Process for the preparation of nifedipine formulations
By using a combination of PEG4000 and PEG1500 as a solid dispersion carrier, along with specific excipients and coating technology, the problem of low water solubility of nifedipine formulations has been solved, achieving high dissolution and rapid efficacy within 30 minutes, making it suitable for the treatment of acute diseases.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- CHANGZHOU KANGPU PHARM CO LTD
- Filing Date
- 2021-05-26
- Publication Date
- 2026-06-09
AI Technical Summary
Existing nifedipine formulations have low solubility in water and slow dissolution rate, resulting in low bioavailability. Furthermore, conventional sustained-release formulations have a delayed effect in the treatment of acute diseases and are difficult to exert their effects quickly.
Using PEG4000 and PEG1500 as a solid dispersion carrier, combined with sodium carboxymethyl starch and corn starch as filler excipients, a nifedipine formulation with more than 90% solubility within 30 minutes was prepared by low-temperature ultrafine grinding and high-efficiency wet granulation technology. The formulation was coated with a pharmaceutical-grade gastric-soluble film coating agent, and the coating weight gain was controlled within 2-4%.
It significantly improved the dissolution rate and solubility of nifedipine, enabling more than 90% to dissolve within 30 minutes, thereby improving bioavailability and meeting the treatment needs of acute diseases.
Abstract
Description
Technical Field
[0001] This invention relates to a preparation process for nifedipine formulations, belonging to the field of pharmaceutical synthesis technology. Background Technology
[0002] Nifedipine is a dihydropyridine calcium channel blocker that selectively inhibits the transmembrane transport of calcium ions into cardiomyocytes and smooth muscle cells, and inhibits the release of calcium ions from intracellular stores without altering plasma calcium concentration. It is currently recognized as one of the safe and effective first-line antihypertensive drugs. Clinically, considering the needs of different conditions and treatments, nifedipine is formulated into various dosage forms for administration via multiple routes. Because nifedipine is insoluble in water, conventional sugar-coated tablets have a slow onset of action, incomplete release, low bioavailability, and significant side effects. This formulation is gradually being replaced by controlled-release tablets, sustained-release microcapsules, and sustained-release capsules to achieve a stable and sustained therapeutic effect. However, these formulations often have a slow onset of action and are not suitable for sudden-onset diseases such as hypertensive crisis, angina pectoris, biliary colic, acute pancreatitis, acute diarrhea, gastrointestinal spasmodic colic, premature birth, and stroke. Therefore, due to the poor water solubility of nifedipine, release inhibitors need to be added during the preparation of sustained-release formulations. In the treatment of certain diseases, this may result in a slow initial release of the drug, preventing it from exerting its effect quickly.
[0003] Therefore, it is necessary to significantly improve its solubility and dissolution rate in water to enhance the bioavailability of nifedipine in vivo. The dissolution rate of nifedipine refers to the speed and extent to which a drug dissolves from solid dosage forms such as tablets in a specified solvent. The addition of many excipients, such as microcrystalline cellulose and hydroxypropyl methylcellulose ester, can affect the drug's dissolution effect. Furthermore, different drugs have different physical properties, so the factors influencing dissolution rate vary from drug to drug. Currently, there is limited research on improving the dissolution rate of nifedipine tablets. In the preparation method of nifedipine tablets (CN201510117370.8), the dissolution rate is significantly improved by controlling the particle size of the raw materials, reaching 96.3%. However, this method does not specify the time frame for this dissolution rate, and therefore, the dissolution rate and the weight gain and dissolution rate after coating are not extensively studied.
[0004] Therefore, the selection of nifedipine formulation components can not only optimize the coating weight gain reaction and ensure that the coating purpose can be achieved within a small coating weight gain range, and well and uniformly coat the tablet core, but also significantly improve the dissolution rate of the formulation product, with more than 90% dissolving within 30 minutes. Summary of the Invention
[0005] To address the problems in the background art, the present invention provides a preparation process for nifedipine formulations, which not only optimizes the coating weight gain reaction and ensures that the coating purpose can be achieved within a small coating weight gain range, and effectively and uniformly coats the tablet core, but also significantly improves the dissolution rate of the formulation product, with more than 90% dissolving within 30 minutes.
