CN112999180A - Clopidogrel hydrogen sulfate crystal form II tablet and preparation method thereof - Google Patents
Clopidogrel hydrogen sulfate crystal form II tablet and preparation method thereof Download PDFInfo
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The invention relates to the technical field of medicines, and in particular relates to a clopidogrel hydrogen sulfate crystal form II tablet and a preparation method thereof. The tablet comprises the following components in parts by weight: 97.9 parts of clopidogrel hydrogen sulfate of crystal form II, 120.4-138.5 parts of filler, 2.5-10.0 parts of disintegrant, 1.2-4.9 parts of lubricant and 6.1-8.5 parts of coating powder. Crushing the clopidogrel bisulfate crystal form II, mixing the crushed clopidogrel bisulfate crystal form II with a filling agent, a disintegrating agent and a lubricating agent, tabletting the mixture by using a rotary tablet machine to prepare a plain tablet, and coating and drying the plain tablet to obtain the clopidogrel bisulfate crystal form II tablet. The invention adopts the direct powder tabletting process, not only solves the problem of excessive sticking and punching of tabletting, but also simplifies the production process, shortens the production time, improves the production efficiency, improves the product stability and reduces the production cost.
Description
Technical Field
The invention relates to the technical field of medicines, and in particular relates to a clopidogrel hydrogen sulfate crystal form II tablet and a preparation method thereof.
Background
Clopidogrel hydrogen sulfate is sulfate of clopidogrel, is an antiplatelet drug, and is mainly used for preventing atherosclerosis and thrombosis events, such as cerebral thrombosis, coronary heart disease and the like. Clopidogrel bisulfate was developed by the company senofenphena, france, and approved by the FDA in the united states for marketing on 17.11.1997 under the trade name Plavix (bolivit), specification 75 mg. The recommended dose is 75mg, once daily, orally administered with or without food.
The main crystal forms of clopidogrel hydrogen sulfate include a I crystal form and a II crystal form, wherein the crystal form II is a thermodynamically stable crystal form, and the crystal form I is a thermodynamically unstable crystal form. The two crystal forms have different preparation methods and are sensitive to heat and humidity. And the crystal form II is easy to have sticking phenomenon in the tabletting process. In the prior art, a dry granulation tabletting method is mostly adopted, and the exposure time of heat and moisture of raw material medicines is inevitably increased in the dry granulation process.
Chinese patent application No. CN20160225348.X discloses a pharmaceutical composition containing a spherical clopidogrel hydrogen sulfate I crystal form and a preparation method thereof, the spherical clopidogrel hydrogen sulfate I crystal form is prepared, and a powder direct compression process can be realized by using the spherical clopidogrel hydrogen sulfate I crystal form. The preparation process of the spherical crystallization raw material is multiple and complicated, and the commercial production is difficult.
Therefore, the realization of direct compression of clopidogrel bisulfate powder still remains an urgent problem in the prior art.
Disclosure of Invention
The invention aims to provide a clopidogrel hydrogen sulfate crystal form II tablet and a preparation method thereof.
In order to achieve the purpose, the invention adopts the technical scheme that:
a clopidogrel hydrogen sulfate crystal form II tablet comprises the following components in parts by weight: 97.9 parts of clopidogrel hydrogen sulfate of crystal form II, 120.4-138.5 parts of filler, 2.5-10.0 parts of disintegrant, 1.2-4.9 parts of lubricant and 6.1-8.5 parts of coating powder.
Further tablet components by weight: 97.9 parts of clopidogrel hydrogen sulfate of crystal form II, 138.5 parts of filling agent, 4.9 parts of disintegrating agent, 1.2 parts of lubricating agent and 7.3 parts of coating powder.
Further, each 1000 tablets of the tablet components comprise 97.9g of clopidogrel bisulfate of a crystal form II, 138.5g of a filling agent, 4.9g of a disintegrating agent, 1.2g of a lubricating agent and 7.3g of coating powder by weight.
