An amorphous nalfurafine hydrochloride and a method for producing the same

Abstract

The application belongs to the technical field of crystal form drug molecules, and particularly relates to a naltrexone hydrochloride amorphous form and a preparation method thereof. The naltrexone hydrochloride amorphous form provided by the application has excellent physical and chemical properties, high purity, good stability, high solubility and high bioavailability, is helpful to improve clinical curative effect, and has a simple and efficient preparation method and is suitable for industrialized production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to an amorphous nalfurafine hydrochloride and a preparation method thereof. BACKGROUND

[0002] Nalfurafine hydrochloride, molecular formula: C 28 H 32 N2O5·HCl, molecular weight: 513.02502, CAS: 152658-17-8, high hygroscopicity, slightly unstable to light, easily soluble in water and methanol, slightly soluble in ethanol, almost insoluble in ethyl acetate and diethyl ether, and the structural formula is as follows:

[0003]

[0004] Nalfurafine hydrochloride is a drug for treating such severe pruritus in hemodialysis patients, which effectively inhibits uremic pruritus in hemodialysis patients with end-stage kidney disease that is not well controlled by existing antihistamines and antiallergics, and is developed by Toray and Torii, and approved for marketing by the Japanese Pharmaceutical and Medical Device Agency (PMDA) on January 21, 2009.

[0005] Nalfurafine hydrochloride has polymorphism, which refers to the phenomenon that the same compound can form two or more than two molecular spatial arrangement modes by controlling different formation conditions, thereby producing different solid crystals. Different crystal forms of the same compound have the same chemical composition but different microcrystal structures, and thus lead to differences in appearance, physicochemical properties and biological activity. Polymorphism directly affects the processing performance of the drug, and affects the stability, solubility and bioavailability of the drug, and further affects the quality, safety, effectiveness and application of the drug.

[0006] US6323212 discloses a preparation method of amorphous nalfurafine hydrochloride, which is unstable in quality and low in purity; CN200680010971.8 discloses nalfurafine hydrochloride crystal forms A, B and C and their characterization data, and the preparation method is complicated and lengthy, and crystal seeds of each crystal form are required to prepare the above-mentioned crystals; CN201410140608.4 discloses nalfurafine hydrochloride crystal form X and various amorphous structures, wherein crystal form X has good pH stability compared with crystal form A and amorphous form.

[0007] In view of this, the system research on nalfurafine hydrochloride crystal forms needs to be improved, which provides a better basis for the application of drug treatment, so as to more efficiently exert the medicinal value of nalfurafine hydrochloride. SUMMARY

[0008] In view of the technical problems existing in the prior art nafagol hydrochloride, the present application provides an amorphous nafagol hydrochloride and a preparation method thereof, and the present application provides a new crystalline form of nafagol hydrochloride, and the inventor accidentally finds that the amorphous nafagol hydrochloride has good solubility and good stability, overcomes the defect that amorphous drugs are unstable due to the influence of external factors, and lays a good foundation for the conversion into a pharmaceutical dosage form and the later industrial production.

[0009] The specific technical content of the present application is as follows:

[0010] In a first aspect of the present application, an amorphous nafagol hydrochloride is provided.

[0011] Preferably, the amorphous nafagol hydrochloride has an X-ray powder diffraction pattern as shown in Figure 1 .

[0012] Preferably, the amorphous nafagol hydrochloride has a TGA / DSC pattern as shown in Figure 2 .

[0013] In a second aspect of the present application, a preparation method of the amorphous nafagol hydrochloride is provided, which specifically comprises the following steps: adding nafagol hydrochloride and purified water into a reaction kettle, stirring, then adding an organic solvent, continuing to stir and dissolve, filtering with an organic filter membrane, and freeze-drying to obtain the product.

[0014] Preferably, the dosage ratio of the nafagol hydrochloride to the purified water is 1:12-20 g / ml.

[0015] Further preferably, the dosage ratio of the nafagol hydrochloride to the purified water is 1:18 g / ml.

[0016] Preferably, the organic solvent is one or a combination of methanol, propylene glycol and polyethylene glycol, and methanol is particularly preferred.

[0017] Further preferably, the polyethylene glycol is selected from polyethylene glycol-200 and polyethylene glycol-400.

[0018] Preferably, the dosage ratio of the nafagol hydrochloride to the organic solvent is 1:5-10 g / ml.

[0019] Further preferably, the dosage ratio of the nafagol hydrochloride to the organic solvent is 1:7 g / ml.

[0020] Preferably, the stirring temperature is room temperature.

[0021] It should be noted that the freeze-drying step is not particularly limited in the present application, and the freeze-drying method of the present application can be used in the present application.

