WO2011130877A1

WO2011130877A1 - Crystalline form of methylprednisolone aceponate monohydrate and preparation methods thereof

Info

Publication number: WO2011130877A1
Application number: PCT/CN2010/000544
Authority: WO
Inventors: 何运良; 李静
Original assignee: 天津金耀集团有限公司
Priority date: 2010-04-21
Filing date: 2010-04-21
Publication date: 2011-10-27

Abstract

A crystalline form of methylprednisolone aceponate monohydrate exhibits an X-ray powder diffraction pattern having characteristic peaks at the diffraction angles 2θ= of 8.6°, 12.2°, 13.6°, 15.3°, and 19.3°. The method for preparing the crystalline form comprises dissolving methylprednisolone aceponate in the mixture of water and organic solvent completely, and then evaporating the organic solvent. Another method comprises dissolving methylprednisolone aceponate in organic solvent completely, and then gradually adding water to precipitate the crystals of methylprednisolone aceponate monohydrate.

Description

Vinegar propylprednisolone monohydrate crystal form and preparation method thereof

The invention belongs to a body compound, in particular to a new crystal form of acetoacetate and a preparation method thereof. Background technique:

The chemical structural formula of Methylprednisolone aceponate (MPA, CAS: 86401-95-8) is as follows:

Vinegar as a derivative of methylprednisolone, developed by Schring AG, Germany, is a glucocorticoid with strong local anti-inflammatory activity for the treatment of skin inflammation. Currently, it is commercially available. The vinegar-methyl-panning nylon skin preparation is a 0.1% vinegar-methylprednisolone cream manufactured by Schring AG of Germany under the trade name Advantan. It can be used to inhibit the reaction of inflamed and allergic skin, and also inhibits the accelerated regeneration of cells. The reaction causes symptoms such as erythema, edema, thickening of the skin, loss of rough surface, and relief from itching, burning and pain. Vinegar propylprednisolone cream is currently a superior topical corticosteroid preparation, which is superior to known corticosteroids, and vinegar-methyl-peptidyl nylon cream is a highly effective corticosteroid without halogen group. Light, is a topical preparation for corticosteroids that can be used in children. The market prospects for this formulation are very broad.

At present, the research work on the crystal form of drugs has become more and more important. Chinese patent ZL200580026414.0 discloses that the crystalline polymorph of a specific drug is often difficult to prepare, stability, solubility, storage stability, and ease of preparation. An important judgment factor in pharmacology in the body. When we developed the acetophenone-precipitated nylon bulk drug, we conducted in-depth research on its crystal form, and found that the conventional synthetic method, such as the method disclosed in EP 0072547, has only one kind of anhydrous vinegar-methyl-peptone. Crystal form (see the content of the invention). In addition, there are no other crystal forms related to acetoacetate.

Summary of the invention:

Surprisingly, during the study of the crystal form of acetophenone-precipitated nylon, we discovered a new type of vinegar-methyl-peptone-methyl-monohydrate. At present, after a stability test, the brand-new vinegar Nylon monohydrate exhibits better stability than existing anhydrous acetoacetin, especially in formulations with better stability and is more susceptible to comminution. Therefore, this new vinegar-propylprednisolone monohydrate bulk drug can be a new choice for vinegar-methyl-peptone nylon preparations.

The chemical structure of acetophenone-peptone nylon monohydrate is as follows:

The present invention also provides a crystal form of the above acetoacetate monohydrate monohydrate and a method for preparing the same. The preparation method of the new crystal form of acetophenone-precipitated nylon monohydrate is stable and repeatable, and is easier to industrialize.

The acetoacetate monomethyl hydrate crystals provided by the present invention are determined by X-ray powder diffraction, and the X-ray powder diffraction has characteristic peaks at diffraction angles of 2 Θ = 8.6 °, 12.2 °, 13.6 °, 15.3 °, 19.3 °, The relative diffraction intensity is substantially the same as its detailed spectrum as shown in Fig. 2. The term "substantially", it should be understood that the diffraction intensity of the characteristic peaks may vary depending on the crystal preparation technique, the sample mounting method, and the measuring instrument, and should also be within the scope of the present invention. In addition, instrumental differences and other factors may affect the diffraction angle 2Θ, so the diffraction angle 2Θ of the above characteristic peaks can be varied within the existing value of ±0.2°.

The invention provides a preparation method of vinegar-propylprednisolone monohydrate crystal as follows:

Method 1 : Slowly add water to an organic solvent solution of acetophenone-precipitated nylon to precipitate a solute, thereby obtaining a crystal of acetophenone-precipitated nylon monohydrate.

