CN113288877A - Method for preparing dipyridamole dispersible tablets - Google Patents
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Abstract
The invention belongs to the field of medicine preparation, and particularly relates to a preparation method of dipyridamole dispersible tablets. The crude dipyridamole is synthesized, and the crude dipyridamole is refined to obtain the dipyridamole crude drug with higher yield and purity after the sulfonate is prepared. The method provided by the invention increases the solubility and dissolution speed of the drug, improves the bioavailability of the drug, and enhances the absorption of the drug in vivo.
Description
Technical Field
The invention belongs to the field of medicine preparation, and particularly relates to a preparation method of dipyridamole dispersible tablets.
Background
Dipyridamole has the chemical name 2,2' - [4, 8-dipiperidinopyrimido [5,4-d ]]Pyrimidine-2, 6-diyl]Dinitrogen radical]-tetraethanol of the formula
As a yellow crystalline powder; no smell, slightly bitter taste. Dissolving in ethanol and hardly dissolving in water; the melting point is 162-168 ℃.
Dipyridamole has main pharmacological actions of dilating blood vessels, inhibiting platelet aggregation and adhesion, has an antithrombotic effect, can inhibit the aggregation of a first phase and the aggregation of a second phase of platelets, can inhibit the release reaction of platelets at a high concentration, is a coronary vasodilator, can enhance coronary blood flow, and has an angina pectoris-resisting effect. In addition, the heparin can be used for preventing thrombosis, 2-stage prevention after myocardial infarction, peripheral vascular disease, ischemic cerebrovascular disease, renal disease and the like after artificial heart valves or artificial blood vessel transplantation, can improve the anticoagulation effect of microcirculation enhancing heparin and oral anticoagulant, and has certain effects on thrombosis and disseminated intravascular coagulation.
Dipyridamole formulations are mainly available as injections, general tablets, sustained-release tablets, etc., but these formulations all have different drawbacks. The injection needs professional administration, the medication of patients is inconvenient and the compliance is low; the common tablet and the sustained-release tablet have the problems of slow absorption, low bioavailability and the like, thereby affecting the curative effect. For elderly patients with cardiovascular disease, fast acting drugs are often needed to quickly relieve symptoms.
Disclosure of Invention
The invention provides a preparation method of dipyridamole dispersible tablets, which comprises the following specific process steps:
(1) synthesis of crude dipyridamole
Heating and preheating the reaction kettle in an oil bath, sequentially adding dichloride, diethanolamine and sodium carbonate, heating to 140-150 ℃, and preserving heat for 2 hours; continuously heating to 165-170 ℃, and preserving heat for 5 hours. Then, cooling to 50 ℃, adding methanol, stirring for 20 minutes, adding water, and stirring for 1-2 hours. Centrifugally drying, washing with drinking water, drying, and drying at 70-80 deg.C.
Wherein the dichloride is: 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D]A pyrimidine having the formula:
the mass ratio of dichloride, diethanolamine, sodium carbonate and methanol is as follows: 1: 2.25: 0.15: 1.2.
(2) synthesis of sulfonate
Adding methanol and the crude dipyridamole into a reaction kettle, heating in water bath to 50 ℃, preserving heat for 0.5 hour, adding p-toluenesulfonic acid, stirring to dissolve, cooling to 5-10 ℃, and preserving heat for 2 hours. Centrifugally drying, washing with 0.5 times of methanol, drying, and drying at 55-65 ℃.
Wherein the mass ratio of the methanol to the crude product to the p-toluenesulfonic acid is as follows: 3.6; 1: 1.
(3) refining
Adding 70% of methanol and sulfonate into a reaction kettle, heating and dissolving, keeping the temperature at 50 ℃ for 0.5 hour, adding 30% of liquid alkali to adjust the pH value to be 8-8.5 after the sulfonate is completely dissolved, adding activated carbon, heating, decoloring and stirring at 60 ℃ for 30 minutes, then carrying out filter pressing, enabling filtrate to enter a D-level clean area, carrying out fine filtration by using a 1-micron precision filter, and then entering a crystallization kettle. After filtering, adding purified water, cooling to below 15 ℃, and stirring for about 2 hours under heat preservation. And after centrifugal drying, washing with purified water for drying, and drying at 75-85 ℃ under the vacuum degree of less than or equal to-0.08 MPa for 8-10 hours.
