Tolvaptan sodium phosphate crystal form and preparation method thereof

Abstract

The invention discloses a tolvaptan sodium phosphate crystal form. The X-ray powder diffraction pattern of the tolvaptan sodium phosphate crystal form has characteristic diffraction peaks at diffraction angles 2theta of 3.8 + / -0.2, 7.7 + / -0.2, 9.8 + / -0.2, 11.5 + / -0.2, 12.5 + / -0.2, 16.2 + / -0.2, 17.4 + / -0.2, 19.2 + / -0.2, 20.8 + / -0.2, 23.2 + / -0.2, 29.6 + / -0.2, 30.3 + / -0.2 and 31.4 + / -0.2. The invention also discloses a preparation method of the tolvaptan sodium phosphate crystal form. According to the preparation method, the flowability of crystal mush during crystallization is improved, the granular sensation is increased, the explosion separation phenomenon is eliminated, the residual solvent of the product is reduced, and the stability of the product is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of crystallization, and in particular relates to a tolvaptan sodium phosphate crystal form and a preparation method thereof. Background Art

[0002] Tolvaptan sodium phosphate is a prodrug of tolvaptan, which is converted into the active drug tolvaptan in the body after administration. Studies have shown that tolvaptan sodium phosphate is rapidly hydrolyzed into tolvaptan after intravenous injection and shows efficacy. The drug was approved in Japan in March 2022 for use in heart failure where other diuretics (such as loop diuretics) are insufficient to control fluid retention. Otsuka Pharmaceutical has applied for it in China in December 2023 and it has been accepted by CDE.

[0003]

[0004] There is no report on the crystal form of tolvaptan sodium phosphate. According to patent CN101346390B, tolvaptan sodium phosphate is prepared by recrystallization in acetone and water. The method comprises the following steps: salting tolvaptan phosphate with sodium hydroxide in a methanol and water system, and then distilling under reduced pressure to remove the solvent, and then directly recrystallizing in water and acetone. However, there is no report on the crystal form.

[0005]

[0006] Patent CN113383001A also reports a method for preparing tolvaptan sodium phosphate, which uses a continuous telescoping process (phosphitidation with phosphorus oxychloride followed by direct addition of sodium hydroxide for salt formation), directly salting out crystals in water, and then recrystallizing with acetone and water to obtain tolvaptan sodium phosphate, but no information related to the crystal form of the product has been reported.

[0007]

[0008] The technicians in this field repeated the preparation of the sodium phosphate tolvaptan prepared in the above two patents, and the product precipitated in water and acetone was detected by X-ray powder diffraction (XRPD), which was basically amorphous or low-crystallinity product. The technicians in this field also found that the material precipitated in this system had a "explosion" phenomenon, a dull appearance, a small particle size and aggregates, which made filtration difficult on the one hand, resulting in high labor intensity, poor environment and low yield for subsequent industrial production workers; on the other hand, the precipitated material was basically an amorphous product or low crystallinity, with a hard appearance and texture, high residual solvent and poor stability. Accelerated tests found that the amorphous product had a fast degradation rate and large impurities.

[0009] Although the original product of Tolvaptan Sodium Phosphate launched in Japan is a lyophilized preparation, if the API does not meet the pharmaceutical standards before lyophilization, the residual solvent exceeds the ICHQ3C standard. For example, solvents such as acetone and alcohol cannot be removed during the lyophilization process, thus affecting the safety and effectiveness of the preparation. Therefore, how to reduce the residual solvent of the API, obtain a crystalline API, and improve its stability during the shelf life has a very huge social and economic value. Summary of the invention

[0010] The invention provides a tolvaptan sodium phosphate crystal form and a preparation method thereof, which improves the fluidity of the crystal slurry during crystallization, increases the granularity, eliminates the explosion phenomenon, reduces the residual solvent of the product, improves the crystallinity, reduces the residual impurities, and thus improves the stability of the product.