Method 2: The acetoacetate is completely dissolved in a mixed solution of water and an organic solvent, and then the organic solvent is evaporated to obtain a crystal of acetophenone-precipitated nylon monohydrate.

The organic solvent has a boiling point of 10 (TC or less, including but not limited to one or more of the following solvents: an ether solvent, preferably diethyl ether, tetrahydrofuran (THF); a ketone solvent such as acetone, methyl ethyl ketone; Lower alcohols such as methanol, ethanol, isopropanol; ester solvents, preferably ethyl acetate; halogenated hydrocarbons such as dichloromethane; hydrocarbon solvents such as n-hexyl, cyclohexane, benzene; and polar aprons The solvent is preferably acetonitrile; more preferably one or more of tetrahydrofuran, acetone, methanol, ethyl acetate, n-hexane and acetonitrile.

The use of acetoacetate monohydrate monohydrate and crystals thereof prepared by the present invention for the preparation of a medicament for treating diseases in human or mammals is preferred. The medicament is preferably prepared as one of a tablet, a paste, a suspension, and an inhalant. It can be seen from the stability test of Example 8 that the aqueous suspension prepared by using the fine powder of acetophenone methyl phosphate monohydrate provided by the present invention is prepared from the existing powder of acetophenone pour nylon. Compared with the aqueous suspension, the smaller particle size of the fine powder can be better maintained, and the particle size of the fine powder is not precipitated due to recrystallization in water. Therefore, when preparing an aqueous pharmaceutical composition containing acetoacetin as an active ingredient, vinegar-methyl-panning nylon-water The composition is capable of maintaining the active ingredient at a lower particle size for a longer storage period, thereby ensuring the stability of aqueous preparations such as suspensions. At the same time, Example 8 also showed that the aqueous suspension using acetoacetate monohydrate monohydrate unexpectedly improved the stability of the content during storage. At the same time, it can be seen from Example 9 that the vinegar-methyl-peptazone monohydrate crystal provided by the present invention is more easily pulverized than the acetophenone-precipitated nylon crystal in the prior art under the same conditions, and thus is used for preparing various kinds. There is a potential advantage when micronized pharmaceutical preparations are needed.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an X-ray powder diffraction pattern of acetoacetate crystals prepared in the examples;

2 is an X-ray powder diffraction spectrum of the crystal of acetoacetate monohydrate obtained in Example 1. FIG. 3 is an X-ray powder diffraction spectrum of the crystal of acetoacetate monohydrate obtained in Example 3. Figure 4 is an X-ray powder diffraction spectrum of the crystal of acetoacetate monohydrate obtained in Example 6; Figure 5 is the X of the precipitate after the storage of the suspension of Group B in Example 8 for 3 months. Ray powder diffraction spectrum. detailed description:

Comparative example

1kg of anhydrous acetoacetate was dissolved in anhydrous acetone, concentrated under reduced pressure until the crystal appeared to cool down to 10 ° C, filtered, dried, and the obtained acetacetin crystal was determined by X-ray powder diffraction, crystal The parameters are as follows: a = 29.7552 A, b = 29.7552 A, c = 6.0272 A _; α = β = 90.00. , γ = 120°; unit cell volume is 4621.4 person 3 . This crystal belongs to the trigonal system. The measured characteristic peak positions were 2 Θ = 6.7 °, 9.0 °, 11.7 °, 13.7 °, 16.1 °, 17.8 °, 20.6 °, 22.3 °, as shown in FIG.

Example 1

1 kg of acetoacetate was completely dissolved in 10 L of tetrahydrofuran, and then a solution of 5 L of water and 5 L of ethanol was added to the tetrahydrofuran in which acetoacetate was dissolved. When adding the eluent, it was slowly added and added. While oscillating, the turbidity that disappeared immediately after the addition of the dissolution agent disappeared. After the addition, the evaporation was carried out under reduced pressure, and the crystals were cooled, filtered, and dried. The crystals after drying were measured for water content by Karl Fischer method, and it was confirmed to be acetophenone-peptone nylon monohydrate.

X-ray powder diffraction measurement showed that the characteristic peak positions were 2 Θ = 8.6 °, 12.2 °, 13.6 °, 15.3 °, 19.3 °, as shown in Fig. 2.

