CN111320632B - Novel crystal form of midazolam hydrochloride and preparation method thereof - Google Patents
Novel crystal form of midazolam hydrochloride and preparation method thereof Download PDFInfo
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- CN111320632B CN111320632B CN201811539800.5A CN201811539800A CN111320632B CN 111320632 B CN111320632 B CN 111320632B CN 201811539800 A CN201811539800 A CN 201811539800A CN 111320632 B CN111320632 B CN 111320632B
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- 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
Abstract
The invention relates to a crystalline form A and a crystalline form B of midazolam hydrochloride and a preparation method thereof, the crystalline form A and the crystalline form B of midazolam hydrochloride obtained by the invention have good crystalline form stability and chemical stability, can be better used for clinical treatment,
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a novel crystalline form of midazolam hydrochloride and a preparation method thereof.
Background
Midazolam hydrochloride is a common drug for anesthesia and sedation, and has the chemical name of 1-methyl-8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a][1,4]-benzodiazepine
The monohydrochloride is currently on the market in China, and is used for pre-anesthesia administration, general anesthesia induction and maintenance, auxiliary medication during intraspinal anesthesia and local anesthesia, patient sedation during diagnosis or therapeutic operation, and ICU patient sedation; the specific chemical structure is as follows:
US4280957A and CN102241679B disclose methods for the preparation of midazolam hydrochloride crystals; both are prepared by mixing an ethanolic solution of midazolam and an ethanolic suspension of dihydrochloride. However, the midazolam hydrochloride obtained by the method has poor crystal form chemical stability, strong water absorption and easy deliquescence. In general, drug substances are generally stored for longer periods of time, and thus deliquescence during storage tends to change the purity, resulting in impurity levels that do not meet pharmacopoeial standards. In addition, the preparation method disclosed in the above patent is complex in preparation process, requires the mixed preparation of two compounds, and is not suitable for large-scale pharmaceutical industrial production.
At present, no other new midazolam hydrochloride crystal forms are reported, and no other simpler and more economic industrial production process is disclosed, so that the new midazolam hydrochloride crystal forms are worthy of deep research.
Disclosure of Invention
The invention aims to provide a midazolam hydrochloride crystal form A and a midazolam hydrochloride crystal form B, which have good crystal form stability and chemical stability and can be better applied to clinic,
the technical scheme of the invention is as follows:
the invention provides a crystalline form A of midazolam hydrochloride, which is characterized in that Cu-Kalpha radiation is used to obtain an X-ray powder diffraction pattern expressed by diffraction angle 2 theta, wherein the X-ray powder diffraction pattern shows characteristic peaks at 9.40, 13.27, 13.65, 17.38, 19.40, 21.04, 21.42, 21.60, 27.42 and 28.26, the error range can be +/-0.3, +/-0.2 or +/-0.1,
in a preferred embodiment of the present invention, said form a shows characteristic peaks expressed in 2 θ angles at 9.40, 13.27, 13.65, 17.38, 19.40, 19.71, 20.63, 21.04, 21.42, 21.60, 25.38, 25.72, 26.64, 26.83, 27.42, 28.26 and 32.72, with a range of error that may be ± 0.3, ± 0.2 or ± 0.1.
In a more preferred embodiment of the present invention, the raman spectrum of form a is 3063.14 ± 2cm-1、2991.72±2cm-1、2919.22±2cm-1、1623.50±2cm-1、1595.87±2cm-1、1570.44±2cm-1、1551.16±2cm-1、1505.63±2cm-1、1434.43±2cm-1、1392.64±2cm-1、1333.52±2cm-1、1281.12±2cm-1、1208.62±2cm-1、1169.81±2cm-1、1033.50±2cm-1、1002.36±2cm-1、823.67±2cm-1、685.69±2cm-1Characteristic peaks are shown.
In a more preferred embodiment of the present invention, the DSC of the form A has a melting endothermic peak selected from 266.2-287.3 ℃, preferably 278.7 ℃.
In a more preferred embodiment of the present invention, the form a conforms to one or more of the following solid state characteristics:
(I) a powder X-ray diffraction pattern substantially in accordance with figure 2;
(II) a DSC thermogram substantially in accordance with figure 3;
(III) substantially in accordance with the raman spectrum of figure 4.
