JPS60243080A - Carbocromene hydrochloride hydrate crystal - Google Patents

Abstract

NEW MATERIAL:3mol hydrate crystal of 3-(beta-diethylamino)-4-methyl-7-(carbethoxymethoxy)coumarin hydrochloride(carbocromene hydrochloride). USE:Useful for preparing a carbocromene hydrochloride tablet, a vasodilator for coronary vessel. PREPARATION:Carbocromene hydrochloride is stored at 5-35 deg.C at >=68% relative humidity and moisture is absorbed in it. Carbocromene hydrochloride is blended with water at <=40 deg.C. Carbocromene hydrochloride is dissolved in water at <=40 deg.C, and recrystallized at a temperature <= the dissolving temperature. The titled crystal is obtained by any of the methods. It has low moisture absorption, is slightly hydrolyzed, and useful as a capsule, granule, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to ice-containing crystals of carbochromene hydrochloride useful in the production of stable carbochromene hydrochloride tablets.

Although carbochromene hydrochloride is effective as a drug having a coronary vasodilator effect, the crystallization technique and crystal form of carbochromene hydrochloride are completely unknown in the literature. Carbochromene hydrochloride has the property of absorbing moisture and being easily hydrolyzed under conditions of moisture or high humidity, and also has a strong irritating effect when it comes in direct contact with the skin. For this reason, conventionally, a manufacturing method that does not use water has been adopted for hydrochloric acid ~ pochromene.
The solid preparation for internal use is a soft capsule in which carbochromene hydrochloride is suspended in edible oil and then wrapped in a gelatin film.
Most of the drugs were made up of detergents. However, in dosage forms with chemical under high humidity and high temperature.

It has poor physical stability, and the main drug ingredient, carbochromene hydrochloride, undergoes hydrolysis and deformation of appearance, so a special moisture-proof packaging form is required. Furthermore, such a dosage form has the disadvantage that the dosage unit of the dosage form cannot be avoided. As a solution to these drawbacks, it has been considered to manufacture sugar-coated tablets, film-coated tablets, etc. using granules made by the melt granulation method (Japanese Patent Application Laid-Open No. 50-88216), but the chemical and physical stability of this method The properties of the tablets were not sufficient, and the sugar coating and film were prone to cracking due to moisture absorption and expansion of the uncoated tablets.

In view of these problems, the present inventors conducted extensive research on the physical properties, crystal form, etc. of carbochromene hydrochloride, and as a result,
We succeeded in obtaining new hydrous crystals of carbochromene hydrochloride, which are extremely useful in pharmaceutical preparations.

Means for solving the problems, that is, the present invention provides 3-(β-diethylaminoethyl)V)-4-methy/
L/-7-(carbetoxime[xy)coumarin hydrochloride (
It concerns H3, a 37-yl ice-containing crystal of carbochromene hydrochloride.

The above-mentioned carbochromene hydrochloride-37 ice-containing crystals (hereinafter referred to as α-crystals) can be produced, for example, by the following method.

(a) m acid power p bochromene at a temperature of about 5 to 35°C,
Store under conditions of relative humidity of approximately 68% or higher to absorb moisture.

(b) Add a small amount of water to m-acid carbochromene and make about 40
Mix at temperatures below °C.

(c) Dissolve carbochromene hydrochloride in water at a temperature of approximately 40°C or lower and reconsolidate it at a temperature lower than the temperature at which it was dissolved (including freeze-drying).

Further, as described below, υ excipients may be added as necessary.

In addition, the present inventors have proposed the above-mentioned (al, (bl, (c)
When carbochromene hydrochloride is treated at a temperature higher than the temperature specified in each method such as 1, new crystals of carbochromene hydrochloride, 27 ice-containing crystals (hereinafter referred to as β crystals), are formed.
As a result of detailed research on each of these crystal forms, we found that the cracking phenomenon of tablets was caused by the force of hydrochloric acid. It has a deep relationship with the crystal form of p-pochromene, and cracks occur when the tablet is compressed using the dry anhydride of the β crystal, but cracks occur when the tablet is compressed using the dry anhydride of the α crystal. We have discovered the unexpected fact that this can be reliably prevented and tablets that are physically and chemically extremely stable can be obtained. Furthermore, since α-crystals have a much higher dehumidification rate than β-crystals, they can be dried under mild conditions and in a short time during the formulation process, and for this reason, hydrolysis of carbochromene hydrochloride hardly occurs. It has the advantage of not being Therefore, the α-crystal of the present invention having such excellent properties is a novel hydrous crystal that is extremely useful for producing physically and chemically stable carbochromene hydrochloride tablets.