[0022] Preferably, the freeze-drying curve is as follows:

[0023]

[0024]

[0025] Preferably, the freeze-drying curve is as follows:

[0026]

[0027] In a third aspect of the present application, the use of amorphous nalfurafine hydrochloride as an active ingredient for the preparation of an anti-pruritus drug is provided.

[0028] In a fourth aspect of the present application, a pharmaceutical composition comprising the amorphous nalfurafine hydrochloride and a pharmaceutically acceptable other component is provided.

[0029] Preferably, the method for preparing the pharmaceutical composition is to use standard and conventional techniques to combine the amorphous nalfurafine hydrochloride of the present application with a pharmaceutically acceptable solid or liquid carrier, and optionally with a pharmaceutically acceptable auxiliary and excipient to prepare a dosage form.

[0030] Further, the dosage form of the pharmaceutical composition includes, but is not limited to, tablets, capsules, granules, pills, injections, and patches, etc.

[0031] Crystal structure confirmation

[0032] (1) X-ray powder diffraction detection

[0033] The X-ray powder diffraction testing instrument and testing conditions for the amorphous nalfurafine hydrochloride of the present application are as follows: X-ray powder diffractometer: PANalytical EMPYREAN; Cu-Kα; sample stage: flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage: 45kv, current: 40mA; divergence slit: 1 / 4°; anti-scattering slit: 1°; soller slit: 0.04 rad; step size: 0.5s; scanning range: 3-50°.

[0034] The X-ray powder diffraction pattern of the amorphous nalfurafine hydrochloride is as shown in Figure 1 .

[0035] (2) TGA / DSC analysis

[0036] The TGA / DSC thermal analysis instrument and test conditions of the amorphous nafuramide hydrochloride of the present application are as follows: Mettler-Toledo TGA / DSC thermal analysis instrument (TGA / DSC3+); dynamic temperature section: 30-350℃; heating rate: 10℃ / min; program section gas N2; gas flow: 50ml / min; crucible: aluminum crucible 40ul.

[0037] The TGA / DSC test results of the amorphous nafuramide hydrochloride of the present application are shown in Figure 2

[0038] The beneficial effects of the present application are:

[0039] (1) The amorphous nafuramide hydrochloride of the present application has high purity, high stability, is suitable for the manufacture and long-term storage of pharmaceutical preparations, has good solubility, and high bioavailability, thereby providing a better basis for the application of nafuramide hydrochloride in drug therapy, and more efficiently exerting the medicinal value of nafuramide hydrochloride;

[0040] (2) The preparation process of the amorphous nafuramide hydrochloride of the present application is simple, has good repeatability, and is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0041] Figure 1 : PXRD spectrum of amorphous nafuramide hydrochloride;

[0042] Figure 2 : TGA / DSC graph of amorphous nafuramide hydrochloride. DETAILED DESCRIPTION

[0043] The present application is further illustrated by the description of specific embodiments, and it should be correctly understood that: the embodiments of the present application are only used to illustrate the present application, and are not a limitation of the present application. Therefore, simple improvements of the present application under the premise of the method of the present application are within the scope of the present application.

[0044] The raw material nafuramide hydrochloride used in the present application has a purity of ≥98%.

[0045] Example 1

[0046] 5g of nafuramide hydrochloride and 90ml of purified water were added to a reaction kettle, stirred at room temperature, then 35ml of methanol was added, and stirring was continued to dissolve. The organic filter membrane was filtered, and freeze-dried to obtain amorphous nafuramide hydrochloride with a HPLC purity of 99.96%, wherein the freeze-drying curve was as follows:

[0047]

[0048] Example 2

[0049] ​5g of nafuraphene hydrochloride and 60ml of purified water were added to a reaction vessel and stirred at room temperature. Then, 25ml of propylene glycol was added, and stirring continued to dissolve the mixture. The solution was filtered through an organic filter membrane and lyophilized to obtain amorphous nafuraphene hydrochloride with an HPLC purity of 99.84%. The lyophilization curve is as follows:

[0050]

[0051]

[0052] Example 3

[0053] Add 5g of nafuraphene hydrochloride and 100ml of purified water to a reaction vessel, stir at room temperature, then add 50ml of polyethylene glycol-200, continue stirring to dissolve, filter through an organic filter membrane, and lyophilize to obtain amorphous nafuraphene hydrochloride with an HPLC purity of 99.91%. The lyophilization curve is as follows:

[0054]

[0055] Example 4

[0056] Add 5g of nafraphine hydrochloride and 80ml of purified water to a reaction vessel, stir at room temperature, then add 40ml of propylene glycol, continue stirring to dissolve, filter through an organic filter membrane, and freeze-dry to obtain amorphous nafraphine hydrochloride with an HPLC purity of 99.95%. The freeze-drying curve is the same as in Example 2.

