CN106995434A - A kind of crystal form of triazole antifungal drug and preparation method thereof - Google Patents

Abstract

The invention provides a crystal form of triazole antifungal drugs and a preparation method thereof, belonging to the field of pharmaceutical chemistry. The crystal form comprises a crystal form I and a crystal form II. Said form I having peaks at about 7.75,12.58,15.27,18.98 degrees 2 θ in its X-ray powder diffraction pattern; the form II has an X-ray powder diffraction pattern with peaks at about 7.68,11.41,15.39,18.92 degrees 2 θ. The crystal form I and the crystal form II do not contain solvents or crystal water, have better solubility or stability, are beneficial to operation in storage, transfer and production processes, and are suitable for being prepared into external preparations.

Description

A kind of crystal form of triazole antifungal drug and preparation method thereof

technical field

The invention relates to a crystal form of a triazole antifungal drug and a preparation method thereof, belonging to the field of medicinal chemistry.

Background technique

Efinaconazole, a triazole topical antifungal drug. In the United States, the drug is used for the topical treatment of onychomycosis caused by Trichophyton rubrum and Trichophyton mentagrophytes; in Japan, the drug is used for the treatment of onychomycosis caused by Trichophyton; its structure is as follows (1 ) as shown:

Drug polymorphism is a common phenomenon in drug research and development, and is an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in physical and chemical properties such as appearance, fluidity, solubility, storage stability, and bioavailability, and there may be great differences, which will affect the storage transfer, application, stability, and efficacy of the drug etc. have different effects; in order to obtain effective crystal forms that are beneficial to production or pharmaceutical preparations, it is necessary to conduct a comprehensive investigation of the crystallization behavior of drugs to obtain crystal forms that meet production requirements.

Contents of the invention

Summary of the invention

The first aspect of the present invention provides two new crystal forms of efluconazole.

The second aspect of the present invention provides a preparation method of the crystalline form of efluconazole.

Definition of Terms

The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including but not limited to defined terms, term usage, described techniques, etc.), this application prevail.

It is further appreciated that certain features of the invention, which, for clarity, have been described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications referred to herein are hereby incorporated by reference in their entirety.

As used herein, the following definitions shall apply unless otherwise stated. For the purposes of the present invention, the chemical elements correspond to the CAS edition of the Periodic Table of the Elements, and the Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, the general principles of organic chemistry can refer to the descriptions in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, Its entire content is incorporated herein by reference.

The term "comprising" or "comprising" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other content.

The term "crystal form" is used to describe the state of existence of solid compounds, and to describe the collection of various parameters of ions, atomic or molecular composition, symmetry properties and periodic arrangement within the crystal.

The term "substantially as shown" refers to a "crystalline form" that is substantially pure by at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks appear in the given X-ray powder diffraction pattern. When the content of a certain crystal form in the sample gradually decreases, some diffraction peaks belonging to the crystal form in the X-ray powder diffraction pattern may become less due to the detection sensitivity of the instrument.

The term "relative intensity" refers to the ratio of the intensity of other peaks to the intensity of the first intense peak when the intensity of the first intense peak in a group of diffraction peaks assigned to a certain crystal form is defined as 100%.

In the context of the present invention, 2Θ (also known as 2theta or diffraction peak) values in an X-ray powder diffraction pattern are in degrees (°).

When referring to a spectrum and/or data in a graph, the term "diffraction peak" refers to a feature that one skilled in the art would not attribute to background noise.

The X-ray powder diffraction peak of the crystal form, the 2θ of its X-ray powder diffraction pattern or the measurement of the diffraction peak have experimental errors, between one machine and another machine and between one sample and another sample , the measurement of 2θ or diffraction peaks of the X-ray powder diffraction pattern may be slightly different, and the value of the experimental error or difference may be +/-0.2 units or +/-0.1 units or +/-0.05 units , so the values of the 2θ or diffraction peaks cannot be regarded as absolute.

The differential scanning calorimetry curve (DSC) of the crystal form has experimental error, and the position and peak value of the endothermic peak may vary slightly between one machine and another machine and between one sample and another sample. The difference, the experimental error or the value of the difference may be less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C, so the peak position or peak value of the DSC endothermic peak The value of is not to be regarded as absolute.

