JPS6373964A - Freeze fine pulverization of crystal - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a method for finely pulverizing crystals of drugs such as pharmaceuticals and agricultural chemicals. Specifically, the present invention relates to a method of finely pulverizing crystals of drugs such as pharmaceuticals and agricultural chemicals. Regarding how to.

Pharmaceuticals, pesticides, etc. obtained by conventional techniques such as extraction, synthesis, and semi-synthetic methods are purified and obtained as crystals, but these drugs are further processed as crystals to formulate tablets, powders, cervical tablets, etc. Purified drugs need to be finely ground.

Conventionally, as a method of pulverizing, a method using a ball minnow vibrating ball minope impact crusher, a jet pulverizer, etc. is common.

Problems to be Solved by the Invention However, when a vibrating ball mill is used, the balls collide with each other and generate heat, so it is necessary to perform pulverization while cooling with cooling water or the like.

In addition, the balls are worn out due to collision, and the worn particles are mixed into the pulverized product, making it difficult to obtain a pure pulverized product.

Furthermore, the structure of the above-mentioned crusher is complicated, and in some cases,
Powder adheres to the inside of the pulverizer, which is a considerable disadvantage when pulverizing a wide variety of products in small quantities, such as pharmaceutical products.

Means for Solving the Problems The present invention aims to provide a method for crushing drug crystals without such disadvantages, and the object is to suspend drug crystals in a liquid medium and form droplets with a diameter of 500 microns or less. After dropping the drug crystals together with the medium into a liquefied gas refrigerant maintained at a low temperature below the melting point of the medium to form micro-frozen particles containing drug crystals with a particle size of 500 microns or less, This is achieved by injecting particles and applying impact force by fir impaction to crush them.

According to the present invention, drug crystals are microfrozen with a medium. That is, if the slightly frozen particles are sandwiched in a hard frozen medium and are forced to collide with a resistor or collide with each other, the frozen medium acts as a grinding agent during the collision, causing the crystals to break down. It is suitable for efficient pulverization and is particularly suitable for pulverizing crystals to a size of 5 to 50 microns or less.

The present invention can be applied without particular limitation as long as it is a drug that can be purified as a crystal. For example, antibiotics (
Penicillin antibiotics such as ampicillin, hetacillin, amoxicillin, cyclacillin, carbenicillin or their non-toxic salts, cephalosporin antibiotics such as cephalexin, cefazolin, cephalothin, cefatridine, cefoxitin or their non-toxic salts, paromomycin, kanamycin, amikacin, Gentamicin.

Aminosugar antibiotics such as tobramycin or its non-toxic salts, chlortetracycline, tetracycline, doxycycline, metacycline antibiotics such as metacycline or its non-toxic salts, erythromycin, oleandomycin, leucomycin, josamycin,
Macrolide antibiotics such as midecamycin or its nontoxic salts, other polymyxin B, colistin, cycloserine, fosfomycin, ampicillin B, lycomycin, nyscutin, or its nontoxic salts), central nervous system drugs (diazepam, niskucilam, etc.) Hypnotic sedatives, phenytoin, meprobamate.

Antiepileptic drugs such as nitrazepam, acetaminophenone, indomethacin, mefenamic acid, diclofenac,
antipyretic analgesic antiinflammatory agents such as flufenamic acid), peripheral nerve drugs (
local anesthetics such as procotylin and lidocaine, muscle relaxants such as trivericin hydrochloride and dantrolene sodium, agents for autonomic nerves such as atropine and levodopa, etc.), agents for the circulatory system (Dikitasos, etc.).

Cardiac inotropes such as ubidecarenone, diuretics such as theophylline, spironolactone, and trypamide, antihypertensive agents such as reserpine, clonidine hydrochloride, methyldopa, syrosingopine,
Vasoconstrictors such as dihydroergotamine mesylate and dihydroergotoxine mesylate; vascular reinforcing agents such as rutin and carbazochrome; coronary vasodilators such as nitroglycerin, isosorbitol nitrate, nifedipine, and dipyridamole;
Others (pentoxifylline, cytochrome C, citicoline, dopamine hydrochloride, etc.), respiratory agents (ephedrine,
Codin and other S, ft0if expectorants, other isoproterenol, cromoglylic acid, dextromethorphan, etc.), digestive system drugs (allantoin, etc.).

peptic ulcer treatment agents such as pirenzepine hydrochloride, urogastrone, cimetidine, etc.), metabolic drugs (vitamin 82,
Vitamins such as dianocobalamin, other veterinary drugs such as glutathione, ATP, gabexate mesylate, etc.), chemotherapeutic agents (clotrimazole, pyrrolni, IJ, nalidixic acid, sulfa drugs, etc.), iron citrate, Sodium citrate, succinic acid, sodium saccharinate, sodium tartrate, potassium sorbate, sodium sorbate, calcium carbonate, thiamine hydrochloride.