[0057] Example 5

[0058] Add 5g of nafraphine hydrochloride and 130ml of purified water to a reaction vessel, stir at room temperature, then add 50ml of methanol, continue stirring to dissolve, filter through an organic filter membrane, and freeze-dry to obtain amorphous nafraphine hydrochloride with an HPLC purity of 98.44%. The freeze-drying curve is the same as in Example 1.

[0059] Comparative Example 1

[0060] The method disclosed in patent CN200680010971.8 was used to prepare sodium furaprin hydrochloride crystal form A.

[0061] Comparative Example 2

[0062] The sodium furaprine hydrochloride crystal form X was prepared according to the method disclosed in patent CN201410140608.4.

[0063] Comparative Example 3

[0064] 5g of nalfuraphen hydrochloride and 250ml of purified water were added to a reaction vessel, stirred and dissolved at room temperature, filtered through an aqueous membrane, and lyophilized. The resulting product did not contain the desired compound. Figure 1 The X-ray powder diffraction pattern of amorphous sodium furaprine hydrochloride is shown below, with the lyophilization curve as follows:

[0065]

[0066]

[0067] Comparative Example 4

[0068] Add 5g of nalfuraphen hydrochloride and 70ml of purified water to a reaction vessel, stir at room temperature, then add 35ml of methanol, continue stirring to dissolve, concentrate under reduced pressure, and dry. The desired product cannot be obtained. Figure 1 The X-ray powder diffraction pattern shown is of amorphous sodium furaprine hydrochloride.

[0069] Stability test of Example 1

[0070] 1. Experimental materials: Nafuraphine hydrochloride prepared in Example 1, Comparative Examples 1 and 2.

[0071] 2. Test methods:

[0072] Light stability test: Nafuraphene hydrochloride prepared in Example 1 and Comparative Examples 1 and 2 were placed in an environment of 25℃±1℃ and 4500lx±500lx light for 15 days. Samples were taken at 5, 10 and 15 days, and the purity (%) was determined by HPLC. Three parallel tests were performed, and the average value of the results was taken.

[0073] High-temperature stability test: Nafuraphene hydrochloride prepared in Example 1 and Comparative Examples 1 and 2 were placed at 60℃±1℃ for 15 days. Samples were taken at 5, 10 and 15 days, and the total impurities (%) were detected by HPLC. Three parallel tests were performed, and the average value of the results was taken.

[0074] 3. Experimental results: The experimental results are shown in Table 1.

[0075] Table 1. Results of stability test of nafpramine hydrochloride

[0076]

[0077] As shown in Table 1, the amorphous sodium furaprine hydrochloride of the present invention exhibits good optical and thermal stability, with minimal purity variation, comparable to crystal form A. Further investigation revealed similar stability test results for Examples 1-5.

[0078] Validation Example 2: Pharmacokinetic Study

[0079] 1. Experimental materials: Nafuraphine hydrochloride prepared in Example 1, Comparative Examples 1 and 2.

[0080] 2. Experimental Methods: Fifteen healthy male CD-1 (ICR) mice, weighing 20-25g, were randomly divided into three groups. The mice were fasted for 12 hours before administration, but had free access to water. Each group was administered 1 mg / kg of nalfupramine hydrochloride via gavage (prepared solution). Blood samples of 300 μl were collected from the abdominal aorta of the mice at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours after administration and placed in heparinized tubes for LC-MS / MS analysis.

[0081] 3. Experimental results: The experimental results are shown in Table 2.

[0082] Table 2. Pharmacokinetic Results of Nafurazone Hydrochloride

[0083]

[0084]

[0085] Pharmacokinetic studies of the crystalline forms of nafraph hydrochloride have shown that the pharmacokinetic parameters of the amorphous nafraph hydrochloride provided by this invention are improved compared to the existing crystalline forms A and X.

Claims

1. A method for preparing amorphous nafraphine hydrochloride, characterized in that, The nafraphine hydrochloride has an X-ray powder diffraction pattern as shown in Figure 1 and a TGA / DSC pattern as shown in Figure 2. The process includes the following steps: adding nafraphine hydrochloride and purified water to a reaction vessel, stirring, then adding an organic solvent, continuing stirring to dissolve, filtering through an organic filter membrane, and lyophilizing to obtain the final product; the ratio of nafraphine hydrochloride to purified water is 1:12~20, g / ml; the ratio of nafraphine hydrochloride to organic solvent is 1:5~10, g / ml; the organic solvent is one or a combination of methanol, propylene glycol, and polyethylene glycol; the lyophilization curve is as follows: 。 2. The preparation method according to claim 1, characterized in that, The organic solvent is methanol.

3. The preparation method according to claim 1, characterized in that, The stirring temperature is room temperature.

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