Novel crystal form of lornoxicam for injection and preparation method thereof

Abstract

The invention provides a lornoxicam crystal form for injection and a preparation method thereof. The 2 theta diffraction of an X-ray powder diffraction pattern of the crystal form has characteristic diffraction peaks at 9.6 + / -0.2 degrees, 20.3 + / -0.2 degrees, 21.1 + / -0.2 degrees, 22.0 + / -0.2 degrees, 24.6 + / -0.2 degrees, 25.2 + / -0.2 degrees, 27.8 + / -0.2 degrees and 36.0 + / -0.2 degrees. The prepared lornoxicam sample solution with the new crystal form for injection is good in clarity, the clarity of the solution is basically unchanged in the storage process, the increase amplitude of related substances is low, and all indexes meet the quality standard. Compared with the prior art, the crystal form provided by the invention has the advantage that the clarity and the stability of a product solution obtained by the invention are better.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical crystal forms, in particular to a new crystal form of lornoxicam for injection and a preparation method thereof. BACKGROUND

[0002] The stability and solubility of preparations of different crystal forms are different. Therefore, the discovery of different crystal forms in the pharmaceutical field can have a profound impact on the shelf life, solubility, configuration characteristics, and preparation difficulty of drugs. Especially for injections, the clarity of the solution and related substances are particularly important, which is related to the safety of patients.

[0003] Lornoxicam for injection belongs to non-steroidal anti-inflammatory analgesics, which has strong analgesic and anti-inflammatory effects. It is mainly used for short-term treatment of acute moderate pain after surgery. Non-steroidal anti-inflammatory active substances are usually difficult to dissolve in water or almost insoluble in water, and are often unstable in liquid preparations. Oxidation and hydrolysis reactions can produce a large amount of by-products, affecting the quality of the product. Lornoxicam for injection is prepared into a loose block by freeze-drying technology, and is reconstituted before use, which improves the stability of the liquid preparation. However, we found during the research that the lornoxicam impurities of lornoxicam for injection obtained by freeze-drying technology increased too quickly during storage, and the clarity of the solution became significantly turbid as the storage time increased.

[0004] Therefore, it is necessary to develop a lornoxicam for injection with good clarity and stability. SUMMARY

[0005] The present application provides a new crystal form of lornoxicam for injection and a preparation method thereof, which solves the problem of poor clarity and stability of lornoxicam for injection in the prior art.

[0006] The technical scheme of the present application is as follows: A crystal form of lornoxicam for injection, wherein the X-ray powder diffraction pattern of the crystal form has characteristic diffraction peaks at 9.6±0.2°, 20.3±0.2°, 21.1±0.2°, 22.0±0.2°, 24.6±0.2°, 25.2±0.2°, 27.8±0.2°, and 36.0±0.2°.

[0007] A preparation method of a crystal form of lornoxicam for injection, comprising the following steps: (1) Control the temperature of water for injection at 40-50℃, add tromethamine, stir and dissolve, then add lornoxicam, stir until the solution is clear, then add mannitol and edetic acid disodium, and finally add water for injection to the full amount, and continue stirring for 5-20 min; (2) The solution treated in step (1) is filled after sterilization and filtration; (3) the above-mentioned filled liquid medicine is semi-pressurized, then is subjected to freeze-drying treatment, and then is pressurized, to obtain the product; The freeze-drying curve is set as follows: 0.5-1 h of cooling to -45 DEG C, 2-6 h of -45 DEG C preservation, 10-50 pa of maintaining the pressure in the freeze-drying box, 5-8 h of warming to -5 DEG C, 6-8 h of -5 DEG C preservation; 0.5-1 h of warming to 5 DEG C, 0.5-1 h of 5 DEG C preservation; 0.5-1 h of warming to 15 DEG C, 0.5-1 h of 15 DEG C preservation; 1-3 h of warming to 40 DEG C, 5-10 h of 40 DEG C preservation.

[0008] In some embodiments, the freeze-drying curve is: 0.5 h of cooling to -45 DEG C, 2-6 h of -45 DEG C preservation, 10-20 pa of maintaining the pressure in the freeze-drying box, 6-8 h of warming to -5 DEG C, 6-8 h of -5 DEG C preservation; 0.5-1 h of warming to 5 DEG C, 0.5-1 h of 5 DEG C preservation; 0.5-1 h of warming to 15 DEG C, 0.5-1 h of 15 DEG C preservation; 1-3 h of warming to 40 DEG C, 5-10 h of 40 DEG C preservation.

