Preparation method for reducing impurity content in moxifloxacin hydrochloride

Abstract

The invention provides a preparation method for reducing the content of impurities in moxifloxacin hydrochloride, and particularly relates to the technical field of medicine synthesis. The preparation method comprises the following steps: adding a water-soluble antioxidant and a hydrochloric acid aqueous solution into a crude product solution of a moxifloxacin monomer, and reacting to obtain moxifloxacin hydrochloride; adding a reducing solvent into the system for solventing-out crystallization, then cooling and continuing crystallization, filtering to obtain a moxifloxacin hydrochloride wet product, and finally drying the moxifloxacin hydrochloride wet product to obtain a moxifloxacin hydrochloride product. Or adding a hydrochloric acid aqueous solution into the crude product solution of the moxifloxacin monomer for reaction to obtain moxifloxacin hydrochloride; the preparation method comprises the following steps: adding a fat-soluble antioxidant and a reducing solvent into a system, carrying out solvent-out crystallization, cooling, continuing crystallization, filtering to obtain a moxifloxacin hydrochloride wet product, and finally drying the moxifloxacin hydrochloride wet product to obtain a moxifloxacin hydrochloride product. According to the preparation method, high purity and high safety of the final product are ensured, and the high-standard requirement of the pharmaceutical industry is met.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method for reducing the impurity content in moxifloxacin hydrochloride. Background Art

[0002] Moxifloxacin hydrochloride is a fourth-generation broad-spectrum fluoroquinolone antibacterial drug, chemical name: 1-cyclopropyl-7-{S,S-2,8-diazo-bicyclo[4.3.0]non-8-yl}-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride, CAS No. 186826-86-8, structural formula is shown in Formula I below:

[0003]

[0004] Moxifloxacin contains secondary and tertiary amines in its structure. During the preparation of moxifloxacin hydrochloride by hydrochloric acid salt-forming reaction and the refining process, due to the presence of certain nitrogen oxides in impurities and some solvents, the nitrogen oxides will be oxidized into nitrites, thereby oxidizing the secondary and tertiary amines in the structure of moxifloxacin, resulting in the generation of N-nitrosamine impurities. This impurity is a typical genotoxic impurity. As countries have increasingly stringent requirements on drug genotoxic impurities, various industries have imposed strict requirements on it.

[0005] Testing of moxifloxacin products produced by some raw material manufacturers on the market found that basically all moxifloxacin products contained more than 0.6 ppm of N-nitrosamine impurities. The N-nitrosamine impurity content is relatively high, posing a certain risk to safe medication.

[0006] In view of this, the present invention is proposed. Summary of the invention

[0007] One of the purposes of the present invention is to provide a preparation method for reducing the impurity content in moxifloxacin hydrochloride, aiming to solve the shortcomings of moxifloxacin hydrochloride prepared in the prior art, such as high N-nitrosamine impurities, small crystal size, easy entrainment of mother liquor, high post-processing cost, etc.

[0008] A second object of the present invention is to provide moxifloxacin hydrochloride.

[0009] In order to solve the above-mentioned technical problems, the present invention particularly adopts the following technical solutions:

[0010] The first aspect of the present invention provides a preparation method for reducing the impurity content in moxifloxacin hydrochloride, comprising the following steps:

[0011] A water-soluble antioxidant and a hydrochloric acid aqueous solution are added to a crude solution of a moxifloxacin monomer to react to obtain moxifloxacin hydrochloride; a reducing solvent is added to the system to dissolve and crystallize, then the temperature is lowered to continue crystallization, and the wet product of moxifloxacin hydrochloride is obtained by filtering, and finally the wet product of moxifloxacin hydrochloride is dried to obtain a moxifloxacin hydrochloride product;

[0012] or,

[0013] A hydrochloric acid aqueous solution is added to a crude solution of moxifloxacin monomer to react to obtain moxifloxacin hydrochloride; a fat-soluble antioxidant and a reducing solvent are added to the system to dissolve and crystallize, then the temperature is lowered to continue crystallization, and the wet product of moxifloxacin hydrochloride is obtained by filtration, and finally the wet product of moxifloxacin hydrochloride is dried to obtain a moxifloxacin hydrochloride product. Furthermore, in the crude solution, the content of moxifloxacin monomer is 9 to 34 wt%, preferably 14 to 29 wt%.

[0014] Furthermore, the water-soluble antioxidant includes at least one of vitamin C and its sodium salt, phytic acid, methionine, proline, glutathione, tea polyphenols and niacinamide.

[0015] Furthermore, the fat-soluble antioxidant includes at least one of vitamin E, coenzyme Q10, grape seed extract, lutein, β-carotene and gallic acid ester.

[0016] Preferably, the amount of the water-soluble antioxidant and / or the fat-soluble antioxidant is 0.05-1%, preferably 0.2-0.6%, of the mass of the moxifloxacin monomer.

[0017] Furthermore, the molar ratio of hydrochloric acid in the hydrochloric acid aqueous solution to the moxifloxacin monomer is 0.8 to 2, preferably 0.9 to 1.2.

