CN109010303B - Industrial preparation method of ranitidine hydrochloride capsule - Google Patents
Industrial preparation method of ranitidine hydrochloride capsule Download PDFInfo
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- CN109010303B CN109010303B CN201810529481.3A CN201810529481A CN109010303B CN 109010303 B CN109010303 B CN 109010303B CN 201810529481 A CN201810529481 A CN 201810529481A CN 109010303 B CN109010303 B CN 109010303B
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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Abstract
The invention relates to a preparation method of a ranitidine hydrochloride capsule, which mainly comprises the following raw and auxiliary materials in percentage by weight: 55-99% of ranitidine hydrochloride; 0-30% of a filler; 0% -10% of adhesive; 0-5% of disintegrating agent; 0.01-5% of lubricant; by adopting the optimized formula and the process preparation method, the process robustness, controllability and feasibility are effectively improved; simplifies the production process of the ranitidine hydrochloride capsule, shortens the production operation period and improves the production efficiency.
Description
Technical Field
The invention relates to an industrial preparation method of ranitidine hydrochloride capsules, belonging to the field of preparation of pharmaceutical preparations.
Background
Ranitidine is a powerful histamine H2 receptor antagonist, can effectively inhibit gastric acid secretion caused by stimulation of histamine, pentagastrin and carbamoylcholine, and reduces gastric acid and gastric enzyme activity, but has no influence on secretion of gastrin and sex hormone. The ranitidine is fast to absorb orally, is not affected by food and antacid, has high curative effect on gastric ulcer and duodenal ulcer, has the characteristics of quick acting and long acting, and is small in side effect and safe.
Ranitidine, like cimetidine, is currently the most widely used drug for the treatment of ulcers. Developed by glaxo corporation, british. It was synthesized by pruris (price) et al, uk in 1976, and its pharmacology was elucidated by bradshaw (bradshaw) in 1979, and beststa (berstad) reported to be effective for duodenal ulcer in 1980, and marketed in 1981 for use in nearly hundreds of countries around the world. The effect of ranitidine is 5-8 times stronger than that of cimetidine, and the acting time is longer. The traditional Chinese medicine composition is mainly used for treating hyperchlorhydria, heartburn, duodenal ulcer, benign gastric ulcer, postoperative ulcer, reflux esophagitis, Zollinger-Ellison syndrome and the like clinically, and can be used for treating upper gastrointestinal hemorrhage by intravenous injection.
In the production of medicines, capsules are preparations in which medicine powder or granules are filled in empty capsules, which can cover up the peculiar smell and irritation of medicines, facilitate the swallowing of the medicines, and prevent the medicines from being affected with damp, light and oxidation to a certain extent, so that the medicines are stable. Ranitidine hydrochloride is white or yellow crystalline powder, has poor liquidity, is unstable to damp and heat, is extremely easy to deliquesce, has hygroscopicity, has strict requirements on environment temperature and humidity, and has poor process operability in the preparation process. The product is unstable when exposed to high temperature and high humidity for a long time, which easily causes the increase of impurities and the yellowing of coloring materials, and brings influence to the product quality. The ranitidine hydrochloride raw material medicine is generally granulated, and the powder property of the ranitidine hydrochloride raw material medicine is improved, and then filling is carried out.
The existing preparation method of the ranitidine capsule preparation can not completely avoid the phenomena of instability, moisture induction and the like of the ranitidine hydrochloride in the preparation method of the capsule preparation. The phenomenon of adhesion with equipment is easy to occur in the granulation preparation process, and the process is more, the equipment is more, the period of each process is longer, and the product stability is not facilitated. Therefore, there is a need for developing a process for preparing a ranitidine capsule preparation which can prepare a ranitidine capsule preparation with good stability and is suitable for industrial amplification.
Disclosure of Invention
The invention provides a technical preparation method of a ranitidine hydrochloride capsule preparation, which mainly comprises the following raw and auxiliary materials in percentage by weight:
mainly comprises the following steps:
step 1: mixing ranitidine hydrochloride and filler in the formula amount to enable the mixture to be in a fluidized state;
step 2: preheating the mixed material in the step 1, atomizing and spraying an adhesive solution, and granulating the material to obtain a granular material;
and step 3: drying the granular material in the step 2;
and 4, step 4: preparing the granules dried in the step 3 into mixed granules, wherein the step of preparing the mixed granules comprises the operations of granulating and adding a disintegrating agent and a lubricating agent for uniform mixing;
and 5: and (4) filling the mixed granules in the step (4) into capsules to obtain the ranitidine hydrochloride capsules.