The invention provides a method for preparing a crystal form A, which is characterized by comprising the following steps:
dissolving midazolam in ethanol;
secondly, slowly adding a hydrochloric acid/ethanol solution into the solution obtained in the step one under the condition of low-temperature stirring, and stirring at room temperature for crystallization to obtain midazolam hydrochloride solid;
dissolving midazolam hydrochloride solid obtained in step (II) at a high temperature, adding activated carbon, stirring, and filtering while hot to obtain a filtrate;
and fourthly, slowly adding an inert organic solvent into the filtrate obtained from the third step at the temperature of 45-60 ℃, and standing to separate out the precipitate of the A crystal form of the imidazole hydrochloride.
In a preferred embodiment of the invention, the dissolving process in the step (i) is to obtain an ethanol solution containing midazolam under stirring at room temperature.
In a preferred embodiment of the present invention, the ethanol is preferably absolute ethanol.
In the preferable embodiment of the invention, the room temperature is 20-30 ℃.
In the scheme of the preferred embodiment of the invention, the low temperature in the step II is selected from-5 to 10 ℃, preferably 0 to 5 ℃.
In the preferable embodiment of the invention, in the hydrochloric acid/ethanol solution in the step (II), the content of hydrochloric acid is 10-20% (w/w), preferably 10-15%.
In a more preferable embodiment of the invention, in the second step, the pH condition and the temperature condition need to be controlled during the process of slowly adding the hydrochloric acid ethanol solution, and the pH condition is preferably 4-5; the temperature condition is preferably 0-30 ℃.
In the preferable embodiment of the invention, in the process of slowly adding the ethanol hydrochloride solution in the second step, the adding speed is controlled to be 1-5 mL/s, preferably 1-3 mL/s.
In the scheme of the preferred embodiment of the invention, the high temperature in the step (c) is selected from 80-100 ℃, preferably 85 ℃.
In a more preferable embodiment of the invention, the temperature condition is controlled in the stirring process of the activated carbon in the third step, and the temperature condition is selected from 60-70 ℃.
In a more preferable embodiment of the invention, the mass ratio of midazolam hydrochloride to activated carbon in the step (c) is selected from 10: 1-20: 1, preferably 20: 1.
In a preferred embodiment of the invention, the inert organic solvent is selected from C5-10And saturated alkanes.
In the scheme of the preferred embodiment of the invention, C in the step (iv)5-10The saturated alkane is selected from one or more of n-pentane, n-hexane, cyclohexane or n-heptane, preferably n-heptane.
In the scheme of the preferred embodiment of the invention, C in the step (iv)5-10The adding speed of the saturated alkane is controlled to be 1-5 mL/s, preferably 1-3 mL/s.
The invention preferably further provides a subsequent purification process of the preparation method of the crystal form A, which specifically comprises the following steps:
fifthly, continuously stirring the suspension containing the imidazole hydrochloride crystal form A precipitate obtained in the step (iv) for 1-3 hours at a low temperature, and filtering to obtain an imidazole hydrochloride solid;
sixthly, the obtained solid is treated with C5-10And (3) eluting the solid with a saturated alkane solvent, and drying the solid to constant weight at the temperature of 80-100 ℃ to obtain pure midazolam hydrochloride A crystal form solid.
In a preferred embodiment of the present invention, the low temperature in the fifth step is selected from-10 to 10 ℃, preferably 0 to 10 ℃.
In the scheme of the preferred embodiment of the invention, the step C5-10The saturated alkane is selected from one or more of n-pentane, n-hexane, cyclohexane or n-heptane, preferably n-heptane.
In a preferred embodiment of the present invention, the drying in the step (c) is preferably vacuum drying; the temperature condition is further preferably 85 to 95 ℃.
The invention provides a crystalline form B of midazolam hydrochloride, which is characterized in that Cu-Kalpha radiation is used to obtain an X-ray powder diffraction pattern expressed by diffraction angle 2 theta, wherein the X-ray powder diffraction pattern shows characteristic peaks at 8.76, 9.44, 11.66, 13.23, 16.97, 17.42, 18.43, 19.44, 21.07, 23.10, 24.38 and 27.46, the error range can be +/-0.3, +/-0.2 or +/-0.1,
in a preferred embodiment of the present invention, form B shows characteristic peaks expressed in degrees 2 θ at 8.76, 9.44, 11.66, 13.23, 13.69, 16.97, 17.42, 18.43, 19.44, 21.07, 21.47, 23.10, 23.90, 24.38, 27.01 and 27.46, with a tolerance range of ± 0.3, ± 0.2 or ± 0.1.
