CN103961333B - Paroxetine mesylate capsule and preparation method thereof - Google Patents
Paroxetine mesylate capsule and preparation method thereof Download PDFInfo
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- CN103961333B CN103961333B CN201410196356.7A CN201410196356A CN103961333B CN 103961333 B CN103961333 B CN 103961333B CN 201410196356 A CN201410196356 A CN 201410196356A CN 103961333 B CN103961333 B CN 103961333B
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- paroxetine methanesulfonate
- capsule
- paroxetine
- phosphate dihydrate
- lubricant
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Abstract
The invention provides a paroxetine methanesulfonate capsule and a preparation method thereof. The paroxetine methanesulfonate capsule prepared by the method has stable and controllable quality and simple process.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a paroxetine methanesulfonate capsule and a preparation method thereof.
Background
The united states Food and Drug Administration (FDA) approved paroxetine (trade name brisdell) for treating moderate to severe hot flashes at 28.6.2013, which is commonly known as paroxetine methanesulfonate Capsule and english name brisdell (parexene) Capsule, which is the first non-hormonal drug for treating climacteric hot flashes.
Paroxetine methanesulfonate has the following structural formula:
the molecular formula is as follows: c19H20FNO3·CH3SO3H
Molecular weight: 425.5
According to the specifications of products on the market, the products are packaged by aluminum plastics and stored in a dry and dark place at the temperature of 20-25 ℃. Accelerated test examination of a commercial product shows that the sample has a color change problem, and after 6 months of acceleration, the total impurities are increased from 0.11% to 0.34%.
Poor stability and stringent storage conditions can increase the cost of storing and transporting the product and increase the risk of purchasing and taking an abnormal product by the patient. There is therefore a need to provide new, more stable paroxetine methanesulfonate capsules.
Disclosure of Invention
The invention provides a paroxetine methanesulfonate capsule with specification of 7.5mg (calculated according to paroxetine), which only consists of paroxetine methanesulfonate, calcium hydrogen phosphate dihydrate and a lubricant; the invention also provides a preparation method of the paroxetine methanesulfonate capsule, which adopts a wet granulation process commonly used in the field of pharmaceutical preparations to produce the paroxetine methanesulfonate capsule, and specifically comprises the following steps: a) mixing paroxetine methanesulfonate with dibasic calcium phosphate dihydrate; b) carrying out wet granulation by using purified water, and drying, wherein the moisture content of the dry granules is less than 4.0%; c) mixing the granules obtained in step (b) with lubricant, optionally adding calcium hydrogen phosphate dihydrate, and encapsulating.
The paroxetine methanesulfonate capsule prepared according to the invention has better quality stability than the commercial product.
The paroxetine methanesulfonate used in the present invention has the same crystal form as that described in CN 1127502C. The XRD characteristic peaks are as follows: 8.3, 10.5, 15.6, 16.3, 17.7, 18.2, 19.8, 20.4, 21.5, 22.0, 22.4, 23.8, 24.4, 25.0, 25.3, 25.8, 26.6, 30.0, 30.2, 31.6 ± 0.2 degrees theta.
The granularity D (0.9) of the paroxetine methanesulfonate used in the invention is less than or equal to 150 μm. It is measured using a laser particle size analyzer Malvern Mastersizer2000 and represents the particle diameter for which the cumulative percentage of volume reaches 90%.
According to the invention, the weight of the dibasic calcium phosphate dihydrate and the paroxetine methanesulfonate in the step a is 10: 1-30: 1, preferably 15: 1-25: 1
The inventors have found that the weight ratio of dibasic calcium phosphate dihydrate to paroxetine methanesulfonate in the wet granulation section is related to product stability, which is poor when the ratio is low and good when the weight ratio of dibasic calcium phosphate dihydrate to paroxetine methanesulfonate is greater than 10: 1. And the stability of the product when the granulating solution is water is greatly superior to that of a sample prepared by adding solution of macromolecular binders such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvidone and the like into the granulating solution. This is probably because the drug is easily dissolved in water, and during wet granulation, the drug is dissolved in the solution and dispersed on the surface of calcium hydrogen phosphate dihydrate, and after drying, the drug is embedded in the voids on the surface of calcium hydrogen phosphate dihydrate, and when granulation is performed using a solution having viscosity, the drug dispersion and embedding effect is deteriorated. The ratio of dibasic calcium phosphate dihydrate to drug also affects the efficacy of drug dispersion and intercalation. Tests prove that the degree of dispersion and embedding of the medicament in auxiliary materials directly influences the impurity stability of the product. When the proportion of the calcium hydrophosphate dihydrate is larger, more contents are contained, so that the capsule volume is increased, and the capsule volume is not beneficial to swallowing of a patient, therefore, the weight ratio of the calcium hydrophosphate dihydrate to the paroxetine methanesulfonate is more suitable to be 10-30, and the preferable range is 15-25.