[0018] Furthermore, the mass concentration of the hydrochloric acid aqueous solution is 5-30%, preferably 10-20%.

[0019] Furthermore, the reducing solvent is an organic solvent miscible with water.

[0020] Preferably, the reducing solvent comprises lower alcohol and / or lower ketone.

[0021] Preferably, the lower alcohol includes at least one of methanol, ethanol and isopropanol.

[0022] Preferably, the lower ketone comprises acetone and / or butanone.

[0023] Furthermore, the amount of the reducing solvent used is 0.5 to 5 times the mass of water in the system, preferably 1 to 3 times.

[0024] Furthermore, the reaction temperature is 80-100° C. and the reaction time is 0.5-2 h.

[0025] Further, the temperature of the system is lowered to 50-70° C. and then a reducing solvent is added.

[0026] The time for adding the reducing solvent is 0.5 to 5 hours, preferably 1 to 3 hours.

[0027] Furthermore, the cooling rate is 8-12°C / h, and the final temperature drops to 3-7°C.

[0028] Preferably, the drying method comprises vacuum drying.

[0029] The second aspect of the present invention provides moxifloxacin hydrochloride, which is prepared by the preparation method described in the first aspect.

[0030] Compared with the prior art, the present invention has at least the following beneficial effects:

[0031] The preparation method provided by the present invention introduces an antioxidant in the salt-forming reaction or the dissolution crystallization process, effectively preventing the oxidation of nitrogen oxides in the system, thereby blocking the formation of nitrite ions and fundamentally reducing the generation pathway of N-nitrosamines. This strategy not only ensures the stability of the reaction system, but also improves the safety of the final product; a reducing solvent is also used in the dissolution crystallization stage, which reduces the impurities generated by oxidation through reduction on the one hand, and improves the selectivity of the reaction; on the other hand, it accurately controls the morphology of moxifloxacin hydrochloride crystals, prompting the crystals to form a square morphology with a relatively small aspect ratio. This square crystal has better sedimentation and filtration characteristics in physical properties, and is easier to achieve rapid separation from the mother liquor during centrifugation or filtration than traditional long needle-shaped crystals. This efficient separation process not only improves the separation efficiency, but also significantly reduces the residual amount of the mother liquor. More importantly, since the N-nitrosamine impurities that may be contained in the mother liquor are greatly reduced in this process, the preparation method of the present invention not only ensures the purity of the crystal, but also significantly improves the overall quality of the product, ensures the high purity and high safety of the final product, and meets the high standards of the pharmaceutical industry.

[0032] The moxifloxacin hydrochloride provided by the present invention has an N-nitrosamine content reduced to below 48 ppb, and a removal rate of at least 97%, thereby improving the quality of moxifloxacin hydrochloride, enhancing the safety, stability and effectiveness of treatment, and also promoting the technological progress of the pharmaceutical industry and the improvement of quality standards. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0034] Figure 1 This is a scanning electron microscope image of moxifloxacin hydrochloride obtained in Example 5;

[0035] Figure 2 This is a scanning electron microscope image of moxifloxacin hydrochloride obtained in Comparative Example 1. DETAILED DESCRIPTION

[0036] To make the purpose, technical solution and advantages of the present invention clearer, the technical solution in the embodiment of the present invention will be clearly and completely described below in combination with the embodiment of the present invention. Obviously, the described embodiment is a part of the embodiment of the present invention, but not all of the embodiments. The components of the embodiment of the present invention can be arranged and designed in various different configurations.

[0037] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device.

[0038] The first aspect of the present invention provides a preparation method for reducing the impurity content in moxifloxacin hydrochloride, comprising the following steps:

[0039] A water-soluble antioxidant and a hydrochloric acid aqueous solution are added to a crude solution of a moxifloxacin monomer to react to obtain moxifloxacin hydrochloride; a reducing solvent is added to the system to dissolve and crystallize, then the temperature is lowered to continue crystallization, and the wet product of moxifloxacin hydrochloride is obtained by filtering, and finally the wet product of moxifloxacin hydrochloride is dried to obtain a moxifloxacin hydrochloride product;

[0040] or,

[0041] A hydrochloric acid aqueous solution is added to a crude solution of moxifloxacin monomer to react to obtain moxifloxacin hydrochloride; a fat-soluble antioxidant and a reducing solvent are added to the system to dissolve and crystallize, then the temperature is lowered to continue crystallization, and the wet product of moxifloxacin hydrochloride is obtained by filtering, and finally the wet product of moxifloxacin hydrochloride is dried to obtain a moxifloxacin hydrochloride product.

