Crystal form X norfloxacin and preparation method thereof

Abstract

The invention discloses crystal form X norfloxacin and a preparation method thereof, and belongs to the technical field of medicines. Compared with norfloxacin in other crystal forms, the norfloxacin in the crystal form X has the advantages of being good in thermal stability, not prone to being decomposed when meeting light, low in hygroscopicity and the like, a new selection way is provided for norfloxacin medicine preparations, the norfloxacin can be obtained through simple crystal form conversion of existing commercial norfloxacin, the method is simple, efficient and low in cost, and the industrial production requirement is met.

Description

Technical Field

[0001] The invention relates to norfloxacin, in particular to a crystal form X norfloxacin and a preparation method thereof, belonging to the technical field of medicine. Background Art

[0002] Norfloxacin is a fluoroquinolone antibiotic with a broad-spectrum antibacterial effect, especially high antibacterial activity against Gram-negative bacteria. For example, it has good antibacterial effects on a variety of bacteria in vitro: most bacteria of the Enterobacteriaceae family, including Citrobacter, Enterobacter cloacae, Enterobacter aerogenes and other Enterobacter species, Escherichia coli, Klebsiella, Proteus, Salmonella, Shigella, Vibrio, Yersinia, etc. Norfloxacin also has antibacterial effects on a variety of drug-resistant bacteria in vitro. Norfloxacin is a bactericide that acts on the A subunit of bacterial DNA helicase, inhibiting DNA synthesis and replication, leading to bacterial death. The original product of norfloxacin oral preparation is norfloxacin tablets (trade name: BACCIDAL, Baccidal) produced by KYORIN Pharmaceutical Co., Ltd., Japan, which was approved for marketing in Japan in 1984 and is a reference preparation included in the Japanese Orange Book and my country's consistency evaluation. The literature ("Complete characterization and relativestability of its trimorphic system", R. Barbas, et al., Journal of Thermal Analysis and Calorimetry, Vol. 89 (2007) 3, 687-692) reported the characteristics of the three crystalline forms of norfloxacin (Form A, Form B, Form C), as shown in Table 1:

[0003] Table 1

[0004]

[0005] Norfloxacin is a low-solubility, low-permeability drug and should be classified as Class IV in the BCS classification. It has low oral availability, unstable properties, is easily decomposed by light, and is easily hygroscopic. In addition, due to the existence of polymorphic forms of norfloxacin, crystal transformation may occur during the wet-heat process of granulation, resulting in poor stability. Summary of the invention

[0006] The norfloxacin reported in the prior art mainly includes A, B, C, and E. Among them, the norfloxacin crystal form C is relatively stable, but its dissolution effect in the preparation is slightly poor. The stability of the crystal forms A and B is poor and it is easy to absorb moisture during storage. The stability of the crystal forms D and E is average and the hygroscopicity is weak. The first object of the present invention is to provide a crystal form X norfloxacin, which has good stability, weak hygroscopicity, and good dissolution performance.

[0007] The second object of the present invention is to provide a method for preparing crystal form X norfloxacin, which is simple, efficient, low-cost and meets the requirements of industrial production. In particular, the present invention can directly prepare crystal form X norfloxacin using commercialized norfloxacin, and can also be obtained using industrial crude products. The prepared crystal form X norfloxacin has a uniform particle size distribution and a suitable particle size, and can be used for preparations without being crushed.

[0008] In order to achieve the above technical objectives, the present invention provides a crystal form X of norfloxacin.

[0009] The chemical structure of the crystal form X norfloxacin of the present invention is as follows:

[0010]

[0011] Compared with other existing crystalline forms of norfloxacin, it is identical in chemical structure, but only in crystal configuration. In terms of physical and chemical properties, crystalline form X norfloxacin has advantages over other crystalline forms of norfloxacin, such as good thermal stability, not easy to decompose when exposed to light, and low hygroscopicity.

[0012] As a preferred embodiment, the X-ray powder diffraction pattern of the X-crystalline form norfloxacin has diffraction peaks at the following 2θ angles: 9.88°±0.2°, 11.77°±0.2°, 12.03°±0.2°, 25.17°±0.2°, and 25.45°±0.2°.