In the technical preparation method of the ranitidine hydrochloride capsule preparation, the granule finishing mode in the step 4 comprises sieving granule finishing and crushing granule finishing;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the step of preparing the mixed particles in the step 4 is as follows: sieving and granulating the dried granules in the step 3, and then uniformly mixing the granules with a disintegrating agent and a lubricating agent to obtain mixed granules;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the step of preparing the mixed particles in the step 4 is as follows: mixing the dried granules obtained in the step 3 with a lubricant, granulating, and then uniformly mixing with a disintegrant and a lubricant to obtain mixed granules;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the weight percentage content of the filling agent, the adhesive and the disintegrating agent is not 0 completely, preferably the weight percentage content of the adhesive and the disintegrating agent is not 0 completely, and most preferably the weight percentage content of the disintegrating agent is not 0;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the filling agent is selected from one or more of starch, sucrose, dextrin, calcium sulfate, microcrystalline cellulose and lactose;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the adhesive is selected from one or more of starch slurry, povidone (PVP), sodium carboxymethylcellulose and hydroxypropyl methylcellulose;
the adhesive solution is selected from one or more of an aqueous adhesive solution or an alcoholic adhesive solution, preferably an aqueous adhesive solution; wherein, the adhesive alcohol solution is preferably an adhesive ethanol solution; the binder solution can also be independently sprayed by atomizing water or alcohol solution, such as water or ethanol;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the disintegrant is selected from one or more of starch, sodium carboxymethyl starch, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, crospovidone and croscarmellose sodium;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate, sodium dodecyl sulfate, talcum powder, superfine silica powder and silicon dioxide;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the mixing time of the ranitidine hydrochloride and the filling agent in the step 1 is 10-40 min;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the preheating temperature of the materials in the step 2 is 20-50 ℃, preferably 25-50 ℃, and more preferably 25-45 ℃;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the preheating temperature of the materials in the step 2 is 25-45 ℃;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the concentration of the sprayed adhesive solution in the step 2 is 0-15% (w/w), preferably 0.05-15% (w/w); more preferably 3-8% (w/w); most preferably the concentration of the binder solution is 5% (w/w);
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the concentration of the sprayed adhesive in the step 2 is 0.05-15% (w/w); preferably, the concentration of the sprayed-in binder is 3-8% (w/w); more preferably the concentration of binder is 5% (w/w);
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the spraying speed of the adhesive solution sprayed in the step 2 is 0.2-5 g/kg/min;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the atomization pressure of the sprayed adhesive solution in the step 2 is 0.1-0.6 MPa;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the material in the step 3 is dried until the water content of the material is not higher than 3%;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the mesh number sieved in the step 4 is 40 meshes;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the mixing time of the particles, the disintegrant and the lubricant in the step 4 is 5-40 min.
Further, the air conditioner is provided with a fan,
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the filling agent is preferably one or more of starch, microcrystalline cellulose and lactose;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the adhesive is preferably starch slurry, the using concentration is preferably 3-8%, and the most preferably 5%;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the disintegrant is preferably one or more of sodium carboxymethyl starch, crospovidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the lubricant is preferably one or more of magnesium stearate, silicon dioxide and talcum powder;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the steps 1 to 3 are preferably completed in the same equipment, such as a fluidized bed;
it is still further preferred that the first and second substrates are,
in the above technical preparation method of the ranitidine hydrochloride capsule preparation, the ranitidine hydrochloride is 80-97% by weight, preferably 90-97%, such as 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the weight percentage of the filler is 0-29.5%, preferably 0-18%, preferably 0-15%, preferably 0-7%, for example, the filler is not added or a small amount of filler is not added;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the weight percentage of the adhesive is 0-5.0%, preferably 0.5-5.0%;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the weight percentage of the disintegrant is 0.5-2.0%, preferably 0.5-1.5%;
in the technical preparation method of the ranitidine hydrochloride capsule preparation, the weight percentage of the lubricant is 0.5-3.5%, preferably 2-3.5%;
in a preferred embodiment of the present invention, the ranitidine hydrochloride capsule preparation comprises the following raw and auxiliary materials by weight: 80-97% of ranitidine hydrochloride; 0-29.5% of a filler; 0 to 5.0 percent of adhesive; 0.5 to 2.0 percent of disintegrant; 0.5 to 3.5 percent of lubricant.
In a preferred embodiment of the present invention, the ranitidine hydrochloride capsule preparation comprises the following raw and auxiliary materials by weight: 80-97% of ranitidine hydrochloride; 0-18% of a filler; 0 to 5.0 percent of adhesive; 0.5 to 2.0 percent of disintegrant; 0.5 to 3.5 percent of lubricant.
In a preferred embodiment of the present invention, the ranitidine hydrochloride capsule preparation comprises the following raw and auxiliary materials by weight: 90-97% of ranitidine hydrochloride; 0-15% of a filler; 0.5 to 5.0 percent of adhesive; 0.5 to 1.5 percent of disintegrant; 2 to 3.5 percent of lubricant.
