COATED GRANULE, SOLID DISPERSION, AND PREPARATION CONTAINING VORTIOXETINE HYDROBROMIDE FOR ORAL TASTE MASKING

Abstract

A coated granule, a solid dispersion, a composition, and a preparation for oral masking, which improve the taste masking effect of vortioxetine hydrobromide, and improve the patient adherence and compliance.

Claims

1. An orally dispersible composition of vortioxetine hemihydrobromide, which comprises vortioxetine hemihydrobromide and pharmaceutically acceptable excipients.

2. The orally dispersible composition according to claim 1, which is tablet, granule, capsule, powder, suspension, dry suspension or solution; preferably, the tablet is an orally disintegrating tablet or a dispersible tablet; more preferably, the tablet is orally disintegrating tablet.

3. An orally dispersible taste masking composition of vortioxetine hemihydrobromide or vortioxetine hydrobromide, which comprises vortioxetine hemihydrobromide or vortioxetine hydrobromide and pharmaceutically acceptable taste masking excipients.

4. The orally dispersible taste masking composition according to claim 3, wherein the vortioxetine hemihydrobromide or vortioxetine hydrobromide is coated with the taste masking excipient to form coated granules; preferably, the taste masking excipient is cellulose acetate, ethyl cellulose, hydroxypropyl cellulose, methacrylic acid copolymer, chitosan, copovidone, or polyvinyl alcohol; optionally, the taste masking excipient contains alkaline excipients; optionally, the coated granules contain an anticaking agent.

5. The orally dispersible taste masking composition according to claim 3, wherein the vortioxetine hemihydrobromide or vortioxetine hydrobromide is dispersed in the taste masking excipient to form α solid dispersion; preferably, the taste masking excipient is cellulose acetate, ethyl cellulose, hydroxypropyl cellulose, methacrylic acid copolymer, chitosan, copovidone, povidone, polyvinyl alcohol, or polyethylene glycol; optionally, the taste masking excipient includes an alkaline excipient.

6. The orally dispersible taste masking composition according to claim 3, wherein the vortioxetine hemihydrobromide or vortioxetine hydrobromide is mixed with alkaline excipients, preferably, vortioxetine hemihydrobromide or vortioxetine hydrobromide is mixed with at least one of trisodium phosphate, disodium hydrogen phosphate, disodium hydrogen phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium citrate, sodium acetate, calcium hydroxide, sodium hydroxide, potassium hydroxide, or meglumine, then form α composition.

7. A taste masking coated granule of vortioxetine hemihydrobromide or vortioxetine hydrobromide, wherein the taste masking coating excipient is cellulose acetate, ethyl cellulose, hydroxypropyl cellulose, methacrylic acid copolymer, chitosan, copovidone, or polyvinyl alcohol; optionally, the taste masking coating excipient includes an alkaline excipient; optionally, the taste masking coating excipient includes an anticaking agent.

8. A taste masking solid dispersion of vortioxetine hemihydrobromide or vortioxetine hydrobromide, wherein the taste masking excipient is cellulose acetate, ethyl cellulose, hydroxypropyl cellulose, methacrylic acid copolymer, chitosan, copovidone, povidone, polyvinyl alcohol, or polyethylene glycols; optionally, the taste masking excipient includes alkaline excipient.

9. A taste masking combination of vortioxetine hemihydrobromide or vortioxetine hydrobromide, which comprises vortioxetine hemihydrobromide or vortioxetine hydrobromide and an alkaline excipient; preferably, the alkaline excipient is at least one of trisodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium citrate, sodium acetate, calcium hydroxide, sodium hydroxide, potassium hydroxide, or meglumine.

10. The orally dispersible taste masking composition according to claim 4 or claim 5, the taste masking coating granule according to claim 7, or the taste masking solid dispersion according to claim 8, wherein the methacrylic copolymer is polyacrylic resin, preferably polyacrylic resin is polyacrylic resin II or polyacrylic resin IV.

11. The orally dispersible taste masking composition according to claim 4 or the taste masking coated granule according claim 7, wherein the vortioxetine hemihydrobromide or vortioxetine hydrobromide is coated with the taste masking excipient to form coated granules, and the coated granules are further dispersed in the taste masking excipient to form α solid dispersion; optionally; the formed solid dispersion is further mixed with alkaline excipient.

12. The orally dispersible taste masking composition according to claim 5 or the solid dispersion according to claim 8, wherein the vortioxetine hemihydrobromide or vortioxetine hydrobromide is dispersed in the taste masking excipient to form α solid dispersion, and the solid dispersion is further coated with the taste masking excipient to form α coated granule; optionally; the formed coated granule is further mixed with alkaline excipient.

13. The orally dispersible taste masking composition according to claim 4 or the taste masking coated granule according claim 7, wherein the vortioxetine hemihydrobromide or vortioxetine hydrobromide is coated with the taste masking excipient to form α coated granule, and the coated granule is further mixed with alkaline excipient.

14. The orally dispersible taste masking composition according to claim 5 or the solid dispersion according to claim 8, wherein the vortioxetine hemihydrobromide or vortioxetine hydrobromide is dispersed in the taste masking excipient to form α solid dispersion, and the solid dispersion is further mixed with alkaline excipient.

15. The orally dispersible taste masking composition according to claim 3, the taste masking coated granule according claim 7, the taste masking solid dispersion according to claim 8 or the taste masking combination according to claim 9, wherein the weight ratio of vortioxetine hemihydrobromide or vortioxetine hydrobromide to pharmaceutically acceptable taste masking excipient is 1:0.1-1:5, preferably, 1:0.3-1:3, more preferably, 1:0.5-1:1.5; wherein the weight ratio of vortioxetine hemihydrobromide or vortioxetine hydrobromide to pharmaceutically acceptable alkaline excipient is 1:0.01-1:1.1, preferably, 1:0.03-1:1.

16. The orally dispersible taste masking composition according to claim 3, the taste masking coated granule according claim 7, the taste masking solid dispersion according to claim 8 or the taste masking combination according to claim 9, which is crystalline or amorphous substance.

17. The orally dispersible taste masking composition according to claim 3, the taste masking coated granule according claim 7, the taste masking solid dispersion according to claim 8, the taste masking combination according to claim 9, or the orally dispersible taste masking composition according to claim 15, which further comprises a filler, a flavoring agent, a release regulator agent, a plasticizer, an anticaking agent, and/or a disintegrant agent; preferably, the anticaking agent is talc, which accounts for 5%-25% of the total weight of the taste masking coated granule, for example, 10%-20%; wherein the disintegrant agent is sodium starch glycolate, croscarmellose sodium, crospovidone, and combinations thereof, which accounts for 1%-8% of the total weight of the orally dispersible taste masking composition, preferably, 2%-6%; preferably, wherein the flavoring agent is neotame, which accounts for 0.05%-0.5% of the total weight of the orally dispersible taste masking composition, preferably, 0.1%-0.3%.

18. The orally dispersible taste masking composition according to claim 3, the taste masking coated granule according claim 7, the taste masking solid dispersion according to claim 8 or the taste masking combination according to claim 9, which is (or is prepared as) tablets, granules, capsules, powders, suspensions, dry suspensions, solutions; preferably, wherein the tablets are orally disintegrating tablets or dispersible tablets, more preferably, the tablets are orally disintegrating tablets.

19. The orally dispersible composition according to claim 1 or claim 2, the orally dispersible taste masking composition according to claim 3, the taste masking coated granule according claim 7, the taste masking solid dispersion according to claim 8 or the taste masking combination according to claim 9, wherein the vortioxetine hemihydrobromide or vortioxetine hydrobromide is amorphous or crystal.

20. Use of vortioxetine hemihydrobromide in the preparation of orally dispersible composition, taste masking coated granule, taste masking solid dispersion, taste masking combination or orally dispersible taste masking composition, preferably, wherein the orally dispersible preparation or the orally dispersible taste masking preparation is tablets, granules, capsules, powders, suspensions, dry suspensions, and solutions, preferably, wherein the tablets are orally disintegrating tablets or dispersible tablets, more preferably, the tablets are orally disintegrating tablets.

21. Use of vortioxetine hydrobromide in the preparation of orally dispersible composition, taste masking coated granule, taste masking solid dispersion, taste masking combination or orally dispersible taste masking composition, preferably, wherein the orally dispersible composition or the orally dispersible taste masking composition is tablets, granules, capsules, powders, suspensions, dry suspensions, and solutions, preferably, wherein the tablets are orally disintegrating tablets or dispersible tablets, more preferably, the tablets are orally disintegrating tablets.

22. A method for preparing taste masking coated granules of vortioxetine hemihydrobromide or vortioxetine hydrobromide or their compositions thereof, which comprises: (1) crushing vortioxetine hemihydrobromide or vortioxetine hydrobromide to obtain vortioxetine hydrobromide half salt or one salt powder; preferably, sieving of materials through a 20-300 mesh sieve after crushing, more preferably, sieving through a 100-200 mesh; (2a) dispersing the taste masking excipients in a solvent, coating the vortioxetine hemihydrobromide or vortioxetine hydrobromide powder with the taste masking excipients through a fluid bed and removing the solvent to obtain the vortioxetine hemihydrobromide or vortioxetine hydrobromide coated with the taste masking excipients; preferably, dispersing taste masking excipient and release regulator agent in a solvent; more preferably, wherein the release regulator agent is polyethylene glycol or alkaline excipient; preferably, wherein the solvent is water, ethanol or dichloromethane; or (2b) adding the vortioxetine hemihydrobromide or vortioxetine hydrobromide powder and taste masking excipients to solvent to form α suspension, removing the solvent through a fluid bed, spray drying or evaporation, then obtaining the vortioxetine hemihydrobromide or vortioxetine hydrobromide coated with the taste masking excipients; preferably, wherein the vortioxetine hemihydrobromide or vortioxetine hydrobromide, taste masking excipient, release regulator agent and/or plasticizer are added to solvent to form suspension of vortioxetine hemihydrobromide or vortioxetine hydrobromide; preferably, wherein the plasticizer is polyethylene glycol or triethyl citrate; preferably, wherein the solvent is water, ethanol or dichloromethane. (3) optionally, the coated vortioxetine hemihydrobromide or vortioxetine hydrobromide is prepared as a composition.

23. A method for preparing taste masking coated granules of vortioxetine hemihydrobromide or vortioxetine hydrobromide or their compositions thereof, which comprises: (1) crushing vortioxetine hemihydrobromide or vortioxetine hydrobromide to obtain vortioxetine hydrobromide half salt or one salt powder; preferably, sieving of materials through a 20-300 mesh sieve after crushing, more preferably, sieving through a 100-200 mesh; (2a) mixing the vortioxetine hemihydrobromide or vortioxetine hydrobromide powder with taste masking excipients, heating at 50-150° C. to soften or liquefy, cooling to solidify, and crushing to obtain powder; preferably, wherein the vortioxetine hemihydrobromide or vortioxetine hydrobromide powder, the taste masking excipient and release regulator agent are mixed; or (2b) dissolving the vortioxetine hemihydrobromide or vortioxetine hydrobromide powder and taste masking excipients in a solvent, and removing the solvent by distillation, fluid bed or spray drying to obtain powder; preferably, wherein the solvent is water, ethanol or dichloromethane; (3) optionally, the powder obtained in step (2a) or (2b) is prepared as a composition.

24. The preparation method according to claim 22 or claim 23, wherein the taste masking excipients are cellulose acetate, ethyl cellulose, hydroxypropyl cellulose, methacrylic acid copolymer, chitosan, copovidone, povidone, polyvinyl alcohol, or polyethylene glycols; preferably, wherein the methacrylic acid copolymer is a polyacrylic resin; more preferably, the polyacrylic resin is polyacrylic resin II or polyacrylic resin IV.

25. A method for preparing taste masking coated granules of vortioxetine hemihydrobromide or vortioxetine hydrobromide or their compositions thereof, which comprises: (1) crushing vortioxetine hemihydrobromide or vortioxetine hydrobromide to obtain vortioxetine hemihydrobromide or vortioxetine hydrobromide powder; preferably, sieving of materials through a 50-300 mesh sieve after crushing, more preferably, 100-200 mesh sieve; (2) mixing the vortioxetine hemihydrobromide or vortioxetine hydrobromide powder with the alkaline excipients to obtain taste masking composition; preferably, wherein the alkaline excipients are trisodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium citrate, sodium acetate, calcium hydroxide, sodium hydroxide, potassium hydroxide, or meglumine; (3) optionally, the taste masking combination is prepared as a composition.

26. The preparation method according to any of claim 22-25, wherein the weight ratio of vortioxetine hemihydrobromide or vortioxetine hydrobromide to pharmaceutically acceptable taste masking excipient for forming a coating or solid dispersion is 1:0.1-1:5, preferably, 1:0.3-1:3, more preferably, 1:0.3-1:1.5; wherein the weight ratio of vortioxetine hemihydrobromide or vortioxetine hydrobromide to pharmaceutically acceptable alkaline excipient is 1:0.01-1:1.1, preferably, 1:0.01-1:1.

27. A solid dispersion comprising vortioxetine hemihydrobromide and polyacrylic resin IV, wherein the weight ratio of vortioxetine hemihydrobromide to polyacrylic resin IV is 1:0.1-1:5, preferably, 1:0.3-1:2, more preferably, 1:0.3-1:1.5; preferably, wherein the solid dispersion has characteristic peaks as shown in FIG. 20.

28. A solid dispersion comprising vortioxetine hydrobromide and polyacrylic resin IV, wherein the weight ratio of vortioxetine hydrobromide to polyacrylic resin IV is 1:0.1-1:5, preferably, 1:0.3-1:3, more preferably, 1:0.3-1:1.5; preferably, wherein the solid dispersion has characteristic peaks as shown in FIG. 22.

29. The solid dispersion according to claim 27 or claim 28, wherein Cu-Kα radiation is used, and the X-ray powder diffraction pattern expressed at 20 angles has characteristic peaks at the following positions: 4.2±0.2°, 14.5±0.2°, 17.4±0.2°, 19.2±0.2°, and 22.6±0.2°.

30. The solid dispersion according to claim 27 or claim 28, wherein Cu-Kα radiation is used, and the X-ray powder diffraction pattern expressed at 20 angles has characteristic peaks at the following positions: 4.2±0.2°, 14.5±0.2°, 16.6±0.2°, 17.4±0.2°, 19.2±0.2°, 21.5±0.2°, 22.6±0.2°, 24.4±0.2°, 26.0±0.2°, 28.2±0.2°, and 29.0±0.2°.

31. The solid dispersion according to claim 27 or claim 28, which further comprises at least one of PEG 4000, PEG 6000 and PEG 8000; preferably, wherein the weight ratio of polyacrylic resin IV to at least one of PEG 4000, PEG 6000, and PEG 8000 is 1:0.05-1:2.

32. According to any one of the above claims, vortioxetine hemihydrobromide or vortioxetine hydrobromide orally dispersible taste masking compositions, taste masking coated granules, taste masking solid dispersions and taste masking combination in the use of preparing antidepressant drug.

33. According to any one of the above claims, vortioxetine hemihydrobromide or vortioxetine hydrobromide orally dispersible taste masking compositions, taste masking coated granules, taste masking solid dispersions and taste masking combination, which are used for the treatment of depression disorder or preparing antidepressant drug.

34. A method for the treatment of depression disorder, which comprises administering the vortioxetine hemihydrobromide or vortioxetine hydrobromide orally dispersible taste masking compositions, taste masking coated granules, taste masking solid dispersions, or taste masking combinations to a subject in need.

Description

DESCRIPTION OF THE FIGURES

[0135] FIG. 1: X-ray powder diffraction pattern of vortioxetine hemihydrobromide.

[0136] FIG. 2: X-ray powder diffraction pattern of vortioxetine hydrobromide form α.