[0009] In some embodiments, the freeze-drying curve is: 0.5 h of cooling to -45 DEG C, 2-6 h of -45 DEG C preservation, 10-20 pa of maintaining the pressure in the freeze-drying box, 6-8 h of warming to -5 DEG C, 6-8 h of -5 DEG C preservation; 0.5-1 h of warming to 5 DEG C, 0.5-1 h of 5 DEG C preservation; 0.5-1 h of warming to 15 DEG C, 0.5-1 h of 15 DEG C preservation; 1-3 h of warming to 40 DEG C, 5-10 h of 40 DEG C preservation.

[0010] Compared with the prior art, the present application has the following beneficial effects: The new crystal form of lornoxicam for injection prepared by the present application has good clarity of sample solution, the clarity of the solution is basically unchanged during storage, the growth of related substances is low, and all indexes meet the quality standards. Compared with the prior art, the solution of the product obtained by the present application has better clarity and stability. BRIEF DESCRIPTION OF DRAWINGS

[0011] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the drawings needed to be used in the following embodiment or prior art description will be briefly introduced. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor.

[0012] Figure 1 XRPD spectrum of the new crystal form of Example 1; Figure 2 XRPD spectrum of the new crystal form of Example 2; Figure 3 XRPD spectrum of the new crystal form of Example 3; Figure 4 XRPD spectrum of the commercially available sample. DETAILED DESCRIPTION

[0013] The technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present application, but not all the embodiments. Based on the embodiments in the present application, all the other embodiments obtained by those skilled in the art without creative work belong to the scope of protection of the present application.

[0014] Embodiment 1 A preparation method of a crystalline form of lornoxicam for injection, comprising: 1) Controlling the temperature of water for injection at 45℃, adding 120.0 g tromethamine and stirring to dissolve, slowly adding 80.0 g lornoxicam, and stirring until the liquid is clear. Then adding 1000.0 g mannitol and 2.0 g disodium edetate and dissolving, adding water for injection to the full amount, and continuing to stir for 10 min; 2) After the liquid is filtered through 0.45 μm and 0.22 μm membranes, it is filled; 3) After half-tamping, it is transferred to a freeze-drying box. The freeze-drying curve is set as follows: 0.5 h for cooling to -45℃; -45℃ for 4 h; maintaining the pressure in the freeze-drying box at 10 pa, 8 h for warming to -5℃, -5℃ for 6 h; 1 h for warming to 5℃, 5℃ for 1 h; 1 h for warming to 15℃, 15℃ for 0.5 h; 2 h for warming to 40℃, 40℃ for 5 h, tamping, and taking out of the box.

[0015] 4) Covering, and labeling.

[0016] 5) Detecting the crystalline form, and the spectrum is shown in Figure 1 .

[0017] Figure 1 XRPD spectra of the new crystalline forms are provided, showing 2 theta values on the X axis and relative intensities on the Y axis. It should be understood that there is inherent variability in the values measured in degrees 2 theta (°2 theta) in X-ray powder diffraction spectra or patterns due to, for example, instrument variation (including differences between instruments). Likewise, it should be understood that there is variability in XRPD peak measurements of up to 0.2° 2 theta, however such peak values would still be considered to represent a particular solid state form of the crystalline material described herein. It should also be understood that other measurements from XRPD experiments, such as relative intensities and water content, can vary due to, for example, sample preparation and / or storage and / or environmental conditions, however the measurements would still be considered to represent a particular solid state form of the crystalline material described herein.

[0018] The sample prepared by the embodiment 1 of the present application is used to carry out stability experiment investigation, and the traits, alkalinity, solution clarity, dissolution time, moisture, and related substances are investigated. The experimental results show that after the accelerated experiment, the solution clarity of the sample of the new crystal form of embodiment 1 is basically unchanged, the growth amplitude of the related substances is low, and all indexes meet the quality standard. Compared with the prior art, the solution clarity and stability of the product obtained by the present application are better, and the accelerated 6-month data is added.

[0019] New crystal form of embodiment 1 accelerated 6-month data: .

[0020] Embodiment 2 A preparation method of a lornoxicam crystal form for injection, comprising: 1) control the temperature of the injection water at 50℃, add 12.0 tromethamine and stir to dissolve, slowly add 8.0 lornoxicam, and stir until the solution is clear. Then add 100.0 mannitol and 0.2g edetate disodium to dissolve, add injection water to the full amount, and continue to stir for 5min; 2) after the solution is filtered through 0.45μm and 0.22μm membranes, it is filled; 3) after half-tightening, it is transferred to a freeze-drying box. The freeze-drying curve is set as follows: 0.5h for temperature drop to -45℃; -45℃ for 2h; keep the pressure in the freeze-drying box at 50pa, 6h for temperature rise to -5℃, -5℃ for 8h; 0.5h for temperature rise to 5℃, 5℃ for 0.5h; 0.5h for temperature rise to 15℃, 15℃ for 0.5h; 3h for temperature rise to 40℃, 40℃ for 7h, tighten, and take out the box.

