A crystalline form x of norfloxacin and a preparation method thereof

Abstract

The application discloses a crystalline form X norfloxacin and a preparation method thereof, and belongs to the technical field of medicines. The crystalline form X norfloxacin has the advantages of good thermal stability, low moisture absorption and not easy to decompose under light, compared with other crystalline forms of norfloxacin, provides a new selection way for norfloxacin pharmaceutical preparations, and can be obtained by simple crystalline form conversion of existing commercial norfloxacin, so that the method is simple, efficient, low in cost and meets the requirements of industrial production.

Description

Technical Field

[0001] This invention relates to norfloxacin, specifically to a crystalline form X norfloxacin, and also to its preparation method, belonging to the field of pharmaceutical technology. Background Technology

[0002] Norfloxacin is a fluoroquinolone antibiotic with broad-spectrum antibacterial activity, particularly against Gram-negative bacilli. For example, it exhibits good in vitro antibacterial activity against a variety of bacteria, including most Enterobacteriaceae, such as *Citrobacter*, *Enterobacter cloacae*, *Enterobacter aerogenes*, *Escherichia coli*, *Klebsiella*, *Proteus*, *Salmonella*, *Shigella*, *Vibrio*, and *Yersinia*. Norfloxacin also shows antibacterial activity against many drug-resistant bacteria in vitro. Norfloxacin is a bactericidal agent that inhibits DNA synthesis and replication by acting on the A subunit of bacterial DNA gyrase, leading to bacterial death. The original oral formulation of norfloxacin is norfloxacin tablets (trade name: BACCIDAL, バクシダール) manufactured by KYORIN Pharmaceutical Co., Ltd. in Japan. It was approved for marketing in Japan in 1984 and is a reference formulation 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) reports the characteristics of the three crystal forms of norfloxacin (Form A, Form B, Form C), as detailed in Table 1 below.

[0003] Table 1

[0004]

[0005] Norfloxacin is a drug with low solubility and low permeability, and should be classified as Category 4 in the BCS classification. It has low oral bioavailability, is unstable, easily decomposes when exposed to light, and is hygroscopic. Furthermore, due to the existence of polymorphisms of norfloxacin, it may undergo crystal transformation during the humid heat granulation process, resulting in poor stability. Summary of the Invention

[0006] The existing technologies have reported norfloxacin forms A, B, C, and E. Among them, norfloxacin crystal form C is relatively stable, but its dissolution effect in formulations is slightly poor. Crystal forms A and B have poor stability and are prone to hygroscopicity during storage. Crystal forms D and E have moderate stability and weak hygroscopicity. The first objective of this invention is to provide a crystal form X of norfloxacin that simultaneously possesses good stability, weak hygroscopicity, and good dissolution performance.

[0007] The second objective of this invention is to provide a method for preparing crystalline X norfloxacin, which is simple, efficient, and low-cost, meeting the requirements of industrial production. In particular, this invention can directly prepare crystalline X norfloxacin from commercially available norfloxacin, or obtain it from industrial crude product. Moreover, the prepared crystalline X norfloxacin has a uniform particle size distribution and a suitable particle size, and can be used in formulations without pulverization.

[0008] To achieve the above-mentioned technical objectives, the present invention provides a crystalline form of X norfloxacin.

[0009] The chemical structure of the crystalline X norfloxacin of this invention is as follows:

[0010]

[0011] Compared to other existing crystalline forms of norfloxacin, it has the same chemical structure, differing only in crystal configuration. Crystal form X norfloxacin, compared to other crystalline forms, has advantages in physicochemical properties, including good thermal stability, resistance to light decomposition, and low hygroscopicity.

[0012] As a preferred embodiment, the X-ray powder diffraction pattern of the X-type 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 preferred embodiment, the X-ray powder diffraction pattern of the X-type 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] This invention also provides a method for preparing crystalline X norfloxacin, which includes the following steps:

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

[0016] Step 2: Adjust the pH of the norfloxacin salt solution to weakly acidic using an acid solution for precipitation, then filter to obtain the solid.

[0017] Step 3: Transfer the solid to anhydrous ethanol solvent, heat to reflux, then cool to age, filter and dry to obtain crystalline X norfloxacin.

[0018] In the preparation process of the crystalline form X norfloxacin of this invention, factors such as the solvent used and the precipitation temperature have a significant impact on the crystal form of norfloxacin. For example, anhydrous ethanol is required to obtain crystalline form X norfloxacin. This invention has tried organic solvents such as propanol, isopropanol, and isobutanol, but none of these methods yielded crystalline form X norfloxacin. Furthermore, when water and ethanol were used as solvents, a mixture of polymorphs was obtained. It should be specifically noted that the anhydrous ethanol used in this invention is industrial anhydrous ethanol that has undergone dehydration treatment using molecular sieves and other methods, with a purity of over 99.5%.