The particle size of the clopidogrel bisulfate of the crystal form II is not less than 130 mu m and not more than 150 mu m of D90, and not less than 40 mu m and not more than 80 mu m of D50.
The preferred clopidogrel bisulfate crystal form II has the particle size of D90 which is more than or equal to 130 mu m and less than or equal to 140 mu m, and D50 which is more than or equal to 40 mu m and less than or equal to 60 mu m.
The filler is one or more of spray-dried lactose, anhydrous lactose, microcrystalline cellulose, mannitol or silicified microcrystalline cellulose;
the disintegrating agent is one or more of carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, croscarmellose sodium or crospovidone;
the lubricant is one or more of hydrogenated castor oil, sodium stearyl fumarate, glyceryl behenate or stearic acid;
the coating powder is gastric soluble film coating powder.
The filler is microcrystalline cellulose;
the disintegrant is carboxymethyl starch sodium;
the lubricant is hydrogenated castor oil.
The preparation method of the clopidogrel bisulfate crystal form II tablet comprises the steps of crushing clopidogrel bisulfate of the crystal form II, mixing the crushed clopidogrel bisulfate with a filling agent, a disintegrating agent and a lubricating agent, tabletting the mixture by using a rotary tablet press to prepare a plain tablet, and coating and drying the plain tablet to obtain the clopidogrel bisulfate crystal form II tablet.
The method specifically comprises the following steps:
(1) crushing the clopidogrel bisulfate in the crystal form II by using a hammer mill for later use;
(2) uniformly mixing the crushed clopidogrel bisulfate with a filling agent and a disintegrating agent;
(3) adding a lubricant into the mixture obtained in the step (2), and uniformly mixing for later use;
(4) tabletting the mixture obtained in the step (3) by using a rotary tablet machine, wherein the rotating speed of the tablet machine is 25-45rpm, and the main pressure is 12-15KN, so as to obtain plain tablets;
(5) and (4) coating the plain tablets prepared in the step (4), and drying the coated tablets to obtain clopidogrel hydrogen sulfate crystal form II tablets.
Coating the plain tablets prepared in the step (4) by using a high-efficiency coating machine, stopping spraying the coating solution when the coating weight is increased by more than or equal to 3%, and taking out tablets after the coated tablets are dried to obtain clopidogrel hydrogen sulfate crystal form II tablets;
weighing 7.3g of coating powder which is 1.5 times of the weight of the coating powder, adding the coating powder into 82.3g of purified water, stirring, and stirring for 45-60 minutes to obtain the coating solution.
Compared with the prior art, the invention has the advantages that:
1. the particle size of the raw material medicine has influence on the preparation process, the dissolution rate and the like, and the ideal fluidity and solubility can be achieved by selecting the proper particle size of the raw material medicine. According to the invention, through controlling the particle size of the clopidogrel bisulfate in the crystal form II, when the particle size is 130 microns or more and D90 or more and 150 microns or less and D50 or more and 80 microns or less, the requirements of a direct tabletting process can be met, the flowability and compressibility of a total mixed material are good, the dissolution is good, the increase of the specific surface area caused by excessively fine particle size of a raw material medicine is avoided, the degree of exposure to heat and humidity is reduced, the sticking problem is solved, and the stability of the tablet is increased. When the particle size of the raw material is smaller than the particle size, the flowability and compressibility of the total mixed material are poor, and when the particle size of the raw material is larger than the particle size, the dissolution of the tablet is not satisfactory.
2. The invention adopts the direct powder tabletting process, not only solves the sticking problem in the tabletting process, but also simplifies the production process, shortens the production time, improves the production efficiency, improves the product stability and reduces the production cost.
