Preparation method of moxifloxacin hydrochloride crystal form II large-particle crystal

Abstract

The invention relates to the technical field of medicine crystallization, and discloses a preparation method of moxifloxacin hydrochloride crystal form II large-particle crystals, which comprises the following steps: S1, dissolving moxifloxacin tartrate in an ethanol water solution; s2, sequentially adding concentrated hydrochloric acid and moxifloxacin hydrochloride crystal form II rod-like seed crystals, and stirring to grow the crystals; s3, concentrated hydrochloric acid is continuously added in batches, and stirring and crystal growing are performed once after each batch of concentrated hydrochloric acid is added; the temperature is maintained at 30-60 DEG C during the S2 and S3; and S4, cooling, carrying out crystal growth, and separating out a product, thereby obtaining the moxifloxacin hydrochloride crystal form II large-particle crystal. By adopting the preparation method disclosed by the invention, the obtained moxifloxacin hydrochloride crystal form II crystal has a thick rod-shaped morphology and is relatively large and uniform in size.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug crystallization, and particularly relates to a preparation method of moxifloxacin hydrochloride form II large particle crystals. BACKGROUND

[0002] Moxifloxacin hydrochloride is a fourth generation broad-spectrum quinolone drug, has broad-spectrum antibacterial activity, and has activity on gram-positive bacteria, gram-negative bacteria, anaerobic bacteria, acid-fast bacteria and atypical microorganisms such as mycoplasma, chlamydia and legionella. In addition, the safety is also better than other quinolone drugs. Since the anhydrous moxifloxacin hydrochloride is easy to absorb moisture, the monohydrate is often used as a raw material in medicine, and the CAS number is 192927-63-2, and the molecular structure formula is as follows: Currently, there are 13 kinds of effective crystal forms of moxifloxacin hydrochloride reported, which are as follows: four kinds of anhydrous crystal forms, specifically, crystal form I (US5849752A), III (US7230006B2), X (IN948CHE2005A), and IV (ES2316270B1); seven kinds of crystal forms containing water, specifically, crystal form II (monohydrate, US5849752A), A (containing 1% water, US20070072895A1), A (containing 1.5% water, IN115CHE2005A), Y (monohydrate, IN948CHE2005A), unnamed sesquihydrate (WO2008028959A1), alpha1 (monohydrate, WO2009087151A1), and F (containing 0.15-2.0% water, IN624MUM2011A).

[0003] Among the above crystal forms, the monohydrate crystal form II is used as a pharmaceutical raw material due to its stable physical and chemical properties. However, the moxifloxacin hydrochloride crystal form II prepared by the method in the prior art is mainly in the form of fine rods or needles (1-4 μm wide and 15-50 μm long), and the particles are small or uneven in size, so it is difficult to obtain large particle crystals with uniform size. For example, patent WO2008138759A1 obtains moxifloxacin hydrochloride crystal form II by dissolving moxifloxacin tartrate or fumarate in an ethanol-water system and adding concentrated hydrochloric acid at room temperature, and the morphology is needle-shaped. The small particles cause difficulties in filtration during scale-up production, low production efficiency, and poor product impurity removal effect; the uneven particle size causes the particles to be easy to form lumps during storage, which causes difficulties in use; in addition, the small particles or uneven particles have poor flowability during preparation use, and are difficult to mix with excipients, which may cause sticking and other problems during tabletting. SUMMARY

[0004] In order to solve the above technical problems, the existing method for preparing the crystal of moxifloxacin hydrochloride Form II has the problems of small particle size or uneven size, and the present application provides a preparation method of large particle crystal of moxifloxacin hydrochloride Form II. The preparation method of the present application can obtain the crystal of moxifloxacin hydrochloride Form II with a coarse rod shape, large size and uniform size.

[0005] The specific technical scheme of the present application is: A preparation method of large particle crystal of moxifloxacin hydrochloride Form II, comprising the following steps: S1: dissolving moxifloxacin tartrate in an ethanol aqueous solution; S2: sequentially adding concentrated hydrochloric acid and rod-shaped crystal seeds of moxifloxacin hydrochloride Form II, and stirring and aging; S3: continuously adding concentrated hydrochloric acid in batches, and stirring and aging after each batch; During S2 and S3, the temperature is maintained at 30-60℃; S4: cooling for crystal growth, separating the product, and obtaining the large particle crystal of moxifloxacin hydrochloride Form II.