Food additives such as calcium lactate, iron lactate, calcium pantothenate, riboflavin, sodium malate, chlorine insecticides such as aldrin, dieldrin, edion, phosphorus insecticides, carbamate ester insecticides, chloranil, ziclone, etc. Quinone-based fungicide, thiocarbamate-based fungicide.

Examples include agricultural chemicals such as organic mercury fungicides, organic tin fungicides, phenol fungicides, and triazine fungicides.

In addition, the liquid medium used in the present invention is one that does not dissolve the target drug crystals or exhibits a solubility of 0.5% or less even if dissolved, is liquid at room temperature or room temperature, and has a temperature higher than the boiling point of the refrigerant. There are no limitations at all as long as it has a melting point at that temperature. Furthermore, the lower the boiling point of this medium, the easier it is to remove, and
For example water (mpO<0>C, bploO<0>C) or aqueous salt solutions.

Ethanol (mp-114, 5°C, bp 78.3°C).

Allyl alcohol (mp -129℃, bp97.1
°C), isobutyl alcohol (mp-85, 5 °C).

bp68℃), isopropyl alcohol (mp-86,
0℃, bp82.0℃), propyl alcohol (mp-
126℃, bp97.4℃), methanol (mp-98
℃, bp64.6℃), lower alkyl alcohols,
Isopropylamine (mp-101, 2℃, bp 33℃
), ethylamine (mp-83, 3°C, bp 16°C),
Diethylamine (mp-48°C, bp 55.9°C), dimethylamine (mp-96°C, bp 7°C), butylamine (mp-50,5°C, bp 77.8°C), ter
t-Butylamide 7 (mp-67,5℃, bp45.2℃
), propylamine (mp-83,0℃, bp47.8
℃).

Lower alkylamines such as methylamine (mp-92.5°C, bp-5.5°C), acetone (mp-94°C, b
p56.3°C), ethyl methyl ketone (m p -'8
6.6℃, bp79.4℃), diethylkene (mp-
Lower alkyl ketones such as 42,0℃, bplol, 7℃), ethyl ether (mp-116,3℃, bp34
．． 6°C), propyl ether (mp-122°C, bp9
Lower alkyl ethers such as 0.6°C), ethylene dichloride (mp-35, 3°C, bp 83.7°C),
tert-butyl chloride (mp-28, 5°C, bp
51.0°C), propyl chloride (mp-122,8
℃, bp46.4℃), methylene dichloride (mp-
96℃.

b p 41.6°C), chloral (mp-57.5,
℃.

bp98℃), riooform (mp-63, 5℃).

b p 61.2°C), carbon tetrachloride (mp-22,6°C
.

bp 76.7°C), tert-butyl chloride (mp-20°C, bp 73.3°C), methyl bromide (mp-93°C, bp 4.5°C), methylenebuO'phyto (mp-52, 8°C, bp 97°C), trichloroethylene (mp-73°C, bp 87.2°C), fluorogenzea (mp-41,2°C, bp 85°C), Phosge 7 (
mp-128°C, bp 8°C> and other halogenated hydrocarbons, methyl acetate (mp-98°C).

b p 57.1°C), ethyl propionate (mp-7
3.9°C, bp99.1°C), methyl propionate (m
Lower fatty acid esters such as p-87,5℃, bp79.7℃), imbutylene (mp-146,8t, bp-6
, 6°C), isoprene (mp-120t, bp34.5
°C), cyclohexe 7 (mp-103, 7 °C, bp83
．． 3℃), cyclohexane (mp'D, D℃, bp80
．． 8℃) cyclohentanene (mp-85℃, bp41
℃), cyclohentane (mp-93, 3℃, bp 49℃
) 1 pentene (mp-93, 3℃, bp44℃)
, 2,2-dimethylbuta7 (mp-98, 2°C, bp4
9.7℃), neohentane (mp-19.8℃, bpl
.

°C), butane (mp-135 °C, bp-0,5 °C).