In a more preferred embodiment of the present invention, the raman spectrum of form B is 3061.02 ± 2cm-1、2915.47±2cm-1、1609.28±2cm-1、1564.19±2cm-1、1500.23±2cm-1、1428.14±2cm-1、1388.26±2cm-1、1328.88±2cm-1、1276.59±2cm-1、1244.86±2cm-1、1204.03±2cm-1、1164.50±2cm-1、1028.51±2cm-1、996.86±2cm-1、681.08±2cm-1Characteristic peaks are shown.
In a more preferred embodiment of the present invention, the melting endothermic peak of DSC of the B form is selected from 235.5-288.1 ℃, preferably 279.5 ℃.
In a more preferred embodiment of the present invention, the form B conforms to one or more of the following solid state characteristics:
(I) a powder X-ray diffraction pattern substantially in accordance with figure 5;
(II) a DSC thermogram substantially in accordance with figure 6;
(III) a raman spectrum substantially in accordance with fig. 7.
The invention provides a method for preparing a crystal form B, which is characterized by comprising the following steps:
dissolving midazolam hydrochloride in a mixed organic solvent, standing and crystallizing to obtain midazolam hydrochloride solid;
and secondly, drying the solid obtained in the step I to obtain the midazolam hydrochloride B crystal form.
In a preferred embodiment of the present invention, the mixed organic solvent consists of a benign solvent and a poor solvent of midazolam hydrochloride.
In a preferred embodiment of the invention, the benign solvent is selected from the group consisting of methanol, ethanol, n-butanol, n-propanol, acetonitrile, CH2Cl2、CHCl3、CCl4One or more of dimethyl sulfoxide (DMSO).
In a preferred embodiment of the present invention, the poor solvent is selected from ethers, C5-10One or more of saturated alkanes or ketones.
In a more preferred embodiment of the present invention, the ether is preferably methyl t-butyl ether, petroleum ether or isopropyl ether; c5-10The saturated alkane is selected from n-pentane, n-hexane, cyclohexane or n-heptane; the ketones are selected from acetone or butanone.
In a more preferred embodiment of the present invention, the poor solvent is selected from one or more of methyl tert-butyl ether, petroleum ether, isopropyl ether, n-pentane, n-hexane, cyclohexane, n-heptane, acetone, butanone, water or isopropanol.
In a further preferred embodiment of the present invention, the composition of the mixed organic solvent is selected from the group consisting of CH2Cl2Ether and CH2Cl2/C5-10Saturated alkanes; the CH2Cl2With ethers or C5-10The volume ratio of the saturated alkanes is 10: 1-20: 1, preferably 10:1 and 20: 1.
In a further preferred embodiment of the present invention, the composition of the mixed organic solvent is selected from the group consisting of CH2Cl2Isopropyl alcohol, said CH2Cl2The volume ratio of the isopropanol to the isopropanol is 1: 1-3: 1, preferably 1:1 and 3: 2.
In a more preferable embodiment of the present invention, the process of dissolving midazolam hydrochloride in the mixed organic solvent in step (i) further comprises a heating process; the heating temperature is 50-70 ℃.
In a more preferred embodiment of the invention, the crystallization process in the step I further comprises a heat preservation condition, wherein the heat preservation temperature is 35-50 ℃, and is preferably 40 ℃.
In a more preferable embodiment of the present invention, the drying temperature in the step (II) is selected from 70 to 90 ℃, preferably 80 ℃.
The invention also provides a pharmaceutical composition comprising an active ingredient in form a or form B, and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.
In a preferred embodiment of the invention, the active ingredient contains at least 50 to 99% of form a; preferably, at least 70-99% of said form a; more preferably, it contains at least 90-99% of form a.
In a further preferred embodiment of the invention, form a is present in the active ingredient in substantially pure form.
In a preferred embodiment of the invention, the active ingredient contains at least 50 to 99% of form B; preferably, at least 70-99% of said form B; more preferably, it contains at least 90-99% of form B.
In a further preferred embodiment of the invention, form a is present in the active ingredient in substantially pure form.
In a further preferred embodiment of the invention, form B is present in the active ingredient in substantially pure form.
In a preferred embodiment of the invention, the pharmaceutical composition may be administered by any suitable route, for example orally in the form of capsules, parenterally in the form of injection solutions, topically in the form of ointments or lotions, rectally in the form of suppositories, transdermally in the form of a delivery system for a patch. In a preferred embodiment, the pharmaceutical composition is preferably administered orally.