[0006] In the present application, by comprehensively designing the following aspects: ① adding concentrated hydrochloric acid, crystal seeds and aging process at a specific temperature + ② adding concentrated hydrochloric acid in multiple batches + ③ adding rod-shaped crystal seeds at a specific time during the addition of concentrated hydrochloric acid in batches, the prepared crystal of moxifloxacin hydrochloride Form II has a coarse rod shape, large size and uniform size, which is suitable for industrial production and storage, and mixing with excipients to prepare a preparation. Specifically: (1) In steps S2 and S3, the process of adding concentrated hydrochloric acid, crystal seeds and aging is carried out at 30-60℃, which is beneficial to obtain larger crystals and ensure their stability. When the temperature is too low, the crystallization speed is too fast, which easily generates small needle-shaped crystals, and when the temperature is too high, it is not conducive to the stability of the crystal of moxifloxacin hydrochloride Form II.

[0007] (2) In steps S2 and S3, the concentrated hydrochloric acid is added in multiple batches, and stirring and aging are carried out after each batch, which is beneficial to uniformly release the supersaturation at each stage, and then generate large particle crystals with uniform size.

[0008] (3) After adding a part of concentrated hydrochloric acid, rod-shaped crystal seeds of moxifloxacin hydrochloride Form II are added as crystal seeds, and then the remaining concentrated hydrochloric acid is added, which is beneficial to make the finally prepared crystal have a large and uniform size. When the addition time of the crystal seeds is too early or too late, the above effect cannot be obtained.

[0009] As a preferred, the temperature during steps S2 and S3 is maintained at 40-50℃.

[0010] As preferred, the total amount of concentrated hydrochloric acid in steps S2 and S3 is 1.2-1.5 times the molar amount of moxifloxacin tartrate in step S1, the amount of concentrated hydrochloric acid in step S2 is 0.6-1.0 times the molar amount of moxifloxacin tartrate in step S1, and the amount of concentrated hydrochloric acid added in each batch in step S3 is 0.2-0.3 times the molar amount of moxifloxacin tartrate in step S1.

[0011] Through the above design of the amount of concentrated hydrochloric acid added in each batch, the supersaturation degree is released more uniformly in each stage, so that the formed crystals have a larger size and a higher uniformity of size.

[0012] As preferred, the concentration of the concentrated hydrochloric acid in steps S2 and S3 is 36-38 wt%, the rate of adding the concentrated hydrochloric acid is 0.4-1 mL / min, and the time for each stirring and aging is 0.5-1 h.

[0013] As preferred, in step S2, the width of the rod-shaped seed crystal of moxifloxacin hydrochloride Form II is 5-15 μm, the length is 50-150 μm, and the amount is 1-3% of the mass of moxifloxacin tartrate.

[0014] When the amount of the seed crystal is too low, the supersaturation degree is not released sufficiently in the early stage of crystallization and is accumulated in the later stage, which leads to the formation of fine crystals. When the amount of the seed crystal is too high, the supersaturation degree is released too fast in the early stage of crystallization, which also leads to the formation of more fine crystal particles.

[0015] As preferred, in step S2, the preparation of the rod-shaped seed crystal of moxifloxacin hydrochloride Form II comprises the following steps: dissolving moxifloxacin tartrate in an aqueous ethanol solution, adding concentrated hydrochloric acid at 40-50°C, stirring and crystallizing, and performing multiple temperature cycling, and then cooling and separating the product.

[0016] In the above process, concentrated hydrochloric acid is added to the moxifloxacin tartrate solution to spontaneously crystallize, and multiple temperature cycling is performed to make the seed crystal reach the desired size. The seed crystal formed in this way has a uniform size, which is beneficial to obtaining moxifloxacin hydrochloride Form II large particle crystals with a uniform size.

[0017] Further, the multiple temperature cycling comprises the following process: heating to 60-65°C within 1-1.5 h, maintaining for 0.5-1 h, cooling to 40-50°C within 2-2.5 h, and maintaining for 0.5-1 h, which is cycled for 4-5 times.

[0018] Further, in the preparation of the rod-shaped seed crystal of moxifloxacin hydrochloride Form II, the cooling step comprises cooling at a rate of 5-20°C / h to -5-0°C and stirring for 1-2.5 h.

[0019] Preferably, in step S4, the temperature decreasing process for crystal growth comprises decreasing the temperature to -5-0℃ at a rate of 5-20℃ / h, and stirring for 0.5-1h.

[0020] Further, in step S4, the temperature decreasing rate for crystal growth is 10-15℃ / h.

[0021] Preferably, in step S1, the mass fraction of water in the aqueous ethanol solution is 30-70%, and the amount of the aqueous ethanol solution is 5-8 times the mass of the moxifloxacin tartrate.

[0022] Further, the mass fraction of water in the aqueous ethanol solution is 40%-60%, and the amount of the aqueous ethanol solution is 6-7 times the mass of the moxifloxacin tartrate.

[0023] Preferably, in step S4, the step of separating the product comprises filtering, washing the separated solid with ethanol, and drying; the drying method is static air drying or vacuum reduced pressure drying at a temperature of 50-60℃.

[0024] Preferably, in step S4, the width of the large particle crystal of moxifloxacin hydrochloride Form II is 20-60μm, and the length is 150-600μm.