[0006] To achieve the above objectives, the technical solution adopted in this application is as follows:
[0007] (1) Preparation of solid dispersion carrier: PEG4000 and PEG1500 were weighed at a mass ratio of 1:2 and added to anhydrous ethanol and stirred to dissolve, thus obtaining an excipient solution; nifedipine was weighed and added to anhydrous ethanol and heated to mix, thus obtaining a nifedipine suspension; the excipient solution and nifedipine suspension were mixed evenly at a mass ratio of 1:1 to obtain a mixed solution; the mixed solution was vacuum dried to control the moisture content to be less than 1% to obtain the material;
[0008] The mass concentration of the excipient solution is 30–50%; the mass concentration of the nifedipine suspension is 30–40%.
[0009] (2) Use an air jet mill to perform low-temperature ultrafine grinding on the material obtained in step (1) until the particle size D50 is 5-8 μm. Mix the ground material with sodium carboxymethyl starch and corn starch at a mass ratio of 1:3-10:90-100 at a low temperature below 20°C.
[0010] (3) Prepare adhesive: Place the weighed corn starch in a suitable container and dilute it with an appropriate amount of purified water. After mixing, pour in purified water at about 100°C. When the starch slurry is cooked, stop adding water. Then add an appropriate amount of purified water and weighed sodium dodecyl sulfate to make a total amount of 4% starch slurry (g / g).
[0011] The sodium dodecyl sulfate content is 0.6-1.0% of the starch paste; the mass ratio of nifedipine raw material to starch paste is 100:150-350.
[0012] (4) Pass the material mixed in step (2) through a 100-200 mesh sieve and add it into a high-efficiency wet granulator, and add the binder from step (3). The premixing time of the high-efficiency wet granulator is 5-10 minutes to obtain wet granules. The premixing stirring speed (frequency) is 40Hz, the premixing cutting speed (frequency) is 40-50Hz, the granulation time is 3-5 minutes, the granulation stirring speed (frequency) is 40Hz, and the granulation cutting speed (frequency) is 40-50Hz.
[0013] (5) The prepared wet granules are added to the feed hopper of the high-efficiency fluidized bed dryer for drying. After drying, the granules are discharged and granulated with magnesium stearate. All the granulated granules are then fed into a square cone mixer for mixing.
[0014] Specifically, the granulation equipment is set to a heating temperature of 100℃, a drying time of 10-50 minutes, a particle moisture content control range of 3-10%, and a granulation screen size of 2.0mm.
[0015] The mass ratio of magnesium stearate to nifedipine is 8–10:1.
[0016] (6) Tableting: The granulated particles are compressed into tablets, wherein the hardness after tableting is 8-35N.
[0017] (7) Pour the pressed film core into a high-efficiency coating machine for film coating.
[0018] The coating agent is a commercially available pharmaceutical-grade gastric-soluble film coating (such as Bocolin), which has excellent light-proof and moisture-proof properties and does not affect disintegration and drug release. Pure water is added to the coating machine to prepare a coating solution with a solid content of 15-18% (w / w). The solution is filtered through an 80-mesh sieve. The total amount of coating solution is weighed according to the weight gain range (2%-4%). The coating solution is then pumped into a spray gun, with an atomization pressure between 0.4 and 0.7 MPa.
[0019] Add the tablet core to the pot for preheating 5-10 minutes before coating. Coating can begin when the tablet core temperature is around 30℃.
[0020] Coating procedure: Place the spray gun in the coating pan, adjust its position so that it is perpendicular to the tablet bed, and spray the solution onto one-third of the tablet bed. Maintain a distance of approximately 30 cm between the spray gun and the tablet bed. Start the coating pan rotation speed at 1-3 rpm, gradually increasing it to approximately 9 rpm. Keep the peristaltic pump speed between 60-120 rpm and maintain the tablet bed temperature between 30℃ and 45℃. Monitor the tablet bed temperature continuously during coating to prevent tablet sticking and atomized drying. The film coating weight gain should be 2%-4%. Allow the coating to cool naturally after completion.