[0011] The technical solution of the present invention is as follows:

[0012] A tolvaptan sodium phosphate crystal form, whose X-ray powder diffraction pattern has characteristic diffraction peaks at diffraction angles 2θ of 3.8±0.2, 7.7±0.2, 9.8±0.2, 11.5±0.2, 12.5±0.2, 16.2±0.2, 17.4±0.2, 19.2±0.2, 20.8±0.2, 23.2±0.2, 29.6±0.2, 30.3±0.2 and 31.4±0.2.

[0013] Preferably, the X-ray powder diffraction pattern of the tolvaptan sodium phosphate crystalline form also has characteristic diffraction peaks at diffraction angles 2θ of 8.8±0.2, 11.0±0.2, 13.1±0.2, 13.7±0.2, 14.9±0.2, 21.2±0.2, 26.5±0.2, 27.7±0.2 and 28.4±0.2.

[0014] The present invention also provides a method for preparing the tolvaptan sodium phosphate crystal form, comprising the following steps:

[0015] (1) dissolving a crude product of tolvaptan sodium phosphate in a mixed solvent of water and alcohol to obtain a solution of tolvaptan sodium phosphate;

[0016] (2) adding a poor solvent for tolvaptan sodium phosphate dropwise to the solution of tolvaptan sodium phosphate, cooling the solution to -10 to 30° C. and stirring to allow crystallization;

[0017] (3) After the crystallization is completed, the product is separated, washed and dried.

[0018] The preparation method of crude tolvaptan sodium phosphate can refer to the embodiment described in CN101346390B, and the salt-forming material is concentrated under reduced pressure to obtain crude tolvaptan sodium phosphate.

[0019] Preferably, in step (1), the mass volume ratio of crude tolvaptan sodium phosphate, water and alcohol is 1 g: 1-5 mL: 1-5 mL.

[0020] Further preferably, in step (1), the mass volume ratio of crude tolvaptan sodium phosphate, water and alcohol is 1 g: 1-2 mL: 2-5 mL; further preferably 1 g: 1.5-2 mL: 2.5-5 mL.

[0021] Preferably, the alcohol is a C1-C5 alcohol; further preferably, the alcohol is methanol or ethanol.

[0022] Preferably, in step (1), the dissolution temperature is 35-55°C.

[0023] Preferably, in step (1), a decolorizing agent is added to the alcohol solution of tolvaptan sodium phosphate for decolorization.

[0024] Preferably, the decolorizing agent is activated carbon.

[0025] Preferably, in step (2), the mass volume ratio of the crude tolvaptan sodium phosphate to the poor solvent for tolvaptan sodium phosphate is 1 g:10-50 mL; more preferably 1 g:15-30 mL; more preferably 1 g:20 mL.

[0026] Preferably, the poor solvent of tolvaptan sodium phosphate is acetone.

[0027] Preferably, in step (2), seed crystals are added directly after the poor solvent is added, and then the temperature is lowered for crystallization.

[0028] In step (2), the stirring crystallization is carried out at -10 to 30°C; more preferably 0 to 20°C; and more preferably 10 to 15°C.

[0029] After the crystallization is completed, the feed liquid is centrifuged and washed. The crystal product is dried under reduced pressure at 50-70°C for 10-24 hours and is found to be a crystalline product after X-ray powder diffraction.

[0030] According to the crude tolvaptan sodium phosphate prepared in CN101346390B, after vacuum distillation, it is recrystallized with water and acetone, and the obtained product is basically amorphous. The preparation method of the same reference CN113383001A patent also uses acetone and water for recrystallization, and the product is also basically an amorphous product. The crystallization process of the two existing methods has a "explosive analysis" phenomenon. After drying, the material has a hard texture and a very high residual solvent. It is found through accelerated tests that the product is degraded into tolvaptan with a large impurity content.

