CN116041351A - Novel midazolam hydrochloride crystal form and preparation method thereof - Google Patents

Abstract

The application relates to the field of drug crystal forms, in particular to midazolam hydrochloride crystal forms III and VI and a preparation method thereof. The crystal form III of the compound of the formula (I) obtained by the invention has better physical stability and chemical stability, and the used crystallization solvent has low toxicity and low residue, and is more suitable for large-scale production and amplification.

Description

Novel midazolam hydrochloride crystal form and preparation method thereof

Technical Field

The invention belongs to the field of drug crystal forms, and particularly relates to midazolam hydrochloride crystal forms III and VI and a preparation method thereof.

Background

Oral solutions of Midazolam (Midazolam) were developed by the Rogowski pharmaceutical, marketed in the United states at 1998.10.15, for sedation, anxiolytic and antegrade amnesia in pediatric patients (6 months-16 years) prior to diagnosis, treatment, endoscopic procedures or anesthesia induction. The active ingredient of the oral solution of the midazolam is the midazolam hydrochloride, the chemical name of the compound is 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5- ] [1,4] benzodiazepine hydrochloride, and the structural formula is shown as the formula (I):

patent CN201811539800.5 discloses crystalline form a and crystalline form B of midazolam hydrochloride. According to the patent report, the crystal form A needs to be heated to 85 ℃ during preparation, the drying process is also carried out under the vacuum condition of 80-100 ℃, and the risk of degrading impurities in the process is increased; the preparation method of the crystal form B is standing crystallization, and the target crystal form can be obtained after standing for 5 days, so that the method is not suitable for large-scale industrial production. Patent CN201110119221.7 discloses a process for the preparation of midazolam hydrochloride crystals by reacting midazolam with midazolam dihydrochloride, the resulting solid being designated form C. According to patent CN201811539800.5, form C reports that crystal transformation occurs under high temperature, high humidity and light conditions, and the chemical properties are also unstable.

Therefore, the development of a novel crystal form of the midazolam hydrochloride, which has the advantages of simple preparation method, high stability and high purity and is suitable for industrial production, is necessary.

Disclosure of Invention

The invention aims to provide a midazolam hydrochloride crystal form III and a crystal form VI, and solves the problems that the existing crystal form is unstable, high in degradation impurity and unsuitable for large-scale production.

The invention provides a crystal form III of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern has characteristic peaks at angles of 2 theta of 7.48 degrees+/-0.2 degrees, 9.92 degrees+/-0.2 degrees, 11.32 degrees+/-0.2 degrees, 12.82 degrees+/-0.2 degrees, 13.94 degrees+/-0.2 degrees, 16.02 degrees+/-0.2 degrees, 17.38 degrees+/-0.2 degrees, 19.19 degrees+/-0.2 degrees, 20.66 degrees+/-0.2 degrees, 23.02 degrees+/-0.2 degrees, 24.20 degrees+/-0.2 degrees, 24.72 degrees+/-0.2 degrees, 25.74 degrees+/-0.2 degrees, 28.56 degrees+/-0.2 degrees and 29.94 degrees+/-0.2 degrees.

The compound shown in the formula (I) can obtain different crystal products under different crystallization conditions, XRD and TGA detection is carried out on the obtained crystal products, and the compound shown in the formula (I) can obtain a crystal form with good stability under the conventional crystallization conditions, which is called as a crystal form III.

Form iii in the present application uses Cu-Ka radiation with an X-ray powder diffraction pattern expressed in terms of 2θ, with characteristic peaks around 7.48 ° ± 0.2 °, 9.92 ° ± 0.2 °, 11.32 ° ± 0.2 °, 12.82 ° ± 0.2 °, 13.94 ° ± 0.2 °, 16.02 ° ± 0.2 °, 17.38 ° ± 0.2 °, 19.19 ° ± 0.2 °, 20.66 ° ± 0.2 °, 23.02 ° ± 0.2 °, 24.20 ° ± 0.2 °, 24.72 ° ± 0.2 °, 25.74 ° ± 0.2 °, 28.56 ° ± 0.2 ° and 29.94 ° ± 0.2 °.