[0137] FIG. 3: X-ray powder diffraction pattern of vortioxetine hydrobromide form β.

[0138] FIG. 4: X-ray powder diffraction pattern of UreleaseE100:PEG 6000=1:0.23 after spray drying.

[0139] FIG. 5: X-ray powder diffraction pattern of taste masking powder (vortioxetine hemihydrobromide:UreleaseE100:PEG 6000=1:0.3:0.07).

[0140] FIG. 6: X-ray powder diffraction pattern of taste masking powder (vortioxetine hydrobromide form α:UreleaseE100:PEG 6000=1:0.3:0.07).

[0141] FIG. 7: X-ray powder diffraction pattern of taste masking powder (vortioxetine hydrobromide form β:UreleaseE100:PEG 6000=1:0.3:0.07).

[0142] FIG. 8: UV spectrum of vortioxetine hydrobromide in 0.1N hydrochloric acid.

[0143] FIG. 9: UV spectrum of Eudragit E PO in 0.1N hydrochloric acid.

[0144] FIG. 10: UV spectrum of mixed powder (vortioxetine hydrobromide:Eudragit E PO=1:0.5) in 0.1N hydrochloric acid.

[0145] FIG. 11: UV spectrum of mixed hot melt powder (vortioxetine hydrobromide:Eudragit E PO=1:0.5) in 0.1N hydrochloric acid.

[0146] FIG. 12: UV spectrum of vortioxetine hemihydrobromide in 0.1N hydrochloric acid.

[0147] FIG. 13: UV spectrum of directly mixed powder (vortioxetine hemihydrobromide:Eudragit E PO=1:1.5) in 0.1N hydrochloric acid.

[0148] FIG. 14: UV spectrum of hot-melt powder (vortioxetine hemihydrobromide:Eudragit E PO=1:1.5) in 0.1N hydrochloric acid.

[0149] FIG. 15: UV spectrum of directly mixed powder (vortioxetine hemihydrobromide:Eudragit E PO=1:5) in 0.1N hydrochloric acid.

[0150] FIG. 16: UV spectrum of hot-melt powder (vortioxetine hemihydrobromide:Eudragit E PO=1:5) in 0.1N hydrochloric acid.

[0151] FIG. 17: UV spectrum of polyacrylic resin IV in 0.1N hydrochloric acid.

[0152] FIG. 18: UV spectrum of directly mixed powder (vortioxetine hydrobromide:polyacrylic resin IV=1:1.5) in 0.1N hydrochloric acid.

[0153] FIG. 19: UV spectrum of hot-melt powder (vortioxetine hydrobromide:polyacrylic resin IV=1:1.5) in 0.1N hydrochloric acid.

[0154] FIG. 20: X-ray powder diffraction pattern of solid dispersion of vortioxetine hemihydrobromide-polyacrylic resin IV.

[0155] FIG. 21: X-ray powder diffraction pattern of polyacrylic resin IV after spray drying.

[0156] FIG. 22: X-ray powder diffraction pattern of solid dispersion of vortioxetine hydrobromide-polyacrylic resin IV.

[0157] FIG. 23: Vortioxetine hydrobromide:polyacrylic resin II=1:1.5 solid dispersion X-ray powder diffraction pattern.

[0158] FIG. 24: X-ray powder diffraction pattern of polyacrylic resin II (distilling off the solvent of ethanol).

[0159] FIG. 25: Vortioxetine hemihydrobromide:polyacrylic resin II=1:1.5 solid dispersion X-ray powder diffraction pattern.

EXAMPLES

[0160] The following describes the embodiments of the invention in detail with reference to specific examples, but those skilled in the art should understand that the examples are only used to illustrate the invention, and should not be regarded as limiting the scope of the invention.

[0161] If specific conditions are not indicated in the examples, it shall be carried out in accordance with the conventional conditions and the conditions recommended by the manufacturer or supplier. Those reagents or instruments that do not indicate the manufacturer and specific model are all conventional products that can be purchased commercially.

[0162] For the polyacrylic resin II in this invention, it is named Methyl methacrylate-methacrylic acid copolymer (1:1) in the European Pharmacopoeia and Methacrylic Acid Copolymer Type A in the U.S. Pharmacopoeia, and named polyacrylic resin II in the Chinese Pharmacopoeia. For example, it can be purchased from the supplier Evonik Rohm GmbH Company (for example, the trade name is Eudragit L, Eudragit L100, and Eudmgit L PO) or Anhui Shanhe Pharmaceutical Excipients Co., Ltd. (for example, the product name is polyacrylic resin II).

[0163] For the polyacrylic resin IV in this invention, it is named Amino Methacrylate Copolymer in the U.S. Pharmacopoeia, and named polyacrylic resin IV in the Chinese Pharmacopoeia. For example, it can be purchased from the supplier Evonik Röhm GmbH Company (for example, the trade name is Eudragit E100, Eudragit E PO), Guangzhou Maofeng Pharmaceutical Excipients Co., Ltd. (for example, the product name is Urelease E, Urelease E100), or Anhui Shanhe Pharmaceutical Excipients Co., Ltd. (for example, the product name is polyacrylic resin IV).

[0164] For other polyacrylic resins, they can be purchased from, for example, Evonik Rohm GmbH Corporation, for example, under the trade names Eudragit RL100, Eudragit L100, Eudragit RS PO, and Eudragit 5100. The excipients used in the examples are not associated with this invention, while when preparing compositions using this invention, other known common and functional pharmaceutical excipients can be used according to the dosage form, stability of the composition and the needs of clinical use. In the examples, vortioxetine hydrobromide does not indicate the specific crystal form used, which means that the crystal form α, β or γ is acceptable.

Instruments Used in the Experiment:

[0165] X-ray powder diffraction (XPRD): The instrument is D/max-2200/pc equipped with θ-2θ goniometer RINT2000 Vertical goniometer, MO monochromator and Scintillation counter detector. The acquisition software is XG operation. The instrument is calibrated with the single crystal silicon standard that comes with the instrument. The detection conditions: 2θ angle scan range: 3-40° or 3-50°, step size: 0.02°, speed: 6°/min. Detection process: Using Cu target with a wavelength of 1.54 nm Kα X-rays, K (α1) energy of 40 kV, current intensity of 20 Ma. Samples are tested at room temperature, and the required samples are placed on the Si P non-reflective plate. Samples are sieved before testing.

[0166] Ultraviolet visible spectrophotometer: UV-2600, Shimadzu, Japan.

[0167] Analytical balance: AUW120D, SHIMADZU.

[0168] Rotary evaporator: R205, Taizhou Xinli Electronic Equipment Co., Ltd.

[0169] Hot air circulation oven: DHG-9070A, Shanghai Yiheng Scientific Instrument Co., Ltd.

[0170] Vortex mixer: Vortex-2, Shanghai Huxi Industrial Co., Ltd.

[0171] Multifunctional fluid bed: BWF-1G, Chongqing Enger Granulation Coating Technology Co., Ltd.

[0172] Vacuum freeze dryer: FD-2D, Beijing Boyikang Experimental Instrument Co., Ltd.

[0173] Rotary tablet press: ZP8, Shanghai Xinyuan Pharmaceutical Machinery Co., Ltd.

[0174] High-efficiency coating machine: Labcoating IV, Shenzhen Xinyite Technology Co., Ltd.

[0175] Dry granulator: GL-5B, Zhejiang Future Machinery Co., Ltd.

[0176] Granulator: P100, Shenzhen Xinyite Technology Co., Ltd.

[0177] Portable pH meter: STARTER 300.

[0178] Freeze dryer: SCIENT2-30F, Ningbo Scientz Biotechnology Co., Ltd.

[0179] Flat blister packaging machine: Zhejiang Future Machinery Co., Ltd.

Related Data Collection Methods:

[0180] Test method for pH and exposure (calculated as vortioxetine): Take a tablet of this product (or powder equivalent to 20 mg of vortioxetine), add 5.0 g of purified water, incubate for 5 minutes at 36±2° C. with airtight shaking and disperse, then cool to room temperature, and check the pH of the suspension. Filter through a 0.22 um microporous membrane, take 2.0 ml of the filtrate and dilute to 10 ml with purified water as the test solution, and take the solution quantitatively diluted with purified water to 10 ug/ml (based on vortioxetine) as the reference solution, UV method detects the absorption value at 226 nm wavelength respectively, and calculates the concentration and relative dissolution of vortioxetine.

[00001]$\mathrm{Relative}\mathrm{dissolution}=\frac{\begin{array}{c}\mathrm{UV}\mathrm{absorbance}\mathrm{of}\mathrm{sample}\times \\ \mathrm{Concentration}\mathrm{of}\mathrm{reference}\mathrm{solution}\times 1000\times 25\end{array}}{\mathrm{UV}\mathrm{aborbance}\mathrm{of}\mathrm{refenence}\mathrm{solution}\times 20}\times 100\%.$

[0181] Titration test method to determine the assay of bromine in vortioxetine hydrobromide:

[0182] Prepare 0.1 mol/L silver nitrate titrant first, and then prepare 5 mg/ml Eosin Y test solution. Dissolve 0.3 g of sample in 60 mL of methanol. Add 20 mL of water, 20 mL of glacial acetic acid, and 8 drops of eosin Y TS. Titrate with 0.1 N silver nitrate VS to a pink endpoint. Carry out a blank titration.

Calculation Formula:

[0183] [00002]$\mathrm{Br}\%=\frac{\left(\mathrm{Vs}-\mathrm{Vb}\right)\times N\times 7.990}{0.1\times W\times \left(1-\mathrm{water}\%\right)}\times 100\%$ [0184] Where, [0185] V.sub.s=Volume of 0.1 mol/mL silver nitrate consumed for sample, mL [0186] V.sub.b=Volume of 0.1N silver nitrate consumed for blank, mL [0187] N=Normality of silver nitrate volumetric solution [0188] W=Weight of the sample, mg [0189] Water %=Water of sample [0190] 7.990=Each 7.990 mg of Br is equivalent to 1 mL of 0.1 mol/mL silver nitrate.

[0191] In the examples, the taste masking effects of test samples were evaluated by the subject's perception of the bitterness and irritation of the oral cavity and tongue.

The Taste and Irritation Classification Tested by the Subjects:

[0192]

TABLE-US-00001 0-1 minute instantaneous irritation Delayed irritation Bitterness + + + Strong irritation, intolerable Delayed 1-15minutes Acceptable + + Irritating, tolerable Delayed 15-30minutes +Almost no irritation Delayed more than 30 minutes Unacceptable Tried by 5-10 subjects and take the average value

Preparation Example 1: Preparation of Vortioxetine Free Base

[0193] Vortioxetine was synthesized with reference to the preparation method of Example 24 in Patent Document WO2007/144005A1. The detail process: 40.76 g of NaOBu.sup.t, 0.33 g of Pddba.sub.2 and 0.68 g of rac-BINAP were stirred with 200 ml of toluene. 42 g of 2-bromo-iodobenzene and 19.54 g of 2,4-dimehtylthiophenol were added with 50 ml toluene. The suspension was heated to reflux and reflux continued for 5 hours. The reaction mixture was cooled to room temperature and filtered through filter aid. The filtrate was added to a mixture of 40.76 g of NaOBu.sup.t, 42.2 g of piperazine, 0.33 g of Pddba.sub.2 and 0.68 g of rac-BINAP and heated to reflux for 2 hours.

[0194] The reaction mixture was cooled down to room temperature. 100 ml of water was added and the water phase was separated off. The organic phase was filtered through filter aid and the filtrate was then washed with 3×80 ml of brine. The organic phase was heated to 70° C. and followed by addition of 16.50 ml of 48%-wt % HBr (145.9 mmol) and 8.3 ml of water. The mixture was stirred for about 30 minutes, then cooled to room temperature, and kept at room temperature for 2 hours. The final product (1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide) was collected by filtration and was washed with toluene, dried at 50° C. for 10 hours, producing 40.18 g of off-white powder with molar yield 75%.

[0195] The 40.18 g of vortioxetine hydrobromide (obtained in the previous step) was dissolved in 200 mL of water. 200 mL of dichloromethane was added, the pH was adjusted to 9-10 with 15% sodium hydroxide aqueous solution, then the solution was kept for 30 minutes. The solution was stood still and separated off water phase. The water phase was extracted once with 100 mL of dichloromethane. The combined organic phase was washed with 100 mL of water, and the separated organic phases, was added 5 g of anhydrous sodium sulfate to thy. The organic phase was filtered, and then was concentrated to obtain 29.7 g of off-white crystals 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide, which was vortioxetine free base, with molar yield of 94.0%.

Preparation Example 2: Preparation of Vortioxetine Hemihydrobromide

[0196] Vortioxetine hemihydrobromide was synthesized with reference to the preparation method of Example 1 in Patent Document U.S. Pat. No. 9,562,024B2. The detail process: 8.00 g (26.8 mmol) vortioxetine was dissolved in 122 ml of ethanol by sonication in a 250 ml of round-bottom flask; 2.70 g of hydrobromic acid (40% w/w, 13.3 mmol) was dissolved in 16 ml of ethanol by sonication; with stirring, the hydrobromic acid solution was slowly added dropwise to the vortioxetine solution; solids precipitated out during the dropwise-addition process; the solvent was removed by rotary evaporation at 40° C.; after drying under vacuum at 40° C. for 24 h, 8.91 g (13.1 mmol) of white solids of the vortioxetine hemihydrobromide were obtained. The percent yield was 98.5%. The bromine assay measured by the titration method was 11.60%.

Preparation Example 3: Preparation of Vortioxetine Hydrobromide Form α

[0197] Vortioxetine hydrobromide form α was synthesized with reference to the preparation method of Example 4a in Patent Document WO2007/144005A1. The detail process: 2.0 g of 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine was dissolved in hot 30 ml of ethyl acetate and added 0.73 ml of 48%-wt HBr (aq). This addition caused formation of a thick slurry and addition 10 ml of ethyl acetate was added in order to have proper stirring. The slurry was stirred at room temperature for one hour. Filtration and drying in vacuum (20° C.) overnight produced 2.0 g of the product as a white solid (yield 80%). The product was the a crystal form of vortioxetine hydrobromide. The bromine assay measured by the titration method was 20.76%.

Preparation Example 4: Preparation of Vortioxetine Hydrobromide Form β

[0198] Vortioxetine hydrobromide form β was synthesized with reference to the preparation method of Example 4c in Patent Document WO2007/144005A1. The detail process: 49.5 g of 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine was dissolved in 500 ml of ethyl acetate and added 18.5 ml of 48%-wt HBr (aq). This addition caused formation of a thick slurry which was stirred over night at room temperature. Filtration and drying in vacuum (50° C.) overnight produced the product in 29.6 g as white solid (yield 47%). The bromine assay measured by the titration method was 20.69%.

Preparation Example 5: Preparation of Vortioxetine Hydrobromide Form γ

[0199] Vortioxetine hydrobromide form γ was synthesized with reference to the preparation method of Example 4e in Patent Document WO2007/144005A1. The detail process: 1 g of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide was dissolved in 20 ml of water and heated to 85° C. The solution was almost clear. Addition of 1 drop of HBr made it clear. HBr was added until cloud point was observed. The solution was cooled to room temperature and dried. The product was the γ crystal form of vortioxetine hydrobromide. The bromine assay measured by the titration method was 20.73%.

Example 1: Vortioxetine Hydrobromide+Coating Material Taste Masking Powder Preparation

[0200] 1a) Vortioxetine hemihydrobromide:UreleaseE100:PEG6000=1:0.3:0.07 taste masking powder preparation

[0201] 30.00 g of UreleaseE100 and 7.00 g of PEG6000 were added to 470.02 g of medicinal ethanol, stirred to dissolve, set aside.

