CN117756798A - New crystal of ipratropium bromide and preparation method thereof - Google Patents
New crystal of ipratropium bromide and preparation method thereof Download PDFInfo
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of crystal form drug molecules, and particularly relates to a novel ipratropium bromide crystal and a preparation method thereof. The novel crystal of ipratropium bromide provided by the invention uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has diffraction peaks at 8.76+/-0.2 degrees, 10.26+/-0.2 degrees, 12.68+/-0.2 degrees, 13.75+/-0.2 degrees, 14.08+/-0.2 degrees, 15.23+/-0.2 degrees, 15.59+/-0.2 degrees, 17.21+/-0.2 degrees, 18.40+/-0.2 degrees, 20.30+/-0.2 degrees, 22.43+/-0.2 degrees, 25.11+/-0.2 degrees, 27.37+/-0.2 degrees and 29.04+/-0.2 degrees; the novel crystal of ipratropium bromide provided by the invention has excellent properties, excellent stability, solubility and lower moisture absorption and weight gain, and provides a high-quality raw material selection for the preparation production of ipratropium bromide.
Description
Technical Field
The invention belongs to the technical field of crystal form drug molecules, and particularly relates to a novel ipratropium bromide crystal and a preparation method thereof.
Background
Ipratropium bromide (Ipratropium Bromide), chemical name (8 r) -3 alpha-hydroxy-8-isopropyl-1 alpha H,5 alpha H-brominated tropine (±) -tropine acid salt, is a potent anticholinergic agent with higher selectivity for bronchial smooth muscle M receptors, developed by brinzhugline, approved for market in the united states in 1986 for the treatment of Chronic Obstructive Pulmonary Disease (COPD) and asthma exacerbations by inhalation administration, and also for the treatment and prevention of mild and moderate bronchial asthma, especially asthma accompanied by cardiovascular system diseases, in combination with albuterol. It is a white or off-white crystalline powder, CAS number: 22254-24-6, the chemical structural formula of which is shown as follows:
the different crystal forms of the medicine can influence the physicochemical properties of the medicine, directly influence the dissolution and absorption efficiency of the medicine under the physiological pH 7.4 condition, and further influence the bioavailability, clinical curative effect and the like of the medicine. The ipratropium bromide belongs to a multi-crystalline compound, different crystallization methods can produce different crystal forms, and different ipratropium bromide crystals have different stability, physical properties, solubility and the like, and the properties can directly influence the stability of bulk drugs and preparations and the preparation process of the preparations.
Numerous literature reports are currently available concerning ipratropium bromide, and studies concerning its preparation and its crystals have been reported, for example, in the literature (Journal of Pharmacy And Pharmacology,2012,64,1326-1336) by Jagdeep Shur et al, which reports the use of supercritical CO 2 A method for preparing anhydrous crystals of ipratropium bromide by separating solvent from solute in saturated solution of ipratropium bromide as antisolvent, and a method for preparing crystals of ipratropium bromide monohydrate by culturing appropriate amount of crystals from supersaturated solution of ipratropium bromide, screening a certain amount of crystals as seed crystals, adding the seed crystals into saturated solution of ipratropium bromide and crystallizing. However, the method for preparing the amorphous form requires the use of supercritical CO 2 And continuous high-pressure supply, high requirements on equipment are high, high-purity crystals are difficult to obtain stably, and the two methods are complex in operation steps and severe in conditions, and are not suitable for large-scale production. In addition, the literature does not make a detailed study on the stability, solubility and the like of the corresponding crystal forms of ipratropium bromide.
In addition, patent CN110845491a discloses a crystalline ipratropium bromide and a preparation method thereof: adding ipratropium bromide into benign solvent, slowly heating, stirring for dissolution, dropwise adding poor solvent after the solution is clarified, slowly reducing the temperature for crystallization, standing for crystallization after the temperature is reduced to a certain temperature, and filtering and drying to obtain the anhydrous crystal of ipratropium bromide. Patent CN110845492a discloses a method for preparing ipratropium bromide monohydrate: adding ipratropium bromide into benign solvent, slowly heating, stirring, dissolving, dripping a certain amount of purified water, after the solution is clarified, dripping poor solvent, slowly reducing the temperature for crystallization, reducing the temperature to a certain temperature, standing for crystallization, filtering and drying to obtain ipratropium bromide monohydrate. Patent CN113121522a discloses a crystalline ipratropium bromide and a preparation method thereof: mixing ipratropium bromide with purified water, heating for dissolving, naturally cooling, stirring for at least 1.5h, adding ethanol with mass fraction of more than 95%, cooling, filtering, and drying under reduced pressure to obtain ipratropium bromide crystal.
