CN109369580B - Preparation method of furacilin gamma crystal form - Google Patents
Preparation method of furacilin gamma crystal form Download PDFInfo
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/70—Nitro radicals
- C07D307/71—Nitro radicals attached in position 5
- C07D307/72—Nitro radicals attached in position 5 with hydrocarbon radicals, substituted by nitrogen-containing radicals, attached in position 2
- C07D307/74—Nitro radicals attached in position 5 with hydrocarbon radicals, substituted by nitrogen-containing radicals, attached in position 2 by hydrazino or hydrazono or such substituted radicals
- C07D307/76—Nitro radicals attached in position 5 with hydrocarbon radicals, substituted by nitrogen-containing radicals, attached in position 2 by hydrazino or hydrazono or such substituted radicals having carbonic acyl radicals or their thio or nitrogen analogues directly attached to the hydrazino or hydrazono radical, e.g. semicarbazides
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Abstract
Hair brushThe invention relates to a preparation method of furacilin gamma crystal form. Adding the furacilin crude product into a good solvent, controlling the temperature to be 30-50 ℃, stirring at 200-500 rpm until the furacilin crude product is clear, and preparing into a solution of 0.066-0.24 g/ml; filtering the solution by a filter membrane to remove insoluble impurities; dripping a poor solvent at a rate of 0.3-0.6 ml/min until crystal is formed, and growing the crystal; then, poor solvent is dripped from slow to fast in three stages; cooling to 5-10 ℃ in 90-120 min, and growing the crystals for 20-30 min; and (4) carrying out suction filtration on the feed liquid, washing the feed liquid with a poor solvent twice for 7-9 ml/time, and drying the crystal product to constant weight. The furacilin gamma crystal form provided by the invention has the bulk density of 0.38-0.48 g/cm3The purity is higher than 98.8 percent, the process is simple to operate, short in time consumption and low in energy consumption, and is suitable for industrial production; easy filtration of crystal, good thermodynamic stability and the like.
Description
Technical Field
The invention belongs to the technical field of medicine crystallization, and particularly relates to a crystallization preparation method of a furacilin gamma crystal form.
Background
The furacilin has a Chinese cultural name of 5-nitro-2-furaldehyde semicarbazone, an English chemical name of 5-nitro-2-furaldehyde semi-carbazone, a CAS number of 59-87-0 and a molecular formula of C6H6N4O4And the molecular weight is 198.14. Knot of itThe structure formula is shown as formula (I),
nitrofurazone (Nitrofurazone) is an artificially synthesized antibiotic with antibacterial action against various gram-positive and gram-negative bacteria. Furfural is usually subjected to nitration, esterification and hydrolysis to prepare 5-nitrofurfural, and then the 5-nitrofurfural is condensed with amino hydrochloride to obtain nitrofurazone. The medicament has small irritation to tissues and is not easy to generate drug resistance, is used for treating diseases such as burn, skin infection, suppurative dermatitis, suppurative otitis media and the like at first, and is widely used in animal husbandry and aquaculture due to strong antibacterial effect and price advantage. The purpose of bacteriostasis or sterilization is achieved mainly by interfering the bacterial sugar metabolic process and an oxidase system to cause the bacterial metabolic disorder.
