CN112006995A - Preparation method of hydrobromic acid vortioxetine tablet - Google Patents
Preparation method of hydrobromic acid vortioxetine tablet Download PDFInfo
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- CN112006995A CN112006995A CN202010817084.3A CN202010817084A CN112006995A CN 112006995 A CN112006995 A CN 112006995A CN 202010817084 A CN202010817084 A CN 202010817084A CN 112006995 A CN112006995 A CN 112006995A
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- tablet
- vortioxetine hydrobromide
- air inlet
- vortioxetine
- negative film
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Abstract
The invention provides a preparation method of a hydrobromic acid vortioxetine tablet. The hydrobromic acid vortioxetine tablet consists of a negative film and a coating. The invention controls the air inlet temperature of the fluidized bed to be 75-85 ℃ and the air inlet quantity to be 500m in the granulation process3/h‑700m3The density of the prepared granules is 0.3-0.4g/ml and the moisture content is 1.5% -3%, and compared with a negative film prepared by tabletting, the negative film prepared by tabletting has low defective rate and small difference of tablet weight, and simultaneously solves the problem of slow early dissolution of the negative film of the comparative example, thereby having good industrial application prospect.
Description
Technical Field
The invention belongs to the field of preparation methods, and particularly relates to a preparation method of a vortioxetine hydrobromide tablet.
Background
The valacitin hydrobromide tablet is a quick-release tablet, is developed by Danish Lingbei company, is used for treating adult depression, is approved by FDA for the first time to be marketed in 9 and 30 days in 2013, is approved by China in 11 and 21 days in 2017, has a trade name of Xindayue, and has specifications of 5mg and 10 mg.
The core (bottom) composition of the hydrobromic acid vortioxetine tablet is introduced in the FDA and the Chinese specification: mannitol, microcrystalline cellulose, hydroxypropyl cellulose, sodium starch glycolate and magnesium stearate, and the tablets are prepared by adopting a fluidized bed granulation process.
The patent of CN201080037699.9, entitled enteric coated tablet, describes a tablet core of the same formulation as the original one and also adopts a fluidized bed granulation process in example 5. The applicant adopts the process method in the patent, the obtained tablet is easy to have the problems of cracking, unfilled corners and the like, and the defective rate is high; the tablets with good appearance are selected for further dissolution experiments, and the dissolution rate is only about 20% at a sampling point of 5min, and the tablets are slowly dissolved.
Disclosure of Invention
The invention aims to provide a preparation method of a hydrobromic acid vortioxetine tablet, which aims to improve the yield of negative films and improve the early dissolution speed of the tablet.
The invention provides a preparation method of vortioxetine hydrobromide tablets, which consists of a negative film and a coating, wherein the negative film is prepared by the following steps:
a. weighing the added raw and auxiliary materials, namely vortioxetine hydrobromide, mannitol and microcrystalline cellulose;
b. preparing a 6W/W% hydroxypropyl cellulose aqueous solution;
c. b, adding the raw materials in the step a into a fluidized bed, setting air inlet temperature and air inlet amount, spraying the solution in the step b into the fluidized bed through a peristaltic pump, controlling liquid spraying speed, and spraying the liquid until the spraying is finished to obtain particles;
d. c, sieving the granules obtained in the step c by using a screen mesh for straightening granules, adding an additional auxiliary material of microcrystalline cellulose and carboxymethyl starch sodium, uniformly mixing, adding an additional auxiliary material of magnesium stearate, and uniformly mixing;
e. tabletting the granules obtained in the step d;
the negative film prescription of the vortioxetine hydrobromide tablet comprises the following components in percentage by weight:
it is characterized in that the air inlet temperature in the step c is 75-85 ℃, and the air inlet volume is 500m3/h～700m3H is used as the reference value. Furthermore, the air inlet temperature in the step c is preferably 80-85 ℃, and the air inlet volume is preferably 600m3/h～700m3H is used as the reference value. Furthermore, the air inlet temperature in the step c is preferably 80-85 ℃, and the air inlet volume is preferably 600m3/h。
Further, the liquid spraying speed in the step c is 100-.