[0019] As a preferred embodiment, the cooling and aging process is as follows: cooling to 0-10℃ at a cooling rate of 5-10℃ / h, and maintaining the temperature for aging for 10-20 hours. The cooling rate and temperature control range during the cooling and aging process also significantly affect the crystal form of norfloxacin. If the cooling rate and temperature are not within the preferred range, it is difficult to obtain crystal form X norfloxacin.

[0020] As a preferred embodiment, the drying conditions are as follows: drying at 95–105°C for 8–10 hours under forced-air drying conditions.

[0021] The crystalline X norfloxacin provided by this invention can be used to prepare pharmaceutical formulations, especially to prepare broad-spectrum antibacterial drugs, such as antibacterial drugs using crystalline X norfloxacin as the active ingredient, using pharmaceutically acceptable carriers, excipients, diluents, adjuvants, mediators or combinations thereof.

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

[0023] Compared with existing technologies, the beneficial technical effects of the present invention are as follows:

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

[0025] The preparation method of the present invention for crystalline X norfloxacin is simple and mild. In particular, it can be obtained by simple crystal form conversion of commercial norfloxacin, or by directly using synthetic crude norfloxacin. It is easy to obtain and has low cost. Attached Figure Description

[0026] Figure 1 The image shows the X-ray powder diffraction pattern of norfloxacin prepared in Example 2.

[0027] Figure 2 The image shows the X-ray powder diffraction pattern of the crystalline form of norfloxacin prepared in Example 1.

[0028] Figure 3 The image shows the DSC diagram of the crystalline form X norfloxacin prepared in Example 1.

[0029] Figure 4 The image shows the HPLC spectrum of the crystalline X norfloxacin product prepared in Example 1.

[0030] Figure 5 The HPLC chromatogram of the crystalline X norfloxacin product prepared in Example 1 was obtained after storage in an oven at 100°C for 72 hours.

[0031] Figure 6 The HPLC chromatogram of the purchased active pharmaceutical ingredient norfloxacin after storage in an oven at 100°C for 72 hours is obtained.

[0032] Figure 7 Dissolution curves of the tablets of crystalline X norfloxacin prepared in Example 1 and the reference control. Detailed Implementation

[0033] The technical solution of the present invention will be illustrated below with examples. The scope of protection sought by the present invention includes, but is not limited to, the following embodiments.

[0034] X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions of XRPD spectra depend primarily on the crystal structure and are relatively insensitive to experimental details, while their relative peak heights depend 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 essentially as shown in the XRPD patterns provided in the accompanying drawings. Furthermore, the measurement of 2θ in the XRPD spectrum can be subject to experimental error; the measurement of 2θ in the XRPD spectrum may vary slightly between different instruments and different samples, therefore the value of 2θ cannot be considered absolute. Based on the instrument conditions used in the experiments according to the present invention, there is an error tolerance of ±0.2° for the diffraction peaks.

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

[0036] The term “basically 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 are shown in an X-ray powder diffraction pattern, DSC pattern, Raman spectrum, or infrared spectrum.

[0037] When referring to a spectrum or / and the data appearing in the graph, a "peak" refers to a feature that a person skilled in the art can identify and that is not attributable to background noise.

[0038] Whenever a number with a value N is disclosed, any number having the values ​​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, or N±20 will be explicitly disclosed, where "±" indicates addition or subtraction. Whenever a lower limit, RL, and an upper limit, RU, of a numerical range are disclosed, any value within that disclosed range will be explicitly disclosed.

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

[0040] In the context of this invention, when the words “about” or “approximately” are used, whether or not they are used, it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%. Alternatively, to those skilled in the art, the term “about” or “approximately” means within an acceptable standard error of the average value.

[0041] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0042] Unless otherwise specified, the chemical raw materials used in the following examples are obtained commercially or by referring to existing literature.

[0043] Example 1

[0044]

[0045] 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) and activated carbon (25 g, 5 wt%), heat the system to 45°C and stir for 1 h, add water (1000 ml, mainly for dilution to facilitate filtration and separation), cool to 0°C, filter to remove activated carbon (the introduction of activated carbon is only to remove a small amount of impurities), add acetic acid to the filtrate to adjust the pH to 6.7, filter, transfer the filter cake to anhydrous ethanol (1500 ml), heat to reflux and stir for 1 h, cool to 5°C at a cooling rate of 8°C / h, stop stirring, keep warm and age for 15 h, filter, dry the filter cake in a forced-air drying oven at 100°C for 9 h.

