JPH029799A - Preparation of fine crystal - Google Patents

Abstract

PURPOSE:To easily prepare the extremely fined crystal by consciously preparing an amorphous solid which is of a metastable type with a material which can be easily inverted to a crystallographically stable state and inverting this amorphous solid to a stable type crystal. CONSTITUTION:The previously prepd. amorphous solid of the metastable type is inverted to the stable type crystal. The inversion from the metastable type amorphous solid to the stable type crystal takes place easily in many cases in the presence of external energy, for example, heat, pressure, etc., or in the presence of water and since this inversion varies with materials as well, the specification of the inversion method is not possible. The inversion in the presence of water is simplest and is, therefore, more preferable. The inversion to the crystal is possible, for example, by suspending about 0.1-10%, more preferably 0.3-3% amorphous solid into the water is case of using the water. Since the inversion to the crystal is generally faster as the temp. is higher, the setting of a high temp. condition is advantageous if the desired material has thermal stability; about 30-60 deg.C is more preferable.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a method for preparing crystals, particularly fine crystals, and is used, for example, to make fine drug crystals.

(Prior art) When manufacturing pharmaceuticals, especially for poorly water-soluble drugs, it is important to use fine crystal particles to improve the effectiveness, stability, uniformity of quality as a pharmaceutical, safety of use, etc. Therefore, various reports have been made as a method for preparing fine crystals.

Conventionally proposed methods for preparing fine crystals include mechanical pulverization using a ball mill, hammer mill, etc., a method of adding and mixing a solvent to a solution to precipitate it as crystals, a method via a solvate, and a method using a solvent. (Problems to be Solved by the Invention) The above-mentioned prior art methods, which can be roughly divided into methods of freeze-drying a molten mixture, each have advantages and disadvantages, and they are difficult to solve in terms of drug stability, safety of use, necessary equipment, and cost. The reality is that it cannot always be said to be satisfactory when considering the following. For example, mechanical pulverization not only requires expensive equipment, but also has the possibility of causing thermal decomposition of the drug due to the rise in temperature -E that accompanies pulverization. The problem is that it is difficult to grind, and the resulting pulverized product has a large particle size distribution. The method of precipitating by mixing solvents requires a large amount of solvent, which is costly, and it is difficult to completely remove the solvent, which may cause problems with safety in use. However, the method via solvation, which does not have a good degree of oxidation and is difficult to set the precipitation conditions, produces hydrates and solvated compounds when the drug binds to water or organic solvents. On the other hand, the method of freeze-drying a eutectic mixture with a solvent is limited to forming a eutectic mixture with a solvent. This requirement not only limits the applicable drugs, but also requires relatively expensive freeze-drying equipment, and requires the removal of a large amount of solvent, making it difficult to improve efficiency.

(Means and effects for solving the problem) In order to solve the above-mentioned problems in the prior art, the present inventors have made intensive studies and found that in the case of substances that easily transition to a crystallographically stable state, It was unexpectedly discovered that if a stable amorphous solid is intentionally prepared and this amorphous solid is transformed into a stable crystal, an extremely thin crystal can be obtained. I was able to complete it.

The method of the present invention can be applied to any substance that has an amorphous solid state, which is a crystallographically metastable form, and a crystalline state, which is a stable form, regardless of the structure or physicochemical properties of the substance. Although the method of the present invention starts from an amorphous solid, the amorphous solid itself can be prepared, for example, according to the method disclosed in Japanese Patent Publication No. 55-45042. be able to.

Whether or not an amorphous solid state that is a crystallographically metastable form and a crystalline state that is a stable form exist can be confirmed by, for example, a phase diagram or thermal analysis. The transition from a metastable crystalline solid to a stable crystal is caused by external energy such as heat,
It often occurs easily in the presence of pressure, etc. or in the presence of water, but since it varies depending on the substance, it is not possible to specify the method of transition. However, it is preferable to carry out the transfer in the presence of water because it is easiest. When using water, for example, 0.1-10% of the amorphous solid is added to water, preferably 0.3-10%.
By suspending it at 3%, it can be transformed into crystals. The higher the temperature -i, the faster the transition to crystal, so if the target substance has thermal stability, it is advantageous to set the temperature condition high, and about 30-60°C is preferable. promotes the transition from metastable to stable form,
Alternatively, an appropriate substance may be added to cause the transition to occur uniformly or to form finer crystals.

There are no particular restrictions on the type or addition method of this additive, and if the substance for preparing fine crystals is a drug, it may be a pharmaceutically acceptable excipient.

Incidentally, the transition can be easily confirmed using a polarizing microscope or by thermal analysis.

In the case of a drug, the WL4I3 crystals obtained by the method of the present invention can be formulated into oral preparations such as tablets, capsules, syrups, and granules, as well as injections and external preparations by conventional methods. I can do it.

(Examples) Next, the present invention will be explained in its entirety using Examples and Reference Examples. In addition, the average particle diameters described in the following quantities are values measured by observation using an optical W4 microscope. ).

a) Preparation of amorphous solid IO-acetyl 3'°-acetylmidecamycin (trade name [myocamycin J)] was dissolved in 100 ml of a dioxane solution containing 1 g of ethylcellulose.