The present invention also relates to the use of form a or form B as described herein for the preparation of a medicament for pain suppression, preferably anesthesia, sedation.
In a preferred embodiment of the invention, the anesthesia is selected from the group consisting of pre-anesthesia administration, general anesthesia induction and maintenance, intraspinal anesthesia and adjuvant administration during local anesthesia.
In a preferred embodiment of the invention, the sedation is selected from the group consisting of patient sedation at the time of diagnostic or therapeutic procedures, and ICU patient sedation.
Detailed Description
In the description and claims of this application, unless otherwise indicated, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. However, for a better understanding of the present invention, the following provides definitions and explanations of some of the relevant terms. In addition, where the definitions and explanations of terms provided herein are inconsistent with the meanings that would normally be understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.
The "ether" according to the present invention means a chain compound or a cyclic compound containing an ether bond-O-and having 1 to 10 carbon atoms, and specific examples include, but are not limited to: diethyl ether, diisopropyl ether, propylene glycol methyl ether, tetrahydrofuran, methyl tert-butyl ether or 1, 4-dioxane.
The "ketone" according to the present invention refers to a compound in which a carbonyl group (-C (O)) is bonded to two hydrocarbon groups, and the ketone can be classified into aliphatic ketones, alicyclic ketones, aromatic ketones, saturated ketones and unsaturated ketones according to the difference in the hydrocarbon groups in the molecule, and specific examples include, but are not limited to: acetone, acetophenone, methyl isobutyl ketone or methyl pyrrolidone.
The term "saturated hydrocarbon" as used herein means C5-10The chain or cyclic alkane of (1) wherein carbon atoms are all connected by single bonds and the remaining bonds are all hydrogen bonds, and specific examples include, but are not limited to: n-pentane, n-hexane, cyclohexane and n-heptane.
The "X-ray powder diffraction pattern or XRPD" as used herein refers to the pattern obtained by dividing the X-ray beam according to bragg formula 2d sin θ ═ n λ (where λ is the wavelength of the X-ray,
the order n of diffraction is any positive integer, a first-order diffraction peak is generally taken, n is 1, when X-rays are incident on an atomic plane with a d-lattice plane spacing of a crystal or a part of a crystal sample at a grazing angle theta (complementary angle of incidence, also called Bragg angle), the Bragg equation can be satisfied, and the set of X-ray powder diffraction patterns can be measured.
The term "2 theta or 2 theta angle" as used herein means diffraction angle, theta is bragg angle in units of ° or degrees, and the error range of 2 theta is ± 0.1 to ± 0.5, preferably ± 0.1 to ± 0.3, and more preferably ± 0.2.
The "interplanar spacing or interplanar spacing (d value)" referred to herein means that the spatial lattice selects 3 non-parallel unit vectors a, b, c connecting two adjacent lattice points, which divide the lattice into juxtaposed parallelepiped units, called interplanar spacing. The space lattice is divided according to the determined connecting lines of the parallelepiped units to obtain a set of linear grids called space grids or lattices. The lattice and the crystal lattice respectively reflect the periodicity of the crystal structure by using geometrical points and lines, and the surface spacing (namely the distance between two adjacent parallel crystal surfaces) of different crystal surfaces is different; has a unit of
Or angstroms.
The "differential scanning calorimetry or DSC" described in the present invention determines the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or melting of the crystal. For the same crystal form of the same compound, the thermal transition temperature and melting point errors in successive analyses may be within about 5 ℃, typically within about 3 ℃. When a compound is described as having a given DSC peak or melting point, that DSC peak or melting point is referred to as ± 5 ℃. "substantially" also takes such temperature variations into account. DSC provides an auxiliary method to distinguish different crystal forms. Different crystal morphologies can be identified by their different transition temperature characteristics. It is noted that the DSC peak or melting point for the mixture may vary over a larger range. Furthermore, the melting temperature is related to the rate of temperature rise due to decomposition that accompanies the process of melting the substance.
The "fourier Raman spectroscopy" (FT-Raman), as used herein, is generally used to study the structure and chemical bonds of molecules and also as a method to characterize and identify chemical species. In the invention, the error range of the peak position of the Fourier Raman spectrum used for representing the molecular structure and the crystal form FT-Raman can be +/-2 cm-1。
Advantageous effects of the invention
Compared with the prior art, the technical scheme of the invention has the following advantages:
researches show that the midazolam hydrochloride crystal form A and the midazolam hydrochloride crystal form B have high purity and good crystal form stability; the HPLC purity change is small, and the chemical stability is high; the crystalline forms A and B of midazolam hydrochloride obtained by the technical scheme of the invention can meet the medicinal requirements of production, transportation and storage, and the production process is stable, repeatable and controllable, and can be suitable for industrial production.