[0021] 4) cap and label.

[0022] 5) detect the crystal form, and the spectrum is shown in Figure 2 .

[0023] Embodiment 3 A preparation method of a lornoxicam crystal form for injection, comprising: 1) control the temperature of the injection water at 50℃, add 6.0g tromethamine and stir to dissolve, slowly add 4.0g lornoxicam, and stir until the solution is clear. Then add 50.0g mannitol and 0.1g edetate disodium to dissolve, add injection water to the full amount, and continue to stir for 10min; 2) after the solution is filtered through 0.45μm and 0.22μm membranes, it is filled; 3) After semi-pressing, transfer to the freeze-drying box. The freeze-drying curve is set as follows: 1 h to cool to -45℃; -45℃ for 6 h; keep the pressure in the freeze-drying box at 50 pa, 8 h to warm to -5℃, -5℃ for 7 h; 0.5 h to warm to 5℃, 5℃ for 1 h; 0.5 h to warm to 15℃, 15℃ for 1 h; 1.5 h to warm to 40℃, 40℃ for 5 h, press, and take out the box.

[0024] 4) Cap, label.

[0025] 5) Detect the crystal form, and the spectrum is shown in Figure 3 .

[0026] Comparative Example 1 The sample prepared in Example 1 of the present application and a commercially available sample (Xefo, Takeda Austria GmbH) were subjected to influence factor experiments under the same conditions, and the properties, alkalinity, clarity of solution, dissolution time, moisture, and related substances were compared. The experimental results showed that after high temperature and strong light experiments, the clarity of the solution of the commercially available sample changed significantly, and the impurities increased significantly. The clarity of the solution of the new crystal form sample of Example 1 changed little, and the degradation of related substances and the increase of impurities were far lower than those of the commercially available sample. Compared with the prior art, the solution clarity and stability of the product obtained by the present application are better. The influence factor data are attached.

[0027] Influence factor data of new crystal form Example 1: .

[0028] Influence factor data of commercially available sample: .

[0029] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present application, and not to limit them; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that they can still modify the technical solutions described in the foregoing examples, or make equivalent substitutions for part or all of the technical features; and these modifications or substitutions do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A chlornoxicam crystal form for injection, characterized in that, The 2θ diffraction pattern of the X-ray powder diffraction pattern of this crystal form has characteristic diffraction peaks at 9.6±0.2°, 20.3±0.2°, 21.1±0.2°, 22.0±0.2°, 24.6±0.2°, 25.2±0.2°, 27.8±0.2°, and 36.0±0.2°.

2. A method for preparing a chlornoxicam crystal form for injection, characterized in that, Includes the following steps: (1) Control the temperature of water for injection at 40-50℃, add tromethorphan and stir to dissolve, then add lornoxicam and stir until the solution is clear. Then add mannitol and disodium edetate, and finally add water for injection to the total volume. Continue stirring for 5-20 minutes. (2) The medicine solution after step (1) is sterilized and filtered before being filled; (3) After filling the medicine liquid as described above, partially stopper it, freeze-dry it, and then stopper it to obtain the product; The freeze-drying curve is set as follows: 0.5-1h cooling to -45℃, holding at -45℃ for 2-6h while maintaining the pressure inside the freeze-drying chamber at 10-50pa, 5-8h heating to -5℃, holding at -5℃ for 6-8h; 0.5-1h heating to 5℃, holding at 5℃ for 0.5-1h; 0.5-1h heating to 15℃, holding at 15℃ for 0.5-1h; 1-3h heating to 40℃, holding at 40℃ for 5-10h.

3. The method for preparing the crystal form of lornoxicam for injection according to claim 2, characterized in that, The freeze-drying curve is as follows: 0.5 min cooling to -45℃, holding at -45℃ for 2-6 h while maintaining a pressure of 10-20 Pa inside the freeze-drying chamber, 6-8 h heating to -5℃, holding at -5℃ for 6-8 h; 0.5-1 h heating to 5℃, holding at 5℃ for 0.5-1 h; 0.5-1 h heating to 15℃, holding at 15℃ for 0.5-1 h; 1-3 h heating to 40℃, holding at 40℃ for 5-10 h.

4. The method for preparing the crystal form of lornoxicam for injection according to claim 2, characterized in that, The freeze-drying curve is as follows: cool down to -45℃ in 0.5h, maintain the pressure inside the freeze-drying chamber at 10pa, and heat up to -5℃ in 8h.

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