A process for the preparation of beta crystalline amikacin

Abstract

The application provides a method for preparing a beta crystal form of amikacin, comprising the following steps: (1) dissolving an alpha crystal form of amikacin in anhydrous ethanol or a mixed solution of anhydrous ethanol and acetone, and obtaining a beta crystal form of amikacin wet product through recrystallization; and (2) drying the beta crystal form of amikacin wet product in a drying device with a relative humidity of 70% to 100% at 40 to 70 DEG C under normal pressure for 2 to 10 hours or under vacuum for 2 to 18 hours, so as to obtain a beta crystal form of amikacin with an ethanol content of less than 0.5% by weight. In the application, by controlling the humidity of the drying environment when the product is dried, the ethanol can be effectively removed while the moisture content of the amikacin wet product is maintained, so as to reduce the ethanol content of the amikacin product, meet the requirement of the ICH guideline Q3C that the ethanol content is not more than 0.5% by weight, and greatly improve the safety of amikacin clinical medication.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemicals, and more specifically to a method for preparing β-crystal aztreonam with low ethanol content. Background Technology

[0002] Aztreonam is a synthetic monocyclic β-lactam antibiotic with antibacterial activity against Gram-negative bacteria.

[0003]

[0004] Molecular formula: C 13 H 17 Molecular weight of N5O8S2: 435.43

[0005] Several references report on the preparation techniques of aztreonam, such as US patents US4,775,670 and US5,194,606. Aztreonam is polymorphic; US patent US4,826,973 reports four different aztreonam crystals: α, β, γ, and δ. The α crystal is a hydrous crystal, typically containing 7-15% water, and has poor stability. Therefore, it should be converted to the β crystal, which is anhydrous, non-hygroscopic, and has good flowability, a smaller surface area, and better stability, making it more suitable for pharmaceutical use. However, the β crystal typically contains about 2.5% ethanol, exceeding the 0.5% by weight requirement of the ICH guidelines.

[0006] US Patent 4,946,838 discloses a method for preparing β-crystal aztreonam, which involves adding α-crystal crystals to anhydrous ethanol at 55-60°C for crystallization. Under these conditions, the α-crystal can temporarily dissolve in ethanol, and then precipitate crystals to form β-crystal aztreonam. The resulting β-crystal typically has an ethanol content of about 2.5%, far exceeding the ICH guideline standard requirement of no more than 0.5% by weight.

[0007] US Patent 7,452,991B2 reports a method for preparing β-crystalline aztreonam with low ethanol content, which involves crystallizing at a low temperature of -60 to 5°C under rapid stirring (500-700 rpm) to obtain β-crystalline aztreonam with an ethanol content of less than 2.5%. However, the reaction temperature and stirring speed of this method are too low and too fast, which cannot meet the requirements for production and therefore cannot be used for large-scale industrial production.

[0008] CN101195618A discloses a method for producing β-crystalline anhydrous aztreonam, which reduces the ethanol content in the product β-crystalline aztreonam by crystallizing the filtered solution at a lower temperature, i.e., by lowering the crystallization temperature. Summary of the Invention

[0009] The following is an overview of the subject matter described in detail herein. This overview is not intended to limit the scope of protection of this application.

[0010] This application provides a method for preparing β-crystalline aztreonam. In this application, by controlling the humidity of the drying environment during the drying of the wet β-crystalline aztreonam, a certain moisture content is maintained in the wet β-crystalline aztreonam, enabling the effective removal of ethanol and thus reducing the ethanol content in the β-crystalline aztreonam product to meet the ICH Guideline Q3C requirement of an ethanol content not exceeding 0.5% by weight. Therefore, this application enables large-scale industrial production of β-crystalline aztreonam with an ethanol content below 0.5% by weight.

[0011] This application provides a method for preparing β-crystalline aztreonam, comprising the following steps:

[0012] (1) Dissolve α-crystal aztreonam in anhydrous ethanol or a mixture of anhydrous ethanol and acetone, and recrystallize to obtain β-crystal aztreonam wet product; and

[0013] (2) The β-crystal aztreonam wet product is dried in a drying device with a relative humidity of 70%-100% at 40℃-70℃ under normal pressure for 2-10 hours or under vacuum for 2-18 hours to obtain β-crystal aztreonam with an ethanol content of less than 0.5% by weight.

