one of clauses 9 to 16, wherein the mixing is carried out by delivering the acetaminophen solution to a vessel containing the supercritical fluid. 18. The method of claim 17, wherein the acetaminophen solution has a flow rate of from 1 ml/min to 5 ml/min. 19. The method of claim 1, wherein the flow rate of the acetamidine oxime solution is from 毫升·8 ml/min to 丨.5 ml/min. The method of any one of clauses 9 to 16, wherein the mixing is carried out at a pressure of from 80 bar to 160 bar and at a temperature of from 2 〇 ° c to 70 ° C. 21. The method of claim 20, wherein the mixing is carried out at a pressure of from 90 bar to 110 bar and at a temperature of from 30 ° C to 45 t. The method of any one of clauses 9 to 16, further comprising a purification step of removing a solvent remaining in the precipitated acetaminophen microparticles. The method of claim 22, wherein the purifying step comprises introducing the supercritical fluid into the precipitated acetaminophen microparticles. 24. The method of any one of claims 9 to 16, which is a Supercritical Anti-Solvent (SAS) method. 25. Use of an acetophenine amide microparticle according to any one of claims 1 to 7 for the manufacture of a medicament for use in diuresis, intraocular pressure reduction, antiglaucoma, anti-alpine disease, anti-epilepsy Cancer and / or anti-edema. 26. An agent for diuresis, intraocular pressure reduction, anti-glaucoma, anti-alpine disease, anti-epilepsy and/or anti-edema comprising the acetophenone amide particles according to any one of claims 1 to 7. .