In a preferred embodiment of the present invention, the ranitidine hydrochloride capsule preparation comprises the following raw and auxiliary materials by weight: 90-97% of ranitidine hydrochloride; 0-7% of a filler; 0.5 to 5.0 percent of adhesive; 0.5 to 1.5 percent of disintegrant; 2 to 3.5 percent of lubricant.
In a preferred embodiment of the present invention, the ranitidine hydrochloride capsule preparation comprises the following raw and auxiliary materials by weight: 79 to 88 percent of ranitidine hydrochloride, 0 to 15 percent of starch or lactose or microcrystalline cellulose, 1 to 2 percent of croscarmellose sodium, 0.5 to 2.5 percent of silicon dioxide and 1 to 2.6 percent of magnesium stearate.
In a preferred embodiment of the present invention, the ranitidine hydrochloride capsule preparation comprises the following raw and auxiliary materials by weight: 88-94% of ranitidine hydrochloride, 0-10% of starch or microcrystalline cellulose, 0.5-1% of starch or sodium carboxymethyl cellulose, 0.5-1.5% of sodium carboxymethyl starch, 0.5-2.5% of talcum powder or silicon dioxide and 1-1.5% of magnesium stearate.
In a preferred embodiment of the present invention, the ranitidine hydrochloride capsule preparation comprises the following raw and auxiliary materials by weight: 94-97% of ranitidine hydrochloride, 0.5-2% of starch or povidone or sodium carboxymethyl cellulose, 0.5-2% of sodium carboxymethyl starch, 1-2% of silicon dioxide and 0.5-2% of magnesium stearate.
In a preferred embodiment of the present invention, the ranitidine hydrochloride capsule preparation comprises the following raw and auxiliary materials by weight: 94-97% of ranitidine hydrochloride, 0.5-2% of starch or povidone or sodium carboxymethyl cellulose, 0.5-1% of sodium carboxymethyl starch, 1.5-2% of silicon dioxide and 0.5-1% of magnesium stearate.
The solid powder of the ranitidine hydrochloride raw material medicine has poor flowability, is unstable to damp and heat, is very easy to deliquesce, is sensitive to the temperature and humidity in the process preparation process, easily causes the material to be easily colored and yellow due to high temperature, increases impurities, is easy to agglomerate due to poor flowability of the solid powder at low temperature, and cannot form particles in a good state.
The invention obtains the optimized prescription of the ranitidine hydrochloride capsule through a large number of experimental screens, wherein the combination of component selection and proportion ensures that the medicine has good powder fluidity and is suitable for the one-step granulation process and the capsule filling adopted by the invention; particularly, on the premise of remarkably improving the content of main drug ranitidine, the prescription and the one-step granulation and filling process have excellent adaptability through the optimized combination of auxiliary materials, and a satisfactory synergistic effect is obtained. The ranitidine capsule prepared by the invention has good drug dissolution and bioavailability, in-vitro dissolution tests show that the ranitidine capsule can be completely dissolved within 10min, the absolute bioavailability of the ranitidine capsule in oral administration reaches more than 50%, the impurity content is obviously lower than that of the ranitidine capsule prepared by the traditional wet granulation method, and color change does not occur.
On the other hand, the process for preparing the ranitidine capsule preparation is also the optimal process obtained by screening a large number of experiments aiming at the capsule prescription of the invention according to the characteristics of the ranitidine hydrochloride medicament. The physical and chemical properties of ranitidine hydrochloride are greatly influenced by the temperature of materials in the granulating step, the prepared particles are yellow and are aggregated when the temperature is lower than 20 ℃, the particles change color to be yellow when the temperature is higher than 50 ℃, the materials can be prevented from absorbing moisture and aggregating by controlling the proper preheating temperature range of the materials to be 20-50 ℃, white-to-light yellow-color particles which are uniformly distributed are prepared, and the stability of ranitidine hydrochloride is maintained. The atomization pressure of the adhesive is controlled to be 0.1-0.6 MPa and the liquid spraying speed is controlled to be 0.2-5g/kg/min in the granulating process, so that the prepared particles are uniform in size and keep relatively dispersed and are not agglomerated, the adhesive is possibly concentrated locally to form particle agglomeration due to too small atomization pressure or too high liquid spraying speed, the particles are easily adhered to the wall of a pot when the adhesive with too large atomization pressure is sprayed to the inner wall of equipment, the forming efficiency of the particles is reduced due to too small liquid spraying speed, and the granulation time is prolonged, the production efficiency is reduced and unnecessary energy waste is caused. The spraying speed is calculated by the amount of the adhesive sprayed per kilogram of material per minute (g/kg/min), and the requirements of different batches of products on the spraying speed are fully considered, so that the method is suitable for various production scales. The optimization of the parameters such as the operation temperature, the mixing time, the atomization pressure, the liquid spraying speed, the control of the whole preparation period and the like greatly improves the defects of the existing preparation process of the ranitidine hydrochloride capsule preparation, and improves the stability, the medication safety and the like of the ranitidine hydrochloride capsule preparation.