According to the report of patent literature, furacilin crystal has three crystal forms of alpha, beta and gamma. Olszak et al, 1994, originally discovered single crystal data of furacilin alpha crystal form, having a wervue number of CCDC, and found characteristic peaks at 2 θ of 8.8 ± 0.2, 13.7 ± 0.2, 15.4 ± 0.2, 18.6 ± 0.2, 20.6 ± 0.2, 21.0 ± 0.2, 23.0 ± 0.2, 23.9 ± 0.2, 24.2 ± 0.2, 25.3 ± 0.2, 26.6 ± 0.2, 27.9 ± 0.2, 30.2 ± 0.2, 31.7 ± 0.2, and 35.2 ± 0.2 degrees by XRD powder diffraction. The crystal is yellow block crystal, and no other patent documents report the industrial preparation method. Dorota Pogoda et al evaporated in organic solvent in 2016 to crystallize two kinds of crystal structures of yellow needle-like beta crystal form and orange/brown flaky gamma crystal form, which is suitable for single crystal cultivation and is not suitable for industrial production, and the beta crystal form CCDC has a WERVEEU 01 number, from which XRD powder diffraction has peaks at 2 theta of 6.1 + -0.2, 14.0 + -0.2, 17.6 + -0.2, 18.4 + -0.2, 21.2 + -0.2, 22.1 + -0.2, 22.4 + -0.2, 24.7 + -0.2, 25.4 + -0.2, 25.6 + -0.2, 26.1 + -0.2, 27.5 + -0.2, 27.8 + -0.2, 28.4 + -0.2, 31.2 + -0.2, 33.3 + -0.2, 33.8 + -0.2, 35.7 + -0.2 degrees. The gamma crystal form CCDC has a WERVEU02 number, and XRD powder diffraction of the gamma crystal form CCDC is 6.7 +/-0.2, 13.1 +/-0.2, 13.3 +/-0.2, 16.4 +/-0.2, 17.5 +/-0.2, 19.3 +/-0.2, 20.1 +/-0.2, 22.4 +/-0.2, 22.8 +/-0.2, 2Characteristic peaks are at 3.1 +/-0.2, 23.9 +/-0.2, 25.1 +/-0.2, 25.5 +/-0.2, 27.0 +/-0.2, 27.7 +/-0.2, 28.9 +/-0.2, 30.5 +/-0.2 and 35.5 +/-0.2 degrees. In addition, Dorota Pogoda also provides a gamma crystal form infrared spectrum at 3508cm-1、3429cm-1、3386cm-1、3134cm-1、3116cm-1、1818cm-1、1707cm-1、1660cm-1、1627cm-1、1595cm-1、1579cm-1、1565cm-1、1534cm-1、1498cm-1、1468cm-1、1419cm-1、1387cm-1、1349cm-1、1331cm-1、1314cm-1、1288cm-1、1255cm-1、1198cm-1、1148cm-1、1080cm-1、1023cm-1、1013cm-1、970cm-1、919cm-1、912cm-1、866cm-1、826cm-1、810cm-1、784cm-1、758cm-1、733cm-1、712cm-1、675cm-1、650cm-1、562cm-1、547cm-1、474cm-1Has an absorption peak; its Raman spectrum is 1647cm-1、1598cm-1、1575cm-1、1530cm-1、1512cm-1、1502cm-1、1473cm-1、1448cm-1、1388cm-1、1338cm-1、1317cm-1、1258cm-1、1204cm-1、1200cm-1、1193cm-1、1150cm-1、1037cm-1、1026cm-1、972cm-1、924cm-1、910cm-1、832cm-1、813cm-1、786cm-1、736cm-1、663cm-1、578cm-1、554cm-1、427cm-1There are absorption peaks, and no more patent documents report other preparation methods suitable for industrialization of the two crystal forms.
Through detection, the commercial furacilin is in a beta crystal form, the crystal form has the problems of non-centralized particle size distribution, easy coalescence, small bulk density, potential safety hazard and the like, and compared with needle-shaped and flaky crystals, the bulk crystal has higher bulk density and better stability. Therefore, in order to obtain the blocky crystal which is convenient and easy to obtain, large in bulk density and good in thermodynamic stability and facilitate the process of industrial production, so as to ensure the stability of the bulk drug and the preparation thereof in preparation and storage and improve the drug quality and clinical curative effect of nitrofurazone, the blocky gamma crystal form which meets the conditions is researched and prepared by the invention. At present, no industrial production method is reported in the gamma crystal form in the patent literature, and compared with the method for preparing the gamma crystal form single crystal reported by Dorota Pogoda, the method is more suitable for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of a furacilin gamma crystal form, which is elution, cooling and coupled crystallization.
The preparation method of the furacilin gamma crystal form specifically comprises the following steps:
(1) adding the furacilin crude product into a good solvent, controlling the temperature to be 30-50 ℃, stirring at 200-500 rpm until the furacilin crude product is dissolved clearly, and preparing into a solution with the concentration of 0.066-0.24 g/ml, wherein the use time is 5-30 min;
(2) filtering the solution with a 0.22 mu m filter membrane to remove insoluble impurities;
(3) dripping a poor solvent at the speed of 0.3-0.6 ml/min until crystal is produced, wherein the use time is 5-30 min, and the crystal growth is 20-30 min;
(4) dripping a poor solvent at the speed of 0.3-0.6 ml/min for 15-30 min, and growing the crystals for 20-30 min;
(5) dripping a poor solvent at the speed of 0.3-1.2 ml/min for 15-30 min, and growing the crystals for 20-30 min;
(6) dripping a poor solvent at the speed of 0.3-3.6 ml/min for 15-90 min, and growing the crystals for 20-30 min;
(7) cooling to 5-10 ℃ in 90-120 min, and growing the crystals for 20-30 min;
(8) and (4) carrying out suction filtration on the feed liquid, washing the feed liquid with a poor solvent twice for 7-9 ml/time, and drying the crystal product to constant weight.