[0025] Compared with the prior art, the present application has the following advantages: In the present application, through comprehensive design of multiple details in the preparation process, the prepared moxifloxacin hydrochloride Form II crystal is coarse rod-shaped large particle, the crystal growth is perfect, the purity is high, and the size is uniform; the above characteristics make the moxifloxacin hydrochloride Form II crystal not easy to be caked, suitable for industrialized production and storage, and beneficial to mixing with excipients to prepare various preparations. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 Figure 4 is a micrograph of the large particle crystal of moxifloxacin hydrochloride Form II prepared in Example 3.

[0027] Figure 2 Figure 1 is a micrograph of the rod-shaped seed crystal of moxifloxacin hydrochloride Form II prepared in Example 1.

[0028] Figure 3 Figure 2 is a micrograph of the rod-shaped seed crystal of moxifloxacin hydrochloride Form II prepared in Example 2.

[0029] Figure 4 Figure 4 is a micrograph of the large particle crystal of moxifloxacin hydrochloride Form II prepared in Example 3.

[0030] Figure 5 Figure 5 is a micrograph of the large particle crystal of moxifloxacin hydrochloride Form II prepared in Example 5.

[0031] Figure 6 is a PXRD pattern of the large particle crystal of moxifloxacin hydrochloride Form II prepared in Example 5.

[0032] Figure 7 is a micrograph of the large particle crystal of moxifloxacin hydrochloride Form II prepared in Example 6.

[0033] Figure 8 is a PXRD pattern of the large particle crystal of moxifloxacin hydrochloride Form II prepared in Example 6.

[0034] Figure 9 is a micrograph of the large particle crystal of moxifloxacin hydrochloride Form II prepared in Comparative Example 1.

[0035] Figure 10 is a micrograph of the large particle crystal of moxifloxacin hydrochloride Form II prepared in Comparative Example 2.

[0036] Figure 11 is a micrograph of the large particle crystal of moxifloxacin hydrochloride Form II prepared in Comparative Example 3.

[0037] Figure 12 is a micrograph of the large particle crystal of moxifloxacin hydrochloride Form II prepared in Comparative Example 4.

[0038] Figure 13 is a micrograph of the large particle crystal of moxifloxacin hydrochloride Form II prepared in Comparative Example 5. DETAILED DESCRIPTION

[0039] The application will be further described in conjunction with the examples below.

[0040] A preparation method of large particle crystal of moxifloxacin hydrochloride Form II, comprising the following steps: S1: dissolving moxifloxacin tartrate in an ethanol aqueous solution; S2: adding concentrated hydrochloric acid and rod-shaped crystal seeds of moxifloxacin hydrochloride Form II in sequence, and stirring and aging; S3: continuously adding concentrated hydrochloric acid in batches, and stirring and aging after each batch; The temperature is maintained at 30-60°C during S2 and S3; S4: cooling for crystal growth, and separating the product to obtain large particle crystal of moxifloxacin hydrochloride Form II.

[0041] In some embodiments, in step S1, the mass fraction of water in the ethanol aqueous solution is 30-70%, and the amount of the ethanol aqueous solution is 5-8 times the mass of moxifloxacin tartrate.

[0042] In some embodiments, the total amount of concentrated hydrochloric acid used in steps S2 and S3 is 1.2-1.5 times the molar amount of moxifloxacin tartrate in step S1, the amount of concentrated hydrochloric acid used in step S2 is 0.6-1.0 times the molar amount of moxifloxacin tartrate in step S1, and the amount of concentrated hydrochloric acid added in each batch in step S3 is 0.2-0.3 times the molar amount of moxifloxacin tartrate in step S1.

[0043] In some embodiments, the concentration of the concentrated hydrochloric acid in steps S2 and S3 is 36-38 wt%, the rate of adding the concentrated hydrochloric acid is 0.4-1 mL / min, and the time for each stirring and aging step is 0.5-1 h.

[0044] In some embodiments, the step of cooling for crystal growth in step S4 includes cooling at a rate of 5-20 °C / h to -5-0 °C and stirring for 0.5-1 h.

[0045] In some embodiments, the step of separating the product in step S4 includes filtering, washing the separated solid with ethanol, and drying; the drying is performed by static air drying or vacuum reduced pressure drying at a temperature of 50-60 °C.

[0046] In some embodiments, the width of the large particle crystal of moxifloxacin hydrochloride Form II in step S4 is 20-60 μm, and the length is 150-600 μm.

[0047] In some embodiments, the width of the rod-shaped seed crystal of moxifloxacin hydrochloride Form II in step S2 is 5-15 μm, and the length is 50-150 μm; the amount used is 1-3% of the mass of moxifloxacin tartrate.