Example 2

Take lkg vinegar and p-prepared nylon completely dissolved in 40 L of acetonitrile, and then add 4 L of water and 20 L of hexamethylene as a decanting agent to the acetonitrile in which acetoacetate is dissolved, and slowly add it while adding the eluent. The mixture was shaken while being added until the turbidity which appeared immediately after the addition of the dissolution agent disappeared. After the addition, the evaporation was carried out under reduced pressure, and the crystals were cooled, filtered, and dried. The dried crystals were measured for water content by the Karl Fischer method, and it was confirmed to be acetoacetate. X-ray powder diffraction measurement showed that the characteristic peak positions were 2 Θ = 8.6 °, 12.2 °, 13.6. , 15.3°, 19.3°.

Example 3

0.2 g of acetaminophen was added to a mixed solution of 6 mL of tetrahydrofuran, 1 mL of water, and 2 mL of methanol, and stirred until fully dissolved. The solution was transferred to a small beaker, sealed with a parafilm sealing film, and several small holes were formed in the film to facilitate dissolution. 90 agents are volatilized. Crystallization was obtained after standing at room temperature for several days. The dried crystals were measured for water content by the Karl Fischer method, and it was confirmed to be acetoacetate. X-ray powder diffraction measurement showed that the characteristic peak positions were 2 Θ = 8.5 °, 12.1 °, 13.6 °, 15.3. 19.3°, as shown in Figure 3.

Example 4

O.lg acetoacetate nylon was added to a mixed solution of 6 mL of tetrahydrofuran, 1 mL of water, and 2 mL of acetone, and 95 was stirred until fully dissolved. The solution was transferred to a small beaker, sealed with a pamfilm sealing film, and several small holes were placed in the film to facilitate solvent evaporation. Crystallization was obtained after standing at room temperature for several days. The dried crystals were measured for water content by the Karl Fischer method, and it was confirmed to be acetophenone-precipitated nylon monohydrate. The peak position of the characteristic peaks was determined by X-ray powder diffraction to be 2 Θ = 8.6 °, 12.2 °, 13.5 °, 15.3 °, 19.3 °.

Example 5

100 0.3 g of acetaminophen was added to a mixed solution of 5 mL of tetrahydrofuran, 1 mL of water and 2 mL of ethyl acetate, and stirred until fully dissolved. The solution was transferred to a small beaker, sealed with a parafilm sealer, and several small holes were placed in the membrane to facilitate solvent evaporation. Crystallization was obtained after standing at room temperature for several days. The dried crystals were measured for water content by the Karl Fischer method, and it was confirmed to be acetophenone-precipitated nylon monohydrate. The peak position of the characteristic peaks was determined by X-ray powder diffraction to be 2 Θ = 8.6 °, 12.1 °, 13.6. 15.3. 19.3. .

105 Example 6

1 kg of acetoacetate was completely dissolved in 10 L of tetrahydrofuran, and 50 L of water was slowly added to the tetrahydrofuran in which acetoacetate was dissolved. When it was added, it was slowly added, stirred while being added, and after addition, filtered and dried. The dried crystals were measured for water content by the Karl Fischer method, and it was confirmed to be acetophenone-precipitated nylon monohydrate. X-ray powder diffraction measurement showed that the characteristic peak positions were 2 Θ = 8.5 °, 12.1 °, 13.5 °, 15.2 °, 19.3 °, as shown in Fig. 4. 1 10 Example 7

Take lkg vinegar and p-prednisolone completely dissolved in 20L of tetrahydrofuran, and then slowly add 3L of water to tetrahydrofuran in which acetoacetate is dissolved, and shake while adding, until the turbidity that appears when the solvent is added disappears. After evaporation, the crystals are cooled, filtered, and dried. The dried crystals were measured for water content by Karl Fischer method, and it was confirmed to be acetophenone-peptidated nylon monohydrate. X-ray powder diffraction measurement showed that the characteristic peak positions were 2 Θ 1 15 = 8.6 °, 12.2 °, 13.6 °, 15.3 °, 19.3 °.

Example 8 Stability Test Data Comparative Example

Content analysis method:

Determination of vinegar, propyl acetate and nylon content by HPLC analysis:

Chromatographic conditions of HPLC: column octadecyl silane bonded silica

120 mobile phase methanol-water (95: 5) detection wavelength 238nm

In the present embodiment, the acetoacetin-prepared nylon prepared in the comparative example and the acetoacetate-prepared nylon monohydrate prepared in the example 2 were pulverized into fine powder, wherein the acetophenone pour nylon micronized powder ₉ ο=7.5 μιη, vinegar Propylene methylprednisolone monohydrate micro powder D _9Q = 7.6 m. Group A, vinegar-methyl-peptone nylon monohydrate suspension preparation:

125 vinegar methylprednisolone monohydrate, 1.04g micropowder (equivalent to acetophenone pour nylon l.Og); polyvinylpyrrolidone, 5g; add sterile water for injection, 500ml _; mix the above components, fully stirred to get vinegar Propylene methylprednisolone monohydrate suspension.

