CN115385918A - Novel midazolam crystal form and preparation method thereof - Google Patents
Novel midazolam crystal form and preparation method thereof Download PDFInfo
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- 238000000113 differential scanning calorimetry Methods 0.000 claims description 26
- 238000002411 thermogravimetry Methods 0.000 claims description 23
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 17
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- LEJBBGNFPAFPKQ-UHFFFAOYSA-N 2-(2-prop-2-enoyloxyethoxy)ethyl prop-2-enoate Chemical compound C=CC(=O)OCCOCCOC(=O)C=C LEJBBGNFPAFPKQ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The application relates to the field of pharmaceutical crystal forms, in particular to a midazolam crystal form A, B and a preparation method thereof. The crystal form A of the compound shown in the formula (I) obtained by the invention has good physical stability and chemical stability, and the used crystallization solvent has low toxicity and low residue, so that the crystal form A is more suitable for large-scale production and amplification.
Description
Technical Field
The invention belongs to the field of medicine crystal forms, and particularly relates to a midazolam crystal form A, B and a preparation method thereof.
Background
The crystal form of the medicine has influence on the quality of the preparation and the production process, and the research on the crystal form of the medicine provides references for the preparation workers in the aspects of prescription development, new medicament type design, optimization of the production process, medicine quality control and clinical efficacy. Different crystal forms of the same drug may have significant differences in aspects such as appearance, solubility, melting point, dissolution rate, bioequivalence and the like, thereby affecting the stability, bioavailability and curative effect of the drug.
Midazolam (Midazolam) oral solutions were developed by roche and marketed in 1998.10.15 in the united states for sedation, anxiolysis and antegrade amnesia in pediatric patients (6 months-16 years old) prior to diagnosis, treatment, endoscopic procedure or anesthesia induction. The chemical name of midazolam is 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5- ] [1,4] benzodiazepine, and the structural formula of the midazolam is shown as the formula (I):
patent CN102241679B of italian synthesis manufacturing company discloses a preparation method of midazolam, but the patent does not describe crystal form information of midazolam, and other reports about the crystalline form of midazolam are not found yet, so that it is necessary to develop a new crystalline form of midazolam, which has simple preparation method, high stability and is suitable for industrial production.
Disclosure of Invention
The invention aims to provide a crystalline form A and a crystalline form B of midazolam, wherein the crystalline form A has good crystalline form stability and chemical stability and can be better applied to clinic.
The invention provides a crystal form A of a compound shown as a formula (I), wherein an X-ray powder diffraction pattern of the crystal form A has characteristic peaks at 2 theta angles of 11.64 degrees, 13.26 degrees, 14.76 degrees, 18.12 degrees, 20.72 degrees, 23.30 degrees, 25.30 degrees, 26.78 degrees and 28.96 degrees, and the error range of the 2 theta angle is +/-0.2 degrees.
Preferably, the form a has an X-ray powder diffraction pattern substantially as shown in figure 1.
The Differential Scanning Calorimetry (DSC) of form A is shown in figure 2, and it has maximum endothermic peak within 162.03 ℃ + -3 ℃.
The thermogravimetric analysis (TGA) of form a is shown in figure 3, with no significant weight loss over the range of 30-120 ℃.
The single crystal structure of the crystal form A is shown in figure 4, and the structural diagram shows that the crystal form A is an anhydrous crystal form.
The present invention also relates to a process for preparing form a, which comprises the following two:
(1) Adding a compound shown in a formula (I) into an organic solvent, stirring for 24 hours at room temperature, and filtering to obtain a crystal form A.
(2) Dissolving the compound shown in the formula (I) in a binary organic solvent, and slowly volatilizing at room temperature to obtain the crystal form A.
The organic solvent in the method (1) in the above scheme is a single solvent, and the solvent is selected from acetone, ethyl acetate or acetonitrile.
The organic solvent in method (2) described in scheme (i) above is a binary solvent selected from the group consisting of acetone/ethyl acetate, acetone/isopropyl acetate, acetone/methyl t-butyl ether, acetone/toluene, tetrahydrofuran/ethyl acetate, tetrahydrofuran/isopropyl acetate, tetrahydrofuran/methyl t-butyl ether, tetrahydrofuran/toluene, 1,4 dioxane/ethyl acetate, 1,4 dioxane/isopropyl acetate, 1,4 dioxane/methyl t-butyl ether and 1,4 dioxane/toluene.