After freezing this liquid at -40°C (100 m
A completely amorphous solid of IO-acetyl-3''-acetylmidecamycin was obtained by sublimation and removal of the solvent under reduced pressure (1 liter).
It was 0 μm.

b) Preparation of microcrystals 1 g of the above amorphous solid was collected and dispersed in water,
The average particle size of the IO-acetyl-3'°-acetylmidecamycin crystals obtained was 0.2-1.0 .mu.m after being stored for 1 day at .degree. C. to transform the amorphous solid into crystals.

K1 Takumiyu a) Preparation of amorphous solid 10-acetyl-3°“-acetylmidecamycin 1
No. 0 was dissolved in dioxane solution 1001. After freezing this solution at -40°C, the solvent was sublimated and removed under reduced pressure to 100 mm and 11 g to obtain 10-acetyl-3°.
``A completely amorphous solid of acetylmidecamycin was obtained.

The average particle size of this amorphous solid was 100-200 μI.

b) Preparation of microcrystals 1 g of the above amorphous solid was taken and dispersed in water, and polysolve h 80 t! -0,] after adding 25
The amorphous solid was transformed into crystals upon storage at 10 °C. The average particle size of the obtained 10-acetyl-3°-acetylmidecamycin crystals was Oj -0.5 noli.

I) Preparation of amorphous solid 10-acetyl-3°'-acetylmidecamycin 1
111 g was dissolved in dichloromethane solution 1001 containing 1 g of ethyl cellulose. This solution was spray-dried in a conventional manner to obtain a completely amorphous solid of 10-acetyl-3°-acetylmidecamycin. The average particle size of this amorphous solid was 50-150 μm.

b) Preparation of microcrystals 1 g of the above amorphous solid was taken and dispersed in water,
The amorphous solid was transformed into crystals by storage at °C for 1 day. The average particle size of the obtained lO-acetyl-3'-acetylmidecamycin crystals was 0.30.8 μm.

Hise Q-4 a) Preparation of amorphous ff solid IO-acetyl-3″′-acetylmidecamycin 1
0 g of dichloromethane solution containing 1 g of ethyl cellulose 1
001. This solution was spray-dried in a conventional manner to obtain a completely amorphous solid of 10-acetyl-3'-acetylmidecamycin. The average particle size of this amorphous solid was 50-150 μm.

b) Preparation of 1 fine crystals 1 g of the above amorphous solid was collected and dispersed in water, and after adding 1 ml of polysorbate 80, it was stored at 25°C for 1 day to transform the amorphous solid into crystals. I let it happen. The average diameter of the obtained 10-acetyl-3'-acetylmidecamycin crystals was 0.2-0.5 μm.

Example 1 Go L5- a) Preparation of amorphous solid 10 g of novobiocin' was dissolved in dioxane'Fi liquid ioom. After freezing the solution for 140'C7'', the solvent was removed by sublimation under reduced pressure below 1100IIIH to obtain a completely amorphous solid of novobiocin. The average diameter of this amorphous solid was 50-150 μm. Met.

lI) Preparation of microcrystals 1 g of the above amorphous solid was taken and dispersed in water.
The amorphous solid was transformed into crystals by storage at ℃ for 1 day. The average particle size of the obtained novobiocin crystals was 0.5-1
．． It was 0 μm.

11. Grind the log of crystals of Takumi IO-acetyl-3'-acetylmidecamycin using a hammer mill. 10 g of monochromatic crystals of O-acetyl-3'-acetylmidecamycin, which had an average particle size of 10 to 100 μm, was ground in a ball mill. The average particle size of the obtained pulverized product was 30 μm.

Heavy J"L"10-acetyl-3''-acetylmidecamycin I
Dissolve Og in 50 ml of dioxane and add 5 ml of water to this solution.
00ml was added and stirred for 30 minutes to obtain crystals. The average grain size of the crystals was 10-100 μm.

Dissolve 10 pieces of 1-doacetyl-3-acetylmidecamycin in 50ml of dioxane, and add 0.5% to this solution.
Glucose solution 500Q11 was added and stirred for 40 minutes to obtain crystals. The average particle size of these crystals was to -50 μm.

? $415 10-acetyl-3'-acetylmidecamycin IO
Dissolve g in 10 hl of acetone and add 0.5x to this solution.
500 ml of polyvinylpyrrolidone aqueous solution was added and stirred for 1 hour to obtain crystals. The average grain size of this crystal is 3-50
It was μm.

Drop - Consider j L ball 1 ; ] -] Acetyl 3 ° ° - Dissolve 10 g of acetylmidecamycin in 3 acetone 70 a + l, then add 0.5x sodium lauryl sulfate aqueous solution a 30111
n+l was added and stirred for 1 hour to obtain crystals. The average grain size of the crystals was 3-20 μm.

10 g of unovobiocin crystals were dissolved in acetone 501, and this solution was added to 5001 water with stirring to obtain crystals. The average grain size of the crystals was 7-40 μm.

(Effects of the Invention) According to the method of the present invention, as a result of transforming an amorphous solid in a princess-shaped state into a stable crystal, it is possible to obtain crystals so fine that they cannot be obtained by the conventional method.

In particular, if the method of the present invention is applied to a poorly water-soluble drug to form the drug into fine crystal particles, and the drug is formulated using the fine crystal particles, efficacy,
It is possible to produce pharmaceuticals with excellent stability, uniformity, safety, etc.

Claims (1)

[Claims] (1) A method for preparing microcrystals, which is characterized by transforming a previously prepared metastable amorphous solid into a stable crystal.