A method for producing stable carbochromene hydrochloride tablets using α-crystals will be described in detail below.

The α or β crystals of carbochromene hydrochloride are produced by hydrotreating carbochromene hydrochloride as described above, but when the wet method using water, which is a normal formulation method, is applied to carbochromene hydrochloride, β-crystals or their anhydrides are formed due to heat during mixing or drying, making it impossible to obtain stable tablets.

In order to generate α-crystals or their anhydrides, it is necessary to maintain the product temperature at approximately 40°C or less during kneading and drying. Stable and good tablets are produced for the first time under such strict product temperature control. can be manufactured.

The first step in this method in which temperature control is important is the hydrolysis step to generate α crystals. In this process,
Carbochromene hydrochloride and optional excipients are mixed, kneaded, and granulated using about 10 to 30% by weight of water based on the total amount while maintaining the product temperature at about 40° C. or less. Through this treatment, hydrochloric acid p-pochromene is converted into α-crystals, which are water-containing crystals.

Excipients used include the usual excipients such as lactose, sucrose, mannitol, starches, cellulose, lli
Microcrystalline cellulose, kaolin, calcium phosphate, etc. are used either singly or as a mixture of two or more of these. The amount of excipients used can be increased or decreased as appropriate to adjust the tablet weight, but the usual dose of carbochromene hydrochloride is 7.
The amount of excipient added is preferably equal to that of carbochromene hydrochloride because of the need to miniaturize tablets. In addition, in this method, it is usually preferable to use a suitable binder due to the necessity of granulation, and such binders include water-soluble binders such as pregelatinized starches (e.g., pregelatinized starch, starch paste). , gelatin, gum arabic, polyvinylpyrrolidone, water-soluble silane derivatives (e.g., hydroxypropyl cellulose,
One or more of these are used in the form of powder or aqueous solution. The amount of such a binder added is suitably about 2 to 5% by weight based on carbochromene hydrochloride or a mixture thereof. It should be noted that the method of the present invention also includes formulating the main drug carbochromene hydrochloride with other pharmacologically active ingredients (e.g., fumebarbital, digoxin, etc.) that do not cause any problems in formulation. .

The order of mixing and kneading may be as follows: carbochromene hydrochloride may be mixed with excipients, binders, etc. if necessary, and then kneaded with water; The mixture may be kneaded using an aqueous solution of a binder. Carbochromene hydrochloride is usually used in bulk form. Dissolution of carbochromene hydrochloride in water is exothermic. Moreover, its solubility is very high, at 20°C it dissolves about 1f per 1 g of water, and at 30°C it dissolves about 21 g. Therefore, when kneading carbochromene hydrochloride or a mixture thereof using water or an aqueous solution of a binder, the heat of dissolution alone is not enough heat, and the kneading energy is added to this heat of dissolution, so during kneading The temperature rise is significantly large. Therefore, when performing wet kneading using water or an aqueous binder solution in a conventional manner, it is difficult to reliably maintain the product temperature at 40° C. or lower during kneading. Moreover, this temperature increase becomes greater as the content of carbochromene hydrochloride increases.

Therefore, it is necessary to select a kneading board used for kneading in this method that can suppress the rise in product temperature.

The type of kneading machine that can be used is not particularly specified, but kneading type or high-speed type kneading machines are not preferable because they have large integrated energy and may generate localized heat. A kneading machine is suitable. Furthermore, these kneading machines are preferably provided with cooling means such as by attaching a cooling jacket to the outside. The most preferred kneading machine is a rotary vane type kneading machine with a cooling jacket at a low speed or at a reduced speed, or a stirring vane type kneading machine in which the container and the blades move planetally relative to each other.