[0202] 100.00 g of 100-200 mesh vortioxetine hemihydrobromide and 10.00 g of talc with particle size less than 325 mesh were added to the BWF-1G multifunctional fluid bed installed in the bottom spray coating mode. The air inlet volume and the height of the guide tube were adjusted to make the materials in a fluidized state, and the air inlet temperature was set 50-55° C., peristaltic pump speed was 5 rpm and atomization pressure was 1.0-1.5 atm. The prepared special coating liquid was sprayed into the fluid bed. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size 60-150 mesh was collected by sieving. 125.79 g of taste masking powder with yield 85.57% was obtained. The assay (calculated as vortioxetine) of powder was 60.14%.

[0203] If the materials were bonded during the preparation process, an appropriate amount of talcum powder could be added after the machine was stopped to ensure that the materials were in a fluidized state.

[0204] The taste masking powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of taste masking powder was ameliorated.

[0205] Self-made sample: Instantaneous irritation ++, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0206] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0207] Detailed information is listed in Table 1:

TABLE-US-00002 TABLE 1 Comparison test of taste of vortioxetine hemihydrobromide taste masking powder Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + ++ 1-15 15-30 acceptable acceptable N/A N/A Subject 5 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A

[0208] X-ray powder diffraction pattern of Vortioxetine hemihydrobromide:Urelease E100:PEG 6000=1:0.3:0.07 taste masking powder is shown in FIG. 5.

[0209] X-ray powder diffraction pattern of Urelease E100:PEG 6000=1:0.23 powder after spray drying is shown in FIG. 4.

1b) Vortioxetine hydrobromide form α:UreleaseE100:PEG6000=1:0.3:0.07 taste masking powder preparation

[0210] 30.09 g of UreleaseE100 and 7.05 g of PEG6000 were added to 470.20 g of medicinal ethanol, stirred to dissolve, set aside.

[0211] 100.02 g of 100-200 mesh vortioxetine hydrobromide form α and 10.05 g of talc with particle size less than 325 mesh were added to the BWF-1G multifunctional fluid bed installed in the bottom spray coating mode. The air inlet volume and the height of the guide tube were adjusted to make the materials in a fluidized state, and the air inlet temperature was set 50-55° C., peristaltic pump speed was 5 rpm and atomization pressure was 1.0-1.5 atm. The coating liquid prepared by Urelease was sprayed into the fluid bed. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size 60-150 mesh was collected by sieving. 127.81 g of taste masking powder with yield 86.82% was obtained. The assay (calculated as vortioxetine) of powder was 52.77%.

[0212] If the materials were bonded during the preparation process, an appropriate amount of talcum powder could be added after the machine was stopped to ensure that the materials were in a fluidized state.

[0213] The taste masking powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hydrobromide form α equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of taste masking powder was ameliorated.

[0214] Self-made sample: Instantaneous irritation ++, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0215] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0216] Detailed information is listed in Table 2:

TABLE-US-00003 TABLE 2 Comparison test of taste of vortioxetine hydrobromide form α taste masking powder Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A

[0217] X-ray powder diffraction pattern of Vortioxetine hydrobromide form α:Urelease E100:PEG 6000=1:0.3:0.07 taste masking powder is shown in FIG. 6. X-ray powder diffraction pattern of Urelease E100:PEG 6000=1:0.23 powder after spray drying is shown in FIG. 4.

1c) Vortioxetine hydrobromide form β:Urelease E100:PEG6000=1:0.3:0.07 taste masking powder preparation 30.00 g of Urelease E100 and 7.00 g of PEG6000 were added to 470.20 g of medicinal ethanol, stirred to dissolve, set aside.

[0218] 100.00 g of 100-200 mesh vortioxetine hydrobromide form and 10.00 g of talc with particle size less than 325 mesh were added to the BWF-1G multifunctional fluid bed installed in the bottom spray coating mode. The air inlet volume and the height of the guide tube were adjusted to make the materials in a fluidized state, and the air inlet temperature was set 50-55° C., peristaltic pump speed was 5 rpm and atomization pressure was 1.0-1.5 atm. The coating liquid prepared by Urelease was sprayed into the fluid bed. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size 60-150 mesh was collected by sieving. 126.78 g of taste masking powder with yield 86.24% was obtained. The assay (calculated as vortioxetine) of powder was 53.13%.

[0219] If the materials were bonded during the preparation process, an appropriate amount of talcum powder could be added after the machine was stopped to ensure that the materials were in a fluidized state.

[0220] The taste masking powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hydrobromide form β equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of taste masking powder was ameliorated.

[0221] Self-made sample: Instantaneous irritation ++, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0222] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0223] Detailed information is listed in Table 3:

TABLE-US-00004 TABLE 3 Comparison test of taste of vortioxetine hydrobromide form β taste masking powder Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A

[0224] X-ray powder diffraction pattern of Vortioxetine hydrobromide form β: Urelease E100:PEG 6000=1:0.3:0.07 taste masking powder is shown in FIG. 7. X-ray powder diffraction pattern of Urelease E100:PEG 6000=1:0.23 after spray drying is shown in FIG. 4.

1d) Vortioxetine hemihydrobromide:ethyl cellulose N10:PEG 6000=1:3:0.07 taste masking powder preparation

[0225] 150.00 g of ethyl cellulose N10 and 3.50 g of PEG 6000 were added to 1500.00 g of medicinal ethanol, stirred to dissolve, set aside.

[0226] 50.00 g of 100-200 mesh vortioxetine hemihydrobromide and 25.00 g of talc with particle size less than 325 mesh were added to the BWF-1G multifunctional fluid bed installed in the bottom spray coating mode. The air inlet volume and the height of the guide tube were adjusted to make the materials in a fluidized state, and the air inlet temperature was set 50-55° C., peristaltic pump speed was 5 rpm and atomization pressure was 1.0-1.5 atm. The coating liquid prepared by Urelease was sprayed into the fluid bed. After spraying, the materials were continued to fluidize for 30 minutes to remove residual ethanol, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size 60-150 mesh was collected by sieving. 162.91 g of taste masking powder with yield 71.30% was obtained. The assay (calculated as vortioxetine) of powder was 19.57%.

[0227] If the materials were bonded during the preparation process, an appropriate amount of talcum powder could be added after the machine was stopped to ensure that the materials were in a fluidized state.

[0228] The taste masking powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of taste masking powder was ameliorated.

[0229] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0230] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0231] Detailed information is listed in Table 4:

TABLE-US-00005 TABLE 4 Comparison test of taste of vortioxetine hemihydrobromide taste masking powder Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 2 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + ++ 1-15 15-30 acceptable acceptable N/A N/A Subject 5 + +++ 1-15 >30 acceptable unacceptable N/A N/A
1e) Vortioxetine hemihydrobromide:Eudragit RL100:meglumine=1:3:0.07 taste masking powder preparation

[0232] 150.00 g of Eudragit RL100 and 3.50 g of meglumine were added to 1500.00 g of medicinal ethanol, stirred to dissolve, set aside.

[0233] 50.00 g of 100-200 mesh vortioxetine hemihydrobromide and 25.00 g of talc with particle size less than 325 mesh were added to the BWF-1G multifunctional fluid bed installed in the bottom spray coating mode. The air inlet volume and the height of the guide tube were adjusted to make the materials in a fluidized state, and the air inlet temperature was set 50-55° C., peristaltic pump speed was 5 rpm and atomization pressure was 1.0-1.5 atm. The coating liquid prepared by Urelease was sprayed into the fluid bed. After spraying, the materials were continued to fluidize for 30 minutes to remove residual ethanol, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size 60-150 mesh was collected by sieving. The taste masking powder was obtained.

[0234] If the materials were bonded during the preparation process, an appropriate amount of talcum powder could be added after the machine was stopped to ensure that the materials were in a fluidized state.

[0235] The taste masking powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of taste masking powder was ameliorated.

[0236] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0237] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0238] Detailed information is listed in Table 5:

TABLE-US-00006 TABLE 5 Comparison test of taste of vortioxetine hemihydrobromide taste masking powder Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 2 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + ++ 1-15 15-30 acceptable acceptable N/A N/A Subject 5 + +++ 1-15 >30 acceptable unacceptable N/A N/A

Example 2: Vortioxetine Hydrobromide+Coating Material Taste Masking Powder Preparation

[0239] 2a) Vortioxetine hemihydrobromide:Urelease E100=1:0.7 taste masking powder preparation

[0240] 7.73 g of UreleaseE100 was added to 77.20 g of medicinal ethanol, stirred to dissolve, set aside.

[0241] 10.02 g of 200 mesh vortioxetine hemihydrobromide was added to the above prepared solution, stirred to disperse. After sieving through 100 mesh stainless steel screen, the materials were collected and continued stirring to prevent sedimentation.

[0242] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The prepared suspension material was sprayed into the fluid bed, and the material status was observed at any time. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by sieving. 7.81 g of taste masking powder with yield 43.98% was obtained. The assay (calculated as vortioxetine) of powder was 48.63%.

[0243] The remaining materials were lightly ground and then sieved to collect powder with particle size less than 80 mesh. 6.23 g of taste masking powder with yield 35.08% was obtained. The assay (calculated as vortioxetine) of powder was 49.38%.

[0244] The two kinds of taste masking powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of taste masking powders was ameliorated significantly.

[0245] After mixing the two kinds of taste masking powder, the mixed taste masking powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted by 5 subjects, which proved irritation of the treated vortioxetine taste masking powders were improved significantly.

[0246] Self-made sample 1: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0247] Self-made sample 2: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0248] Self-made mixed sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0249] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0250] Detailed information is listed in Table 6:

TABLE-US-00007 TABLE 6 Comparison test of taste of vortioxetine hemihydrobromide taste masking powder Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject mixed sample sample mixed sample sample mixed sample sample mixed sample sample Subject 1 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 3 + +++ 1-15  1-15 acceptable unacceptable N/A N/A Subject 4 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + +++ 1-15 15-30 acceptable unacceptable N/A N/A
2b) Vortioxetine hydrobromide:UreleaseE100=1:0.77 taste masking powder preparation

[0251] 7.70 g of UreleaseE100 was added to 77.10 g of medicinal ethanol, stirred to dissolve, set aside.

[0252] 10.00 g of 200 mesh vortioxetine hydrobromide was added to the above prepared solution, stirred to disperse. After sieving through 100 mesh stainless steel screen, the materials were collected and continued stirring to prevent sedimentation.

[0253] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The prepared suspension material was sprayed into the fluid bed, and the material status was observed at any time. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by sieving. 6.98 g of taste masking powder with yield 39.44% was obtained. The assay (calculated as vortioxetine) of powder was 44.63%.

[0254] The remaining materials were lightly ground and then sieved to collect powder with particle size less than 80 mesh. 5.93 g of taste masking powder with yield 33.50% was obtained. The assay (calculated as vortioxetine) of powder was 45.38%.

[0255] The two kinds of taste masking powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of taste masking powders was ameliorated significantly.

[0256] After mixing the two kinds of taste masking powder, the mixed taste masking powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of taste masking powders were ameliorated significantly.

[0257] Self-made sample 1: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0258] Self-made sample 2: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0259] Self-made mixed sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0260] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0261] Detailed information is listed in Table 7:

TABLE-US-00008 TABLE 7 Comparison test of taste of vortioxetine hydrobromide taste masking powder Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject mixed sample sample mixed sample sample mixed sample sample mixed sample sample Subject 1 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + +++ 1-15 >30 acceptable unacceptable N/A N/A
2c) Vortioxetine hemihydrobromide:cellulose acetate:PEG 6000=1:0.7:0.07 taste masking powder preparation

[0262] 7.00 g of cellulose acetate and 0.70 g of PEG 6000 were added to 70.20 g of medicinal ethanol, stirred to dissolve, set aside.

[0263] 10.00 g of 200 mesh vortioxetine hemihydrobromide was added to the above prepared solution, stirred to disperse. After sieving through 100 mesh stainless steel screen, the materials were collected and continued stirring to prevent sedimentation.

[0264] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The prepared suspension material was sprayed into the fluid bed, and the material status was observed at any time. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by sieving. 6.97 g of taste masking powder with yield 40.76% was obtained. The assay (calculated as vortioxetine) of powder was 47.93%.

[0265] The remaining materials were lightly ground and then sieved to collect powder with particle size less than 80 mesh. 6.00 g of taste masking powder with yield 33.90% was obtained. The assay (calculated as vortioxetine) of powder was 48.98%.

[0266] The two kinds of taste masking powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of taste masking powders were ameliorated significantly.

[0267] After mixing the two kinds of taste masking powder, the mixed taste masking powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted by 5 subjects, which proved irritation of the treated vortioxetine taste masking powders were improved significantly.

[0268] Self-made sample 1: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0269] Self-made sample 2: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0270] Self-made mixed sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0271] Reference sample: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0272] Detailed information is listed in Table 8:

TABLE-US-00009 TABLE 8 Comparison test of taste of vortioxetine hemihydrobromide taste masking powder Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject mixed sample sample mixed sample sample mixed sample sample mixed sample sample Subject 1 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 3 ++ +++ 1-15  1-15 acceptable unacceptable N/A N/A Subject 4 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + +++ 1-15 15-30 acceptable unacceptable N/A N/A
2d) Vortioxetine hemihydrobromide:Polyvinyl alcohol (low viscosity)=1:0.7 taste masking powder preparation

[0273] 7.00 g of polyvinyl alcohol (low viscosity) was added to 100.00 g of purified water, stirred in 90° C. water bath to dissolve, cooled to room temperature, 0.07 g of potassium citrate was added, stirred to dissolve, set aside.

[0274] 10.00 g of 200 mesh vortioxetine hemihydrobromide was added to the above prepared solution, stirred to disperse. After sieving through 100 mesh stainless steel screen, the materials were collected and continued stirring to prevent sedimentation.

[0275] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 30-33 m.sup.3, the inlet temperature was 60-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The prepared suspension material was sprayed into the fluid bed, and the material status was observed at any time. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by sieving. 12.79 g of taste masking powder with yield 75.24% was obtained. The assay (calculated as vortioxetine) of powder was 50.99%.

[0276] The taste masking powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of taste masking powder was ameliorated significantly.

[0277] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0278] Reference sample: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0279] Detailed information is listed in Table 9:

TABLE-US-00010 TABLE 9 Comparison test of taste of vortioxetine hemihydrobromide taste masking powder Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 3 ++ +++ 1-15  1-15 acceptable unacceptable N/A N/A Subject 4 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 ++ ++ 1-15 15-30 acceptable unacceptable N/A N/A

Example 3: Vortioxetine Hemihydrobromide:Coating Material=1:1 Taste Masking Powder Preparation

[0280] 3a) Vortioxetine hemihydrobromide:Eudragit E100:PEG 6000=1:1:0.07 taste masking powder preparation

[0281] 10.00 g of Eudragit E100 and 0.70 g of PEG 6000 were added to 70.00 g of medicinal ethanol, stirred to dissolve, set aside.

[0282] 10.01 g of 200 mesh vortioxetine hemihydrobromide was added to the above prepared solution, stirred to disperse. After sieving through 100 mesh stainless steel screen, the materials were collected and continued stirring to prevent sedimentation.

[0283] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The prepared suspension material was sprayed into the fluid bed, and the material status was observed at any time. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by sieving. 13.78 g of taste masking powder with yield 66.54% was obtained. The assay (calculated as vortioxetine) of powder was 41.79%.

[0284] The taste masking powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of taste masking powder was ameliorated significantly.