Compared with the prior art, the method has the advantages that,
the technical preparation method of the ranitidine hydrochloride capsule preparation ensures that the materials are not easy to agglomerate in the preparation process and can form particles with good state by optimally controlling the parameters of proper temperature of mixed materials, atomization pressure, liquid spraying speed and the like in the granulation process, the prepared ranitidine hydrochloride capsule preparation particles are uniform, the adhesion between API and equipment is reduced, and the problem that the materials are colored and yellow due to the increase of impurities in the preparation process of ranitidine hydrochloride is effectively solved;
according to the preparation method of the ranitidine hydrochloride capsule preparation process, the time for mixing materials is controlled to be 5-40 min in an optimized mode, so that the ranitidine hydrochloride capsule preparation is uniformly mixed in the preparation process, the increase of impurities, yellowing and the like which are possibly generated when ranitidine hydrochloride is exposed to the external environment for a long time are avoided, the requirements on the environment temperature and the environment humidity are reduced, the risk that the capsule disintegration and dissolution are influenced by over-lubrication of magnesium stearate serving as a lubricant caused by overlong mixing time is reduced, and the feasibility of industrial production of process amplification is effectively improved;
the materials in the method for preparing the ranitidine hydrochloride capsule preparation are mixed, granulated and dried in the same equipment, the granulating parameters such as liquid spraying speed and the like are optimized, the operation period is about 1h, the granulating time period of the whole preparation process is preferably shortened, the operation is convenient and fast, the independent drying procedure and drying equipment in the prior art are reduced, the technological process is simpler to operate, the production efficiency is obviously improved, and the energy consumption of the equipment is effectively reduced.
In conclusion, the preparation method has smooth process and the materials are uniform and fine particles by optimizing the prescription and the process of the ranitidine hydrochloride capsule preparation, so that the process robustness, the process controllability and the feasibility are effectively improved; the production process of the ranitidine hydrochloride capsule is simplified, the production operation period is shortened, and the production efficiency is improved; the color and luster of the materials before and after granulation are basically consistent with the impurity content, the impurity content of the preparation is not obviously increased after the preparation is stored for 3 months and 6 months, and the product quality and the medication safety of the ranitidine hydrochloride capsule preparation are obviously improved.
The invention also provides a ranitidine hydrochloride capsule preparation prepared by the technical preparation method of the ranitidine hydrochloride capsule preparation.
The invention also provides application of the ranitidine hydrochloride capsule preparation prepared by the technical preparation method of the ranitidine hydrochloride capsule preparation in preparation of medicines for treating or preventing histamine H2 receptor-related diseases.
The ranitidine hydrochloride capsule prepared by the technical preparation method of the ranitidine hydrochloride capsule preparation can be prepared and used for: treating diseases related to histamine H2 receptor such as hyperchlorhydria, heartburn, duodenal ulcer, benign gastric ulcer, postoperative ulcer, reflux esophagitis, upper gastrointestinal hemorrhage and Zollinger-Ellison syndrome.
In addition to being useful for human therapy, the ranitidine hydrochloride capsules prepared by the process of the present invention are also useful for veterinary therapy of companion, exotic and farm animals including mammals, rodents, and the like, such as horses, dogs and cats.
Detailed Description
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
EXAMPLE 1 preparation of Ranitidine hydrochloride capsules of the invention
The preparation process comprises the following steps:
weighing ranitidine hydrochloride raw material medicine with the prescription dosage, placing the ranitidine hydrochloride raw material medicine into a fluidized bed, spraying 3% concentration starch slurry solution into the fluidized bed in an atomization mode, wherein the atomization pressure is 0.3MPa, the liquid spraying speed is 3g/kg/min, the material temperature is controlled to be 25-30 ℃, and granulating is carried out on ranitidine hydrochloride; continuously drying the materials by using a fluidized bed until the moisture content is less than 3 percent; and (4) sieving the granular materials with a 40-mesh sieve for grading, wherein the granules are uniform in size and are white to light yellow. Adding auxiliary materials such as carboxymethyl starch sodium, silicon dioxide, magnesium stearate and the like with the dosage of the prescription, mixing for 10min, and filling to obtain a ranitidine hydrochloride capsule product with 175mg of capsule content.
EXAMPLE 2 preparation of Ranitidine hydrochloride capsules of the invention
The preparation process comprises the following steps:
weighing ranitidine hydrochloride and starch with the formula dosage, mixing the ranitidine hydrochloride and the starch in a fluidized state, atomizing and spraying water, wherein the atomizing pressure is 0.2MPa, the liquid spraying speed is 4g/kg/min, preheating and controlling the temperature of a mixed material to be 30-35 ℃ for granulation, and drying the prepared granular material until the moisture content is not higher than 3% when the granular state of the mixed material is good; and (4) sieving the granular materials with a 40-mesh sieve for grading, wherein the granules are uniform in size and are white to light yellow. Adding the croscarmellose sodium, the talcum powder, the magnesium stearate and other auxiliary materials with the dosage of the prescription, mixing for 15min, and filling to obtain the ranitidine hydrochloride capsule product with the capsule content of 210 mg.