The kneading liquid used in this method is basically purified water or an aqueous solution of a binder, but if desired, a small amount of organic solvent such as alcohol or acetone may be added to this and used as a kneading liquid. . The amount of kneading liquid to be used is approximately 10 to 30% by weight based on carbochromene hydrochloride or its mixture, in order to prevent heat generation during kneading and to perform appropriate kneading to facilitate drying in the next step. The degree is appropriate. If the amount is less than this, a large amount of kneading energy is required, and as a result, heat generation during kneading, especially local heat generation, becomes large.

In addition, if the amount is higher than this, the kneaded product will have a high water content, so the next step of low-temperature drying may take a very long time, and in some cases, drying may become impossible.

Granulation is usually carried out by pulverizing the mixture into appropriate granules using a suitable crusher or crusher. In addition, depending on the case, this granulation may be performed using a crusher, a crusher, etc. after drying the kneaded product.

The second important step for temperature control in this method is the drying step. As the drying means, vacuum drying method, hot air drying method, fluidized drying method, etc. are usually used. In the general pharmaceutical field, the drying temperature in the wet granulation method that uses water as a kneading liquid is usually 50°C or higher, but in this method, the drying temperature is about 40°C until the water content is at least about 3% by weight or less.
It is necessary to maintain the product temperature below °C. If it is dried at a temperature of 40°C or higher, an α-crystalline anhydride with stable properties cannot be obtained. In addition, in the case of this drying process, the external temperature (eg, vacuum drying temperature 1 hot air temperature, etc.) may be 40° C. or higher as long as the product temperature is kept below the above temperature. If the water content is 3% by weight or less, the product temperature may be raised to 40° C. or higher for drying. When drying, the moisture content is approximately 1.5
It is desirable to carry out the process until the amount is reduced to about % by weight or less. Among the above-mentioned drying methods, the fluidized drying method is the most preferable from the viewpoint of sealing and making the process continuous.Furthermore, if such sealing and continuity are carried out, skin damage to the operator due to adhesion of carbochromene hydrochloride can be avoided. It is possible to prevent such dangers from occurring.

In addition, granules containing good α-crystalline anhydride can be obtained by using the fluidized granulation method, which is also preferable from the viewpoints of sealing and continuity.

In this case, the amount of water used is preferably about 50 to 200% by weight of the total amount according to the usual fluidized granulation method.

The granules thus obtained can be mixed with a lubricant and, if necessary, an excipient by a conventional method, and then compressed into uncoated carbochromene hydrochloride tablets. Examples of the lubricant used include magnesium stearate, calcium stearate, aluminum stearate, etc., and the amount used is usually about 0.3 to 1.2% by weight based on the dry granules. Excipients are appropriately used from among the various excipients described above, if necessary. For the purpose of tablet miniaturization, it is preferable that the content of carbochromene hydrochloride in the uncoated tablet after tableting is 50% or more.

The above-mentioned uncoated tablets may be further coated with sugar or film coated by conventional methods.
1. Hydrochloric acid μpochromene tablets in the form of sugar-coated tablets or film-coated tablets can be obtained by the following steps.

The granules obtained by the above method have characteristics such as low hygroscopicity and resistance to hydrolysis, and can also be used as turnip tablets, granules, etc. with good stability.

The method for producing the above hydrochloric acid μ Bochromene tablets is as follows:
By elucidating the physical properties of a new water-containing crystal of bochromene and utilizing the α-crystal, which has good physical properties in formulations, we have developed a wet method using water for carbochromene hydrochloride, which was previously considered contraindicated to use water. It is what makes the application of the law possible,
According to this method, hydrolysis of carbochromene hydrochloride hardly occurs during the manufacturing process, and the chemical and physical properties of the manufactured tablets are extremely stable. In other words, the carbochromene hydrochloride tablet produced by this method hardly undergoes hydrolysis of the active ingredient, carbochromene hydrochloride, even if it is left for a long time under high humidity conditions, and moreover, the uncoated tablet portion of the sugar-coated tablet and film coach ink fl. It has excellent properties such as no tendency for the sugar coating layer or film layer to crack due to moisture absorption and expansion. These characteristics remain almost unchanged even when the tablets are made smaller by increasing the content of carbochromene hydrochloride. Therefore, the present invention has made it possible to make smaller tablets of carbochromene hydrochloride drugs, which has been difficult in the past. be.