Furthermore, the volume ratio of the binary organic solvent is 1:4-1:2.
More specifically, the ratio range of the binary solvent in the method (2): the binary solvent volume ratio of acetone, tetrahydrofuran or 1,4-dioxane to one of ethyl acetate, isopropyl acetate, methyl tert-butyl ether or toluene is 1:4-1:2.
The invention provides a crystal form B of a compound shown as a formula (I), which has an X-ray powder diffraction pattern with characteristic peaks at 2 theta angles of 9.58, 11.78, 12.52, 15.30, 18.62, 19.42, 20.18, 20.96, 22.70, 23.84, 25.14, 25.68, 27.02, 29.62, 32.98 and 37.28, and the error range of the 2 theta angle is +/-0.2 degrees.
Preferably, the form B has an X-ray powder diffraction pattern substantially as shown in figure 5.
The Differential Scanning Calorimetry (DSC) of form B is shown in FIG. 6, which has maximum endothermic peaks in the ranges of 98.11 ℃ + -3 ℃ and 162.90 ℃ + -3 ℃ respectively.
The thermogravimetric analysis (TGA) of form B is shown in figure 7, with a weight loss of 7.46% over the range of 30-120 ℃.
The invention also relates to a process for preparing form B, which process comprises: and adding midazolam into an organic solvent, stirring and dissolving at room temperature, and then dropwise adding pure water for crystallization to obtain a crystal form B.
The organic solvent in the method of the scheme is a single solvent or a multi-component solvent, and the solvent is selected from one or more of methanol, ethanol, isopropanol, acetone, tetrahydrofuran or 1,4-dioxane.
The invention has the following beneficial effects:
1. the preparation method of the crystal form A has the advantages of mild reaction conditions, simple operation and good process reproducibility, so that the industrial production conditions are controllable, and the industrialization is facilitated.
2. Stability researches show that the crystal form A prepared by the method has better physical stability and chemical stability, and is beneficial to ensuring the safety and effectiveness of pharmaceutical preparations, so that the crystal form A can be better applied to clinic.
Drawings
Figure 1 is an XRD pattern of midazolam form a.
Figure 2 is a DSC profile of midazolam form a.
Figure 3 is a TGA profile of midazolam crystalline form a.
Figure 4 is a single crystal structure of midazolam form a.
Figure 5 is an XRD pattern of midazolam form B.
Figure 6 is a DSC profile of midazolam form B.
Figure 7 is a TGA profile of midazolam crystalline form B.
Figure 8 is an XRD contrast pattern of midazolam form a under influential conditions.
Figure 9 is an XRD contrast pattern of midazolam form B under influential conditions.
Detailed Description
The present invention is described in further detail with reference to the following examples, but the present invention is not limited thereto, and any equivalent replacement in the field made in accordance with the present disclosure is included in the scope of the present invention.
The abbreviations used in this application are explained as follows:
XRD: powder X-ray diffraction
The X-ray powder diffraction (XRD) test described in the present application is carried out by employing powder diffractometer Liaoning Danhaoyuan DX-2700B, and the specific parameters are as follows:
DSC: differential scanning calorimeter
The Differential Scanning Calorimetry (DSC) described herein employs METTLER TOLEDO model DSC-1 for collection, with a temperature rise rate of 10 deg.C/min, a temperature range of 25-250 deg.C, and a nitrogen purge rate of 50mL/min during testing.
TGA: thermogravimetric analyzer
Thermogravimetric analysis (TGA) described herein is measured using a METTLER TOLEDO model TGA-2 with a temperature rise rate of 10 ℃/min, a temperature range of 30-300 ℃, and a nitrogen purge rate of 20mL/min during the test.
X-ray single crystal diffractometer
The single crystal unit cell parameters in the application are collected by an X-ray single crystal diffractometer in Japan science, and the instrument types are as follows: xtlab PRO, with specific parameters as follows:
room temperature: 15-30 DEG C
Solvent screening experiments
In order to find a new crystalline form of midazolam, the inventor adds a proper amount of midazolam into different solvents, and screens the new crystalline form by means of suspension, dissolution or volatilization.
The inventors surprisingly found that five crystal forms of crystal form a, crystal form B, crystal form C, crystal form D and crystal form E can be obtained by using different kinds of solvents when screening reaction solvents, and the results are shown in table 1 below.