EXAMPLE 3 preparation of Ranitidine hydrochloride capsules of the invention
The preparation process comprises the following steps:
weighing Ranitidine hydrochloride raw material medicine and lactose according to the prescription amount, mixing the raw material medicine and the lactose in a fluidized bed, atomizing and spraying povidone aqueous solution with the concentration of 8% into the fluidized bed, wherein the atomizing pressure is 0.5MPa, the spraying speed is 0.2g/kg/min, preheating and granulating after controlling the temperature of the material to be 35-40 ℃, and continuously drying the granular material in the fluidized bed until the moisture is not higher than 3%; after the granular materials are sieved by a 40-mesh sieve for size stabilization, the granules are uniform in size and are white to light yellow. Adding the auxiliary materials of low-substituted hydroxypropyl cellulose, silicon dioxide, magnesium stearate and the like in the prescription amount, mixing for 30min, and filling to obtain a ranitidine hydrochloride capsule product with 280mg of capsule content.
EXAMPLE 4 preparation of Ranitidine hydrochloride capsules of the invention
The preparation process comprises the following steps:
weighing Ranitidine hydrochloride raw material medicine and microcrystalline cellulose in a prescription amount, mixing the raw material medicine and the microcrystalline cellulose in a fluidized bed, atomizing a hydroxypropyl methyl cellulose aqueous solution with the concentration of 3% into the fluidized bed, carrying out granulation after preheating and controlling the temperature of the material to be 40-45 ℃ and carrying out granulation, and drying the granular material until the water content is not higher than 3% after the state of the material particles is good; the particle size is uniform after finishing, and the white to light yellow color is obtained. Adding the auxiliary materials such as croscarmellose sodium, silicon dioxide, magnesium stearate and the like according to the prescription dosage, mixing for 35min, and filling to obtain the ranitidine hydrochloride capsule product with the capsule content of 240 mg.
EXAMPLE 5 preparation of Ranitidine hydrochloride capsules of the invention
The preparation process comprises the following steps:
weighing Ranitidine hydrochloride raw material medicine and lactose according to the prescription amount, mixing the raw material medicine and the lactose in a fluidized bed, atomizing 15% sodium carboxymethylcellulose aqueous solution into the fluidized bed, spraying the sodium carboxymethylcellulose aqueous solution into the fluidized bed at the atomizing pressure of 0.2MPa and the spraying speed of 1g/kg/min, preheating, controlling the temperature of the material to be 35-40 ℃, granulating, and continuously drying the granular material in the fluidized bed until the moisture is not higher than 3%; after the granular materials are sieved by a 40-mesh sieve for size stabilization, the granules are uniform in size and are white to light yellow. Adding the auxiliary materials of low-substituted hydroxypropyl cellulose, silicon dioxide, magnesium stearate and the like in the prescription amount, mixing for 30min, and filling to obtain a ranitidine hydrochloride capsule product with the capsule content of 320 mg.
EXAMPLE 6 preparation of Ranitidine hydrochloride capsules of the invention
The preparation process comprises the following steps:
weighing Ranitidine hydrochloride raw material medicine and lactose according to the prescription amount, mixing the raw material medicine and the lactose in a fluidized bed, atomizing and spraying povidone aqueous solution with the concentration of 8% into the fluidized bed, wherein the atomizing pressure is 0.4MPa, the spraying speed is 4g/kg/min, preheating and granulating the material after controlling the temperature of the material to be 35-40 ℃, and continuously drying the granular material in the fluidized bed until the moisture is not higher than 3%; after the granular materials and the silicon dioxide are crushed and granulated, the granules are uniform in size and are white to light yellow. Adding the auxiliary materials such as low-substituted hydroxypropyl cellulose, magnesium stearate and the like in the prescription amount, mixing for 30min, and filling to obtain a ranitidine hydrochloride capsule product with 280mg of capsule content.
EXAMPLE 7 preparation of Ranitidine hydrochloride capsules of the invention
The preparation process comprises the following steps:
weighing Ranitidine hydrochloride raw material medicine and lactose according to the prescription amount, mixing the raw material medicine and the lactose in a fluidized bed, atomizing 15% sodium carboxymethylcellulose water solution into the fluidized bed, spraying the sodium carboxymethylcellulose water solution into the fluidized bed at the atomizing pressure of 0.2MPa and the spraying speed of 0.8g/kg/min, preheating, controlling the temperature of the material to be 35-40 ℃, granulating, and continuously drying the granular material in the fluidized bed until the moisture is not higher than 3%; after the particle materials are crushed and granulated, the particle sizes are uniform and are white to light yellow. Adding the auxiliary materials of low-substituted hydroxypropyl cellulose, silicon dioxide, magnesium stearate and the like in the prescription amount, mixing for 30min, and filling to obtain a ranitidine hydrochloride capsule product with the capsule content of 320 mg.
