阅读说明：本技术 氯喹那多晶体的制备方法 (Preparation method of chloroquinate crystal ) 是由 张忠政 王琨 刘文杰 孙滨 张宾 张治中 张彤 游亚新 李景坤 张国斌 于 2019-11-29 设计创作，主要内容包括：本发明属于医药技术领域,具体涉及一种氯喹那多晶体的制备方法。采用高分子表面活性剂和溶剂对氯喹那多粗品进行精制,得到氯喹那多晶体。本发明制得的晶体流动性好、晶体稳定、易粉碎、成药性佳、适用于多剂型；制得的氯喹那多片状晶体和柱状晶体可与普罗雌烯片状晶体均匀混合,提高制剂药效的稳定性；制备方法安全环保、操作简便、适合于工业化生产。(The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a chloroquinate crystal. And (3) refining the crude product of the chloroquinate by adopting a high-molecular surfactant and a solvent to obtain a chloroquinate crystal. The crystal prepared by the invention has good fluidity, stable crystal, easy pulverization and good pharmaceutical property, and is suitable for multiple dosage forms; the prepared chloroquinalder flaky crystal and columnar crystal can be uniformly mixed with the promestrene flaky crystal, so that the stability of the drug effect of the preparation is improved; the preparation method is safe, environment-friendly, simple and convenient to operate and suitable for industrial production.)

1. A preparation method of a cloquindol crystal is characterized in that a high-molecular surfactant and a solvent are adopted to refine a crude cloquindol product to obtain the cloquindol crystal.

2. The process for producing a crystal of chloroquinate as claimed in claim 1, wherein the polymeric surfactant is a sorbitan ester-based surfactant.

3. The process for producing a crystal of chloroquinate according to claim 2, wherein the polymeric surfactant is tween-80 or span-60.

4. The method for preparing a crystal of chloroquinate according to claim 1, wherein the mass ratio of the crude chloroquinate to the polymeric surfactant is 1: 0.001-0.005.

5. The method for preparing a crystal of chloroquinate as claimed in claim 1, wherein the ratio of the crude chloroquinate to the solvent is 1:5-10, the crude chloroquinate is calculated by g, and the solvent is calculated by ml.

6. The process for producing a crystal of chloroquinaldine according to any one of claims 1 to 5, characterized in that the solvent is acetone.

7. The method for preparing the chloroquinate crystals according to claim 6, characterized in that under the protection of nitrogen, the crude chloroquinate is added into a solvent, heated to be dissolved, decolored, then thermally filtered, the filtrate is stirred to be cooled, purified water and a high molecular surfactant are added, the mixture is kept warm, kept still and crystallized, then subjected to gradient cooling, stirred and crystallized, then filtered, rinsed, and dried under reduced pressure to obtain the chloroquinate crystals.

8. The process for producing a crystal of chloroquinate as claimed in claim 7, wherein the mass ratio of the crude chloroquinate to the purified water is 1: 2-6.

9. The process for producing a crystalline chloroquinaldine according to any one of claims 1 to 5, characterized in that the solvent is acetonitrile.

10. The preparation method of the chloroquinate crystal as claimed in claim 9, characterized in that under the protection of nitrogen, the crude chloroquinate is added into a solvent, heated to dissolve, decolored, then thermally filtered, the filtrate is stirred to cool, a high molecular surfactant is added, the mixture is kept warm, kept still and crystallized, then gradiently cooled, stirred and crystallized, then filtered, rinsed, decompressed and dried to obtain the chloroquinate crystal.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a chloroquinate crystal.

Background

Cloquinadol is a broad-spectrum bacteriostatic agent. The structural formula is as follows:

the relative molecular mass was 228.07.

It was extensively studied by many pharmaceutical facilities in europe as early as the 50 s, and found to have antimicrobial pathogen activity against fungi, trichomonas, bacteria (G + and G-), chlamydia and mycoplasma, and is a broad spectrum bacteriostatic. The earliest was developed and produced by the pharmaceutical factory of Morage Theramex, and the preparation method disclosed in the first place is that 8-hydroxy-2-methylquinoline is used as a raw material, 20% hydrochloric acid is used as a solvent, and the raw material is synthesized by one-step chlorination reaction under the condition of introducing chlorine.

The synthesis of the chloroquinadol, journal of Chinese medicine industry, 2008, 39(10), Tejiangtong, discloses a synthetic process of the chloroquinadol by using formic acid to replace hydrochloric acid as a solvent. Adding 2-methyl-8-light-radical oualin and formic acid into a reaction bottle, stirring until the mixture is dissolved, cooling to 0-5 ℃, introducing chlorine, stirring at room temperature for reaction until the reaction is complete when the color is not changed any more by using a diazobenzene-acetic acid solution, driving chlorine for 0.5h under the condition of reduced pressure at room temperature, and then recovering the formic acid under reduced pressure. The residue was treated with water and 20% sodium bisulfite solution until no color change was detected by starch potassium iodide paper. And (4) carrying out suction filtration, washing a filter cake with water, drying under reduced pressure, and then recrystallizing with ethanol to obtain yellow needle crystals.

