N-formyl vortioxetine and preparation method thereof and solid preparation of vortioxetine

Abstract

Disclosed is N-formyl vortioxetine, and also disclosed is a method for preparing the N-formyl vortioxetine and a stable solid preparation of vortioxetine.

Claims

1. A method for preparing a storage-stable pharmaceutical composition comprising vortioxetine, the method comprising: combining vortioxetine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is free of a reducing sugar material; and dry granulating the vortioxetine or the pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable excipient; wherein the storage-stable pharmaceutical composition after storage over 6 months at 40° C. and 75% relative humidity contains no greater than 0.2% of N-formyl vortioxetine; wherein the storage-stable pharmaceutical composition consists of following components, based on the total weight of the composition: vortioxetine hydrobromide 16.95% by weight, microcrystalline cellulose 15.0% by weight, mannitol 58.55% by weight, hydroxypropyl cellulose 3.0% by weight, sodium carboxymethyl starch 3.0% by weight, talcum powder 2.0% by weight, and magnesium stearate 1.5% by weight; or the storage-stable pharmaceutical composition consists of following components, based on the total weight of the composition: vortioxetine hydrobromide 16.95% by weight, mannitol 71.55% by weight, copovidone 5.0% by weight, sodium carboxymethyl starch 3.0% by weight, talcum powder 2.0% by weight, and magnesium stearate 1.5% by weight.

2. The method of claim 1, wherein: the step of combining comprises; uniformly mixing vortioxetine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and pressing a mixture of step 1) into a compact; the step of dry granulating comprises 3) converting the compact into granules using dry granulation; and the method further comprises 4) compressing the granules into tablets or filling the granules into capsules.

3. The method of claim 1, wherein the storage-stable pharmaceutical composition after storage over 6 months at 40° C. and 75% relative humidity contains no greater than 0.1% of N-formyl vortioxetine.

Description

DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows high resolution mass spectrometry (HRMS) data of N-formyl vortioxetine prepared by the present invention.

(2) FIG. 2 is .sup.1H-NMR spectrum pattern of N-formyl vortioxetine prepared by the present invention.

(3) FIG. 3 is .sup.13C-NMR spectrum pattern of N-formyl vortioxetine prepared by the present invention.

(4) FIG. 4 is the atom number in the structural formula of the N-formyl vortioxetine prepared by the present invention.

DETAILED DESCRIPTION OF THE INVENTION

(5) The present invention is further illustrated below by examples.

EXAMPLE 1

(6) 1 g of vortioxetine hydrobromide was added to 10 mL of formic acid, heated to 100° C., and reacted for 18 hours. The reaction solution was monitored by HPLC, and the content of N-formyl vortioxetine in the reaction solution was measured as 75%. The formic acid was distilled off with a rotary evaporator, and then the residue was separated by a column chromatography method [HP-Silica normal phase silica gel, eluent: methylene chloride: methanol=(10:1, V/V)] to obtain 0.60 g of N-formyl vortioxetine, with an HPLC purity of 99.8% and a yield of 70%.

EXAMPLE 2

(7) 1 g of vortioxetine hydrobromide was added to 12 mL of formic acid, heated to 110° C., and reacted for 16 hours. The reaction solution was monitored by HPLC, and the content of N-formyl vortioxetine in the reaction solution was measured as 80%. The formic acid was removed with a lyophilizer, and then the residue was recrystallized with 10 mL of methanol to obtain 0.59 g of N-formyl vortioxetine, with an HPLC purity of 95.7% and a yield of 69%.

EXAMPLE 3

(8) 1 g of vortioxetine hydrobromide was added to 12 mL of formic acid, heated to 90° C., and reacted for 16 hours. The reaction solution was monitored by HPLC, and the content of N-formyl vortioxetine in the reaction solution was measured as 71%. After most of the formic acid was distilled off with a rotary evaporator, the residue was diluted with 80 mL of water. Then, the pH was adjusted to about 9 with sodium carbonate, and solids precipitated at this time. The precipitated solid was separated by a column chromatography method [HP-Silica normal phase silica gel, eluent: methylene chloride: methanol=(9:1, V/V)] to obtain 0.47 g of N-formyl vortioxetine, with an HPLC purity of 99.6% and a yield of 55%.