[0031] The inventor surprisingly found that, when the crude product of tolvaptan sodium phosphate is involved in an alcoholic solvent, a poor solvent (such as acetone) is added after the solvent is dissolved and cleared to recrystallize, and the tolvaptan sodium phosphate containing the crystalline product is obtained, and the filtration is extremely fast, the product does not stick to the wall, is dry, and has a friendly operating environment. The obtained product is soft in texture, granular, has strong fluidity, and has low solvent residue, which meets the control requirements for drug residual solvents in ICHQ3C. The product stability obtained by the preparation method of the present invention is high, and it is found through accelerated tests that the impurity content level is low. The above-mentioned product prepared is directly added to the above-mentioned solution as a crystal seed for crystallization investigation, and the obtained product is a product containing the crystal form.

[0032] The inventors also referred to the samples prepared by patents CN101346390B and CN113383001A, which had high residual solvents. However, the products with high residual solvents were recrystallized or directly added with seed crystals through the preparation method of the present invention, and the obtained products contained very low residual solvents and had a crystalline state, which met the pharmaceutical residue standards.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] The present invention provides a tolvaptan sodium phosphate crystal form and a preparation method thereof. The preparation method of the present invention reduces the residual solvent of the product and meets the pharmaceutical standards. Compared with the amorphous state product, the impurity content in the crystalline state is low, the product is more stable and convenient for storage. The preparation method of the present invention is simple to operate, the crystal slurry is easy to filter, wash and dry, the labor intensity of the process operation is low, and it is easy to scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 The XRPD pattern of the tolvaptan sodium phosphate crystalline form prepared in Example 1;

[0036] Figure 2 This is the amorphous XRPD spectrum of tolvaptan sodium phosphate prepared in Comparative Example 2. DETAILED DESCRIPTION

[0037] The present invention will be further described in detail below in conjunction with specific examples. The method of the present invention can be implemented by many different combinations, but is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present invention more thoroughly and comprehensively understood.

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0039] Example 1

[0040] Take 10g of crude tolvaptan sodium phosphate, dissolve it in 15mL of purified water and 25mL of anhydrous ethanol, heat it to 45℃ and stir to dissolve, add 0.5g of activated carbon for decolorization for 30 minutes, filter it and drop 200mL of acetone at this temperature within 30 minutes. After the addition is completed, keep warm and stir for 10 minutes, cool it to 10-15℃, stir it for 24h, and no explosion occurs during the recrystallization process. After the stirring is completed, filter the material, rinse the filter cake with a small amount of acetone, put the filter cake into a vacuum drying oven, and dry it at 60℃ for 12h. Take a sample and test XRD, and the result is as follows Figure 1 The crystalline tolvaptan sodium phosphate product shown has batch number 20240773.

[0041] In the X-ray powder diffraction pattern of the prepared tolvaptan sodium phosphate product, there are characteristic peaks at diffraction angles 2θ of 3.840, 7.701, 9.821, 8.822, 11.078, 11.578, 12.501, 13.103, 13.722, 14.901, 16.238, 17.401, 19.220, 20.822, 21.218, 23.299, 26.520, 27.759, 28.420, 29.601, 30.359 and 31.442, among which the characteristic peaks at 3.840, 7.701 and 20.822 are relatively strong.

[0042] HPLC purity: 100%; Tolvaptan impurity content: not detected.

[0043] Example 2

[0044] Take 10g crude tolvaptan sodium phosphate, dissolve in 20mL purified water and 50mL anhydrous ethanol, heat to 45℃ and stir to dissolve, add 0.5g activated carbon for decolorization for 30 minutes, filter and add 200mL acetone at this temperature within 30 minutes, after the addition is completed, keep warm and stir for 10 minutes, cool to 10-15℃, stir for 24h, no explosion occurs during the recrystallization process. After stirring, filter the material, rinse the filter cake with a small amount of acetone, put the filter cake into a vacuum drying oven, and dry it at 60℃ for 12h. Sampling and XRD detection, its crystal form is consistent with that of Example 1.

[0045] HPLC purity: 100%; Tolvaptan impurity content: not detected.