2-butene (mp-127°C, bp1°C), hene, yn (mp-90°C, bp98.4°C), benzene (mp5
．． 5°C, bpgo, t°C), pentane (mp-130,
8° C., bp 36.2° C.), a single solvent or a mixed solvent of two or more of saturated, unsaturated or cyclic hydrocarbons may be used.

Further, the size and shape of the crystal-containing frozen particles are not particularly fixed as long as they can be ejected from a known nozzle. However, if the particle size is 500 microns or more, it will take a lot of energy to blow it out, so frozen particles with a particle size of 500 microns or less are preferable, especially if they are dropped onto a refrigerant with ripples formed on the surface. Preferably, it is a free-flowing water sphere with a particle size of 500 microns or less produced by this method.

In order to make water spheres with a particle size of 500 microns or less, which is preferably used in the present invention, a height of 5+n is required on the surface of the refrigerant.
It is necessary to form a ripple of n+ to 20 mm.

In addition, the refrigerant is not particularly limited as long as it liquefies below the melting point of the medium used, but generally liquid nitrogen,
-150℃ of liquid helium, liquid argon, liquid air, etc.
The following refrigerants are preferred.

However, in order to continuously produce smooth water spheres, it is preferable to keep the temperature of the refrigerant 10 to 20°C lower than the melting point of the medium.

In addition, if the crystal content of the frozen particles containing drug crystals is too high, the function of the freezing medium as a grinding agent will be reduced, and if the crystal content is too low, it will be difficult for direct impact force to be transmitted to the drug crystals. , the crystal content is 0.005g/mf
It is preferable that it is l~0.5g/mj2.

Further, the distance between the injection position of the crystal-containing frozen particles and the collision surface can be appropriately selected depending on the shape, size, and injection speed of the drug crystal-containing frozen particles, but is usually, for example, 10++ on to 100 m.
The temperature of the crystal-containing frozen particles at the time of injection is maintained at a temperature below the melting point by the above-mentioned refrigerant and then ejected.

As for the above-mentioned collision surface, a hard plate as a resistor is exemplified, and this may be plate-shaped or curved in various shapes. A high ceramic plate, a rigid metal plate, etc. are preferably used.

Moreover, instead of the hard plate, as shown in FIG. 9, the finely frozen particles may be ejected from at least two or more injection devices 91, and the finely frozen particles may be jetted and collided with each other. In this case, the injection angle α is not particularly limited, but when the distance from the collision surface is set to the intersection point of injections from two or more injection devices 91, the injection angle α is 60 to
The collision may be made at an angle of about 120 degrees.

Furthermore, after the collision is made in this manner, a resistor may be installed at the rear of the collision to cause a two-stage collision.

Furthermore, since the finely frozen particles jetted and collided as described above are crushed by the collision and are also floating inside the jetting device, for example, using a sample collection device as shown in FIG. It is preferable to inject it at. By installing one or more of the above-mentioned injection devices in the center of this sample collection device (diameter 500 mm, height 110 mm) and then injecting the particles, the ejected finely frozen particles collide and then spread in the horizontal direction. The pressure is reduced and the speed is reduced by the partition plate 94, and the crushed finely frozen particles are recovered. Further, the crushed finely frozen particles thus collected may be thawed once as necessary, and then re-formed into finely frozen particles and crushed by injection collision two or more times.

The pulverized granules pulverized according to the present invention can be washed by a known method, for example, by raising the temperature to remove the medium, or by raising the temperature and adding another solvent that is miscible with the medium and does not dissolve the drug. The medium and crystals are separated and recovered.

Next, an example of a device suitable for carrying out the present invention will be explained based on FIGS. 1 to 10.

FIG. 1 is a schematic diagram of an apparatus suitable for carrying out the present invention. In FIG. The containing suspension is preferably made into micro-frozen grains of less than 50 (H chrome).

The finely frozen particles are sucked through the beam lid 60 and discharged to a belt conveyor 70 having a screen-like belt,
It is stored in the stocker 80. A pipe 81 is connected to the bottom of the stocker 80, and low-temperature nitrogen gas or air is supplied from the liquid pipe 81 to suspend the slightly frozen particles in the stocker 80. The finely frozen particles in the stocker 80 are led through a pipe 82 to a side port of an injection device 91 provided at the top of a collection box 90. The central part of the injection device 91 has a hard plate 92 for accelerating the finely frozen particles.
Low-temperature nitrogen gas or air is injected into the tube 93.
Supplied via. The distance between the injection position from the nozzle end of the injection device 91 and the hard plate can be selected as appropriate depending on the shape and size of the finely frozen particles, but is usually 10 mm.
It is set between ~100mm. The finely frozen particles injected from the injection device 91 in this manner collide with the hard plate 92 and are crushed. The material of the hard plate 92 can be selected as appropriate depending on the hardness of the finely frozen particles and the injection speed, but a ceramic plate is preferably used.