[0042] The preparation method provided by the present invention introduces an antioxidant during the salt-forming reaction or the dissolution crystallization process, effectively preventing the oxidation of nitrogen oxides in the system, thereby blocking the formation of nitrite ions and fundamentally reducing the generation pathway of N-nitrosamines. The antioxidant will dissolve in the crystallization mother liquor during the crystallization process and will not have an adverse effect on the impurity components of the product. This strategy not only ensures the stability of the reaction system, but also improves the safety of the final product; a reducing solvent is used in the dissolution crystallization stage, on the one hand, to reduce the impurities generated by oxidation through the reduction effect, thereby improving the selectivity of the reaction; on the other hand, it accurately controls the morphology of the moxifloxacin hydrochloride crystals, prompting the crystals to form a square shape with a relatively small aspect ratio. This square crystal has better sedimentation and filtration characteristics in physical properties, and is easier to achieve rapid separation from the mother liquor during centrifugation or filtration than traditional long needle-shaped crystals. This efficient separation process not only improves the separation efficiency, but also significantly reduces the residual amount of the mother liquor. More importantly, since the N-nitrosamine impurities that may be contained in the mother liquor are greatly reduced in this process, the preparation method of the present invention not only ensures the purity of the crystals, but also significantly improves the overall quality of the product, ensures the high purity and high safety of the final product, and meets the high standards of the pharmaceutical industry.

[0043] N-nitrosamines are a class of compounds with the basic structure of -NN=O. They are internationally recognized as a class of strong carcinogens and are widely present in human environmental media such as water, food, pesticides and medicines. As a class of genotoxic impurities with high mutagenicity and strong carcinogenicity, trace levels of imine compounds can induce gene mutations, chromosomal abnormalities and DNA repair disorders. Long-term exposure may induce the formation of tumors in different organs in animals. In moxifloxacin hydrochloride, the N-nitrosamine compounds detected include N-nitrosopiperidine, N-nitrosodiethylamine, N-nitrosopyrrolidine, N-nitrosomethylethylamine and N-nitrosodi-n-butylamine.

[0044] Furthermore, in the crude solution, the content of moxifloxacin monomer is 9 to 34 wt%, preferably 14 to 29 wt%.

[0045] The content of moxifloxacin monomer is within the above range, which can ensure the quality of moxifloxacin hydrochloride, the batch production amount, and the time of subsequent crystallization, ensuring that the production process is both economical and efficient.

[0046] Typically but not limiting, the content of moxifloxacin monomer in the crude solution can be 9wt%, 11wt%, 12wt%, 13wt%, 14wt%, 15wt%, 16wt%, 17wt%, 18wt%, 19wt%, 20wt%, 21wt%, 22wt%, 23wt%, 24wt%, 25wt%, 26wt%, 27wt%, 28wt%, 29wt%, 30wt%, 31wt%, 32wt%, 33wt%, 34wt%, 35wt%, 36wt%, 37wt%, 38wt%, 39wt%, 40wt%, 41wt%, 42wt%, 43wt%, 44wt%, 45wt%, 46wt%, 47wt%, 48wt%, 49wt%, 50wt%, 51wt%, 52wt%, 53wt%, 54wt%, 55wt%, 56wt%, 57wt%, 58wt%, 59wt%, 60wt%, 61wt%, 62wt%, 63wt%, 64wt%, 65wt%, 66wt%, 67wt%, 68wt%, 69wt%, 70wt%, 71wt%, 72wt%, 73wt%, 74wt%, 75wt%, 76wt%, 77wt%, 78wt%, 79wt%, 80wt%, 81wt%, 82 wt%, 33wt% or 34wt%, or it can be any value in the range of 9wt% to 34wt%; the preferred content range can be 14wt%, 16wt%, 17wt%, 18wt%, 19wt%, 20wt%, 21wt%, 22wt%, 23wt%, 24wt%, 25wt%, 26wt%, 27wt%, 28wt% or 29wt%, or it can be any value in the range of 14wt% to 29wt%.

[0047] Furthermore, the water-soluble antioxidant includes at least one of vitamin C and its sodium salt, phytic acid, methionine, proline, glutathione, tea polyphenols and niacinamide.

[0048] Preferably, the fat-soluble antioxidant includes at least one of vitamin E, coenzyme Q10, grape seed extract, lutein, β-carotene and gallic acid ester.

[0049] During the salt-forming reaction or dissolution crystallization process, antioxidants are added to prevent the oxidation of nitrogen oxides in the system to form nitrites, thereby preventing nitrites from reacting with moxifloxacin to form N-nitrosamines, fundamentally reducing the formation pathway of N-nitrosamines.

[0050] It should be noted that the antioxidants described in the present invention refer to water-soluble antioxidants or fat-soluble antioxidants. When the antioxidant is a water-soluble antioxidant, it is directly added in the salt-forming reaction because it can dissolve well in water, fully contact with the reactants, and exert an antioxidant effect. However, fat-soluble antioxidants have poor solubility in water, and directly adding them may not be evenly dispersed, affecting their effect. Therefore, it is necessary to mix with a reducing solvent to increase the solubility and dispersibility of the fat-soluble antioxidant in the aqueous phase to ensure that it can effectively contact with the reactants and exert an antioxidant effect.

[0051] Preferably, the amount of the water-soluble antioxidant and / or the fat-soluble antioxidant is 0.05-1%, preferably 0.2-0.6%, of the mass of the moxifloxacin monomer.

