CN114315822A - A kind of Palonosetron hydrochloride hydrate crystal form and preparation method thereof - Google Patents

Abstract

The invention relates to a hydrate crystal form of palonosetron hydrochloride and a preparation method thereof. The crystal form of the palonosetron hydrochloride hydrate disclosed by the invention has favorable performances of good stability, low hygroscopicity, developable process, easy processing and the like. The preparation method of the hydrate crystal form is simple, low in cost and easy for industrial production.

Description

A kind of Palonosetron hydrochloride hydrate crystal form and preparation method thereof

technical field

The invention relates to a crystal form of palonosetron hydrochloride and a preparation method thereof.

technical background

Palonosetron is a highly efficient and highly selective 5-HT3 receptor antagonist. Compared with traditional 5-HT3 receptor antagonists, it has high efficacy, long duration of action, small dosage, less adverse reactions, It has the advantage of good tolerance and is mainly used in the treatment of nausea and vomiting caused by chemotherapy.

Even a single use of some chemotherapy agents can cause vomiting for several days, requiring multiple doses of antiemetics. At present, antiemetics such as palonosetron and granisetron are usually administered by intravenous injection, which is very inconvenient for patients to self-medicate, and injections have special problems related to the stability and storage period of active drugs.

Common solid dosage forms include tablets, capsules, powders, dripping pills, films, etc. Compared with liquid preparations, they have good chemical stability of materials, lower production costs, and are easy to take and carry. It accounts for about 70%, and the crystal form of the API will directly affect the processing performance of the solid preparation, thereby affecting the stability, solubility and bioavailability of the drug. Therefore, in the process of drug research and development, it is necessary to comprehensively study the crystal form of the API.

At present, it is known that palonosetron hydrochloride has three crystal forms, namely crystal form I, crystal form II and amorphous crystal form. Patent WO2008073757A1 or US20160214976A1 discloses the DSC and powder diffraction characterization of these three crystal forms. Among them, the amorphous crystal form is easy to absorb moisture when exposed to the air, which is not conducive to storage, transportation and pharmaceutical preparations; the crystal form II is easily converted into the crystal form I in a specific environment, and there is a problem of crystal stability; the current pharmaceutical crystal forms are mainly used. It is crystal form I, and it is mainly used for injection.

In addition to the above-mentioned known 3 crystal forms of palonosetron hydrochloride, the inventor of the present application is preparing the crude palonosetron hydrochloride:

It was found that an unidentified organic substance was precipitated in the post-treatment process. After identification by means of nuclear magnetic resonance, mass spectrometry, and high performance liquid chromatography, it was confirmed that the precipitate was palonosetron hydrochloride. The precipitate is recrystallized from an organic solvent, and dried to obtain a crystal form of palonosetron hydrochloride hydrate. The preparation method is simple, the cost is low, and the industrial production is easy.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a hydrated crystal form of palonosetron hydrochloride, which has good stability, low hygroscopicity, and is more suitable for the preparation of solid preparations of palonosetron hydrochloride. The optimization and development of drugs is of great value.

The present invention also provides a preparation method of palonosetron hydrochloride hydrate crystal form.

The first object of the present invention is to provide a hydrated crystal form of palonosetron hydrochloride. The X-ray powder diffraction pattern of the hydrate crystal form measured with CuKa rays includes a 2θ diffraction angle of 5.6±0.2°. , characteristic diffraction peaks at 10.9±0.2°, 13.4±0.2°, 16.9±0.2°, 22.6±0.2°.

Further, the X-ray powder diffraction pattern of the hydrate crystal form measured with CuKa rays also includes 2θ diffraction angles of 12.3±0.2°, 17.9±0.2°, 18.6±0.2°, 19.7±0.2°, 20.8 At least one of characteristic diffraction peaks at ±0.2°, 21.1±0.2°, 22.1±0.2°, 23.0±0.2°, 26.9±0.2°.

More specifically, the crystalline form of palonosetron hydrochloride hydrate is irradiated with Cu-Kα, and its X-ray powder diffraction pattern is shown in Fig. 1 , the DSC diagram is shown in Fig. 2 , and the TGA diagram is shown in Fig. 3 .

It can be seen from the DSC chart of the hydrate crystal form that there are endothermic peaks at 66.5°C and 227.5°C.

The moisture content of the hydrate crystal form is 5.1%-5.6%.