[0014] In the embodiments of this application, in step (2), the relative humidity in the dryer is controlled to be 70%-100% by ultrasonic humidification or by humidification through a shallow water tray.

[0015] In the embodiments of this application, in step (2), the drying equipment is a rotary vacuum dryer or an atmospheric pressure drying oven.

[0016] In the embodiments of this application, in step (2), the atmospheric pressure drying temperature is 50℃-70℃, preferably 60℃-70℃.

[0017] In the embodiments of this application, in step (2), the vacuum drying temperature is 40℃-70℃, preferably 40℃-50℃.

[0018] In the embodiments of this application, in step (2), the relative humidity inside the drying equipment is maintained at 70%-100%, preferably 80%-100%.

[0019] In the embodiments of this application, in step (2), the β-crystalline aztreonam wet product is dried under rotary vacuum dryer at 40℃-70℃ for 1-3 hours. Then, under normal pressure, the humidity inside the dryer is humidified to 80%-100% for 30 minutes to 1 hour. Humidification is stopped, and then rotary vacuum drying is performed for 1-3 hours. This process is repeated more than twice. Finally, rotary vacuum drying is performed for 1-3 hours to obtain β-crystalline aztreonam with an ethanol content of less than 0.5% by weight.

[0020] In the embodiments of this application, in step (1), α-crystalline aztreonam is dissolved in anhydrous ethanol or a mixed solution of anhydrous ethanol and acetone at 1-10°C, stirred for 1-3 hours, then heated to 30°C-35°C to crystallize for 2-3 hours, filtered, and β-crystalline aztreonam wet product is obtained.

[0021] In the embodiments of this application, in step (1), when using a mixed solution of anhydrous ethanol and acetone, the volume ratio of anhydrous ethanol to acetone is 5:1 to 2:1, preferably 3:1 to 2:1.

[0022] The α-crystal aztreonam used in this application can be prepared using known methods, such as those disclosed in CN1681812A, US Patent 5,194,604, etc., or can be commercially available.

[0023] In this application, by humidifying the wet β-crystal aztreonam during the drying process, a certain amount of moisture is added simultaneously with the drying of the wet product, ensuring that the ethanol content is dried to no more than 0.5% by weight. That is, this application controls the moisture content of β-crystal aztreonam during the drying process, thereby drying out the ethanol from the wet β-crystal aztreonam. This application solves the problem of high ethanol content in β-crystal aztreonam products from the perspective of large-scale industrial production, ensuring that the ethanol content meets the ICH Guideline Q3C requirement of no more than 0.5% by weight.

[0024] Other features and advantages of this application will be set forth in the following description, and will be apparent in part from the description, or may be learned by practicing the application. Other advantages of this application may be realized and obtained by means of the methods described in the description. Attached Figure Description

[0025] Figure 1 This is a chromatogram of the residual ethanol test sample in β-crystal aztreonam obtained according to Example 1 of this application.

[0026] Figure 2 This is a chromatogram of the residual ethanol test sample in β-crystal aztreonam obtained according to Example 2 of this application.

[0027] Figure 3 This is a chromatogram of the residual ethanol test sample in β-crystal aztreonam obtained according to Example 3 of this application.

[0028] Figure 4 This is a chromatogram of the residual ethanol test sample in β-crystal aztreonam obtained according to Example 4 of this application.

[0029] Figure 5 This is a chromatogram of the residual ethanol test sample in β-crystal aztreonam obtained according to Example 5 of this application.

[0030] Figure 6 The chromatogram is of the residual ethanol sample in β-crystal aztreonam obtained according to Comparative Example 1 of this application.

[0031] Figure 7 The chromatogram is of the residual ethanol sample in β-crystal aztreonam obtained according to Comparative Example 2 of this application. Detailed Implementation

[0032] To make the objectives, technical solutions, and advantages of this application clearer, the embodiments of this application will be described in detail below. It should be noted that, unless otherwise specified, the embodiments and features described in these embodiments can be arbitrarily combined with each other.