The mass ratio of 70% methanol to sulfonate is: 5-6: 1.
(4) preparation of solid Dispersion
Weighing dipyridamole, adding 95% ethanol (ml/ml) and dissolving to obtain main drug solution; weighing sodium dodecyl sulfate and mannitol, adding deionized water, and stirring to dissolve to obtain adjuvant solution; uniformly mixing the auxiliary material solution and the main medicine solution to obtain a mixed solution; removing the solvent by spray drying to obtain solid dispersion.
The air inlet temperature of spray drying is 65 ℃, the outlet temperature is 40 ℃, and the liquid spraying speed is 3 ml/min.
(5) And preparing dipyridamole dispersible tablet
Crushing the solid dispersion, and sieving the crushed solid dispersion by a 100-mesh standard sieve to obtain solid dispersion powder; putting the solid dispersion powder and lactose into a granulator, dry-mixing for 10min, adding 40-50% ethanol (ml/ml) for wetting, setting the frequency of a shearing knife to be 20-30 Hz, and shearing and granulating for 10 min; sieving the materials with a 20-30-mesh sieve, carrying out wet granulation, and then transferring to a fluidized bed dryer for drying until the moisture content is 5-8%; and sieving the dried granules with a 20-30-mesh sieve, granulating, mixing the obtained granules with a lubricant for 10min, and tabletting to obtain the dipyridamole dispersible tablet.
The obtained dipyridamole dispersible tablet has the following formula:
the dosage of each 1000 tablets is as follows: 10g of dipyridamole, 40-45 g of lactose, 15-25 g of mannitol, 15-25 g of sodium dodecyl sulfate and 5g of magnesium stearate.
Has the advantages that:
(1) the yield of the dipyridamole synthesized by the method is high, and the product purity is improved by refining.
(2) The solid dispersion is prepared by preparing the auxiliary material solution, mixing the auxiliary material solution with the main medicine solution and adopting a spray drying method, so that the solubility and the dissolution speed of the medicine are increased, the bioavailability of the medicine is improved, and the absorption of the medicine in the body is enhanced.
Detailed Description
The present invention will be described in detail with reference to specific examples.
Example 1
(1) Heating and preheating the reaction kettle in an oil bath, sequentially adding 1kg of 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine, 2.25kg of diethanolamine and 0.15kg of sodium carbonate, heating to 150 ℃, and keeping the temperature for 2 hours; the temperature is continuously increased to 165 ℃, the temperature is kept for 5 hours, then the mixture is cooled to 50 ℃, 1.2kg of methanol is added and stirred for 20 minutes, and then water is added and stirred for 1 hour. Centrifugally drying, washing by drinking water, drying by drying, and drying for about 24 hours at 70 ℃ to obtain the dipyridamole crude product with the yield of 99.8%.
(2) Adding 3.6kg of methanol and 1kg of crude dipyridamole into a reaction kettle, heating in water bath to 50 ℃, keeping the temperature for 0.5 hour, adding 1kg of p-toluenesulfonic acid, stirring to dissolve, cooling to 5 ℃, and keeping the temperature for 2 hours. Centrifugally drying, washing with 0.5 times of methanol, drying, and drying at 65 ℃ to obtain the sulfonate with the yield of 99.6%.