The recovered finely frozen particles are separated into a solvent and crystals by a known sorting method.

Next, the microfrozen grain manufacturing apparatus 50 shown in FIG. 1 will be explained in detail.

FIG. 2 is a flow sheet of the micro-frozen grain manufacturing apparatus 50 shown in FIG. 4 is a seed generator for applying kinetic energy to the refrigerant liquid surface and generating ripples on the liquid surface; 4 is a spraying device for mixing the gas and the crystal-containing suspension and atomizing it; 5 is a seed generator for generating ripples on the liquid surface of the refrigerant; control device, 60
7 is a cooling device for the crystal-containing suspension to be frozen and the gas mixed therein; 8 is a refrigerant liquid supply device; 9 is a supply device for the crystal-containing suspension; 10 is a mixing device This is a gas supply device.

The refrigerant liquid storage container 1 is made of stainless steel (SUS304)
It is a rectangular body-shaped container made of aluminum, with the lower part shaped like an inverted square pyramid. The container 1 has external dimensions of 400 mm in width, 400 mm in length, and 1200 mm in total height, and the outer wall of the container is provided with vacuum insulation (not shown).

In the refrigerant liquid storage container 1, liquid nitrogen supplied from the refrigerant liquid supply device 8 through the refrigerant liquid supply pipe 11 is stored as the refrigerant liquid 2, and the liquid level is about 500 m above the bottom of the container.
The height is set and maintained at mm.

The refrigerant liquid level is controlled by a liquid level detector 5a and a liquid level control panel 5.
This is carried out by a liquid level control device 5 comprising a control valve 5C and a control valve 5C, and the liquid level is always maintained at a predetermined set level.

The seed generator 3 is used to produce water spheres with a particle size of 500 microns or less, which is preferably used in the present invention,
It gives kinetic energy to the refrigerant liquid to generate ripples on the liquid surface, and includes an aeration pipe 3a, an aeration adjustment valve 3b, and a flow meter 3C.
It is composed of etc.

As shown in FIGS. 3 and 4, the diffuser pipe 3a is formed in a rectangular shape and is horizontally disposed at a position of 40 to 150 m+m below the liquid level. Note that if the depth of the aeration tube 3a is too deep, the gas will be cooled and the effect of the bubble flow as described later will be reduced, and the consumption of the refrigerant liquid and the aeration gas (refrigerant gas) will increase. Therefore, the depth of the diffuser pipe 3a is preferably within 100 mII1.

Gas ejection holes 3 are provided in the diffuser pipe 3a at a pitch of 50 to 100 mm.
d is opened substantially horizontally toward the center, and is connected to the refrigerant gas supply pipe 1 from the gas phase part of the refrigerant liquid supply device 8 shown in FIG.
2. Refrigerant gas is supplied through the regulating valve 3b and is ejected into the refrigerant liquid.

The flow rate of the refrigerant gas ejected from the diffuser pipe 3a is 200
~400n/m2. The optimal value is about 100 min, and as a result, as shown in FIG. 6, an upward flow of bubbles 13 is generated in the surface layer of the refrigerant liquid, and the bubbles 13 that have risen burst near the liquid surface. The kinetic energy imparted to the surface layer of the refrigerant liquid by these bubble flows generates ripples W with a wave height of 5 to 20 mm on the surface of the refrigerant liquid, and as will be described later, connecting branches that fall into the refrigerant liquid and are connected. is swung to prevent frozen particles from sticking to each other.

Furthermore, the presence of bubble flow reduces the liquid density at the surface layer of the refrigerant liquid, increasing the density difference between the refrigerant and the frozen particles, and promoting its settling.

The wave height of the ripples is optimally about 5 to 1 (bnm); if the wave height is 20 mm or more, the settling of frozen particles will be inhibited by the stirring action of the surface layer of the refrigerant liquid.