[0052] It should be noted that the above dosage is calculated based on the total amount of antioxidants, and antioxidants include water-soluble antioxidants and fat-soluble antioxidants. Typically but not limiting, the dosage of antioxidants can be, for example, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.7%, 0.8%, 0.9% or 1% of the mass of moxifloxacin monomer, or any value within the range of 0.05% to 1%; the preferred dosage range can be, for example, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55% or 0.6%, or any value within the range of 0.2% to 0.6%.

[0053] Furthermore, the molar ratio of hydrochloric acid in the hydrochloric acid aqueous solution to the moxifloxacin monomer is 0.8 to 2, preferably 0.9 to 1.2.

[0054] Typically but not limiting, the molar ratio of hydrochloric acid in the aqueous hydrochloric acid solution to the moxifloxacin monomer can be, for example, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2, or any value in the range of 0.8 to 2; the preferred molar ratio range can be, for example, 0.9, 1.0, 1.1 or 1.2, or any value in the range of 0.9 to 1.2.

[0055] Preferably, the mass concentration of the hydrochloric acid aqueous solution is 5 to 30%, preferably 10 to 20%.

[0056] Further, the reducing solvent is an organic solvent miscible with water. The reducing solvent is an organic solvent miscible with water, and its purpose is to form a mixed solvent system consisting of a reducing solvent and water, and this mixed solvent system can regulate the solubility of moxifloxacin hydrochloride, change the growth conditions of the crystal, and thus regulate the crystal form of moxifloxacin hydrochloride. Since there is a difference between the solubility of moxifloxacin hydrochloride in the mixed solvent and its solubility in water, this difference causes the solubility of moxifloxacin hydrochloride to decrease and crystallize, thereby achieving dissolution crystallization.

[0057] Preferably, the reducing solvent comprises lower alcohol and / or lower ketone.

[0058] Reducing solvents can donate electrons or hydrogen atoms (H + and e -) to other substances to help reduce other substances in the system. The α-hydrogen (hydrogen atom directly connected to the carbon atom) in lower alcohols (such as methanol and ethanol) and lower ketones (such as acetone) is relatively active and can be removed by other substances (such as free radicals or oxidants), thereby providing hydrogen atoms for reduction reactions. Lower alcohols and lower ketones can also form free radicals during the reaction, and these free radicals can further participate in the reduction reaction.

[0059] The oxygen atoms in lower alcohol and lower ketone molecules can form hydrogen bonds, and this ability helps stabilize free radicals or other intermediates, thereby promoting the reduction reaction. The oxygen atoms of lower alcohols and lower ketones have high electronegativity and can attract electron density, which enables them to participate in the reduction reaction as electron donors. The reducing properties of lower alcohols and lower ketones help control the reaction conditions and reduce the formation of oxidation by-products. Therefore, lower alcohols and lower ketones are called reducing solvents because of their ability to provide hydrogen atoms and electrons and their ability to promote the reduction process in chemical reactions.

[0060] In the synthesis process of moxifloxacin hydrochloride, this reducibility is an important property for controlling the reaction path and improving the purity of the product.

[0061] Preferably, the lower alcohol includes at least one of methanol, ethanol and isopropanol.

[0062] Preferably, the lower ketone comprises acetone and / or butanone.

[0063] Furthermore, the amount of the reducing solvent used is 0.5 to 5 times the mass of water in the system, preferably 1 to 3 times.

[0064] Typically but not limiting, the amount of the reducing solvent may be, for example, 0.5 times, 1 times, 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times or 5 times the mass of water in the crude solution, or any value within the range of 0.5 to 5 times; the preferred amount range may be, for example, 1 times, 1.5 times, 2 times or 2.5 times, or any value within the range of 1 to 3 times. By controlling the ratio of the reducing solvent and water to obtain a mixed solvent system, the solubility and crystal form of moxifloxacin hydrochloride are regulated.

[0065] Furthermore, the reaction temperature is 80-100° C. and the reaction time is 0.5-2 h.

[0066] Typically but not limiting, the reaction temperature can be, for example, 80°C, 85°C, 90°C, 95°C or 100°C, or any value within the range of 80°C to 100°C; the reaction time can be, for example, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 1.75h or 2h, or any value within the range of 0.5h to 2h.

[0067] Further, the temperature of the system is lowered to 50-70° C. and then a reducing solvent is added.

[0068] Typically but not limiting, the temperature of the system can be lowered to, for example, 50° C., 55° C., 60° C., 65° C. or 70° C., or any value within the range of 50° C. to 70° C. Adding a reducing solvent within this temperature range can prevent the reducing solvent from boiling, reduce the solubility of the mixed solvent system in moxifloxacin hydrochloride, and at the same time, such a temperature will also reduce the occurrence of side reactions.

[0069] The time for adding the reducing solvent is 0.5 to 5 hours, preferably 1 to 3 hours.

[0070] Typically but not limiting, the reducing solvent may be added for, for example, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h. This uniform addition of reducing solvent may form different mixed solvent systems, aiming to control the nucleation and growth process of the crystal, leaving enough time for the growth of the crystal form, so as to ensure the uniformity and efficiency of the dissolution crystallization.