[0033] The present invention is illustrated by non-limiting examples. The method for determining the ethanol content is as follows: a flame ionization detector is used as the detector; a capillary packed column with 6% cyanopropylphenyl and 94% dimethylsiloxane as the stationary phase is used as the chromatographic column; the injection port temperature is 150°C; the column temperature is maintained at 60°C for 3 minutes; the temperature is then increased to 180°C at a rate of 25°C per minute and maintained for 4 minutes; the detector temperature is 250°C; the carrier gas flow rate is 2.0 ml / min (nitrogen); the split ratio is 20:1; and a solution containing 500 μg / ml of ethanol is prepared using dimethyl sulfoxide as the solvent as the reference solution. 1 g of the sample is dissolved and diluted to 10 ml with dimethyl sulfoxide to prepare the test solution. 0.5 μL each of the test solution and the reference solution are accurately measured and injected into the gas chromatograph; the chromatograms are recorded; and the ethanol content is calculated by peak area using the external standard method.

[0034] The α-crystalline aztreonam used in the embodiments and comparative examples of this application can be prepared by known methods, such as those disclosed in CN1681812A, US Patent 5,194,604, etc., or can be commercially available.

[0035] Example 1

[0036] In a glass reactor, 20 g of α-crystalline aztreonam was added to 80 ml of anhydrous ethanol solution pre-cooled to 1-10 °C, stirred to dissolve, filtered, and the filtrate was transferred to 120 ml of anhydrous ethanol solution pre-heated to 30-35 °C. The mixture was stirred at 30-35 °C for 3 hours to induce crystallization, filtered, and the filter cake was washed with anhydrous ethanol to obtain wet β-crystalline aztreonam. The wet β-crystalline aztreonam was transferred to a forced-air drying oven and dried at 50 °C for 8 hours. During the drying process, the relative humidity inside the drying oven was maintained at 70-100% using a humidifier. Humidification was stopped, and forced-air drying continued for 2 hours to obtain 14.5 g of the product. X-ray powder diffraction confirmed the presence of β-crystalline aztreonam.

[0037] According to the above-described method for determining ethanol content, the chromatogram of the residual ethanol sample in β-crystalline aztreonam was obtained in... Figure 1 As shown in the figure, the ethanol content, calculated by peak area using the external standard method, is 0.42%.

[0038] Example 2

[0039] In a glass reactor, 20 g of α-crystalline aztreonam was added to 80 ml of a mixture of anhydrous ethanol and acetone (volume ratio 3:1) pre-cooled to 1-10 °C. The mixture was stirred to dissolve, filtered, and the filtrate was transferred to 120 ml of a mixture of anhydrous ethanol and acetone (volume ratio 3:1) pre-heated to 30-35 °C. The mixture was stirred at 30-35 °C for 3 hours to allow crystallization. The mixture was then filtered, and the filter cake was washed with anhydrous ethanol to obtain wet β-crystalline aztreonam. The wet β-crystalline aztreonam was transferred to a forced-air drying oven and dried at 70 °C for 5 hours. During drying, the relative humidity inside the drying oven was maintained at 70%-100% using a humidifier. Humidification was stopped, and forced-air drying continued for 2 hours to obtain 14.5 g of the product. X-ray powder diffraction confirmed the presence of β-crystalline aztreonam.

[0040] According to the above-described method for determining ethanol content, the chromatogram of the residual ethanol sample in β-crystalline aztreonam was obtained in... Figure 2 As shown in the figure, the ethanol content, calculated by peak area using the external standard method, is 0.37%.