Researches show that the ipratropium bromide has the problems of poor chemical stability and easy deterioration, and the impurity content of the ipratropium bromide in a solution state can be increased along with the increase of the ambient temperature, so that the product purity and the preparation stability are greatly influenced, and the problem also brings a certain potential problem for the storage or the use of the ipratropium bromide. Although the stability and the solubility of the ipratropium bromide crystals prepared in the above patent are improved to a certain extent, in order to further reduce the generation of ipratropium bromide impurities and improve the stability and the bioavailability of the preparation, it is still necessary to further research and find ipratropium bromide crystals with more medicinal advantages, and a better basis is provided for the application of ipratropium bromide in the aspect of medicament treatment, so that the medicinal value of the ipratropium bromide is exerted more efficiently.
Disclosure of Invention
Based on the defects existing in the prior art, the invention provides a novel crystal of ipratropium bromide, which has better stability and lower moisture absorption and weight gain, and provides a high-quality raw material selection for the preparation production of ipratropium bromide.
The specific technical scheme of the invention is as follows:
in a first aspect, the present invention provides a novel crystal of ipratropium bromide having an X-ray diffraction pattern expressed in 2θ of at least 8.76±0.2°,10.26±0.2°,12.68±0.2°,13.75±0.2°,14.08±0.2°,15.23±0.2°,15.59±0.2°,17.21±0.2°,18.40±0.2°,20.30±0.2°,22.43±0.2°,25.11±0.2°,27.37±0.2°, and 29.04±0.2°.having characteristic peaks.
Preferably, the novel crystals of ipratropium bromide use Cu-K alpha radiation, the characteristic peaks of which have the X-ray powder diffraction pattern shown in figure 1.
Preferably, the novel crystals of ipratropium bromide have an endothermic peak in a Differential Scanning Calorimetry (DSC) curve of 247.61 ℃, and the crystals have a DSC-TGA spectrum as shown in FIG. 2.
The second aspect of the invention provides a preparation method of a novel crystal of ipratropium bromide, which comprises the following specific steps: adding ipratropium bromide into a mixed solvent of n-butyl alcohol and methanol, heating and stirring until the mixed solvent is completely dissolved, cooling and crystallizing, filtering and drying to obtain new crystals of ipratropium bromide.
Preferably, the mass volume ratio of the ipratropium bromide to the n-butyl alcohol is 1:3 to 5 g/ml, preferably: 1:4, g/ml.
Preferably, the volume ratio of the methanol to the n-butanol is 1:1 to 3, preferably: 1:2.
preferably, the heating dissolution temperature is 60 to 75 ℃, preferably 68 to 72 ℃.
Preferably, the cooling speed is 0-5 ℃/h.
Preferably, the crystallization temperature is 20 to 30 ℃, preferably 20 to 25 ℃.
Preferably, the crystallization time is 3 to 6 hours, preferably 3 to 4 hours.
Preferably, the drying mode is vacuum drying, the drying temperature is 50-70 ℃, and the drying time is 5-8 h.
In a third aspect the present invention provides the use of a novel crystal of ipratropium bromide as defined in the present invention as an active ingredient in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease and asthma.
In a fourth aspect, the present invention provides a pharmaceutical composition comprising ipratropium bromide crystals according to the present invention admixed with other pharmaceutically acceptable components.
Preferably, the pharmaceutical composition is prepared as follows: the compounds of the present invention are formulated into useful dosage forms by combining them with pharmaceutically acceptable solid or liquid carriers, and optionally with pharmaceutically acceptable adjuvants and excipients, using standard and conventional techniques.
Preferably, the other pharmaceutically acceptable components include other active ingredients, excipients, fillers, and the like, which may be used in combination.
Preferably, the pharmaceutical composition is an inhalant, a tablet, a capsule, a solution, an injection, or the like.