[0285] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0286] Reference sample: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0287] Detailed information is listed in Table 10:

TABLE-US-00011 TABLE 10 Comparison test of taste of vortioxetine hemihydrobromide taste masking powder Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 + ++ 1-15 15-30  acceptable unacceptable N/A N/A Subject 3 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + +++ 1-15 1-15 acceptable unacceptable N/A N/A Subject 5 + +++ 1-15 1-15 acceptable unacceptable N/A N/A
3b) Vortioxetine hemihydrobromide:Eudragit L100:PEG 6000=1:1:0.07 taste masking powder preparation

[0288] 10.00 g of Eudragit L100 and 0.70 g of PEG 6000 were added to 70.00 g of medicinal ethanol, stirred to dissolve, set aside.

[0289] 10.00 g of 200 mesh vortioxetine hemihydrobromide was added to the above prepared solution, stirred to disperse. After sieving through 100 mesh stainless steel screen, the materials were collected and continued stirring to prevent sedimentation.

[0290] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The prepared suspension material was sprayed into the fluid bed, and the material status was observed at any time. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by sieving. 14.14 g of taste masking powder with yield 68.31% was obtained. The assay (calculated as vortioxetine) of powder was 42.01%.

[0291] The taste masking powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of taste masking powders was ameliorated significantly and almost non-irritating.

[0292] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0293] Reference sample: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0294] Detailed information is listed in Table 11:

TABLE-US-00012 TABLE 11 Comparison test of taste of vortioxetine hemihydrobromide taste masking powder Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 + ++ 1-15 15-30  acceptable unacceptable N/A N/A Subject 3 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + +++ 1-15 1-15 acceptable unacceptable N/A N/A Subject 5 + +++ 1-15 1-15 acceptable unacceptable N/A N/A
3c) Vortioxetine hemihydrobromide:copovidone AV64=1:1 taste masking powder preparation

[0295] 10.00 g of copovidone AV64 was added to 70.00 g of medicinal ethanol, stirred to dissolve, set aside.

[0296] 10.00 g of 200 mesh vortioxetine hemihydrobromide was added to the above prepared solution, stirred to disperse. After sieving through 100 mesh stainless steel screen, the materials were collected and continued stirring to prevent sedimentation.

[0297] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The prepared suspension material was sprayed into the fluid bed, and the material status was observed at any time. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by sieving. 14.16 g of taste masking powder with yield 70.80% was obtained. The assay (calculated as vortioxetine) of powder was 42.78%.

[0298] The taste masking powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of taste masking powder was ameliorated significantly.

[0299] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0300] Reference sample: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0301] Detailed information is listed in Table 12:

TABLE-US-00013 TABLE 12 Comparison test of taste of vortioxetine hemihydrobromide taste masking powder Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 3 ++ ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + ++ 1-15 >30 acceptable unacceptable N/A N/A

Example 4: Vortioxetine Hydrobromide:Eudragit=1:0.5 Mixture Preparation

[0302] 4a) Vortioxetine hemihydrobromide:Eudragit E PO=1:0.5 mixture preparation

[0303] 5.00 g of vortioxetine hemihydrobromide that had passed through a 200-mesh stainless steel sieve and 2.50 g of Eudragit E PO were placed in a clean and dry 50 ml screw-top glass reagent bottle. The mixture was mixed with Vortex-2 vortex mixer for 5 minutes. After passing through a 100-mesh stainless steel sieve, the mixture was continued to mix with Vortex-2 vortex mixer for 5 minutes. 0.50 g of the sample was took out for testing. The remaining materials were collected and piled up in a 75 mm diameter stainless steel tray, and the stainless steel tray was placed in DHG-9070A hot air circulating oven at 120-130° C. After heating for 30 minutes, the material became a semi-fluid state. After it was taken out and left to cool, it was milled through a 100-mesh stainless steel sieve with a BJ-300A multifunctional pulverizer several times to obtain a 1:0.5 mixture powder.

[0304] The mixture powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of mixture powder was ameliorated.

[0305] Self-made sample: Instantaneous irritation ++, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0306] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0307] Detailed information is listed in Table 13:

TABLE-US-00014 TABLE 13 Comparison test of taste of vortioxetine hemihydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 ++ ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 3 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + ++ 1-15 15-30 acceptable unacceptable N/A N/A
4b) Vortioxetine hydrobromide:Eudragit E PO=1:0.5 mixture preparation

[0308] 5.00 g of vortioxetine hydrobromide that had passed through a 200-mesh stainless steel sieve and 2.50 g of Eudragit E PO were placed in a clean and dry 50 ml screw-top glass reagent bottle. The mixture was mixed with Vortex-2 vortex mixer for 5 minutes. After passing through a 100-mesh stainless steel sieve, the mixture was continued to mix with Vortex-2 vortex mixer for 5 minutes. 0.50 g of the sample was took out for testing. The remaining materials were collected and piled up in a 75 mm diameter stainless steel tray, and the stainless steel tray was placed in DHG-9070A hot air circulating oven at 120-130° C. After heating for 30 minutes, the material became a semi-fluid state. After it was taken out and left to cool, it was milled through a 100-mesh stainless steel sieve with a BJ-300A multifunctional pulverizer several times to obtain a 1:0.5 mixture powder.

[0309] The mixture powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of mixture powder was ameliorated.

[0310] Self-made sample: Instantaneous irritation ++, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0311] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0312] Detailed information is listed in Table 14:

TABLE-US-00015 TABLE 14 Comparison test of taste of vortioxetine hydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 ++ +++ >30 >30 acceptable unacceptable N/A N/A Subject 4 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 +++ +++ 1-15 >30 acceptable unacceptable N/A N/A

[0313] The UV scan showed that the maximum absorption wavelength and peak intensity of the treated material vortioxetine did not change significantly. The results are shown in FIG. 8, FIG. 9, FIG. 10 and FIG. 11.

4c) Vortioxetine hydrobromide:Eudragit RS PO=1:0.5 mixture preparation

[0314] 5.00 g of vortioxetine hydrobromide that had passed through a 200-mesh stainless steel sieve and 2.50 g of Eudragit RS PO were placed in a clean and dry 50 ml screw-top glass reagent bottle. The mixture was mixed with Vortex-2 vortex mixer for 5 minutes. After passing through a 100-mesh stainless steel sieve, the mixture was continued to mix with Vortex-2 vortex mixer for 5 minutes. 0.50 g of the sample was took out for testing. The remaining materials were collected and piled up in a 75 mm diameter stainless steel tray, and the stainless steel tray was placed in DHG-9070A hot air circulating oven at 120-130° C. After heating for 30 minutes, the material became a semi-fluid state. After it was taken out and left to cool, it was milled through a 100-mesh stainless steel sieve with a BJ-300A multifunctional pulverizer several times to obtain a 1:0.5 mixture powder.

[0315] The mixture powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of mixture powder was ameliorated.

[0316] Self-made sample: Instantaneous irritation ++, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0317] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0318] Detailed information is listed in Table 15:

TABLE-US-00016 TABLE 15 Comparison test of taste of vortioxetine hydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 ++ +++ >30 >30 acceptable unacceptable N/A N/A Subject 4 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 +++ +++ 1-15 >30 acceptable unacceptable N/A N/A

Example 5: Vortioxetine Hemihydrobromide:Eudragit E PO=1:1.5 Mixture Preparation

[0319] 5.00 g of vortioxetine hemihydrobromide that had passed through a 200-mesh stainless steel sieve and 7.50 g of Eudragit E PO were placed in a clean and dry 50 ml screw-top glass reagent bottle. The mixture was mixed with Vortex-2 vortex mixer for 5 minutes. After passing through a 100-mesh stainless steel sieve, the mixture was continued to mix with Vortex-2 vortex mixer for 5 minutes. 0.50 g of the sample was took out for testing. The remaining materials were collected and piled up in a 75 mm diameter stainless steel tray, and the stainless steel tray was placed in DHG-9070A hot air circulating oven at 120-130° C. After heating for 30 minutes, the material became a semi-fluid state. After it was taken out and left to cool, it was milled through a 100-mesh stainless steel sieve with a BJ-300A multifunctional pulverizer several times to obtain a 1:1.5 mixture powder.

[0320] The 1:1.5 mixture powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of mixture powder was ameliorated significantly.

[0321] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0322] Reference sample: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0323] Detailed information is listed in Table 16:

TABLE-US-00017 TABLE 16 Comparison test of taste of vortioxetine hemihydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + +++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 2 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 4 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + +++ 1-15 15-30 acceptable unacceptable N/A N/A

[0324] The UV scan showed that the maximum absorption wavelength and peak intensity of the treated material vortioxetine did not change significantly. The results are shown in FIG. 9, FIG. 12, FIG. 13 and FIG. 14.

Example 6: Vortioxetine Hemihydrobromide:Eudragit E PO=1:5 Mixture Preparation

[0325] 5.00 g of vortioxetine hemihydrobromide that had passed through a 200-mesh stainless steel sieve and 25.00 g of Eudragit E PO were placed in a clean and dry 100 ml screw-top glass reagent bottle. The mixture was mixed with Vortex-2 vortex mixer for 5 minutes. After passing through a 100-mesh stainless steel sieve, the mixture was continued to mix with Vortex-2 vortex mixer for 5 minutes. 0.50 g of the sample was took out for testing. The remaining materials were collected and piled up in a 75 mm diameter stainless steel tray, and the stainless steel tray was placed in DHG-9070A hot air circulating oven at 120-130° C. After heating for 30 minutes, the material became a semi-fluid state. After it was taken out and left to cool, it was milled through a 100-mesh stainless steel sieve with a BJ-300A multifunctional pulverizer several times to obtain a 1:5 mixture powder with assay (calculated as vortioxetine) 14.39%.

[0326] The 1:5 mixture powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of mixture powder was ameliorated significantly.

[0327] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0328] Reference sample: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0329] Detailed information is listed in Table 17:

TABLE-US-00018 TABLE 17 Comparison test of taste of vortioxetine hemihydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + +++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 2 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 4 + +++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 5 + ++ 1-15 >30 acceptable unacceptable N/A N/A

[0330] The UV scan showed that the maximum absorption wavelength and peak intensity of the treated material vortioxetine did not change significantly. The results are shown in FIG. 9, FIG. 12, FIG. 15 and FIG. 16.

Example 7: Vortioxetine Hydrobromide:Polyacrylic Resin IV=1:1.5 Mixture Preparation

[0331] 7a) Vortioxetine hemihydrobromide:Polyacrylic resin IV=1:1.5 mixture preparation

[0332] 5.00 g of vortioxetine hemihydrobromide that had passed through a 200-mesh stainless steel sieve and 7.50 g of Polyacrylic resin IV that had passed through a 100-mesh stainless steel sieve were placed in a clean and dry 100 ml screw-top glass reagent bottle. The mixture was mixed with Vortex-2 vortex mixer for 5 minutes. After passing through a 100-mesh stainless steel sieve, the mixture was continued to mix with Vortex-2 vortex mixer for 5 minutes. 0.50 g of the sample was took out for testing. The remaining materials were collected and piled up in a 75 mm diameter stainless steel tray, and the stainless steel tray was placed in DHG-9070A hot air circulating oven at 120-130° C. After heating for 30 minutes, the material became a semi-fluid state. After it was taken out and left to cool, it was milled through a 100-mesh stainless steel sieve with a BJ-300A multifunctional pulverizer several times to obtain 10.98 g of 1:1.5 mixture powder with yield 87.84% and assay (calculated as vortioxetine) 35.71%.

[0333] The 1:1.5 mixture powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of mixture powder was ameliorated significantly.

[0334] Self-made sample: Instantaneous irritation ++, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0335] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0336] Detailed information is listed in Table 18:

TABLE-US-00019 TABLE 18 Comparison test of taste of vortioxetine hemihydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 ++ +++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 3 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 4 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + ++ 1-15 >30 acceptable unacceptable N/A N/A
7b) Vortioxetine hydrobromide:Polyacrylic resin IV=1:1.5 mixture preparation

[0337] 5.00 g of vortioxetine hydrobromide that had passed through a 200-mesh stainless steel sieve and 7.50 g of Polyacrylic resin IV that had passed through a 100-mesh stainless steel sieve were placed in a clean and dry 100 ml screw-top glass reagent bottle. The mixture was mixed with Vortex-2 vortex mixer for 5 minutes. After passing through a 100-mesh stainless steel sieve, the mixture was continued to mix with Vortex-2 vortex mixer for 5 minutes. 0.50 g of the sample was took out for testing. The remaining materials were collected and piled up in a 75 mm diameter stainless steel tray, and the stainless steel tray was placed in DHG-9070A hot air circulating oven at 120-130° C. After heating for 30 minutes, the material became a semi-fluid state. After it was taken out and left to cool, it was milled through a 100-mesh stainless steel sieve with a BJ-300A multifunctional pulverizer several times to obtain 11.23 g of 1:1.5 mixture powder with yield 89.84% and assay (calculated as vortioxetine) 31.12%.

[0338] The 1:1.5 mixture powder equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of mixture powder was ameliorated significantly.

[0339] Self-made sample: Instantaneous irritation ++, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0340] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0341] Detailed information is listed in Table 19:

TABLE-US-00020 TABLE 19 Comparison test of taste of vortioxetine hydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 ++ ++ 1-15 >30 acceptable unacceptable N/A N/A

[0342] The UV scan showed that the maximum absorption wavelength and peak intensity of the treated material vortioxetine did not change significantly. The results are shown in FIG. 8, FIG. 17, FIG. 18 and FIG. 19.

Example 8: Vortioxetine Hemihydrobromide:Polyacrylic Resin=1:0.3 Solid Dispersion Preparation

[0343] 8a) Vortioxetine hemihydrobromide:Polyacrylic resin IV=1:0.3 solid dispersion preparation

[0344] 10.00 g of vortioxetine hemihydrobromide, 3.00 g of polyacrylic resin IV and 0.70 g of PEG 4000 were added to 300.00 g of medicinal ethanol, stirred to dissolve, set aside.

[0345] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The above prepared solution was sprayed into the fluid bed, the material status was observed at any time, and the parameters were adjusted appropriately to ensure normal atomization and drying. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by grinding and sieving. 10.29 g of material powder with yield 75.11% was obtained. The assay (calculated as vortioxetine) of powder was 62.97%.

[0346] The solid dispersion equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of the untreated material was obvious and could hardly be tolerated, while, the irritation of treated vortioxetine solid dispersion was mild and could be tolerated.

[0347] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0348] Reference sample: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0349] Detailed information is listed in Table 20:

TABLE-US-00021 TABLE 20 Comparison test of taste of vortioxetine hemihydrobromide taste masking powder Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + +++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 2 ++ ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 3 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + ++ 1-15 15-30 acceptable unacceptable N/A N/A
8b) Vortioxetine hemihydrobromide:Polyacrylic resin 11=1:0.3 solid dispersion preparation

[0350] 10.00 g of vortioxetine hemihydrobromide and 3.00 g of polyacrylic resin II were added to 300.00 g of medicinal ethanol, stirred to dissolve, set aside.

[0351] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The above prepared solution was sprayed into the fluid bed, the material status was observed at any time, and the parameters were adjusted appropriately to ensure normal atomization and drying. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by grinding and sieving.

[0352] The solid dispersion equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of the untreated material was obvious and could hardly be tolerated, while, the irritation of treated vortioxetine solid dispersion was mild and could be tolerated.