[0041] Example 3

[0042] In a glass reactor, 20 g of α-crystalline aztreonam was added to 80 ml of anhydrous ethanol solution pre-cooled to 1-10 °C, stirred to dissolve, filtered, and the filtrate was transferred to 120 ml of anhydrous ethanol solution pre-heated to 30-35 °C. The mixture was stirred at 30-35 °C for 3 hours to induce crystallization, filtered, and the filter cake was washed with anhydrous ethanol to obtain wet β-crystalline aztreonam. The wet β-crystalline aztreonam was transferred to a rotary vacuum dryer and dried under vacuum at 40 °C for 2 hours, then the vacuum was removed. Humidification was then applied using a humidifier to maintain a relative humidity of 80%-100% inside the dryer, and the dryer was dried under vacuum for 1 hour while humidifying. Humidification was stopped, and the dryer was dried under vacuum for another 2 hours. This cycle of humidification was repeated 5 times, followed by vacuum drying for 2 hours to obtain 14.9 g of product. X-ray powder diffraction confirmed the presence of β-crystalline aztreonam.

[0043] According to the above-described method for determining ethanol content, the chromatogram of the residual ethanol sample in β-crystalline aztreonam was obtained in... Figure 3 As shown in the figure, the ethanol content, calculated by peak area using the external standard method, is 0.44%.

[0044] Example 4

[0045] In a glass reactor, 20 g of α-crystalline aztreonam was added to 80 ml of anhydrous ethanol solution pre-cooled to 1-10 °C, stirred to dissolve, filtered, and the filtrate was transferred to 120 ml of anhydrous ethanol solution pre-heated to 30-35 °C. The mixture was stirred at 30-35 °C for 3 hours to induce crystallization, filtered, and the filter cake was washed with anhydrous ethanol to obtain β-crystalline aztreonam wet product. The β-crystalline aztreonam wet product was transferred to a rotary vacuum dryer and dried under vacuum at 50 °C for 2 hours, then the vacuum was removed. Humidification was then applied using a humidifier to maintain a relative humidity of 80%-100% inside the dryer, and the dryer was rotated and dried for 30 minutes while humidifying. Humidification was stopped, and the dryer was rotated and dried under vacuum for another 2 hours. This humidification cycle was repeated four times, followed by vacuum drying for a final 2 hours to obtain 14.6 g of product. X-ray powder diffraction confirmed the presence of β-crystalline aztreonam.

[0046] According to the above-described method for determining ethanol content, the chromatogram of the residual ethanol sample in β-crystalline aztreonam was obtained in... Figure 4 As shown in the figure, the ethanol content, calculated by peak area using the external standard method, is 0.35%.

[0047] Example 5

[0048] In a glass reactor, 20 g of α-crystalline aztreonam was added to 80 ml of a mixture of anhydrous ethanol and acetone (volume ratio 3:1) pre-cooled to 1-10 °C. The mixture was stirred to dissolve, filtered, and the filtrate was transferred to 120 ml of a mixture of anhydrous ethanol and acetone (volume ratio 3:1) pre-heated to 30-35 °C. The mixture was stirred at 30-35 °C for 3 hours to induce crystallization. The mixture was then filtered, and the filter cake was washed with anhydrous ethanol to obtain wet β-crystalline aztreonam. The wet β-crystalline aztreonam was transferred to a rotary vacuum dryer and dried under vacuum at 60 °C for 1 hour. The vacuum was then released. Humidification was applied using a humidifier to maintain a relative humidity of 80%-100% inside the dryer, and the dryer was dried under vacuum for 1 hour while humidifying. Humidification was stopped, and the dryer was dried under vacuum for another 2 hours. This cycle of humidification was repeated four times, followed by vacuum drying for a final 2 hours to obtain 14.4 g of product. X-ray powder diffraction confirmed the presence of β-crystalline aztreonam.

[0049] According to the above-described method for determining ethanol content, the chromatogram of the residual ethanol sample in β-crystalline aztreonam was obtained in... Figure 5 As shown in the figure, the ethanol content, calculated by peak area using the external standard method, is 0.40%.

[0050] Comparative Example 1

[0051] In a glass reactor, 20 g of α-crystal aztreonam was added to 80 ml of anhydrous ethanol solution pre-cooled to 1-10 °C, stirred to dissolve, filtered, and the filtrate was transferred to 120 ml of anhydrous ethanol solution pre-heated to 30-35 °C. The mixture was stirred at 30-35 °C for 3 hours to induce crystallization, filtered, and the filter cake was washed with anhydrous ethanol to obtain wet β-crystal aztreonam. The wet β-crystal aztreonam was transferred to a forced-air drying oven and dried at 60 °C for 12 hours to obtain 14.8 g of product. X-ray powder diffraction confirmed the presence of β-crystal aztreonam.