In addition, as shown in FIG. 2, an aeration pipe 3a is used as a seed generator 3.
is used to supply the refrigerant gas from the gas phase part of the refrigerant liquid supply device 8, but it is also possible to provide a separate refrigerant gas storage facility and supply the refrigerant gas from there to the diffuser pipe 3a. good. Furthermore, as long as the gas has a low dew point or a gas containing CO2, it is also possible to use, for example, air that has been subjected to CO2 removal treatment instead of the refrigerant gas.

As the seed generator 3, a device having the following configuration can be used in this pond.

(a) Sprinkle tube type generator A liquid suction pipe with small holes is provided below the surface of the refrigerant liquid, and the refrigerant liquid from the refrigerant liquid supply device 8 is spouted from the liquid suction pipe.

In this case, the refrigerant liquid supply pipe 11 shown in FIG. 1 becomes unnecessary, and a refrigerant liquid return pipe is provided in its place to maintain a constant refrigerant liquid level.

(b) Oscillator type ripple generator As shown in FIG. 5 and FIG. The oscillator is operated by a motor 21 or the like installed outside the container 1, and mechanical vibrational energy is applied to the refrigerant liquid 2 to generate ripples on the refrigerant liquid surface.

(C) Vibrator-type ripple generator 5 As shown in FIG. 11, a sonic vibrator 22 that emits a vibration force of a desired frequency is provided outside or inside the refrigerant liquid storage container 1, and sonic energy is transmitted through the vibrator. It is applied to the refrigerant liquid 2 to generate ripples on the refrigerant liquid surface.

ω) Injection type ring generator An injection pipe is arranged above the refrigerant liquid surface, and the refrigerant gas,
A gas with a relatively high dew point, such as air that has been subjected to CO□ removal, or a refrigerant liquid is injected toward the liquid surface, giving kinetic energy to the refrigerant liquid and generating ripples on the liquid surface.

(e) Concussion type ripple generator As shown in FIG. By applying this, a shaking action is applied to the refrigerant liquid 2 inside the container, and ripples are generated on the liquid surface.

The spraying device 4 mixes the frozen stock solution to be made into frozen particles with gas, and converts the frozen stock solution in the gas-liquid mixture into droplets of 500 microns or less. FIG. 7 shows an example, in which a liquid inlet 4b and a gas inlet 4 are provided at the rear of the main body 4a.
C is formed, and both passages 4b' and 4c' are combined to form a throat portion 4d, where liquid and gas are mixed. The gas-liquid mixture exiting the throat portion 4d is further guided into the mixing chamber 4e, where it is stirred and dispersed by the guide vanes 4f, and then jetted out from the nozzle hole 4g.

It goes without saying that the spray device 4 may have any structure or form as long as it is equipped with a gas-liquid mixing mechanism and a mechanism that atomizes and sprays the gas-liquid mixture. .

The crystal-containing suspension to be made into finely frozen particles is supplied to the liquid inlet 4b of the spray device 4 from the crystal-containing suspension supply device 9 shown in FIG. It is supplied through a cooling device 7 etc., and the supply pressure is selected to be 1.0 to 2.0 kg/cd g. Further, gas that is relatively difficult to dissolve in liquid is supplied to the gas population 4C of the spray device 4 from the mixing gas supply device 10 through the pressure reducing valve 17,
1.0 through the flow meter 18, control valve 19, and cooling device 7
It is supplied with a pressing force of ~2.0 kg/Cig.

Further, in the apparatus shown in FIG. 2, the mixing gas supply device 10 is provided separately, but the mixing gas may be supplied from the gas phase portion of the refrigerant liquid supply device 8 to the spray bag W4.

The mixing ratio of the crystal-containing suspension and gas (liquid b/H + gas Nj7/m1n) is optimally selected to be 0.5 to 1.5, and by changing the mixing ratio, gas-liquid supply can be controlled. Even when the pressure is constant, the particle size of the frozen particles can be reduced to at least 1/10 of the diameter.

In addition, the smaller the diameter of the nozzle hole 4g, the better, but since there are problems such as difficulty in machining and occurrence of clogging,
A diameter of approximately ˜L Om+++φ is desirable.

The gas-liquid mixture formed in the throat portion 4d and mixing chamber 4e of the spray device 4 is evenly distributed in the outer circumferential direction by the guide vanes 4f, and is ejected from above from the nozzle 4g toward the refrigerant liquid surface. At this time, when the mixed gas passes through the nozzle 4g, it will be present inside the atomized liquid particles and between the liquid particles, and the gas contained in the liquid particles will expand. The liquid particles are further divided into fine particles, which are then dispersed. In addition, the air bubbles interposed between the liquid particles will cause the liquid particles to scatter more strongly.
Collision between fine particles during scattering acts to make them even finer particles.