The thermogravimetric analysis curve (TGA) of the crystal form has experimental error, and between one machine and another machine and between one sample and another sample, the endothermic curve or the weight loss rate may be slightly different, the experiment The value of the error or difference may be less than or equal to 0.004% or 0.003% or 0.002% or 0.001%, so the thermogravimetric analysis curve or its weight loss rate cannot be regarded as absolute.

In the context of the present invention, all numbers disclosed herein are approximations, whether or not the word "about" or "approximately" is used. The value of each number may vary by 1%, 2%, or 5%. When approximate is used to describe the 2θ (also known as 2theta or diffraction peak) value of an X-ray powder diffraction peak, approximately means that the 2θ value may have +/-0.2 units or +/-0.1 units or +/-0.05 unit difference.

"Room temperature" means a temperature between about 20°C to 35°C or about 23°C to 28°C or about 25°C.

The term "good solvent" can be a single solvent or a mixed solvent, which means that the solubility of efluconazole in the single solvent or mixed solvent is greater than 1g/L, or greater than 2g/L, or greater than 3g/L, or greater than 4g/L , or greater than 5g/L, or greater than 6g/L, or greater than 7g/L, or greater than 8g/L, or greater than 9g/L, or greater than 10g/L, or greater than 15g/L, or greater than 20g/L, or Greater than 30g/L, or greater than 40g/L, or greater than 50g/L, or greater than 60g/L, or greater than 70g/L, or greater than 80g/L, or greater than 100g/L. In some embodiments, the solubility of efluconazole in a good solvent is greater than in a poor solvent; in some embodiments, the difference between the solubility of efluconazole in a good solvent and a poor solvent is about 10%, 20%, 30%. %, 40%, 50%, 60%, 70%, 80% or 90%; in some embodiments, the solubility of efluconazole in the good solvent is greater than that of the poor solvent, greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.

The term "poor solvent" refers to a solvent that promotes supersaturation or crystallization of a solution. In some embodiments, the solubility of efluconazole in a poor solvent is less than 0.001g/L, or less than 0.01g/L, or less than 0.1g/L, or less than 0.2g/L, or less than 0.3g/L, Or less than 0.4g/L, or less than 0.5g/L, or less than 0.6g/L, or less than 0.8g/L, or less than 1g/L, or less than 2g/L, or less than 3g/L, or less than 4g/L L, or less than 5g/L, or less than 6g/L, or less than 7g/L, or less than 8g/L, or less than 9g/L, or less than 10g/L.

Detailed description of the invention

In the first aspect, the inventor has developed the crystal form I and the crystal form II of efluconazole through research.

The crystal form I of efluconazole has the following characteristics: in its X-ray powder diffraction pattern, there are peaks at 2θ of 7.75, 12.58, 15.27, 15.48, 16.79, and 18.98 degrees.

In some embodiments, in the X-ray powder diffraction diagram of the crystal form I of efluconazole, one of the positions at 2θ of 7.75, 10.65, 12.58, 15.27, 15.48, 16.79, 18.98, 20.20, 23.87, 26.38, 33.88 degrees There are peaks at one or more places.

In some embodiments, the X-ray powder diffraction pattern of the crystal form I of efluconazole is 7.75, 10.65, 12.58, 15.27, 15.48, 16.79, 18.98, 20.20, 21.29, 23.87, 24.57, 26.38, 27.34, One or more peaks at the position of 33.88 degrees.

In some embodiments, the X-ray powder diffraction pattern of the crystal form I of efluconazole is 7.75, 10.65, 12.58, 15.27, 15.48, 16.79, 18.98, 20.20, 21.29, 23.87, 24.57, 25.41, 26.11, There are peaks at one or more positions at 26.38, 27.34, 30.22, and 33.88 degrees.

In some embodiments, the X-ray powder diffraction pattern of crystalline form I of efluconazole is substantially as shown in Figure 1, wherein the relative intensity of the peak at 2θ of 15.48 degrees is greater than 50%, or greater than 70%, or Greater than 80%, or greater than 90%, or greater than 99%.

The crystal form I of efluconazole also has the following characteristics: its differential scanning calorimetry curve (DSC) has an endothermic peak at 84°C-89°C. In a specific embodiment, its differential scanning calorimetry curve (DSC) has an endothermic peak at 84°C-88°C, and the peak value of the endothermic peak is about 88°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form I of efluconazole is shown in FIG. 2 . DSC of Form I revealed that it began to melt upon heating to about 84°C.

