CN115232132A - Midazolam hydrochloride G crystal form and preparation method thereof - Google Patents
Midazolam hydrochloride G crystal form and preparation method thereof Download PDFInfo
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- CN115232132A CN115232132A CN202210877782.1A CN202210877782A CN115232132A CN 115232132 A CN115232132 A CN 115232132A CN 202210877782 A CN202210877782 A CN 202210877782A CN 115232132 A CN115232132 A CN 115232132A
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- midazolam
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- hydrochloric acid
- hydrochloride
- acetate
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- PLYSCVSCYOQVRP-UHFFFAOYSA-N midazolam hydrochloride Chemical compound Cl.C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F PLYSCVSCYOQVRP-UHFFFAOYSA-N 0.000 title claims abstract description 55
- 239000013078 crystal Substances 0.000 title claims abstract description 49
- 229960002853 midazolam hydrochloride Drugs 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 70
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims abstract description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- 229960003793 midazolam Drugs 0.000 claims description 30
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 29
- 238000002425 crystallisation Methods 0.000 claims description 16
- 230000008025 crystallization Effects 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 15
- 239000012065 filter cake Substances 0.000 claims description 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 4
- 229940011051 isopropyl acetate Drugs 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 3
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- 238000001237 Raman spectrum Methods 0.000 claims description 2
- 229940043232 butyl acetate Drugs 0.000 claims description 2
- -1 ethyl isopropyl Chemical group 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 2
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 2
- 229940090181 propyl acetate Drugs 0.000 claims description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000000862 absorption spectrum Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 230000009286 beneficial effect Effects 0.000 abstract description 6
- 238000011161 development Methods 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- 230000003321 amplification Effects 0.000 abstract 1
- 238000003199 nucleic acid amplification method Methods 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 239000012535 impurity Substances 0.000 description 14
- 229940079593 drug Drugs 0.000 description 11
- 239000003960 organic solvent Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000002994 raw material Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000007791 liquid phase Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
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- 239000011259 mixed solution Substances 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 206010039897 Sedation Diseases 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 230000036280 sedation Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical compound N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- FZJLREPRIOUQQO-UHFFFAOYSA-N 1h-1,4-benzodiazepine;hydrochloride Chemical compound Cl.N1C=CN=CC2=CC=CC=C12 FZJLREPRIOUQQO-UHFFFAOYSA-N 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000031091 Amnestic disease Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 229940122226 Benzodiazepine receptor agonist Drugs 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000006986 amnesia Effects 0.000 description 1
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- 229940035674 anesthetics Drugs 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 239000003759 ester based solvent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
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- 239000003193 general anesthetic agent Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
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- 238000002690 local anesthesia Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
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Classifications
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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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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a midazolam hydrochloride G crystal form and a preparation method thereof. The preparation method disclosed by the invention is used for dissolving in an ester solvent and salifying by adopting hydrochloric acid, and the obtained finished product has the advantages of stable crystal form, high purity, high yield, economy and environmental friendliness, is particularly suitable for industrial amplification production, and is beneficial to development of pharmaceutical preparations.
Description
Technical Field
The invention relates to the technical field of organic synthesis, and particularly relates to a midazolam hydrochloride G crystal form and a preparation method thereof.
Background
Midazolam, chemically known as 8-chloro-6- (2-fluorobenzene) -1-methyl-4H-imidazo (1,5-alpha) (1,4) benzodiazepine, is a benzodiazepine receptor agonist developed by roche, switzerland and, first marketed in the uk in 1983. The midazolam serving as benzodiazepine can be used for synthesizing clinical medicines, has the curative effects of other similar medicines, has the advantages of the midazolam, has certain water solubility, short in-vivo half-life period and fewer side effects. Midazolam formulations with different base groups have been used clinically. The maleate tablet can be used for treating insomnia, anxiety and other symptoms; the midazolam hydrochloride injection is used for pre-anesthesia administration, general anesthesia induction and maintenance, ICU patient sedation, intraspinal anesthesia and local anesthesia auxiliary administration, can play a good auxiliary role, reduces the dosage of other anesthetics, and provides certain guarantee for safer operation of patients. Midazolam hydrochloride syrup or oral solutions are suitable for pediatric patients for diagnosis, treatment, or pre-endoscopic surgery or pre-anesthesia induction sedation, anxiolysis, and amnesia.