Compared with the prior art, the novel crystal of ipratropium bromide provided by the invention has excellent chemical stability and solubility, and animal experiments prove that the novel crystal of ipratropium bromide provided by the invention has better treatment effect on rats with COPD model, and the invention provides a high-quality raw material selection for preparation production of ipratropium bromide. And secondly, the preparation method of the novel ipratropium bromide crystal provided by the invention is simple to operate, mild in condition, capable of preparing a target product with high yield and high purity, better applicable to pharmaceutical preparations and large-scale production, and wide in application prospect.
Drawings
Fig. 1: x-ray powder diffraction pattern of new crystals of ipratropium bromide.
Fig. 2: DSC-TGA spectrum of the new crystals of ipratropium bromide.
Detailed Description
The foregoing of the invention is further described in detail by the following detailed description of the invention, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed. The present invention generally and/or specifically describes the materials used in the test as well as the test methods.
The raw material ipratropium bromide (the purity is 80% -100%) can be prepared according to any method in the prior art or purchased from a commercial product, other reagent materials are commercially available, and the water content of methanol and n-butanol in the embodiment is 0.5% -1%.
Crystal structure confirmation:
x-ray powder diffraction test instrument and test conditions: x-ray powder diffractometer: PANalytical Emprem; cu-K alpha; sample stage: a flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40mA; divergence slit: 1/4; anti-scatter slit: 1, a step of; a cable pull slit: 0.04rad; step size: 0.5s; scanning range: 3 to 50 (° 2θ). According to the crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in the accompanying figure 1 and the table 2.
TABLE 1 major XRPD peaks for novel crystals of ipratropium bromide
The samples prepared in examples 1 to 3 of the present invention all conform to the X-ray powder diffraction pattern.
Example 1
Adding ipratropium bromide (10.0 g, purity 95%) into a mixed solvent of n-butyl alcohol/methanol (V: V=2:1, ml/ml,60 ml), controlling the temperature to 68-72 ℃, stirring until the material liquid is dissolved, cooling to 20-25 ℃ at a cooling rate of 0-5 ℃/h, stirring and crystallizing for 3-4 h, filtering, and drying a filter cake at 60-70 ℃ under reduced pressure for 5-6 h to obtain ipratropium bromide crystals with the yield of 93.3% and the purity of 99.97%.
Example 2
Adding ipratropium bromide (10.0 g, purity 90%) into a mixed solvent of n-butyl alcohol/methanol (V: V=1:1, ml/ml,60 ml), controlling the temperature to be 60-65 ℃, stirring until the material liquid is dissolved, cooling to 20-25 ℃ at the cooling rate of 0-5 ℃/h, stirring and crystallizing for 4-5 h, filtering, and drying a filter cake at 50-60 ℃ under reduced pressure for 7-8 h to obtain ipratropium bromide crystals with the yield of 88.6% and the purity of 99.94%.
Example 3
Adding ipratropium bromide (10.0 g, purity 85%) into a mixed solvent of n-butyl alcohol/methanol (V: V=3:1, ml/ml,60 ml), controlling the temperature to be 70-75 ℃, stirring until the material liquid is dissolved, cooling to 25-30 ℃ at the cooling rate of 0-5 ℃/h, stirring and crystallizing for 5-6 h, filtering, and drying a filter cake at 60-70 ℃ under reduced pressure for 5-6 h to obtain ipratropium bromide crystals with the yield of 82.8% and the purity of 99.93%.
Comparative example 1
1g of ipratropium bromide (purity 90%) was added to 20ml of N, N-dimethylformamide, heated to 50℃and dissolved with stirring and 1.5ml of purified water was added dropwise to obtain a clear solution; slowly dripping 20ml of tetrahydrofuran into the clear solution for 30 minutes, stirring, cooling and crystallizing (controlling the cooling speed to be 0.5 ℃/min), cooling to 5-15 ℃, standing and crystallizing for 48 hours at a controlled temperature, filtering, and vacuum drying for 10 hours at 50 ℃ to obtain the ipratropium bromide monohydrate, wherein the yield is 83.6% and 99.91%.
Comparative example 2
2g of ipratropium bromide (purity 90%) was added to 40ml of N, N-dimethylformamide, heated to 50℃and dissolved with stirring to obtain a clear solution; slowly dripping 40ml tetrahydrofuran into the clear solution for 30 minutes, stirring, cooling and crystallizing (controlling the cooling speed to be 0.3 ℃/min), cooling to 5-10 ℃, standing and crystallizing for 48 hours at the controlled temperature, filtering, and vacuum drying for 18 hours at 70 ℃ to obtain the ipratropium bromide crystal with the yield of 80.9% and the purity of 99.90%.
