CN109010303A - A kind of industrial production process of ranitidine hydrochloride capsules - Google Patents
A kind of industrial production process of ranitidine hydrochloride capsules Download PDFInfo
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- CN109010303A CN109010303A CN201810529481.3A CN201810529481A CN109010303A CN 109010303 A CN109010303 A CN 109010303A CN 201810529481 A CN201810529481 A CN 201810529481A CN 109010303 A CN109010303 A CN 109010303A
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- ranitidine hydrochloride
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—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
- A61K9/1682—Processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—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
- 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
- A61K9/1611—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—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
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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 present invention relates to a kind of preparation method of ranitidine hydrochloride capsules, main includes the supplementary material of following weight percent: ranitidine hydrochloride 55-99%；Filler 0-30%；Adhesive 0%-10%；Disintegrating agent 0-5%；Lubricant 0.01-5%；Using the prescription and preparation process after optimization, technique robustness, controllability and feasibility are effectively increased；The production process of ranitidine hydrochloride capsules is simplified, shortens the production operation period, improves production efficiency.
Description
Technical field
The present invention relates to a kind of industrial production process of ranitidine hydrochloride capsules, belong to pharmaceutical preparation preparation field.
Background technique
Ranitidine is potent histamine H2 receptor antagonist, can effectively inhibit histamine, pentagastrin and carbamyl gallbladder
Caused gastric acid secretion after alkali stimulation, reduces gastric acid and gastric activity, but on the secretion of gastrin and sex hormone without influence.Thunder Buddhist nun
It is fast for fourth oral absorption, it is not influenced by food and antiacid, it is high to the curative effect of gastric and duodenal ulcer, have quick-acting and long
The characteristics of effect, Small side effects and safety.
Ranitidine is the drug of most widely used treatment canker at present as Cimetidine.By Britain Ge Lan element
(glaxo) company develops.Synthesized by Britain's Price (price) etc. within 1976,1979 Bradshaw (bradshaw) illustrate
Its pharmacology, bass tower (berstad) report in 1980 is effective for duodenal ulcer, lists within 1981, in the world more or less a hundred
Countries use.Ranitidine effect is 5~8 times stronger than Cimetidine, and action time is more longlasting.Clinically it is mainly used for treating stomach
Hyper acid, heartburn, duodenal ulcer, benign gastric ulcer, postoperative ulcer, reflux esophagitis and zes etc., intravenous
It can be used for upper gastrointestinal bleeding.
In pharmaceutical production, capsule is by drug powder or the particles filled preparation in capsulae vacuus, it can cover medicine
The peculiar smell of object, irritation make it easy to swallow, and can also prevent drug dampness, light-exposed, oxidation to a certain extent, make its stabilization.
Ranitidine hydrochloride is off-white color or yellow crystalline powder, and mobility is poor, to damp and hot unstable, easily deliquesce and has and draw
It is moist, it is more harsh to ambient temperature and humidity requirement, and process operability is poor during preparation process thereof.It is exposed to for a long time
Operated products are unstable under high temperature and super-humid conditions, easily lead to impurity increase with material colour turn yellow, bring shadow to product quality
It rings.Usually by ranitidine hydrochloride bulk pharmaceutical chemicals by granulation, improve carry out after its dry jet mixing pile it is filling.
Current existing Ranitidine Capsules preparation process preparation method cannot avoid ranitidine hydrochloride in capsule completely
Unstable in preparation process thereof method and draw phenomena such as wet.Easily occur to show with what equipment adhered in granulation preparation process
As, and process is more and is related to that equipment is more, and each process period is longer, is unfavorable for the stabilization of product.So to one kind is developed
The good Ranitidine Capsules preparation of stability can be prepared, and is suitable for the Ranitidine Capsules preparation process system for industrializing amplification
There are demands for Preparation Method.
Summary of the invention
The present invention provides a kind of preparation process of ranitidine hydrochloride capsules preparation, wherein mainly comprising following
The supplementary material of weight percentage:
Mainly include following step:
Step 1: taking ranitidine hydrochloride, the filler mixing of above-mentioned formula ratio, make mixture at fluidized state；
Step 2: after mixed material preheating in step 1, atomization sprays into binder solution, while pelletize to material
Granule materials；
Step 3: granule materials in step 2 are dried；
Step 4: by the particle preparation in step 3 after drying at hybrid particles, described the step of preparing hybrid particles, includes
Whole grain and addition disintegrating agent, the mixed uniformly operation of lubricant；
Step 5: it is filling to get ranitidine hydrochloride capsules that the hybrid particles in step 4 being subjected to capsule filling.