[0013] As a more preferred embodiment, the X-ray powder diffraction pattern of the X-crystalline form norfloxacin has diffraction peaks at the following 2θ angles: 7.83°±0.2°, 9.88°±0.2°, 11.77°±0.2°, 12.03°±0.2°, 12.39°±0.2°, 18.79°±0.2°, 20.10°±0.2°, 22.80°±0.2°, 23.71°±0.2°, 25.17°±0.2°, 25.45°±0.2°, and 26.39°±0.2°.

[0014] The present invention also provides a method for preparing crystal form X norfloxacin, which comprises the following steps:

[0015] Step 1: dissolving norfloxacin in an alkaline solution to obtain a norfloxacin salt solution;

[0016] Step 2: adjusting the pH of the norfloxacin salt solution to a weakly acidic state with an acid solution for precipitation, and filtering to obtain a solid;

[0017] Step 3: Transfer the solid matter into an anhydrous ethanol solvent, first heat it up to reflux, then cool it down to age, filter and dry, and thus obtain Form X norfloxacin.

[0018] In the preparation process of the crystal form X norfloxacin of the present invention, factors such as the solvent used and the precipitation temperature have an important influence on the crystal form of norfloxacin. For example, the crystal form X norfloxacin can only be obtained by using anhydrous ethanol. The present invention tried organic solvents such as propanol, isopropanol, and isobutanol, but no crystal form X norfloxacin was obtained, and when water and ethanol were used as solvents, a mixture of polymorphs was obtained. It should be particularly noted that the anhydrous ethanol used in the present invention is industrial anhydrous ethanol that has been dehydrated by means of molecular sieves and the like, and its purity is above 99.5%.

[0019] As a preferred solution, the cooling and aging process is: cooling to 0-10°C at a cooling rate of 5-10°C / h, and keeping the temperature for aging for 10-20h. The cooling rate and temperature control range during the cooling and aging process are also very important for the crystal form of norfloxacin. If the cooling rate and temperature are not within the preferred range, it is difficult to obtain the crystal form X norfloxacin.

[0020] As a preferred solution, the drying condition is to dry at a temperature of 95 to 105° C. for 8 to 10 hours under blast drying conditions.

[0021] The crystal form X norfloxacin provided by the present invention can be used to prepare pharmaceutical preparations, in particular to prepare broad-spectrum antibacterial drugs, such as antibacterial drugs using the crystal form X norfloxacin as an active ingredient and using pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles or combinations thereof.

[0022] The crystal form X norfloxacin of the present invention is crystalline and has at least 50% crystallinity, preferably at least 60% crystallinity, more preferably at least 70% crystallinity, and most preferably at least 80% crystallinity. Crystallinity or crystallinity can be evaluated by conventional X-ray diffraction techniques.

[0023] Compared with the prior art, the technical solution of the present invention has the following beneficial technical effects:

[0024] Compared with the existing known crystalline form of norfloxacin, the crystalline form X norfloxacin provided by the present invention has the characteristics of better stability, weaker hygroscopicity, and better dissolution performance.

[0025] The preparation method of the crystal form X norfloxacin of the present invention is simple and has mild conditions. In particular, it can be obtained by simple crystal form transformation of commercial norfloxacin, or directly prepared by using a synthetic crude norfloxacin product. It is easy to obtain and has low cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is the X-ray powder diffraction pattern of norfloxacin prepared in Example 2.

[0027] Figure 2 This is the X-ray powder diffraction pattern of Form X norfloxacin prepared in Example 1.

[0028] Figure 3 This is the DSC graph of Form X norfloxacin prepared in Example 1.

[0029] Figure 4 This is the HPLC detection spectrum of the finished product of Form X norfloxacin prepared in Example 1.

[0030] Figure 5 This is the HPLC detection spectrum of the crystalline form X norfloxacin product prepared in Example 1 stored in an oven at 100° C. for 72 h.

[0031] Figure 6 This is the HPLC detection spectrum of the purchased raw material norfloxacin finished product stored in an oven at 100℃ for 72h.

[0032] Figure 7 The dissolution curves of the tablets of Form X norfloxacin prepared in Example 1 and the reference control. DETAILED DESCRIPTION

[0033] The technical solution of the present invention is illustrated below by way of example, and the scope of protection requested by the present invention includes but is not limited to the following embodiments.