In the preparation method, the crude furacilin product is crystal form beta or crystal form alpha solid powder, and the purity of the crude furacilin product is more than or equal to 98 percent.
In the above preparation method, the good solvent is one of N, N-dimethylformamide or dimethyl sulfoxide.
In the above preparation method, the poor solvent is one of water, isopropanol, n-propanol, methanol, ethanol, acetonitrile and acetone.
In the preparation method, the drying condition is that the temperature is 50-80 ℃ and the normal pressure is adopted.
The nitrofurazone prepared by the invention has the characteristic peaks at diffraction angles 2 theta of 6.7 +/-0.2, 13.1 +/-0.2, 13.3 +/-0.2, 16.4 +/-0.2, 17.5 +/-0.2, 19.3 +/-0.2, 20.1 +/-0.2, 22.4 +/-0.2, 22.8 +/-0.2, 23.1 +/-0.2, 23.9 +/-0.2, 25.1 +/-0.2, 25.5 +/-0.2, 27.0 +/-0.2, 27.7 +/-0.2, 28.9 +/-0.2, 30.5 +/-0.2 and 35.5 +/-0.2 degrees, and the wider diffraction angles are 6.7 +/-0.2, 13.1 +/-0.2, 16.4 +/-0.2, 17.5 +/-0.2, 19.3 +/-0.2, 20.1 +/-0.2, 20.2, 22.5 +/-0.2, 25.9 +/-0.2, 23.2, 23.5 +/-0.2, 25.2, 23.2, 25.9 +/-0.2, 23.2 +/-0.2, 25.9 +/-0.2, 23.2, 23.3 +/-0.2, 23.2, 3 +/-0.2, 23.9 +/-0.2, 23.2, 3 +/-0.2, 23.2, 23.9 +/-0.9 +/-0.2, 23.2, 3 +/-0.2, 23.9 +/-0.2, 23.2 and gamma is consistent with the prepared by the crystal form of the data of the crystal form of the document, 3 +/-0.2, 2, 3 +/-0.2, 2, 3 +/-0.2, 3 +/-0.9, 3 +/-0.2, 23.9, 3 +/-0.2, 23.2, 3 +/-0.2, 3 +/-0.9, 23.2, 3 +/-0.2 and the crystal form of the crystal form, 2, the crystal form of the data of the crystal form, the crystal form of the data of the document and the document, the document is shown in the document, the document. As shown in particular in figure 1.
The infrared spectrum of the furacilin gamma crystal form is 3507 +/-2 cm-1、3428±2cm-1、3385±2cm-1、3134±2cm-1、3116±2cm-1、1816±2cm-1、1705±2cm-1、1657±2cm-1、1625±2cm-1、1593±2cm-1、1564±2cm-1、1532±2cm-1、1496±2cm-1、1467±2cm-1、1417±2cm-1、1387±2cm-1、1348±2cm-1、1327±2cm-1、1312±2cm-1、1286±2cm-1、1253±2cm-1、1195±2cm-1、1146±2cm-1、1077±2cm-1、1022±2cm-1、1011±2cm-1、967±2cm-1、919±2cm-1、911±2cm-1、826±2cm-1、808±2cm-1、782±2cm-1、758±2cm-1、733±2cm-1、710±2cm-1、674±2cm-1、564±2cm-1、547±2cm-1、473±2cm-1Absorption peaks are present, and the data are consistent with gamma crystal form data in the literature, so that the product prepared by the preparation method is gamma crystal form, and is shown in figure 2 specifically.
The Raman spectrum of the furacilin gamma crystal form is 1647 +/-2 cm-1、1598±2cm-1、1574±2cm-1、1531±2cm-1、1515±2cm-1、1473±2cm-1、1448±2cm-1、1388±2cm-1、1352±2cm-1、1337±2cm-1、1318±2cm-1、1260±2cm-1、1200±2cm-1、1923±2cm-1、1151±2cm-1、1037±2cm-1、1026±2cm-1、972±2cm-1、922±2cm-1、910±2cm-1、833±2cm-1、813±2cm-1、786±2cm-1、738±2cm-1、663±2cm-1、580±2cm-1、552±2cm-1、429±2cm-1Absorption peaks are present, and the data are consistent with gamma crystal form data in the literature, so that the product prepared by the preparation method is gamma crystal form, and is shown in figure 3 specifically.