(3) Adding 5kg of 70% methanol and 1kg of sulfonate into a reaction kettle, heating for dissolving, preserving heat at 50 ℃ for 0.5 hour, adding 30% liquid alkali to adjust the pH value to be 8-8.5 after the sulfonate is completely dissolved, adding 30g of medicinal activated carbon, heating, decoloring and stirring at 60 ℃ for 30 minutes, then carrying out filter pressing, enabling filtrate to enter a D-grade clean area, carrying out fine filtration by using a 1-micron precision filter, and then entering a crystallization kettle. After filtering, adding purified water, cooling to below 15 ℃, and stirring for about 2 hours under heat preservation. And (3) after centrifugal drying, washing with purified water, drying for 10 hours at 75 ℃ under the vacuum degree of less than or equal to-0.08 MPa to obtain refined dipyridamole with the yield of 69% and the purity of 98%.
(4) Preparation of solid Dispersion
Weighing 10g dipyridamole, adding 30ml 95% ethanol, and dissolving to obtain main drug solution; weighing 20g of sodium dodecyl sulfate and 20g of mannitol, adding 50ml of deionized water, and stirring to dissolve to obtain an auxiliary material solution; uniformly mixing the auxiliary material solution and the main medicine solution to obtain a mixed solution; removing the solvent by spray drying to obtain solid dispersion.
The air inlet temperature of spray drying is 65 ℃, the outlet temperature is 40 ℃, and the liquid spraying speed is 3 ml/min.
(5) And preparing dipyridamole dispersible tablet
Crushing the solid dispersion, and sieving the crushed solid dispersion by a 100-mesh standard sieve to obtain solid dispersion powder; putting the solid dispersion powder and 45g of lactose into a granulator, dry-mixing for 10min, adding 40% ethanol for wetting, setting the frequency of a shearing knife to be 20Hz, and shearing for granulating for 10 min; sieving the material with a 20-mesh sieve, performing wet granulation, transferring to a fluidized bed dryer, and drying until the moisture content is 8%; sieving the dried granules with 20 mesh sieve, grading, mixing the obtained granules with 5g magnesium stearate for 10min, tabletting with 6KN, and making into 1000-tablet dipyridamole dispersible tablet.
Example 2
(1) Heating and preheating the reaction kettle in an oil bath, sequentially adding 1kg of 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine, 2.25kg of diethanolamine and 0.15kg of sodium carbonate, heating to 140 ℃, and keeping the temperature for 2 hours; the temperature is continuously increased to 170 ℃, the temperature is kept for 5 hours, then the mixture is cooled to 50 ℃, 1.2kg of methanol is added and stirred for 20 minutes, and then water is added and stirred for 1 hour. Centrifugally drying, washing by drinking water, drying by drying, and drying for about 24 hours at 70 ℃ to obtain the dipyridamole crude product with the yield of 99.6%.
(2) Adding 3.6kg of methanol and 1kg of crude dipyridamole into a reaction kettle, heating in water bath to 50 ℃, keeping the temperature for 0.5 hour, adding 1kg of p-toluenesulfonic acid, stirring to dissolve, cooling to 10 ℃, and keeping the temperature for 2 hours. Centrifugally drying, washing with 0.5 times of methanol, drying, and drying at 65 ℃ to obtain the sulfonate with the yield of 98.9%.
(3) Adding 5kg of 70% methanol and 1kg of sulfonate into a reaction kettle, heating for dissolving, preserving heat at 50 ℃ for 0.5 hour, adding 30% liquid alkali to adjust the pH value to be 8-8.5 after the sulfonate is completely dissolved, adding 20g of medicinal activated carbon, heating, decoloring and stirring at 60 ℃ for 30 minutes, then carrying out filter pressing, enabling the filtrate to enter a D-grade clean area, carrying out fine filtration by using a 1-micron precision filter, and then entering a crystallization kettle. After filtering, adding purified water, cooling to below 15 ℃, and stirring for about 2 hours under heat preservation. And (3) after centrifugal drying, washing with purified water, drying for 10 hours at 75 ℃ under the vacuum degree of less than or equal to-0.08 MPa to obtain refined dipyridamole with the yield of 69% and the purity of 97.6%.