3. The formula of the invention has fewer types of auxiliary materials, only four auxiliary materials of the filling agent, the disintegrating agent, the lubricating agent and the coating powder are used, and the preparation time during production can be saved, wherein the filling agent has influence on the fluidity and the compressibility of the mixture, and the filling agent has better fluidity and compressibility and is also beneficial to the realization of the powder direct compression process. The type and amount of filler is also selected to obtain a desired dissolution rate. The invention selects microcrystalline cellulose as filler, and the dissolution rate of the tablet meets the requirement. The microcrystalline cellulose acts as a filler and a binder, so that the corresponding effect can be achieved under the condition of not using the binder. The results of the investigation on the dissolution rate of different disintegrating agent dosage show that: when the dosage of the clopidogrel bisulfate in the crystal form II is 97.9g, the dosage of the disintegrating agent is 2.5-10.0 g, the dissolution curve of the medicine is ideal, and the stable quality of the product can be ensured.
Drawings
FIG. 1 is a graph of in vitro dissolution profiles of examples 1-3 of the present invention, comparative examples 1-2, and a reference formulation.
Detailed Description
The present invention will be further described with reference to the following examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
The clopidogrel bisulfate crystal form II tablets of all the embodiments are trial-manufactured, and the obtained products meet the relevant national regulations through the researches such as dissolution rate investigation, content determination, relevant substance inspection and the like.
Example 1
The clopidogrel hydrogen sulfate crystal form II tablet comprises the following components (1000 tablets in batch):
97.9g of crystal II clopidogrel hydrogen sulfate, 138.5g of microcrystalline cellulose, 4.9g of carboxymethyl starch sodium, 1.2g of hydrogenated castor oil and 7.3g of gastric-soluble film coating powder.
The preparation method comprises the following steps:
(1) and (3) crushing the clopidogrel bisulfate raw material of the crystal form II by a hammer mill into D90 which is more than or equal to 130 microns and less than or equal to 140 microns, and D50 which is more than or equal to 40 microns and less than or equal to 60 microns for later use.
(2) 97.9g of ground clopidogrel bisulfate, 138.5g of microcrystalline cellulose and 4.9g of carboxymethyl starch sodium are uniformly mixed.
(3) Adding 1.2g of hydrogenated castor oil into the mixture obtained in the step (2), and uniformly mixing for later use.
(4) And (4) preparing the mixture obtained in the step (3) into plain tablets with smooth surfaces by using a rotary tablet press, wherein the rotating speed of the tablet press is 35rpm, and the main pressure is 13.5 KN.
(5) And (4) coating the plain tablets prepared in the step (4) by using a high-efficiency coating machine, stopping spraying the coating liquid when the weight of the coated tablets is increased by more than or equal to 3%, and taking the tablets out after the coated tablets are dried to obtain the clopidogrel hydrogen sulfate crystal form II tablets.
The coating solution is prepared by weighing coating powder 7.3g of which is 1.5 times of the coating solution, adding the coating powder into 82.3g of purified water, stirring for 45-60 minutes to obtain a coating solution with a solid content of 12% (w/w).
Example 2
The clopidogrel hydrogen sulfate crystal form II tablet comprises the following components (1000 tablets in batch):
97.9g of crystal form II clopidogrel hydrogen sulfate, 80.0g of mannitol, 55.4g of microcrystalline cellulose, 8.0g of crospovidone, 1.2g of hydrogenated castor oil and 7.3g of gastric-soluble film coating powder.
The preparation method comprises the following steps:
(1) and (3) crushing the clopidogrel bisulfate raw material of the crystal form II by a hammer mill into D90 which is more than or equal to 130 microns and less than or equal to 140 microns, and D50 which is more than or equal to 40 microns and less than or equal to 60 microns for later use.
(2) 97.9g of pulverized clopidogrel bisulfate, 80.0g of mannitol, 55.4g of microcrystalline cellulose and 8.0g of crospovidone.
(3) Adding 1.2g of hydrogenated castor oil into the mixture obtained in the step (2), and uniformly mixing for later use.
(4) And (4) preparing the mixture obtained in the step (3) into plain tablets with smooth surfaces by using a rotary tablet press, wherein the rotating speed of the tablet press is 35rpm, and the main pressure is 13.5 KN.