[0048] In some embodiments, the preparation step of the rod-shaped seed crystal of moxifloxacin hydrochloride Form II in step S2 includes dissolving moxifloxacin tartrate in an ethanol aqueous solution, stirring and crystallizing after adding concentrated hydrochloric acid at 40-50 °C, performing multiple temperature cycling, and then cooling and separating the product.

[0049] In the above preparation process of the rod-shaped seed crystal of moxifloxacin hydrochloride Form II, the following steps can be selected or preferred: The multiple temperature cycling step includes cycling the following processes 4-5 times: heating to 60-65 °C in 1-1.5 h, maintaining for 0.5-1 h, cooling to 40-50 °C in 2-2.5 h, and maintaining for 0.5-1 h; The cooling step includes cooling at a rate of 5-20 °C / h to -5-0 °C and stirring for 1-2.5 h; The step of separating the product comprises filtering, washing the separated solid with ethanol, and drying; the drying is carried out by static air drying or vacuum reduced pressure drying at a temperature of 50-60°C.

[0050] The application will be described in detail below with reference to specific examples. It should be understood that these examples are only used to illustrate the application and not to limit the scope of the application, and any changes and advantages that can be thought of by those skilled in the art without departing from the spirit and scope of the application are included in the application, and the appended claims and any equivalents thereof are the protection scope of the application.

[0051] Unless otherwise defined, all technical and scientific terms used in the application have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The raw materials and equipment used in the application are conventional raw materials and equipment in the art unless otherwise specified, which can be obtained from conventional commercial channels; the methods used in the application are conventional methods in the art unless otherwise specified.

[0052] Example 1: Preparation of moxifloxacin hydrochloride crystal form II rod-shaped seeds Moxifloxacin hydrochloride crystal form II rod-shaped seeds were prepared by the following steps: 6 g of moxifloxacin tartrate was added to 18 g of an ethanol aqueous solution (40% by mass of water), and the solution was dissolved at 40°C. 1.63 mL of 37% by mass hydrochloric acid was slowly added at a rate of 0.5 mL / min, and the solution was stirred at 40°C. Crystallization occurred after about 10 min. The following process was then repeated four times: the temperature was increased from 40°C to 60°C in 1 h, the temperature was maintained at 60°C for 0.5 h, the temperature was decreased from 60°C to 40°C in 2 h, and the temperature was maintained at 40°C for 0.5 h. After the cycle was completed, the temperature was decreased to -5°C at a rate of 20°C / h, and the solution was stirred at -5°C for 2.5 h. The separated solid was then filtered, washed with 2 x 6 mL of ethanol, and dried at 55°C by static air drying overnight to obtain 4.69 g of dry product, i.e., moxifloxacin hydrochloride crystal form II rod-shaped seeds, with a yield of 81.7%.

[0053] The microscopic image of the moxifloxacin hydrochloride crystal form II rod-shaped seeds prepared in this example is shown in FIG. 1. Figure 2 The image shows that the seeds prepared in this example are rod-shaped, most of the crystals have a width in the range of 5-15 μm and a length in the range of 50-150 μm, and the size is relatively uniform. Figure 2

[0054] Example 2: Preparation of moxifloxacin hydrochloride crystal form II rod-shaped seeds Moxifloxacin hydrochloride crystal form II rod-shaped seeds were prepared by the following steps: ​Add 12 g of moxifloxacin tartrate into 36 g of ethanol aqueous solution (40% of water by mass fraction), and dissolve at 40°C. Slowly add 3.3 mL of 37% hydrochloric acid at a rate of 0.7 mL / min, and stir at 40°C. After 6 min, the precipitation occurs. Then, repeat the following process 4 times: increase the temperature from 40°C to 60°C in 1 h, maintain at 60°C for 0.5 h, decrease the temperature from 60°C to 40°C in 2 h, and maintain at 40°C for 0.5 h. After the cycle, decrease the temperature to -5°C at a rate of 10°C / h, and stir at -5°C for 1 h. Then, filter, wash the separated solid with 2 x 12 mL of ethanol, and dry at 55°C overnight to obtain 9.4 g of dry product, i.e. moxifloxacin hydrochloride crystal form II rod-like seed crystal, with a yield of 81.9%.

[0055] The microscopic image of the moxifloxacin hydrochloride crystal form II rod-like seed crystal prepared in this example is shown in Fig. 1. Figure 3 Figure 3 It is shown that the seed crystal prepared in this example is rod-like, most of the crystals have a width of 5-15 μm and a length of 50-150 μm, and the size is uniform.