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, the mode of whole grain includes that sieving is whole in step 4
Grain and crushing and pelletizing；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, the step of hybrid particles are prepared in step 4 are as follows:
Particle after will be dry in step 3 carries out sieving whole grain, then with disintegrating agent, mix lubricant it is uniform hybrid particles；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, the step of hybrid particles are prepared in step 4 are as follows:
Whole grain is carried out after particle and mix lubricant after will be dry in step 3, is then uniformly made with disintegrating agent, mix lubricant again
Hybrid particles；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, the weight of filler, adhesive and disintegrating agent
Percentage composition is not all 0, and preferably adhesive and disintegrating agent is not all 0, and most preferably disintegrating agent is not 0；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, filler is selected from starch, sucrose, dextrin, sulphur
One of sour calcium, microcrystalline cellulose, lactose are a variety of；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, adhesive is selected from starch slurry, povidone
(PVP), one of sodium carboxymethylcellulose, hypromellose or a variety of；
Binder solution is selected from one of binder aqueous solution or adhesive alcoholic solution or a variety of, preferably adhesive water
Solution；Wherein, adhesive alcoholic solution is preferably adhesive ethanol solution；Described adhesive solution can also individually select water or alcohol molten
Liquid mistization sprays into, such as selection water or ethyl alcohol；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, disintegrating agent be selected from starch, sodium carboxymethyl starch,
One of hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium are a variety of；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, lubricant is selected from stearic acid, magnesium stearate, hard
One of resin acid calcium, lauryl sodium sulfate, talcum powder, superfine silica gel powder, silica are a variety of；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, the work of above-mentioned ranitidine hydrochloride capsules preparation
In skill preparation method, the time that ranitidine hydrochloride, filler mix in step 1 is 10-40min；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, the temperature that material preheats in step 2 is 20 DEG C
~50 DEG C, preferably 25 DEG C~50 DEG C, more preferable 25 DEG C~45 DEG C；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, the temperature that material preheats in step 2 is 25 DEG C
~45 DEG C；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, the concentration of binder solution is sprayed into step 2
For 0-15% (w/w), preferably 0.05-15% (w/w)；More preferably 3-8% (w/w)；The most preferably concentration of binder solution
For 5% (w/w)；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, the concentration that adhesive is sprayed into step 2 is
0.05-15% (w/w)；It is preferred that the concentration for spraying into adhesive is 3-8% (w/w)；The concentration of more preferable adhesive is 5% (w/w)；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, the hydrojet of binder solution is sprayed into step 2
Speed is 0.2-5g/kg/min；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, the atomization of binder solution is sprayed into step 2
Pressure is 0.1~0.6MPa；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, material is dried to material water in step 3
Divide and is not higher than 3%；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, the mesh number being sieved in step 4 is 40 meshes；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, particle and disintegrating agent, lubricant are mixed in step 4
The time of conjunction is 5min~40min.
Further,
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, filler preferred starch, microcrystalline cellulose, cream
One of sugar is a variety of；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, adhesive preferred starch is starched, it is preferable to use dense
Spending is 3-8%, most preferably 5%；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, the preferred sodium carboxymethyl starch of disintegrating agent, crosslinking
One of povidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose are a variety of；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, the preferred magnesium stearate of lubricant, silica,
One of talcum powder is a variety of；
In the preparation process of ranitidine hydrochloride capsules preparation of the present invention, step 1 to step 3 is preferably in same equipment
Middle completion is such as completed in a fluidized bed；
It is further preferred that
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, the weight percentage of ranitidine hydrochloride is
80-97%, preferably 90-97%, such as 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, the weight percentage of filler is 0-
29.5%, preferably 0-18%, preferably 0-15%, preferably 0-7%, such as filler or a small amount of filler are not added；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, the weight percentage of adhesive is 0-
5.0%, preferably 0.5-5.0%；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, the weight percentage of disintegrating agent is 0.5-
2.0%, preferably 0.5-1.5%；
In the preparation process of above-mentioned ranitidine hydrochloride capsules preparation, the weight percentage of lubricant is 0.5-
3.5%, preferably 2-3.5%；
In the preferred embodiment of the invention, above-mentioned ranitidine hydrochloride capsules preparation includes the original of following weight percent
Auxiliary material: ranitidine hydrochloride 80-97%；Filler 0-29.5%；Adhesive 0-5.0%；Disintegrating agent 0.5-2.0%；Lubricant
0.5-3.5%.
In the preferred embodiment of the invention, above-mentioned ranitidine hydrochloride capsules preparation includes the original of following weight percent
Auxiliary material: ranitidine hydrochloride 80-97%；Filler 0-18%；Adhesive 0-5.0%；Disintegrating agent 0.5-2.0%；Lubricant
0.5-3.5%.
In the preferred embodiment of the invention, above-mentioned ranitidine hydrochloride capsules preparation includes the original of following weight percent
Auxiliary material: ranitidine hydrochloride 90-97%；Filler 0-15%；Adhesive 0.5-5.0%；Disintegrating agent 0.5-1.5%；Lubricant
2-3.5%.
In the preferred embodiment of the invention, above-mentioned ranitidine hydrochloride capsules preparation includes the original of following weight percent
Auxiliary material: ranitidine hydrochloride 90-97%；Filler 0-7%；Adhesive 0.5-5.0%；Disintegrating agent 0.5-1.5%；Lubricant 2-
3.5%.