Table 1 experimental results for screening new crystal forms with different solvent systems
| Solvent system | Crystal form | Solvent system | Crystal form |
| Acetone (II) | Crystal form A | Methanol: water (1:4) | Crystal form B |
| Ethyl acetate | Crystal form A | Ethanol: water (1:4) | Crystal form B |
| Acetonitrile | Crystal form A | Isopropyl alcohol: water (1:4) | Crystal form B |
| Acetone: ethyl acetate (1:2) | Crystal form A | Acetone: water (1:2) | Crystal form B |
| Acetone: methyl tert-butyl ether (1:2) | Crystal form A | Tetrahydrofuran: water (1:4) | Crystal form B |
| Tetrahydrofuran: ethyl acetate (1:4) | |
1,4-dioxane: water (1:4) | Crystal form B |
| Tetrahydrofuran: toluene (1:4) | Crystal form A | Trifluoroethanol | |
| 1,4-dioxane: ethyl acetate (1:4) | Crystal form A | Trifluoroethanol | |
| 1,4-dioxane: ethyl acetate (1:4) | Crystal form A | Isopropanol (I-propanol) | Crystal form E |
As can be seen from the above table 1, when the reaction solvent is acetone, acetonitrile, ethyl acetate single solvent or a binary solvent volume ratio of 1:4 to 1:2 consisting of acetone, tetrahydrofuran, 1,4-dioxane and other organic solvents, the obtained product is the crystal form A; when the reaction solvent contains water, the obtained product is in a crystal form B; when the reaction solvent is trifluoroethanol, the obtained product is in a crystal form C or a crystal form D; when the reaction solvent is isopropanol, the resulting product is form E.
Example 1: preparation of midazolam crystal form A
100mg of midazolam was added to 0.5mL of ethyl acetate, stirred at room temperature for 24h and filtered to give a white powdery solid.
Subjecting the obtained sample to Differential Scanning Calorimetry (DSC) as shown in FIG. 2, wherein the sample has a melting endothermic peak in the range of 160.70-164.56 deg.C; the resulting sample was subjected to Differential Scanning Calorimetry (DSC) as shown in FIG. 3, and showed no significant weight loss in the range of 30-120 ℃. This crystalline form is designated form a.
X-ray powder measurements were performed using Cu-ka radiation, which patterns had diffraction angles, interplanar spacings and relative intensities as shown in Table 2:
TABLE 2 diffraction angles, interplanar spacings and relative intensities for form A
The error of the 2 θ diffraction angle was ± 0.20.
Further, crystalline form a of midazolam prepared in example 1 has an X-ray powder diffraction pattern substantially as shown in figure 1.
Example 2: preparation of midazolam crystal form A
100mg of midazolam was added to 0.5mL of acetone, stirred at room temperature for 24h, and filtered to give a white powdery solid. The powder diffraction pattern, differential scanning calorimetry pattern and thermogravimetric analysis pattern are basically consistent with those of example 1.
Example 3: preparation of midazolam crystal form A
100mg of midazolam was added to 1mL of acetonitrile, stirred at room temperature for 24h and filtered to give a white powdery solid. The powder diffraction pattern, differential scanning calorimetry pattern and thermogravimetric analysis pattern are basically consistent with those of example 1.
Example 4: preparation of midazolam crystal form A
100mg of midazolam was added to 1mL of acetone and 2mL of ethyl acetate, dissolved with stirring at room temperature, and then slowly volatilized to obtain a white solid. The powder diffraction pattern, differential scanning calorimetry pattern and thermogravimetric analysis pattern are basically consistent with those of example 1.
Example 5: preparation of midazolam crystal form A
100mg of midazolam was added to 1mL of acetone and 2mL of methyl tert-butyl ether, dissolved with stirring at room temperature, and then slowly evaporated to give a white solid. The powder diffraction pattern, differential scanning calorimetry pattern and thermogravimetric analysis pattern are basically consistent with those of example 1.
Example 6: preparation of midazolam crystal form A
100mg of midazolam was added to 0.5mL of tetrahydrofuran and 2mL of methyl tert-butyl ether, dissolved with stirring at room temperature, and then slowly evaporated to give a white solid. The powder diffraction pattern, differential scanning calorimetry pattern and thermogravimetric analysis pattern are basically consistent with those of example 1.