[0021] Compared with the prior art, the superior effects of the present invention are as follows:
[0022] This invention uses a compound of PEG4000 and PEG1500 as a solid dispersion carrier, with the main components distributed in a molecular state within the carrier. Sodium carboxymethyl starch and corn starch are selected as filler excipients, which significantly promote and improve the dissolution of the active pharmaceutical ingredient (API) and reduce the adsorption of nifedipine. These factors, combined with the solid dispersion carrier, further eliminate the adsorption of API molecules, improving the degree of drug dissolution and resulting in a rapid dissolution rate. Ultimately, this invention further improves the dissolution rate and solubility of the prepared nifedipine formulation, achieving over 90% dissolution within 30 minutes, ultimately reaching near 100% dissolution, significantly improving drug bioavailability. Detailed Implementation
[0023] The present invention will now be further described in conjunction with specific embodiments. The following examples are intended to illustrate the present invention and not to further limit the present invention.
[0024] Example 1
[0025] (1) Preparation of solid dispersion carrier: PEG4000 and PEG1500 were weighed at a mass ratio of 1:2 and added to anhydrous ethanol and stirred to dissolve, resulting in an excipient solution with a mass concentration of 30%; nifedipine was weighed and added to anhydrous ethanol and heated to mix, resulting in a nifedipine suspension with a mass concentration of 40%; the excipient solution and nifedipine suspension were mixed at a mass ratio of 1:1 to obtain a mixed solution, and the mixed solution was vacuum dried to control the moisture content to be less than 1% to obtain the material;
[0026] (2) Use an air jet mill to perform low-temperature ultrafine grinding on the material obtained in step (1) until the particle size D50 is 5-8 μm. Mix the ground material with sodium carboxymethyl starch and corn starch at a mass ratio of 1:3:95 at 15°C.
[0027] (3) Prepare the binder: Dilute the weighed corn starch with an appropriate amount of purified water and mix well. Pour in purified water at about 100°C. When the starch slurry is cooked, stop adding water. Then add an appropriate amount of purified water and weighed sodium dodecyl sulfate to prepare a starch slurry with a total content of 4% (g / g). The content of sodium dodecyl sulfate is 0.6% of the starch slurry.
[0028] (4) Pass the material mixed in step (2) through a 100-mesh sieve, add it into a high-efficiency wet granulation machine, and add the binder from step (3). Add the binder according to the mass ratio of nifedipine raw material to starch paste of 100:200.
[0029] The high-efficiency wet granulation machine has a premixing time of 5 minutes, a premixing stirring frequency of 40 Hz, a premixing cutting frequency of 45 Hz, a granulation time of 3 minutes, a granulation stirring frequency of 40 Hz, and a granulation cutting frequency of 45 Hz.
[0030] (5) The prepared wet granules are added to the feed hopper of a high-efficiency fluidized bed dryer for drying. After drying, the granules are discharged and granulated with magnesium stearate. All the granulated granules are then fed into a cone mixer for mixing. The mass ratio of magnesium stearate to nifedipine is 10:1. Specifically, the heating temperature of the granulation equipment is set to 100℃, the drying time is 20 minutes, the granule moisture content is controlled within 5%, and the granulation screen size is 2.0mm.
[0031] (6) Tableting: The granulated particles are compressed into tablets, with a hardness of 20N after compression; the compressed tablet cores are poured into a high-efficiency coating machine for film coating.
[0032] The coating agent is a commercially available pharmaceutical gastric-soluble film coating (e.g., Tianjin Bokelin Pharmaceutical Packaging Technology Co., Ltd.). Pure water is added to prepare a coating solution with a 16% (w / w) solid content. The solution is filtered through an 80-mesh sieve, and the total amount of coating solution is weighed based on a 2% weight gain range. The coating solution is pumped into a spray gun, with an atomization pressure between 0.4 and 0.7 MPa. The tablet cores are preheated in a pan 10 minutes before coating. Coating can begin when the tablet core temperature is around 30°C. After coating, the tablets can be allowed to cool naturally.