On the other hand, the liquid particles ejected from the spray device 4 become spherical due to surface tension while falling within the container 1, and fall onto the refrigerant liquid surface. Therefore, the falling distance from the spray device 4 to the refrigerant liquid level and the temperature of the container space have a large influence on the particle size and morphology of the frozen fine particles, and the falling distance is
~1500 mm, the temperature of the container space may be kept at -15°C or less, but experiments have shown that it is desirable to keep it at -20°C or less.

The refrigerant liquid level control device 5 has the function of keeping the distance between the liquid level and the spray device 4 substantially constant, and uses a known liquid level detector 5.
a, a liquid level controller 5b, a control valve 5C interposed in the refrigerant liquid supply pipe 11, and the like.

Since the liquid level of the refrigerant liquid constantly fluctuates due to ripples, the liquid level is controlled so that the crest of the ripples is located within a predetermined level range.

The cooling device 7 lowers the temperature of the frozen stock solution and the mixing gas that are sprayed into the container 1, thereby reducing the amount of refrigerant liquid consumed. The cooling device 7 includes a liquid cooler 7a and a gas cooler 7.
b, and the refrigerant gas in the storage container 1 is introduced to cool the liquid and gas.

In the apparatus shown in FIG. 2, the liquid and gas are individually cooled, and after cooling, they are mixed and atomized by the spray device 4, but the gas-liquid mixing section and the atomization section are A configuration may also be adopted in which the mixture is separated, first mixed with gas and liquid, and then the mixture is cooled and then atomized.

The fine particles of the frozen stock solution ejected from the spray device 4 fall onto the refrigerant liquid surface and are frozen and hardened, and due to the action of the ripples on the refrigerant liquid surface, the frozen fine particles stick together and form a film. prevented and separate sequential sedimentation. The frozen fine particles that have settled to the bottom of the container are transported to the outside by a transport device 60 via a pipe connected to the bottom of the device 50.

The carry-out device 60 is a pneumatic transport type lid 60 and supplies the finely frozen particles carried out from the device 50 to a conveyor 70. In the device shown in FIG. 2, the above-mentioned pneumatic glue lid 60 was used as the +i release device, but as shown in FIG. It may be a screw conveyor type 11 output device consisting of a rotatably arranged screw rotating body 6b and a drive mokro C, etc., or a belt conveyor type unloading device or other type of conveyance device, such as the above-mentioned conveyance device. A microfrozen grain extraction pipe is opened from inside the microfrozen grain manufacturing equipment to the outside of the equipment container, and an upward flow accompanied by air bubbles is generated at the lower end of the extraction pipe inside the equipment, and the produced microfrozen grains are removed along with this upward flow. The frozen grains are taken out of the container together with the refrigerant through a take-out pipe, and the refrigerant and the finely frozen grains are separated into a transport bag (filed on July 23, 1985, patent application with the title of the invention: "Frozen grain removal device") Of course, it may also be used (see the specification of Sho 61-173317).

Next, examples of the present invention will be given, but the present invention is not limited by these in any way.

EXAMPLE Next, an example of the method of freezing and pulverizing crystals of the present invention will be described.

Example 1 150 g of cephalexin was suspended in 1000 mβ water at room temperature, and concentrated hydrochloric acid was added dropwise to dissolve the cephalexin (pH 1.8 to 1.9).

Then, after heating the mixture to 55° C., a concentrated aqueous ammonia solution was added under stirring to adjust the pH to 4.3. Thereafter, the precipitated columnar crystals (diameter of 30 to 50 microns) of cephalexin 1 were collected by filtration, further washed with a small amount of water, and dried.

The cephalexin 1 permanent crystals were dispersed in chloroform to prepare a 0.1 g/ml cephalexin suspension. Then, an experiment was conducted using the apparatus shown in FIG. 1 described above. In this device, the refrigerant liquid reservoir 1 has a single folded surface of 400 mm x 400 mm.

Forming a container in which the height of the square body is 900 mm and an inverted square pyramid part with a height of 300 mm is provided below the body,
Liquid nitrogen was poured as the refrigerant liquid 2 to a height of 500 mm from the bottom of the container. That is, the distance from the container ceiling to the refrigerant liquid level was 700 mm.

In addition, a square air diffuser (350 mm
X 350++un) was installed horizontally, and nitrogen gas from the gas phase of the liquid nitrogen supply tank was supplied at a rate of 300β/m' from the diffuser pipe toward the center of the container.