The invention relates to a preparation method of a furacilin gamma crystal form. Adding the furacilin crude product into a good solvent, controlling the temperature to be 30-50 ℃, stirring at 200-500 rpm until the furacilin crude product is clear, and preparing into a solution of 0.066-0.24 g/ml; filtering the solution by a filter membrane to remove insoluble impurities; dripping a poor solvent at a rate of 0.3-0.6 ml/min until crystal is formed, and growing the crystal; then, poor solvent is dripped from slow to fast in three stages; cooling to 5-10 ℃ in 90-120 min, and growing the crystals for 20-30 min; and (4) carrying out suction filtration on the feed liquid, washing the feed liquid with a poor solvent twice for 7-9 ml/time, and drying the crystal product to constant weight. The furacilin gamma crystal form provided by the invention has the bulk density of 0.38-0.48 g/cm3The purity is higher than 98.8 percent, the process is simple to operate, short in time consumption and low in energy consumption, and is suitable for industrial production; easy filtration of crystal, good thermodynamic stability and the like.
In the preparation method of the furacilin gamma crystal form disclosed by the application, elution cooling coupling crystallization is adopted, so that after the crystal is dissolved, the molecular arrangement mode and conformation are changed under the action of a poor solvent.
The product of the invention is subjected to long-term stability test, the color and the shape of the product are not obviously changed after the product is stored for 5 months under the conditions of normal temperature and normal pressure and light shielding, the stability of the product is good, and the X-ray powder diffraction investigation result is shown in figure 4.
The preparation method of the furacilin gamma crystal form provided by the invention has the advantages of simple process, suitability for industrial production and the like. The scanning electron microscope pictures of the gamma crystal forms of furacilin prepared by the method are respectively shown as the attached drawing 5, the scanning electron microscope picture of the alpha crystal form of the used raw material is shown as the attached drawing 6, and the scanning electron microscope picture of the beta crystal form of the raw material is shown as the attached drawing 7. Therefore, the furacilin gamma crystal form prepared by the preparation method provided by the invention has the advantages of easiness in filtration, good stability and the like. Compared with the method for preparing the gamma-crystal form single crystal by room-temperature evaporation proposed by Dorota Pogola in 2016, the preparation method provided by the invention has the advantages of short time consumption, low energy consumption, suitability for industrial production and the like, and the specific comparison shows in Table 1, and the gamma-crystal form of nitrofurazone prepared by the preparation method provided by the invention has the purity of more than or equal to 98.8% and the bulk density of 0.38-0.48 g/cm3Compared with the raw material beta crystal form with the purity of 98 percent and the bulk density of 0.18-0.20 g/cm3The purity of the raw material alpha crystal form is 98.5 percent, and the bulk density is 0.35-0.38 g/cm3The method has the advantages of improvement, contribution to subsequent preparation, storage and transportation and great advantage in medicinal preparation.
TABLE 1 Dorota Pogoda gamma crystal form preparation method and method of preparing gamma crystal form according to the invention and comparison of the obtained products
Drawings
FIG. 1: an X-ray powder diffraction pattern of a furacilin gamma crystal form;
FIG. 2: an infrared spectrogram of a furacilin gamma crystal form;
FIG. 3: a Raman spectrogram of furacilin gamma crystal form;
FIG. 4: the stability of the furacilin gamma crystal form is researched by an X-ray powder diffraction pattern;
FIG. 5: a scanning electron microscope image of the furacilin gamma crystal form prepared by the method;
FIG. 6: scanning electron microscope picture of furacilin alpha crystal form;
FIG. 7: scanning electron microscope picture of furacilin beta crystal form.