EXAMPLE 4

(9) 1 g of vortioxetine free base was added to 20 mL of water-formic acid (1:1, V/V), heated to 90° C., and reacted for 20 hours. The reaction solution was monitored by HPLC, and the content of N-formyl vortioxetine in the reaction solution was measured as 74%. After most of the formic acid was distilled off with a rotary evaporator, the residue was diluted with 80 mL of water. Then, the pH was adjusted to about 9 with sodium carbonate, and solids precipitated at this time. The solid was recrystallized with 12 mL of ethanol to obtain 0.59 g of N-formyl vortioxetine, with an HPLC purity of 93.8% and a yield of 54%.

EXAMPLE 5

(10) 1 g of vortioxetine free base was added to 12 mL of N,N-dimethylformamide, then 2 mL of methyl formate was added, heated to 90° C., and reacted for 20 hours. The reaction solution was monitored by HPLC, and the content of N-formyl vortioxetine in the reaction solution was measured as 66%. The N,N-dimethylformamide and unreacted methyl formate were removed by a lyophilizer, and then the residue was separated by a column chromatography method [HP-Silica normal phase silica gel, eluent: methylene chloride: methanol=(9:1, V/V)] to obtain 0.57 g of N-formyl vortioxetine, with an HPLC purity of 99.1% and a yield of 52%.

EXAMPLE 6

(11) 1 g of vortioxetine free base was added to 12 mL of N,N-dimethylformamide, then 3 mL of ethyl formate was added, heated to 90° C., and reacted for 20 hours. The reaction solution was monitored by HPLC, and the content of N-formyl vortioxetine in the reaction solution was measured as 68%. N,N-dimethylformamide and unreacted ethyl formate were removed by a lyophilizer, and then the residue was recrystallized with 20 mL of ethyl acetate to obtain 0.60 g of N-formyl vortioxetine with an HPLC purity of 91.3% and a yield of 55%.

EXAMPLE 7

(12) 1 g of vortioxetine hydrobromide was added to 12 mL of dimethyl sulfoxide, and then 3 mL of benzyl formate was added, heated to 110° C., and reacted for 20 hours. The reaction solution was monitored by HPLC, and the content of N-formyl vortioxetine in the reaction solution was measured as 75%. The dimethyl sulfoxide and unreacted benzyl formate were removed by a lyophilizer, and then the residue was separated by a column chromatography method [HP-Silica normal phase silica gel, eluent: methylene chloride: methanol=(8:1, V/V)] to obtain 0.59 g of N-formyl vortioxetine, with an HPLC purity of 99.5% and a yield of 68%.

EXAMPLE 8

(13) 1 g of vortioxetine hydrobromide was added to 12 mL of N,N-dimethylformamide, then 4 mL of benzyl formate was added, heated to 110° C., and reacted for 20 hours. The reaction solution was monitored by HPLC, and the content of N-formyl vortioxetine in the reaction solution was measured as 73%. N,N-dimethylformamide and unreacted benzyl formate were removed by a lyophilizer, and then the residue was recrystallized with 20 mL of ethyl acetate to obtain 0.49 g of N-formyl vortioxetine with an HPLC purity of 90.6% and a yield of 57%.

EXAMPLE 9

(14) 1 g of vortioxetine hydrobromide was added to 10 mL of formic acid, and then 5 mL of acetic anhydride was added, heated to 110° C., and reacted for 15 hours. The reaction solution was monitored by HPLC, and the content of N-formyl vortioxetine in the reaction solution was measured as 67%. The formic acid and acetic anhydride were removed by a lyophilizer, and the residue was recrystallized with 10 mL of acetone to obtain 0.44 g of N-formyl vortioxetine, with an HPLC purity of 91.7% and a yield of 51%.

EXAMPLE 10

(15) 1 g of vortioxetine free base was added to 10 mL of formic acid, and then 5 mL of acetic anhydride was added, heated to 90° C., and reacted for 20 hours. The reaction solution was monitored by HPLC, and the content of N-formyl vortioxetine in the reaction solution was measured as 61%. The formic acid and acetic anhydride were removed by a lyophilizer, and then the residue was separated by a thin layer chromatography method [HP-Silica normal phase silica gel, eluent: methylene chloride: methanol=(15:1, V/V)] to obtain 0.60 g of N-formyl vortioxetine, with an HPLC purity of 99.1% and a yield of 55%.