The crystalline form I of efluconazole is non-hygroscopic, does not contain crystallization solvent or water of crystallization, and is non-solvate or non-hydrate. In some embodiments, the thermogravimetric analysis curve (TGA) of crystalline form I of efluconazole is shown in FIG. 2 .

The crystalline form I of efluconazole is a powder with good appearance and fluidity, and has good performance in terms of solubility, stability, fluidity, etc., which is beneficial to storage, transfer, and operation in the production process, and is suitable for the preparation of into its external preparation.

The crystal form II of efluconazole has the following characteristics: in its X-ray powder diffraction pattern, there are peaks at 2θ of 7.68, 11.41, 13.82, 16.05, 16.71, 17.84, and 20.19 degrees.

In some embodiments, in the X-ray powder diffraction pattern of the crystal form II of efluconazole, one or more positions at 2θ are 7.68, 11.41, 13.82, 15.38, 16.05, 16.71, 17.84, 18.92, 20.19 degrees There are peaks.

In some embodiments, in the X-ray powder diffraction diagram of the crystal form II of efluconazole, the 2θ is 7.68, 11.41, 13.82, 15.38, 16.05, 16.71, 17.84, 18.92, 20.19, 23.12, 23.54, 26.14 degrees One or more peaks.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form II of efluconazole is 7.68, 11.41, 13.82, 15.38, 16.05, 16.71, 17.84, 18.92, 20.19, 23.12, 23.54, 26.14, 27.27, There are peaks at one or more positions at 30.19, 31.87 degrees.

In some embodiments, the X-ray powder diffraction pattern of crystalline form II of efluconazole is substantially as shown in Figure 3, wherein the relative intensity of the peak at 2θ of 15.38 degrees is greater than 50%, or greater than 70%, or Greater than 80%, or greater than 90%, or greater than 99%.

The crystal form II of efluconazole also has the following characteristics: its differential scanning calorimetry curve (DSC) has an endothermic peak at 84°C-89°C. In a specific embodiment, its differential scanning calorimetry curve (DSC) has an endothermic peak at 84°C-88°C, and the peak value of the endothermic peak is about 85°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form II of efluconazole is shown in FIG. 4 . DSC of Form II revealed that it starts to decompose upon heating to about 82°C.

The crystalline form II of efluconazole is non-hygroscopic, does not contain crystallization solvent or crystal water, and is non-solvate or non-hydrate. In some embodiments, the thermogravimetric analysis curve (TGA) of crystalline form II of efluconazole is as shown in FIG. 4 .

The crystalline form II of efluconazole is a powder with good fluidity, has good performance in terms of solubility, fluidity, etc., is beneficial to storage, transfer, and operation in the production process, and is suitable for preparation as its external preparation.

In a second aspect, the present invention provides a method for preparing the aforementioned crystal form I or II of efluconazole.

Specifically, a method for preparing crystalline form I of efluconazole comprises: dissolving efluconazole in a good solvent, then placing in air to evaporate the solvent at room temperature or evaporate the solvent to dryness under reduced pressure to precipitate crystals, and collect the crystals Form I was obtained.

In some embodiments, the good solvent is methanol, ethanol, trifluoroethanol, n-propanol, n-butanol, sec-butanol, isobutanol, acetone, ethyl acetate, acetonitrile, isopropyl acetate, ethyl formate One or more of esters, butyl formate, methyl acetate, diethyl ether, isopropyl ether and ethylene glycol dimethyl ether.

In some embodiments, the good solvent is preferably one or more of trifluoroethanol, ethyl formate, butyl formate, methyl acetate and ethylene glycol dimethyl ether.

In some embodiments, the amount of the good solvent relative to efluconazole is 1ml/g-50ml/g.

In some embodiments, the amount of the good solvent relative to efluconazole is preferably 2ml/g-30ml/g.

A method for preparing crystal form I of efluconazole comprises: dissolving efluconazole in a good solvent, raising the temperature to 50°C-70°C, then adding a poor solvent to precipitate crystals, collecting the crystals, removing the solvent, and obtaining the crystal form I.

In some embodiments, the good solvent is methanol, ethanol, absolute ethanol, trifluoroethanol, n-propanol, n-butanol, sec-butanol, isobutanol, acetone, ethyl acetate, acetonitrile, isopropyl acetate ester, ethyl formate, butyl formate, methyl acetate, ether, isopropyl ether and ethylene glycol dimethyl ether; the poor solvent is water, n-hexane, n-pentane, cyclohexane One or more of alkanes and n-heptanes.

