A crystalline form of fluvoxetine hemipamoyate salt

Abstract

The present application provides a new crystal form of fluvoxetine pamoate, and the present application also relates to the use of the crystal form of fluvoxetine pamoate in treating and / or preventing nervous system diseases. The crystal form of fluvoxetine pamoate of the present application greatly prolongs the in-vivo action time of fluvoxetine, delays the release rate of fluvoxetine, and releases more smoothly and safely.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical research and development, specifically to a new crystal form of vortioxetine hemipamoate, its preparation method, and its uses. Technical Background

[0002] Vortioxetine, chemically known as 1-[2-(2,4-dimethylphenylthio)phenyl]piperazine.

[0003] Vortioxetine, as a 5-HT transporter (SERT) inhibitor, exerts its therapeutic effects on depression and anxiety by inhibiting serotonin reuptake. Furthermore, vortioxetine also possesses 5-HT... 1A receptor agonists, 5-HT 1B partial receptor agonists and 5-HT3, 5-HT 1D Compared with existing antidepressants, vortioxetine has almost no effect on norepinephrine and dopaminergic neurons, and has a faster onset of action, fewer toxic side effects, and better antidepressant effects, especially in the treatment of major depressive disorder, where it has good efficacy, safety and tolerability.

[0004] Free vortioxetine has low bioavailability in vivo, and existing technologies typically prepare different salts of the free base to improve its efficacy. For example, patents WO2007144005 and WO2014044721 disclose various pharmaceutically acceptable salts of vortioxetine, specifically reporting methods for preparing vortioxetine hydrobromide and its five crystal forms; WO2010121621 discloses a method for preparing vortioxetine lactate; CN104628677 discloses vortioxetine p-hydroxybenzoate and its hydrate crystal forms; CN104610195 discloses vortioxetine aspartate and its hydrate crystal forms. Compared to free vortioxetine compounds, these various forms of vortioxetine salts show varying degrees of improvement in solubility, stability, and bioavailability.

[0005] For antipsychotic drugs, high relapse rates and poor medication adherence are major problems. Long-acting formulations, such as long-acting injections, can greatly improve patient adherence. After administration, the drug is slowly released into the patient's body, maintaining a stable blood drug concentration over a long period, which may be a better way to solve these problems. CN109311832 discloses vortioxetine's pamoic acid and its crystal form, which can achieve a certain long-acting release effect. However, during the research process, it was found that the crystal form disclosed in this patent has a significant burst release effect in vivo, and the release is not stable enough, which are undesirable results when developing long-acting formulations. Obtaining a long-acting formulation that can be stably released in vivo remains a difficult problem to be solved. Summary of the Invention

[0006] The purpose of this invention is to provide a novel crystal form of vortioxetine hemipamoate that can be slowly and sustainably released in vivo, thereby achieving the technical effect of maintaining a stable blood drug concentration in patients over a long period of time and greatly improving medication adherence.

[0007] The present invention provides a crystal form E of vortioxetine hemipamoate, characterized by characteristic peaks at 9.5±0.2°, 13.8±0.2°, 15.0±0.2°, 17.1±0.2°, and 18.7±0.2° when X-ray powder diffraction is performed using Cu-Kα radiation and expressed in 2θ angle.

[0008] Preferably, the crystal form E of the vortioxetine hemipamoate, when expressed in X-ray powder diffraction at a 2θ angle, also has one or more characteristic peaks at 11.9±0.2°, 15.9±0.2°, and 20.0±0.2°.

[0009] Further preferably, the crystal form E of the vortioxetine hemipamoate has one or more characteristic peaks at 4.1±0.2°, 7.8±0.2°, and 23.8±0.2° in X-ray powder diffraction at a 2θ angle.

[0010] Furthermore, preferably, the crystal form E of the vortioxetine hemipamoate has one or two characteristic peaks at 22.3±0.2° and 23.3±0.2° in X-ray powder diffraction at a 2θ angle.

[0011] More preferably, the crystal form E of the vortioxetine hemipamoate has substantially the following properties: Figure 2 The X-ray powder diffraction pattern shown is shown.

[0012] In some embodiments of the present invention, the crystal form E of the vortioxetine hemipamoate has an endothermic peak at 232℃±10℃ in its differential scanning calorimetry curve.

[0013] Preferably, the crystal form E of the vortioxetine hemipamoate has an endothermic peak at 232℃±5℃ in its differential scanning calorimetry curve.

[0014] More preferably, the crystal form E of the vortioxetine hemipamoate has essentially the following properties: Figure 3 The DSC spectrum shown.

[0015] In some embodiments of the present invention, the crystal form E of the vortioxetine hemipamoate has essentially the following properties: Figure 4 The TGA spectrum shown.

[0016] The crystal form E described in this invention is substantially pure, meaning that the purity of the crystal form is at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 98%, or at least 99%.