The common midazolam preparation is maleate, has good stability, and is beneficial to being prepared into tablets. The conventional midazolam hydrochloride has limited pharmaceutical activity due to the hygroscopicity and solvent adsorption property. The hygroscopicity is not beneficial to storage and transportation of the raw material medicines, the hygroscopicity causes moisture increase, impurities are easily increased, the content is reduced, and the preparation specification is not qualified. The nature of the adsorption solvent causes that organic solvents contained in the raw material medicines cannot be dried and removed, and the residual organic solvents have harm to human bodies and cannot be used for preparing medicinal preparations.
The preparation method of the conventional midazolam hydrochloride preparation comprises the steps of suspending midazolam raw material medicaments in water, and adding hydrochloric acid to adjust the pH value for dissolving the midazolam raw material medicaments, wherein the method has the following defects: the midazolam solid is insoluble in water, and the dissolution time is long in the process of adjusting the pH value with hydrochloric acid to dissolve, so that the production efficiency is influenced; in addition, the hydrochloric acid of the aqueous solution is greatly excessive relative to the midazolam which is dissolved initially, so that the local acidity is strong, the related substances are easily increased, and the medication safety is influenced. Therefore, a crystalline form bulk drug of midazolam hydrochloride with good pharmacy is urgently needed, and a preparation manufacturer can directly dissolve the midazolam hydrochloride in water to prepare a pharmaceutical preparation for clinical use.
US4280957 and CN102241679 disclose a preparation method of midazolam hydrochloride crystals, and the midazolam hydrochloride crystal form C obtained by the method is high in water absorption, easy to deliquesce and not suitable for research of preparation patent medicines.
CN111320632 reports the preparation of midazolam hydrochloride form a and form B. The crystal has good crystal form stability and chemical stability. However, the crystal form A is prepared by crystallization of absolute ethyl alcohol, HCl/ethanol solution and alkane solvents, and the method uses mixed solvents for crystallization, so that three wastes are difficult to recover or treat, and is not environment-friendly. In addition, the purity of the obtained midazolam hydrochloride solid HPLC is only 98.0-99.0% due to the high-temperature dissolution process of the hydrochloride and crystallization by using an alkane organic solvent with extremely low polarity, and the yield of the method is not high. The crystal form B is prepared by dissolving the previously obtained midazolam hydrochloride in two mixed solvents and standing for about 5 days, the production period is overlong, the purity is still lower than 99.0 percent, namely, the raw and auxiliary materials are high in cost, the solvent is difficult to recover, the production period is long, the purity is low, the yield is low, and the industrial production of raw material drug manufacturers is not facilitated.
Because midazolam hydrochloride has a relatively high solubility in an aqueous solution, all the documents reported so far for improving the salt formation yield use an organic solvent of HCl gas as a salt forming reagent, such as an ethanol solution of HCl, an ethyl acetate solution of HCl, and the like, but the use of an organic solvent of HCl gas has the following safety risks, which are not favorable for industrial scale-up production: 1) The solution of HCl gas organic solvent needs to be prepared by HCl gas, which has high requirements on environmental protection, safety and equipment facilities; 2) The HCl gas solution in organic solvent is not favorable for storage and transportation, and has low boiling point and high volatility, so that positive pressure is easy to generate during sealed storage, and the explosion risk is high. A dedicated low temperature ventilated warehouse is required to avoid the risk.
Besides the crystal form A and the crystal form B reported in the patent, other crystal forms of midazolam hydrochloride are not reported for a while. The raw material medicine for clinical medication needs good quality stability, is simple and convenient to operate, and is suitable for industrial development and preparation processes. The existing reported preparation process of midazolam hydrochloride is complex, the obtained product is poor in stability, and the problems of strong hygroscopicity, excessive impurities and the like easily occur in the storage process of the product. The development of an industrial preparation process of midazolam hydrochloride, which is simple and convenient to operate and is environment-friendly, is very necessary.