[0353] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0354] Reference sample: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0355] Detailed information is listed in Table 21:

TABLE-US-00022 TABLE 21 Comparison test of taste of vortioxetine hemihydrobromide taste masking powder Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + +++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 2 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 3 ++ ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 ++ ++ 1-15 15-30 acceptable unacceptable N/A N/A

Example 9: Vortioxetine Hemihydrobromide:Taste Masking Excipient=1:0.7 Solid Dispersion Preparation

[0356] 9a) Vortioxetine hemihydrobromide:Polyacrylic resin IV=1:0.7 solid dispersion preparation

[0357] 10.00 g of vortioxetine hemihydrobromide, 7.70 g of polyacrylic resin IV (Eudragit E100 or Eudragit E PO—purchased from supplier Evonik Rohm GmbH Company, or Urelease E or Urelease E100—purchased from supplier Guangzhou Maofeng Pharmaceutical Excipients Co., Ltd., or Polyacrylic resin IV (trade name)—purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.) were added to 170.00 g of medicinal ethanol, heated to 50-55° C., stirred to dissolve, set aside at 50-55° C.

[0358] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The above prepared solution was sprayed into the fluid bed, the material status was observed at any time, and the parameters were adjusted appropriately to ensure normal atomization and drying. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by sieving. 12.69 g of material powder with yield 71.69% was obtained. The assay (calculated as vortioxetine) of powder was 49.47%.

[0359] The solid dispersion equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of the untreated material was obvious and could hardly be tolerated, while, the treated vortioxetine solid dispersion was almost non-irritation.

[0360] Self-made sample: Instantaneous irritation ++, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0361] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0362] Detailed information is listed in Table 22:

TABLE-US-00023 TABLE 22 Comparison test of taste of vortioxetine hemihydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 3 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + +++ 1-15 15-30 acceptable unacceptable N/A N/A

[0363] The X-ray powder diffraction pattern of the solid dispersion of vortioxetine hemihydrobromide:polyacrylic resin IV=1:0.7 is shown in FIG. 20, and the X-ray powder diffraction pattern of polyacrylic resin IV after spray drying is shown in FIG. 21.

[0364] The solid dispersion in Example 9a) was tested for stability according to the requirements of the 2015 Edition of the Pharmacopoeia of the People's Republic of China (accelerated for 6 months, 40±2° C., humidity 75%±5%), and the stability was good. The dissolution rate of the solid dispersion in Example 9a) in 0.1N hydrochloric acid and pH 4.5 acetate buffer (paddle method, 50 revolutions/min) dissolution speed (10 minutes data) was fast with complete dissolution (30 minutes), the results are shown in Table 23.

TABLE-US-00024 TABLE 23 Stability Test Table of Vortioxetine hemihydrobromide Test Dissolution rate in Dissolution rate in pH 4.5 Max single Identification 0.1N HCl (%) acetate buffer (%) impurity Time Free base Br 10 minutes 10 minutes 30 minutes (%) Initial + + 95 94 98 0.11 6 months + + 96 97 99 0.12
9b) Vortioxetine hydrobromide:Polyacrylic resin IV=1:0.77 solid dispersion preparation

[0365] 10.00 g of vortioxetine hydrobromide, 7.70 g of polyacrylic resin IV (Eudragit E100 or Eudragit E PO—purchased from supplier Rohm Company, or Urelease E or Urelease E100—purchased from supplier Guangzhou Maofeng Pharmaceutical Excipients Co., Ltd., or Polyacrylic resin IV (trade name)—purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.) were added to 300.00 g of medicinal ethanol, stirred to dissolve, set aside.

[0366] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The above prepared solution was sprayed into the fluid bed, the material status was observed at any time, and the parameters were adjusted appropriately to ensure normal atomization and drying. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by grinding and sieving. 11.73 g of material powder with yield 66.27% was obtained. The assay (calculated as vortioxetine) of powder was 44.47%, and the assay (calculated as vortioxetine hydrobromide) of powder was 11.83%.

[0367] The solid dispersion equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of the untreated material was obvious and could hardly be tolerated, while, the treated vortioxetine solid dispersion was slightly irritation.

[0368] Self-made sample: Instantaneous irritation ++, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0369] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0370] Detailed information is listed in Table 24:

TABLE-US-00025 TABLE 24 Comparison test of taste of vortioxetine hydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A

[0371] The X-ray powder diffraction pattern of the solid dispersion of vortioxetine hydrobromide:polyacrylic resin IV=1:0.77 is shown in FIG. 22, and the X-ray powder diffraction pattern of polyacrylic resin IV after spray drying is shown in FIG. 21.

[0372] The solid dispersion in Example 9b) was tested for stability according to the requirements of the 2015 Edition of the Pharmacopoeia of the People's Republic of China (accelerated for 6 months, 40±2° C., humidity 75%±5%), and the stability was good. The dissolution rate of the solid dispersion in Example 9b) in 0.1N hydrochloric acid and pH 4.5 acetate buffer (paddle method, 50 revolutions/min) dissolution speed (10 minutes data) was fast with complete dissolution (30 minutes), the results are shown in Table 25.

TABLE-US-00026 TABLE 25 Stability Test Table of Vortioxetine Hydrobromide Test Dissolution rate in Dissolution rate in pH 4.5 Max single Identification 0.1N HCl (%) acetate buffer (%) impurity Time Free base Br 10 minutes 10 minutes 30 minutes (%) Initial + + 95 93 97 0.10 6 months + + 96 95 99 0.11
9c) Vortioxetine hemihydrobromide:Eudragit RL100:PEG 6000=1:0.7:0.07 solid dispersion preparation

[0373] 10.00 g of vortioxetine hemihydrobromide, 7.00 g of Eudragit RL100 and 0.70 g of PEG 6000 were added to 300.00 g of medicinal ethanol, stirred to dissolve, set aside.

[0374] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The above prepared solution was sprayed into the fluid bed, the material status was observed at any time, and the parameters were adjusted appropriately to ensure normal atomization and drying. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by sieving.

[0375] The solid dispersion equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of the untreated material was obvious and could hardly be tolerated, while, the treated vortioxetine solid dispersion was almost non-irritation.

[0376] Self-made sample: Instantaneous irritation ++, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0377] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0378] Detailed information is listed in Table 26:

TABLE-US-00027 TABLE 26 Comparison test of taste of vortioxetine hemihydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 ++ ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 ++ +++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 3 ++ ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + +++ 1-15 15-30 acceptable unacceptable N/A N/A
9d) Vortioxetine hemihydrobromide:Eudragit S100=1:0.7 solid dispersion preparation

[0379] 10.00 g of vortioxetine hemihydrobromide and 7.00 g of Eudragit S100 were added to 300.00 g of medicinal ethanol, stirred to dissolve, set aside.

[0380] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The above prepared solution was sprayed into the fluid bed, the material status was observed at any time, and the parameters were adjusted appropriately to ensure normal atomization and drying. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by grinding and sieving.

[0381] The solid dispersion equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of the untreated material was obvious and could hardly be tolerated, while, the treated vortioxetine solid dispersion was almost non-irritation.

[0382] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0383] Reference sample: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0384] Detailed information is listed in Table 27:

TABLE-US-00028 TABLE 27 Comparison test of taste of vortioxetine hemihydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 + +++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 3 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 ++ ++ 1-15 15-30 acceptable unacceptable N/A N/A
9e) Vortioxetine hemihydrobromide:Eudragit L100=1:0.7 solid dispersion preparation

[0385] 10.00 g of vortioxetine hemihydrobromide and 7.00 g of Eudragit L100 were added to 300.00 g of medicinal ethanol, stirred to dissolve, set aside.

[0386] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The above prepared solution was sprayed into the fluid bed, the material status was observed at any time, and the parameters were adjusted appropriately to ensure normal atomization and drying. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by grinding and sieving.

[0387] The solid dispersion equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of the untreated material was obvious and could hardly be tolerated, while, the treated vortioxetine solid dispersion was almost non-irritation.

[0388] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0389] Reference sample: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0390] Detailed information is listed in Table 28:

TABLE-US-00029 TABLE 28 Comparison test of taste of vortioxetine hemihydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 ++ ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 + +++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 3 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + ++ 1-15 15-30 acceptable unacceptable N/A N/A

Example 10: Vortioxetine Hemihydrobromide:Polyacrylic Resin IV=1:1 Solid Dispersion Preparation

[0391] 10.00 g of vortioxetine hydrobromide, 10.00 g of polyacrylic resin IV and 0.70 g of PEG 6000 were added to 300.00 g of medicinal ethanol, stirred to dissolve, set aside.

[0392] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The above prepared solution was sprayed into the fluid bed, the material status was observed at any time, and the parameters were adjusted appropriately to ensure normal atomization and drying. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by grinding and sieving. 13.31 g of material with yield 64.30% was obtained. The assay (calculated as vortioxetine) of powder was 43.38%.

[0393] The solid dispersion equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of the untreated material was obvious and could hardly be tolerated, while, the treated vortioxetine solid dispersion was slightly irritation.

[0394] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0395] Reference sample: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0396] Detailed information is listed in Table 29:

TABLE-US-00030 TABLE 29 Comparison test of taste of vortioxetine hemihydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 3 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 4 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + ++ 1-15 15-30 acceptable unacceptable N/A N/A

Example 11: Vortioxetine Hydrobromide:Taste Masking Excipient=1:1.5 Solid Dispersion Preparation

[0397] 11a) Vortioxetine hemihydrobromide:Polyacrylic resin IV=1:1.5 solid dispersion preparation

[0398] 10.00 g of vortioxetine hemihydrobromide and 15.00 g of polyacrylic resin IV were added to 300.00 g of medicinal ethanol, stirred to dissolve, set aside.

[0399] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The above prepared solution was sprayed into the fluid bed, the material status was observed at any time, and the parameters were adjusted appropriately to ensure normal atomization and drying. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by grinding and sieving. 18.11 g of material with yield 72.44% was obtained. The assay (calculated as vortioxetine) of powder was 34.47%.

[0400] The solid dispersion equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of the untreated material was obvious and could hardly be tolerated, while, the treated vortioxetine solid dispersion was almost non-irritation.

[0401] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0402] Reference sample: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0403] Detailed information is listed in Table 30:

TABLE-US-00031 TABLE 30 Comparison test of taste of vortioxetine hemihydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 3 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 4 + +++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 5 + ++ 1-15 15-30 acceptable unacceptable N/A N/A
11b) Vortioxetine hydrobromide:Polyacrylic resin IV=1:1.5 solid dispersion preparation

[0404] 10.00 g of vortioxetine hydrobromide, 15.00 g of polyacrylic resin IV and 0.70 g of PEG 6000 were added to 300.00 g of medicinal ethanol, stirred to dissolve, set aside.

[0405] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The above prepared solution was sprayed into the fluid bed, the material status was observed at any time, and the parameters were adjusted appropriately to ensure normal atomization and drying. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by grinding and sieving. 17.17 g of material with yield 66.81% was obtained. The assay (calculated as vortioxetine) of powder was 30.57%.

[0406] The solid dispersion equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of the untreated material was obvious and could hardly be tolerated, while, the treated vortioxetine solid dispersion was almost non-irritation.

[0407] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0408] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0409] Detailed information is listed in Table 31:

TABLE-US-00032 TABLE 31 Comparison test of taste of vortioxetine hydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + +++ 1-15 >30 acceptable unacceptable N/A N/A
11c) Vortioxetine hydrobromide:Ethyl cellulose N10=1:1.5 solid dispersion preparation

[0410] 10.00 g of vortioxetine hydrobromide and 15.00 g of ethyl cellulose N10 were added to 300.00 g of medicinal ethanol, stirred to dissolve. then 1.00 g of potassium citrate after passing through 200 mesh sieve was added, stirred to dispersed to prevent sedimentation. set aside.

[0411] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The above prepared solution was sprayed into the fluid bed, the material status was observed at any time, and the parameters were adjusted appropriately to ensure normal atomization and drying. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by grinding and sieving.

[0412] The solid dispersion equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of the untreated material was obvious and could hardly be tolerated, while, the treated vortioxetine solid dispersion was almost non-irritation.

[0413] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0414] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0415] Detailed information is listed in Table 32:

TABLE-US-00033 TABLE 32 Comparison test of taste of vortioxetine hydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + +++ 1-15 >30 acceptable unacceptable N/A N/A

Example 12: Vortioxetine Hemihydrobromide:Taste Masking Excipient=1:2 Solid Dispersion Preparation

[0416] 12a) Vortioxetine hemihydrobromide:polyacrylic resin IV=1:2 solid dispersion preparation

[0417] 10.00 g of vortioxetine hemihydrobromide, 20.00 g of polyacrylic resin IV and 0.70 g of PEG 6000 were added to 300.00 g of medicinal ethanol, stirred to dissolve, set aside.

[0418] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The above prepared solution was sprayed into the fluid bed, the material status was observed at any time, and the parameters were adjusted appropriately to ensure normal atomization and drying. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by grinding and sieving. 20.20 g of material with yield 65.80% was obtained. The assay (calculated as vortioxetine) of powder was 27.99%.

[0419] The solid dispersion equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of the untreated material was obvious and could hardly be tolerated, while, the treated vortioxetine solid dispersion was almost non-irritation.

[0420] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0421] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0422] Detailed information is listed in Table 33:

TABLE-US-00034 TABLE 33 Comparison test of taste of vortioxetine hemihydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 2 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + ++ 1-15 15-30 acceptable unacceptable N/A N/A
12b) Vortioxetine hemihydrobromide:Cellulose acetate=1:2 solid dispersion preparation

[0423] 10.00 g of vortioxetine hemihydrobromide, 20.00 g of cellulose acetate and 0.70 g of PEG 8000 were added to 300.00 g of medicinal ethanol, stirred to dissolve, set aside.

[0424] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The above prepared solution was sprayed into the fluid bed, the material status was observed at any time, and the parameters were adjusted appropriately to ensure normal atomization and drying. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by grinding and sieving.

[0425] The solid dispersion equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of the untreated material was obvious and could hardly be tolerated, while, the treated vortioxetine solid dispersion was almost non-irritation.

[0426] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0427] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0428] Detailed information is listed in Table 34:

TABLE-US-00035 TABLE 34 Comparison test of taste of vortioxetine hemihydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 2 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 5 + ++ 1-15 >30 acceptable unacceptable N/A N/A

Example 13: Vortioxetine Hemihydrobromide+Taste Masking Excipient Solid Dispersion Preparation

[0429] 13a) Vortioxetine hemihydrobromide:polyacrylic resin IV=1:5 solid dispersion preparation

[0430] 10.00 g of vortioxetine hemihydrobromide and 50.00 g of polyacrylic resin IV were added to 500.00 g of medicinal ethanol, stirred to dissolve, set aside.

[0431] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The above prepared solution was sprayed into the fluid bed, the material status was observed at any time, and the parameters were adjusted appropriately to ensure normal atomization and drying. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by grinding and sieving. 49.29 g of material with yield 82.15% was obtained. The assay (calculated as vortioxetine) of powder was 14.67%.

[0432] The solid dispersion equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of the untreated material was obvious and could hardly be tolerated, while, the treated vortioxetine solid dispersion was almost non-irritation.

[0433] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0434] Reference sample: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0435] Detailed information is listed in Table 35:

TABLE-US-00036 TABLE 35 Comparison test of taste of vortioxetine hemihydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 2 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 4 + +++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 5 + ++ 1-15 >30 acceptable unacceptable N/A N/A
13b) Vortioxetine hemihydrobromide:Hydroxypropyl cellulose LF=1:3 solid dispersion preparation

[0436] 10.00 g of vortioxetine hemihydrobromide, 30.00 g of hydroxypropyl cellulose LF and 1 g of meglumine were added to 300.00 g of medicinal ethanol, stirred to dissolve, set aside.

[0437] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The above prepared solution was sprayed into the fluid bed, the material status was observed at any time, and the parameters were adjusted appropriately to ensure normal atomization and drying. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 80 mesh was collected by grinding and sieving.

[0438] The solid dispersion equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of the untreated material was obvious and could hardly be tolerated, while, the treated vortioxetine solid dispersion was almost non-irritation.