Preferably, the X-ray powder diffraction pattern of form iii is substantially as shown in figure 4.

The thermogravimetric analysis (TGA) of form iii is shown in fig. 5, and has a weight loss in the range of 30-120 ℃ of about 4.73% to 5.95%.

The single crystal structure of form III is shown in FIG. 6, which shows that form III contains 1 molecule of crystal water.

The moisture content of the crystal form III is about 4.73% -5.95%.

The invention also relates to a method for preparing the crystal form III, which comprises the following three steps:

(1) The midazolam is added into isopropanol, water is added after stirring and dissolving at room temperature, the solution is transferred into an ice bath for stirring, HCl/ethanol solution is added dropwise until a large amount of solid is separated out, n-heptane is added dropwise, stirring is carried out at room temperature overnight, and crystal form III is obtained after filtering.

(2) Adding the compound shown in the formula (I) into a mixed solvent, stirring for 5-24 hours at 15-30 ℃, and filtering to obtain a crystal form III.

(3) Adding a compound shown in a formula (I) into a mixed solvent, heating to 50-65 ℃ to enable a solid to be completely dissolved, cooling to 40-50 ℃, adding 0.5% -2% of crystal form III seed crystal, and slowly cooling to 15-30 ℃ to obtain crystal form III.

The solvent in the method (2) or (3) in the scheme is a mixed solvent, and one of the mixed solvents is water; the other solvent is selected from one or more of methanol, N-propanol, isopropanol, acetone, butanone, acetonitrile, tetrahydrofuran, 1, 4-dioxane, and N, N-dimethylformamide, preferably isopropanol and acetonitrile. The water content in the mixed solvent is 1% -10%, preferably 1% -3%.

The invention provides a crystal form VI of a compound shown in a formula (I), wherein the X-ray powder diffraction pattern has characteristic peaks at angles of 2 theta of 11.66 degrees, 12.86 degrees, 14.52 degrees, 15.90 degrees, 16.96 degrees, 18.42 degrees, 20.60 degrees, 23.08 degrees, 24.38 degrees, 25.64 degrees and 27.04 degrees.

Form VI in the present application uses Cu-Ka radiation with an X-ray powder diffraction pattern expressed in terms of 2θ with characteristic peaks near about 11.66 °, 12.86 °, 14.52 °, 16.96 °, 18.42 °, 20.60 °, 23.08 °, 24.38 °, 25.64 ° and 27.04 °.

Preferably, the X-ray powder diffraction pattern of form VI is substantially as shown in fig. 7.

The thermogravimetric analysis (TGA) of form VI is as shown in figure 8, with a weight loss of less than 0.5% in the range of 30-120 ℃.

The single crystal structure of form VI is shown in fig. 9, which shows that form VI is anhydrous.

The invention also relates to a method for preparing the crystal form VI, which is characterized by comprising the following steps: the midazolam is added into isopropanol, stirred and dissolved at 15-30 ℃, and then the solution is transferred into an ice bath and HCl/ethanol solution is slowly added dropwise, so that the crystal form VI is obtained.

In the above method, the amount of the HCl/ethanol solution is 1.1 to 1.5 times the equivalent weight of the midazolam.

The beneficial effects brought by the invention are as follows:

1. the accelerated stability research shows that the crystal form III prepared by the method has better physical stability and chemical stability.

2. The preparation method of the crystal form III has mild conditions and is simple to operate. The crystal form A reported in the patent needs to be heated to 85 ℃ during preparation, and the drying process needs to be carried out under the vacuum condition of 80-100 ℃, so that the risk of degrading impurities in the process is increased; the preparation method of the crystal form B is standing crystallization, and the target crystal form can be obtained after standing for 5 days, so that the method is not suitable for large-scale industrial production.

3. By controlling each key parameter in the preparation process of the crystal form III, the preparation method can obtain a single crystal form, has good process reproducibility and high purity (HPLC purity is more than 99.8%), ensures that the industrialized production condition is controllable, and is beneficial to large-scale industrialization.