Chinese patent CN108341776A discloses a process for synthesizing cloquindol, which comprises the steps of taking 8-hydroxy-2-methylquinoline as a raw material, taking chlorine atoms in an active state generated by the reaction of sodium hypochlorite and hydrochloric acid as a chlorinated raw material, and generating the cloquindol through one-step chlorination reaction; the process uses sodium hypochlorite as a chlorinated raw material instead of chlorine.

Chinese patent CN110143919A discloses a process for synthesizing chloroquinate, which comprises using 8-hydroxy-2-methylquinoline and N-chlorosuccinimide as raw materials, using Lewis acid as a catalyst, and carrying out one-step chlorination reaction under the conditions of solvent and dark place to generate the chloroquinate.

At present, a great deal of literature and patents are available for studying the synthesis process of chloroquinate, but the appearance of chloroquinate polymorph is not studied. In the prior art, the refined solvent of the chloroquinate is methanol and ethanol, the chloroquinate crystals obtained by crystallization are all yellow needle-shaped crystals, and researches show that the needle-shaped crystals have poor liquidity, uneven dispersion, difficult pulverization and poor drug property.

China imported in 1997 for use of cloquindol/promestrene vaginal tablets (trade name "Colubetryn"), Chinese patent CN1600315A discloses a cloquindol/promestrene soft capsule composition for vagina, which is a cloquindol/promestrene soft capsule for vagina and contains a main drug of cloquindol/promestrene and a proper amount of solvent, surfactant and the like to form an opaque liquid suitable for vagina. Chinese patent CN102038688A discloses a self-emulsifying microemulsion soft capsule for cloquindol-promestrene vagina and a preparation method thereof, the self-emulsifying microemulsion soft capsule for the cloquindol-promestrene vagina is a soft capsule for the vagina which has no local stimulation and good melting time limit, and the system is a uniform transparent solution formed by the cloquindol, the promestrene, an oil phase, a surfactant and a cosurfactant.

Cloquindol is often used in combination with promestrene, which is a lamellar crystal, and the needle-shaped crystals of cloquindol and the lamellar crystal of promestrene cannot be uniformly mixed, resulting in poor stability of the drug effect of the preparation.

Disclosure of Invention

The invention aims to provide a preparation method of a chloroquinate crystal, which is safe, environment-friendly, simple and convenient to operate, suitable for industrial production, good in flowability of the prepared crystal, stable in crystal, easy to crush, good in pharmacy and suitable for multiple dosage forms.

The preparation method of the cloquindol crystal adopts a high molecular surfactant and a solvent to refine a crude product of the cloquindol to obtain the cloquindol crystal.

The polymer surfactant is sorbitan ester surfactant, preferably tween-80 or span-60, and more preferably tween-80.

The mass ratio of the crude chloroquinader to the high molecular surfactant is 1: 0.001-0.005.

The ratio of the crude chloroquinader to the solvent is 1:5-10, wherein the crude chloroquinader is counted by g, and the solvent is counted by ml.

The solvent is acetone or acetonitrile, preferably acetone.

When the solvent is acetone, the preparation method of the cloquindol crystal comprises the steps of adding a crude cloquindol product into the solvent under the protection of nitrogen, heating to dissolve, decoloring, then performing heat filtration, stirring and cooling filtrate, adding purified water and a high molecular surfactant, preserving heat, standing and growing crystals, then performing gradient cooling, stirring and crystallizing, then filtering, leaching, and drying under reduced pressure to obtain the cloquindol crystal.

The mass ratio of the crude product of the chloroquinader to the purified water is 1: 2-6.

When the solvent is acetonitrile, the preparation method of the cloquindol crystal comprises the steps of adding a crude cloquindol product into the solvent under the protection of nitrogen, heating to dissolve, decoloring, then carrying out heat filtration, stirring and cooling filtrate, adding a high molecular surfactant, keeping the temperature, standing, growing crystals, then carrying out gradient cooling, stirring and crystallizing, then filtering, leaching, and drying under reduced pressure to obtain the cloquindol crystal.

The temperature rise is 56-82 ℃.

The decolorization is realized by adopting medicinal carbon, and the mass ratio of the crude chloroquinader to the medicinal carbon is 1: 0.01-0.05.

The stirring speed of the filtrate is 20-50 Hz.

The stirring blade is in a helical blade turbine type, so that the flow field is mainly axial, the shearing is small, the flow is large, the nucleation is weakened, and the crystal growth is promoted.

Standing and growing the crystal at the temperature of 30-60 ℃ for 10-20 hours.