[0046] Comparative Example 1

[0047] Take 10g of crude tolvaptan sodium phosphate, add it to 50mL of anhydrous ethanol, heat it to 45℃ and stir to dissolve, add 0.5g of activated carbon for decolorization for 30 minutes, filter it and drop 200mL of acetone at this temperature within 30 minutes, after the addition is completed, keep warm and stir for 10 minutes, cool it to 10-15℃, and stir it for 24h. After stirring, filter the material, rinse the filter cake with a small amount of acetone, put the filter cake into a vacuum drying oven, and dry it at 60℃ for 12h. Take a sample for XRD detection to obtain an amorphous tolvaptan sodium phosphate product.

[0048] HPLC purity: 99.95%, tolvaptan impurity content: 0.02%.

[0049] Example 3

[0050] Take 10g crude tolvaptan sodium phosphate, dissolve in 15mL purified water and 20mL anhydrous methanol, heat to 55℃ and stir to dissolve, add 0.5g activated carbon for decolorization for 30 minutes, filter and add 200mL acetone at this temperature within 30 minutes, after the addition is completed, keep warm and stir for 10 minutes, cool to 10-15℃, stir for 24h, no explosion occurs during the recrystallization process. After stirring, filter the material, rinse the filter cake with a small amount of acetone, put the filter cake into a vacuum drying oven, and dry it at 60℃ for 12h. Sampling and XRD detection, its crystal form is consistent with that of Example 1.

[0051] In the X-ray powder diffraction pattern of the prepared tolvaptan sodium phosphate product, there are characteristic peaks at diffraction angles 2θ of 3.858, 7.719, 9.839, 11.595, 12.519, 16.241, 17.420, 19.222, 20.840, 23.303, 29.620, 30.362 and 31.461, among which the characteristic peaks at 3.858, 7.719 and 20.840 are relatively strong.

[0052] HPLC purity: 100%; Tolvaptan impurity content: not detected.

[0053] Example 4

[0054] Take 10g crude tolvaptan sodium phosphate, dissolve in 15mL purified water and 25mL anhydrous ethanol, heat to 50℃ and stir to dissolve, add 0.5g activated carbon for decolorization for 30 minutes, filter and drip 200mL acetone at this temperature within 30 minutes, after the addition is completed, keep warm and stir for 10 minutes, add the seed prepared in Example 1, cool to 10-15℃, stir for 10h, and no explosion occurs during the recrystallization process. After stirring, filter the material, rinse the filter cake with a small amount of acetone, put the filter cake into a vacuum drying oven, and dry it at 60℃ for 12h. Sample and detect XRD, which is the same crystal form as the product in Example 1.

[0055] HPLC purity: 100%; Tolvaptan impurity content: not detected.

[0056] Comparative Example 2

[0057] Referring to patent CN101346390B, 5g crude tolvaptan sodium phosphate was recrystallized using water and acetone (the weight ratio of water to acetone was 5:95). Explosion occurred during the recrystallization process. The material was filtered, and the filter cake was placed in a vacuum drying oven and dried at 60°C for 12h. Samples were taken for XRD testing, and the results were as follows: Figure 2 The substantially amorphous tolvaptan sodium phosphate product, batch number 20240703, is shown.

[0058] HPLC purity: 99.92%, tolvaptan impurity content: not detected.

[0059] Example 5

[0060] The amorphous product obtained in Comparative Example 1 was recrystallized by the operation of Example 1. The obtained product was detected by XRD, and it was found to be the same crystal form as the product in Example 1.

[0061] test

[0062] The stability comparison test results of the accelerated test are shown in Table 1.