Example 7: preparation of midazolam crystal form A
100mg of midazolam was added to 0.5mL of tetrahydrofuran and 2mL of toluene, dissolved with stirring at room temperature, and then slowly evaporated to give a white solid. The powder diffraction pattern, differential scanning calorimetry pattern and thermogravimetric analysis pattern are basically consistent with those of example 1.
Example 8: preparation of midazolam crystal form A
100mg of midazolam was added to 0.5mL of 1, 4-dioxane and 2mL of isopropyl acetate, dissolved with stirring at room temperature, and then slowly volatilized to give a white solid. The powder diffraction pattern, differential scanning calorimetry pattern and thermogravimetric analysis pattern are basically consistent with those of example 1.
Example 9: preparation of midazolam crystal form A
100mg of midazolam was added to 0.5mL of 1, 4-dioxane and 2mL of methyl tert-butyl ether, dissolved with stirring at room temperature, and then slowly volatilized to give a white solid. The powder diffraction pattern, differential scanning calorimetry pattern and thermogravimetric analysis pattern are basically consistent with those of example 1.
Example 10: preparation of midazolam crystal form A
Adding 200mg of midazolam into 2mL of methyl tert-butyl ether, stirring and dissolving, standing and volatilizing at room temperature to obtain a granular single crystal product. The powder diffraction pattern, differential scanning calorimetry pattern and thermogravimetric analysis pattern are basically consistent with those of example 1. The single crystal structure was analyzed, the unit cell parameters are shown in Table 3, and the single crystal structure is shown in FIG. 4.
TABLE 3 cell parameters for form A
Example 11: preparation of midazolam crystal form B
Adding 100mg of midazolam into 0.5mL of methanol, stirring and dissolving at room temperature, slowly dropwise adding 2mL of purified water, stirring and crystallizing, and filtering to obtain a white powdery solid.
The obtained sample was subjected to Differential Scanning Calorimetry (DSC) as shown in FIG. 6, and it had endothermic peaks in the ranges of 81.37 to 109.34 ℃ and 161.96 to 165.35 ℃, respectively; the obtained sample was subjected to Differential Scanning Calorimetry (DSC) as shown in FIG. 7, and its weight loss in the range of 30-120 ℃ was 7.46%. The crystal form is obviously different from the crystal form A and is named as a crystal form B.
X-ray powder measurements were performed using Cu-ka radiation, which patterns had diffraction angles, interplanar spacings and relative intensities as shown in Table 4:
TABLE 4 diffraction angles, interplanar spacings and relative intensities for form B
The error of the 2 θ diffraction angle was ± 0.20.
Further, crystalline form B of midazolam prepared in example 11 has an X-ray powder diffraction pattern substantially as shown in figure 5.
Example 12: preparation of midazolam crystal form B
Adding 100mg of midazolam into 0.5mL of ethanol, stirring and dissolving at room temperature, slowly dropwise adding 2mL of purified water, stirring and crystallizing, and filtering to obtain a white powdery solid. The powder diffraction pattern, differential scanning calorimetry pattern and thermogravimetric analysis pattern are basically consistent with those of example 11.
Example 13: preparation of midazolam crystal form B
Adding 100mg of midazolam into 0.5mL of isopropanol, stirring and dissolving at room temperature, slowly dropwise adding 2mL of purified water, stirring and crystallizing, and filtering to obtain a white powdery solid. The powder diffraction pattern, differential scanning calorimetry pattern and thermogravimetric analysis pattern are basically consistent with those of example 11.
Example 14: preparation of midazolam crystal form B
Adding 100mg of midazolam into 1mL of acetone, stirring and dissolving at room temperature, slowly dropwise adding 2mL of purified water, stirring and crystallizing, and filtering to obtain a white powdery solid. The powder diffraction pattern, differential scanning calorimetry pattern and thermogravimetric analysis pattern are basically consistent with those of example 11.
Example 15: preparation of midazolam crystal form B
Adding 100mg of midazolam into 0.5mL of tetrahydrofuran, stirring and dissolving at room temperature, slowly dropwise adding 2mL of purified water, stirring and crystallizing, and filtering to obtain a white powdery solid. The powder diffraction pattern, differential scanning calorimetry pattern and thermogravimetric analysis pattern are basically consistent with those of example 11.