Comparative example 3
10g of ipratropium bromide (purity 90%) is added into 30ml of purified water, stirring is started, heating is carried out until the ipratropium bromide is completely dissolved at 60 ℃, then natural cooling is carried out to 30 ℃, stirring is carried out for 2 hours, then 120ml of absolute ethyl alcohol (1.5 hours is added) is slowly added under stirring, after the addition is finished, cooling is carried out to 5 ℃ within 1 hour, crystallization is carried out for 3.5 hours at 5 ℃, filtration is carried out, and drying is carried out at 60 ℃ under reduced pressure (-0.09 MPa, standard atmospheric pressure is 0), thus obtaining ipratropium bromide crystals with the yield of 84.1% and 99.93%.
Comparative example 4
50g (0.3 mol) of tolmetic acid and 59g (0.75 mol 1) of acetyl chloride are added into a reaction bottle, the temperature is kept between 20 and 30 ℃ for reaction for 2 hours, and the reaction solution is concentrated to dryness under reduced pressure to obtain colorless oily matter 1 which can be directly used for the next reaction.
60g (0.29 mol) of the colorless oily substance 1 and 180ml of thionyl chloride were added to the reaction flask, the mixture was stirred at 50 to 60℃for 2 hours, the reaction solution was concentrated to dryness under reduced pressure, 100ml of toluene was added to the concentrate, and then concentrated to dryness under reduced pressure to give colorless oily substance 2, which was used directly in the next reaction.
500ml of methylene chloride is added into a reaction bottle, 48.5g (0.29 mol) of isopropyl tropine is added, 32.7g (0.29 mol) of trifluoroacetic acid is added, stirring reaction is carried out for 0.5 hour, 65g (0.29 mol) of colorless oily substance 2 is added, reaction is carried out for 24 hours at 30-40 ℃, 300ml of water is added into the reaction liquid, 1N sodium hydroxide solution is used for adjusting pH to be 10-11, an organic phase and an aqueous phase are separated, 100ml of methylene chloride is used for extraction, the organic phases are combined, and reduced pressure concentration is carried out until dryness is achieved, thus obtaining yellow brown oily substance 3 which can be directly used for the next reaction.
500ml of absolute methanol was added to the reaction flask, 95g (0.26 mo 1) of oily substance 3 was added, 5.7g (0.11 mol) of sodium methoxide was added, the reaction was stirred at 40 to 50℃for 5 hours, the reaction solution was concentrated to dryness under reduced pressure, 200ml of water and 400ml of methylene chloride were added to the concentrate, a methylene chloride layer and a water layer were separated, the water layer was washed with 200ml of methylene chloride, the methylene chloride layers were combined, concentrated to dryness under reduced pressure, the concentrate was recrystallized with 200ml of acetone, and white solid 4 was obtained after drying, which was 95.16% pure and was directly used for the next reaction.
700ml of absolute ethyl alcohol is added into a reaction kettle, 70g (0.22 mol) of white solid 4 is added, the mixture is cooled to 0-5 ℃, 42g (0.44 mo 1) of bromomethane with the temperature reduced to-5 ℃ is added, the mixture is immediately sealed after the bromomethane is added, the temperature is raised to 40-50 ℃ for reaction for 8 hours, the reaction solution is decompressed and concentrated to 100ml, the temperature is reduced to 5-10 ℃ for crystallization, the filtration and the decompression and drying at 60 ℃ are carried out, and 79.6 white solid is obtained, namely ipratropium bromide with the purity of 98.25 percent.
Comparative example 5
White solid 4 (1.0 g), chloroform (10 mL) and tetrahydrofuran (5 mL) prepared in the comparative example 4 are sequentially added into a reaction bottle, the temperature is reduced to 0 ℃, bromomethane (0.9 g) is added, T=0-10 ℃ is reacted for 15h, suction filtration and drying are carried out, and ipratropium bromide is obtained, the yield is 39.7%, and the purity is 96.88%.