Detailed Description
Example 1:
adding 1.65g of dried furacilin alpha crystal form into 25ml of N, N-dimethylformamide, controlling the temperature at 30 ℃, stirring for 30min at 200rpm to dissolve, and filtering through a 0.22 mu m filter membrane to remove insoluble impurities. Adding water at 0.3ml/min for 5min to obtain crystal, and growing crystal for 30 min; adding water at a rate of 0.3ml/min for 30min, and growing crystal for 30 min; adding water at a rate of 0.6ml/min for 30min, and growing crystal for 30 min; adding water at a rate of 1.8ml/min for 30min, cooling to 5 deg.C for 120min, and growing crystal at 5 deg.C for 30 min; and (3) carrying out suction filtration on the feed liquid, washing twice with 8 ml/time of water, and drying the product at 50 ℃ and normal pressure to constant weight to obtain the gamma crystal furacilin.
The X-ray powder diffraction of the crystal obtained in this example is shown in fig. 1, and it has characteristic peaks at diffraction angles 2 θ of 6.645, 13.136, 16.399, 17.517, 19.265, 20.045, 22.342, 22.816, 23.059, 23.661, 25.081, 25.479, 26.92, 27.64, 28.9, 30.401, 32.054, 33.175, 35.478, 40.043, and 46.34 °, and it can be proved that the obtained product is γ crystal form nitrofural, specifically shown in fig. 1.
The infrared spectrum of the furacilin gamma crystal form obtained in the embodiment is 3506.49cm-1、3427.01cm-1、3383.83cm-1、3133.83cm-1、3116.07cm-1、1816.29cm-1、1704.77cm-1、1657.53cm-1、1625.12cm-1、1593.06cm-1、1564.24cm-1、1532.46cm-1、1496.09cm-1、1467.86cm-1、1417.40cm-1、1387.0cm-1、1348.97cm-1、1327.66cm-1、1312.30cm-1、1286.11cm-1、1253.59cm-1、1194.88cm-1、1146.47cm-1、1077.34cm-1、1022.52cm-1、1011.75cm-1、967.53cm-1、919.22cm-1、911.02cm-1、825.68cm-1、808.60cm-1、782.63cm-1、757.64cm-1、733.69cm-1、710.10cm-1、674.20cm-1、564.81cm-1、547.58cm-1、472.94cm-1An absorption peak is detected, and the obtained product is proved to be gamma crystal furacilin, which is shown in the attached figure 2.
The Raman spectrum of the furacilin gamma crystal form obtained in the embodiment is 1648.6cm-1、1597.4cm-1、1573.6cm-1、1531.9cm-1、1515.1cm-1、1473.9cm-1、1448.6cm-1、1388.4cm-1、1352.5cm-1、1336.1cm-1、1318.2cm-1、1260.3cm-1、1200.1cm-1、1192.9cm-1、1152.1cm-1、1036.5cm-1、1028.0cm-1、972.1cm-1、921.7cm-1、909.3cm-1、833.8cm-1、812.1cm-1、787.1cm-1、738.8cm-1、664.8cm-1、581.6cm-1、551.8cm-1、430.6cm-1An absorption peak is detected, and the obtained product is proved to be gamma crystal furacilin, which is shown in figure 3.
The gamma-crystal furacilin obtained in the embodiment has the UV purity of 99.01% and the bulk density of 0.48g/cm3。
Example 2:
adding 1.65g of dried furacilin alpha crystal form into 25ml of N, N-dimethylformamide, controlling the temperature at 40 ℃, stirring at 300rpm for 20min to dissolve, and filtering through a 0.22 mu m filter membrane to remove insoluble impurities. Adding isopropanol at 0.5ml/min for 10min to obtain crystal, and growing crystal for 30 min; adding isopropanol at 0.5ml/min for 30min, and growing crystal for 30 min; adding isopropanol at 0.6ml/min for 30min, and growing crystal for 30 min; adding isopropanol at a rate of 1.8ml/min for 30min, cooling to 5 deg.C for 90min, and keeping constant temperature at 5 deg.C for 30 min; and (3) carrying out suction filtration on the feed liquid, washing twice with isopropanol of 8ml per time, and drying the product at 60 ℃ under normal pressure to constant weight to obtain the gamma crystal furacilin.