Furthermore, the moisture content of the particles obtained in the step c is 1.5-3%.
Further, the bulk density of the granules obtained in step c is 0.3-0.4 g/ml.
Through a great deal of research, we find that the inlet air temperature of the fluidized bed is controlled to be 75-85 ℃ and the inlet air volume is controlled to be 500m in the granulation process3/h-700m3The density of the prepared granules is 0.3-0.4g/ml and the water content is 1.5% -3%, the defective rate of the finally tabletted negative films is low, the difference of the tablet weights is small, the early dissolution speed can be improved, and the industrial application prospect is good.
Detailed Description
The following examples are provided to illustrate the preparation of the vortioxetine hydrobromide tablet according to the present invention, but the present invention is not limited to the following examples. Any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are exemplary only.
The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
The dissolution method comprises the following steps:
ph6.8 phosphate buffer: 6.805g of monopotassium phosphate and 0.944g of sodium hydroxide are taken, dissolved and diluted to 1000ml by water and shaken up to obtain the compound.
The dissolution method comprises the following steps: according to the second method of 0931, paddle method, 50rpm, 900ml of phosphate buffer solution with pH6.8 in Chinese pharmacopoeia 2015 edition. Sampling time points are as follows: 5. 10, 15, 20, 30, 45, 60 and 90 min.
The dissolution detection method comprises the following steps: performing high performance liquid chromatography (China pharmacopoeia 2015 year version 0512)
A chromatographic column: phenyl silane bonded silica gel as filler
Mobile phase: pH4.5 ammonium acetate buffer solution, water methanol (10:30:60)
Detection wavelength: 226nm
Column temperature: 40 deg.C
Flow rate: 1.0ml/min
Sample introduction volume: 10 μ l
Tablet formulation (20 ten thousand tablets):
TABLE 1 prescription information
Injecting: standard 5mg (in Volvisu Siting)
Comparative example 1:
using the preparation method of example 5 bottom tablet (core tablet) in patent CN201080037699.9 and the recipe in table 1, 20 ten thousand tablets were prepared:
(1) weighing the added raw auxiliary materials of hydrobromic acid vortioxetine (1.271kg), mannitol (22.140kg), microcrystalline cellulose (3kg) and the added auxiliary material of carboxymethyl starch sodium (0.900 kg).
(2) Preparing a 6W/W% hydroxypropyl cellulose aqueous solution.
(3) Adding the raw and auxiliary materials in the step (1) into a fluidized bed, setting the air inlet temperature at 60 ℃ and the air volume at 500m3And/h, the outlet air temperature is 26 ℃, the atomization pressure is 3bar, the solution in the step (2) is sprayed into the fluidized bed through a peristaltic pump, the spraying speed is controlled to be 500-.
(4) Sieving the granules obtained in step (3) with 1.5mm sieve, grading, adding microcrystalline cellulose (1.500kg) as adjuvant, and mixing for 8min (7 r/min). Adding additional adjuvant magnesium stearate (0.300kg), and mixing for 3min (7 rpm).
(5) And (4) tabletting the mixture obtained in the step (4) by adopting a 7mm punch to obtain a bottom sheet.
Note: patent CN201080037699.9 example 5 premixes sodium starch glycolate (i.e. sodium carboxymethyl starch) with vortioxetine hydrobromide, mannitol, part of microcrystalline cellulose and granulates, so the present comparative example refers to this method to adjust the additional sodium carboxymethyl starch in the formulation to an internal addition.
Table 2 particles and negative film Properties
Injecting: the yield was (20 ten thousand pieces-residue) piece weight/total charge 100%
TABLE 3 dissolution Profile of film in pH6.8 Medium
The sample obtained by the preparation process of the bottom sheet in the patent application CN201080037699.9 has a large number of tablets with unqualified appearances, 4.96 pieces of residual tablets exist in 20 ten thousand tablets, and the yield is only 75.2%. Meanwhile, the difference of the tablet weight of the obtained negative film is more than 3 percent, and the risk that the tablet weight does not meet the requirements of pharmacopoeia exists in large-scale production. And the dissolution rate of the base sheet obtained by the preparation method of the patent is only 21.5% at 5min, and the dissolution rate is slow. Further optimization of the manufacturing process is necessary to improve the yield and the early dissolution rate.