[0034] X-ray powder diffraction (XRPD) can detect information such as changes in crystal forms, crystallinity, and crystal structure states, and is a common means of identifying crystal forms. The peak position of the XRPD spectrum depends mainly on the structure of the crystal form, is relatively insensitive to experimental details, and its relative peak height depends on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by an XRPD pattern with certain peak positions, which is substantially as shown in the XRPD pattern provided in the accompanying drawings of the present invention. At the same time, the measurement of 2θ of the XRPD spectrum may have experimental errors, and the measurement of 2θ of the XRPD spectrum may be slightly different between different instruments and different samples, so the value of 2θ cannot be regarded as absolute. According to the instrument conditions used in the test of the present invention, there is an error tolerance of ±0.2° for the diffraction peak.

[0035] In the context of the present invention, 2θ values ​​in X-ray powder diffraction patterns are given in degrees (°).

[0036] The term "substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern, or the DSC pattern, or the Raman spectrum pattern, or the infrared spectrum pattern are shown in the pattern.

[0037] When referring to a spectrum and / or data appearing in a graph, a "peak" refers to a feature that can be identified by one skilled in the art and which cannot be attributed to background noise.

[0038] Whenever a number having the value N is disclosed, any number having the value N±0.01, N±0.02, N±0.03, N±0.05, N±0.07, N±0.08, N±0.1, N±0.15, N±0.2, N±1, N±2, N±1.5, N±3, N±4, N±5, N±6, N±7, N±8, N±9, N±10, N±15, N±20 is specifically disclosed, where "±" means plus or minus. Whenever a lower limit, RL, and an upper limit, RU, are disclosed in a numerical range, any value within the disclosed range is specifically disclosed.

[0039] “Relative intensity” refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak among all diffraction peaks in an X-ray powder diffraction pattern (XRPD) when the intensity of the first strongest peak is 100%.

[0040] In the context of the present invention, when or whether the word "about" or "approximately" is used, it means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, for a person of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error range of the mean value.

[0041] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0042] Unless otherwise specified, the chemical raw materials involved in the following examples were obtained through commercial channels or by reference to existing literature.

[0043] Example 1

[0044]

[0045] 1. Compound 1 (commercial product, analytical grade, 500.00 g, 1 eq) was added to a three-necked flask, and 10% sodium hydroxide aqueous solution (2.50 kg, 4 eq) and activated carbon (25 g, 5 wt%) were added. The system was heated to 45°C and stirred for 1 h. Water (1000 ml, mainly for dilution to facilitate filtration and separation) was added to the system, and the temperature was lowered to 0°C. The activated carbon was filtered out (the introduction of activated carbon was only to remove a small amount of impurities). Acetic acid was added to the filtrate to adjust the pH to 6.7, and the filter cake was transferred to anhydrous ethanol (1500 ml), heated and refluxed with stirring for 1 h, cooled to 5°C at a cooling rate of 8°C / h, and the stirring was stopped. The system was aged for 15 h and filtered. The filter cake was dried in a forced air drying oven at 100°C for 9 h.

[0046] 2. Collect the material to obtain 481.23 g of Form X norfloxacin, with a yield of 96.24% and a purity of 99.83%. The X-ray powder diffraction pattern of Form X norfloxacin is as follows: Figure 2 shown.

[0047] Example 2

[0048]

[0049] 1. Add compound 1 (commercial product, analytical grade, 500.00 g, 1 eq) to a three-necked flask, add 10% sodium hydroxide aqueous solution (2.50 kg, 4 eq), activated carbon (25 g, 5%), heat the system to 45°C and stir for 1 hour. Add water (1000 ml) to the system, cool to 0°C, filter to remove the activated carbon, add acetic acid to the filtrate to adjust the pH to 6.7, filter, transfer the filter cake to ethanol aqueous solution (750 mL ethanol, 750 ml water), heat and reflux and stir for 1 hour, cool to 5°C at a cooling rate of 8°C / h, stop stirring, keep warm for 15 hours, filter, and dry the filter cake in a forced air drying oven at 100°C for 24 hours.

[0050] 2. Collect the material to obtain 456.15 g of Form X norfloxacin with a yield of 91.23%. The XRD results are as follows: Figure 1 Compared with Example 1, it can be seen that the introduction of water has a significant effect on the norfloxacin crystal form. After the introduction of water, polymorphic crystal form X norfloxacin is obtained, not a single crystal form X norfloxacin.