[0017] The present invention also provides a method for preparing vortioxetine hemipamoate crystal form E, the method comprising the following steps: adding vortioxetine and pamolic acid in a molar ratio of 2:1 to anhydrous ethanol, heating and stirring to carry out the reaction, after the reaction is completed, cooling the reaction system to room temperature, filtering, washing the filter cake with anhydrous ethanol, drying it under vacuum to obtain the product.

[0018] Preferably, in the preparation method, the weight (g) ratio of vortioxetine to the volume (mL) ratio of anhydrous ethanol is 1:10 to 1:40, preferably 1:30.

[0019] Preferably, in the preparation method, the reaction temperature is 40–70°C, more preferably 60°C.

[0020] Preferably, in the preparation method, the reaction time is 5 to 30 hours, more preferably 24 hours.

[0021] The present invention also provides a pharmaceutical composition comprising crystal form E of the above-mentioned vortioxetine hemipamoate as an active ingredient, and pharmaceutically acceptable excipients and / or carriers.

[0022] The present invention also provides the use of crystal form E of the vortioxetine hemipamoate and pharmaceutical compositions thereof for the treatment and / or prevention of neurological disorders, including depression, anxiety, obsessive-compulsive disorder, panic disorder, substance abuse, alcoholism, nicotine addiction, carbohydrate addiction, Alzheimer's disease, cognitive impairment, chronic pain, neuropathic pain, nociceptive pain, inflammatory pain, visceral pain, migraine, and cancer-related pain.

[0023] The present invention also provides the use of crystal form E of the vortioxetine hemipamoate, and pharmaceutical compositions thereof, in the preparation of medicaments for the treatment and / or prevention of neurological disorders, including depression, anxiety, obsessive-compulsive disorder, panic disorder, substance abuse, alcoholism, nicotine addiction, carbohydrate addiction, Alzheimer's disease, cognitive impairment, chronic pain, neuropathic pain, nociceptive pain, inflammatory pain, visceral pain, migraine, and cancer-related pain.

[0024] Beneficial effects

[0025] The vortioxetine hemipamoate crystal form E of the present invention greatly prolongs the duration of action of vortioxetine in vivo and slows down the release rate of vortioxetine. In particular, compared with the vortioxetine hemipamoate crystal form in the prior art, the vortioxetine hemipamoate crystal form E of the present invention does not have obvious burst release behavior, and the release is more stable and safer. Attached Figure Description

[0026] Figure 1 For vortioxetine hemipamoate crystal form E 1 HNMR spectrum.

[0027] Figure 2 The XRPD spectrum of vortioxetine hemipamoate crystal form E is shown.

[0028] Figure 3 The DSC spectrum of vortioxetine hemipamoate crystal form E is shown.

[0029] Figure 4 The TGA spectrum of vortioxetine hemipamoate crystal form E is shown.

[0030] Figure 5 The figure shows the plasma concentration-time curves of different crystal forms of vortioxetine hemipamoate in rats.

[0031] Figure 6 The graph shows the plasma concentration-time (0-24h) curves of different crystal forms of vortioxetine hemipamoate in rats. Specific Implementation

[0032] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. The following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0033] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0034] Test instruments and parameters used in the experiment

[0035] 1. X-ray powder diffractometer Bruker D2 PHASER: Cu target, tube voltage (30kV), tube current (10mA), 2θ scanning range 3-40°, scanning speed 0.10s, step size 0.020°.

[0036] 2. Differential Scanning Calorimeter (DSC 3500): Place the sample in an aluminum sample pan and determine the thermal analysis according to the General Chapter 0661 of the 2020 edition of the Chinese Pharmacopoeia. The initial temperature is 50℃, and the temperature is increased to 500℃ at a rate of 20℃ per minute.

[0037] 3. Thermogravimetric analyzer TGA2: Place the sample in a ceramic sample pan and determine the thermogravimetric analysis according to the General Chapter 0661 of the 2020 edition of the Chinese Pharmacopoeia. The initial temperature is 40℃, and the temperature is increased to 500℃ at a rate of 10℃ per minute.

[0038] 4. Nuclear magnetic resonance analysis (NMR) 1 H NMR: Solid samples were dissolved in dimethyl sulfoxide-d6 solvent and analyzed by NMR on a Bruker AVANCE-III 600MHz instrument.