[0056] Example 3: Preparation of moxifloxacin hydrochloride crystal form II large particle crystal The moxifloxacin hydrochloride crystal form II large particle crystal is prepared by the following steps: Add 6 g of moxifloxacin tartrate into 36 g of ethanol aqueous solution (60% of water by mass fraction), and dissolve at 30°C. Maintain the temperature at 30°C, slowly add 0.81 mL of 37% hydrochloric acid at a rate of 0.4 mL / min, and then add 60 mg of moxifloxacin hydrochloride crystal form II rod-like seed crystal prepared according to the method of Example 1, and stir for 30 min. During the stirring, the solid is observed to increase slowly. Then, maintain the temperature at 30°C, and drop 0.23 mL of 37% hydrochloric acid at a rate of 0.4 mL / min, stir for 30 min, drop 0.23 mL of 37% hydrochloric acid at a rate of 0.4 mL / min, stir for 30 min, and then drop 0.35 mL of 37% hydrochloric acid at a rate of 0.5 mL / min, and stir for 60 min. After that, decrease the temperature to -5°C at a rate of 20°C / h, and stir at -5°C for 0.5 h. Filter, wash the separated solid with 2 x 6 mL of ethanol, and dry at 55°C overnight to obtain 4.65 g of dry product, i.e. moxifloxacin hydrochloride crystal form II large particle crystal, with a yield of 81.0%.

[0057] The microscopic image of the moxifloxacin hydrochloride crystal form II large particle crystal prepared in this example is shown in Fig. 2. Figure 1 Figure 1 ​​The crystals prepared in this example are rod-shaped, most of the crystals have a width of 20-60 μm and a length of 150-600 μm, and the size is relatively uniform.

[0058] Example 4: Preparation of large particle crystals of moxifloxacin hydrochloride Form II The large particle crystals of moxifloxacin hydrochloride Form II were prepared by the following steps: The 6 g of moxifloxacin tartrate was added to 36 g of an aqueous ethanol solution (40% by mass of water) and warmed to 60°C until dissolved. The temperature was maintained at 60°C, and 0.81 mL of 37% by mass hydrochloric acid was slowly added at a rate of 1 mL / min, followed by the addition of 180 mg of rod-shaped seed crystals of moxifloxacin hydrochloride Form II prepared according to the method of Example 1. The mixture was stirred and aged for 30 min, during which time the solid increased slowly. The temperature was then maintained at 60°C, and 0.23 mL of 37% by mass hydrochloric acid was added dropwise at a rate of 1 mL / min. The mixture was stirred and aged for 30 min, and then 0.23 mL of 37% by mass hydrochloric acid was added dropwise at a rate of 1 mL / min. The mixture was stirred and aged for 30 min. The temperature was then decreased to -5°C at a rate of 20°C / h, and the mixture was stirred at this temperature for 0.5 h. The mixture was filtered, and the separated solid was washed with 2 x 6 mL of ethanol. The washed solid was dried by standing in a 55°C forced air oven overnight, to give 4.67 g of dry product, i.e., large particle crystals of moxifloxacin hydrochloride Form II, in a yield of 81.4%.

[0059] The micrograph of the large particle crystals of moxifloxacin hydrochloride Form II prepared in this example is shown in Figure 2. Figure 4 Figure 4 The crystals prepared in this example are rod-shaped, most of the crystals have a width of 20-60 μm and a length of 150-600 μm, and the size is relatively uniform.

[0060] Example 5: Preparation of large particle crystals of moxifloxacin hydrochloride Form II The large particle crystals of moxifloxacin hydrochloride Form II were prepared by the following steps: ​24 g of moxifloxacin tartrate was added to 130 g of an aqueous ethanol solution (40% water by mass), and the solution was heated to 40 °C to dissolve completely. While maintaining the temperature at 40 °C, 3.55 mL of 37 wt% concentrated hydrochloric acid was slowly added at a rate of 1 mL / min, followed by 480 mg of moxifloxacin hydrochloride crystals (type II rod-shaped) prepared according to Example 1. The mixture was stirred and allowed to crystallize for 37 min, during which a slow increase in solid content was observed. The temperature was then maintained at 40 °C, and 0.88 mL of 37 wt% concentrated hydrochloric acid was added dropwise at a rate of 0.4 mL / min, with stirring for 30 min. This was repeated for 30 min, followed by the addition of 1.32 mL of 37 wt% concentrated hydrochloric acid at a rate of 0.7 mL / min, with stirring for 30 min. The mixture was then cooled to -5 °C at a rate of 10 °C / h and stirred at this constant temperature for 1 h. The solid was filtered and washed with 2×24mL of ethanol (i.e., washed twice with ethanol, each time using 24mL of ethanol). It was then dried overnight at 55℃ by forced air drying to obtain 19.09g of dried product, which is moxifloxacin hydrochloride crystal form II large particle crystals, with a yield of 83.1%.

[0061] Micrograph of the large-particle crystals of moxifloxacin hydrochloride (type II) prepared in this embodiment is shown below. Figure 5 As shown. Figure 5 The crystals obtained in this embodiment are rod-shaped, with most crystals having a width in the range of 20 to 60 μm and a length in the range of 150 to 600 μm, and their dimensions are relatively uniform.