Comparative example 6
10g of ipratropium bromide (purity 90%) was taken and added to ethanol: 20ml of a mixed solution with water=7:3, stirring for 3 hours at 30-40 ℃, cooling to 0-5 ℃, slowly stirring for 3 hours, filtering, and drying to obtain the ipratropium bromide with the yield of 78.8% and the purity of 97.53%.
Verification embodiment
1. Stability test
(1) Influence factor test: the stability of each crystal under the conditions of light (5000 Lx), high temperature (60 ℃) and high humidity (92.5%) was tested by using an HPLC method, and the specific test results are shown in Table 1 by referring to the guidance method of the fourth section on stability study of the Chinese pharmacopoeia 2015.
TABLE 1 stability test results of ipratropium bromide crystals influencing factors
The stability test results of examples 1 to 3 of the present invention are basically consistent with the results of example 2 in table 1, and the data in table 1 show that the purity and appearance of the ipratropium bromide crystals prepared by the present invention are not significantly changed under the conditions of light irradiation, high temperature and high humidity, so that the samples prepared by the present invention have good chemical stability.
(2) Acceleration test: the ipratropium bromide crystals prepared in example 2 and comparative examples 1 to 6 were placed at a temperature of 40.+ -. 2 ℃ and a relative humidity of 75.+ -. 5%, and were sampled and tested at the end of month 1, 2, 3 and 6 to examine their respective stability, and the purity was tested by HPLC method, and the moisture absorption gain (W%) under the conditions was examined, and the test results are shown in Table 2.
TABLE 2 accelerated test results of ipratropium bromide crystals
The stability test results of the examples 1-3 are basically consistent with the results recorded in the example 2 in the table 2, and the data in the table 2 show that the ipratropium bromide crystal prepared by the invention has no obvious change in purity of the sample and no obvious moisture absorption and weight increase phenomenon after the stability test for 6 months, which indicates that the ipratropium bromide crystal provided by the invention has stable form, good chemical stability and lower moisture absorption and weight increase.
2. Solubility test
The solubility of example 2 and comparative examples 1 to 6 in water and solutions of different pH were measured, respectively. 10ml of medium (water, 0.01mol/L HCl solution) is respectively measured in a penicillin bottle, excessive medicine is added, the penicillin bottle is sealed and placed in a constant temperature water bath at 25 ℃ for stirring for 1 hour, the mixture is filtered by a 0.45 mu m filter membrane, the absorbance of the filtrate is respectively measured at the wavelength of 257nm, and the solubility of the filtrate is calculated by testing the absorbance of a standard reference substance.
TABLE 3 solubility of ipratropium bromide in various media (mg/ml)
The results of the solubility tests of examples 1 to 3 of the present invention are substantially identical to those of example 2 in Table 3, and as can be seen from the data in Table 3, the solubility of the ipratropium bromide crystals prepared in accordance with the present invention in water and in 0.01mol/L HCl solution is significantly improved compared with the crystal forms described in the prior art.
3. Rat model test
(1) The experimental method comprises the following steps: 72 SD rats (220+ -20 g) were taken and each half of the male and female rats were divided into 9 groups: model group, treatment group×7, control group (8 each, male and female halves). Wherein the model group and the treatment group adopt a compound stimulation method for continuously smoking for 8 weeks and instilling Lipopolysaccharide (LPS) into the trachea twice to prepare a COPD rat model (refer to Song Yiping and the like. The establishment of a COPD rat model and the influence of drug intervention [ J ]. J.Chinese medical journal 2000,39 (8): 51-52, 73-74). The following day after cessation of smoking for each treatment group was treated with ipratropium bromide by atomization as prepared in example 2 and comparative examples 1-6, respectively, by the method of: rats were placed in a 30L sealed box and inhaled with an ultrasonic nebulizer 4ml of 0.025% ipratropium bromide solution 2 times/d for 4 weeks without treatment in the control and model groups. The model group and the control group were subjected to index detection the next day after the end of smoking, and rats of each treatment group were subjected to index detection the next day after 4 weeks of treatment.
(2) Detecting the index: (1) lung function assay: reference Wang Cuiru et al effects of lung tonifying Capsule on pulmonary function and arterial blood gas in rats with chronic obstructive pulmonary disease model [ J ]]The method described in Shizhen national medicine, 2012,23 (1): 104-106, calculates the Forced Expiratory Volume (FEV) of 0.3 seconds 0.3 ) FEV (FEV) 0.3 Percentage of vital capacity (FEV) 0.3 FVC), the specific data are shown in table 4; (2) IL-8, IL-10, TNF- α level assay: whole blood is extracted from the artery cannula, the blood serum is separated by centrifugation (3000 r/min, 20 min) after standing for 20min at room temperature, the blood serum is frozen at-20 ℃, the IL-8, IL-10 and TNF-alpha levels are detected by ELISA, and specific data are shown in Table 5.