Drawings
Figure 1 is an X-ray powder diffraction pattern of midazolam hydrochloride comparative example C crystalline form.
Figure 2 is an X-ray powder diffraction pattern of midazolam hydrochloride form a.
Figure 3 is a DSC profile of midazolam hydrochloride form a.
Figure 4 is a raman spectrum of midazolam hydrochloride form a.
Figure 5 is an X-ray powder diffraction pattern of midazolam hydrochloride form B.
Figure 6 is a DSC profile of midazolam hydrochloride form B.
Figure 7 is a raman spectrum of midazolam hydrochloride form B.
Figure 8 is an X-ray powder diffraction pattern of midazolam hydrochloride amorphous form.
Detailed Description
The present invention will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit and scope of the present invention.
Test conditions of the apparatus used for the experiment:
1. x-ray Powder Diffraction Spectroscopy (XRPD)
The instrument model is as follows: bruker D8Focus powder X-ray diffractometer.
X-ray parameters:
voltage: 40 KV (kV)
Current: 40 milliampere (mA)
Scanning range: from 3.0 to 60 degrees
Scanning step length: 0.02 degree
Scanning pace speed: 0.5 sec/step
2. DSC thermogram (DSC)
The instrument model is as follows: german relaxation-resistant DSC 200F3 differential scanning calorimeter
And (3) purging gas: nitrogen gas
The heating rate is as follows: 10.0K/min
Temperature range: 30-300 deg.C
3. Fourier Raman Spectroscopy (FT-Raman Spectrometer, FT-RM)
The instrument model is as follows: thermo Scientific DXR Smart Raman spectrometer
Diaphragm: 50 μm
Exposure time: 10s
Exposure times: 32 times (twice)
Laser: 780nm (nanometers)
Laser energy: 150mw
4. High Performance Liquid Chromatography (HPLC)
The instrument model is as follows: agilent 1260(DAD) binary pump liquid chromatography
A chromatographic column: agilent Eclipse XDB (4.6 x 150mm,5 μm) C18 column
Mobile phase:
a: 0.1mol/L ammonium acetate solution (pH 5.2) -methanol (47:53)
B: 0.1mol/L ammonium acetate solution (pH 5.2) -methanol (35:65)
Flow rate: 1.2ml/min column temperature: 35 deg.C
Wavelength: sample volume at 254 nm: 20 μ L
Gradient conditions (volume ratio):
example 1, comparative example C preparation of crystalline forms
Prepared by referring to the methods described in patent US4280957A, example 25 (column 45 of the specification) or CN102241679B, example 10 (page 11 of the specification), the LC purity of the final product is 95.6%, the X-ray powder diffraction thereof is shown in fig. 1, the crystal form is defined as C crystal form, and the characteristic peak positions are shown in table 1:
TABLE 1
Example 2 preparation of form A
Midazolam (110.0g, 0.338mol) and 1650ml absolute ethanol were added to a four-necked round bottom flask and stirred at room temperature to be completely dissolved. Under the conditions of cooling in an ice water bath and stirring, 116.8g (0.371mol) of HCl/ethanol solution (the HCl content is 11.61 percent, the pH value of the solution is 4-5) is slowly dripped into the midazolam ethanol solution, and the temperature is controlled to be less than 30 ℃ in the dripping process. After dripping, stirring at room temperature until the reaction solution is turbid, and then stirring for crystallization for 10min, wherein a large amount of white solid is separated out. Heating the mixture to 85 ℃ in an oil bath, and stirring the mixture until the solid is completely dissolved. And (3) adding 5.5g of activated carbon at the temperature of 60-70 ℃, refluxing and stirring, and filtering while the solution is hot. And (3) transferring the filtrate into a reaction bottle, slowly adding 2500mL of n-heptane into the reaction bottle under the stirring condition when the temperature is 45-60 ℃, and separating out solids in the dropping process. And cooling the suspension in an ice bath, and stirring and crystallizing for 2 hours at the temperature of 0-10 ℃. Filtration and rinsing the filter cake with 330mL of n-heptane. And drying the obtained solid in a vacuum drying oven at the temperature of 80-100 ℃ to constant weight. The final product is obtained. The LC purity was 98.2%. The X-ray powder diffraction pattern is shown in figure 2, the DSC pattern is shown in figure 3, and the Raman pattern is shown in figure 4. During the DSC temperature rise, the endothermic peak appears at 266.2 ℃ at the starting point, 287.3 ℃ at the ending point and 278.7 ℃ at the peak. This form was defined as form a and its characteristic peak positions are shown in table 2 below:
TABLE 2
Example 3 preparation of form A