Drawings

Figure 1 shows the XRD pattern of midazolam hydrochloride form A

Figure 2 is an XRD pattern of midazolam hydrochloride form B

Figure 3 is an XRD pattern of midazolam hydrochloride form C

Figure 4 is an XRD pattern of crystalline form iii of midazolam hydrochloride.

Figure 5 is a TGA profile of midazolam hydrochloride form iii.

Figure 6 shows the single crystal structure of midazolam hydrochloride form iii.

Figure 7 is an XRD pattern of midazolam hydrochloride form VI.

Figure 8 is a TGA profile of midazolam hydrochloride form VI.

Fig. 9 shows a single crystal structure of midazolam hydrochloride form VI.

Figure 10 is an XRD contrast pattern of midazolam hydrochloride form C under accelerated conditions.

Figure 11 is an XRD contrast pattern of midazolam hydrochloride form III under accelerated conditions.

Detailed Description

The present invention is described in further detail below with reference to examples, but is not limited to the following examples, and any equivalents in the art, which are in accordance with the present disclosure, are intended to fall within the scope of the present invention.

Abbreviations used in this application are explained as follows:

XRD: powder diffraction by X-rays

The X-ray powder diffraction (XRD) measurements described in examples 1-13 and comparative example 3 of the present application were performed using a Liaoning Dandong DX-2700B powder diffractometer, with the following specific parameters:

the X-ray powder diffraction (XRD) test described in comparative examples 1, 2 of the present application was performed using a malvern panaceae Empyrea powder diffractometer, and the specific parameters are as follows:

TGA: thermogravimetric analyzer

The thermogravimetric analysis (TGA) described herein was performed using a METTER TOLEDOO model TGA-2, with a heating rate of 10 ℃/min, a temperature range of 30-300 ℃, and a nitrogen purge rate of 20mL/min during the test.

KF: carshi moisture tester

Moisture as described herein was measured using a karman moisture meter model 870KF Titrino plus.

HPLC: high performance liquid chromatography

HPLC spectra were determined using an Agilent1260DAD liquid chromatograph. In this application, the HPLC purity of form iii was performed by the following method:

(1) Chromatographic column: inertsil ODS-3

(2) A detector: ultraviolet detector (wavelength 254 nm)

(3) Flow rate: 1.0mL/min

(5) Test solution: 1mg of the product is precisely weighed, dissolved and diluted by a solvent to prepare a solution containing about 1mg of the product per 1mL, and the solution is used as a test solution

(6) Sample injection amount: and 50 μl, measuring the solution of the test sample by an automatic integration method, and calculating the purity of the midazolam hydrochloride in the test sample according to the peak area.

Room temperature: 15-30 DEG C

Solvent screening experiments

In order to find a new crystal form of the midazolam hydrochloride, the inventor screens the new crystal form by adding a certain amount of the midazolam hydrochloride into different solvents and cooling crystallization or suspension crystal transformation.

When the reaction solvent was selected, it was surprisingly found that a new form III was obtained when the reaction solvent was a mixed solvent and the solvent contained a certain proportion of water, and a new form VI was obtained when the reaction solvent was a single isopropyl alcohol, acetone or acetonitrile, and the results are shown in Table 1 below.

TABLE 1 Experimental results for the preparation of novel crystalline forms from different solvent systems

Solvent system	Crystal form
		Ethanol	Crystal form C
Ethanol: water = 7.5mL:0.05mL	Crystal form C
		Ethanol: water = 7.5mL:0.37mL	Crystal form C
Isopropyl alcohol	Crystal form VI
		Acetone (acetone)	Crystal form VI
Acetonitrile	Crystal form VI
		Isopropyl alcohol: water = 7.5mL:0.2mL	Crystal form III
Acetonitrile: water = 7.5mL:0.1mL	Crystal form III
		Acetone: water = 1mL:0.1mL	Crystal form III
Butanone: water = 1mL:0.1mL	Crystal form III
		Tetrahydrofuran: water = 1mL:0.1mL	Crystal form III
1, 4-dioxane: water = 1mL:0.1mL	Crystal form III
		N, N-dimethylformamide: water = 1mL:0.1mL	Crystal form III

As can be seen from table 1 above, when pure ethanol or ethanol-water mixed solvents with different proportions are used, the obtained product is form C; when other aqueous solvents are used as the reaction solvent, such as isopropyl alcohol-water mixed solvent, acetone-water mixed solvent, butanone-water mixed solvent, acetonitrile-water mixed solvent, tetrahydrofuran-water, 1, 4-dioxane-water, N-dimethylformamide-water, the resulting product is form iii.