EXAMPLE 11

(16) 1 g of vortioxetine mesylate was added to 10 mL of formic acid, and then 2.0 mL of phenyl formate was added, heated to 150° C., and reacted for 15 hours. The reaction solution was monitored by HPLC, and the content of N-formyl vortioxetine in the reaction solution was measured as 69%. The formic acid and unreacted phenyl formate were removed by a lyophilizer, and then the target product was separated from the residue by a column chromatography method [HP-Silica normal phase silica gel, eluent: methylene chloride: methanol=(9:1, V/V)] to obtain 0.47 g of N-formyl vortioxetine with high purity, with an HPLC purity of 99.2% and a yield of 57%.

EXAMPLE 12

(17) 1 g of vortioxetine citrate was added to 10 mL of formic acid, and then 2.8 mL of a mixture of formic acid and ethyl chloroformate (1:1, V/V) was added, heated to 30° C., and reacted for 14 hours. The reaction solution was monitored by HPLC, and the content of N-formyl vortioxetine in the reaction solution was measured as 74%. The formic acid and unreacted formic acid and ethyl chloroformate were removed by a lyophilizer, and then the target product was separated from the residue by a column chromatography method [HP-Silica normal phase silica gel, eluent: methylene chloride: methanol=(10:1, V/V)] to obtain 0.40 g of N-formyl vortioxetine with high purity, with an HPLC purity of 98.9% and a yield of 60%.

EXAMPLE 13

(18) The formulation of the solid preparation of vortioxetine in this example was shown in the following table:

(19) TABLE-US-00003 Vortioxetine hydrobromide 16.95% Microcrystalline cellulose 15.0% Mannitol 58.55% Hydroxypropyl cellulose 3.0% Sodium carboxymethyl starch 3.0% talcum powder 2.0% Magnesium stearate 1.5%

(20) The method for preparing vortioxetine solid preparation was as follows:

(21) 1) sieving vortioxetine hydrobromide, mannitol, hydroxypropyl cellulose, talcum powder, and magnesium stearate, respectively, for later use;

(22) 2) uniformly mixing the sieved vortioxetine hydrobromide with microcrystalline cellulose, mannitol, hydroxypropyl cellulose, sodium carboxymethyl starch, and magnesium stearate;

(23) 3) adding the mixed powder obtained in step 2) into a dry granulator for dry granulation;

(24) 4) uniformly mixing the granules obtained in step 3) with talcum powder and magnesium stearate, for later use;

(25) 5) adding the mixed granules obtained in step 4) into the hopper of a tablet press to perform tabletting.

EXAMPLE 14

(26) The formulation of the solid preparation of vortioxetine in this example was shown in the following table:

(27) TABLE-US-00004 Vortioxetine hydrobromide 16.95% Mannitol 71.55% Copovidone 5.0% Sodium carboxymethyl starch 3.0% talcum powder 2.0% Magnesium stearate 1.5%

(28) The method for preparing vortioxetine solid preparation is as follows:

(29) 1) sieving formulation amount of vortioxetine hydrobromide, mannitol, copovidone, talcum powder, and magnesium stearate, respectively, for later use;

(30) 2) uniformly mixing the sieved vortioxetine hydrobromide with mannitol, copovidone, sodium carboxymethyl starch, and magnesium stearate;

(31) 3) adding the mixed powder obtained in step 2) into a dry granulator for dry granulation;

(32) 4) uniformly mixing the material obtained in step 3) with talcum powder and magnesium stearate, for later use;

(33) 5) filling the mixed granules in step 4) into the hollow capsules.

COMPARATIVE EXAMPLE 1

(34) The formulation of the solid preparation of vortioxetine in this example was shown in the following table:

(35) TABLE-US-00005 Vortioxetine hydrobromide 16.95% Microcrystalline cellulose 15.0% Mannitol 58.55% Hydroxypropyl cellulose 3.0% Sodium carboxymethyl starch 3.0% talcum powder 2.0% Magnesium stearate 1.5%

(36) The method for preparing vortioxetine solid preparation was as follows:

(37) 1) sieving mannitol, hydroxypropyl cellulose, talcum powder, and magnesium stearate, respectively, for later use;

(38) 2) adding vortioxetine hydrobromide, microcrystalline cellulose, and sieved mannitol, hydroxypropyl cellulose, and sodium carboxymethyl starch into a high-shear wet granulator for premixing;

(39) 3) adding purified water as a wetting agent into the wet granulator for wet granulation;

(40) 4) wet granulating the wet granules obtained in step 3) with a rotary granulator;

(41) 5) putting the wet granules obtained in step 4) into a fluidized bed to dry to LOD≤3.0%;

(42) 6) adding the dry granules obtained in step 5) and the sieved talcum powder in step 1) to the total mixing tank and mixing them for later use;

(43) 7) adding the sieved magnesium stearate to the total mixing tank of step 6) and mixing them for later use

(44) 8) adding the mixed granules obtained in step 7) into the hopper of a tablet press to perform tabletting.