Midazolam (55.0g, 0.169mol) and 800ml absolute ethanol were added to a four-necked round-bottomed flask and stirred at room temperature until completely dissolved. Under the conditions of cooling in an ice water bath and stirring, 58.4g (0.186mol) of HCl/ethanol solution (the HCl content is 12.31 percent, the pH value of the solution is 4-5) is slowly dripped into the midazolam ethanol solution, and the temperature is controlled to be less than 30 ℃ in the dripping process. After dripping, stirring at room temperature until the reaction solution is turbid, and then stirring for crystallization for 10min, wherein a large amount of white solid is separated out. Heating the mixture to 85 ℃ in an oil bath, and stirring the mixture until the solid is completely dissolved. And (3) adding 2.8g of activated carbon at the temperature of 60-70 ℃, refluxing and stirring, and filtering while the solution is hot. And (3) transferring the filtrate into a reaction bottle, slowly adding 1400mL of normal hexane into the reaction bottle under the stirring condition when the temperature is 45-60 ℃, and separating out solids in the dropping process. And cooling the suspension in an ice bath, and stirring and crystallizing for 2 hours at the temperature of 0-10 ℃. Filtration was carried out and the filter cake was rinsed with 200mL of n-hexane. And drying the obtained solid in a vacuum drying oven at the temperature of 80-100 ℃ to constant weight. The final product is obtained. The LC purity was 98.7%. Obtaining a final product, and determining the product as a crystal form A through X-ray powder diffraction detection.
Example 4 preparation of form B
Weighing about 500mg of midazolam hydrochloride in a small beaker, adding 12.5ml of isopropanol and 12.5ml of dichloromethane solvent, dissolving in a water bath at 60 ℃, sealing after the solution is clarified, standing at 40 ℃ for crystallization, separating out a large amount of crystals after standing for about 5 days, collecting, and drying at 80 ℃ for 4 hours to obtain a final product. The LC purity was 98.7%. The X-ray powder diffraction pattern is shown in figure 4, the DSC pattern is shown in figure 5, and the Raman pattern is shown in figure 6. In the DSC temperature rising process, the starting point of an endothermic peak is 235.5 ℃, the end point is 288.1 ℃ and the peak value is 279.5 ℃; this form was defined as form B and its characteristic peak positions are shown in table 3 below:
TABLE 3
Example 5 preparation of form B
Weighing about 200mg of midazolam hydrochloride in a small beaker, adding 2mL of petroleum ether and 20mL of dichloromethane, dissolving under the condition of water bath at 60 ℃, sealing after the solution is clarified, standing at 40 ℃ for crystallization, separating out a large amount of crystals after standing for about 5 days, collecting, and drying at 80 ℃ for 4 hours to obtain a final product, wherein the product is determined to be a B crystal form through X-ray powder diffraction detection.
Example 6 preparation of form B
Weighing about 200mg of midazolam hydrochloride in a small beaker, adding 1mL of cyclohexane and 20mL of dichloromethane, dissolving under the condition of water bath at 60 ℃, sealing after the solution is clarified, standing at 40 ℃ for crystallization, separating out a large amount of crystals after standing for about 5 days, collecting, and drying at 80 ℃ for 4 hours to obtain a final product, wherein the product is determined to be a B crystal form through X-ray powder diffraction detection.
Example 7 preparation of form B
Weighing about 200mg of midazolam hydrochloride in a small beaker, adding 20mL of n-propanol and 5mL of acetone, dissolving in a water bath at 55 ℃, sealing after the solution is clarified, standing at room temperature for crystallization, separating out a large amount of crystals after standing for about 5 days, collecting, drying at 90 ℃ for 3.5 hours to obtain a final product, and determining the product as a B crystal form through X-ray powder diffraction detection.
Example 8 preparation of form B
Weighing about 250mg of midazolam hydrochloride into a small beaker, adding 10mL of acetonitrile and 10mL of isopropanol, dissolving under the condition of water bath at 60 ℃, sealing after the solution is clarified, standing at room temperature for crystallization, separating out a large amount of crystals after standing for about 5 days, collecting, drying at 70 ℃ for 4h to obtain a final product, and determining the product as a B crystal form through X-ray powder diffraction detection.