[0439] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0440] Reference sample: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0441] Detailed information is listed in Table 36:

TABLE-US-00037 TABLE 36 Comparison test of taste of vortioxetine hemihydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 2 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 4 + +++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 5 + ++ 1-15 >30 acceptable unacceptable N/A N/A

Example 14: Vortioxetine Hemihydrobromide+Polyacrylic Resin Solid Dispersion Preparation

[0442] 14a) Vortioxetine hemihydrobromide:polyacrylic resin 11=1:5 solid dispersion preparation

[0443] 10.00 g of vortioxetine hemihydrobromide and 50.00 g of polyacrylic resin II were added to 500.00 g of medicinal ethanol, stirred and dissolved in water bath at 40-50° C. water bath, filtered with 0.45 um microporous membrane. In the stirred state, the pH of the filtrate was adjusted with 5% of (g/g) sodium hydroxide solution until there was no more precipitates appear in the material (pH was 8.54 at this time), then ethanol was removed with the vacuum rotary evaporator, and the resulting solid was removed with the vacuum freeze dryer at 40-50° C., then the solid was passed through the 100-mesh stainless steel sieve. 50.54 g of solid dispersion contained vortioxetine with yield 84.23% was obtained. The assay (calculated as vortioxetine) of powder was 14.79%.

[0444] The solid dispersion equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The unique irritation of vortioxetine was not felt.

[0445] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0446] Reference sample: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0447] Detailed information is listed in Table 37:

TABLE-US-00038 TABLE 37 Comparison test of taste of vortioxetine hemihydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 2 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + ++ 1-15 15-30 acceptable unacceptable N/A N/A
14b) Vortioxetine hydrobromide:polyacrylic resin 11=1:1.5 solid dispersion preparation

[0448] 10.00 g of vortioxetine hydrobromide and 15.00 g of polyacrylic resin II were added to 250.00 g of medicinal ethanol, stirred and dissolved in water bath at 40-50° C. water bath, filtered with 0.45 um microporous membrane. In the stirred state, the pH of the filtrate was adjusted with 5% of (g/g) sodium hydroxide solution until there was no more precipitates appear in the material (pH was 8.32 at this time), then ethanol was removed with the vacuum rotary evaporator, and the resulting solid was removed with the vacuum freeze dryer at 40-50° C., then the solid was passed through the 100-mesh stainless steel sieve. 19.67 g of solid dispersion contained vortioxetine with yield 78.68% was obtained. The assay (calculated as vortioxetine) of powder was 29.97%.

[0449] The solid dispersion equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The unique irritation of vortioxetine was not felt.

[0450] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0451] Reference sample: Instantaneous irritation +++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0452] Detailed information is listed in Table 38:

TABLE-US-00039 TABLE 38 Comparison test of taste of vortioxetine hydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + +++ 1-15 >30 acceptable unacceptable N/A N/A

[0453] The X-ray powder diffraction pattern of vortioxetine hydrobromide:polyacrylic resin 11=1:1.5 solid dispersion is shown in FIG. 23, and the X-ray powder diffraction pattern of polyacrylic resin II (ethanol rotary evaporation) is shown in FIG. 24.

Example 15: Vortioxetine Hemihydrobromide:Polyacrylic Resin 11=1:1.5 Solid Dispersion Preparation

[0454] 10.00 g of vortioxetine hemihydrobromide and 15.00 g of polyacrylic resin II were added to 250.00 g of medicinal ethanol, stirred and dissolved in water bath at 40-50° C. water bath, filtered with 0.45 um microporous membrane. In the stirred state, the pH of the filtrate was adjusted with 5% of (g/g) sodium hydroxide solution until there was no more precipitates appear in the material (pH was 8.47 at this time), then the insoluble matter was separated and added to 400 g of purified water. After homogenizing through a 100-mesh sieve at 40-50° C., it was granulated by BWF-1G multifunctional fluid bed top spraying. Then the obtained powder was passed through the 100-mesh stainless steel sieve. 12.94 g of solid dispersion contained vortioxetine with yield 51.76% was obtained. The assay (calculated as vortioxetine) of powder was 35.77%.

[0455] The solid dispersion equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The unique irritation of vortioxetine can not be felt.

[0456] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0457] Reference sample: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0458] Detailed information is listed in Table 39:

TABLE-US-00040 TABLE 39 Comparison test of taste of vortioxetine hemihydrobromide solid dispersion Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 2 + +++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 3 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + +++ 1-15  1-15 acceptable unacceptable N/A N/A Subject 5 + ++ 1-15 >30 acceptable unacceptable N/A N/A

[0459] The X-ray powder diffraction pattern of vortioxetine hemihydrobromide:polyacrylic resin 11=1:1.5 solid dispersion is shown in FIG. 25, and the X-ray powder diffraction pattern of polyacrylic resin II (ethanol rotary evaporation) is shown in FIG. 24.

Example 16: Preparation of Taste Masking Granules with Taste Masking Coating Powder

[0460] 10.00 g of Eudragit RS100 was added to 150.00 g of ethanol, stirred to dissolve, set aside.

[0461] 10.00 g of powder prepared in Example 1d) was added to the above prepared solution, stirred to dispersed. After sieving through 60 mesh stainless steel screen, the materials were continued stirring to prevent sedimentation.

[0462] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 50-55° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The prepared suspension material was sprayed into the fluid bed, and the material status was observed at any time. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 50 mesh was collected by grinding and sieving. 15.87 g of powder with yield 79.35% was obtained. The assay (calculated as vortioxetine) of powder was 25.47%.

[0463] The taste masking granules equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects. The irritation of the untreated material was obvious and could hardly be tolerated, while, the treated vortioxetine granules was slightly irritation and could be tolerated.

[0464] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0465] Reference sample: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0466] Detailed information is listed in Table 40:

TABLE-US-00041 TABLE 40 Comparison test of taste of vortioxetine hemihydrobromide taste masking granules Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 2 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 3 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + +++ 1-15 15-30 acceptable unacceptable N/A N/A

Example 17: Preparation of Taste Masking Powder with Solid Dispersion

[0467] 5.00 g of chitosan (degree of deacetylation greater than or equal to 85%) was added to 100.00 g of purified water, stirred to dissolve, set aside.

[0468] 10.00 g of powder prepared in Example 9a) was added to the above prepared solution, stirred to dispersed. After sieving through 60 mesh stainless steel screen, the materials were continued stirring to prevent sedimentation.

[0469] The BWF-1G multifunctional fluid bed was installed according to the top spray granulation mode, and the air volume was set 33 m.sup.3, the inlet temperature was 60-65° C., the peristaltic pump speed was 8 rpm and the atomization pressure was 1.0-1.5 atm. The prepared suspension material was sprayed into the fluid bed, and the material status was observed at any time. After spraying, the materials were continued to fluidize for 30 minutes, then stopped heating, and waited until the temperature of the materials was cooled to room temperature. The materials were collected, and the powder with particle size less than 60 mesh was collected by grinding and sieving. 11.11 g of powder with yield 74.07% was obtained. The assay (calculated as vortioxetine) of powder was 35.17%.

[0470] The taste masking granules equivalent to 20 mg of vortioxetine and the 100-mesh powder of vortioxetine hemihydrobromide equivalent to 20 mg vortioxetine were tasted and compared by 5 subjects, which proved irritation of the untreated material was obvious and could hardly be tolerated, while, the treated vortioxetine powder was slightly irritation and could be tolerated.

[0471] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0472] Reference sample: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0473] Detailed information is listed in Table 41:

TABLE-US-00042 TABLE 41 Comparison test of taste of vortioxetine hemihydrobromide taste masking powder Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Self-made Reference Self-made Reference Self-made Reference Self-made Reference Subject sample sample sample sample sample sample sample sample Subject 1 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 2 + ++ 1-15 15-30 acceptable unacceptable N/A N/A Subject 3 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 + ++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + +++ 1-15 15-30 acceptable unacceptable N/A N/A

Example 18: Preparation of 10 mg/Table Vortioxetine Hydrobromide Film-Coated Tables

[0474] The formula of 100 tablets weighing 0.152 g each made from the Vortioxetine hydrobromide was as follows:

TABLE-US-00043 Powder prepared from Example 9b 2.25 g (equal to 1.0 g of Vortioxetine) Microcrystalline cellulose  4.15 g Mannitol P 100 SD  8.00 g Sodium starch glycolate  0.70 g Magnesium stearate  0.10 g Stomach-soluble coating material q.s. (0.456 g) Total 15.20 g

Preparation Process:

[0475] (1) The prescription amount of powder prepared from Example 9b, microcrystalline cellulose, mannitol P100SD, sodium starch glycolate, and magnesium stearate were placed in a clean and dry 50 ml screw-top glass reagent bottle. After mixing in a vortex blender for five minutes, the mixture was taken out after passing through 80 mesh sieve. After mixing for another five minutes, the mixture was taken out after passing through 80 mesh sieve, and finally after mixing for another five minutes, the compressed premix was obtained;
(2) The compressed premix was pressed by using ZP8 rotary tablet press with a diameter of 8.0 mm mold, controlling the tablet weight of 147-157 mg/tablet and hardness 40-60N, and obtaining the tablet core;
(3) The stomach-soluble coating material was added to purified water to prepared a suspension with the solid content of about 10%, continued stirring, set aside;
(4) Using the coating liquid prepared in step (3), the tablet core was coated with a high-efficiency coating machine, and the actual weight gain of the tablet core is about 1%.

[0476] The commercially available product (10 mg/tablet) and the grounded powder of the finished product in this invention were tasted and compared by 10 subjects. The irritation of the commercially available product was obvious and could hardly be tolerated, while, the taste of the self-made product in this invention was acceptable.

[0477] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0478] Commercially available product: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0479] Detailed information is listed in Table 42:

TABLE-US-00044 TABLE 42 Comparison test of taste of vortioxetine hydrobromide film-coated tablet Instantaneous irritation Delayed irritation (min) Bitterness Grittiness Commercially Commercially Commercially Commercially Self-made available Self-made available Self-made available Self-made available Subject sample product sample product sample product sample product Subject 1 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 2 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 3 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 4 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 5 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 6 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 7 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 8 ++ +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 9 + +++ 1-15 >30 acceptable unacceptable N/A N/A Subject 10 + +++ 1-15 >30 acceptable unacceptable N/A N/A

[0480] The self-made finished product of this invention was tested for preliminary stability according to the requirements of the 2015 Edition of the Pharmacopoeia of the People's Republic of China Compared with the commercially available product, dissolution rate of the self-made finished product of this invention in 0.1N hydrochloric acid and pH 4.5 acetate buffer (paddle method, 50 r/min) was significantly faster, and the dissolution degree (30 minutes) is significantly better.

[0481] The results are shown in Table 43.

TABLE-US-00045 TABLE 43 Preliminary Stability Test Table of Vortioxetine Hydrobromide (Temperature: 50° C. ± 2° C., Humidity: 75% ± 5%) Test Identification Dissolution rate Dissolution rate in pH 4.5 Max single Free Content in 0.1N HCl (%) acetate buffer (%) impurity Time Source base Br uniformity 10 minutes 10 minutes 30 minutes (%) Initial Commercially + + Pass 81 68 78 0.12 available Self-made + + Pass 94 93 98 0.10  5 days Commercially + + Pass 79 71 79 0.13 available Self-made + + Pass 98 97 99 0.11 10 days Commercially + + Pass 84 65 81 0.14 available Self-made + + Pass 95 97 99 0.12

Example 19: Preparation of 20 mg/Table Orally Disintegrating Tables (Compressed Tablet)

[0482] 19a) The formula of 100 tablets weighing 0.088 g each made from the Vortioxetine hemihydrobromide was as follows:

TABLE-US-00046 Vortioxetine hemihydrobromide 2.28 g (equal to 2 g of Vortioxetine) Mannitol P100 SD  5.14 g Trisodium phosphate 0.228 g Crospovidone XL 0.352 g Croscarmellose Sodium 0.352 g Sodium starch glycolate 0.352 g Magnesium stearate 0.044 g Neotame 0.010 g Red Ferric Oxide 0.044 g Total 8.802 g

Preparation Process:

[0483] (1) Neotame and red iron oxide passed 200 mesh, and other raw materials passed 100 mesh sieve, set aside;
(2) The prescription amount of vortioxetine hemihydrobromide, trisodium phosphate, mannitol P100SD, crospovidone XL, croscarmellose sodium, sodium starch glycolate, magnesium stearate, Neotame, and red iron oxide were placed in a clean and dry 50 ml screw-top glass reagent bottle. After mixing in a vortex blender for five minutes, the mixture was taken out after passing through 80 mesh sieve. After mixing for another five minutes, the mixture was taken out after passing through 80 mesh sieve, and finally after mixing for another five minutes, the compressed premix was obtained;
(3) The compressed premix was pressed by using ZP8 rotary tablet press with a diameter of 6.0 mm shallow concave mold, controlling the tablet weight of 86-90 mg/tablet and hardness 0.7-1.5 kG, and obtaining the tablet.
19b: The formula of 100 tablets weighing 0.088 g each made from the Vortioxetine hydrobromide was as follows:

TABLE-US-00047 Vortioxetine hydrobromide 2.54 g (equal to 2 g of Vortioxetine) Mannitol PlOOSD  4.88 g Trisodium phosphate 0.228 g Crospovidone XL 0.352 g Croscarmellose Sodium 0.352 g Sodium starch glycolate 0.352 g Magnesium stearate 0.044 g Neotame 0.010 g Red Ferric Oxide 0.044 g Total 8.802g

Preparation Process:

[0484] (1) Neotame and red iron oxide passed 200 mesh, and other raw materials passed 100 mesh sieve, set aside;
(2) The prescription amount of vortioxetine hydrobromide, trisodium phosphate, mannitol P100SD, crospovidone XL, croscarmellose sodium, sodium starch glycolate, magnesium stearate, Neotame, and red iron oxide were placed in a clean and dry 50 ml screw-top glass reagent bottle. After mixing in a vortex blender for five minutes, the mixture was taken out after passing through 80 mesh sieve. After mixing for another five minutes, the mixture was taken out after passing through 80 mesh sieve, and finally after mixing for another five minutes, the compressed premix was obtained;
(3) The compressed premix was pressed by using ZP8 rotary tablet press with a diameter of 6.0 mm shallow concave mold, controlling the tablet weight of 86-90 mg/tablet and hardness 0.7-1.5 kG, and obtaining the tablet.

[0485] After 10 subjects tried the taste, the two samples had no grittiness feeling; the sample made of vortioxetine hemihydrobromide hardly felt irritation, and the taste was better; while, the sample made of vortioxetine hydrobromide was significantly more irritating than the vortioxetine hemihydrobromide samples, and showed mild discomfort.

[0486] Self-made sample 19a: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0487] Self-made sample 19b: Instantaneous irritation ++, disappear after more than 30 minutes after delayed irritation, and the bitterness was unacceptable.