Example 1: influence of intake air temperature
By adopting the formula in the table 1, when other parameters in the process are the same, the influence of different inlet air temperatures is examined, and the specific preparation process is as follows:
(1) weighing the added raw and auxiliary materials of vortioxetine hydrobromide, mannitol and microcrystalline cellulose.
(2) Preparing a 6W/W% hydroxypropyl cellulose aqueous solution.
(3) Adding the raw and auxiliary materials added in the step (1) into the fluidized bed, setting the air inlet temperature as shown in table 4, and setting the air volume to be 500m3And h, atomizing at 3bar, spraying the solution in the step (2) into the fluidized bed through a peristaltic pump, controlling the spraying speed at 100-.
(4) Sieving the granules obtained in step (3) with a 1.5mm sieve for granulating, adding additional adjuvants including microcrystalline cellulose and carboxymethyl starch sodium, and mixing for 8min (7 r/min). Adding additional adjuvant magnesium stearate, and mixing for 3min (7 rpm).
(5) And (4) tabletting the granules obtained in the step (4) by adopting a 7mm punch.
Table 4 particles and negative film Properties
TABLE 5 dissolution Profile of film in pH6.8 Medium
The results in tables 4 and 5 show that when the inlet air temperature is 90 ℃, the obtained granules have low moisture content and bulk density, and the tablets are pressed into tablets with a small amount of cracks, so that the tablet yield is only 82.9%; taking the tablets with qualified appearance to perform dissolution test, wherein the dissolution rate is lower than 40% in 5 min.
When the air inlet temperature is within the range of 75-85 ℃, the bulk density of the prepared particles can be controlled to be 0.3-0.4g/ml, the moisture content is 1.5-3%, the particles are used for pressing a bottom sheet, the cracking phenomenon does not occur, and the yield is improved to more than 95%; and the difference in tablet weight is significantly smaller than that of the comparative example. As can be seen from Table 5, the dissolution rate of the backsheet at 5min is more than 40%, so that the problem of slow early dissolution of the backsheet obtained by the comparative example is solved.
Example 2: influence of air volume
The formula in table 1 is adopted to examine the influence of different air volumes, and the specific preparation process is as follows:
(1) weighing the added raw and auxiliary materials of vortioxetine hydrobromide, mannitol and microcrystalline cellulose.
(2) Preparing a 6W/W% hydroxypropyl cellulose aqueous solution.
(3) And (2) adding the raw and auxiliary materials in the step (1) into the fluidized bed, setting the air inlet temperature to be 85 ℃, setting the air volume to be shown in table 6, spraying the solution in the step (2) into the fluidized bed through a peristaltic pump, controlling the spraying speed to be 100 plus materials for 300g/min, stopping the machine after the spraying is finished, and sampling to measure the moisture of the particles.
(4) Sieving the granules obtained in step (3) with a 1.5mm sieve for granulating, adding adjuvants including microcrystalline cellulose and carboxymethyl starch sodium, and mixing for 8min (7 r/min). Adding additional adjuvant magnesium stearate, and mixing for 3min (7 rpm).
(5) And (4) tabletting the granules obtained in the step (4) by adopting a 7mm punch.
Table 6 particles and negative film Properties
TABLE 7 dissolution Profile of film in pH6.8 Medium
Selection of lower limit of intake sampling point: according to the fluidization state of the materials, the air quantity is 500m3The volume of the air is already the lower limit, and the air quantity is not less than 500m to ensure the fluidized state of the materials3Investigation of/h.
The results in Table 7 show that when the inlet air temperature is 85 ℃, the air volume is 500-700 m3When the density is 0.3-0.4g/cm3The water content is 1.5-3%, the rate of finished products of the negative films made of the particles can reach more than 95%, and the phenomenon of cracking does not occur. And the air volume is 800m3Bulk density at/h (0.28 g/cm)3) And the moisture (1.2%) is reduced, the manufactured film has splinters, and the yield is only 81.3%.