Example 1: preparation of midazolam hydrochloride crystal form III

1.02g of midazolam and 6mL of isopropyl alcohol were added to the flask, and after stirring and dissolution at room temperature, 200. Mu.L of water was added, the solution was transferred to an ice bath and stirred, and 0.26g of HCl/ethanol solution (HCl content: 15%) was slowly added dropwise, no solid was precipitated after the addition, then 0.72g of HCl/ethanol solution was added dropwise again, a large amount of solid was precipitated after the addition, followed by adding 10mL of n-heptane dropwise with a dropping funnel and stirring overnight at room temperature, and filtration was performed to obtain a white powdery solid.

The resulting samples were subjected to thermogravimetric analysis (TGA) with a loss of weight of 5.50% in the range of 30-120 ℃. The water content of the crystalline sample was measured by the KF method and found to be 5.79%. This form is significantly different from the three forms reported previously, and is designated form III.

The X-ray powder measurement was performed using Cu-ka rays, whose spectra have diffraction angles, interplanar spacings, and relative intensities shown in the following table:

TABLE 2 diffraction angle, interplanar spacing and relative intensity for form III

The error of the 2 theta diffraction angle is + -0.20 deg..

Furthermore, the midazolam hydrochloride form III prepared in example 1 has an X-ray powder diffraction pattern substantially as shown in figure 4.

Example 2: preparation of midazolam hydrochloride crystal form III

100mg of midazolam hydrochloride was added to a mixed solvent of 1mL of isopropyl alcohol and 100. Mu.L of water, and suspended at room temperature for 12 hours to give a white powdery solid. Its thermogravimetric analysis pattern and powder diffraction data were substantially in accordance with example 1.

Example 3: preparation of midazolam hydrochloride crystal form III

100mg of midazolam hydrochloride was added to a mixed solvent of 1mL of acetone and 100. Mu.L of water, and suspended at room temperature for 12 hours to give a white powdery solid. Its thermogravimetric analysis pattern and powder diffraction data were substantially in accordance with example 1.

Example 4: preparation of midazolam hydrochloride crystal form III

100mg of midazolam hydrochloride was added to a mixed solvent of 1mL of butanone and 100. Mu.L of water, and suspended at room temperature for 12 hours to give a white powdery solid. Its thermogravimetric analysis pattern and powder diffraction data were substantially in accordance with example 1.

Example 5: preparation of midazolam hydrochloride crystal form III

100mg of midazolam hydrochloride was added to a mixed solvent of 1mL of acetonitrile and 100. Mu.L of water, and suspended at room temperature for 12 hours to give a white powdery solid. Its thermogravimetric analysis pattern and powder diffraction data were substantially in accordance with example 1.

Example 6: preparation of midazolam hydrochloride crystal form III

100mg of midazolam hydrochloride was added to a mixed solvent of 1mL of tetrahydrofuran and 100. Mu.L of water, and the mixture was suspended at room temperature for 12 hours to give a white powdery solid. Its thermogravimetric analysis pattern and powder diffraction data were substantially in accordance with example 1.

Example 7: preparation of midazolam hydrochloride crystal form III

100mg of midazolam hydrochloride was added to a mixed solvent of 1mL of 1, 4-dioxane and 100. Mu.L of water, and the mixture was suspended at room temperature for 12 hours to give a white powdery solid. Its thermogravimetric analysis pattern and powder diffraction data were substantially in accordance with example 1.

Example 8: preparation of midazolam hydrochloride crystal form III

100mg of midazolam hydrochloride was added to a mixed solvent of 1 mM LN, N-dimethylformamide and 100. Mu.L of water, and suspended at room temperature for 12 hours to give a white powdery solid. Its thermogravimetric analysis pattern and powder diffraction data were substantially in accordance with example 1.