[0488] Detailed information is listed in Table 44:

TABLE-US-00048 TABLE 44 Comparison test of taste of orally disintegrating tables Instantaneous irritation delayed irritation (min) bitterness Grittiness vortioxetine vortioxetine vortioxetine vortioxetine hemihydro- vortioxetine hemihydro- vortioxetine hemihydro- vortioxetine hemihydro- vortioxetine bromide hydrobromide bromide hydrobromide bromide hydrobromide bromide hydrobromide Subject samples samples samples samples samples samples samples samples Subject 1 + ++ 1-15 15-30 acceptable acceptable No No Subject 2 ++ +++ 1-15 >30 acceptable unacceptable No No Subject 3 + + 1-15 15-30 acceptable unacceptable No No Subject 4 ++ +++ 1-15 >30 acceptable unacceptable No No Subject 5 + ++ 1-15 15-30 acceptable unacceptable No No Subject 6 ++ +++ 1-15 15-30 acceptable unacceptable No No Subject 7 + ++ 1-15 15-30 acceptable acceptable No No Subject 8 + ++ 1-15 15-30 acceptable unacceptable No No Subject 9 ++ +++ 1-15 >30 acceptable unacceptable No No Subject 10 + + 1-15  1-15 acceptable acceptable No No

Example 20: Preparation of 20 mg/Table Orally Disintegrating Tables (Compressed Tablet)

[0489] The formula of 100 tablets weighing 0.152 g each made from the Vortioxetine hemihydrobromide was as follows:

TABLE-US-00049 Powder prepared from Example 10 4.61 g (equal to 2.0 g of Vortioxetine) Mannitol P 100 SD  8.30 g Trisodium phosphate 0.304 g Crospovidone XL 0.608 g Cro scarmello se Sodium 0.608 g Sodium starch glycolate 0.608 g Magnesium stearate 0.076 g Neotame 0.015 g Red Ferric Oxide 0.076 g Total 15.205 g

Preparation Process:

[0490] (1) Neotame and red iron oxide passed 200 mesh, and other raw materials passed 100 mesh sieve, set aside;
(2) The prescription amount of solid dispersion, trisodium phosphate, mannitol P100SD, crospovidone XL, croscarmellose sodium, sodium starch glycolate, magnesium stearate, Neotame, and red iron oxide were placed in a clean and dry 50 ml screw-top glass reagent bottle. After mixing in a vortex blender for five minutes, the mixture was taken out after passing through 80 mesh sieve. After mixing for another five minutes, the mixture was taken out after passing through 80 mesh sieve, and finally after mixing for another five minutes, the compressed premix was obtained;
(3) The compressed premix was pressed by using ZP8 rotary tablet press with a diameter of 8.0 mm shallow concave mold, controlling the tablet weight of 145-149 mg/tablet and hardness 15-30N, and obtaining the tablet.

[0491] The detection value of pH and relative exposure: 8.92, 0.19% (7.5 ug/ml).

[0492] After 10 subjects tried the taste, the sample dissolved in the oral cavity within 10 seconds, there was no feeling of grittiness, almost no irritation, and the taste was good.

[0493] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0494] Detailed information is listed in Table 45:

TABLE-US-00050 TABLE 45 Comparison test of taste of orally disintegrating tables Instantaneous Delayed Subject irritation irritation (min) Bitterness Grittiness Subject 1 + 1-15 acceptable No Subject 2 + 1-15 acceptable No Subject 3 + 1-15 acceptable No Subject 4 + 1-15 acceptable No Subject 5 + 1-15 acceptable No Subject 6 + 1-15 acceptable No Subject 7 + 1-15 acceptable No Subject 8 + 1-15 acceptable No Subject 9 + 1-15 acceptable No Subject 10 ++ 1-15 acceptable No

Example 21: Preparation of 20 mg/Table Orally Disintegrating Tables (Lyophilized Tablets)

The Formula:

[0495]

TABLE-US-00051 Vortioxetine hemihydrobromide 0.912 g Mannitol 1.876 g Sorbitol 2.000 g PEG 4000 1.030 g Trisodium phosphate 0.248 g Medicinal Type B Gelatin 0.124 g Neotame 0.001 g Red Ferric Oxide 0.003 g Total 6.194 g

[0496] Purified water was added to 16 g to make 40 tablets, each of which was about 0.4 g, and contained about 0.1548 g of solids.

Preparation Process:

[0497] (1) Vortioxetine hemihydrobromide and red iron oxide passed 100 mesh sieve, set aside;
(2) The prescription amount of mannitol, Sorbitol, PEG 4000, medicinal type B gelatin and Neotame were placed in a clean and dry 20 ml screw-top glass reagent bottle, then 8 g of purified water was added, tightened the cap. After shaking to dissolve at 50° C., the solution was cooled to room temperature, then the prescription amount of vortioxetine hemihydrobromide, red iron oxide, and anhydrous trisodium phosphate were added, shaking and dispersing, then purified water was added to prescription amount. After shaking and dispersing, mixture was passed through the 80-mesh stainless steel screen for 3 times, the suspension was obtained for separate loading, and the suspension was continuously stirred to prevent sedimentation;
(3) The suspension for dispensing was 0.4 g per hole into the mold hole, freeze-dried;
(4) The freeze-dried sample was heat-sealed to obtain freeze-dried orally disintegrating tablets.

[0498] The detection value of pH and relative exposure: 10.42, 0.27% (10.7 ug/ml).

[0499] After testing by 10 volunteer subjects, the sample disintegrated within 5 seconds in the oral cavity, with no grit feeling and minimal irritation.

[0500] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0501] Detailed information is listed in Table 46:

TABLE-US-00052 TABLE 46 Comparison test of taste of orally disintegrating tables Instantaneous Subject irritation Delayed irritation (min) Bitterness Grittiness Subject 1 + 1-15 acceptable No Subject 2 + 1-15 acceptable No Subject 3 ++ 1-15 acceptable No Subject 4 + 1-15 acceptable No Subject 5 + 1-15 acceptable No Subject 6 + 1-15 acceptable No Subject 7 + 1-15 acceptable No Subject 8 ++ 1-15 acceptable No Subject 9 + 1-15 acceptable No Subject 10 ++ 1-15 acceptable No

Example 22: Preparation of 20 mg/Tablet Orally Disintegrating Tables (Compressed Tablets, Lyophilized Tablets)

[0502] 22a: The formula of 100 tablets weighing 0.152 g each made from the Vortioxetine hemihydrobromide micronized powder coated powder was as follows:

TABLE-US-00053 Powder prepared from Example 3a 4.79 g (equal to 2.0 g of Vortioxetine) Mannitol P 100 SD  8.15 g Sodium bicarbonate  0.304 g Crospovidone XL  0.608 g Cro scarmello se Sodium  0.608 g Sodium starch glycolate  0.608 g Magnesium stearate  0.076 g Neotame  0.015 g Red Ferric Oxide  0.076 g Total 15.205 g

Preparation Process:

[0503] (1) Neotame and red iron oxide passed 200 mesh, and other raw materials passed 80 mesh sieve, set aside;
(2) The prescription amount of powder prepared from Example 3a, sodium bicarbonate, mannitol P100SD, crospovidone XL, croscarmellose sodium, sodium starch glycolate, magnesium stearate, Neotame, and red iron oxide were placed in a clean and dry 20 ml screw-top glass reagent bottle. After mixing in a vortex blender for five minutes, the mixture was taken out after passing through 80 mesh sieve. After mixing for another five minutes, the mixture was taken out after passing through 80 mesh sieve, and finally after mixing for another five minutes, the compressed premix was obtained;
(3) The compressed premix was pressed by using ZP8 rotary tablet press with a diameter of 8.0 mm shallow concave mold, controlling the tablet weight of 145-149 mg/tablet and hardness 15-30N, and obtaining the tablet.
22b: The formula of coated powder of vortioxetine hemihydrobromide micronized powder made into freeze-dried orally disintegrating tablets was as follows:

TABLE-US-00054 Powder prepared from Example 3a 1.914 g (equal to 0.8 g of Vortioxetine) Mannitol 2.000 g Sorbitol 2.000 g PEG 4000 1.030 g Sodium bicarbonate 0.124 g Medicinal Type B Gelatin 0.124 g Neotame 0.001 g Red Ferric Oxide 0.003 g Total 7.196g

[0504] Purified water was added to 16 g to make 40 tablets, each of which was about 0.4 g, and contained about 0.1799 g of solids.

Preparation Process:

[0505] (1) API passed 100 mesh sieve, set aside;
(2) The prescription amount of mannitol, Sorbitol, PEG 4000, medicinal type B gelatin and Neotame were placed in a clean and dry 20 ml screw-top glass reagent bottle, then about 8 g of purified water was added, tightened the cap. After shaking to dissolve at 50° C., the solution was cooled to room temperature, then the prescription amount of powder prepared from Example 3a, red iron oxide, and sodium bicarbonate were added, shaking and dispersing, then purified water was added to prescription amount. After shaking and dispersing, mixture was passed through the 80-mesh stainless steel screen for 3 times, the suspension was obtained for separate loading, and the suspension was continuously stirred to prevent sedimentation;
(3) The suspension for dispensing was 0.4 g per hole into the mold hole, freeze-dried;
(4) The freeze-dried sample was heat-sealed to obtain freeze-dried orally disintegrating tablets.

[0506] The detection value of pH and relative exposure:

[0507] Self-made sample 22a: pH 8.02, 0.21% (8.3 ug/ml);

[0508] Self-made sample 22b: pH 9.79, 0.25% (9.9 ug/ml).

[0509] After testing by 10 volunteer subjects, the sample 22a disintegrated in the oral cavity within 10 seconds, and the sample 22b disintegrated in the oral cavity within 5 seconds, and there was no grit feeling and minimal irritation both.

[0510] Self-made sample 22a: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0511] Self-made sample 22b: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0512] Detailed information is listed in Table 47:

TABLE-US-00055 TABLE 47 Comparison of taste of vortioxetine hemihydrobromide micro-powder coated orally disintegrating tablets Instantaneous Delayed irritation (min) Bitterness Grittiness Sample Sample Sample Sample Sample Sample Sample Sample Subject 22a 22b 22a 22b 22a 22b 22a 22b Subject 1 + + 1-15 1-15 acceptable acceptable No No Subject 2 + + 1-15 1-15 acceptable acceptable No No Subject 3 + + 1-15 1-15 acceptable acceptable No No Subject 4 ++ ++ 1-15 1-15 acceptable acceptable No No Subject 5 + + 1-15 1-15 acceptable acceptable No No Subject 6 + + 1-15 1-15 acceptable acceptable No No Subject 7 + + 1-15 1-15 acceptable acceptable No No Subject 8 + + 1-15 15-30  acceptable unacceptable No No Subject 9 + + 1-15 15-30  acceptable unacceptable No No Subject 10 + + 1-15 1-15 acceptable acceptable No No

Example 23: Preparation of 20 mg/Tablet Orally Disintegrating Tables (Compressed Tablets, Lyophilized Tablets)

[0513] 23a: The formula of 100 tablets weighing 0.152 g each made from the Vortioxetine hemihydrobromide micronized powder coated powder was as follows:

TABLE-US-00056 Powder prepared from Example 7a 5.60 g (equal to 2.0 g of Vortioxetine) Mannitol P100 SD  7.31 g Tripotassium Phosphate Anhydrous  0.304 g Crospovidone XL  0.608 g Croscarmellose Sodium  0.608 g Sodium starch glycolate  0.608 g Magnesium stearate  0.076 g Neotame  0.015 g Red Ferric Oxide  0.076 g Total 15.205 g

Preparation Process:

[0514] (1) Neotame and red iron oxide passed 200 mesh, and other raw materials passed 80 mesh sieve, set aside;
(2) The prescription amount of powder prepared from Example 7a, tripotassium phosphate anhydrous, mannitol P100SD, crospovidone XL, croscarmellose sodium, sodium starch glycolate, magnesium stearate, Neotame, and red iron oxide were placed in a clean and dry 50 ml screw-top glass reagent bottle. After mixing in a vortex blender for five minutes, the mixture was taken out after passing through 80 mesh sieve. After mixing for another five minutes, the mixture was taken out after passing through 80 mesh sieve, and finally after mixing for another five minutes, the compressed premix was obtained;
(3) The compressed premix was pressed by using ZP8 rotary tablet press with a diameter of 8.0 mm shallow concave mold, controlling the tablet weight of 145-149 mg/tablet and hardness 15-30N, and obtaining the tablet.
23b: The formula of coated powder of vortioxetine hemihydrobromide micronized powder made into freeze-dried orally disintegrating tablets was as follows:

TABLE-US-00057 Powder prepared from Example 7a 2.240 g (equal to 0.8 g of Vortioxetine) Mannitol 2.000 g Sorbitol 2.000 g PEG 4000 1.030 g Tripotassium Phosphate Anhydrous 0.124 g Medicinal Type B Gelatin 0.124 g Neotame 0.001 g Red Ferric Oxide 0.003 g Total 7.522 g

[0515] Purified water was added to 16 g to make 40 tablets, each of which was about 0.4 g, and contained about 0.1881 g of solids.

Preparation Process:

[0516] (1) API passed 100 mesh sieve, set aside;
(2) The prescription amount of mannitol, Sorbitol, PEG 4000, medicinal type B gelatin and Neotame were placed in a clean and dry 20 ml screw-top glass reagent bottle, then about 8 g of purified water was added, tightened the cap. After shaking to dissolve at 50° C., the solution was cooled to room temperature, then the prescription amount of powder prepared from Example 7a, red iron oxide, and tripotassium Phosphate Anhydrous were added, shaking and dispersing, then purified water was added to prescription amount. After shaking and dispersing, mixture was passed through the 100-mesh stainless steel screen for 3 times, the suspension was obtained for separate loading, and the suspension was continuously stirred to prevent sedimentation;
(3) The suspension for dispensing was 0.4 g per hole into the mold hole, freeze-dried;
(4) The freeze-dried sample was heat-sealed to obtain freeze-dried orally disintegrating tablets.

[0517] The detection value of pH and relative exposure:

[0518] Self-made sample 23a: pH 8.02, 0.21% (8.3 ug/ml);

[0519] Self-made sample 23b: pH 9.79, 0.25% (9.9 ug/ml).

[0520] After testing by 10 volunteer subjects, the sample 23a disintegrated in the oral cavity within 10 seconds, and the sample 23b disintegrated in the oral cavity within 5 seconds, and there was no grit feeling and minimal irritation both.

[0521] Self-made sample 23a: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0522] Self-made sample 23b: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0523] Detailed information is listed in Table 48:

TABLE-US-00058 TABLE 48 Comparison of taste of vortioxetine hemihydrobromide solid dispersion orally disintegrating tablets Instantaneous Delayed irritation (min) Bitterness Grittiness Sample Sample Sample Sample Sample Sample Sample Sample Subject 23a 23b 23a 23b 23a 23b 23a 23b Subject 1 + + 1-15 1-15 acceptable acceptable No No Subject 2 + + 1-15 1-15 acceptable acceptable No No Subject 3 + + 1-15 1-15 acceptable acceptable No No Subject 4 + ++ 1-15 1-15 acceptable acceptable No No Subject 5 ++ + 1-15 1-15 acceptable acceptable No No Subject 6 + + 1-15 1-15 acceptable acceptable No No Subject 7 + + 1-15 1-15 acceptable acceptable No No Subject 8 + + 1-15 1-15 acceptable acceptable No No Subject 9 + + 1-15 1-15 acceptable acceptable No No Subject 10 + + 1-15 1-15 acceptable acceptable No No

Example 24: Preparation of 20 mg/Tablet Orally Disintegrating Tables (Compressed Tablets, Lyophilized Tablets)

[0524] 24a: The formula of 100 tablets weighing 0.152 g each made from the Vortioxetine hemihydrobromide micronized powder coated powder was as follows:

TABLE-US-00059 Powder prepared from Example 11a  5.80 g (equal to 2.0 g of Vortioxetine) Mannitol P100 SD  7.140 g Disodium hydrogen phosphate anhydrous  0.304 g Crospovidone XL  0.608 g Croscarmellose Sodium  0.608 g Sodium starch glycolate  0.608 g Magnesium stearate  0.076 g Neotame  0.015 g Red Ferric Oxide  0.076 g Total 15.235 g

Preparation Process:

[0525] (1) Neotame and red iron oxide passed 200 mesh, and other raw materials passed 80 mesh sieve, set aside;
(2) The prescription amount of powder prepared from Example 11a, disodium hydrogen phosphate anhydrous, mannitol P100SD, crospovidone XL, croscarmellose sodium, sodium starch glycolate, magnesium stearate, Neotame, and red iron oxide were placed in a clean and dry 50 ml screw-top glass reagent bottle. After mixing in a vortex blender for five minutes, the mixture was taken out after passing through 80 mesh sieve. After mixing for another five minutes, the mixture was taken out after passing through 80 mesh sieve, and finally after mixing for another five minutes, the compressed premix was obtained;
(3) The compressed premix was pressed by using ZP8 rotary tablet press with a diameter of 8.0 mm shallow concave mold, controlling the tablet weight of 147-157 mg/tablet and hardness 15-30N, and obtaining the tablet.
24b: The formula of coated powder of vortioxetine hemihydrobromide micronized powder made into freeze-dried orally disintegrating tablets was as follows:

TABLE-US-00060 Powder prepared from Example 11a 2.321 g (equal to 0.8 g of Vortioxetine) Mannitol 2.000 g Sorbitol 2.000 g PEG 4000 1.030 g Disodium hydrogen phosphate anhydrous 0.124 g Medicinal Type B Gelatin 0.124 g Neotame 0.001 g Red Ferric Oxide 0.003 g Total 7.603 g

[0526] Purified water was added to 16 g to make 40 tablets, each of which was about 0.4 g, and contained about 0.1901 g of solids.