The second object of the present invention: a preparation method of palonosetron hydrochloride hydrate crystal form, the method comprises the following steps:

a). (S)-N-(((S)-1,2,3,4-tetrahydronaphthalene-1-yl)methyl)quinuclidin-3-amine (abbreviation: imine), react The solvent was added to the reaction flask and triphosgene was added. After the addition was completed, the reaction was refluxed for 2 hours, and boron trifluoride ether was added. After the addition was completed, the reaction was refluxed for 6 hours. It was lowered to room temperature, water was added, the addition was completed, the reaction was refluxed for 4 hours, lowered to below 0-20° C., filtered, and washed with water. The filter cake is dried to obtain crude palonosetron hydrochloride;

b). The crude palonosetron hydrochloride is heated, dissolved and clarified in an organic solvent, cooled to 0-5° C., stirred for 2 hours, filtered, washed with an organic solvent, and dried to obtain palonosetron hydrochloride hydrate crystals.

The reaction solvent in step a) is selected from at least one of toluene, xylene, chloroform, acetone, ethyl acetate, and isopropyl acetate.

Further, in the above preparation method, the reaction solvent in step a is preferably toluene; the addition method of triphosgene is preferably the dropwise addition method.

Further, in step b), the crystallization solvent is selected from one or more of water, methanol, ethanol, isopropanol, acetone, and acetonitrile.

The crystallization temperature in step b) is 0-30°C.

In step b), the mass ratio of the crude palonosetron hydrochloride to the organic solvent is 1:5 to 35.

In step b), the drying temperature is 30-80° C.; the drying time is 1-24 hours.

Further, in the above-mentioned preparation method, the crystallization solvent in step b is preferably a mixed system of methanol or ethanol or isopropanol and water; the amount of crystallization solvent is preferably the mass ratio of the crude palonosetron acid to the organic solvent of 1:5 to 20. The crystallization temperature is preferably 0 to 10°C; the drying temperature is preferably 40 to 50°C, and the drying is performed for 5 to 10 hours.

The positive effects of the present invention due to the above technical solutions are obvious, that is, the crystalline form of palonosetron hydrochloride provided by the present invention has good stability, low hygroscopicity, process development and easy handling, etc. Beneficial performance. The preparation method of the palonosetron hydrochloride hydrate crystal form provided by the invention is simple, the cost is low, and the industrial production is easy.

Description of drawings

Fig. 1 is the X-ray powder diffraction pattern of the palonosetron hydrochloride hydrate crystal form prepared in Example 1;

Fig. 2 is the DSC diagram of the crystal form of Palonosetron hydrochloride hydrate prepared in Example 1;

FIG. 3 is a TGA diagram of the crystalline form of palonosetron hydrochloride prepared in Example 1. FIG.

Detailed ways

The structure characterization of the palonosetron hydrochloride hydrate crystal form of the present invention adopts X-ray powder diffraction and differential thermal scanning calorimetry. Compound purity was checked using Waters high performance liquid chromatography.

扫描范围(°2TH)3°-40°；扫描步长(°2TH)0.0131；每步扫描时间(s)97.767。X-ray powder diffraction was acquired on a PANalytical X'Pert3 X-ray powder diffraction analyzer using high-resolution transmission mode XRPD patterns. The XRPD test parameters are as follows: X-ray

Scanning range (°2TH) 3°-40°; scanning step size (°2TH) 0.0131; scanning time per step (s) 97.767.

Differential scanning calorimetry uses T-A differential thermal calorimetry and DSC2000, operation method: use t-zero bottle, the heating range is 30-350°C, the heating rate is 5°C per minute, and the nitrogen flow rate is 80ml/min.

The technical scheme of the present invention will be further described below in conjunction with specific examples