Table 4 results of lung function measurements for each group
As can be seen from Table 4, the model FEV is compared with the control group 0.3 、FEV 0.3 FVC is significantly reduced; FEV of each treatment group compared to model group 0.3 、FEV 0.3 FVC is elevated; but the treatment effect of the treatment group of the example 2 is obviously better than that of the treatment group of each comparative example, and the ipratropium bromide crystal provided by the invention has better protection effect on lung function.
Table 5 serum IL-8, IL-10, TNF- α levels were measured for each group (ng/L,)
| group of | IL-8 | IL-10 | TNF-α |
| Control group | 374.05±8.81 | 288.37±7.19 | 60.04±3.62 |
| Model group | 503.26±7.40 | 350.13±7.68 | 35.54±3.39 |
| Example 2 | 380.11±7.09 | 290.00±4.25 | 58.28±2.56 |
| Comparative example 1 | 388.43±8.52 | 301.36±6.65 | 53.50±3.12 |
| Comparative example 2 | 388.80±8.75 | 302.87±7.04 | 52.79±3.48 |
| Comparative example 3 | 386.92±7.88 | 297.25±6.33 | 55.06±3.20 |
| Comparative example 4 | 390.55±7.60 | 305.10±5.76 | 52.27±2.95 |
| Comparative example 5 | 393.04±8.61 | 311.03±7.80 | 49.83±3.66 |
| Comparative example 6 | 391.10±8.24 | 306.84±6.97 | 52.09±3.47 |
As can be seen from Table 5, the IL-8 and TNF- α levels in the model group were significantly increased and the IL-10 levels in the model group were significantly decreased as compared with the control group; IL-8 and TNF- α levels were reduced and IL-10 levels were increased in each treatment group compared to the model group; however, the effect of the treatment group of example 2 on reducing IL-8 and TNF-alpha and increasing IL-10 is most remarkable, and the effect of the treatment group of example 2 on reducing IL-8 and TNF-alpha reaches a similar level with the control group, so that the effect of the ipratropium bromide crystal provided by the invention on protecting the lung function of COPD rats is superior to that of each treatment group of comparative examples.
Claims (10)
1. A novel crystal of ipratropium bromide, characterized in that the X-ray diffraction pattern expressed in 2Θ has characteristic peaks at 8.76±0.2°,10.26±0.2°,12.68±0.2°,13.75±0.2°,14.08±0.2°,15.23±0.2°,15.59±0.2°,17.21±0.2°,18.40±0.2°,20.30±0.2°,22.43±0.2°,25.11±0.2°,27.37±0.2°,29.04±0.2°, using Cu-ka radiation.
2. The novel crystal of ipratropium bromide according to claim 1, wherein the characteristic peak has an X-ray powder diffraction pattern as shown in fig. 1.
3. The novel crystal of ipratropium bromide according to claim 1, wherein said crystal is present in the DSC-TGA profile shown in figure 2.
4. A process for the preparation of a novel crystal of ipratropium bromide according to any one of claims 1-3, comprising the specific steps of: adding ipratropium bromide into a mixed solvent of n-butyl alcohol and methanol, heating and stirring until the mixed solvent is completely dissolved, cooling and crystallizing, filtering and drying to obtain new crystals of ipratropium bromide.
5. The preparation method according to claim 4, wherein the mass-to-volume ratio of ipratropium bromide to n-butanol is 1: 3-5 g/ml.
6. The method according to claim 4, wherein the volume ratio of methanol to n-butanol is 1:1 to 3.
7. The method according to claim 4, wherein the heating and dissolving temperature is 60 to 75 ℃.
8. The method according to claim 4, wherein the crystallization temperature is 20 to 30 ℃.
9. The method according to claim 4, wherein the crystallization time is 3 to 6 hours.
10. A pharmaceutical composition comprising a novel crystal of ipratropium bromide according to any one of claims 1-3 admixed with other pharmaceutically acceptable components.
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