Disclosure of Invention
Against the background, the invention aims to provide a preparation method of midazolam hydrochloride crystal form medicine which is suitable for industrial production, high in product purity and stable in quality. The crystalline form of midazolam hydrochloride obtained by the method is not reported, and the applicant names the crystalline form of midazolam hydrochloride G. The traditional Chinese cultural name of midazolam hydrochloride prepared by the invention is as follows: 1-methyl-8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5- α ] [1,4] benzodiazepine hydrochloride of the following formula:
the invention adopts the following technical scheme:
the designed synthetic route is as follows:
a method for preparing midazolam G hydrochloride crystalline form, said method comprising the steps of:
a. dissolving midazolam in an ester solvent;
b. slowly adding concentrated hydrochloric acid or a mixed solvent of the concentrated hydrochloric acid and an ester solvent into the clear solution;
c. stirring and crystallizing;
d. filtering, washing a filter cake, and drying to obtain the midazolam G hydrochloride crystal form.
Further, in the above method for preparing midazolam G hydrochloride crystal form, the ester solvent in step a and step b is selected from ethyl formate, ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate, and preferably is methyl acetate, ethyl acetate or ethyl isopropyl acetate.
Further, in the preparation method of the midazolam hydrochloride G crystal form, the dissolving temperature in the step a is 0-80 ℃, and preferably 10-30 ℃.
Further, in the preparation method of the midazolam hydrochloride G crystal form, in the step b, the concentrated hydrochloric acid is slowly added in drops at the temperature of-10-40 ℃, preferably 0-30 ℃, wherein the molar amount of the hydrochloric acid is 0.90-1.20 equivalents of the feeding amount of the midazolam, preferably 0.95-1.05 equivalents.
Further, in the preparation method of the midazolam G hydrochloride crystal form, in the crystallization in the step c, the crystallization temperature is-10-40 ℃, and preferably 0-30 ℃.
Further, in the preparation method of the midazolam G hydrochloride crystal form, the drying in the step d is reduced pressure drying, and the drying temperature is 40-120 ℃, preferably 80-100 ℃.
Further, the preparation method of the midazolam hydrochloride G crystal form specifically comprises the following steps:
a. adding an ester solvent and midazolam into a reaction bottle or a reaction kettle, heating to 10-30 ℃, stirring for dissolving, and cooling to 0-30 ℃ after dissolving;
b. adding 0.95 to 1.05 equivalent of concentrated hydrochloric acid into another reaction bottle or reaction kettle, or adding 0.95 to 1.05 equivalent of concentrated hydrochloric acid and an ester solvent into another bottle, and stirring and mixing uniformly. Dripping concentrated hydrochloric acid or a mixed solution of the concentrated hydrochloric acid and an ester solvent into an ester solution clear solution of midazolam, and controlling the temperature of a salt forming system to be 0 to 30 ℃ when dripping is carried out;
c. after dripping, stirring and crystallizing at 0 to 30 ℃ for 0.5 to 2.0 hours;
d. filtration and washing of the filter cake with solvent. And (3) drying the filter cake at 80-100 ℃ under reduced pressure, cooling to obtain powder after the water content is qualified, and obtaining midazolam hydrochloride.
The invention has the following beneficial effects:
(1) A single ester solvent is used for salifying, so that the solvent recovery is facilitated, and the method is environment-friendly;
(2) Common concentrated hydrochloric acid is adopted for salifying instead of the organic solvent solution using HCl gas reported at present, so that the influence of the organic solvent solution for preparing HCl gas on environmental protection, safety and equipment facilities is avoided.
(3) The method adopts a low-temperature dissolving process, avoids the problem of impurities introduced by high-temperature dissolving, has good impurity removing effect by using ester solvents with medium polarity for crystallization, and ensures that the purity of the prepared midazolam hydrochloride liquid phase is as high as 99.8 percent and the single impurity is not more than 0.10 percent.
(4) The preparation process of midazolam hydrochloride disclosed by the invention has the yield of 90-95%, and the single organic solvent and concentrated hydrochloric acid are combined, so that the raw material cost and the production cost are obviously reduced compared with those of the traditional process, and the preparation process is beneficial to benefiting people to the public.