In some embodiments, the good solvent is preferably one or more of trifluoroethanol, ethyl formate, butyl formate, methyl acetate and ethylene glycol dimethyl ether.

In some embodiments, the amount of the good solvent relative to efluconazole is 1ml/g-50ml/g.

In some embodiments, the amount of the good solvent relative to efluconazole is preferably 2ml/g-30ml/g.

In some embodiments, the poor solvent is one or more of water, cyclohexane, n-pentane and n-heptane.

In some embodiments, the poor solvent is preferably one or both of n-pentane and n-heptane.

In some embodiments, the poor solvent is preferably water.

In some embodiments, the amount of the poor solvent relative to efluconazole is 1ml/g-50ml/g.

In some embodiments, the amount of the poor solvent relative to efluconazole is preferably 5ml/g-20ml/g.

In some embodiments, the volume ratio of the good solvent to the poor solvent is 1:6˜1:0.5.

In some embodiments, the volume ratio of the good solvent to the poor solvent is preferably 1:5˜1:1.

Specifically, a method for preparing efluconazole crystal form II comprises: dissolving efluconazole in isopropanol, tetrahydrofuran, methyl tert-butyl ether, n-amyl alcohol, methyl ethyl ketone, dichloromethane, trichloro One or more solvents among methane and 1,2-dichloroethane, and then placed in the air to evaporate the solvent at room temperature, and the crystals were collected to obtain the crystal form II.

A method for preparing efluconazole crystal form II comprises: dissolving efluconazole in one or more of acetone, butanone, dichloromethane, dichloroethane, tetrahydrofuran and methyl tert-butyl ether solvent, then evaporate the solvent under reduced pressure at room temperature and precipitate crystals, and collect the crystals to obtain Form II.

A method for preparing efluconazole crystal form II comprises: dissolving efluconazole in one or more of acetone, butanone, dichloromethane, dichloroethane, tetrahydrofuran and methyl tert-butyl ether solvent, and then spray-dried to collect crystals to obtain Form II.

A method for preparing crystalline form II of efluconazole comprises: dissolving efluconazole in a good solvent, controlling the low-temperature reaction, adding a poor solvent to precipitate crystals, collecting the crystals, and removing the solvent to obtain the crystalline form II.

In some embodiments, the good solvent is methanol, ethanol, trifluoroethanol, n-propanol, n-butanol, sec-butanol, isobutanol, acetone, ethyl acetate, acetonitrile, isopropyl acetate, ethyl formate One or more of esters, butyl formate, methyl acetate, diethyl ether, isopropyl ether and ethylene glycol dimethyl ether.

In some embodiments, the amount of the good solvent relative to efluconazole is 1ml/g-100ml/g.

In some embodiments, the amount of the good solvent relative to efluconazole is preferably 5ml/g-60ml/g.

In some embodiments, the poor solvent is one or more of water, n-hexane, n-pentane, cyclohexane and n-heptane.

In some embodiments, the poor solvent is preferably one or more of water, n-hexane, n-pentane and n-heptane.

In some embodiments, the amount of the poor solvent relative to efluconazole is 1ml/g-100ml/g.

In some embodiments, the amount of the poor solvent relative to efluconazole is preferably 10ml/g-50ml/g.

In some embodiments, the volume ratio of the good solvent to the poor solvent is 1:8˜1:0.2.

In some embodiments, the volume ratio of the good solvent to the poor solvent is preferably 1:5˜1:1.

In some embodiments, the cryogenic temperature is -15°C to 25°C.

In some embodiments, the low temperature is preferably -5°C-15°C.

Description of drawings

Figure 1 shows the X-ray powder diffraction pattern of efluconazole crystal form I.

Figure 2 shows the differential scanning thermal curve and thermogravimetric analysis (DSC&TGA) of efluconazole crystal form I.

Figure 3 shows the X-ray powder diffraction pattern of efluconazole crystal form II.

Figure 4 shows the differential scanning thermal curve and thermogravimetric analysis (DSC&TGA) of efluconazole crystal form II.

detailed description

In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.

The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.

In the present invention, g means gram, mL means milliliter, L means liter, h means hour, and min means minute.

Instrument parameters

All analyzes below were performed at room temperature unless otherwise specified in the parameters.