The gradient cooling is that the temperature is reduced to 15-25 ℃ at the rate of 5 ℃ per 1 hour, the temperature is kept and stirred for 1-2 hours, and then the temperature is reduced to-5-15 ℃ at the rate of 10 ℃ per 1 hour.

The stirring speed is 20-50 Hz.

The gradient cooling can change crystal habit, prevent crystal fracture, make its crystal appearance no longer be acicular, and the gradient cooling can avoid exploding and separating moreover, improves crystal purity.

The stirring crystallization temperature is-5-15 ℃, the stirring crystallization time is 6-10 hours, and the stirring speed in the stirring crystallization is 20-50 Hz.

The leaching is performed by adopting absolute ethyl alcohol, and the temperature of the absolute ethyl alcohol is-5-15 ℃.

The reduced pressure drying temperature is 30-60 deg.C, preferably 40-50 deg.C.

Research shows that in the preparation process of the chloroquinalder crystal, when no high molecular surfactant is added, the precipitated crystal is needle-shaped. After the addition of the high molecular surfactant, the crystal habit is changed, so that the appearance of the precipitated crystal is changed. In order to avoid the influence of the added high molecular surfactant on the purity of the precipitated crystals, an ionic surfactant cannot be selected, and a nonionic surfactant is selected. The nonionic surfactant is divided into polyoxyethylene type and polyhydric alcohol type, and experiments show that crystals precipitated by adding polyoxyethylene type (such as alkylphenol ethoxylates, polyoxyethylene fatty acid, etc.) are still needle-shaped crystals, crystals precipitated by adding polyhydric alcohol type (such as Tween-80, span-60, hydroxyethyl cellulose, polyacrylamide, polyvinylpyrrolidone, etc.) are one or more of needle-shaped crystals, sheet-shaped crystals or columnar crystals, but the crystal precipitated by adding hydroxyethyl cellulose, polyacrylamide, polyvinylpyrrolidone and the like is a mixed crystal of two or three of needle-shaped crystal, flaky crystal or columnar crystal, the crystal precipitated by adding the sorbitan esters such as the Tween-80, the span-60 and the like is a crystal with a single shape, wherein the crystal precipitated by adding the Tween-80 is more stable.

Further research shows that under the condition of adding sorbitan ester surfactants such as tween-80, span-60 and the like, methanol, ethanol, THF, 1,4 dioxane, DMF and the like are used as solvents, and the refined chloroquindol is needle-shaped crystal; taking acetone as a solvent, and taking the refined chloroquinadol as a flaky crystal; acetonitrile is used as a solvent, and the refined chloroquinadol is a columnar crystal. When acetonitrile is used as a solvent, no purified water is added, and therefore, the yield is not affected.

According to the classical nucleation theory, if the surface energy of a certain crystal phase is small, the energy barrier for becoming a critical nucleus is low, and thus has a relatively high nucleation rate. The interaction energy of the solvent and different crystal faces is different, so that the relative growth rate of the crystal faces is changed, and the growth morphology of the crystal is influenced and changed. When acetone and acetonitrile are used as solvents, different intermolecular forces are generated between the acetone and the acetonitrile and different crystal faces, so that different crystal shapes can be grown.

The X-ray diffraction method detects that unit cell parameters such as diffraction angles of the flaky crystal, the columnar crystal and the needle crystal are completely consistent, parameters such as infrared absorption spectrum absorption band frequency, peak shape, peak position and peak intensity are also completely consistent, and analysis results such as DSC, DTA, TGA and the like are also the same, so that the flaky crystal, the columnar crystal and the needle crystal are of the same crystal form.

The appearance of the chloroquinate crystal prepared by the invention is sheet-shaped or columnar.

The invention has the following beneficial effects:

1. the crystal prepared by the invention has good fluidity, stable crystal, easy pulverization and good pharmaceutical property, and is suitable for multiple dosage forms.

2. The cloquindol flaky crystal and the columnar crystal prepared by the invention can be uniformly mixed with the promestrene flaky crystal, so that the stability of the drug effect of the preparation is improved.

3. The preparation method of the chloroquinalder crystal is safe, environment-friendly, simple and convenient to operate and suitable for industrial production.

4. Aiming at the defects of the needle-shaped crystal of the chloroquinate in practical application, the invention prepares the flaky crystal and the columnar crystal of the chloroquinate and improves the refining yield of the chloroquinate and the stability of the drug effect of the preparation of the chloroquinate. The yield of the cloquinalder refined product is 95-98%, and the purity is more than 99.9%.

Drawings

FIG. 1 is a morphology chart of the layered crystal of chloroquinader prepared in example 1.

FIG. 2 is a topographical map of the chloroquinalder columnar crystals prepared in example 3.

FIG. 3 is a morphology chart of needle-shaped crystals of chloroquinate prepared in comparative example 1.

Detailed Description

The present invention is further described below with reference to examples.