Ripples with an average wave height of 8 mm were generated on the outer surface of the liquid nitrogen.

On the other hand, the frozen stock solution was the above cephalexin suspension, and the mixing gas was nitrogen gas (25°C) stored in a high-pressure container.
The suspension was supplied at a flow rate of 0.2j'/min and nitrogen gas at lj! Mix both at a flow rate of 0.5 m/min.
From a spray device (located approximately 700 mm above the liquid nitrogen level) having a nozzle hole of mφ, the mixed fluid is directed toward the liquid surface at a spray pressure of 2 to 2.5 kg/aI11 after mixing. Sprayed. Further, the maximum temperature in the upper space inside the container at this time was -20°C.

Furthermore, in order to maintain a constant level of liquid nitrogen in the container, the flow rate of liquid nitrogen supplied into the container is 2OR/H, and the water and nitrogen gas for mixing are cooled by a cooling device before being discharged. Nitrogen gas (i.e. vaporized gas extracted from inside the container)
was 20×0.65 Nm'/Hr.

Under the conditions described above, when the mixed fluid (cephalexin suspension 10 nitrogen) was continuously injected for about 10 minutes, about 1 liter of free-flowing water spheres containing cephalexin crystals were obtained, and the average particle size was 200 to 300. It was a micron.

This water polo is 0. The water balls were stored in a stocker to which nitrogen gas at a pressure of 2 kg/ci and 85°C was fed to suspend the water balls from the bottom by a conveyor 70 to maintain the water balls at a temperature of -85°C, and then a nozzle with a diameter of 8.3 n+m It was injected from an injector 91 having a. At this time, the nitrogen gas for acceleration supplied from the central inlet of the injection device 91 has an acceleration pressure of 4°7 to 5 kg/cffl,
The temperature was -85°C, and the temperature at the time of injection from the water sphere nozzle was -85°C. Under the above conditions, the injection distance is 2
The water ball was jetted with the setting set to 0 mm.

The crushed grains were then collected.

In the case of using chloroform, the crushed grains were placed in a constant temperature bath at 65°C to evaporate and remove the chloroform to obtain crushed crystals of cephalexin 1 hydrate crushed into 10 to 20 micron particles.

Example 2 Theophylline crystals obtained by recrystallization were dispersed in water to prepare a 0.1 g/ml suspension. Using this suspension, theophylline crystal-containing ice grains (particle size 200 to 300 microns) were obtained using the same apparatus as in Example 1, and the crushed grains were collected by spraying under the same conditions. Then, it was filtered at room temperature and placed in a dryer to obtain crushed theophylline crystals (10 to 20 microns).

Example 3 The nalidixic acid crystals obtained by the recrystallization method were dispersed in water to give a dispersion of 0.05 g/m! A suspension was prepared.

Using this suspension, ice grains containing nalidixic acid crystals (particle size 200 to 300 microns) were obtained using the same apparatus as in Example 1, and further jetted under the same conditions (the jetting distance was set to 50 m + m). The crushed grains were collected. The mixture was then filtered at room temperature and placed in a dryer to obtain crushed nalidixic acid crystals (15 to 25 microns).

Example 4 Cephalexin 1 permanent granular crystals (30 to 50 micron diameter) were dispersed in chloroform, and 0.05 g/mA
A suspension of cephalexin was prepared.

Next, using the same apparatus as in Example 1, the cephalexin suspension was heated at a flow rate of 0.2 A'/min, and the nitrogen gas was heated at a flow rate of 1β/min.
Ice grains were prepared under the following conditions: a flow rate of min, a nozzle hole of 0.7 n+mφ, and a spray pressure of 4 kg/ci. The resulting ice particles had a diameter of 50 to 100 microns.

Furthermore, the ice particles were injected under the same conditions as in Example 1, and the crushed ice particles were collected. The crushed grains were then placed in a 65° C. constant temperature bath to remove the chloroform content to obtain crushed cephalexin monohydrate crystals crushed into 5-20 micron particles.

Effects of the Invention According to the present invention, it becomes possible to continuously pulverize crystals, and it becomes possible to easily pulverize a wide variety of crystals. Furthermore, a novel pulverization method is provided in which pure microcrystals can be recovered without the contamination of foreign substances as seen in pulverization using a ball mill or the like, and no heat is generated during the pulverization.