Group B, vinegar-methyl-panning nylon suspension preparation:

Vinegar propylprednisolone l.Og; polyvinylpyrrolidone, 5 g; add sterile water for injection, 500 ml; mix the above 130 components and stir well to obtain a suspension of acetophenone.

Comparison of content stability: Take A and B water suspensions separately, use Xilin bottles according to lml/bottle size, take 10 bottles each, store at 35 °C, 75 % relative humidity for 3 months, The contents of the storage on the 0th, 3rd, 7th, 30th, 60th, and 90th days (measured by acetoacetate) are shown in the following table: () ±s, n

= 10)

135 suspension stability comparison

Take A and B two groups of water suspensions, each taking 100ml, and storing at 25 °C for 3 months to observe: There is no significant change in group A suspension;

The group B suspension showed significant precipitation, and 0.5 g of polyvinylpyrrolidone was added and stirred vigorously, and it was still difficult to maintain the suspension state. The precipitate was taken out and observed under a microscope, and it was found that the solid particles had become significantly larger. The precipitate was washed and filtered to obtain a particle size, ϋ ₉ . = 35.7 μιη, The above precipitate was subjected to X-ray powder diffraction measurement at 2 Θ = 8.5 ° and 12.1. , 13.6. There are characteristic peaks at 15.3° and 19.3°, as shown in Figure 5.

Example 9 Crushing experiment

Experimental equipment: WLFM-P-85 jet mill Beijing Weiling Muxin Machinery Co., Ltd. produces particle size measuring instruments: Ea _S ysi _Z er20 laser particle size analyzer, Zhuhai Omega Technology Co., Ltd.

145 Sample grouping:

Group A is 5 kg of acetoacetate-precipitated nylon monohydrate crystals prepared by the method of Example 2, and the average is divided into ten parts, and the air flow is pulverized. The feed size is 80-90 mesh, and the ten-time pulverized particle diameter D _9Q is re-averaged. .

Group B is 5 kg of acetoacetate crystals prepared by the method of the comparative example, and the average is divided into ten parts, and the air flow is pulverized, the feed size is 80-90 mesh, and the particle size D _{9Q of} ten times is re-averaged;

150 Crushing conditions: pulverizing airflow l.OMpa feeding speed 0.5kg/h

The above-mentioned Group A and Group B samples were subjected to jet pulverization according to the above pulverization conditions, and the obtained product particle size was: the average Ο ₉ ο=23.1 μπ of the sample of Group A, and the average D _{9Q of the} Β group sample of 32.5 m.

Claims

A acetophenone-precipitated nylon monohydrate as shown in the following formula.

The acetoacetate monomethyl hydrate according to claim 1, wherein the compound is present in a crystal form, and the X-ray powder is diffracted at diffraction angles of 2 Θ = 8.6 °, 12.2 °, 13.6 °, 15.3 °. There are characteristic peaks at 19.3°.

The method for preparing acetoacetate monohydrate crystal according to claim 2, wherein the vinegar is splashed with nylon

In the organic solvent solution, water is slowly added to cause the solute to precipitate, and acetonitrile-peptone nylon monohydrate crystals are obtained.

The method for preparing crystals of acetoacetate monohydrate according to claim 2, wherein: the acetoacetate is completely dissolved in a mixed solution of water and an organic solvent, and then the organic solvent is evaporated. The crystal of acetophenone pour nylon monohydrate can be obtained.

The method according to any one of claims 3 to 4, wherein the organic solvent has a boiling point of 100 ° C or less, and is selected from the group consisting of an ether solvent, a ketone solvent, an ester solvent, and three carbons or less. One or more of a lower alcohol, a hydrocarbon solvent, a halogenated hydrocarbon, and a polar aprotic solvent.

The preparation method according to claim 5, wherein the organic solvent is preferably diethyl ether, tetrahydrofuran, acetone, methyl ethyl ketone, methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, n-hexane, cyclohexane, One or more of benzene and acetonitrile.

The process according to claim 6, wherein the organic solvent is preferably one or more of tetrahydrofuran, acetone, methanol, ethyl acetate, n-hexyl hydrazine, and acetonitrile.

The use of the acetophenone-peptidyl nylon monohydrate according to any one of claims 1 to 2 for the preparation of a medicament for treating a human or mammalian disease.

The use of acetoacetate monohydrate according to claim 8, wherein the medicament is preferably prepared as one of a tablet, a paste, a suspension, and an inhalant.