Example 9: preparation of midazolam hydrochloride crystal form III

1.00g of midazolam hydrochloride was added to a mixed solvent of 8mL of isopropyl alcohol, 8mL of methylene chloride and 500. Mu.L of water, and after stirring and dissolution, the mixture was allowed to stand at room temperature for volatilization to obtain a granular single crystal product. Its thermogravimetric analysis pattern and powder diffraction data were substantially in accordance with example 1. The single crystal analysis was performed on this sample, the unit cell parameters are shown in table 3, and the single crystal structure is shown in fig. 6.

TABLE 3 unit cell parameters for form III

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Example 10: preparation of midazolam hydrochloride crystal form III

The method comprises the steps of adding 0.50g of midazolam hydrochloride into a mixed solvent of 15mL of acetonitrile and 200 mu L of water, heating to 65 ℃ to enable solids to be completely dissolved, then cooling to 40 ℃, adding 1% of seed crystals prepared in the example 1, continuing stirring for 1h, slowly cooling to room temperature, stirring for crystallization, and filtering to obtain white powdery solids. Its thermogravimetric analysis pattern and powder diffraction data were substantially in accordance with example 1.

Example 11: preparation of midazolam hydrochloride crystal form III

The method comprises the steps of adding 0.50g of midazolam hydrochloride into a mixed solvent of 7.5mL of isopropyl alcohol and 200 mu L of water, heating to 65 ℃ to completely dissolve solids, cooling to 50 ℃, adding 1% of seed crystals prepared in the example 1, slowly cooling to room temperature, stirring for crystallization, and filtering to obtain white powdery solids. Its thermogravimetric analysis pattern and powder diffraction data were substantially in accordance with example 1.

Example 12: preparation of midazolam hydrochloride crystal form VI

1.00g of midazolam was added to 10mL of isopropanol, and after stirring and dissolution at room temperature, the solution was transferred to an ice bath, and 0.90g of HCl/ethanol solution (HCl content: 15%) was slowly added dropwise, and stirring was carried out overnight at room temperature at the end of the addition, to obtain 0.86g of a white powdery solid.

The resulting samples were subjected to thermogravimetric analysis (TGA) with a loss of weight of 0.38% in the range of 30-120 ℃. This form is significantly different from the three forms reported previously, and is designated form VI.

The X-ray powder measurement was performed using Cu-ka rays, whose spectra have diffraction angles, interplanar spacings, and relative intensities shown in the following table:

TABLE 4 diffraction angle, interplanar spacing and relative intensity for form VI

The error of the 2 theta diffraction angle is + -0.20 deg..

Further, the midazolam hydrochloride form VI prepared in example 12 has an X-ray powder diffraction pattern substantially as shown in fig. 7.

Example 13: preparation of midazolam hydrochloride crystal form VI

1.03g of midazolam hydrochloride was added to 5mL of isopropanol and suspended at room temperature for 18h to give a white powdery solid. Its thermogravimetric analysis profile and powder diffraction data were substantially in accordance with example 12.

Example 14: preparation of midazolam hydrochloride crystal form VI

200mg of midazolam hydrochloride is added into a mixed solvent of 1mL of methanol and 1mL of dichloromethane, stirred and dissolved, and then the mixture is left to stand and volatilize at room temperature to obtain a granular single crystal product. Its thermogravimetric analysis profile and powder diffraction data were substantially in accordance with example 12. The single crystal analysis was performed on this sample, the unit cell parameters are shown in table 5, and the single crystal structure is shown in fig. 9.

TABLE 5 unit cell parameters for form VI

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Comparative example 1: preparation of comparative example form A

3.00g of midazolam and 45mL of ethanol were added to the flask, and after stirring and dissolution at room temperature, the solution was transferred to an ice bath and stirred, and 2.95g of HCl/ethanol solution (HCl content: 15%) was slowly added dropwise, and a solid was precipitated immediately after the completion of the addition. Transferring the solution into an oil bath at 80 ℃, stirring until the solid is completely dissolved, then cooling to 60 ℃, dropwise adding 68mL of n-heptane by using a dropping funnel, precipitating the solid in the dropping process, transferring to an ice bath, continuously stirring and crystallizing for 2 hours, filtering, eluting a filter cake by using the n-heptane, and drying the obtained solid in a vacuum drying box at 80 ℃ for 14 hours to obtain a white powdery solid, namely the crystal form A. The X-ray powder diffraction pattern is shown in figure 1.