[Brief explanation of the drawing]

FIG. 1 is a schematic diagram of an apparatus suitable for carrying out the invention. FIG. 2 is a flow sheet of the microfrozen grain manufacturing apparatus in FIG. 1. 3 is a plan view showing the arrangement of the air diffuser 3a of the apparatus shown in FIG. 2, and FIG. 4 is a side view thereof. Figure 5 11. Figure 5 11. FIGS. 5 and 11 show a specific example of a line generating device that can be substituted for the air diffuser 3a in FIG. 3. FIG. 6 is an explanatory diagram of the action of the air bubbles from the air diffuser shown in FIG. 3. FIG. 7 is a longitudinal sectional view showing an example of the spray device 4 of the device shown in FIG. FIG. 8 is a sectional view showing an example of the finely frozen particle delivery device 6 of the device shown in FIG. 2. FIG. 9 is a schematic diagram with two or more injection devices. FIG. 10 is an overall schematic diagram of the sample recovery device after injection, and FIG. 10 is a side sectional view of the device shown in FIG. 10. In the drawing, ■ Finely frozen particles K Fine particles of frozen stock solution L Refrigerant liquid level W Ripple 1 Refrigerant liquid storage container 2 Refrigerant liquid 3 Line generator 4 Spraying device 5 Refrigerant liquid level control device 6 Frozen fine particles delivery device 7 Cooling device 8 Refrigerant liquid supply device 9 Frozen stock liquid supply device 10 Mixing gas supply device 11 Refrigerant liquid supply pipe 12 Refrigerant gas supply pipe 13 Bubbles
50 Microfrozen grain manufacturing device 60 Lifter
70 Belt conveyor 80 Stocker
91 Nozzle 92 This is a hard plate. Agent Masao Miyake and 1 other person Figure 3 Figure 5 (A) Figure 5 (B) Te Fuuri Neichi Seisho (Method) December 4, 1985 Commissioner of the Patent Office Kuro 1) Akio Tono 1 Case Indication of 1985 Patent Application No. 220715 2 Name of the invention Crystal freezing and pulverization method 3 Relationship with the case of the person making the amendment Name of patent applicant Fuji Seiki Seisakusho Co., Ltd. (2 others) 4
Agent 〒100 5 Date of amendment order November 5, 1985 6 Number of inventions increased by amendment 0 7 Each column of "Brief explanation of drawings" and "Detailed explanation of invention" of the specification subject to amendment (1) “Figure 5 ratio Figure 5 11” on page 31, line 17 of the specification
, FIG. 511 and FIG. 5 II," are corrected to "FIG. 5(A), FIG. 5(B), FIG. 5(C), and FIG. 5(D),". (2) "Figure 10 11J" in page 32, line 7 of the same page.
Figure (A)” is corrected. (3) The rt510 figure 11 on page 32, line 8 is the 10th
Figure 11 of the apparatus is changed to Figure 10 (B) and Figure 10 (A).
"of the device" is corrected. (4) “Figure 5 11 and Figure 5 11” on page 19, line 9 of the same
"As shown in FIG. 5(A) and FIG. 5(B)" is corrected to "as shown in FIG. 5(A) and FIG. 5(B)." (5) "As shown in Figure 5 II" on page 19, line 17.
is corrected to "as shown in FIG. 5(C)". (6) "As shown in FIG. 5 (D)" in line 9 of page 20 is corrected to "as shown in FIG. 5 (D)."

Claims (5)

[Claims] (1) Drug crystals suspended in a liquid medium are dropped together with the medium into droplets with a diameter of 500 microns or less into a liquefied gas refrigerant maintained at a low temperature below the melting point of the medium to substantially reduce the particle size to 500 microns. A method of freezing and pulverizing drug crystals, which is characterized in that the micro-frozen particles containing drug crystals are formed into submicron-sized micro-frozen particles, and then the micro-frozen particles containing drug crystals are pulverized by applying an impact force through collision. (2) The pulverization method according to claim 1, wherein the drug crystals suspended in the medium are dropped into a refrigerant having ripples formed on its surface. (3) The medium contains the crystals at a concentration of 0.005 g/ml to 0.00 g/ml.
The pulverization method according to claim 1 or 2, characterized in that the pulverization method contains 5 g/ml. (4) The pulverization method according to claim 1, which comprises jetting and colliding finely frozen particles containing drug crystals against a resistor. (5) The pulverization method according to claim 1, which comprises jetting and colliding finely frozen particles containing drug crystals with each other.