The crystals obtained in this example were characterized by X-ray powder diffraction, infrared and Raman spectroscopy in the same manner as in example 1, a UV purity of 98.85% and a bulk density of 0.38g/cm3。
Example 3:
adding 1.80g of dried furacilin beta crystal form into 20ml of N, N-dimethylformamide, controlling the temperature at 50 ℃, stirring at 400rpm for 20min to dissolve, and filtering through a 0.22 mu m filter membrane to remove insoluble impurities. Adding n-propanol at a rate of 0.6ml/min for 15min to obtain crystal, and growing crystal for 30 min; adding n-propanol at a rate of 0.6ml/min for 15min, and growing crystal for 30 min; adding n-propanol at a concentration of 1.2ml/min for 15min, and growing crystal for 30 min; adding n-propanol at a rate of 3.6ml/min for 15min, cooling to 8 deg.C for 100min, and keeping constant temperature at 8 deg.C for crystal growth for 30 min; and (3) carrying out suction filtration on the feed liquid, washing twice with 9 ml/time of n-propanol, and drying the product at 70 ℃ under normal pressure to constant weight to obtain the gamma crystal furacilin.
The X-ray powder diffraction, infrared and Raman spectra of the crystal obtained in this example were the same as those of example 1, and the UV purity was 98.81%, and the bulk density was 0.40g/cm3。
Example 4:
adding 1.80g of dried furacilin beta crystal form into 20ml of N, N-dimethylformamide, controlling the temperature at 50 ℃, stirring for 5min at 500rpm to dissolve, and filtering through a 0.22 mu m filter membrane to remove insoluble impurities. Adding acetonitrile at 0.6ml/min for 30min to obtain crystal, and growing crystal for 20 min; adding acetonitrile at 0.6ml/min for 20min, and growing crystal for 20 min; adding acetonitrile at a rate of 1.2ml/min for 20min, and growing crystal for 20 min; adding acetonitrile at 3.6ml/min for 20min, cooling to 8 deg.C for 110min, and growing crystal at 8 deg.C for 20 min; and (3) carrying out suction filtration on the feed liquid, washing twice with acetonitrile 9 ml/time, and drying the product at 60 ℃ under normal pressure to constant weight to obtain the gamma crystal furacilin.
The crystals obtained in this example were characterized by X-ray powder diffraction, infrared and Raman spectroscopy in the same manner as in example 1, a UV purity of 98.89% and a bulk density of 0.41g/cm3。
Example 5:
adding 2.40g of dried furacilin beta crystal form into 10ml of dimethyl sulfoxide, controlling the temperature at 45 ℃, stirring at 200rpm for 20min to dissolve, and filtering through a 0.22 mu m filter membrane to remove insoluble impurities. Adding acetone at 0.3ml/min for 10min to obtain crystal, and growing crystal for 30 min; adding acetone at 0.3ml/min for 30min, and growing crystal for 30 min; adding acetone at 0.6ml/min for 30min, and growing crystal for 30 min; adding acetone at a concentration of 1.8ml/min for 30min, cooling to 10 deg.C for 110min, and keeping constant temperature at 10 deg.C for 30 min; and (3) carrying out suction filtration on the feed liquid, washing twice with 9 ml/time of acetone, and drying the product at 80 ℃ and normal pressure to constant weight to obtain the gamma crystal furacilin.
The crystals obtained in this example were characterized by X-ray powder diffraction, infrared and Raman spectroscopy in the same manner as in example 1, a UV purity of 98.85% and a bulk density of 0.38g/cm3。
Example 6:
adding 2.40g of dried furacilin alpha crystal form into 10ml of dimethyl sulfoxide, controlling the temperature at 45 ℃, stirring for 5min at 200rpm to dissolve, and filtering through a 0.22 mu m filter membrane to remove insoluble impurities. Adding water at 0.3ml/min for 5min to obtain crystal, and growing crystal for 25 min; adding water at 0.3ml/min for 30min, and growing crystal for 25 min; adding water at a rate of 0.6ml/min for 30min, and growing crystal for 25 min; adding water at a rate of 1.8ml/min for 30min, cooling to 10 deg.C for 110min, and growing crystal at 10 deg.C for 25 min; and (3) carrying out suction filtration on the feed liquid, washing twice with 8 ml/time of water, and drying the product at 70 ℃ and normal pressure to constant weight to obtain the gamma crystal furacilin.