(4) Preparation of solid Dispersion
Weighing 10g dipyridamole, adding 30ml 95% ethanol, and dissolving to obtain main drug solution; weighing 20g of sodium dodecyl sulfate and 20g of mannitol, adding 50ml of deionized water, and stirring to dissolve to obtain an auxiliary material solution; uniformly mixing the auxiliary material solution and the main medicine solution to obtain a mixed solution; removing the solvent by spray drying to obtain solid dispersion.
The air inlet temperature of spray drying is 65 ℃, the outlet temperature is 40 ℃, and the liquid spraying speed is 3 ml/min.
(5) And preparing dipyridamole dispersible tablet
Crushing the solid dispersion, and sieving the crushed solid dispersion by a 100-mesh standard sieve to obtain solid dispersion powder; putting the solid dispersion powder and 45g of lactose into a granulator, dry-mixing for 10min, adding 40% ethanol for wetting, setting the frequency of a shearing knife to be 30Hz, and shearing for granulating for 10 min; sieving the material with a 20-mesh sieve, performing wet granulation, transferring to a fluidized bed dryer, and drying until the moisture content is 8%; sieving the dried granules with 20 mesh sieve, grading, mixing the obtained granules with 5g magnesium stearate for 10min, tabletting with 6KN, and making into 1000-tablet dipyridamole dispersible tablet.
Example 3
Steps (1) to (3) were the same as in example 1.
(4) Preparation of solid Dispersion
Weighing 10g dipyridamole, adding 30ml 95% ethanol, and dissolving to obtain main drug solution; weighing 15g of sodium dodecyl sulfate and 15g of mannitol, adding 40ml of deionized water, and stirring to dissolve to obtain an auxiliary material solution; uniformly mixing the auxiliary material solution and the main medicine solution to obtain a mixed solution; removing the solvent by spray drying to obtain solid dispersion.
The air inlet temperature of spray drying is 65 ℃, the outlet temperature is 40 ℃, and the liquid spraying speed is 3 ml/min.
(5) And preparing dipyridamole dispersible tablet
Crushing the solid dispersion, and sieving the crushed solid dispersion by a 100-mesh standard sieve to obtain solid dispersion powder; putting the solid dispersion powder and 40g of lactose into a granulator, dry-mixing for 10min, adding 40% ethanol for wetting, setting the frequency of a shearing knife to be 20Hz, and shearing for granulation for 10 min; sieving the material with a 30-mesh sieve, carrying out wet granulation, transferring to a fluidized bed dryer, and drying until the moisture content is 8%; sieving the dried granules with 30 mesh sieve, grading, mixing the obtained granules with 5g magnesium stearate for 10min, tabletting, and 6KN to obtain 1000-tablet dipyridamole dispersible tablet.
1. Hardness and friability test
The dipyridamole dispersible tablets prepared according to the above examples were tested for friability and hardness according to the inspection method of appendix XG of the second division of the chinese pharmacopoeia, version 2010. The results are shown in Table 1.
2. Dissolution test
The dipyridamole dispersible tablets obtained according to the above examples were prepared in 6 tablets each, and the dissolution rate was measured according to XC, appendix II of version 2010 of the Chinese pharmacopoeia. The results are shown in Table 1.
TABLE 1 hardness, friability, dissolution test results
| Sample (I) | Example 1 | Example 2 | Example 3 |
| hardness/N | 28 | 28 | 29 |
| Friability/% | <0.1 | <0.1 | <0.1 |
| Amount of dissolution/%) | 96 | 95 | 95 |
3. Content uniformity test
10 dipyridamole dispersible tablets obtained according to the above examples were taken, and the content uniformity was examined according to the second appendix XE of the 2010 version of the Chinese pharmacopoeia. The relative content of each tablet is measured as indicated by the quantity 100, and the average of the relative contents of 10 tablets is taken. Example 1, example 2, example 3 content uniformity a +1.8S < 10.
Claims (6)
1. A dipyridamole dispersible tablet, wherein the dispersible tablet is formulated as follows:
the dosage of each 1000 tablets is as follows: 10g of dipyridamole, 40-45 g of lactose, 15-25 g of mannitol, 15-25 g of sodium dodecyl sulfate and 5g of magnesium stearate.