[0046] 2. The material was collected, yielding 481.23 g of crystalline X norfloxacin, with a yield of 96.24% and a purity of 99.83%. The X-ray powder diffraction pattern of crystalline X norfloxacin is shown below. Figure 2 As shown.

[0047] Example 2

[0048]

[0049] 1. Compound 1 (commercial product, analytical grade, 500.00 g, 1 eq) was added to a three-necked flask, along with 2.50 kg (4 eq) of 10% sodium hydroxide aqueous solution and 25 g (5%) of activated carbon. The system was heated to 45°C and stirred for 1 h. Water (1000 ml) was added to the system, and the temperature was lowered to 0°C. The activated carbon was removed by filtration. Acetic acid was added to the filtrate to adjust the pH to 6.7. The filtrate was filtered again, and the filter cake was transferred to an ethanol-water solution (750 mL ethanol, 750 mL water). The mixture was heated to reflux and stirred for 1 h. The temperature was lowered to 5°C at a rate of 8°C / h. Stirring was stopped, and the mixture was aged at this temperature for 15 h. The filter cake was then filtered and dried in a forced-air drying oven at 100°C for 24 h.

[0050] 2. The material was collected, yielding 456.15 g of crystalline X norfloxacin, with a yield of 91.23%. The XRD pattern was as follows. Figure 1 As shown in the comparison with Example 1, it can be seen that the introduction of water has a significant impact on the crystal form of norfloxacin. After the introduction of water, the polymorphic crystal form X norfloxacin is obtained, rather than the single crystal form X norfloxacin.

[0051] Performance testing:

[0052] This invention was identified by Empyrean X-ray powder diffraction (XRPD) analysis using Cu-Kα radiation, exhibiting the following characteristic peaks expressed in terms of angle 2θ: XRD data are shown in Table 2 below. Figure 2 As shown:

[0053] Table 2

[0054]

[0055]

[0056] Note: Only data with an intensity of 25% or higher are recorded.

[0057] The thermal stability of this product was tested under a high-temperature (100°C) blower environment. The purity of the finished product was 99.83% in the initial test. Figure 4 After being stored in a forced-air drying oven at a high temperature of 100℃ for 72 hours, the purity remained at 99.77%. Figure 5 The purchased raw materials, after being stored in a forced-air drying oven at 100°C for 72 hours with air circulation, showed a significant increase in impurities and a decrease in purity to 99.04%. Figure 6 ).

[0058] Table 3. Hygroscopicity test (RH 65%)

[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] Based on the hygroscopicity data, the hygroscopicity of crystalline X norfloxacin is not significantly different from that of the previously reported crystalline D norfloxacin (24h hygroscopicity data is 1.7%) and crystalline E norfloxacin (24h hygroscopicity data is 2.01%).

[0061] Table 4 Dissolution data at pH = 6.8

[0062]

[0063]

[0064] The results showed that in a medium of pH 6.8 (pH 6.8 refers to a sodium phosphate buffer solution, prepared as follows: take 6.9g of sodium dihydrogen phosphate, 0.9g of sodium hydroxide, and 5g of sodium dodecyl sulfate, add 800ml of water, sonicate for 30 minutes, adjust the pH to 6.8 with 2mol / L sodium hydroxide solution, dilute with water to 1000mL, shake well, sonicate, and set aside), the dissolution curves of the active pharmaceutical ingredient (API) and the reference formulation of crystalline X norfloxacin were similar. Figure 7 As shown.

[0065] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A crystalline form of norfloxacin X, wherein the X-ray powder diffraction pattern of the crystalline form of norfloxacin X 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°.

2. The method for preparing crystalline X norfloxacin according to claim 1, characterized in that: Includes the following steps: Step 1: Dissolve norfloxacin in an alkaline solution to obtain a norfloxacin salt solution; Step 2: Adjust the pH of the norfloxacin salt solution to weakly acidic using an acid solution for precipitation, then filter to obtain the solid. Step 3: Transfer the solid to anhydrous ethanol solvent, heat it to reflux, then cool it down for aging, filter and dry it to obtain crystalline X norfloxacin; the cooling and aging process is as follows: cool down to 0~10℃ at a cooling rate of 5~10℃ / h, and keep it at that temperature for 10~20h.

3. The method for preparing crystalline X norfloxacin according to claim 2, characterized in that: The alkaline solution includes at least one of sodium hydroxide solution and 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.

4. The method for preparing crystalline X norfloxacin according to claim 2, characterized in that: The pH is adjusted to be greater than or equal to 6.5 and less than 7.

5. The method for preparing crystalline X norfloxacin according to claim 2, characterized in that: The reflux time is 1 to 3 hours.

6. The method for preparing crystalline X norfloxacin according to claim 2, characterized in that: The drying conditions are as follows: drying under vacuum at a temperature of 60-70°C for 8-10 hours.

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