[0062] The PXRD pattern of the large-particle crystals of moxifloxacin hydrochloride (type II) obtained in this embodiment is as follows: Figure 6 As shown, the crystal obtained in this embodiment is a pure crystal form II, without impurities of other crystal forms.

[0063] Example 6: Preparation of large-particle crystals of moxifloxacin hydrochloride crystal form II Large-particle crystals of moxifloxacin hydrochloride (type II) were prepared using the following steps: To 180 g of an ethanol aqueous solution (40% by mass of water) was added 24 g of the mosifloxacin tartrate salt, and the temperature was raised to 40°C to dissolve the solid. The temperature was maintained at 40°C, and 3.55 mL of 37% by mass hydrochloric acid was added at a rate of 0.7 mL / min, followed by the addition of 480 mg of the seed crystal of the mosifloxacin hydrochloride Form II prepared according to the method of Example 2, and the mixture was stirred for 30 min to allow the crystals to grow. During this time, the solid was observed to increase slowly. The temperature was then maintained at 40°C, and 0.88 mL of 37% by mass hydrochloric acid was added at a rate of 0.4 mL / min, the mixture was stirred for 30 min to allow the crystals to grow, and then 0.88 mL of 37% by mass hydrochloric acid was added at a rate of 0.4 mL / min, the mixture was stirred for 30 min to allow the crystals to grow, and then 1.32 mL of 37% by mass hydrochloric acid was added at a rate of 0.7 mL / min, the mixture was stirred for 30 min to allow the crystals to grow. The temperature was then lowered to -5°C at a rate of 10°C / h, and the mixture was stirred at this temperature for 1 h. The solid was filtered, washed with 2 x 24 mL of ethanol, and dried at 50°C under reduced pressure for 8 h to give 18.98 g of the mosifloxacin hydrochloride Form II macrocrystals, which had a yield of 82.7%.

[0064] The micrograph of the mosifloxacin hydrochloride Form II macrocrystals prepared in this example is shown in Figure 2. Figure 7 Figure 7 As shown, the crystals prepared in this example were rod-shaped, and most of the crystals had a width of 20-60 μm and a length of 150-600 μm, and the size was uniform.

[0065] The PXRD pattern of the mosifloxacin hydrochloride Form II macrocrystals prepared in this example is shown in Figure 3, which indicates that the crystals prepared in this example were pure Form II crystals and did not contain impurities of other crystal forms. Figure 8

[0066] Comparative Example 1: Preparation of Mosifloxacin Hydrochloride Form II Crystals The difference between this comparative example and Example 3 is that in this comparative example, the seed crystals were added before the first batch of the concentrated hydrochloric acid. Specifically, the mosifloxacin hydrochloride Form II crystals were prepared by the following steps in this comparative example: ​​6 g of moxifloxacin tartrate was added to 36 g of an aqueous ethanol solution (containing 60% water by mass), and the solution was heated to 30 °C to dissolve completely. 60 mg of moxifloxacin hydrochloride crystals (type II rod-shaped) prepared according to Example 1 were added. The temperature was maintained at 30 °C, and 0.81 mL of 37 wt% concentrated hydrochloric acid was slowly added at a rate of 0.4 mL / min, with stirring for 30 min. During this time, a rapid increase in solid content was observed. The temperature was then maintained at 30 °C, and 0.23 mL of 37 wt% concentrated hydrochloric acid was added dropwise at a rate of 0.4 mL / min, with stirring for 30 min. This was repeated for 30 min, followed by the addition of 0.23 mL of 37 wt% concentrated hydrochloric acid at a rate of 0.4 mL / min, and stirring for another 30 min. Finally, 0.35 mL of 37 wt% concentrated hydrochloric acid was added dropwise at a rate of 0.5 mL / min, with stirring for 60 min. The temperature was then lowered to -5 °C at a rate of 20 °C / h, and the mixture was stirred at this constant temperature for 0.5 h. The solid was filtered and washed with 2×6mL of ethanol (i.e., washed twice with ethanol, each time using 6mL of ethanol). It was then dried overnight at 55℃ by forced air drying to obtain 4.54g of dried product, which is moxifloxacin hydrochloride crystal form II crystal, with a yield of 79.1%.

[0067] Micrographs of moxifloxacin hydrochloride crystal form II prepared in this comparative example are shown below. Figure 9 As shown. Figure 9 The crystals are slender rod-shaped, with most crystals having a width of less than 10 μm and a length ranging from 100 to 250 μm.

[0068] Comparative Example 2: Preparation of Moxifloxacin Hydrochloride Crystal Form II Crystals The only difference between this comparative example and Example 3 is that the temperature for adding concentrated hydrochloric acid, seed crystals, and the crystal growth process is lowered in this comparative example. Specifically, this comparative example prepares moxifloxacin hydrochloride crystal form II crystals through the following steps: Example 4: Preparation of crystalline form II of moxifloxacin hydrochloride

[0069] The micrograph of the crystalline form II of moxifloxacin hydrochloride prepared in this comparative example is shown in Fig. 4. Figure 10 Figure 10 It can be seen that the crystals are thin rod-like, and most of the crystals have a width of less than 10 μm and a length in the range of 50-150 μm.