Comparative example 2: preparation of comparative example form B

5.00g of midazolam and 50mL of isopropanol are added into a flask, after stirring and dissolution at room temperature, the solution is transferred into an ice bath, crystal form B seed crystals are added, 4.56g of HCl/ethanol solution (15% of HCl) is slowly added dropwise, stirring is continued for 3 hours after the addition is finished, filtration is carried out, and the obtained solid is dried at room temperature to obtain white powdery solid, namely crystal form B. The X-ray powder diffraction pattern is shown in figure 2.

Comparative example 3: preparation of comparative example form C

10.02g of midazolam and 140mL of ethanol are added into a flask, after stirring and dissolution at room temperature, the solution is transferred to an ice bath for stirring, and 10.03g of HCl/ethanol solution (the content of HCl is 15%) is slowly added dropwise, stirring is continued until solid is precipitated after the addition is finished, then 140mL of n-heptane is added dropwise by using a dropping funnel, stirring is continued at room temperature for 1 hour, and filtering is performed to obtain white powdery solid, namely crystal form C. The X-ray powder diffraction pattern is shown in figure 3.

Test example 1: stability investigation experiment

To examine the stability of the midazolam hydrochloride crystals III, VI and the crystals A, B and C of the comparative examples, the crystals A, B, C and C of the comparative examples 1, 3 and 12 were left to stand for 3 months under the accelerated test conditions of 25 ℃, 60% RH and 40 ℃ and 75% RH, respectively, and were sampled for 1 month, 2 months and 3 months, respectively, XRD and HPLC were tested, and compared with the results of 0 day, as follows:

TABLE 6 accelerated stability test data for different crystal forms

From table 6 and fig. 10, it is clear that form A, B, C is not stable in crystal morphology under accelerated test conditions and has been completely converted to form iii after acceleration for 1 month at 25 ℃ and 40 ℃.

From Table 6 and FIG. 11, it is understood that form III was stable in crystal morphology and did not change significantly in purity when left under accelerated test conditions for 3 months.

In summary, both the physical and chemical stability of form iii are superior to those of forms a, B and C.

Test example 2: bioavailability investigation

In vivo pharmacokinetic testing in rats

1. Purpose of test

After examining the same dosage, rats were given the different crystalline forms of midazolam hydrochloride in a single oral administration, the concentration level of the drug substance in the plasma and the pharmacokinetic characteristics thereof were examined.

2. Materials and methods

2.1, test agent

The midazolam hydrochloride crystal form A, white powdery solid and comparative example 1 are prepared;

midazolam hydrochloride crystal form B, white powdery solid, and comparative example 2;

midazolam hydrochloride crystal form C, white powdery solid, and comparative example 3;

midazolam hydrochloride crystal form III, white powdery solid, and the preparation of example 1;

midazolam hydrochloride in form VI, white powdery solid, prepared in example 12;

2.2 test animals

30 SD rats, 15 females each, weight 220-240g, were purchased from Hunan Style Lakkera laboratory animal Co., ltd., license number: SCXK (Hunan) 2019-0004.

2.3 test methods

The test drug was formulated into a uniform suspension of 1.25mg/kg with corn oil, immediately administered orally to rats in a volume of 5mL/kg, and 0.1mL of blood was taken from the jugular vein of 15min, 30min, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 24h before and after administration, placed in EDTA-K2 tube, centrifuged for 10min, plasma was isolated, and frozen and stored in a refrigerator at-80 ℃.

2.4, LC/MS biological sample analysis:

mixing 50 μl of blood plasma with 5 μl of working solution or blank diluent, adding 150 μl of acetonitrile precipitant containing internal standard, vortex shaking for 2min, centrifuging 12000r/min for 10min, collecting supernatant 2 μl and 200 μl of pure water: after acetonitrile (1:1) was mixed, the samples were taken at a volume of 3. Mu.L for analysis.