2. A process for the preparation of a dipyridamole dispersible tablet according to claim 1, comprising the following steps:
(1) synthesis of crude dipyridamole
Heating and preheating the reaction kettle in an oil bath, sequentially adding dichloride, diethanolamine and sodium carbonate, heating to 140-150 ℃, and preserving heat for 2 hours; continuously heating to 165-170 ℃, and preserving heat for 5 hours; then cooling to 50 ℃, adding methanol, stirring for 20 minutes, adding water, stirring for 1-2 hours, centrifugally drying, washing with drinking water, drying for 24 hours at 70-80 ℃;
(2) synthetic sulfonate
Adding methanol and the crude dipyridamole into a reaction kettle, heating in a water bath to 50 ℃, preserving heat for 0.5 hour, adding p-toluenesulfonic acid, stirring to dissolve the p-toluenesulfonic acid, cooling to 5-10 ℃, preserving heat for 2 hours, centrifugally drying, washing with 0.5 times of methanol, drying, and drying at 55-65 ℃;
(3) refining
Adding 70% methanol and sulfonate into a reaction kettle, heating for dissolving, keeping the temperature at 50 ℃ for 0.5 hour, adding liquid alkali to adjust the pH value after the sulfonate is completely dissolved, adding active carbon for adding medicaments, heating, decoloring and stirring at 60 ℃ for 30 minutes, then performing pressure filtration, enabling filtrate to enter a D-grade clean area, performing fine filtration through a 1-micron precision filter, then entering a crystallization kettle, adding purified water after the filtration is finished, cooling to below 15 ℃, keeping the temperature and stirring for about 2 hours, performing centrifugal drying, washing with purified water for drying, drying at 75-85 ℃, keeping the vacuum degree at less than or equal to-0.08 MPa, and drying for 8-10 hours;
(4) preparation of solid Dispersion
Weighing dipyridamole, adding 95% ethanol, and dissolving to obtain main drug solution; weighing sodium dodecyl sulfate and mannitol, adding deionized water, and stirring to dissolve to obtain adjuvant solution; uniformly mixing the auxiliary material solution and the main medicine solution to obtain a mixed solution; removing the solvent by a spray drying method to obtain a solid dispersion;
(5) and preparing dipyridamole dispersible tablet
Crushing the solid dispersion, and sieving the crushed solid dispersion by a 100-mesh standard sieve to obtain solid dispersion powder; putting the solid dispersion powder and lactose into a granulator, dry-mixing for 10min, adding 40-50% ethanol for wetting, setting the frequency of a shearing knife to be 20-30 Hz, and shearing for granulating for 10 min; sieving the materials with a 20-30-mesh sieve, carrying out wet granulation, and then transferring to a fluidized bed dryer for drying until the moisture content is 5-8%; and sieving the dried granules with a 20-30-mesh sieve, granulating, mixing the obtained granules with magnesium stearate for 10min, and tabletting to obtain the dipyridamole dispersible tablet.
3. The process for the preparation of a dipyridamole dispersible tablet according to claim 2, wherein the dichloride of step (1) is: 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine; the mass ratio of dichloride, diethanolamine, sodium carbonate and methanol is as follows: 1: 2.25: 0.15: 1.2.
4. the process for the preparation of dipyridamole dispersible tablets according to claim 2, wherein the mass ratio of methanol, crude product and p-toluenesulfonic acid in step (2) is: 3.6; 1: 1.
5. the process for the preparation of dipyridamole dispersible tablets according to claim 2, wherein the mass ratio of 70% methanol to sulfonate in step (3) is: 5-6: 1; adding alkali liquor to adjust the pH value to 8-8.5.
6. The process for preparing dipyridamole dispersible tablets according to claim 2, wherein the spray drying of step (3) is carried out with an inlet temperature of 65 ℃, an outlet temperature of 40 ℃ and a spray rate of 3 ml/min.
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