(5) The preparation process of midazolam hydrochloride obtains the G crystal form, solves the problems of hygroscopicity and organic solvent adsorption, and ensures the pharmaceutical property of midazolam hydrochloride. In a word, the midazolam hydrochloride G crystal form and the preparation process thereof disclosed by the patent have the following advantages: economic and environment-friendly, low cost of raw materials, high product purity, high yield, good pharmaceutical property and the like, and is a process which is extremely beneficial to industrial scale-up production.
Description of the drawings:
FIG. 1: an X-ray powder diffraction pattern of midazolam hydrochloride G crystal form.
FIG. 2: raman spectrum of midazolam hydrochloride form G.
FIG. 3: infrared spectroscopy of midazolam hydrochloride form G.
FIG. 4: DSC profile of midazolam hydrochloride form G.
FIG. 5 is a schematic view of: liquid phase purity profile of midazolam hydrochloride form G.
The specific implementation mode is as follows:
the invention is further described in connection with the following specific examples, which are intended to be illustrative of the invention and are not to be construed as limiting the invention.
The preparation of the midazolam hydrochloride G crystal form according to the reaction route of the invention comprises the following steps:
example 1
a. Adding 20.00g of midazolam and 360.00g of ethyl acetate into a 500ml three-necked flask, heating to 10-30 ℃, stirring for dissolving, and cooling to 0-30 ℃.
b. In another reaction flask were added 7.70g concentrated hydrochloric acid and 250.73g ethyl acetate, and mixed well with stirring. And (b) dropwise adding 205.24g of mixed solution of concentrated hydrochloric acid and ethyl acetate into the midazolam ethyl acetate solution obtained in the step a, and controlling the temperature of a crystallization system to be 0-30 ℃ in the dropwise adding process. Solid is gradually separated out in the dropping process.
c. After dripping, the mixture is kept at the temperature of 0 to 30 ℃ for crystallization for about 1 hour.
d. Filtering, and washing a filter cake by using a solvent. And drying the filter cake under reduced pressure at 80-100 ℃, stopping drying after detecting that the water content is lower than 0.5%, and collecting 21.20G of midazolam hydrochloride G crystal form solid. The yield is 95.3%, the purity of the liquid phase is 99.83%, and the single impurity is not more than 0.10%.
Example 2
a. 20.00g of midazolam and 400.00g of methyl acetate are added into a 500ml three-neck flask, the temperature is increased to 10 to 30 ℃, the materials are stirred and dissolved, and the temperature is reduced to 0 to 30 ℃.
b. In another reaction flask were added 7.80g of concentrated hydrochloric acid and 250.00g of methyl acetate, and the mixture was stirred well. B, dropwise adding 206.0g of mixed solution of concentrated hydrochloric acid and methyl acetate into the midazolam methyl acetate solution obtained in the step a, and controlling the temperature of a crystallization system to be in the dropwise adding process
0 to 30 ℃. Solid is gradually separated out in the dropping process.
c. After dripping, crystallization is carried out for about 1 hour at the temperature of 0 to 30 ℃.
d. Filtering, and washing a filter cake by using a solvent. And drying the filter cake under reduced pressure at 80-100 ℃, stopping drying after detecting that the water content is lower than 0.5%, and collecting 21.00G of midazolam hydrochloride G crystal form solid. The yield is 94.4%, the purity of the liquid phase is 99.86%, and the single impurity is not more than 0.10%.
Example 3
a. Adding 20.00g of midazolam and 300.00g of ethyl acetate into a 500ml three-necked flask, heating to 10 to 30 ℃, stirring for dissolving, and cooling to 0 to 30 ℃.
b. And (b) slowly dripping 6.10g of concentrated hydrochloric acid into the midazolam ethyl acetate solution obtained in the step (a), and controlling the temperature of a crystallization system to be 0-30 ℃ in the dripping process. Solid is gradually separated out in the dropping process.
c. After dripping, crystallization is carried out for about 1 hour at the temperature of 0 to 30 ℃.
d. Filtering, and washing a filter cake by using a solvent. And drying the filter cake under reduced pressure at 80-100 ℃, stopping drying after detecting that the water content is lower than 0.5%, and collecting 20.50G of midazolam hydrochloride G crystal form solid. The yield is 92.2%, the purity of the liquid phase is 99.85%, and the single impurity is not more than 0.10%.