[0039] Example 1

[0040] Take a 250 mL three-necked flask, add 2.09 g of vortioxetine, 1.36 g of pamoic acid, and 63 mL of anhydrous ethanol. Heat the reaction system to 60 °C and stir at this temperature for 24 h. After the reaction is complete, cool the system to room temperature, filter, wash the filter cake with 4.2 mL of anhydrous ethanol, dry under vacuum at 45 ± 5 °C for 6 h to obtain 3.19 g of vortioxetine hemipamoate, yield: 92.46%. The obtained solid is named vortioxetine hemipamoate crystal form E. The XRPD detection results of this crystal form E by the aforementioned instrument 1 are as follows: Figure 2 As shown, the DSC and TGA test results obtained by instruments 2 and 3 are as follows: Figure 3 and 4 As shown below, the XRPD diffraction peak data for this crystal form E are as follows.

[0041] 2θ angle (°) Relative strength (%) 4.080 8.2 7.793 17.5 9.515 37.0 11.892 16.9 13.830 31.5 15.026 100.0

[0042] 2θ angle (°) Relative strength (%) 15.947 27.7 17.126 32.1 18.712 51.8 19.969 19.5 22.307 13.9 23.278 18.4 23.849 18.5

[0043] Example 2

[0044] A 250 mL three-necked flask was filled with 2.09 g of vortioxetine, 1.36 g of pamoic acid, and 21 mL of anhydrous ethanol. The reaction mixture was heated to 60 °C and stirred at this temperature for 24 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filter cake was washed with 4.2 mL of anhydrous ethanol. After drying under vacuum at 45 ± 5 °C for 6 h, 3.02 g of vortioxetine hemipamoate was obtained, with a yield of 87.54%. XRPD analysis confirmed that vortioxetine hemipamoate crystal form E was also obtained.

[0045] Example 3

[0046] A 250 mL three-necked flask was filled with 2.09 g of vortioxetine, 1.36 g of pamoic acid, and 84 mL of anhydrous ethanol. The reaction mixture was heated to 60 °C and stirred at this temperature for 24 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filter cake was washed with 4.2 mL of anhydrous ethanol. After drying under vacuum at 45 ± 5 °C for 6 h, 3.13 g of vortioxetine hemipamoate was obtained, with a yield of 90.72%. XRPD analysis confirmed that vortioxetine hemipamoate crystal form E was also obtained.

[0047] Example 4

[0048] A 250 mL three-necked flask was filled with 2.09 g of vortioxetine, 1.36 g of pamoic acid, and 63 mL of anhydrous ethanol. The reaction mixture was heated to 40 °C and stirred at this temperature for 24 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filter cake was washed with 4.2 mL of anhydrous ethanol. After drying under vacuum at 45 ± 5 °C for 6 h, 2.83 g of vortioxetine hemipamoate was obtained, with a yield of 82.03%. XRPD analysis confirmed that vortioxetine hemipamoate crystal form E was also obtained.

[0049] Example 5

[0050] A 250 mL three-necked flask was filled with 2.09 g of vortioxetine, 1.36 g of pamoic acid, and 63 mL of anhydrous ethanol. The reaction mixture was heated to 70 °C and stirred at this temperature for 24 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filter cake was washed with 4.2 mL of anhydrous ethanol. After drying under vacuum at 45 ± 5 °C for 6 h, 3.17 g of vortioxetine hemipamoate was obtained, with a yield of 91.88%. XRPD analysis confirmed that vortioxetine hemipamoate crystal form E was also obtained.

[0051] Example 6

[0052] A 2L four-necked flask was used to add 50.00g of vortioxetine, 32.53g of pamoic acid, and 1500mL of anhydrous ethanol. The reaction system was heated to 60℃ and stirred at this temperature for 24h. After the reaction was completed, the system was cooled to room temperature, filtered, and the filter cake was washed with 100mL of anhydrous ethanol. After drying under vacuum at 45±5℃ for 6h, 79.26g of vortioxetine hemipamoate was obtained, with a yield of 96.04%. XRPD analysis also yielded vortioxetine hemipamoate crystal form E.

[0053] Example 7: In vivo rat experiment

[0054] 1.1 Experimental Objective

[0055] The release behavior of vortioxetine hemipamoate crystal form in vivo was investigated.

[0056] 1.2 Sample Preparation

[0057] Three crystal forms of vortioxetine hemipamoate from Example 1—form E, form A (prepared by the method of Example 3 in prior art patent CN109311832A), and form B (prepared by the method of Example 4 in prior art patent CN109311832A)—were dispersed in an aqueous solution with an appropriate amount of surfactant to form a suspension of vortioxetine hemipamoate at a concentration of 100 mg / ml (forms E, A, and B are named Group 1 (T1), Group 2 (T2), and Group 3 (T3), respectively).

[0058] 1.3 Animal administration

[0059] Male SD rats (purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.)

[0060]

[0061]

[0062] Note: Dosage and concentration are calculated as vortioxetine pamoate.