[0033] According to the 2010 edition of the Pharmacopoeia, the dissolution rate of nifedipine tablets was determined using the slurry method with a 0.25% sodium dodecyl sulfate solution as the dissolution medium and a rotation speed of 120 r / min. Ultraviolet spectrophotometry was used, with a maximum absorption wavelength of 237 nm. The dissolution rate was determined based on the relationship between nifedipine concentration and absorbance (a standard detection method). Six nifedipine tablets were tested; the average dissolution rate reached 92.6% within 30 minutes, and the cumulative dissolution rate was 99.7% after 60 minutes.
[0034] Example 2
[0035] (1) Preparation of solid dispersion carrier: PEG4000 and PEG1500 were weighed at a mass ratio of 1:2 and added to anhydrous ethanol and stirred to dissolve, resulting in an excipient solution with a mass concentration of 40%; nifedipine was weighed and added to anhydrous ethanol and heated to mix, resulting in a nifedipine suspension with a mass concentration of 30%; the excipient solution and nifedipine suspension were mixed at a mass ratio of 1:1 to obtain a mixed solution, and the mixed solution was vacuum dried to control the moisture content to be less than 1% to obtain the material;
[0036] (2) Use an air jet mill to perform low-temperature ultrafine grinding on the material obtained in step (1) until the particle size D50 is 5-8 μm. Mix nifedipine micro powder, sodium carboxymethyl starch, and corn starch at a mass ratio of 1:10:100 at 15°C.
[0037] (3) Prepare the binder: Dilute the weighed corn starch with an appropriate amount of purified water and mix well. Pour in purified water at about 100°C. When the starch slurry is cooked, stop adding the water. Then add an appropriate amount of purified water and weighed sodium dodecyl sulfate to prepare a starch slurry with a total content of 4% (g / g). The content of sodium dodecyl sulfate is 1.0% of the starch slurry.
[0038] (4) Pass the material mixed in step (2) through a 150-mesh sieve, add it into a high-efficiency wet granulation machine, and add the binder from step (3). Add the binder at a mass ratio of nifedipine raw material to starch paste of 100:150.
[0039] The high-efficiency wet granulation machine has a premixing time of 8 minutes, a premixing stirring frequency of 40 Hz, a premixing cutting frequency of 45 Hz, a granulation time of 3 to 5 minutes, a granulation stirring frequency of 40 Hz, and a granulation cutting frequency of 45 Hz.
[0040] (5) The prepared wet granules are added to the feed hopper of a high-efficiency fluidized bed dryer for drying. After drying, the granules are discharged and granulated with magnesium stearate. All the granulated granules are then fed into a cone mixer for mixing. The mass ratio of magnesium stearate to nifedipine is 10:1.
[0041] Specifically, the granulation equipment is set to a heating temperature of 100℃, a drying time of 30 minutes, a particle moisture content control range of 5%, and a granulation screen size of 2.0mm.
[0042] (6) Tableting: The granulated particles are compressed into tablets, with a hardness of 20N after compression; the compressed tablet cores are poured into a high-efficiency coating machine for film coating.
[0043] The coating agent is a commercially available pharmaceutical gastric-soluble film coating (e.g., Tianjin Bokelin Pharmaceutical Packaging Technology Co., Ltd.). Pure water is added to prepare a coating solution with a 16% (w / w) solid content. The solution is filtered through an 80-mesh sieve, and the total amount of coating solution is weighed based on a weight gain range of 3%. The coating solution is pumped into a spray gun, with an atomization pressure between 0.6 MPa and 1.7 MPa. The tablet cores are preheated in a pan 7 minutes before coating. Coating can begin when the tablet core temperature is around 30°C. After coating, the tablets can be allowed to cool naturally.
[0044] Six nifedipine tablets (same as in Example 1) were tested, and the average dissolution rate reached 91.9% within 30 minutes; the cumulative dissolution rate was 99.3% at 60 minutes.
[0045] Comparative Example 1
[0046] The difference between Comparative Example 1 and Example 1 is that PEG4000 and PEG1500 are replaced with PEG6000, while other operations remain unchanged.