According to two embodiments, when the inlet air temperature is 75-85 ℃, the air volume is 500-700 m3Within the range of/h, the defective rate of the negative films is low, the weight difference is small, and the problem that the negative films in the comparative example are slowly dissolved out in 5min is solved.
Claims (6)
1. A preparation method of vortioxetine hydrobromide tablets comprises the following steps of:
a. weighing the added raw and auxiliary materials, namely vortioxetine hydrobromide, mannitol and microcrystalline cellulose;
b. preparing a 6W/W% hydroxypropyl cellulose aqueous solution;
c. b, adding the raw and auxiliary materials added in the step a into a fluidized bed, setting air inlet temperature and air inlet amount, spraying the solution in the step b into the fluidized bed through a peristaltic pump, and controlling the liquid spraying speed until the liquid spraying is finished;
d. c, sieving the granules obtained in the step c by using a screen mesh for straightening granules, adding an additional auxiliary material of microcrystalline cellulose and carboxymethyl starch sodium, uniformly mixing, adding an additional auxiliary material of magnesium stearate, and uniformly mixing;
e. tabletting the mixture obtained in the step d;
the negative film prescription of the vortioxetine hydrobromide tablet comprises the following components in percentage by weight:
it is characterized in that the air inlet temperature in the step c is 75-85 ℃, and the air inlet volume is 500m3/h～700m3/h。
2. The vortioxetine hydrobromide tablet of claim 1, wherein the inlet air temperature in step c is 80 ℃ to 85 ℃ and the inlet air volume is 600m3/h～700m3/h。
3. The vortioxetine hydrobromide tablet of claim 2, wherein the inlet air temperature in step c is 80 ℃ to 85 ℃ and the inlet air volume is 600m3/h。
4. The vortioxetine hydrobromide tablet of claim 1, wherein the spray rate in step c is 100-.
5. The vortioxetine hydrobromide tablet of claim 1, wherein the moisture content of the particles obtained in step c is 1.5-3%.
6. The vortioxetine hydrobromide tablet of claim 1, wherein the bulk density of the particles obtained in step c is 0.3-0.4 g/ml.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010817084.3A CN112006995A (en) | 2020-08-14 | 2020-08-14 | Preparation method of hydrobromic acid vortioxetine tablet |
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| CN202010817084.3A CN112006995A (en) | 2020-08-14 | 2020-08-14 | Preparation method of hydrobromic acid vortioxetine tablet |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114965720A (en) * | 2021-02-20 | 2022-08-30 | 成都康弘药业集团股份有限公司 | Method for determining related substances of vortioxetine hydrobromide |
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| CN102639117A (en) * | 2009-08-24 | 2012-08-15 | H.隆德贝克有限公司 | New compositions of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine |
| CN102970982A (en) * | 2010-04-30 | 2013-03-13 | 武田药品工业株式会社 | Enteric tablet |
| CN104736526A (en) * | 2013-09-12 | 2015-06-24 | 杭州普晒医药科技有限公司 | Vortioxetine salt and crystal thereof, their preparation method, pharmaceutical compositions and usage |
| CN104797566A (en) * | 2012-09-19 | 2015-07-22 | 桑多斯股份公司 | Novel crystalline form of vortioxetine hydrobromide |
| CN110787144A (en) * | 2018-08-03 | 2020-02-14 | 南京济群医药科技股份有限公司 | Film coated tablet containing hydrobromic acid vortioxetine and preparation method thereof |
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2020
- 2020-08-14 CN CN202010817084.3A patent/CN112006995A/en active Pending
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114965720A (en) * | 2021-02-20 | 2022-08-30 | 成都康弘药业集团股份有限公司 | Method for determining related substances of vortioxetine hydrobromide |
| CN114965720B (en) * | 2021-02-20 | 2024-02-23 | 成都康弘药业集团股份有限公司 | Method for determining related substances of hydrobromic acid voltammetric acid |
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