[0051] Performance Testing:

[0052] The present invention was identified by Empyrean X-ray powder diffraction (XRPD) analysis using Cu-Kα radiation and had the following characteristic peaks expressed in angles 2θ: XRD data are shown in Tables 2 and Figure 2 As shown:

[0053] Table 2

[0054]

[0055]

[0056] Note: Only data with strength above 25% are recorded.

[0057] The thermal stability of the crystal form X norfloxacin was tested under high temperature conditions of 100°C. The purity of the finished product was 99.83% ( Figure 4 ), after being stored in a blast drying oven with air circulation at 100°C for 72 hours, the purity still remains at 99.77% ( Figure 5 ), the purity of the purchased raw materials increased significantly after being stored in a blast drying oven with air circulation at 100°C for 72 hours, and the purity dropped to 99.04% ( Figure 6 ).

[0058] Table 3 Hygroscopicity test (RH65%)

[0059] 1h 2h 3h 4h 6h 8h 24h X crystal form 0.69％ 0.97％ 1.09％ 1.20％ 1.39％ 1.60％ 1.97％

[0060] From the hygroscopicity data, the hygroscopicity of crystal X norfloxacin is not significantly different from the reported crystal form D norfloxacin (24h hygroscopicity data is 1.7%) and crystal form E norfloxacin (24h hygroscopicity data is 2.01%).

[0061] Table 4 pH = 6.8 dissolution data

[0062]

[0063]

[0064] The results showed that in a pH = 6.8 medium (pH = 6.8 medium refers to sodium phosphate buffer solution, the specific preparation method is as follows: take 6.9g of sodium dihydrogen phosphate, 0.9g of sodium hydroxide, 5g of sodium dodecyl sulfate, add 800ml of water, ultrasonic for 30 minutes, adjust the pH value to 6.8 with 2mol / L sodium hydroxide solution, dilute to 1000mL with water, shake well, ultrasonic, and set aside), the dissolution curves of the raw materials of crystal form X norfloxacin and are similar to those of the reference preparation, such as Figure 7 shown.

[0065] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention is described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A crystal form X of norfloxacin.

2. A crystal form X norfloxacin according to claim 1, characterized in that: The X-ray powder diffraction pattern of the X-crystalline form norfloxacin has diffraction peaks at the following 2θ angles: 9.88°±0.2°, 11.77°±0.2°, 12.03°±0.2°, 25.17°±0.2°, and 25.45°±0.2°.

3. A crystal form X norfloxacin according to claim 1 or 2, characterized in that: The X-ray powder diffraction pattern of the X-crystalline form norfloxacin has diffraction peaks at the following 2θ angles: 7.83°±0.2°, 9.88°±0.2°, 11.77°±0.2°, 12.03°±0.2°, 12.39°±0.2°, 18.79°±0.2°, 20.10°±0.2°, 22.80°±0.2°, 23.71°±0.2°, 25.17°±0.2°, 25.45°±0.2°, and 26.39°±0.2°.

4. A method for preparing a crystal form X of norfloxacin according to any one of claims 1 to 3, characterized in that: The following steps are involved: Step 1: dissolving norfloxacin in an alkaline solution to obtain a norfloxacin salt solution; Step 2: adjusting the pH of the norfloxacin salt solution to a weakly acidic state with an acid solution for precipitation, and filtering to obtain a solid; Step 3: Transfer the solid matter into an anhydrous ethanol solvent, first heat it up to reflux, then cool it down to age, filter and dry it to obtain Form X norfloxacin.

5. The method for preparing a crystal form X norfloxacin according to claim 4, characterized in that: The alkaline solution includes at least one of a sodium hydroxide solution and a potassium hydroxide solution; The acid solution includes at least one of acetic acid, boric acid, hydrochloric acid, sulfuric acid, tartaric acid, phosphoric acid, and citric acid.

6. The method for preparing a crystal form X norfloxacin according to claim 4, characterized in that: The pH is adjusted to be greater than or equal to 6.5 and less than 7.

7. The method for preparing a crystalline form X norfloxacin according to claim 4, characterized in that: The reflux time is 1 to 3 hours.

8. The method according to claim 4, characterized in that: The cooling and aging process is: cooling to 0-10°C at a cooling rate of 5-10°C / h, and keeping the temperature for 10-20h.

9. The method for preparing a crystal form X norfloxacin according to claim 4, characterized in that: The drying conditions are: under vacuum conditions, at a temperature of 60 to 70° C., for 8 to 10 hours.

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