Example 9 examination of Crystal form stability
The experimental method comprises the following steps:
referring to the four general rules 9001 raw material medicament and preparation stability test guiding principles of the Chinese pharmacopoeia 2015 annual edition (see page 354 of Chinese pharmacopoeia 4), specifically, stability influence factor tests are respectively carried out on the crystal form A (prepared according to example 2), the crystal form B (prepared according to example 3) and the crystal form C (hereinafter referred to as crystal form C, prepared according to example 1) under the conditions of high humidity (R.H.92.5%), high temperature (60 ℃) and illumination (4500 +/-500 lx), PXRD (polycrystalline X-ray diffraction) detection is respectively carried out on sampling at 5 days and 10 days, HPLC content (w/w,%) measurement is carried out at the same time, and the result is compared with the result of 0 day.
TABLE 4 stability influencing factor test of crystal form A and B
The experimental results are as follows:
from the data in table 4, it is known that the crystal forms a and B can be well kept stable in morphology under the conditions of 10 days at high humidity, 10 days at high temperature and 10 days under illumination, and have stable chemical properties, the content of the crystal forms a is almost unchanged from that of the crystal forms a at 0 day, and the content of the crystal forms a can reach more than 98.0%.
Compared with the crystal form C, the purity of the crystal form C is lower than that of the crystal form A and that of the crystal form B, the crystal form can not be kept stable under the experimental conditions of 10 days at high humidity, 10 days at high temperature and 10 days under illumination, the crystal form gradually changes to the crystal form A, the chemical property is unstable, the content is changed compared with that of the crystal form C at 0 day, and the content can not be kept above 95%.
In conclusion, the stability of the crystal form A and the stability of the crystal form B are superior to that of the crystal form C.
Example 10 examination of mechanical stress of Crystal form
The experimental method comprises the following steps:
weighing about 1000mg of a crystal form A (prepared according to example 2), a crystal form B (prepared according to example 3) and a crystal form C (hereinafter, referred to as crystal form C and prepared according to example 1) of a comparative example, placing the samples into an agate mortar of a ball mill, setting the rotating speed of the ball mill to be 400r/min, stopping the ball mill for 15min every 30min, respectively carrying out ball milling for 30min, 5h and 10h, then carrying out PXRD test, observing the change condition of the crystal forms, carrying out the test twice in parallel, and obtaining the specific test result shown in Table 5.
Table 5 investigation experiment of mechanical stress of crystal form a and crystal form B
The experimental results are as follows:
from table 5, it can be seen that the crystal form a and the crystal form B are stable under the ball milling pressure condition and unchanged by detection under the conditions of ball milling for 30min, 5h and 10h respectively; the crystal form C is gradually transformed into amorphous form under the condition of ball milling pressure (specifically shown in figure 8) respectively under the conditions of ball milling for 30min, 5h and 10h after detection, the crystal form is obviously changed, and the fact that the crystal form A and the crystal form B are suitable for the crushing process of pharmaceutical industry compared with the crystal form C is shown, so that the crystal form C is suitable for large-scale production of pharmaceutical industry.
Claims (13)
1. Crystalline form a of midazolam hydrochloride characterized in that, using Cu-ka radiation, an X-ray powder diffraction pattern is obtained showing characteristic peaks at 9.40, 13.27, 13.65, 15.11, 17.38, 19.02, 19.40, 19.71, 20.63, 21.04, 21.42, 21.60, 22.28, 22.72, 24.38, 25.38, 25.72, 26.64, 26.83, 27.42, 28.26, 28.75, 31.77 and 32.72 in diffraction angle 2 Θ, wherein the error range of each characteristic peak 2 Θ is ± 0.2.
2. Form a according to claim 1, having a raman spectrum at 3063.14 ± 2cm-1、2991.72±2cm-1、2919.22±2cm-1、1623.50±2cm-1、1595.87±2cm-1、1570.44±2cm-1、1551.16±2cm-1、1505.63±2cm-1、1434.43±2cm-1、1392.64±2cm-1、1333.52±2cm-1、1281.12±2cm-1、1208.62±2cm-1、1169.81±2cm-1、1033.50±2cm-1、1002.36±2cm-1、823.67±2cm-1、685.69±2cm-1Characteristic peaks are shown.