Preparation Process:

[0527] (1) Red iron oxide passed 200 mesh, set aside;
(2) The prescription amount of mannitol, Sorbitol, PEG 4000, medicinal type B gelatin and Neotame were placed in a clean and dry 20 ml screw-top glass reagent bottle, then about 8 g of purified water was added, tightened the cap. After shaking to dissolve at 50° C., the solution was cooled to room temperature, then the prescription amount of powder prepared from Example 11a, red iron oxide, and disodium hydrogen phosphate anhydrous were added, shaking and dispersing, then purified water was added to prescription amount. After shaking and dispersing, mixture was passed through the 100-mesh stainless steel screen for 3 times, the suspension was obtained for separate loading, and the suspension was continuously stirred to prevent sedimentation;
(3) The suspension for dispensing was 0.4 g per hole into the mold hole, freeze-dried;
(4) The freeze-dried sample was heat-sealed to obtain a freeze-dried orally disintegrating tablets.

[0528] The detection value of pH and relative exposure:

[0529] Self-made sample 24a: pH 7.98, 0.29% (11.5 ug/ml);

[0530] Self-made sample 24b: pH 9.79, 0.35% (13.9 ug/ml).

[0531] After testing by 10 volunteer subjects, the sample 24a disintegrated in the oral cavity within 10 seconds, and the sample 24b disintegrated in the oral cavity within 5 seconds, and there was no grit feeling and minimal irritation both.

[0532] Self-made sample 24a: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0533] Self-made sample 24b: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0534] Detailed information is listed in Table 49:

TABLE-US-00061 TABLE 49 Comparison of taste of vortioxetine hemihydrobromide solid dispersion orally disintegrating tablets Instantaneous Delayed irritation (min) Bitterness Grittiness Sample Sample Sample Sample Sample Sample Sample Sample Subject 24a 24b 24a 24b 24a 24b 24a 24b Subject 1 + + 1-15 1-15 acceptable acceptable No No Subject 2 + + 1-15 1-15 acceptable acceptable No No Subject 3 + + 1-15 1-15 acceptable acceptable No No Subject 4 + + 1-15 1-15 acceptable acceptable No No Subject 5 + + 1-15 1-15 acceptable acceptable No No Subject 6 + + 1-15 1-15 acceptable acceptable No No Subject 7 + + 1-15 1-15 acceptable acceptable No No Subject 8 + + 1-15 1-15 acceptable acceptable No No Subject 9 + ++ 1-15 1-15 acceptable acceptable No No Subject 10 + + 1-15 1-15 acceptable acceptable No No

Example 25: Preparation of 20 mg/Tablet Dispersible Tablets

[0535] The formula of 100 tablets each weighing 0.152 grams was as follows:

TABLE-US-00062 Powder prepared from Example 10 4.61 g (equal to 2.0 g of Vortioxetine) Microcrystalline cellulose 2.68 g Mannitol P100SD 7.35 g Calcium hydroxide 0.02 g Sodium starch glycolate 0.60 g Neotame 0.001 g Magnesium stearate 0.05 g Total 15.17 g

Preparation Process:

[0536] (1) The prescription amount of powder prepared from Example 10, microcrystalline cellulose, mannitol P100SD, calcium hydroxide, sodium starch glycolate, Neotame and magnesium stearate were placed in a clean and dry 50 ml screw-top glass reagent bottle. After mixing in a vortex blender for five minutes, the mixture was taken out after passing through 80 mesh sieve. After mixing for another five minutes, the mixture was taken out after passing through 80 mesh sieve, and finally after mixing for another five minutes, the compressed premix was obtained;
(2) The compressed premix was pressed by using ZP8 rotary tablet press with a diameter of 8.0 mm shallow concave mold, controlling the tablet weight of 147-157 mg/tablet and hardness 50-80N, and obtaining the tablet.

[0537] The detection value of pH and relative exposure: pH 8.79, 0.45% (17.9 ug/ml).

[0538] After the sample was ground into powder, the powder equivalent to 20 mg of vortioxetine was tested by 10 subjects. The taste of the finished product was acceptable with mild irritation within 1 minute.

[0539] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0540] Detailed information is listed in Table 50:

TABLE-US-00063 TABLE 50 Comparison test of taste of vortioxetine hemihydrobromide solid dispersion dispersible tables Instantaneous Delayed Subject irritation irritation (min) Bitterness Grittiness Subject 1 + 1-15 acceptable No Subject 2 + 1-15 acceptable No Subject 3 + 1-15 acceptable No Subject 4 ++ 1-15 acceptable No Subject 5 + 1-15 acceptable No Subject 6 + 1-15 acceptable No Subject 7 ++ 1-15 acceptable No Subject 8 + 1-15 acceptable No Subject 9 + 1-15 acceptable No Subject 10 + 1-15 acceptable No

Example 26: Preparation of 20 mg/Tablet Dispersible Tablets

[0541] The formula of 100 tablets each weighing 0.152 g was as follows:

TABLE-US-00064 Powder prepared from Example 17 5.69 g (equal to 2.0 g of Vortioxetine) Microcrystalline cellulose 5.35 g Mannitol P100SD 3.50 g Sodium starch glycolate 0.60 g Neotame 0.01 g Magnesium stearate 0.05 g Total 15.20 g

Preparation Process:

[0542] (1) The prescription amount of powder prepared from Example 17, microcrystalline cellulose, mannitol P100SD, sodium starch glycolate, Neotame and magnesium stearate were placed in a clean and dry 50 ml screw-top glass reagent bottle. After mixing in a vortex blender for five minutes, the mixture was taken out after passing through 80 mesh sieve. After mixing for another five minutes, the mixture was taken out after passing through 80 mesh sieve, and finally after mixing for another five minutes, the compressed premix was obtained;
(2) The compressed premix was pressed by using ZP8 rotary tablet press with a diameter of 8.0 mm shallow concave mold, controlling the tablet weight of 147-157 mg/tablet and hardness 50-80N, and obtaining the tablet.

[0543] The detection value of pH and relative exposure: 8.79, 0.45% (17.9 ug/ml).

[0544] After the sample was ground into powder, the powder equivalent to 20 mg of vortioxetine was tested by 10 subjects. The taste of the finished product was acceptable with mild irritation within 1 minute.

[0545] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0546] Detailed information is listed in Table 51:

TABLE-US-00065 TABLE 51 Comparison test of taste of vortioxetine hemihydrobromide solid dispersion dispersible tables Instantaneous Delayed Subject irritation irritation (min) Bitterness Grittiness Subject 1 + 1-15 acceptable No Subject 2 + 1-15 acceptable No Subject 3 + 1-15 acceptable No Subject 4 + 1-15 acceptable No Subject 5 + 1-15 acceptable No Subject 6 + 1-15 acceptable No Subject 7 + 1-15 acceptable No Subject 8 + 1-15 acceptable No Subject 9 + 1-15 acceptable No Subject 10 + 1-15 acceptable No

Example 27: Preparation of Granules or Dry Suspension (5 g Per Bag, Containing 20 mg of Vortioxetine)

[0547] The formula of 100 bags each weighing 5 g was as follows:

TABLE-US-00066 Vortioxetine hemihydrobromide 2.38 g (equal to 2.0 g of Vortioxetine) Xylitol 180 g Mannitol P100SD 180 g Microcrystalline cellulose 104 g Colloidal silicon dioxide 5 g Carboxymethylcellulose sodium 5 g Tripotassium citrate 2.5 g Sodium starch glycolate 20 g Neotame 0.5 g Magnesium stearate 1 g Total 500.28 g

Preparation Process:

[0548] (1) API and excipients passed 100 mesh sieve, set aside;
(2) The prescription amount of vortioxetine hemihydrobromide, Xylitol, mannitol P100SD, microcrystalline cellulose, colloidal silicon dioxide, carboxymethylcellulose sodium, tripotassium citrate, sodium starch glycolate, Neotame and magnesium stearate were placed in a clean and dry 2 L stainless steel hopper. Installed the hopper on the hopper mixing machine, mixed them at 10 rpm for 10 minutes and took them out. After granulating with a rotary granulator and 0.5 mm stainless steel round hole mesh plate, continued to mix with a hopper mixer for 10 minutes at 10 rpm to obtain the premix for granulation;
(3) The premix for granulation was pressed into thin slices with a dry granulator, then granulated by using a 1.5 mm stainless steel round mesh plate. After sieving with a 40-mesh stainless steel screen, the fine powder was returned for re-granulating. 461.34 grams of granules were obtained, and the yield was 92.2%.
(4) The prepared particles were packed into aluminum-plastic heat-sealed bags at 5 g/bag, and then heat-sealed.

[0549] A bag of samples was dispersed in 20 ml of purified water. After 10 subjects tried the taste, the finished product tasted acceptable.

[0550] Self-made sample: Instantaneous irritation +, disappeared within 1-15 minutes after delayed irritation, and the bitterness was acceptable.

[0551] Detailed information is listed in Table 52:

TABLE-US-00067 TABLE 52 Taste test of vortioxetine hemihydrobromide granules Instantaneous Delayed Subject irritation irritation (min) Bitterness Grittiness Subject 1 + 1-15 acceptable No Subject 2 + 1-15 acceptable No Subject 3 + 1-15 acceptable No Subject 4 ++ 1-15 acceptable No Subject 5 + 1-15 acceptable No Subject 6 + 1-15 acceptable No Subject 7 + 1-15 acceptable No Subject 8 + 1-15 acceptable No Subject 9 + 1-15 acceptable No Subject 10 + 1-15 acceptable No

Example 28: Preparation of Oral Suspension (5 ml Per Bottle, Containing 20 mg of Vortioxetine)

[0552] The formula of vortioxetine hemihydrobromide solid dispersion made into 5 ml:20 mg oral suspension was as follows:

TABLE-US-00068 Solid dispersion prepared 13.63 g from Example 13a (equal to 2.0 g of Vortioxetine) Xylitol    50 g Carboxymethylcellulose sodium   0.5 g Sodium acetate   0.5 g

[0553] Purified water was added to 50 ml,

Preparation Process:

[0554] (1) The prescription amount of solid dispersion prepared from Example 13a, xylitol, carboxymethylcellulose sodium and sodium acetate were added to 400 ml of purified water. The mixture was homogenized at 12,000 rpm for 2 minutes, and continued to stir for later use;
(2) After the suspension obtained in the above step was passed through a 100 mesh stainless steel sieve, the pH value was adjusted to 8.0-8.5 with 1N HCl or 1N NaOH solution, and the purified water was added to the prescription amount and stirred for use;
(3) The suspension was divided into a vial of 5 ml per bottle, stoppered and capped it.

[0555] Detailed information is listed in Table 53:

TABLE-US-00069 TABLE 53 Taste test of oral suspension of vortioxetine hemihydrobromide solid dispersion Instantaneous Delayed Subject irritation irritation (min) Bitterness Grittiness Subject 1 + 1-15 acceptable No Subject 2 + 1-15 acceptable No Subject 3 + 1-15 acceptable No Subject 4 + 1-15 acceptable No Subject 5 + 1-15 acceptable No Subject 6 + 1-15 acceptable No Subject 7 + 1-15 acceptable No Subject 8 + 1-15 acceptable No Subject 9 + 1-15 acceptable No Subject 10 + 1-15 acceptable No

Comparative Example 1: Comparison of Taste of Different Salts

[0556] The vortioxetine lactate salt, vortioxetine hydrobromide and vortioxetine hemihydrobromide equivalent to 5 mg of vortioxetine respectively over 100 mesh powders were put directly in front of the upper part of the tongue for one minute. There were 10 subjects in each salt-type group, and each subject randomly tried each salt-type 3 times. After trying one salt-type taste, rinsed your mouth, and try another salt-type after there was no irritation. After trying the taste, record the bitterness level and tongue irritation, spit it out a few seconds later, rinse your mouth, record the time for the irritation to subside, eat 1-1.5 hours later, and record the irritation again. The following table 54 showed the comparison of the salt-type taste of different vortioxetine in 30 attempts by 10 subjects.

TABLE-US-00070 TABLE 54 Comparison of taste of different vortioxetine salt type by 10 subjects for 30 attempts (unit: times) Number of subjects who felt different Number of subjects experiencing different levels of bitterness irritation Extremely Slightly Not Slightly irritating, Basically no Salt type bitter bitter bitter unbearable tolerable irritation lactate salt 29 1 0 27.sup.(1) 3.sup.(2) 0 Monosalt 28 2 0 28.sup.(1) 2.sup.(2) 0 hydrobromate hemihydrobromide 12 18 0 12.sup.(1) 17.sup.(2)  1 Note: .sup.(1)Because the irritation was so strong that it was almost unbearable, and it couldn't subside even after mouthwashes for many times. The subside time was more than 1 hour, and the irritation could not be subsided after eating. .sup.(2)There was no irritation after gargling.

Comparative Example 2: Comparison of Taste of Solid Dispersions in this Invention and Commercially Available Drug Product

[0557] The solid dispersion equivalent to 10 mg vortioxetine prepared in Example 9b, vortioxetine hemihydrobromide powder equivalent to 10 mg vortioxetine, and the powder compressed by vortioxetine hydrobromide marketed drug product equivalent to 10 mg of vortioxetine hydrobromide passed through 100 mesh sieve, then they were put directly in front of the upper part of the tongue for one minute. There were 20 subjects in each powder group. After trying one powder taste, rinsed your mouth, and try another powder after there was no irritation. After trying the taste, record the bitterness level and tongue irritation, spit it out a few seconds later, rinse your mouth, record the time for the irritation to subside, eat 1-1.5 hours later, and record the irritation again. The following table 55 showed the comparison of taste of the different vortioxetine powder by 20 subjects.

TABLE-US-00071 TABLE 55 Comparison of taste of different vortioxetine powder by 20 subjects Number of subjects who felt different Number of subjects experiencing levels of bitterness different irritation Extremely Slightly Not Slightly irritating, Basically no Powder bitter bitter bitter unbearable tolerable irritation Vortioxetine hemihydrobromide 9 11 0 2.sup.(1) 12.sup.(2)  6 powder Solid dispersion prepared from 2 18 0 1.sup.(1) 6.sup.(2) 13 Example 9b Pressed powder from marketed 20 0 0 20.sup.(1)  0.sup.  0 drug product Note: .sup.(1)Because the irritation was so strong that it was almost unbearable, and it couldn't subside even after mouthwashes for many times. The subside time was more than 2 hours, and the irritation could not be subsided after eating. .sup.(2)There was no irritation after gargling.