(5) And (4) coating the plain tablets prepared in the step (4) by using a high-efficiency coating machine, stopping spraying the coating liquid when the weight of the coated tablets is increased by more than or equal to 3%, and taking the tablets out after the coated tablets are dried to obtain the clopidogrel hydrogen sulfate crystal form II tablets.
The coating solution is prepared by weighing coating powder 7.3g of which is 1.5 times of the coating solution, adding the coating powder into 82.3g of purified water, stirring for 45-60 minutes to obtain a coating solution with a solid content of 12% (w/w).
Example 3
The clopidogrel hydrogen sulfate crystal form II tablet comprises the following components (1000 tablets in batch):
97.9g of crystal form II clopidogrel hydrogen sulfate, 88.9g of spray-dried lactose, 47.8g of microcrystalline cellulose, 6.7g of croscarmellose sodium, 1.2g of hydrogenated castor oil and 7.3g of gastric-soluble film coating powder.
The preparation method comprises the following steps:
(1) the crystal form II clopidogrel bisulfate raw material is crushed into D90 which is more than or equal to 130 mu m and less than or equal to 140 mu m and D50 which is more than or equal to 40 mu m and less than or equal to 60 mu m by a hammer mill for later use.
(2) 97.9g of ground clopidogrel bisulfate, 88.9g of spray-dried lactose, 47.8g of microcrystalline cellulose and 6.7g of croscarmellose sodium are mixed uniformly.
(3) Adding 1.2g of hydrogenated castor oil into the mixture obtained in the step (2), and uniformly mixing for later use.
(4) And (4) preparing the mixture obtained in the step (3) into plain tablets with smooth surfaces by using a rotary tablet press, wherein the rotating speed of the tablet press is 35rpm, and the main pressure is 13.5 KN.
(5) And (4) coating the plain tablets prepared in the step (4) by using a high-efficiency coating machine, stopping spraying the coating liquid when the weight of the coated tablets is increased by more than or equal to 3%, and taking the tablets out after the coated tablets are dried to obtain the clopidogrel hydrogen sulfate crystal form II tablets.
The coating solution is prepared by weighing coating powder 7.3g of which is 1.5 times of the coating solution, adding the coating powder into 82.3g of purified water, stirring for 45-60 minutes to obtain a coating solution with a solid content of 12% (w/w).
Comparative example 1
The clopidogrel hydrogen sulfate crystal form II tablet comprises the following components (1000 tablets in batch):
97.9g of crystal form II clopidogrel hydrogen sulfate raw material medicine, 126.4g of microcrystalline cellulose, 12.1g of hydroxypropyl methylcellulose E5 (adhesive), 4.9g of carboxymethyl starch sodium, 1.2g of hydrogenated castor oil and 7.3g of gastric-soluble film coating powder.
(1) And (3) crushing the clopidogrel bisulfate raw material of the crystal form II by a hammer mill into D90 which is more than or equal to 130 microns and less than or equal to 140 microns, and D50 which is more than or equal to 40 microns and less than or equal to 60 microns for later use.
(2) 97.9g of ground clopidogrel hydrogen sulfate, 126.4g of microcrystalline cellulose, 12.1g of hydroxypropyl methylcellulose E5 and 4.9g of carboxymethyl starch sodium are uniformly mixed.
(3) Adding 1.2g of hydrogenated castor oil into the mixture obtained in the step (2), and uniformly mixing for later use.
(4) And (4) preparing the mixture obtained in the step (3) into plain tablets with smooth surfaces by using a rotary tablet press, wherein the rotating speed of the tablet press is 35rpm, and the main pressure is 13.5 KN.
(5) And (4) coating the plain tablets prepared in the step (4) by using a high-efficiency coating machine, stopping spraying the coating liquid when the weight of the coated tablets is increased by more than or equal to 3%, and taking the tablets out after the coated tablets are dried to obtain the clopidogrel hydrogen sulfate crystal form II tablets.
The coating solution is prepared by weighing coating powder 7.3g of which is 1.5 times of the coating solution, adding the coating powder into 82.3g of purified water, stirring for 45-60 minutes to obtain a coating solution with a solid content of 12% (w/w).