[0063] 1.4 Sample Collection and Processing

[0064] In male rats, a vertical intramuscular injection of 103 mg / kg (calculated as vortioxetine hemipamoate) was administered into the right biceps brachii muscle. Following intramuscular injection, 350 μL of blood was collected from the orbital venous plexus at 0.25 h, 0.5 h, 6 h, 24 h, 96 h, 168 h, 336 h, 408 h, 504 h, 576 h, and 672 h. The blood samples were placed in anticoagulant tubes containing heparin sodium and centrifuged to obtain plasma. Centrifugation conditions were 3000 g, 4 °C for 10 min. Plasma samples were stored at -70 °C until analysis.

[0065] 1.5 Pharmacokinetic Analysis

[0066] The drug concentration in plasma samples was determined by LC-MS / MS, and the pharmacokinetic parameters were calculated using the WinNonlin 8.0 non-compartmental model.

[0067] 1.6 Results and Analysis

[0068] The plasma drug concentration-time curves after intramuscular injection of vortioxetine hemipamoate in male rats are shown below. Figure 5 and Figure 6 As shown.

[0069] The experimental results show that the drugs in groups 1-3 maintained a certain drug concentration in rat plasma for a relatively long period after administration, allowing for dosing every two or four weeks. In terms of burst release concentration from 0-24 hours, group 2 > group 3 > group 1. Furthermore, the pharmacokinetic curves indicate that the overall release of the drug in group 1 was more stable. Therefore, vortioxetine hemipamoate crystal form E, while prolonging the release time of vortioxetine in vivo, maintains a more stable blood drug concentration and offers higher safety.

Claims

1. A crystal form E of vortioxetine hemipamoate, characterized in that, Using Cu-Kα radiation, X-ray powder diffraction, expressed in 2θ angles, exhibits characteristic peaks at 4.1±0.2°, 7.8±0.2°, 9.5±0.2°, 11.9±0.2°, 13.8±0.2°, 15.0±0.2°, 17.1±0.2°, and 18.7±0.2°.

2. The crystal form E of vortioxetine hemipamoate as described in claim 1, characterized in that, The X-ray powder diffraction, expressed at a 2θ angle, also exhibits characteristic peaks at 15.9±0.2° and 20.0±0.2°.

3. The crystal form E of vortioxetine hemipamoate as described in claim 1 or 2, characterized in that, The X-ray powder diffraction, expressed at a 2θ angle, also has a characteristic peak at 23.8 ± 0.2°.

4. The crystal form E of vortioxetine hemipamoate as described in claim 1 or 2, characterized in that, The X-ray powder diffraction, expressed at a 2θ angle, also exhibits characteristic peaks at 22.3±0.2° and 23.3±0.2°.

5. The crystal form E of vortioxetine hemipamoate as described in claim 1, characterized in that, It has an X-ray powder diffraction pattern that is essentially as shown in Figure 2.

6. The crystal form E of vortioxetine hemipamoate as described in claim 1 or 2, characterized in that, Its differential scanning calorimetry curve has an endothermic peak at 232℃±10℃.

7. The crystal form E of vortioxetine hemipamoate as described in claim 1 or 2, characterized in that, Its differential scanning calorimetry curve has an endothermic peak at 232℃±5℃.

8. The crystal form E of vortioxetine hemipamoate as described in claim 1 or 2, characterized in that, It has a basic DSC spectrum as shown in Figure 3.

9. The crystal form E of vortioxetine hemipamoate as described in claim 1 or 2, characterized in that, It has a basic TGA spectrum as shown in Figure 4.

10. A method for preparing the crystal form E of vortioxetine hemipamoate according to any one of claims 1-9, comprising the following steps: adding vortioxetine and pomolic acid in a molar ratio of 2:1 to anhydrous ethanol, heating and stirring to carry out the reaction, after the reaction is completed, cooling the reaction system to room temperature, filtering, washing the filter cake with anhydrous ethanol, drying it under vacuum to obtain the product. In the preparation method, the weight (g) ratio of vortioxetine to the volume (mL) ratio of anhydrous ethanol is 1:10 to 1:

40. In the preparation method, the reaction temperature is 40~70℃; In the preparation method, the reaction time is 5-30 hours.

11. A pharmaceutical composition, characterized in that, It comprises crystal form E of vortioxetine hemipamoate as an active ingredient as described in any one of claims 1-9, and pharmaceutically acceptable excipients and / or carriers.

12. Use of the crystal form E of vortioxetine hemipamoate according to any one of claims 1-9 or the pharmaceutical composition according to claim 11 for the preparation of a medicament for the treatment and / or prevention of neurological diseases.

13. The use as described in claim 12, wherein, The neurological disorders mentioned include depression, anxiety, obsessive-compulsive disorder, panic disorder, substance abuse, alcoholism, nicotine addiction, carbohydrate addiction, Alzheimer's disease, cognitive impairment, chronic pain, neuropathic pain, nociceptive pain, inflammatory pain, visceral pain, migraine, and cancer-related pain.

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