EXAMPLE 8 preparation of Ranitidine hydrochloride capsules of the invention
The preparation process comprises the following steps:
weighing Ranitidine hydrochloride raw material medicine and microcrystalline cellulose in a prescription amount, mixing in a fluidized bed, atomizing and spraying 10% polyvidone water solution into the fluidized bed, wherein the atomizing pressure is 0.3MPa, the spraying speed is 3g/kg/min, preheating and controlling the temperature of the material to be 45-50 ℃, granulating, and continuously drying the granular material in the fluidized bed until the water content is not higher than 3%; after the particle materials are sieved by a 40-mesh screen for size stabilization, the particle sizes are uniform and are white to light yellow. Adding the cross-linked sodium carboxymethylcellulose, the silicon dioxide, the magnesium stearate and other auxiliary materials according to the prescription amount, mixing for 30min, and filling to obtain the ranitidine hydrochloride capsule product with the capsule content of 320 mg.
EXAMPLE 9 preparation of Ranitidine hydrochloride capsules of the invention
The preparation process comprises the following steps:
weighing Ranitidine hydrochloride raw material medicine and lactose according to the prescription amount, mixing the raw material medicine and the lactose in a fluidized bed, atomizing and spraying povidone aqueous solution with the concentration of 8% into the fluidized bed, wherein the atomizing pressure is 0.2MPa, the spraying speed is 1g/kg/min, preheating and granulating the material after controlling the temperature of the material to be 25-30 ℃, and continuously drying the granular material in the fluidized bed until the moisture is not higher than 3%; after the particle materials are crushed and granulated, the particle sizes are uniform and are white to light yellow. Adding the auxiliary materials such as low-substituted hydroxypropyl cellulose, silicon dioxide, magnesium stearate and the like according to the prescription amount, mixing for 30min, and filling to obtain a ranitidine hydrochloride capsule product with 280mg of capsule content.
EXAMPLE 10 preparation of Ranitidine hydrochloride capsules of the invention
The preparation process comprises the following steps:
weighing Ranitidine hydrochloride raw material medicine and lactose according to the prescription amount, mixing the raw material medicine and the lactose in a fluidized bed, atomizing 15% povidone aqueous solution into the fluidized bed at the atomizing pressure of 0.2MPa and the spraying speed of 0.5g/kg/min, preheating, controlling the temperature of the material to be 20-25 ℃, granulating, and continuously drying the granular material in the fluidized bed until the moisture is not higher than 3%; after the particles and the silicon dioxide are crushed and granulated, the particles are uniform in size and are white to light yellow. Adding the cross-linked sodium carboxymethylcellulose, magnesium stearate and other auxiliary materials according to the prescription amount, mixing for 30min, and filling to obtain the ranitidine hydrochloride capsule product with the capsule content of 320 mg.
Comparative example 1
The ranitidine hydrochloride capsule is prepared by the prescription of the embodiment 2 of the invention by adopting the existing preparation process method.
The preparation process comprises the following steps:
adding ranitidine hydrochloride and starch in the amount of the prescription into a wet granulator, dropwise adding the aqueous solution into the wet granulator to prepare a soft material, sieving the soft material with a 30-mesh sieve to prepare wet granules, and drying the wet granules by using an oven until the moisture content is less than 3%. Sieving the granular materials with a 40-mesh sieve, grading, adding auxiliary materials such as croscarmellose sodium, talcum powder and magnesium stearate with the dosage of the prescription, mixing for 15min, and filling to obtain the ranitidine hydrochloride capsule product with the capsule content of 210 mg.
Comparative example 2
Ranitidine hydrochloride granulation was performed on the formulation of example 11 of the invention and the material temperature parameters were screened.
The preparation process comprises the following steps:
weighing Ranitidine hydrochloride raw material medicine and microcrystalline cellulose in a prescription amount, mixing in a fluidized bed, atomizing and spraying hydroxypropyl methyl cellulose water solution with the concentration of 3% into the fluidized bed, controlling the temperature of materials at 15-18 ℃, and granulating the Ranitidine hydrochloride.
The obtained granules are yellow and aggregated into clusters, which is not beneficial to drying and granule finishing.
Comparative example 3
Ranitidine hydrochloride granulation was performed on the formulation of example 1 of the invention and the material temperature parameters were screened.
The preparation process comprises the following steps:
weighing Ranitidine hydrochloride raw material medicine with a prescription dosage, placing the Ranitidine hydrochloride raw material medicine into a fluidized bed, spraying 3-5% starch slurry solution into the fluidized bed in an atomization mode, controlling the material temperature to be 60-65 ℃, and granulating the Ranitidine hydrochloride.