Furthermore, as for the method itself, this method using water does not pose the risk of explosion or the problem of residual solvent in the product, unlike when using organic solvents, and is extremely effective compared to the conventional method for formulating carbochromene hydrochloride. This is a safe, simple and industrially advantageous method.

The present invention will be explained in more detail below using Examples, Reference Examples, and Test Examples, but these do not limit the scope of the present invention in any way.

Example 1 Production of ice-containing crystals (α crystals) of carbochromene hydrochloride 37 (1) Carbochromene hydrochloride was heated to 100 y at a temperature of 2
When stored for one week at 5°C and 75% relative humidity, α
113 g of crystals are obtained.

Elemental analysis value molecular formula C2oH27NO6・HCl・3H120C (
%) H (%) N (%) Calculation i: 5a. 15 7.58 3.10 Actual value -53
゜6; (7, 46a, 11 Moisture measurement by Karl Fischer method i: 11.86% Powder X-ray diffraction pattern and engineering R (infrared absorption) spectrum are shown in Figures 1 and 3. For reference only. Figure 2 shows the powder X-ray diffraction pattern of the bulk powder used as the raw material.The pattern of bumps differs depending on the production lot.

(2) Add about 1.4 g of purified water to bulk 10F of hydrochloric acid p-pochromene and knead in a mortar to obtain α-crystals.

(3) When 1 hp of hydrochloric acid μpochromene is kneaded with 140 g of purified water in a jacketed, slow-speed super mixer, α crystals are obtained. During mixing and kneading, cold water at 15°C was passed through the jacket, and the maximum temperature of carbochromene hydrochloride during this period was 38°C.

(4) Paring 20f of carbochromene hydrochloride at 8'/℃
It is dissolved in 10 g of purified water, allowed to stand at room temperature (about 20° C.) to crystallize, and then filtered to obtain about 1 of α-crystal.

Reference Example 1゜Production of ice-containing crystals (β crystals) of carbochromene hydrochloride 2 moss When 100 g of pulp of carbochromene hydrochloride is stored for one week at a temperature of 50°C and a relative humidity of 75%, 109 g of β crystals are obtained.
is obtained.

Elemental analysis value molecular formula C20H2'l NO5・HCl・2H20C
(%) H (%) N (%) Calculated value: 55°36 7.4a a, 22 Actual value: 55
．． 67 7.41 a. The moisture content measured by the 15 Kerr μ Fisher method, 94%, and the powder X-ray diffraction pattern are shown in FIGS. 1 and 5.

Example 2 75 mfi parts of carbochromene hydrochloride 25 parts by weight of lactose 5 parts by weight of hydroxygprolcellulose were mixed in a slow-speed Gooper mixer with a jacket, and then 1 part of purified water was mixed.
7 parts by weight (about 14% by weight) were added and kneaded. During mixing and kneading, cold water at 15°C was passed through the jacket. The highest product temperature during that time was 38°C. Analyze the obtained mixture and calculate α
It was confirmed that crystals were generated. This kneaded product was vacuum-dried as it was for 16 hours at a circulating water temperature of 40°C. The obtained dry powder was sized, and a mixture of 4.5 parts by weight of starch and 0.5 parts by weight of magnesium stearate was mixed with the sized powder and then tableted to obtain sugar-coated uncoated tablets of 110111y/tablet.

The uncoated tablets were coated with sugar in the usual manner to yield 200q.

The properties of the finished plain tablets and sugar-coated tablets were as follows.