[0047] Six nifedipine tablets (same as in Example 1) were tested, and the average dissolution rate reached 83.6% within 30 minutes; the cumulative dissolution rate was 97.2% at 60 minutes.
[0048] Comparative Example 2
[0049] The difference between Comparative Example 2 and Example 1 is that PEG4000 was removed and replaced with PEG1500 in equal quantities, while other operations remained unchanged.
[0050] Six nifedipine tablets (same as in Example 1) were tested, and the average dissolution rate reached 85.1% within 30 minutes; the cumulative dissolution rate was 98.6% at 60 minutes.
[0051] Comparative Example 3
[0052] The difference between Comparative Example 3 and Example 1 is that PEG 1500 was removed and replaced with an equal amount of PEG 4000, while other operations remained unchanged.
[0053] Six nifedipine tablets (same as in Example 1) were tested, and the average dissolution rate reached 72.4% within 30 minutes; the cumulative dissolution rate was 91.3% at 60 minutes.
[0054] Comparative Example 4
[0055] Compared with Example 1, Comparative Example 4 differs in that sodium carboxymethyl starch is replaced by β-cyclodextrin in equal mass, while other operations remain unchanged.
[0056] Six nifedipine tablets (same as in Example 1) were tested, and the average dissolution rate reached 87.3% within 30 minutes; the cumulative dissolution rate was 96.4% at 60 minutes.
[0057] Comparative Example 5
[0058] The difference between Comparative Example 5 and Example 1 is that sodium dodecyl sulfate was not added to the starch slurry, while other operations remained the same.
[0059] Six nifedipine tablets (same as in Example 1) were tested, and the average dissolution rate reached 86.4% within 30 minutes; the cumulative dissolution rate was 95.7% at 60 minutes.
Claims
1. A preparation process for nifedipine formulations, characterized in that: The preparation steps are as follows: (1) Preparation of solid dispersion carrier: PEG4000 and PEG1500 were weighed at a mass ratio of 1:2, added to anhydrous ethanol and stirred to dissolve, resulting in an excipient solution with a mass concentration of 30%; nifedipine was weighed and added to anhydrous ethanol, heated and mixed to obtain a nifedipine suspension with a mass concentration of 40%; the excipient solution and nifedipine suspension were mixed evenly at a mass ratio of 1:1 to obtain a mixed solution; the mixed solution was vacuum dried to control the moisture content to be less than 1% to obtain the material; (2) Use an air jet mill to perform low-temperature ultrafine grinding of the material obtained in step (1) at a temperature below 20°C until the particle size D50 is 5~8μm; mix the ground material with sodium carboxymethyl starch and corn starch at a mass ratio of 1:3:95 at low temperature and pass through a 100~200 mesh sieve. (3) Preparation of binder: Weigh corn starch and dilute it with an appropriate amount of purified water. Mix well and pour in purified water at 100°C. When the starch slurry is cooked, stop adding water. Then add purified water and sodium dodecyl sulfate to prepare a starch slurry with a mass concentration of 4%. The content of sodium dodecyl sulfate is 0.6~1.0% of the mass of the starch slurry. (4) Add the material after sieving in step (2) into a high-efficiency wet granulation machine, and add the starch slurry binder from step (3) to granulate to obtain wet granules; the mass ratio of nifedipine raw material to starch slurry is 100:
200. (5) The prepared wet granules are added to the feed hopper of the high-efficiency fluidized bed dryer for drying. After drying, the granules are discharged and granulated with magnesium stearate. All the granulated granules are fed into a square cone mixer for mixing. The granulated granules are then compressed into tablets. The hardness of the tablets is 20N. The mass ratio of magnesium stearate to nifedipine is 10:
1. (6) Pour the pressed tablet core into a high-efficiency coating machine for film coating: the coating agent is a stomach-soluble film coating agent. Add pure water to prepare a coating solution with a mass content of 15~18%. Weigh the total amount of coating solution according to the weight gain range of 2%~4%. Pump the coating solution into the spray gun and perform coating treatment with an atomization pressure between 0.4 and 0.7 MPa.