(45) Under an accelerated condition (at a temperature of 40° C., and a relative humidity of 75%), the impurity content of vortioxetine hydrobromide tablets prepared in Examples 13, 14 and Comparative Example 1 was examined. The experimental results are shown in the following table:

(46) TABLE-US-00006 Maximum Single N-formyl Unknown Total Batch Time vortioxetine Impurity Impurities Example 13 Month 0 N.D 0.07% 0.07% Month 1 N.D 0.09% 0.14% Month 3 <RL(RL = 0.05%) 0.07% 0.07% Month 6 <RL(RL = 0.05%) 0.07% 0.12% Example 14 Month 0 N.D 0.07% 0.07% Month 1 N.D 0.08% 0.13% Month 3 <RL(RL = 0.05%) 0.06% 0.06% Month 6 <RL(RL = 0.05%) 0.07% 0.12% Comparative Month 0 <RL(RL = 0.05%) 0.07% 0.07% Example 1 Month 1 0.09% 0.08% 0.22% Month 3 0.13% 0.06% 0.29% Month 6 0.25% 0.07% 0.43%

(47) The above data shows that, on the one hand, the solid preparation of vortioxetine according to the present invention not only has a significant lower N-formyl vortioxetine content, but also has a significant reduced content of total impurities, compared with the solid preparation of Comparative Example 1. On the other hand, the N-formyl vortioxetine content in the solid preparation of vortioxetine according to the present invention remained below the detection limit, while the solid preparation in Comparative Example 1 contains up to 0.25% of N-formyl vortioxetine after 6 months of storage under the accelerated condition. In addition, the total impurity content of the vortioxetine solid preparation of the present invention is also lower than the total impurity content in Comparative Example 1. Compared with the prior art vortioxetine solid preparation, the vortioxetine solid preparation of the present invention has good stability, lower impurity content and less degradation of the main drug, which is helpful to improve the safety and effectiveness of vortioxetine solid preparation.

EXAMPLE 15

(48) This example illustrates a method for controlling the quality of vortioxetine solid preparation.

(49) Chromatographic conditions

(50) Instrument: HPLC equipped with a UV detector

(51) Column: Waters Xterra MS C.sub.18, 150×4.6 mm, 3.5 μm

(52) Mobile phase A: Weighing 1.2 g of ammonium acetate and dissolving it in 1000 mL of water and adjusting the pH to 6.0 with glacial acetic acid

(53) Mobile phase B: acetonitrile

(54) Detection wavelength: 250 nm

(55) Flow rate: 1.0 mL/min

(56) Injection volume: 10 μL

(57) Column temperature: 40° C.

(58) Running time: 50 min

(59) Mobile phase gradient:

(60) TABLE-US-00007 Time (min) A (%, V/V) B (%, V/V) 0 80 20 2 80 20 18 58 42 38 10 90 45 10 90 46 80 20 50 80 20

(61) Diluent: acetonitrile: water=(7:3, V/V)

(62) Blank solution: same as diluent

(63) Preparation of N-formyl vortioxetine control solution: weighing 1 mg of N-formyl vortioxetine and dissolve it in 1 ml of dilution.

(64) Test solution: weighing a few samples of vortioxetine tablets stored under accelerated conditions for three months in Comparative Example 1, and placing them into a volumetric flask with corresponding volume, and adding the diluent to a volume of about ⅔ of the volumetric flask, shaking for 1 h to disperse, sonicating for 5 min to dissolve vortioxetine tablets, cooling to room temperature, adding diluent to reach the mark and uniformly shaking Let it stand for a while, precisely transferring 5 mL of the sample solution to a 50 mL volumetric flask, adding the dilution solution to reach the mark, and uniformly shaking. Then, filtering it through a 0.45 μm PTFE syringe filter, and the filtrate was used as a test solution.

(65) The test solution was detected by the above-mentioned HPLC method, positioned with the N-formyl vortioxetine reference substance solution and quantified by the external standard method. In a vortioxetine tablet stored for 3 months under the accelerated condition, the content of N-formyl vortioxetine was 0.13%.

(66) The above only describes the preferred examples of the present invention in detail.

(67) The present invention is not limited to the above examples, and any changes and modifications to the present invention belong to the protection scope of the present invention.