Hardness Disintegration time Tablet 5゜3 paste 5゜2 minutes Sugar-coated tablet 8゜5kti 10.3 minutes Example 3゜The composition used in Example 2 was followed in the same manner up to kneading, and the kneaded product was coarsely crushed. After granulation, fluidized drying was performed. Initially, the product contains approximately 14% water by weight, so the first stage drying was carried out at a blowing temperature of 40°C to ensure that the product temperature did not rise above 40°C and that the water content was below 3% by weight. Confirmation (specifically 40℃.

After drying for 45 minutes (actual moisture content: 2.7%), a second stage drying was performed for 30 minutes at a blowing temperature of 50°C. The obtained dry powder is sized, and starch 4-5 MftC is added to the sized powder.
A mixture of 0.5 parts by weight of calcium stearate and 0.5 parts by weight of calcium stearate was mixed and tableted to obtain 110q/tablet of uncoated tablets. The uncoated tablets were coated with sugar using the usual method to give 220 Da. In addition, when the tablet was analyzed, β crystals and their anhydrides were not observed at all.

The properties of the finished plain tablets and sugar-coated tablets were as follows.

Hardness Disintegration time Uncoated tablet 6. Okg 5゜0 minutes Sugar-coated tablet 9.2k (J 12.8 minutes Example 4゜ Carbochromene hydrochloride 75 parts by weight Lactose After mixing 65 parts by weight in a mixed mixer with a jacket, 17.8% by weight 28 parts by weight of starch paste was added and kneaded.The starch paste was cooled to 20°C before use, and during kneading, cold water at 15°C was passed through a jacquera. The maximum temperature of the kneaded product during kneading was 35°C. Analysis of the obtained mixture confirmed the formation of α-crystals, but no β-crystals were observed.

The mixture was vacuum dried at 40°C for 16 hours, sized, and 9.5 parts by weight of starch and 0.5 parts of magnesium stearate were added to it.
The parts by weight of the mixture were mixed and then tableted to obtain 150 #/tablet of uncoated tablets for film coating. The uncoated tablets were coated with a film using a conventional method to obtain 16011tg.

The properties of the finished plain tablets and film-coated tablets were as follows.

Hardness Disintegration Tablet 6.5 to 9 5.5 minutes Film coach ink tablet 10.8 to 9 8.2 minutes Example 5 Carbochromene hydrochloride 75 parts by weight Lactose 15 parts by weight Pregelatinized starch 4 Mi parts The mixture was placed in a fluidized granulator, mixed while being fluidized, and then fluidized granulated at a blowing temperature of 60° C. and sprayed with 120 parts by weight of purified water to form granules. When granules were collected and analyzed immediately after spraying in the operation process, the formation of α crystals was observed.

The finished granules had an average particle diameter of about 250 μm, had good fluidity, contained little fine powder, had little fumes or scattering, and were easy to handle and safe. A mixture of 5.5 parts by weight of starch and 0.5 parts by weight of magnesium nutearate was mixed with the granules and then tableted to obtain a sugar-coated tablet of 100 Ny. The uncoated tablets were sugar-coated to 200W using the usual method.

The properties of the finished plain tablets and sugar-coated tablets were as follows.

Hardness Disintegration time Uncoated tablet 6. '1kg 6.1 minute sugar-coated tablet 10. Example 6: 75 parts by weight of carbochromene hydrochloride and 15 parts by weight of lactose were mixed in a fluidized granulator, and then 80 parts by weight of a 5% by weight aqueous solution of hydroxypropyl cellulose was mixed at a blowing temperature of 40°C. Granules were made by fluid granulation from the bottom spray. α crystals were observed in the granules immediately after spraying. The finished granules had an average particle size of about 200 μm and contained relatively little fine powder, but even a small amount of fine powder was sufficiently granulated, and therefore not only had fluidity but also little dusting. A mixture of 5.5 parts by weight of starch and 0.5 parts by weight of calcium stearate was mixed with the granules and then tableted to obtain 100# uncoated tablets for film coating. The uncoated tablets were coated with a film using a conventional method to obtain a film coating of 110η.

The properties of the finished plain tablets and film-coated tablets were as follows.