The selection of the process also has certain influence on the stability of the product, and the stability of the wet granulation process is obviously superior to that of a direct mixing process or a dry process by adopting the same formula. This is different from the general formulation rule. The reason for this may be that the wet granulation process facilitates the dispersion and insertion of the drug into the voids on the surface of the dibasic calcium phosphate dihydrate, thereby increasing the stability of the drug.
In addition, the disintegrant is often necessary for the tablet production process, but not necessary for the capsule production process, and the inventors found that the addition of the disintegrant deteriorates the stability because the disintegrant absorbs water strongly, and the addition of the disintegrant increases moisture around the drug, which affects the stability of the drug.
In the drying process of the paroxetine methanesulfonate capsules, the moisture content was controlled to 4.0% or less, which was measured by an infrared moisture meter, and the background temperature was set at 105 ℃.
The lubricant can be selected from magnesium stearate, sodium stearyl fumarate, and micropowder silica gel, and has a lubricant content of 0.5-3%, preferably 1-2%.
The calcium hydrogen phosphate dihydrate can be partially added, and the inventor finds that when the filler commonly used for solid preparations such as microcrystalline cellulose and lactose is selected, the stability of the product is reduced, and particularly, when the lactose is selected as the filler, the impurities are increased remarkably. Therefore, the invention only adopts calcium hydrophosphate dihydrate as the filler.
The dissolution of the invention is measured by adopting a basket rotating method collected in Chinese pharmacopoeia, the rotating speed is 75rpm, the volume of a medium is 1000ml, the medium is hydrochloric acid solution with pH1.0, the dissolution of the product is more than 85 percent within 15 minutes.
Detailed Description
The present invention will be described in further detail with reference to examples, but the present invention is not limited to the examples.
Comparative examples 1 to 4
The process comprises the following steps:
the processes of comparative examples 1 to 3 were as follows:
1. mixing the medicine with adjuvants except magnesium stearate;
2. adding the mixed powder in the step 1 into magnesium stearate and then continuously mixing;
3. and (3) directly filling the mixed powder obtained in the step (2) into capsules.
Comparative example 4 the process is as follows:
1. mixing the medicine with calcium hydrogen phosphate dihydrate and half of magnesium stearate;
2. rolling the mixture and sieving;
3. adding magnesium stearate into the sieved substance in the step 2 and then continuously mixing;
4. and (4) directly filling the granules obtained in the step (3) into capsules.
Comparative examples 5 to 7
The process comprises the following steps:
1. respectively dissolving hydroxypropyl methylcellulose, hydroxypropyl cellulose and polyvidone in water, stirring, and making into granulating solution;
2. mixing paroxetine methanesulfonate and dicalcium phosphate dihydrate;
3. adding the granulation solution in the step 1 into the mixed powder in the step 2 for granulation, and drying until the moisture of the granules is less than 4.0%;
4. and (3) adding sodium carboxymethyl starch and magnesium stearate into the granules obtained in the step (3), mixing and filling into capsules.
Comparative examples 8 to 10
The process comprises the following steps:
1. mixing paroxetine methanesulfonate and dibasic calcium phosphate dihydrate;
2. adding purified water into the mixed powder in the step 1 for granulation, and drying, wherein the water content of the granules is less than 4.0%;
3. and (3) adding the mixed granules obtained in the step (2) into sodium carboxymethyl starch and magnesium stearate, mixing, and filling into capsules.
Examples 1 to 5
The process comprises the following steps:
1. mixing paroxetine methanesulfonate and dibasic calcium phosphate dihydrate;
2. adding purified water into the mixed powder in the step 1 for granulation, drying, wherein the water content of the granules is less than 4.0 percent,
3. adding the superfine silica gel powder, the magnesium stearate and the sodium stearyl fumarate into the mixed granules obtained in the step 2, mixing, and filling into capsules.
The capsules prepared in comparative examples 1 to 10 and examples 1 to 5 were packed in a polyvinyl chloride/polyvinylidene chloride/aluminum foil packing format, and the commercially available original capsules (trade name: BRISDELE) were put into an acceleration test chamber (temperature: 40 ℃ C., relative humidity: 75%) for examination, and the relevant substances were detected.