[0071] Furthermore, the cooling rate is 8-12°C / h, and the final temperature is reduced to 3-7°C. By precisely controlling the cooling rate and the final temperature, it is not only possible to ensure that moxifloxacin hydrochloride is effectively precipitated during the cooling process, thereby maximizing the yield, but also to provide sufficient time for the formation of square crystals. This temperature management helps to optimize the crystal growth process and ensure the regularity of the crystal morphology and the consistency of quality.

[0072] Typically but not limiting, the cooling rate of the cooling may be, for example, 8°C / h, 9°C / h, 10°C / h, 11°C / h or 12°C / h, or any value within the range of 8°C / h to 12°C / h. During the cooling process, the final temperature of the system may be reduced to, for example, 3°C, 4°C, 5°C, 6°C or 7°C, or any value within the range of 3°C to 7°C.

[0073] Preferably, the preparation method further comprises a solid-liquid separation process after obtaining the wet product of moxifloxacin hydrochloride and before drying.

[0074] Preferably, the solid-liquid separation method includes centrifugation, and the precipitate is dried after centrifugation.

[0075] Preferably, the drying method comprises vacuum drying.

[0076] The present invention does not specifically limit the temperature and time of vacuum drying, and the temperature and time that can remove the mixed solvent shall prevail.

[0077] The second aspect of the present invention provides moxifloxacin hydrochloride, which is prepared by the preparation method described in the first aspect.

[0078] In the following, some embodiments of the present invention are described in detail in conjunction with the examples. In the absence of conflict, the following examples and features in the examples can be combined with each other. The raw materials in the following examples and comparative examples are purchased from the market unless otherwise specified.

[0079] In the following examples, the raw material used was a crude moxifloxacin monomer produced under conventional production conditions, wherein the N-nitrosamine impurity contained therein was about 2000 ppb, and the N-nitrosamine impurity concentration in the crude moxifloxacin monomer and the dry product was measured by liquid chromatography-mass spectrometry (LC-MS).

[0080] Unless otherwise specified in the following examples and comparative examples, all raw materials are commercially available analytical reagents or prepared by conventional methods in the art.

[0081] Example 1

[0082] This embodiment provides a moxifloxacin hydrochloride, when the antioxidant is water-soluble vitamin C, the preparation steps are as follows:

[0083] 1. Put 20g of crude moxifloxacin monomer into a 200mL crystallization kettle, add 50g of purified water, add 0.06g of vitamin C, heat to 90°C, stir at 200rpm to dissolve, add 18g of 10% hydrochloric acid aqueous solution dropwise, react for 1h, and then cool down.

[0084] 2. Cool the system to 60°C, add 80 mL of methanol to the crystallization kettle at 1 mL / min (1.33 h), then cool to 5°C at 10°C / h, filter and wash to obtain 21.67 g of moxifloxacin hydrochloride wet product, and vacuum dry to obtain 19.58 g of moxifloxacin hydrochloride dry product.

[0085] Example 2

[0086] This embodiment provides a moxifloxacin hydrochloride, when the antioxidant is fat-soluble vitamin A, the preparation steps are as follows:

[0087] 1. Put 20 g of crude moxifloxacin monomer into a 200 mL crystallization kettle, add 50 g of purified water, heat to 90° C., stir at 200 rpm to dissolve, drop 18 g of 10% hydrochloric acid aqueous solution, react for 1 hour, and then cool down.

[0088] 2. Add 0.06 g of vitamin A to 100 mL of methanol, stir and dissolve to obtain a methanol solution containing vitamin A, cool the system to 60°C, add the above methanol solution containing vitamin A to the crystallization kettle at 1 mL / min (1.67 h), then cool to 5°C at 10°C / h, filter and wash to obtain 22.12 g of moxifloxacin hydrochloride wet product, and vacuum dry to obtain 19.73 g of moxifloxacin hydrochloride dry product.

[0089] Example 3

[0090] This embodiment provides a moxifloxacin hydrochloride, and the preparation steps when the antioxidant is fat-soluble vitamin E are as follows:

[0091] 1. Put 20g of crude moxifloxacin monomer into a 200mL crystallization kettle, add 50g of purified water, heat to 90°C, stir at 200rpm to dissolve, and drop 18g of 10% hydrochloric acid aqueous solution to react for 1h.

[0092] 2. Add 0.06 g of vitamin E to 100 mL of ethanol, stir and dissolve to obtain an ethanol solution containing vitamin E, cool the system to 60° C., add the ethanol solution containing vitamin E to the crystallization kettle at 1 mL / min (1.67 h), then cool to 5° C. at 10° C. / h, filter and wash to obtain 21.53 g of wet moxifloxacin hydrochloride, and vacuum dry to obtain 19.82 g of dry moxifloxacin hydrochloride.