Comparative example 2
The clopidogrel hydrogen sulfate crystal form II tablet comprises the following components (1000 tablets in batch):
97.9g of crystal II clopidogrel hydrogen sulfate, 138.5g of microcrystalline cellulose, 4.9g of carboxymethyl starch sodium, 1.2g of hydrogenated castor oil and 7.3g of gastric-soluble film coating powder.
(1) And (3) crushing the clopidogrel bisulfate raw material of the crystal form II by using a hammer mill to obtain D90 of more than or equal to 160 microns and less than or equal to 180 microns for later use.
(2) 97.9g of ground clopidogrel bisulfate, 138.5g of microcrystalline cellulose and 4.9g of carboxymethyl starch sodium are uniformly mixed.
(3) Adding 1.2g of hydrogenated castor oil into the mixture obtained in the step (2), and uniformly mixing for later use.
(4) And (4) preparing the mixture obtained in the step (3) into plain tablets with smooth surfaces by using a rotary tablet press, wherein the rotating speed of the tablet press is 35rpm, and the main pressure is 13.5 KN.
(5) And (4) coating the plain tablets prepared in the step (4) by using a high-efficiency coating machine, stopping spraying the coating liquid when the weight of the coated tablets is increased by more than or equal to 3%, and taking the tablets out after the coated tablets are dried to obtain the clopidogrel hydrogen sulfate crystal form II tablets.
The coating solution is prepared by weighing coating powder 7.3g of which is 1.5 times of the coating solution, adding the coating powder into 82.3g of purified water, stirring for 45-60 minutes to obtain a coating solution with a solid content of 12% (w/w).
Comparative example 3
The clopidogrel hydrogen sulfate crystal form II tablet comprises the following components (1000 tablets in batch):
97.9g of crystal II clopidogrel hydrogen sulfate, 138.5g of microcrystalline cellulose, 4.9g of carboxymethyl starch sodium, 1.2g of hydrogenated castor oil and 7.3g of gastric-soluble film coating powder.
(1) And (3) crushing the clopidogrel bisulfate raw material of the crystal form II by a hammer mill into D90 which is more than or equal to 130 microns and less than or equal to 140 microns, and D50 which is more than or equal to 40 microns and less than or equal to 60 microns for later use.
(2) 97.9g of ground clopidogrel bisulfate, 138.5g of microcrystalline cellulose and 4.9g of carboxymethyl starch sodium are uniformly mixed.
(3) Granulating the mixture obtained in the step (2) by using a dry granulating machine, wherein the granulating feeding speed is 10-15rpm, the extrusion pressure is 12-15kg, the extrusion speed is 10-15rpm, a 24-mesh screen is selected, re-granulating fine powder smaller than 80 meshes by screening, collecting particles of 24-80 meshes and particles smaller than 80 meshes, uniformly mixing, adding hydrogenated castor oil, and uniformly mixing.
(4) And (4) preparing the total mixed particles in the step (3) into plain tablets with smooth surfaces by using a rotary tablet press, wherein the rotating speed of the tablet press is 35rpm, and the main pressure is 13.5 KN.
(5) And (4) coating the plain tablets prepared in the step (4) by using a high-efficiency coating machine, stopping spraying the coating liquid when the weight of the coated tablets is increased by more than or equal to 3%, and taking the tablets out after the coated tablets are dried to obtain the clopidogrel hydrogen sulfate crystal form II tablets.
The coating solution is prepared by weighing coating powder 7.3g of which is 1.5 times of the coating solution, adding the coating powder into 82.3g of purified water, stirring for 45-60 minutes to obtain a coating solution with a solid content of 12% (w/w).