2.5, test results:

animal experiments are respectively carried out on different crystal forms of the midazolam hydrochloride, average concentrations (ng.mL-1) of the APIs in blood plasma of different times are tested after single oral administration of the female and male rats, and an average drug concentration-time curve in the blood plasma of the female and male rats after single oral administration is drawn. The results show that the bioavailability of the crystal form III and the crystal form VI is obviously higher.

It will be apparent to those skilled in the art that various modifications and variations can be made in the compounds of the present application and in the methods of making them without departing from the spirit or scope of the application, and therefore, the scope of the application encompasses numerous modifications and variations as come within the scope of the claims and their equivalents.

Claims (10)

1. A crystalline form iii of a compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles of 7.48 ° ± 0.2 °, 9.92 ° ± 0.2 °, 11.32 ° ± 0.2 °, 12.82 ° ± 0.2 °, 13.94 ° ± 0.2 °, 16.02 ° ± 0.2 °, 17.38 ° ± 0.2 °, 19.19 ° ± 0.2 °, 20.66 ° ± 0.2 °, 23.02 ° ± 0.2 °, 24.20 ° ± 0.2 °, 24.72 ° ± 0.2 °, 25.74 ° ± 0.2 °, 28.56 ° ± 0.2 ° and 29.94 ° ± 0.2 °.

2. Form iii of the compound of formula (I) according to claim 1, characterized in that the X-ray powder diffraction pattern of form iii of the compound of formula (I) is substantially as shown in fig. 4.

3. Form iii of the compound of formula (I) according to claim 1 or 2, characterized in that the thermogravimetric analysis of form iii is shown in figure 5.

4. The crystalline form iii of the compound of formula (I) according to claim 1 or 2, characterized in that the water content of the crystalline form iii is 4.73% to 5.95%.

5. A process for the preparation of crystalline form iii of a compound of formula (I) according to claim 1, wherein midazolam is added to isopropanol, after dissolution by stirring at room temperature, water is added, the solution is transferred to an ice bath and stirred, and HCl/ethanol solution is added dropwise until a large amount of solids are precipitated, and then n-heptane is added dropwise, and stirred at room temperature overnight, and filtered to give crystalline form iii; or, the preparation method comprises the following steps: adding the midazolam hydrochloride into a mixed solvent, stirring at room temperature, and filtering to obtain a crystal form III; or, adding the midazolam hydrochloride into the mixed solvent, heating and stirring until the solid is completely dissolved, and then adding seed crystals for cooling and crystallizing to obtain the crystal form III.

6. The process for preparing crystalline form iii of the compound of formula (I) according to claim 5, wherein one of the mixed solvents is water and the other solvent is one or more selected from the group consisting of methanol, N-propanol, isopropanol, acetone, butanone, acetonitrile, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, preferably isopropanol, acetonitrile; the water content in the mixed solvent is 1% -10%, preferably 1% -3%.

7. A crystalline form vi of a compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at 2Θ angles of 11.66 ° ± 0.2 °, 12.86 ° ± 0.2 °, 14.52 ° ± 0.2 °, 16.96 ° ± 0.2 °, 18.42 ° ± 0.2 °, 20.60 ° ± 0.2 °, 23.08 ° ± 0.2 °, 24.38 ° ± 0.2 °, 25.64 ° ± 0.2 ° and 27.04 ° ± 0.2 °.

8. The crystalline form vi of the compound of formula (I) according to claim 7, characterized in that the X-ray powder diffraction pattern of the crystalline form vi of the compound of formula (I) is substantially as shown in figure 7.

9. The crystalline form vi of the compound of formula (I) according to claim 7, characterized in that the thermogravimetric analysis of said crystalline form vi is shown in figure 8.

10. A process for the preparation of a crystalline form vi of a compound of formula (I) according to claim 7 or 8, characterized in that it comprises: the method comprises the steps of adding midazolam into isopropanol, stirring at room temperature for dissolution, transferring the solution into an ice bath, and dropwise adding HCl/ethanol solution to obtain a crystal form VI; preferably, the dosage of the HCl/ethanol solution is 1.1-1.5 times of the equivalent weight of the midazolam.

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