[0070] Comparative Example 3: Preparation of crystalline form II of moxifloxacin hydrochloride The difference between this comparative example and Example 5 is that the amount of seed crystal is reduced in this comparative example. Specifically, crystalline form II of moxifloxacin hydrochloride is prepared in this comparative example by the following steps: ​To 24 g of moxifloxacin tartrate, 130 g of ethanol aqueous solution (40% by mass of water) was added, and the mixture was warmed to 40°C to dissolve. The temperature was maintained at 40°C, and 3.55 mL of 37% by weight hydrochloric acid was added at a rate of 1 mL / min, and 120 mg of seed crystal of moxifloxacin hydrochloride Form II prepared according to the method of Example 1 was added, and the mixture was stirred for 35 min, during which time the solid increased rapidly. Then the temperature was maintained at 40°C, and 0.88 mL of 37% by weight hydrochloric acid was added at a rate of 0.4 mL / min, and the mixture was stirred for 30 min, and 0.88 mL of 37% by weight hydrochloric acid was added at a rate of 0.4 mL / min, and the mixture was stirred for 30 min, and 1.32 mL of 37% by weight hydrochloric acid was added at a rate of 0.7 mL / min, and the mixture was stirred for 30 min. Thereafter, the temperature was decreased to -5°C at a rate of 10°C / h, and the mixture was stirred at -5°C for 1 h. The solid was filtered, and the isolated solid was washed with 2 x 24 mL of ethanol, and the solid was dried by standing in a 55°C forced air oven overnight, to give 18.86 g of dry product, i.e., moxifloxacin hydrochloride Form II crystals, in a yield of 82.1%.

[0071] The micrograph of the moxifloxacin hydrochloride Form II crystals prepared in this comparative example is shown in Fig. 2. Figure 11 Figure 11 The micrograph shows that the crystal particle size is not uniform, and there are a small number of coarse rod-shaped crystals about 30 μm wide and about 400 μm long, and most of the crystals are thin rod-shaped or needle-shaped crystals less than 10 μm wide.

[0072] Comparative Example 4: Preparation of Moxifloxacin Hydrochloride Form II Crystals The only difference between this comparative example and Example 5 is that the amount of seed crystal was increased in this comparative example. Specifically, moxifloxacin hydrochloride Form II crystals were prepared in this comparative example by the following procedure: ​To 24 g of moxifloxacin tartrate, 130 g of ethanol aqueous solution (40% by mass of water) was added, and the solution was warmed to 40°C until it became clear. The temperature was maintained at 40°C, and 3.55 mL of 37% by mass hydrochloric acid was added at a rate of 1 mL / min, followed by the addition of 600 mg of seed crystal of moxifloxacin hydrochloride Form II prepared according to the method of Example 1, and the solution was stirred for 35 min, during which time the solid increased rapidly. The temperature was then maintained at 40°C, and 0.88 mL of 37% by mass hydrochloric acid was added at a rate of 0.4 mL / min, the solution was stirred for 30 min, and then 0.88 mL of 37% by mass hydrochloric acid was added at a rate of 0.4 mL / min, the solution was stirred for 30 min, and then 1.32 mL of 37% by mass hydrochloric acid was added at a rate of 0.7 mL / min, the solution was stirred for 30 min. The temperature was then decreased to -5°C at a rate of 10°C / h, and the solution was stirred at this temperature for 1 h. The solid was filtered, and the isolated solid was washed with 2 x 24 mL of ethanol, and then dried by placing it in a 55°C forced air oven overnight. The yield of dry product was 18.04 g of moxifloxacin hydrochloride Form II crystals, which was 78.6% of the theoretical yield.

[0073] The micrograph of the moxifloxacin hydrochloride Form II crystals prepared in this comparative example is shown in Figure 2. Figure 12 Figure 12 As shown in Figure 2, the crystal particles were not uniform in size, and there were long rod-shaped crystals with a width of about 20-60 μm and a length of about 500-1000 μm, and there were also a significant proportion of thin rod-shaped or needle-shaped crystals with a width of less than 10 μm.