[0052] According to the above-described method for determining ethanol content, the chromatogram of the residual ethanol sample in β-crystalline aztreonam was obtained in... Figure 6 As shown in the figure, the ethanol content, calculated by peak area using the external standard method, is 2.3%.

[0053] Comparative Example 2

[0054] In a glass reactor, 20 g of α-crystalline aztreonam was added to 80 ml of a mixture of anhydrous ethanol and acetone (3:1) pre-cooled to 1-10 °C, stirred to dissolve, filtered, and the filtrate was transferred to 120 ml of a mixture of anhydrous ethanol and acetone (3:1) pre-heated to 30-35 °C. The mixture was stirred at 30-35 °C for 3 hours to induce crystallization, filtered, and the filter cake was washed with anhydrous ethanol to obtain wet β-crystalline aztreonam. The wet β-crystalline aztreonam was transferred to a rotary vacuum dryer and dried under rotary vacuum at 50 °C for 12 hours to obtain 14.5 g of product. X-ray powder diffraction confirmed the presence of β-crystalline aztreonam.

[0055] According to the above-described method for determining ethanol content, the chromatogram of the residual ethanol sample in β-crystalline aztreonam was obtained in... Figure 7 As shown in the figure, the ethanol content, calculated by peak area using the external standard method, is 1.7%.

[0056] Although the embodiments disclosed in this application are as described above, the content described is merely for the purpose of understanding this application and is not intended to limit this application. Any person skilled in the art to which this application pertains may make any modifications and changes in the form and details of the implementation without departing from the spirit and scope disclosed in this application; however, the scope of patent protection of this application shall still be determined by the scope defined in the appended claims.

Claims

1. A method for preparing β-crystal aztreonam, characterized in that, Includes the following steps: (1) Dissolve α-crystal aztreonam in anhydrous ethanol or a mixed solution of anhydrous ethanol and acetone, and recrystallize to obtain β-crystal aztreonam wet product; as well as (2) The β-crystalline aztreonam wet product is dried in a drying device with a relative humidity of 70%-100% at 40-70°C and normal pressure for 2-10 hours, or The β-crystalline aztreonam wet product is dried under rotary vacuum in a rotary vacuum dryer for 1-3 hours at 40-70°C. Then, under normal pressure, the relative humidity inside the dryer is increased to 80%-100% for 30 minutes to 1 hour. Humidification is then stopped, and rotary vacuum drying is repeated for 1-3 hours. This process is repeated 3-5 times, and finally, rotary vacuum drying is performed for 1-3 hours. β-crystalline aztreonam with an ethanol content of less than 0.5% by weight was obtained. In step (1), α-crystal aztreonam is dissolved in anhydrous ethanol or a mixed solution of anhydrous ethanol and acetone at 1-10°C, stirred for 1-3 hours, then heated to 30°C-35°C to crystallize for 2-3 hours, filtered, and β-crystal aztreonam wet product is obtained.

2. The method according to claim 1, wherein, In step (2), the relative humidity in the drying equipment is controlled by ultrasonic humidification or by humidification through a shallow water tray.

3. The method according to claim 1, wherein, In step (2), the drying equipment is a rotary vacuum dryer or an atmospheric pressure drying oven.

4. The method according to claim 1, wherein, In step (2), the atmospheric pressure drying temperature is 50°C - 70°C.

5. The method according to claim 4, wherein, The atmospheric pressure drying temperature is 60°C - 70°C.

6. The method according to claim 1, wherein, In step (2), the vacuum drying temperature is 40°C - 70°C.

7. The method according to claim 6, wherein, The vacuum drying temperature is 40°C - 50°C.

8. The method according to any one of claims 1-7, wherein, In step (1), when using a mixed solution of anhydrous ethanol and acetone, the volume ratio of anhydrous ethanol to acetone is 5:1 to 2:

1.

9. The method according to claim 8, wherein, The volume ratio of anhydrous ethanol to acetone is 3:1 to 2:1.

Images