X-ray powder diffraction (XRPD)

X-ray powder diffraction (XRPD) patterns were collected on a Dutch PANalytical Empyrean X-ray diffractometer equipped with a transflectance sample stage with an automated 3*15 zero background sample holder. The radiation source used is (Cu, kα, Kα1 1.540598; Kα2 1.544426; Kα2/Kα1 intensity ratio: 0.50), wherein the voltage is set at 45KV, and the current is set at 40mA. The beam divergence of the X-ray, that is, the effective size of the X-ray constraint on the sample, is 10mm. Use θ-θ In continuous scanning mode, an effective 2θ range of 3° to 40° is obtained. Take an appropriate amount of sample in the circular groove of the zero-background sample holder under ambient conditions (about 18 ° C ~ 32 ° C), lightly press it with a clean glass slide to obtain a flat plane, and fix the zero-background sample rack. The sample was scanned with a step size of 0.0168° to generate a traditional XRPD pattern in the range of 3-40°2θ±0.2°. The software used for data collection is Data Collector, and the data is analyzed and displayed with Data Viewer and HighScore Plus.

Differential Scanning Calorimetry (DSC)

DSC measurements were performed in a TA Instruments™ model Q2000 with a sealed disk setup. Weigh the sample (approximately 1-3 mg) in an aluminum pan, press the cap with Tzero, accurately record to one hundredth of a milligram, and transfer the sample to the instrument for measurement. The instrument was purged with nitrogen at 50 mL/min. Data were collected between room temperature and 300°C at a heating rate of 10°C/min. The endothermic peaks were plotted downwards, and the data were analyzed and displayed with TA Universal Analysis.

Thermogravimetric Analysis (TGA)

TGA data were acquired on a TA Instruments Q500. Calibrate the temperature of the instrument using a certified nickel. Typically 8-12 mg of sample is loaded onto a pre-weighed platinum crucible and heated from room temperature to 300 °C at 10 °C/min. A nitrogen purge of 60 mL/min was maintained over the sample. In the TGA diagram, the abscissa represents temperature (Temperature, °C), and the ordinate represents the percentage of weight loss (Weight (%)).

Embodiment 1 prepares crystal form I

Add 0.30g of crude efluconazole to 1mL of absolute ethanol, place it in an oil bath at 60°C and stir to obtain a clear solution, then slowly add 5mL of water dropwise, stir at constant temperature for 30 minutes, cool down to precipitate a white solid, suction filter and place Vacuum-dried at room temperature in a drying oven to obtain about 0.23 g of white crystals. It was determined to be crystal form I, and its X-ray powder diffraction pattern was basically consistent with Figure 1, and its DSC-TGA pattern was basically consistent with Figure 2.

Embodiment 2 prepares crystal form I

Add 0.30 g of crude efluconazole into 2 mL of trifluoroethanol, place it in an oil bath at 50°C and stir to obtain a clear solution, then slowly add 6 mL of water dropwise, stir at constant temperature for 30 minutes, cool down to precipitate a white solid, filter with suction and place Vacuum-dry at room temperature in a drying oven to obtain about 0.20 g of white crystals. It was determined to be crystal form I, and its X-ray powder diffraction pattern was basically consistent with Figure 1, and its DSC-TGA pattern was basically consistent with Figure 2.

Embodiment 3 prepares crystal form I

Add 0.30 g of crude efluconazole into 1 mL of ethyl formate, place it in an oil bath at 50°C and stir to obtain a clear solution, then slowly add 5 mL of n-pentane dropwise, stir at constant temperature for 30 minutes, cool down to precipitate a white solid, and filter with suction and placed in a drying oven at room temperature to dry under vacuum to obtain about 0.21 g of white crystals. It was determined to be crystal form I, and its X-ray powder diffraction pattern was basically consistent with Figure 1, and its DSC-TGA pattern was basically consistent with Figure 2.

Embodiment 4 prepares crystal form I

Add 0.30g of crude efluconazole to 1mL of ethylene glycol dimethyl ether, place it in an oil bath at 70°C and stir to obtain a clear solution, then slowly add 5mL of n-heptane dropwise, stir at constant temperature for 30 minutes, cool down and precipitate a white solid , suction filtered and placed in a drying oven at room temperature to dry under vacuum to obtain about 0.19 g of white crystals. It was determined to be crystal form I, and its X-ray powder diffraction pattern was basically consistent with Figure 1, and its DSC-TGA pattern was basically consistent with Figure 2.