Example 1 Preparation of Palonosetron Hydrochloride Hydrate Crystal Form

Weigh (S)-N-(((S)-1,2,3,4-tetrahydronaphthalene-1-yl)methyl)quinuclidin-3-amine (referred to as imine) 20.0g, toluene 200.0g g, was added to the reaction flask, and the toluene solution of triphosgene was added dropwise at room temperature (37.0 g of triphosgene was added to 150.0 g of toluene and dissolved with stirring). After the dropwise addition was completed, the reaction was refluxed for 2 hours, and 37.0 g of boron trifluoride ether was added. After the addition was completed, the reaction was refluxed for 8 hours. The temperature was lowered to room temperature, 200.0 g of water was added, the addition was completed, the reaction was refluxed for 4 to 6 hours, lowered to 0 to 20° C., filtered, washed with water, and dried to obtain crude palonosetron hydrochloride. Weigh 10.0 g of crude palonosetron hydrochloride, add 140 g of anhydrous ethanol and 30.0 g of water, heat to dissolve and clarify, cool down to 10-20 ° C, stir for 2 hours, filter, wash with 10.0 g of anhydrous ethanol, and filter cake in 50-60 DEG C, drying, to obtain 6.25 g of palonosetron hydrochloride hydrate crystal form, the yield is 62.5%, the purity is 99.80%, and the water content is 5.3%. Its XRPD is shown in Figure 1, DSC is shown in Figure 2, and TGA is shown in Figure 3.

Example 2 Preparation of Palonosetron Hydrochloride Hydrate Crystal Form

Weigh (S)-N-(((S)-1,2,3,4-tetrahydronaphthalene-1-yl)methyl)quinuclidin-3-amine (referred to as imine) 65.0g, xylene 650.0 g was added to the reaction flask, and the xylene solution of triphosgene was added dropwise at room temperature (121.9 g of triphosgene was added to 487.0 g of xylene and stirred to dissolve). After the dropwise addition was completed, the reaction was refluxed for 2 hours, and 122.0 g of boron trifluoride ether was added. After the addition was completed, the reaction was refluxed for 8 hours. The temperature was lowered to room temperature, 650.0 g of water was added, and after the addition was completed, the reaction was refluxed for 4 to 6 hours, lowered to 0 to 20° C., filtered, washed with water, and dried to obtain crude palonosetron hydrochloride. Weigh 50.0 g of crude palonosetron hydrochloride, add 400.0 g of ethanol, and 200.0 g of water, heat to dissolve and clarify, warm to 0-10 ° C, stir for 2 hours, filter, wash with 50.0 g of absolute ethanol, and place the filter cake in 50 ～60°C, drying, to obtain 28.1 g of palonosetron hydrochloride hydrate crystal form, the yield is 56.2%, the purity is 99.78%, and the water content is 5.5%.

Example 3 Preparation of Palonosetron Hydrochloride Hydrate Crystal Form

Weigh (S)-N-(((S)-1,2,3,4-tetrahydronaphthalene-1-yl)methyl)quinuclidine-3-amine (referred to as imine) 40.0g, toluene 400.0g g, was added to the reaction flask, and 75.0 g of triphosgene was added in batches. After the addition was completed, the reaction was refluxed for 2 hours, and 75.0 g of boron trifluoride ether was added. After the addition was completed, the reaction was refluxed for 8 hours. The temperature was lowered to room temperature, 400.0 g of water was added, the addition was completed, the reaction was refluxed for 4-6 hours, cooled to 0-20° C., filtered, washed with water, and dried to obtain the crude palonosetron hydrochloride. Weigh 15.0 g of crude palonosetron hydrochloride, add 150.0 g of isopropanol and 50.0 g of water, heat to dissolve and clarify, gradually cool down to 0-10 ° C, stir for 2 hours, filter, use 15.0 g of cold isopropanol and The mixture was washed with 5.0 g of water, and the filter cake was dried at 50-60° C. to obtain 10.05 g of palonosetron hydrochloride hydrate crystal form with a yield of 67.0%, a purity of 99.85% and a water content of 5.6%.

Example 4 Preparation of Palonosetron Hydrochloride Hydrate Crystal Form

Weigh (S)-N-(((S)-1,2,3,4-tetrahydronaphthalene-1-yl)methyl)quinuclidine-3-amine (referred to as imine) 20.0g, toluene 200.0g g, was added to the reaction flask, and the toluene solution of triphosgene was added dropwise at room temperature (37.0 g of triphosgene was added to 150.0 g of toluene and dissolved with stirring). After the dropwise addition was completed, the reaction was refluxed for 2 hours, and 37.0 g of boron trifluoride ether was added. After the addition was completed, the reaction was refluxed for 8 hours. The temperature was lowered to room temperature, 200.0 g of water was added, the addition was completed, the reaction was refluxed for 4 to 6 hours, lowered to 0 to 20° C., filtered, washed with water, and dried to obtain crude palonosetron hydrochloride. Weigh 10.0 g of crude palonosetron hydrochloride, add 100 g of methanol and 20.0 g of water, heat to dissolve and clarify, cool down to 0 to 10 ° C, stir for 2 hours, filter, wash with a mixture of methanol and water, and the filter cake at 40 ~50°C, drying to obtain 4.86 g of palonosetron hydrochloride hydrate crystal form, the yield is 48.6%, the purity is 99.87%, and the water content is 5.2%.