[0093] Example 4

[0094] This embodiment provides a moxifloxacin hydrochloride, wherein the antioxidant is fat-soluble coenzyme Q10, and the preparation steps are as follows:

[0095] 1. Put 20g of crude moxifloxacin monomer into a 200mL crystallization kettle, add 50g of purified water, heat to 90°C, stir at 200rpm to dissolve, and drop 18g of 10% hydrochloric acid aqueous solution to react for 1h.

[0096] 2. Add 0.06 g of coenzyme Q10 to 100 mL of acetone, stir and dissolve to obtain an acetone solution containing coenzyme Q10, cool the system to 60° C., add the above acetone solution containing coenzyme Q10 to the crystallization kettle at 1 mL / min (1.67 h), then cool to 5° C. at 10° C. / h, filter and wash to obtain 22.09 g of moxifloxacin hydrochloride wet product, and vacuum dry to obtain 19.85 g of moxifloxacin hydrochloride dry product.

[0097] Example 5

[0098] This embodiment provides a moxifloxacin hydrochloride, wherein the antioxidants are water-soluble vitamin C and fat-soluble coenzyme Q10, and the preparation steps are as follows:

[0099] 1. Put 20g of crude moxifloxacin monomer into a 200mL crystallization kettle, add 50g of purified water, add 0.03g of vitamin C, heat to 90°C, stir at 200rpm to dissolve, add 18g of 10% hydrochloric acid aqueous solution dropwise and react for 1h.

[0100] 2. Add 0.03 g of coenzyme Q10 to 100 mL of acetone, stir and dissolve to obtain an acetone solution containing coenzyme Q10, cool the system to 60° C., add the above acetone solution containing coenzyme Q10 to the crystallization kettle at 1 mL / min (1.67 h), then cool to 5° C. at 10° C. / h, filter and wash to obtain 21.82 g of moxifloxacin hydrochloride wet product, and vacuum dry to obtain 19.75 g of moxifloxacin hydrochloride dry product.

[0101] Example 6

[0102] This embodiment provides a moxifloxacin hydrochloride, wherein the antioxidant is fat-soluble β-carotene, and the preparation steps are as follows:

[0103] 1. Put 20g of crude moxifloxacin monomer into a 200mL crystallization kettle, add 50g of purified water, heat to 90°C, stir at 200rpm to dissolve, and drop 18g of 10% hydrochloric acid aqueous solution to react for 1h.

[0104] 2. Add 0.04 g of β-carotene to 150 mL of acetone, stir and dissolve to obtain an acetone solution containing β-carotene, cool the system to 60°C, add the acetone solution containing β-carotene to the crystallization kettle at 1 mL / min (2.5 h), then cool to 5°C at 10°C / h, filter and wash to obtain 21.73 g of wet moxifloxacin hydrochloride, and vacuum dry to obtain 19.54 g of dry moxifloxacin hydrochloride.

[0105] Example 7

[0106] This embodiment provides a moxifloxacin hydrochloride, wherein the antioxidants are water-soluble vitamin C and fat-soluble coenzyme Q10, and the preparation steps are as follows:

[0107] 1. Put 20g of crude moxifloxacin monomer into a 200mL crystallization kettle, add 162g of purified water, add 0.03g of vitamin C, heat to 80°C, stir at 200rpm to dissolve, add 18g of 10% hydrochloric acid aqueous solution dropwise and react for 0.75h.

[0108] 2. Add 0.03 g of coenzyme Q10 to 104 mL of acetone, stir and dissolve to obtain an acetone solution containing coenzyme Q10. Cool the system to 50° C., add the above acetone solution containing coenzyme Q10 to the crystallization kettle at 0.5 mL / min (3.47 h), then cool to 3° C. at 8° C. / h, filter and wash to obtain 20.62 g of moxifloxacin hydrochloride wet product, and vacuum dry to obtain 18.52 g of moxifloxacin hydrochloride dry product.

[0109] Example 8

[0110] This embodiment provides a moxifloxacin hydrochloride, wherein the antioxidants are water-soluble vitamin C and fat-soluble coenzyme Q10, and the preparation steps are as follows:

[0111] 1. Put 20g of crude moxifloxacin monomer into a 200mL crystallization kettle, add 40g of purified water, add 0.03g of vitamin C, heat to 100°C, stir at 200rpm to dissolve, add 9g of 20% hydrochloric acid aqueous solution dropwise and react for 2h.

[0112] 2. Add 0.03 g of coenzyme Q10 to 102 mL of acetone, stir and dissolve to obtain an acetone solution containing coenzyme Q10, cool the system to 60° C., add the above acetone solution containing coenzyme Q10 to the crystallization kettle at 0.5 mL / min (3.4 h), then cool to 7° C. at 12° C. / h, filter and wash to obtain 22.15 g of moxifloxacin hydrochloride wet product, and vacuum dry to obtain 19.91 g of moxifloxacin hydrochloride dry product.

[0113] Example 9

[0114] This embodiment provides moxifloxacin hydrochloride. The difference from Example 5 is that the amount of vitamin C added is 0.005 g, the amount of coenzyme Q10 added is 0.005 g, and the remaining raw materials and methods are the same as those in Example 5, which will not be repeated here.