Example 16: preparation of midazolam crystal form B
Adding 100mg of midazolam into 0.5mL1, 4-dioxane, stirring and dissolving at room temperature, slowly dropwise adding 2mL of purified water, stirring and crystallizing, and filtering to obtain a white powdery solid. The powder diffraction pattern, differential scanning calorimetry pattern and thermogravimetric analysis pattern are basically consistent with those of example 11.
Test example 1: stability investigation experiment
In order to examine the stability of crystalline form a and crystalline form B of midazolam prepared according to the present invention, crystalline form a and crystalline form B were respectively left for 30 days under three conditions of high temperature (60 ℃), high humidity (92.5% rh) and illumination (4500 lx ± 500 lx), sampled for 5 days, 10 days, 30 days, respectively, XRD was tested and compared with the results of 0 day, and the results were as follows:
TABLE 5 stability test data for influencing factors of form A and form B
As is clear from Table 5 and FIG. 8, form A was stable in crystal morphology and did not undergo crystal transformation even after being left for 30 days under the three conditions of high temperature (60 ℃ C.), high humidity (92.5% RH) and light irradiation.
As is apparent from Table 5 and FIG. 9, form B was completely converted to form A after being left at high temperature (60 ℃ C.) for 5 days, and the crystal morphology was stable under high humidity (92.5% RH) and light conditions.
In conclusion, the stability of form a is superior to form B.
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 the methods of making the same without departing from the spirit or scope of the application, and therefore, the scope of the invention encompasses all modifications and variations that fall within the scope of the claims and their equivalents.
Claims (10)
1. A crystal form A of a compound shown as a formula (I) has characteristic peaks at 2 theta angles of 11.64 +/-0.2 degrees, 13.26 +/-0.2 degrees, 14.76 +/-0.2 degrees, 18.12 +/-0.2 degrees, 20.72 +/-0.2 degrees, 23.30 +/-0.2 degrees, 25.30 +/-0.2 degrees, 26.78 +/-0.2 degrees and 28.96 +/-0.2 degrees in an X-ray powder diffraction pattern.
2. Form a of the compound of formula (I) according to claim 1, having an X-ray powder diffraction pattern substantially as shown in figure 1.
3. Form A of a compound of formula (I) according to claim 1 or 2, wherein the differential scanning calorimetry pattern of form A has a maximum endothermic peak in the range 162.03 ± 3 ℃, preferably the differential scanning calorimetry pattern of form A is as shown in figure 2.
4. Form a of the compound of formula (I) according to claim 1 or 2, wherein the thermogravimetric analysis of form a shows no significant weight loss in the range of 30-120 ℃, preferably the thermogravimetric analysis of form a is shown in figure 3.
5. Form a of the compound of formula (I) according to claim 1 or 2, wherein the single crystal structure of form a is depicted in figure 4.
6. A process for the preparation of the compound of formula (I) in form a according to claim 1, characterized in that it comprises: and adding midazolam into an organic solvent, and suspending at room temperature for 24h to obtain the crystal form A.
7. The process for the preparation of form a of the compound of formula (I) according to claim 6, wherein the organic solvent is acetone, ethyl acetate or acetonitrile.
8. A process for the preparation of the compound of formula (I) in form a according to claim 1, characterized in that it comprises: and dissolving midazolam in a binary organic solvent, and volatilizing at room temperature to obtain the crystal form A.
9. A process for the preparation of form a of the compound of formula (I) according to claim 8, wherein the dibasic organic solvent is selected from acetone/ethyl acetate, acetone/isopropyl acetate, acetone/methyl tert-butyl ether, acetone/toluene, tetrahydrofuran/ethyl acetate, tetrahydrofuran/isopropyl acetate, tetrahydrofuran/methyl tert-butyl ether, tetrahydrofuran/toluene, 1,4-dioxane/ethyl acetate, 1,4-dioxane/isopropyl acetate, 1,4-dioxane/methyl tert-butyl ether or 1,4-dioxane/toluene.
10. The method for preparing the crystal form A of the compound shown in the formula (I) as claimed in claim 9, wherein the volume ratio of the binary organic solvent is 1:4-1:2.
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| EP0835874A2 (en) * | 1996-10-09 | 1998-04-15 | Ranbaxy Laboratories, Ltd. | A process for the manufacture of 8-chloro-6-(2-fluorophenyl)-1-methyl-4h-imidazo (1,5a)(1,4) benzodiazepine (midazolam) |
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