[0074] Comparative Example 5 The only difference between this comparative example and Example 3 is that in this comparative example, the amount of hydrochloric acid added before the seed crystal was increased, and the amount of hydrochloric acid added after the seed crystal was decreased, while the total amount of hydrochloric acid was kept constant. Specifically, moxifloxacin hydrochloride Form II crystals were prepared by the following steps: ​Example 2 6 g of Mosifloxacin tartrate was added to 36 g of ethanol aqueous solution (60% by mass of water) and warmed to 30°C to dissolve. The temperature was maintained at 30°C, 1.25 mL of 37% hydrochloric acid was added at a rate of 0.4 mL / min, and 60 mg of seed crystal of Mosifloxacin hydrochloride Form II prepared according to the method of Example 1 was added, and the mixture was stirred for 30 min. During this time, the solid increased rapidly. Then the temperature was maintained at 30°C, 0.11 mL of 37% hydrochloric acid was added at a rate of 0.4 mL / min, and the mixture was stirred for 30 min. Then 0.11 mL of 37% hydrochloric acid was added at a rate of 0.4 mL / min, and the mixture was stirred for 30 min. Then 0.15 mL of 37% hydrochloric acid was added at a rate of 0.5 mL / min, and the mixture was stirred for 60 min. After that, the temperature was decreased to -5°C at a rate of 20°C / h, and the mixture was stirred at -5°C for 0.5 h. The mixture was filtered, and the separated solid was washed with 2 x 6 mL of ethanol, and dried at 55°C overnight. The dried product was 4.54 g of Mosifloxacin hydrochloride Form II, and the yield was 79.1%.

[0075] The micrograph of the Mosifloxacin hydrochloride Form II crystal prepared in this comparative example is shown in Fig. 2. Figure 13 Figure 13 As shown in Fig. 2, the crystal particles were substantially elongated rod-shaped or needle-shaped crystals of uneven size, with a small amount of crystals having a width of 10-20 μm, and most of the crystals having a width of less than 10 μm.​

Claims

1. A method for preparing large-particle crystals of moxifloxacin hydrochloride crystal form II, characterized in that, Includes the following steps: S1: Dissolve moxifloxacin tartrate in an aqueous ethanol solution; S2: Add concentrated hydrochloric acid and moxifloxacin hydrochloride crystal type II rod-shaped seed crystals in sequence, and stir to grow crystals; S3: Continue to add concentrated hydrochloric acid in batches, stirring and crystallizing after each batch. During both S2 and S3, the temperature was maintained at 30~60℃; S4: Cool down to grow crystals, separate the product, and obtain large-particle crystals of moxifloxacin hydrochloride crystal form II.

2. The preparation method according to claim 1, characterized in that, Based on HCl, the total amount of concentrated hydrochloric acid used in steps S2 and S3 is 1.2 to 1.5 times the molar amount of moxifloxacin tartrate in step S1, the amount of concentrated hydrochloric acid used in step S2 is 0.6 to 1.0 times the molar amount of moxifloxacin tartrate in step S1, and the amount of concentrated hydrochloric acid added in each batch in step S3 is 0.2 to 0.3 times the molar amount of moxifloxacin tartrate in step S1.

3. The preparation method according to claim 1 or 2, characterized in that, In steps S2 and S3, the concentration of the concentrated hydrochloric acid is 36-38 wt%, the rate of addition of the concentrated hydrochloric acid is 0.4-1 mL / min, and the stirring and crystallization time for each step is 0.5-1 h.

4. The preparation method according to claim 1, characterized in that, In step S2, the moxifloxacin hydrochloride crystal type II rod-shaped seed crystals have a width of 5~15 μm and a length of 50~150 μm, and the amount used is 1~3% of the mass of moxifloxacin tartrate.

5. The preparation method according to claim 4, characterized in that, In step S2, the preparation steps of the moxifloxacin hydrochloride crystal form II rod-shaped seed crystals include: dissolving moxifloxacin tartrate in an ethanol aqueous solution, adding concentrated hydrochloric acid at 40~50℃ and stirring to spontaneously crystallize, performing multiple heating and cooling cycles, and then cooling to separate the product.

6. The preparation method according to claim 5, characterized in that, The multiple heating and cooling cycles include repeating the following process 4 to 5 times: heating to 60 to 65°C within 1 to 1.5 hours and maintaining it for 0.5 to 1 hour, then cooling to 40 to 50°C within 2 to 2.5 hours and maintaining it for 0.5 to 1 hour.

7. The preparation method according to claim 1, characterized in that, In step S4, the step of cooling to grow crystals includes: cooling to -5 to 0°C at a rate of 5 to 20°C / h and stirring for 0.5 to 1 h.

8. The preparation method according to claim 1, characterized in that, In step S1, the water content in the ethanol-water solution is 30-70% by mass, and the amount used is 5-8 times the mass of moxifloxacin tartrate.

9. The preparation method according to claim 1, characterized in that, In step S4, the step of separating the product includes: filtration, washing the separated solid with ethanol, and drying; the drying method is static air drying or vacuum drying, and the temperature is 50~60℃.

10. The preparation method according to claim 1, characterized in that, In step S4, the moxifloxacin hydrochloride crystal type II large particle crystals have a width of 20~60 μm and a length of 150~600 μm.

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