[0115] Example 10

[0116] This embodiment provides moxifloxacin hydrochloride. The difference from Example 5 is that the amount of vitamin C added is 0.06 g, the amount of coenzyme Q10 added is 0.06 g, and the remaining raw materials and methods are the same as those in Example 5, which will not be repeated here.

[0117] Embodiment 11

[0118] This embodiment provides moxifloxacin hydrochloride, which is different from Example 5 in that the amount of vitamin C added is 0.1 g, the amount of coenzyme Q10 added is 0.1 g, and the remaining raw materials and methods are the same as those in Example 5, which will not be repeated here.

[0119] Comparative Example 1

[0120] This comparative example provides a moxifloxacin hydrochloride, and the preparation steps are as follows:

[0121] 1. Put 20g of crude moxifloxacin monomer into a 200mL crystallization kettle, add 50g of purified water, heat to 90°C, stir at 200rpm to dissolve, and drop 18g of 10% hydrochloric acid aqueous solution to react for 1h.

[0122] 2. The system was cooled to 5°C at a rate of 10°C / h, filtered and washed to obtain 25.31 g of wet moxifloxacin hydrochloride, and vacuum dried to obtain 18.36 g of dry moxifloxacin hydrochloride.

[0123] Comparative Example 2

[0124] This comparative example provides a moxifloxacin hydrochloride, and the preparation steps are as follows:

[0125] 1. Put 20g of crude moxifloxacin monomer into a 200mL crystallization kettle, add 50g of purified water, heat to 90°C, stir at 200rpm to dissolve, and drop 18g of 10% hydrochloric acid aqueous solution to react for 1h.

[0126] 2. Cool the system to 60°C, add 100 mL of methanol at 1 mL / min (1.67 h), then cool to 5°C at 10°C / h, filter and wash to obtain 21.75 g of moxifloxacin hydrochloride wet product, and vacuum dry to obtain 19.68 g of moxifloxacin hydrochloride dry product.

[0127] Comparative Example 3

[0128] This comparative example provides a moxifloxacin hydrochloride, and the preparation steps are as follows:

[0129] 1. Put 20g of crude moxifloxacin monomer into a 200mL crystallization kettle, add 50g of purified water, heat to 90°C, stir at 200rpm to dissolve, and drop 18g of 10% hydrochloric acid aqueous solution to react for 1h.

[0130] 2. Cool the system to 60°C, add 150 mL of acetone at 1 mL / min (2.5 h), then cool to 5°C at 10°C / h, filter and wash to obtain 22.15 g of moxifloxacin hydrochloride wet product, and vacuum dry to obtain 19.73 g of moxifloxacin hydrochloride dry product.

[0131] Comparative Example 4

[0132] This comparative example provides a moxifloxacin hydrochloride, and the preparation steps are as follows:

[0133] 1. Put 20g of crude moxifloxacin monomer into a 200mL crystallization kettle, add 50g of purified water, add 0.06g of vitamin C, heat to 90°C, stir at 200rpm to dissolve, add 18g of 10% hydrochloric acid aqueous solution dropwise and react for 1h.

[0134] 2. The system was cooled to 5°C at a rate of 10°C / h, filtered and washed to obtain 25.48 g of wet moxifloxacin hydrochloride, and vacuum dried to obtain 18.63 g of dry moxifloxacin hydrochloride.

[0135] Comparative Example 5

[0136] This comparative example provides a moxifloxacin hydrochloride, and the preparation steps are as follows:

[0137] 1. Put 20g of crude moxifloxacin monomer into a 200mL crystallization kettle, add 50g of purified water, add 0.4g of aminosulfonic acid, heat to 90°C, stir at 200rpm to dissolve, add 18g of 10% hydrochloric acid aqueous solution dropwise and react for 1h.

[0138] 2. The system was cooled to 5°C at a rate of 10°C / h, filtered and washed to obtain 25.42 g of wet moxifloxacin hydrochloride, and vacuum dried to obtain 18.58 g of dry moxifloxacin hydrochloride.

[0139] Comparative Example 6

[0140] 1. Put 20g of crude moxifloxacin monomer into a 200mL crystallization kettle, add 50g of purified water, add 0.2g of vitamin E, heat to 90°C, stir at 200rpm to dissolve, add 18g of 10% hydrochloric acid aqueous solution dropwise and react for 1h.

[0141] 2. The system was cooled to 5°C at a rate of 10°C / h, filtered and washed to obtain 25.39 g of wet moxifloxacin hydrochloride, and vacuum dried to obtain 18.57 g of dry moxifloxacin hydrochloride.

[0142] Characterization example

[0143] The moxifloxacin hydrochloride dry product obtained in Example 5 and Comparative Example 1 was subjected to scanning electron microscopy, and the obtained scanning electron microscopy images correspond to the following: Figure 1 and Figure 2 shown.