Embodiment 5 prepares crystal form I

Add 0.30 g of crude efluconazole into 1 mL of ethyl formate, place in a 60°C oil bath and stir to obtain a clear solution, then slowly add 15 mL of n-heptane dropwise, stir at constant temperature for 30 minutes, cool down to precipitate a white solid, and filter with suction And placed in a drying oven at room temperature and vacuum-dried to obtain about 0.22 g of white crystals. It was determined to be crystal form I, and its X-ray powder diffraction pattern was basically consistent with Figure 1, and its DSC-TGA pattern was basically consistent with Figure 2.

Embodiment 6 prepares crystal form I

0.30 g of crude efluconazole was added to 5 mL of methanol and water (methanol: water = 1:1, volume ratio) mixed solvent, placed at room temperature for suspension and stirring, and suction filtered after 30 minutes to obtain a white solid, and Place in a drying oven at room temperature and vacuum-dry to obtain about 0.20 g of white crystals. It was determined to be crystal form I, and its X-ray powder diffraction pattern was basically consistent with Figure 1, and its DSC-TGA pattern was basically consistent with Figure 2.

Example 7 Preparation of Form I

Add 0.10 g of crude efluconazole into 3 mL of ethanol, stir and volatilize naturally at room temperature, a white solid precipitates out in 24 hours, and place it in a drying oven for vacuum drying at room temperature to obtain about 0.08 g of white crystals. It was determined to be crystal form I, and its X-ray powder diffraction pattern was basically consistent with Figure 1, and its DSC-TGA pattern was basically consistent with Figure 2.

Example 8 Preparation of Form II

Add 0.20g of crude efluconazole to 1mL of absolute ethanol, place it in a low-temperature tank at 5°C and stir to obtain a clear solution, then slowly add 5mL of water dropwise, a white solid precipitates, stir at constant temperature for 30 minutes, suction filter and place in Vacuum drying at room temperature in a drying oven yielded about 0.18 g of white crystals. It was determined to be crystal form II, and its X-ray powder diffraction pattern was basically consistent with Figure 3, and its DSC-TGA pattern was basically consistent with Figure 4.

Example 9 Preparation of Form II

Add 1.01 g of crude efluconazole into 50 mL of dichloromethane, stir at room temperature to obtain a clear solution, and then spray dry to obtain white crystals. It was determined to be crystal form II, and its X-ray powder diffraction pattern was basically consistent with Figure 3, and its DSC-TGA pattern was basically consistent with Figure 4.

Example 10 Preparation of Form II

Add 0.20 g of crude efluconazole into 5 mL of acetone, carry out rotary evaporation under reduced pressure at room temperature, a white solid precipitates, and continue rotary evaporation for 30 minutes, take out the sample and place it in a drying oven for vacuum drying at room temperature to obtain a white crystal of about 0.15 g. It was determined to be crystal form II, and its X-ray powder diffraction pattern was basically consistent with Figure 3, and its DSC-TGA pattern was basically consistent with Figure 4.

Example 11 Preparation of Form II

Add 0.20g of crude efluconazole to 1mL of n-propanol, place it in a low-temperature bath to control the temperature -5°C-15°C, stir to obtain a clear solution, then slowly add 5mL of water dropwise, a white solid is precipitated, and stir at constant temperature for 30 Minutes, suction filtration and vacuum drying at room temperature in a drying oven to obtain about 0.15 g of white crystals. It was determined to be crystal form II, and its X-ray powder diffraction pattern was basically consistent with Figure 3, and its DSC-TGA pattern was basically consistent with Figure 4.

Example 12 Preparation of Form II

Add 0.10g of crude efluconazole to 2mL of acetone, place it in a low-temperature bath to control the temperature -5°C-15°C, stir to obtain a clear solution, then slowly add 5mL of n-hexane dropwise, a white solid is precipitated, and stir at constant temperature for 30 minutes , suction filtered and placed in a drying oven at room temperature to dry under vacuum to obtain about 0.05 g of white crystals. It was determined to be crystal form II, and its X-ray powder diffraction pattern was basically consistent with Figure 3, and its DSC-TGA pattern was basically consistent with Figure 4.

Example 13 Preparation of Form II

Add 0.10 g of crude efluconazole to 2 mL of ethyl acetate, place it in a low-temperature bath to control the temperature -5°C-15°C, stir to obtain a clear solution, then slowly add 3 mL of n-heptane dropwise, a white solid precipitates, and keep the temperature constant Stir for 30 minutes, filter with suction and vacuum-dry at room temperature in a drying oven to obtain about 0.06 g of white crystals. It was determined to be crystal form II, and its X-ray powder diffraction pattern was basically consistent with Figure 3, and its DSC-TGA pattern was basically consistent with Figure 4.