The prepared particles are uniformly distributed, but become yellow under the high-temperature condition, and the product properties are influenced.
Comparative example 4
Ranitidine hydrochloride granulation was performed on the formulation of example 1 of the invention, and the atomization pressure was screened.
The preparation process comprises the following steps:
weighing ranitidine hydrochloride raw material medicine with the prescription dosage, placing the ranitidine hydrochloride raw material medicine into a fluidized bed, spraying 3-5% starch slurry solution into the fluidized bed in an atomization mode, controlling the material temperature to be 25-30 ℃ and the atomization pressure to be 0.05MPa, and granulating the ranitidine hydrochloride.
The obtained granules are yellow and aggregated into clusters, which is not beneficial to drying and granule finishing.
Comparative example 5
Ranitidine hydrochloride granulation was performed on the formulation of example 1 of the invention, and the atomization pressure was screened.
The preparation process comprises the following steps:
weighing ranitidine hydrochloride raw material medicine with the prescription dosage, placing the ranitidine hydrochloride raw material medicine into a fluidized bed, spraying 3-5% starch slurry solution into the fluidized bed in an atomization mode, controlling the material temperature to be 25-30 ℃ and the atomization pressure to be 0.7MPa, and granulating the ranitidine hydrochloride.
The produced particles are adhered to the inner wall of the fluidized bed in a large amount, which is disadvantageous for drying and causes a decrease in yield.
Comparative example 6
Ranitidine hydrochloride granulation was performed on the formulation of example 1 of the invention and the binder spray rate was selected.
The preparation process comprises the following steps:
weighing ranitidine hydrochloride raw material medicine with the dosage of a prescription, placing the ranitidine hydrochloride raw material medicine into a fluidized bed, spraying 3-5% starch slurry solution into the fluidized bed in an atomization mode, controlling the temperature of the material to be 25-30 ℃ and the liquid spraying speed to be 0.1g/kg/min, and granulating the ranitidine hydrochloride.
The granulation time is as long as 2 hours, the efficiency of granule formation is low, the production efficiency is reduced, and unnecessary time and energy waste is caused.
Comparative example 7
Ranitidine hydrochloride granulation was performed on the formulation of example 1 of the invention and the binder spray rate was selected.
The preparation process comprises the following steps:
weighing ranitidine hydrochloride raw material medicine with the dosage of a prescription, placing the ranitidine hydrochloride raw material medicine into a fluidized bed, spraying 3-5% starch slurry solution into the fluidized bed in an atomization mode, controlling the temperature of the material to be 25-30 ℃ and the liquid spraying speed to be 6g/kg/min, and granulating the ranitidine hydrochloride.
The obtained granules are yellow and aggregated into clusters, which is not beneficial to drying and granule finishing.
Relevant quality parameters of the ranitidine hydrochloride capsule product prepared by the preparation method of the invention and the ranitidine hydrochloride capsule product prepared by the comparative example 1 are detected and compared through tests to prove the beneficial effects of the invention.
The method for measuring the impurities comprises the following steps:
an octadecylsilane chemically bonded silica chromatographic column is adopted, a mobile phase A is a phosphate buffer solution and acetonitrile (phosphate buffer solution: acetonitrile 98:2) system, a mobile phase B is a phosphate buffer solution and acetonitrile (phosphate buffer solution: acetonitrile: 78:22) system, the detection wavelength is 230nm, the flow rate is 1.0ml per minute, and the column temperature is 30 ℃.
Taking a product to be detected, adding a proper amount of a mobile phase A as a solution of the product to be detected, and taking the mobile phase A with the same volume as the solution of the product to be detected as a reference solution; detecting the solution to be detected and the solution to be compared by using a liquid chromatograph, and recording chromatograms. And subtracting the chromatogram of the reference solution from the chromatogram of the solution to be detected, and reading to obtain the content of the impurities in the sample to be detected.
Test example 1
According to the impurity detection method, the maximum single impurity content and total impurity content and appearance of the ranitidine hydrochloride capsule product prepared by the preparation method of the invention and the ranitidine hydrochloride capsule product prepared in the comparative example 1 are detected and observed, and the results are shown in table 1.
TABLE 1
| Traits | Maximum single impurity (%) | Total impurities (%) | |
| Example 1 | White to light yellow granules | 0.043 | 0.17 |
| Example 2 | White to light yellow granules | 0.045 | 0.18 |
| Example 3 | White to light yellow granules | 0.05 | 0.18 |
| Example 4 | White to light yellow granules | 0.05 | 0.17 |
| Comparative example 1 | Yellow granules | 0.071 | 0.35 |
The test data in table 1 show that the maximum single impurity content of the ranitidine hydrochloride capsule product prepared by the preparation process method is 0.04-0.05%, the total impurity content is 0.17-0.18%, and the content is obviously lower than that of the single impurity and total impurity in the comparative example 1. Test example 2
The ranitidine hydrochloride capsule product prepared by the preparation method of the invention and the ranitidine hydrochloride capsule product prepared in the comparative example 1 are stored for 3 months at the temperature of 40 ℃, and the maximum single impurity content and the maximum total impurity content of the ranitidine hydrochloride capsule product are detected, and the results are shown in table 2.