Example 5 Preparation of Palonosetron Hydrochloride Hydrate Crystal Form

Weigh (S)-N-(((S)-1,2,3,4-tetrahydronaphthalene-1-yl)methyl)quinuclidin-3-amine (referred to as imine) 20.0g, toluene 200.0g g, was added to the reaction flask, and 37.5 g of triphosgene was added in batches. After the addition was completed, the reaction was refluxed for 2 hours, and 37.5 g of boron trifluoride ether was added. After the addition was completed, the reaction was refluxed for 8 hours. The temperature was lowered to room temperature, 200.0 g of water was added, the addition was completed, the reaction was refluxed for 4-6 hours, cooled to 0-20° C., filtered, washed with water, and dried to obtain crude palonosetron hydrochloride. Weigh 10.0 g of crude palonosetron hydrochloride, add 200.0 g of acetone, and 150.0 g of purified water, heat up to dissolve, slowly cool down to 0 to 10 ° C, filter, and wash with a mixture of acetone and water. ℃, drying to obtain 6.8 g of palonosetron hydrochloride hydrate crystal form, the yield is 68.0%, the purity is 99.76%, and the water content is 5.2%.

Example 6 Preparation of Palonosetron Hydrochloride Hydrate Crystal Form

Weigh (S)-N-(((S)-1,2,3,4-tetrahydronaphthalene-1-yl)methyl)quinuclidin-3-amine (referred to as imine) 20.0g, toluene 200.0g g, was added to the reaction flask, and 37.5 g of triphosgene was added in batches. After the addition was completed, the reaction was refluxed for 2 hours, and 37.5 g of boron trifluoride ether was added. After the addition was completed, the reaction was refluxed for 8 hours. The temperature was lowered to room temperature, 200.0 g of water was added, the addition was completed, the reaction was refluxed for 4-6 hours, cooled to 0-20° C., filtered, washed with water, and dried to obtain crude palonosetron hydrochloride. Weigh 10.0 g of crude palonosetron hydrochloride, add 150.0 g of acetonitrile and 200.0 g of purified water, heat up to dissolve, slowly cool down to 0 to 10 ° C, filter, and wash with a mixture of acetonitrile and water, and the filter cake is heated to 40 to 50 ℃, drying to obtain 6.1 g of palonosetron hydrochloride hydrate crystal form, the yield is 61.0%, the purity is 99.78%, and the water content is 5.4%.

Example 7 Evaluation of the stability of the crystal form of palonosetron hydrochloride hydrate

The prepared palonosetron hydrochloride crystals were tested for influencing factors and accelerated stability tests. For the test methods, please refer to Appendix XIXC "Guidelines for Stability Tests of Raw Materials and Pharmaceutical Preparations" in "Chinese Pharmacopoeia (2015)".

(1) Influencing factor test:

1. High temperature test: take the crystal form of Palonosetron hydrochloride hydrate prepared in the above-mentioned embodiment, place it at 60° C. for 10 days, take samples on the 10th day, measure each index and compare it with 0 days. The test results are shown in Table 1.

2. High-humidity test: take the crystal form of Palonosetron hydrochloride hydrate prepared in the above-mentioned embodiment, place it at a humidity of 75% for 10 days, take samples on the 10th day, measure each index and compare it with 0 days. The test results See Table 1.

3. Strong light irradiation test: get the palonosetron hydrochloride prepared in the above-mentioned embodiment, place 10 days under the condition that illumination intensity is (4500 ± 500) Lux, take a sample on the 10th day, measure each index and compare with 0 day , and the test results are shown in Table 1.

Table 1 Test of factors affecting the crystal form of palonosetron hydrochloride hydrate

(2) Accelerated stability test:

Palonosetron hydrochloride prepared in the above example was subjected to an accelerated stability test for 1 month in a constant temperature and humidity chamber. Test conditions Humidity: 40° C./75% relative humidity (RH), take samples after 1 month, and carry out the detection of purity, related substances and XRPD. The results are shown in Table 2.