Example 4
a. Adding 1.40kg of midazolam and 20.70kg of ethyl acetate into a 100L reaction kettle, heating to 10-30 ℃, stirring and dissolving, filtering to a clean area through a filter element, and washing the reaction kettle and a pipeline by using 7.00kg of ethyl acetate. Collecting the filtrate and washing liquid, and cooling to 0-30 ℃.
b. 0.61kg of concentrated hydrochloric acid and 32.57kg of ethyl acetate are added into another reaction kettle, stirred uniformly and filtered to a clean area through a filter element. And (b) dropwise adding 16.47kg of mixed solution of concentrated hydrochloric acid and ethyl acetate into the midazolam ethyl acetate solution obtained in the step (a), and controlling the temperature of a crystallization system to be 0-30 ℃ in the dropwise adding process. Solid is gradually separated out in the dropping process.
c. After dripping, the mixture is kept at the temperature of 0 to 30 ℃ for crystallization for about 1 hour.
d. Filtering, and washing a filter cake by using a solvent. And drying the filter cake under reduced pressure at 80-100 ℃, stopping drying after detecting that the water content is lower than 0.5%, and collecting to obtain 1.42kg of midazolam hydrochloride G crystal form solid. The yield is 91.2%, the purity of the liquid phase is 99.92%, and the single impurity is not more than 0.10%.
Example 5
The elementary analysis of midazolam hydrochloride obtained in example 4 confirmed that the product obtained was midazolam monohydrochloride.
(1) Instrument type
Vario EL cube type element analyzer and IC-2010 ion chromatograph
(2) The elemental analysis data are shown in Table 1 below
TABLE 1 results of elemental analysis
(3) And (4) conclusion: and comparing the test values of the elements C, H, N, cl and F of the test sample with the theoretical value of midazolam hydrochloride, wherein errors are less than 0.3%, and the result shows that the element composition of the test sample conforms to the structure of midazolam hydrochloride.
Example 6
The midazolam hydrochloride prepared in example 4 is analyzed and detected, and the detection items and contents are as follows:
TABLE 2 summary of sample testing items
Example 7 the results of examining the crystal form stability and quality stability of the midazolam hydrochloride G crystal form prepared in example 4 are shown in tables 3 to 5.
TABLE 3 stability test results under different conditions
TABLE 4 stability test results under accelerated conditions
TABLE 5 Long term stability test results
Through stability experiment investigation, the midazolam hydrochloride G crystal form disclosed by the invention is packaged or exposed under high-temperature and high-humidity conditions for 30 days, and the illumination condition is investigated for 15 days, compared with 0 day, related substances are basically unchanged, no new impurities are added, the change of a single impurity is less than 0.05%, and the change of the total impurities is less than 0.1%; the characters, clarity and color have no significant change compared with 0 month. The results of accelerated 6-month and long-term 6-month tests show that the midazolam hydrochloride G crystal form obtained by the preparation process disclosed by the invention is stable in crystal form and quality, and is suitable for pharmaceutical preparation research and clinical application.
Conclusion the patent CN111320632 reports stability data of midazolam hydrochloride in crystal form a, crystal form B and crystal form C, which are shown in table 6. TABLE 6A, B, C stability test results
Compared with the stability research data of the crystal form in the published literature data, the crystal form of midazolam hydrochloride G prepared by me si is superior to the prior art: (1) The A, B crystal form has better stability, but the HPLC purity is lower than 99.0%, the impurities are large, and the defect of more obvious safety in medication is realized, while the total impurities in the G crystal form prepared by I are not more than 0.1%, and the HPLC purity is as high as 99.9%, so that the medication safety is facilitated. (2) The crystal form C has poor stability and has crystal transformation phenomenon, and the midazolam hydrochloride G crystal form prepared by me is stable after long-term examination for 6 months and accelerated examination for 6 months without crystal transformation phenomenon.