TABLE 2
| Traits | Maximum single impurity (%) | Total impurities (%) | |
| Example 1 | White to light yellow granules | 0.046 | 0.32 |
| Example 2 | White to light yellow granules | 0.072 | 0.34 |
| Example 3 | White to light yellow granules | 0.078 | 0.35 |
| Example 4 | White to light yellow granules | 0.069 | 0.35 |
| Comparative example 1 | Yellow granules | 0.10 | 0.66 |
The experimental data in table 2 show that after the ranitidine hydrochloride capsule product prepared by the preparation method of the invention is placed for 3 months, the maximum single impurity content is below 0.08%, the total impurity content is below 0.35%, and compared with the single impurity content of 0.1% and the total impurity content of 0.66% in the comparative example 1, the impurity content of the ranitidine hydrochloride capsule product prepared by the preparation method of the invention is obviously reduced.
Test example 3:
the ranitidine hydrochloride capsule product prepared by the preparation method of the invention and the ranitidine hydrochloride capsule product prepared in the comparative example 1 are stored for 6 months at the temperature of 40 ℃, and the maximum single impurity content and the maximum total impurity content of the ranitidine hydrochloride capsule product are detected, and the results are shown in table 3.
TABLE 3
| Traits | Maximum single impurity (%) | Total impurities (%) | |
| Example 1 | White to light yellow granules | 0.051 | 0.32 |
| Example 2 | White to light yellow granules | 0.069 | 0.35 |
| Example 3 | White to light yellow granules | 0.077 | 0.34 |
| Example 4 | White to light yellow granules | 0.072 | 0.36 |
| Comparative example 1 | Yellow granules | 0.15 | 0.87 |
The experimental data in table 3 show that after the ranitidine hydrochloride capsule product prepared by the preparation method of the invention is placed for 6 months, the maximum single impurity content is below 0.08%, the total impurity content is below 0.36%, and compared with the single impurity content of 0.15% and the total impurity content of 0.87% in the comparative example 1, the impurity content of the ranitidine hydrochloride capsule product prepared by the preparation method of the invention is obviously reduced.
The data in tables 1-3 show that, compared with comparative example 1, the ranitidine hydrochloride capsule prepared by the preparation method of the invention has the appearance of white to light yellow particles, and the appearance does not change after being stored at the temperature of 40 ℃ for 3-6 months; the ranitidine hydrochloride capsule product prepared by the preparation method of the invention has lower impurity content, and the impurity content after the ranitidine hydrochloride capsule product is placed is lower. The preparation method of the invention has the advantages of good product stability, reduced drug toxicity, and improved drug safety.
Claims (1)
1. A technical preparation method of a ranitidine hydrochloride capsule preparation is characterized by comprising the following steps: the preparation comprises the following components in percentage by weight:
ranitidine hydrochloride 95%
0.5 percent of starch
Sodium carboxymethyl starch 1.5%
1 percent of silicon dioxide
2% of magnesium stearate;
the preparation process comprises the following steps:
weighing ranitidine hydrochloride raw material medicine with the prescription dosage, placing the ranitidine hydrochloride raw material medicine into a fluidized bed, spraying 3% concentration starch slurry solution into the fluidized bed in an atomization mode, wherein the atomization pressure is 0.3MPa, the liquid spraying speed is 3g/kg/min, the material temperature is controlled to be 25-30 ℃, and granulating is carried out on ranitidine hydrochloride; continuously drying the materials by using a fluidized bed until the moisture content is less than 3 percent; sieving the granular materials with a 40-mesh sieve for granule stabilization, wherein the granules are uniform in size and are white to light yellow; adding the sodium carboxymethyl starch, the silicon dioxide and the magnesium stearate with the prescription dosage, mixing for 10min, and filling to obtain a ranitidine hydrochloride capsule product with 175mg of capsule content.
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| CN111272893A (en) * | 2020-02-28 | 2020-06-12 | 佛山手心制药有限公司 | Detection method and application of ranitidine hydrochloride |
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| CN1488345A (en) * | 2003-07-31 | 2004-04-14 | 雅来（佛山）制药有限公司 | Ranitidine hydrochloride capsule producing process |
| CN101002739A (en) * | 2005-09-26 | 2007-07-25 | 刘凤鸣 | Slow release preparation of ranitidine |
| CN101032479B (en) * | 2007-04-29 | 2010-09-22 | 丽珠医药集团股份有限公司 | Ranitidine bismuth citrate medicine and its preparing process |
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