Table 2 Accelerated stability test of palonosetron hydrochloride

Test conditions time purity(%) relative substance(%) XRPD 0 days 99.864 0.042 --- 40℃/75%(RH) January 99.855 0.045 unchanged

It can be seen from the above-mentioned influencing factor test and accelerated test that the palonosetron hydrochloride prepared by the present invention has no obvious increase in impurities, no obvious change in purity, and no change in crystal form under high temperature, high humidity and light conditions; accelerated stability The sex test proves that the product has good quality and stability.

To sum up, the crystalline form of palonosetron hydrochloride disclosed in the present invention has favorable properties such as good stability, low hygroscopicity, process development and easy handling. The preparation method of the hydrate crystal form is simple, the cost is low, the industrial production is easy, and it has important value for the optimization and development of future drugs.

Claims (10)

1. A crystalline form of palonosetron hydrochloride hydrate, characterized in that: the X-ray powder diffraction pattern obtained by measuring the hydrate crystal form by CuKa rays comprises characteristic diffraction peaks at 2 theta diffraction angles of 5.6 +/-0.2 degrees, 10.9 +/-0.2 degrees, 13.4 +/-0.2 degrees, 16.9 +/-0.2 degrees and 22.6 +/-0.2 degrees.

2. The crystalline form of palonosetron hydrochloride hydrate according to claim 1, characterized in that: in an X-ray powder diffraction pattern obtained by measuring the hydrate crystal form by CuKa rays, at least one of characteristic diffraction peaks at 2 theta diffraction angles of 12.3 +/-0.2 degrees, 17.9 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.7 +/-0.2 degrees, 20.8 +/-0.2 degrees, 21.1 +/-0.2 degrees, 22.1 +/-0.2 degrees, 23.0 +/-0.2 degrees and 26.9 +/-0.2 degrees is also included.

3. The crystalline form of palonosetron hydrochloride hydrate according to claim 1 or 2, characterized in that: the DSC chart of the hydrate crystal form has endothermic peaks at 66.5 ℃ and 227.5 ℃.

4. The crystalline form of palonosetron hydrochloride hydrate according to any one of claims 1 to 3, characterized in that: the water content of the hydrate crystal form is 5.1-5.6%.

5. A process for preparing the crystalline form of palonosetron hydrochloride hydrate of any one of claims 1 to 4, characterized in that: comprises the following steps:

a) adding (S) -N- (((S) -1,2,3, 4-tetrahydronaphthalene-1-yl) methyl) quinuclidine-3-amine and a reaction solvent into a reaction bottle, adding triphosgene, carrying out reflux reaction for 2 hours, adding boron trifluoride diethyl etherate, carrying out reflux reaction for 6 hours, cooling to room temperature, adding water, carrying out reflux reaction for 4 hours, cooling to 0-20 ℃, filtering, washing with water, and drying to obtain a palonosetron hydrochloride crude product;

b) adding a crystallization solvent into the crude palonosetron hydrochloride product, heating up, refluxing, dissolving, clarifying, carrying out gradient cooling, stirring at a low temperature for 2 hours, filtering, washing by using an organic solvent, and drying to obtain a palonosetron hydrochloride hydrate crystal.

6. The process of preparing a crystalline form of palonosetron hydrochloride hydrate according to claim 5, characterized in that: the reaction solvent in the step a) is at least one selected from toluene, xylene, chloroform, acetone, ethyl acetate and isopropyl acetate.

7. The process of preparing a crystalline form of palonosetron hydrochloride hydrate according to claim 5, characterized in that: the crystallization solvent in the step b) is one or more selected from water, methanol, ethanol, isopropanol, acetone and acetonitrile.

8. The process of preparing a crystalline form of palonosetron hydrochloride hydrate according to claim 5, characterized in that: the crystallization temperature in the step b) is 0-30 ℃.

9. The process of preparing a crystalline form of palonosetron hydrochloride hydrate according to claim 5, characterized in that: the mass ratio of the crude palonosetron hydrochloride to the organic solvent in the step b) is 1: 5 to 35.

10. The process of preparing a crystalline form of palonosetron hydrochloride hydrate according to claim 5, characterized in that: the drying temperature in the step b) is 30-80 ℃; the drying time is 1-24 hours.

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