3. Form a according to claim 1, wherein the DSC of form a has a melting endotherm peak selected from 266.2-287.3 ℃.
4. Form a according to claim 1, having a DSC with a melting endotherm at 278.7 ℃.
5. A process for preparing the crystalline form A of any one of claims 1-4, comprising the steps of:
dissolving midazolam in ethanol;
slowly adding a hydrochloric acid/ethanol solution into the solution obtained in the step I under the conditions of cooling and stirring in an ice water bath, controlling the temperature to be less than 30 ℃ in the dropping process, controlling the pH to be 4-5, stirring at room temperature for crystallization to obtain midazolam hydrochloride solid, wherein the content of hydrochloric acid in the hydrochloric acid/ethanol solution is 10% -20%, and the dropping amount of the hydrochloric acid is 1.1 times of the molar amount of the midazolam;
thirdly, heating the mixture to 85 ℃ in an oil bath, and stirring the mixture until the solid is completely dissolved; adding active carbon at 60-70 deg.C, stirring, and filtering to obtain filtrate;
fourthly, slowly adding an inert organic solvent into the filtrate obtained in the third step at the temperature of 45-60 ℃, separating out solids in the dropping process, cooling the suspension in an ice bath, and stirring and crystallizing for 2 hours at the temperature of 0-10 ℃ to obtain a midazolam hydrochloride A crystal form;
wherein the inert organic solvent is selected from n-heptane or n-hexane.
6. Crystalline form B of midazolam hydrochloride characterized in that, using Cu-ka radiation, an X-ray powder diffraction pattern is obtained, expressed in diffraction angle 2 Θ angles, showing characteristic peaks at 8.76, 9.44, 11.66, 13.23, 13.69, 16.97, 17.42, 18.43, 19.44, 21.07, 21.47, 23.10, 23.90, 24.38, 26.70, 27.01, 27.46, 28.33 and 35.79, wherein the error range of 2 Θ for each characteristic peak is ± 0.2.
7. Form B according to claim 6, having a raman spectrum at 3061.02 ± 2cm-1、2915.47±2cm-1、1609.28±2cm-1、1564.19±2cm-1、1500.23±2cm-1、1428.14±2cm-1、1388.26±2cm-1、1328.88±2cm-1、1276.59±2cm-1、1244.86±2cm-1、1204.03±2cm-1、1164.50±2cm-1、1028.51±2cm-1、996.86±2cm-1、681.08±2cm-1Characteristic peaks are shown.
8. Form B according to claim 6, wherein the DSC of form B has a melting endotherm peak selected from 235.5-288.1 ℃.
9. Form B according to claim 6, having a DSC with a melting endotherm at 279.5 ℃.
10. A process for preparing the form B according to any one of claims 6 to 9, comprising the steps of:
dissolving midazolam hydrochloride in a mixed organic solvent, dissolving in a water bath at 60 ℃, standing for crystallization at 40 ℃ after the solution is clarified, and obtaining midazolam hydrochloride solid;
secondly, drying the solid obtained in the first step to obtain solid of the midazolam hydrochloride B crystal form;
wherein the content of the first and second substances,
the mixed organic solvent is selected from any one of the following combinations:
isopropyl alcohol and CH2Cl2Combination, petroleum ether and CH in a volume ratio of 1:12Cl2Combination of volume ratio 1:10, cyclohexane and CH2Cl2A combination of volume ratio 1:20, a combination of n-propanol and acetone in volume ratio 4:1, and a combination of acetonitrile and isopropanol in volume ratio 1: 1.
11. A pharmaceutical composition comprising the form a according to any one of claims 1-4 or the form B according to any one of claims 6-9, one or more excipients, carriers, adjuvants, vehicles or combinations thereof.
12. Use of the crystalline form a according to any one of claims 1 to 4 or the crystalline form B according to any one of claims 6 to 9 for the preparation of a medicament for the inhibition of pain.
13. The use according to claim 12, wherein the pain suppression is anesthesia or sedation.
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| WO2016149540A1 (en) * | 2015-03-18 | 2016-09-22 | Regents Of The University Of Minnesota | Therapeutic compounds and formulations for intranasal delivery |
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| US7776852B2 (en) * | 2007-09-11 | 2010-08-17 | Chemagis Ltd. | Process for producing highly pure midazolam and salts thereof |
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| US4440685A (en) * | 1974-09-11 | 1984-04-03 | Hoffmann-La Roche Inc. | Imidazodiazepines and processes therefor |
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