Comparing the accelerated data, it can be seen that the stability of the capsule prepared by the invention is superior to that of the original capsule sold in the market, which shows that the invention can better inhibit the rising of impurities and better ensure the stability of the product compared with the prior art.
Claims (5)
1. A paroxetine methanesulfonate capsule, its capsule content only comprises paroxetine methanesulfonate, dihydrate calcium hydrogen phosphate, lubricant; and is prepared by the following steps:
a. directly mixing paroxetine methanesulfonate and dibasic calcium phosphate dihydrate; the weight ratio of the calcium hydrogen phosphate dihydrate to the paroxetine methanesulfonate is 10: 1-30: 1;
b. adding purified water into the mixture obtained in the step a for granulation, and drying to obtain particles, wherein the drying weight loss of the particles is less than or equal to 4.0%;
c. mixing the granules of step b with lubricant, optionally adding calcium hydrogen phosphate dihydrate, and encapsulating.
2. A paroxetine methanesulfonate capsule according to claim 1, wherein in step "a", the weight ratio of dibasic calcium phosphate dihydrate to paroxetine methanesulfonate is from 15:1 to 25: 1.
3. The paroxetine methanesulfonate capsule of claim 1, wherein the lubricant is one or more of magnesium stearate, sodium stearyl fumarate, and aerosil.
4. A paroxetine methanesulfonate capsule according to claim 3, wherein the lubricant comprises from 0.5 to 3.0% by weight of the total capsule contents.
5. A paroxetine methanesulfonate capsule according to claim 1, containing a paroxetine methanesulfonate dose of 7.5mg of paroxetine.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410196356.7A CN103961333B (en) | 2014-05-07 | 2014-05-07 | Paroxetine mesylate capsule and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410196356.7A CN103961333B (en) | 2014-05-07 | 2014-05-07 | Paroxetine mesylate capsule and preparation method thereof |
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| Publication Number | Publication Date |
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| CN103961333A CN103961333A (en) | 2014-08-06 |
| CN103961333B true CN103961333B (en) | 2020-02-21 |
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| CN201410196356.7A Active CN103961333B (en) | 2014-05-07 | 2014-05-07 | Paroxetine mesylate capsule and preparation method thereof |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105963273A (en) * | 2016-05-02 | 2016-09-28 | 杭州富阳伟文环保科技有限公司 | Paroxetine mesylate capsules and preparation method thereof |
| CN110840855B (en) * | 2019-11-27 | 2022-04-12 | 哈尔滨珍宝制药有限公司 | Etoricoxib tablets and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1279608A (en) * | 1997-11-21 | 2001-01-10 | 史密丝克莱恩比彻姆有限公司 | Formulations comprising dissolved paroxetine |
| CN1294512A (en) * | 1998-03-24 | 2001-05-09 | 史密丝克莱恩比彻姆有限公司 | Paroxetine compsns. |
| CN1309557A (en) * | 1998-05-13 | 2001-08-22 | 史密丝克莱恩比彻姆有限公司 | Formulation contg. paroxetine |
| CN1315949A (en) * | 1998-07-02 | 2001-10-03 | 史密丝克莱恩比彻姆有限公司 | Salts of paroxetine |
| CN103520131A (en) * | 2013-10-12 | 2014-01-22 | 浙江华海药业股份有限公司 | Preparation method of paroxetine hydrochloride semihydrate capsule |
-
2014
- 2014-05-07 CN CN201410196356.7A patent/CN103961333B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1279608A (en) * | 1997-11-21 | 2001-01-10 | 史密丝克莱恩比彻姆有限公司 | Formulations comprising dissolved paroxetine |
| CN1294512A (en) * | 1998-03-24 | 2001-05-09 | 史密丝克莱恩比彻姆有限公司 | Paroxetine compsns. |
| CN1309557A (en) * | 1998-05-13 | 2001-08-22 | 史密丝克莱恩比彻姆有限公司 | Formulation contg. paroxetine |
| CN1315949A (en) * | 1998-07-02 | 2001-10-03 | 史密丝克莱恩比彻姆有限公司 | Salts of paroxetine |
| CN103520131A (en) * | 2013-10-12 | 2014-01-22 | 浙江华海药业股份有限公司 | Preparation method of paroxetine hydrochloride semihydrate capsule |
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| CN103961333A (en) | 2014-08-06 |
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