Embodiment 14 Humidity test

According to the current guiding principles of the hygroscopicity test in the Chinese Pharmacopoeia, experiments were designed to investigate the hygroscopicity of various crystal forms, and the results are shown in Table 1 below:

Table 1: Investigation results of hygroscopicity of crystal forms

The results showed that the crystal forms I and II were almost non-hygroscopic.

Embodiment 15 solubility test

Experimental method: take a small flask, add a mixed solvent of water and ethanol (water:ethanol=1:3, volume ratio), add samples of each crystal form, and consider it saturated until the solid is no longer dissolved, and then accurately take a certain amount of the upper layer with a syringe After the clear liquid is filtered, it is placed in a weighing bottle and evaporated to dryness, and the weight before and after the weighing bottle is recorded. Calculate the weight of the solute and then calculate the solubility at room temperature.

Experimental results:

temperature crystal form Solubility 25°C Form I 87.43mg/mL 25°C Form II 193.15mg/mL

Embodiment 16 stability investigation

According to the guidelines for the stability test of raw materials and pharmaceutical preparations in Appendix XIX C of the Chinese Pharmacopoeia 2010 edition, samples of crystal form I and crystal form II were sealed and packaged in double-layer PE bags for accelerated experiments.

Storage conditions: 40℃±2℃, relative humidity: 75%±5%, constant temperature and humidity chamber; and

30℃±2℃, relative humidity: 65%±5% constant temperature and humidity chamber;

Storage time: 1 month; on the 3rd, 15th, and 30th day, detect DSC, X-ray powder diffraction, and HPLC to detect related substances and contents.

Test results: DSC and X-ray powder diffraction test showed that the crystal form of the crystal form I and the crystal form II samples did not change after being placed for 1 month; HPLC test found that the related substances and content of each sample did not change more than 0.05%, and there was no significant change .

The method of the present invention has been described through preferred embodiments, and relevant persons can obviously make changes or appropriate changes and combinations to the methods and applications described herein within the content, spirit and scope of the present invention to realize and apply the technology of the present invention . Those skilled in the art can refer to the content of this article to appropriately improve the process parameters to achieve. In particular, it should be pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims (20)

1. the crystal formation for the Fluconazole that ends, the crystal formation is crystal formation I, or crystal formation II；Wherein, the X-ray powder diffraction of the crystal formation I There is peak in 2 θ for the position of 7.75,12.58,15.27,15.48,16.79,18.98 degree in figure；The X-ray powder of the crystal formation II There is peak in 2 θ for the position of 7.68,11.41,13.82,16.05,16.71,17.84,20.19 degree in last diffraction pattern.

2. the crystal formation of Chinese mugwort Fluconazole according to claim 1, wherein, 2 in the X-ray powder diffraction figure of the crystal formation I θ has for 38,33.88 degree of 7.75,10.65,12.58,15.27,15.48,16.79,18.98,20.20,23.87,26. position Peak；Or in the X-ray powder diffraction figure of the crystal formation I 2 θ be 7.75,10.65,12.58,15.27,15.48,16.79, 18.98,20.20,21.29,23.87,24.57,26.38,27.34,33.88 there is peak the position of degree；Or the X- of the crystal formation I In ray powder diffraction pattern 2 θ be 7.75,10.65,12.58,15.27,15.48,16.79,18.98,20.20,21.29, 23.87,24.57,25.41,26.11,26.38,27.34,30.22,33.88 there is peak the position of degree；Or the X- of the crystal formation I Ray powder diffraction pattern as shown in figure 1, wherein, 2 θ for 15.46 degree of peak relative intensity more than 50%, or more than 70%, Or more than 80%, or more than 90%, or more than 99%.

3. the crystal formation of Chinese mugwort Fluconazole according to claim 2, wherein, the differential scanning calorimetric curve of the crystal formation I is about There is endothermic peak at 84 DEG C -89 DEG C.