Claims (10)
1. A crystalline form G of midazolam hydrochloride, characterized in that: the X-ray powder diffraction 2 theta angle has characteristic peaks at 13.3 + -0.2, 13.7 + -0.2, 17.4 + -0.2, 19.4 + -0.2, 19.8 + -0.2, 21.1 + -0.2, 21.7 + -0.2, 22.8 + -0.2, 24.4 + -0.2, 25.4 + -0.2, 25.8 + -0.2, 26.9 + -0.2, 27.4 + -0.2 and 28.3 + -0.2.
Characteristic peaks are shown at 2.2cm-1, 2929 + -2 cm-1, 2860 + -2 cm-1, 1613 + -2 cm-1, 1570 + -2 cm-1, 1509 + -2 cm-1, 1453 + -2 cm-1, 1415 + -2 cm-1, 1335 + -2 cm-1, 1036 + -2 cm-1 and 688 + -2 cm-1.
3. The crystalline form G of claim 1, characterized in that: the crystal form G of claim 1, having a Raman spectrum at 3070 ± 2cm "1, 2990 ± and characterized in that: the infrared absorption spectrum has characteristic peaks at 1624 cm-1, 1508 cm-1, 1450 cm-1, 1485 cm-1, 1313 cm-1, 1215 cm-1, 1101 cm-1, 937 cm-1, 769 cm-1 and 750 cm-1, and the wave number error of the band is about 0.5% of a specified value.
4. A crystalline form G of midazolam hydrochloride, characterized in that: the crystal form G of claim 1, which has an X-ray powder diffraction 2 theta angle of 13.3 +/-0.2, and an endothermic peak at DSC of 254-259 ℃.
5. A process for the preparation of midazolam hydrochloride form G according to claims 1-4, comprising the following steps: a, dissolving midazolam in an ester solvent; b. slowly adding concentrated hydrochloric acid or a mixed solvent of the concentrated hydrochloric acid and an ester solvent into the clear solution; c, stirring and crystallizing; d. filtering, washing a filter cake, and drying to obtain the midazolam G hydrochloride crystal form.
6. The method according to claim 5, wherein the ester solvent in step a and step b is selected from the group consisting of ethyl formate, ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate, preferably methyl acetate, ethyl acetate and ethyl isopropyl acetate.
7. The method of claim 5, wherein the dissolution temperature in step a is 0-80 ℃, preferably 10-30 ℃.
8. The preparation method according to claim 5, wherein in the step b, the slowly adding concentrated hydrochloric acid is dropwise adding concentrated hydrochloric acid, and the dropwise adding temperature is-10 ℃ to 40 ℃, preferably 0 ℃ to 30 ℃, wherein the molar amount of the hydrochloric acid is 0.90 to 1.20 equivalents, preferably 0.95 to 1.05 equivalents, of the dosage of midazolam.
9. The method of claim 5, wherein the crystallization temperature of the crystallization in step c is-10 ℃ to 40 ℃, preferably 0 ℃ to 30 ℃.
10. The process according to claim 5, wherein the drying in step d is carried out under reduced pressure at a temperature of from 40 ℃ to 120 ℃, preferably from 80 ℃ to 100 ℃.
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| CN111320632A (en) * | 2018-12-14 | 2020-06-23 | 江苏恩华药业股份有限公司 | Novel crystal form of midazolam hydrochloride and preparation method thereof |
| CN113149992A (en) * | 2021-01-15 | 2021-07-23 | 福安药业集团重庆礼邦药物开发有限公司 | Preparation method and application of midazolam hydrochloride F crystal form |
| CN114773348A (en) * | 2021-09-02 | 2022-07-22 | 成都硕德药业有限公司 | Preparation method and intermediate of midazolam |
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| CN102241679A (en) * | 2010-05-04 | 2011-11-16 | 意大利合成制造有限公司 | Process for the synthesis of 4h-imidazo [1,5-a] [1,4] benzodiazepines, in particular midazolam and salts thereof |
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| CN114773348A (en) * | 2021-09-02 | 2022-07-22 | 成都硕德药业有限公司 | Preparation method and intermediate of midazolam |
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