The crystals obtained in this example were characterized by X-ray powder diffraction, infrared and Raman spectroscopy in the same manner as in example 1, a UV purity of 98.88% and a bulk density of 0.38g/cm3。
Example 7:
adding 2.40g of dried furacilin beta crystal form into 10ml of dimethyl sulfoxide, controlling the temperature at 50 ℃, stirring for 15min at 200rpm to dissolve, and filtering through a 0.22 mu m filter membrane to remove insoluble impurities. Adding 0.3ml/min ethanol for 25min to obtain crystal, and growing crystal for 20 min; adding 0.3ml/min ethanol for 30min, and growing crystal for 20 min; adding 0.6ml/min ethanol for 30min, and growing crystal for 20 min; adding ethanol at a concentration of 1.8ml/min for 30min, cooling to 5 deg.C for 100min, and growing crystal at 5 deg.C for 20 min; and (3) carrying out suction filtration on the feed liquid, washing twice with 9 ml/time of ethanol, and drying the product at 70 ℃ and normal pressure to constant weight to obtain the gamma crystal furacilin.
The crystals obtained in this example were characterized by X-ray powder diffraction, infrared and Raman spectroscopy in the same manner as in example 1, a UV purity of 98.85% and a bulk density of 0.38g/cm3。
Example 8:
adding 1.80g of dried furacilin alpha crystal form into 20ml of N, N-dimethylformamide, controlling the temperature at 45 ℃, stirring for 15min at 400rpm to dissolve the furacilin alpha crystal form, and filtering the mixture by a 0.22 mu m filter membrane to remove insoluble impurities. Adding methanol at 0.3ml/min for 30min until crystal appears, and growing crystal for 30 min; adding methanol at 0.3ml/min for 30min, and growing crystal for 30 min; adding methanol at 0.3ml/min for 30min, and growing crystal for 30 min; adding methanol at 0.3ml/min for 90min, cooling to 5 deg.C for 120min, and keeping constant temperature at 5 deg.C for crystal growth for 30 min; and (3) carrying out suction filtration on the feed liquid, washing twice with 7 ml/time of methanol, and drying the product at 60 ℃ under normal pressure to constant weight to obtain the gamma crystal furacilin.
The crystals obtained in this example were characterized by X-ray powder diffraction, infrared and Raman spectroscopy in the same manner as in example 1, and had a UV purity of 99.01% and a bulk density of 0.39g/cm3。
The preparation method of the furacilin gamma crystal form disclosed and proposed by the invention can be realized by appropriately changing links such as raw materials, process parameters and the like by taking the contents of the text as reference. While the methods and products of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and products described herein may be made and equivalents employed to practice the techniques of the present invention without departing from the spirit and scope of the invention. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and content of the invention.
Claims (2)
1. A preparation method of furacilin gamma crystal form is characterized by comprising the following steps:
(1) adding the furacilin crude product into a good solvent, controlling the temperature to be 30-50 ℃, stirring at 200-500 rpm until the furacilin crude product is dissolved clearly, and preparing into a solution with the concentration of 0.066-0.24 g/ml, wherein the use time is 5-30 min;
(2) filtering the solution with a 0.22 mu m filter membrane to remove insoluble impurities;
(3) dripping a poor solvent at the speed of 0.3-0.6 ml/min until crystal is produced, wherein the use time is 5-30 min, and the crystal growth is 20-30 min;
(4) dripping a poor solvent at the speed of 0.3-0.6 ml/min for 15-30 min, and growing the crystals for 20-30 min;
(5) dripping a poor solvent at the speed of 0.3-1.2 ml/min for 15-30 min, and growing the crystals for 20-30 min;
(6) dripping a poor solvent at the speed of 0.3-3.6 ml/min for 15-90 min, and growing the crystals for 20-30 min;
(7) cooling to 5-10 ℃ in 90-120 min, and growing the crystals for 20-30 min;
(8) carrying out suction filtration on the feed liquid, washing the feed liquid with a poor solvent twice for 7-9 ml/time, and drying a crystal product to constant weight;
the crude furacilin product is crystal form beta or crystal form alpha solid powder, and the purity of the crude furacilin product is more than or equal to 98 percent; the good solvent is one of N, N-dimethylformamide or dimethyl sulfoxide; the poor solvent is one of water, isopropanol, n-propanol, methanol, ethanol, acetonitrile or acetone.
2. The method according to claim 1, wherein the drying condition is a temperature of 50 to 80 ℃ and a normal pressure.
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| 5-Nitro-2-furaldehyde Semicarbazone;TOMASZ A. OLSZAK等;《Acta cryst.》;19941231;第C50卷;全文 * |
| New polymorphs of an old drug: conformational and synthon polymorphism of 5-nitrofurazone;Dorota Pogoda等;《Acta Cryst.》;20161231;第B72卷;全文 * |
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