Application example
Determination of dissolution
The method comprises the following steps:
taking the product, according to a dissolution release rate determination method (a second method of 0931), taking 1000ml of a hydrochloric acid buffer solution (taking 250ml of 0.2mol/L potassium chloride solution, adding 65.0ml of 0.2mol/L hydrochloric acid solution, adding water for dilution to 1000ml) with pH2.0 as a dissolution medium, operating according to a method at a rotating speed of 50 revolutions per minute, taking the solution after 30 minutes, filtering, taking a proper amount of a subsequent filtrate precisely, diluting with the dissolution medium quantitatively to prepare a solution containing about 25 mu g of clopidogrel per 1ml, taking a clopidogrel hydrogen sulfate reference substance precisely, weighing, adding 20ml of methanol for dissolution, and diluting with the dissolution medium to prepare a solution containing about 25 mu g of clopidogrel per 1 ml. The two solutions were taken and subjected to ultraviolet-visible spectrophotometry (general rule 0401), and the absorbance was measured at a wavelength of 240nm, respectively, to calculate the amount of elution of each tablet. The limit is 80% of the indicated amount and should be met.
The dissolution rates were determined as described above for the reference formulation tablet (Xenoffy, batch No. 5A305) and the tablets prepared in examples 1-3 and comparative examples 1-2. The results are shown in tables 1 and 2.
Table 1 dissolution test results of examples and comparative examples, reference formulation
TABLE 2 test results of dissolution curves of examples and comparative examples, and reference formulation
As is clear from the results in tables 1 and 2, the dissolution rates of the drug of the present invention at 30 minutes were all in accordance with the regulations.
The results of the dissolution similarity factor f2 fitting of examples 1-3 and the reference preparation at four time points of 5 min, 10 min, 15 min and 30min are all greater than 50, which indicates that the dissolution of examples 1-3 and the reference preparation is consistent in the hydrochloric acid buffer solution with the pH value of 2.0.
Stability determination
The method comprises the following steps:
accelerated stability studies were performed on the sample and reference formulations of examples 1-3 and comparative examples 1-3. The conditions (40 + -2 deg.C, RH75 + -5%) were examined, and samples were taken at 0, 1, 3, and 6 months, and the results of the measurements of the content, the related substances, and the dissolution rate are shown in Table 3.
TABLE 3 accelerated stability test results for the sample and reference formulations of examples 1-3 and comparative examples 1-3
As can be seen from Table 3, (1) the accelerated stability at 6 months in examples 1 to 3 is significantly better than that in comparative examples 1 to 3 and the reference formulation, and the dissolution curve similarity factor f2>50 in the medium in examples 1 to 3 and the reference formulation indicates that the dissolution is consistent with that in the reference formulation.
(2) Compared with the example 1, the binder hypromellose E5 is added in the comparative example 1, the dosage of each auxiliary material is determined after the dosage of the prescription is screened, and the result shows that although the fluidity and the compressibility meet the requirements, the dissolution is slower than that in the example 1, and the factor f2 is similar to that of the reference preparation in the dissolution curve in the medium and is less than 50, which indicates that the dissolution is inconsistent with the reference preparation.
(3) Comparative example 2 the particle size of the starting material was increased compared to example 1, resulting in a slower dissolution than example 1 and a similar factor f2<50 to the dissolution profile of the reference formulation in this medium, indicating that the dissolution is not consistent with the reference formulation.
(4) Comparative example 3 compared with example 1, the formula is the same, the process is different, the dry granulation process is adopted, but related substances in the medicine are obviously increased. The invention adopts the powder direct-pressing process to reduce the preparation process and the material exposure time as much as possible, reduces the increase of related substances caused by the preparation process, obviously reduces the level of the related substances in the preparation, and improves the stability of the preparation during the storage period.
The drug of the invention accelerates stability investigation for 6 months, and the content, related substances and dissolution rate all meet the requirements and are consistent with the stability of a reference preparation. The invention controls the particle size range of the crystal form II of the clopidogrel hydrogen sulfate raw material medicine, so that the liquidity of the raw material medicine can meet the requirements of the powder direct-pressing process; the powder direct compression technology is adopted, the granulation process is not needed, the time of exposing the bulk drugs to moisture and heat is reduced, the problem of excessive sticking of the tabletting is solved, the production process is simplified, the production time is shortened, the production efficiency is improved, and the production cost is reduced.