[0063] Table 1

[0064] Comparative Example 1 (anhydrous) Comparative Example 2 (no alcohol) Example 1 Purity before accelerated test 99.95 99.92％ 100％ One month after acceleration 99.73 99.50％ 99.97％ Tolvaptan Impurities (Before Acceleration) 0.02％ Not detected Not detected Tolvaptan Impurities (Accelerated) 0.13％ 0.10％ 0.03％

[0065] From the above data, it can be concluded that the tolvaptan sodium phosphate with a stable crystalline form prepared in Example 1 has a degradation impurity content of only 0.03% after one month of accelerated treatment, while the degradation impurities of the substantially amorphous products prepared in Comparative Examples 1 and 2 increased from undetectable to 0.13% and 0.10% after one month of accelerated treatment.

[0066] The residual solvent test was performed and the results are shown in Table 2.

[0067] Table 2

[0068] Comparative Example 1 (anhydrous) Comparative Example 2 (no alcohol) Example 1 Acetone residue (pharmaceutical standard ≤ 0.5%) 0.66％ 0.7％ 0.05％

[0069] From the above data, it can be concluded that the residual acetone in the tolvaptan sodium phosphate product with a stable crystalline form prepared in Example 1 is 0.05%, while the residual acetone in the substantially amorphous products prepared in Comparative Examples 1 and 2 is 0.66% and 0.7%, respectively, which do not meet the pharmaceutical standards.

[0070] The embodiments described above provide a detailed description of the technical solutions and beneficial effects of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, supplements and equivalent substitutions made within the scope of the principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A tolvaptan sodium phosphate crystal form, characterized in that: Its X-ray powder diffraction pattern has characteristic diffraction peaks at diffraction angles 2θ of 3.8±0.2, 7.7±0.2, 9.8±0.2, 11.5±0.2, 12.5±0.2, 16.2±0.2, 17.4±0.2, 19.2±0.2, 20.8±0.2, 23.2±0.2, 29.6±0.2, 30.3±0.2 and 31.4±0.

2.

2. The tolvaptan sodium phosphate crystal form according to claim 1, characterized in that Its X-ray powder diffraction pattern also has characteristic diffraction peaks at diffraction angles 2θ of 8.8±0.2, 11.0±0.2, 13.1±0.2, 13.7±0.2, 14.9±0.2, 21.2±0.2, 26.5±0.2, 27.7±0.2 and 28.4±0.

2.

3. A method for preparing the tolvaptan sodium phosphate crystal form according to any one of claims 1 or 2, characterized in that: The steps include: (1) dissolving a crude product of tolvaptan sodium phosphate in a mixed solvent of water and alcohol to obtain a solution of tolvaptan sodium phosphate; (2) adding a poor solvent for tolvaptan sodium phosphate dropwise to the solution of tolvaptan sodium phosphate, cooling the solution to -10 to 30° C. and stirring to allow crystallization; (3) After the crystallization is completed, the product is separated, washed and dried.

4. The method for preparing tolvaptan sodium phosphate crystal according to claim 3, characterized in that: In step (1), the mass volume ratio of crude tolvaptan sodium phosphate, water and alcohol is 1 g: 1-5 mL: 1-5 mL.

5. The method for preparing tolvaptan sodium phosphate crystal according to claim 3, characterized in that: The alcohols are C1-C5 alcohols.

6. The method for preparing the tolvaptan sodium phosphate crystal form according to claim 5, characterized in that: The alcohol is methanol or ethanol.

7. The method for preparing the tolvaptan sodium phosphate crystal form according to claim 3, characterized in that: In step (2), the mass volume ratio of the crude tolvaptan sodium phosphate to the poor solvent for tolvaptan sodium phosphate is 1 g:10-50 mL.

8. The method for preparing the tolvaptan sodium phosphate crystal form according to claim 3, characterized in that: The poor solvent of tolvaptan sodium phosphate is acetone.

9. The method for preparing the tolvaptan sodium phosphate crystal form according to claim 3, characterized in that: In step (2), seed crystals are directly added after the poor solvent is added, and then the temperature is lowered for crystallization.

10. The method for preparing the tolvaptan sodium phosphate crystal form according to claim 3, characterized in that: In step (2), stirring crystallization is carried out at -10 to 30°C.

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