4. it is according to claim 1 Chinese mugwort Fluconazole crystal formation, wherein, in the X-ray powder diffraction figure of the crystal formation II 2 θ have peak for 7.68,11.41,13.82,16.05,16.71,17.84,20.19 degree of position, or the X- of the crystal formation II is penetrated In 2 θ for 7.68,11.41,13.82,15.38,16.05,16.71,17.84,18.92,20.19 degree in line powder diagram There is peak position；Or in the X-ray powder diffraction figure of the crystal formation II 2 θ be 7.68,11.41,13.82,15.38, 16.05,16.71,17.84,18.92,20.19,23.12,23.54,26.14 there is peak the position of degree；Or the crystal formation II In X-ray powder diffraction figure 2 θ be 7.68,11.41,13.82,15.38,16.05,16.71,17.84,18.92,20.19, 23.12,23.54,26.14,27.27,30.19,31.87 there is peak the position of degree；Or the X-ray powder of the crystal formation II spreads out Figure is penetrated as shown in figure 3, wherein, being more than 50% in 2 θ for the relative intensity at 15.38 degree of peak, or more than 70%, or more than 80%, Or more than 90%, or more than 99%.

5. the crystal formation of Chinese mugwort Fluconazole according to claim 4, wherein, the differential scanning calorimetric curve of the crystal formation II is about There is endothermic peak at 84 DEG C -89 DEG C.

6. a kind of method for preparing crystal formation I described in claim 2, including：Chinese mugwort Fluconazole is dissolved in good solvent, is subsequently placed in Solvent flashing, or evaporated under reduced pressure solvent at room temperature in air, or poor solvent is added, crystal is then separated out, crystal is collected and obtains To crystal formation I；Or by the mixed solvent of the Chinese mugwort Fluconazole input containing good solvent and poor solvent, room temperature, which is suspended, to be stirred, and is removed molten Agent, obtains crystal formation I.

7. method according to claim 6, the volume ratio of the good solvent and poor solvent is 1:5~1:1.

8. method according to claim 6, the good solvent is trifluoroethanol, Ethyl formate, butyl formate, acetic acid first One or more in ester, glycol dimethyl ether.

9. method according to claim 6, the good solvent is 2ml/g-30ml/g relative to the consumption of Chinese mugwort Fluconazole.

10. method according to claim 6, the poor solvent is one or both of pentane, normal heptane.

11. method according to claim 6, the poor solvent is 5ml/g-20ml/ relative to the consumption of Chinese mugwort Fluconazole g。

12. a kind of method for preparing crystal formation II described in claim 4, including：Chinese mugwort Fluconazole is dissolved in isopropanol, tetrahydrochysene furan Mutter, one or more solvents in methyl tertiary butyl ether(MTBE), n-amyl alcohol, butanone, dichloromethane, chloroform and 1,2- dichloroethanes In, solvent flashing at room temperature is subsequently placed in air, crystal is collected and obtains crystal formation II.

13. a kind of method for preparing crystal formation II described in claim 4, including：Chinese mugwort Fluconazole is dissolved in acetone, butanone, dichloro In one or more solvents in methane, dichloroethanes, tetrahydrofuran and methyl tertiary butyl ether(MTBE), then reduced pressure at room temperature solvent evaporated After separate out crystal, collect crystal and obtain crystal formation II.

14. a kind of method for preparing crystal formation II described in claim 4, including：Chinese mugwort Fluconazole is dissolved in acetone, butanone, dichloro In one or more solvents in methane, dichloroethanes, tetrahydrofuran and methyl tertiary butyl ether(MTBE), then it is spray-dried, collects brilliant Body obtains crystal formation II.

15. a kind of method for preparing crystal formation II described in claim 4, including：Chinese mugwort Fluconazole is dissolved in good solvent, temperature control -5 DEG C of -15 DEG C reactions, then add poor solvent, separate out crystal, collect crystal, remove solvent, obtain crystal formation II.

16. method according to claim 15, the volume ratio of the good solvent and poor solvent is 1:5~1:1.

17. method according to claim 15, the good solvent is trifluoroethanol, normal propyl alcohol, n-butanol, sec-butyl alcohol, different In butanol, acetone, ethyl acetate, acetonitrile, isopropyl acetate, Ethyl formate, butyl formate, methyl acetate and glycol dimethyl ether One or more.

18. method according to claim 15, the good solvent is 5ml/g-60ml/g relative to the consumption of Chinese mugwort Fluconazole.

19. method according to claim 15, the poor solvent is water, n-hexane, one in pentane and normal heptane Plant or a variety of.

20. method according to claim 15, the poor solvent is 10ml/g- relative to the consumption of Chinese mugwort Fluconazole 50ml/g。