Hardness Disintegration time Tablet 6. akg 6.6 minute film coated tablet 10. 2 to 9 8. Effect test example 1 of the 9-minute invention (1) Example 1. α crystal obtained in Reference Example 1. FIG. 7 shows the results of continuous measurement of the dehumidification properties of the β-crystals obtained at 25° C. and 11% relative humidity using a Curno electric balance.

As is clear from FIG. 7, the α-crystal is much easier to dehumidify than the β-crystal, and therefore has an industrial advantage in that it can be quickly dried under mild conditions during the formulation process.

(2) Hygroscopicity at 25°C and relative humidity of 75% of α-crystal anhydride obtained by vacuum-drying α-crystal at 35°C and β-crystal anhydride obtained by vacuum-drying β-crystal at 45°C. Figure 8 shows the results measured using a Curno electric balance.

As is clear from FIG. 8, the moisture absorption rate of the α-crystal anhydride is extremely low compared to the β-crystal anhydride, and it has properties suitable as a stable tablet-containing ingredient.

The powder X-ray diffraction diagram and spectrum μ of the α-crystal anhydride are shown in Figures 1 and 4, and the X-ray diffraction diagram and spectrum μ of the β-crystal anhydride are shown in Figures 1 and 6. Shown below.

Test Example 2゜ Sugar-coated tablets and film-coated tablets made in each example were subjected to high humidity conditions, that is, 40°C, 75% R, H, which is often used as a normal humidity resistance test.

The tablets were left in a capless bottle in a desiccator at (relative humidity) and the stability of the active ingredient and the appearance stability were tested in comparison with the dosage forms prepared by the preparation methods of properties 1.2 and 3 below. The test results are shown in Table 1.

(Margins below) Table 1 (Note 1) Preparation of soft gelatin capsules Hydrochloric acid 75 parts by weight of pokromene 85 parts by weight of 11B oil were suspended under high-speed stirring conditions to make a paste, and the paste was prepared in the usual manner. Gelatin encapsulation was performed.

(Note 2) Preparation of sugar-coated tablets by the usual wet granulation method. After mixing 75 parts by weight of carbochromene hydrochloride, 25 parts by weight of lactose, and 5 parts by weight of pregelatinized starch in a high-speed type super mixer (normal commercially available machine), 18 parts by weight of purified water was mixed. The ingredients were added and kneaded.

The highest product temperature during that time was 48°C. Analysis of the composite confirmed the formation of β crystals, but no α crystals were observed. After granulating this kneaded product, fluidized drying was performed at a blowing temperature of 60°C, and the resulting dried rice was sized, and the subsequent steps were as in Example 8. Uncoated tablets and sugar-coated tablets were made according to . The characteristics are as in Example 3. Although there was no significant difference in either case, about 5% by weight of carbochromene hydrochloride was hydrolyzed.

(Note 3) Preparation of sugar-coated tablets by melting method Example 1 of JP-A-50-88216. Based on this, melt granulation was carried out to produce granules, and the auxiliary agents described above were added in the same manner to produce uncoated tablets and sugar-coated tablets containing carbochromene hydrochloride 75q.

[Brief explanation of the drawing]

Figure 1 shows the powder X-ray diffraction diagram of each crystal form, Figure 2 shows the bulk powder X-ray diffraction diagram, Figure 3 shows the α-crystal R (infrared absorption) nubector, and Figure 4 shows the α-crystal X-ray diffraction diagram. Figure 5 shows the IR spectrum of the anhydride, Figure 6 shows the IR spectrum of the β crystal anhydride, Figure 7 shows the IR spectrum of the β crystal anhydride, and Figure 7 shows the IR spectrum of the β crystal anhydride.
Figure 8 shows the dehumidification properties of α-crystals and β-crystals at 1%.
℃. The hygroscopic properties of α-crystalline anhydride-1 and β-crystalline anhydride-T at RH=75% are shown. 2e ('l - do U doko 30 Fig. 7 last time (, hrs) Fig. 8 Time (hrs)

Claims (1)

[Claims] 3-Mole hydrated crystals of 3-(β-diethyμaminoethyl/l/)-4-methyIV-'I-(carbetoxime)xy)coumarin hydrochloride (carbochromene hydrochloride).