The present invention is not limited to the embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents and are included in the scope of the present invention.
Claims (10)
1. A clopidogrel hydrogen sulfate crystal form II tablet is characterized by comprising the following components in parts by weight: 97.9 parts of clopidogrel hydrogen sulfate of crystal form II, 120.4-138.5 parts of filler, 2.5-10.0 parts of disintegrant, 1.2-4.9 parts of lubricant and 6.1-8.5 parts of coating powder.
2. The crystalline form II clopidogrel bisulfate tablet of claim 1,
tablet components by weight: 97.9 parts of clopidogrel hydrogen sulfate of crystal form II, 138.5 parts of filling agent, 4.9 parts of disintegrating agent, 1.2 parts of lubricating agent and 7.3 parts of coating powder.
3. The crystalline form II clopidogrel bisulfate tablet of claim 2,
the tablet comprises, by weight, 97.9g of clopidogrel bisulfate in a crystal form II, 138.5g of a filling agent, 4.9g of a disintegrating agent, 1.2g of a lubricating agent and 7.3g of coating powder in every 1000 tablets.
4. The clopidogrel bisulfate crystal form II tablet according to claim 1, wherein the particle size of the clopidogrel bisulfate of the crystal form II is 130 μm or more and 150 μm or less of D90 or more, and 40 μm or more and 80 μm or less of D50 or more.
5. The clopidogrel bisulfate crystal form II tablet according to claim 4, wherein the particle size of clopidogrel bisulfate of the crystal form II is 130 μm or more and 140 μm or less from D90 and 40 μm or more and 60 μm or less from D50.
6. The clopidogrel bisulfate crystal form II tablet according to claim 1, wherein the filler is one or more of spray-dried lactose, anhydrous lactose, microcrystalline cellulose, mannitol or silicified microcrystalline cellulose;
the disintegrating agent is one or more of carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, croscarmellose sodium or crospovidone;
the lubricant is one or more of hydrogenated castor oil, sodium stearyl fumarate, glyceryl behenate or stearic acid;
the coating powder is gastric soluble film coating powder.
7. The clopidogrel bisulfate crystal form II tablet according to claim 6, wherein the filler is microcrystalline cellulose;
the disintegrant is carboxymethyl starch sodium;
the lubricant is hydrogenated castor oil.
8. A process for the preparation of clopidogrel hydrogen sulfate crystalline form ii tablets according to any one of claims 1 to 7, characterized in that:
crushing the clopidogrel bisulfate crystal form II, mixing the crushed clopidogrel bisulfate crystal form II with a filling agent, a disintegrating agent and a lubricating agent, tabletting the mixture by using a rotary tablet machine to prepare a plain tablet, and coating and drying the plain tablet to obtain the clopidogrel bisulfate crystal form II tablet.
9. The process for the preparation of clopidogrel hydrogen sulfate crystal form ii tablets according to claim 8, characterized in that:
(1) crushing the clopidogrel bisulfate in the crystal form II by using a hammer mill for later use;
(2) uniformly mixing the crushed clopidogrel hydrogen sulfate with the crystal form II with a filling agent and a disintegrating agent;
(3) adding a lubricant into the mixture obtained in the step (2), and uniformly mixing for later use;
(4) tabletting the mixture obtained in the step (3) by using a rotary tablet machine, wherein the rotating speed of the tablet machine is 25-45rpm, and the main pressure is 12-15KN, so as to obtain plain tablets;
(5) and (4) coating the plain tablets prepared in the step (4), and drying the coated tablets to obtain clopidogrel hydrogen sulfate crystal form II tablets.
10. The process for the preparation of clopidogrel hydrogen sulfate crystal form ii tablets according to claim 8, characterized in that:
and (5) coating the plain tablets prepared in the step (4) by using a high-efficiency coating machine, stopping spraying the coating solution when the coating weight is increased by more than or equal to 3%, and taking out tablets after the coated tablets are dried to obtain the clopidogrel hydrogen sulfate crystal form II tablets.
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