[0144] from Figure 1 It can be seen that the crystals in moxifloxacin hydrochloride are square in shape, with a low aspect ratio, and are relatively easy to be centrifuged and washed; Figure 2 It can be seen that the crystals in moxifloxacin hydrochloride are long needle-shaped, slender, and easy to stack, resulting in a large amount of mother liquor residue.

[0145] Results

[0146] The crude moxifloxacin monomer and the dry moxifloxacin hydrochloride used in the examples and comparative examples were tested for N-nitrosamine content using LC-MS method, and the obtained data are shown in Table 1 below.

[0147] Table 1

[0148]

[0149] From the data in Table 1, it can be analyzed that the crystallization process and the use of antioxidants have significant differences in the control effect of the nitrosamine content in the product. First, in the case of no antioxidant, only by cooling crystallization (Comparative Example 1), the mother liquor residual rate is high, resulting in a nitrosamine content of 472ppb in the product, and this value may further increase during subsequent processing and storage. When an antioxidant is added during the crystallization process (Comparative Examples 4-6), even if the crystallization process is not changed, the nitrosamine content in the product can be preliminarily controlled and reduced to less than 350ppb. Among them, the effect of water-soluble antioxidants is better than that of fat-soluble antioxidants, although some antioxidants require a larger dosage and the effect is relatively poor. Further, if the crystallization process is changed without an antioxidant (Comparative Examples 2-3), for example, by dissolution crystallization, the moisture content of the wet product will be significantly reduced, and the nitrosamine content will also be reduced to about 150ppb, which shows that only changing the crystallization process is better than simply adding an antioxidant to reduce the nitrosamine content.

[0150] When the crystallization process is changed and antioxidants are added at the same time (Examples 1-11), the nitrosamine impurity content in the product is more significantly controlled, usually below 60 ppb. This shows that the optimization of the crystallization process combined with the use of antioxidants can more effectively reduce the nitrosamine content in the product.

[0151] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein by equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A preparation method for reducing the impurity content in moxifloxacin hydrochloride, characterized in that: The following steps are involved: Adding a water-soluble antioxidant and an aqueous solution of hydrochloric acid to a crude solution of moxifloxacin monomer to react, thereby obtaining moxifloxacin hydrochloride; Adding a reducing solvent into the system for dissolution and crystallization, then cooling and continuing crystallization, filtering to obtain a wet product of moxifloxacin hydrochloride, and finally drying the wet product of moxifloxacin hydrochloride to obtain a moxifloxacin hydrochloride product; or, A hydrochloric acid aqueous solution is added to a crude solution of moxifloxacin monomer to react to obtain moxifloxacin hydrochloride; a fat-soluble antioxidant and a reducing solvent are added to the system to dissolve and crystallize, then the temperature is lowered to continue crystallization, and the wet product of moxifloxacin hydrochloride is obtained by filtering, and finally the wet product of moxifloxacin hydrochloride is dried to obtain a moxifloxacin hydrochloride product.

2. The preparation method according to claim 1, characterized in that: In the crude solution, the content of moxifloxacin monomer is 9 to 34 wt %, preferably 14 to 29 wt %.

3. The preparation method according to claim 1, characterized in that: The water-soluble antioxidant includes at least one of vitamin C and its sodium salt, phytic acid, methionine, proline, glutathione, tea polyphenols and niacinamide; The fat-soluble antioxidant includes at least one of vitamin E, coenzyme Q10, grape seed extract, lutein, β-carotene and gallic acid ester; Preferably, the amount of the water-soluble antioxidant and / or the fat-soluble antioxidant is 0.05-1%, preferably 0.2-0.6%, of the mass of the moxifloxacin monomer.

4. The preparation method according to claim 1, characterized in that: The molar ratio of hydrochloric acid in the hydrochloric acid aqueous solution to the moxifloxacin monomer is 0.8 to 2, preferably 0.9 to 1.2; Preferably, the mass concentration of the hydrochloric acid aqueous solution is 5 to 30%, preferably 10 to 20%.

5. The preparation method according to claim 1, characterized in that: The reducing solvent is an organic solvent miscible with water; Preferably, the reducing solvent comprises lower alcohol and / or lower ketone; Preferably, the lower alcohol comprises at least one of methanol, ethanol and isopropanol; Preferably, the lower ketone comprises acetone and / or butanone.

6. The preparation method according to claim 1, characterized in that: The amount of the reducing solvent used is 0.5 to 5 times the mass of water in the system, preferably 1 to 3 times.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The reaction temperature is 80-100° C. and the reaction time is 0.5-2 h.

8. The preparation method according to any one of claims 1 to 6, characterized in that: Lower the temperature of the system to 50-70°C and then add the reducing solvent; The time for adding the reducing solvent is 0.5 to 5 hours, preferably 1 to 3 hours.

9. The preparation method according to any one of claims 1 to 6, characterized in that: The cooling rate of the cooling is 8-12°C / h, and the final temperature drops to 3-7°C; Preferably, the drying method comprises vacuum drying.

10. A moxifloxacin hydrochloride, characterized in that: The preparation is obtained by the preparation method according to any one of claims 1 to 9.

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