In the preferred embodiment of the invention, above-mentioned ranitidine hydrochloride capsules preparation includes the original of following weight percent
Auxiliary material: ranitidine hydrochloride 79-88%, starch or lactose or microcrystalline cellulose 0-15%, croscarmellose sodium 1-
2%, silica 0.5-2.5%, magnesium stearate 1-2.6%.
In the preferred embodiment of the invention, above-mentioned ranitidine hydrochloride capsules preparation includes the original of following weight percent
Auxiliary material: ranitidine hydrochloride 88-94%, starch or microcrystalline cellulose 0-10%, starch or sodium carboxymethylcellulose 0.5-1%,
Sodium carboxymethyl starch 0.5-1.5%, talcum powder or silica 0.5-2.5%, magnesium stearate 1-1.5%.
In the preferred embodiment of the invention, above-mentioned ranitidine hydrochloride capsules preparation includes the original of following weight percent
Auxiliary material: ranitidine hydrochloride 94-97%, starch or povidone or sodium carboxymethylcellulose 0.5-2%, sodium carboxymethyl starch 0.5-
2%, silica 1-2%, magnesium stearate 0.5-2%.
In the preferred embodiment of the invention, above-mentioned ranitidine hydrochloride capsules preparation includes the original of following weight percent
Auxiliary material: ranitidine hydrochloride 94-97%, starch or povidone or sodium carboxymethylcellulose 0.5-2%, sodium carboxymethyl starch 0.5-
1%, silica 1 .5-2%, magnesium stearate 0.5-1%.
The bulk pharmaceutical chemicals solid powder mobility of ranitidine hydrochloride is poor, to damp and hot unstable, easily deliquesces, to technique system
Temperature and humidity is more sensitive during standby, and temperature height is easy to cause material easy coloring to turn yellow, and impurity increases, and temperature is low can be due to solid
The poor fluidity of powder and be easy agglomeration, particle in good condition can not be formed.
The present invention screen through a large number of experiments obtain ranitidine hydrochloride capsules optimization formulation, wherein component selection and
The combination of ratio makes drug have good powder flowbility, is suitable for one-step method granulating process and capsule of the present invention
Filling；Especially under the premise of significantly improving main ingredient ranitidine content, by the optimum organization of auxiliary material so that prescription with
One-step method granulation and filling technique have excellent adaptability, achieve satisfactory synergy.The present invention is prepared
Ranitidine Capsules have good drug dissolution and bioavilability, In Vitro Dissolution is experiments have shown that capsule of the present invention
It can be dissolved out completely in 10min, take orally absolute bioavailability up to 50% or more, impurity content is significantly lower than conventional wet legal system
Grain, and discoloration does not occur.
On the other hand, it is also inventor according to ranitidine hydrochloride medicine that the present invention, which prepares the technique of Ranitidine Capsules preparation,
Object own characteristic screens the optimum process of acquisition for capsule prescription of the present invention through a large number of experiments.Material in granulation step
Temperature has large effect to the physicochemical property of ranitidine hydrochloride, and the particle prepared when temperature is less than 20 DEG C is in yellow and aggregation
Agglomerating, particle discoloration is yellow when temperature is greater than 50 DEG C, and controlling 20 DEG C~50 DEG C of suitable material preheating temperature range can avoid
Material moisture absorption is gathered, and the white being evenly distributed is made to pale yellow coloured particles, maintains the stability of ranitidine hydrochloride.Control system
0.1~the 0.6MPa of atomizing pressure and hydrojet 0.2~5g/kg/min of speed of adhesive during grain can make particle obtained big
It is small uniformly and to keep relative distribution not assemble agglomerating, atomizing pressure is too small or the excessive adhesive that may cause of hydrojet speed is in part
It concentrates and forms particle aggregation, the excessive adhesive of atomizing pressure is sprayed onto equipment inner wall and then easily causes particle in pot wall adherency, spray
Liquid speed spends the small efficiency that can reduce particle formation, causes Granulation time to extend, production efficiency reduces and unnecessary energy wave
Take.Hydrojet speed is calculated with the amount (g/kg/min) that every kilogram of material sprays into adhesive per minute, and it is different to fully take into account production
Requirement of the bulk article to hydrojet speed, is suitble to various production scales.To operation temperature, incorporation time, atomizing pressure, hydrojet speed
The optimization for spending, controlling the parameters such as entire preparation period, substantially improves existing ranitidine hydrochloride capsules preparation process preparation side
Deficiency in method improves the stability of ranitidine hydrochloride capsules preparation, drug safety etc..
Compared in the prior art,
It is suitable in optimal control pelletization that ranitidine hydrochloride capsules preparation process preparation method of the invention passes through
The parameters such as mixed material temperature, atomizing pressure and hydrojet speed, keep material in formulation process prevented from caking, can form state
Good particle, the ranitidine hydrochloride capsules preparation granules being prepared are uniform, reduce API and equipment room adhesiveness, have
Effect improves ranitidine hydrochloride in formulation process since impurity increases the problem of making material coloring turn yellow；
The time that ranitidine hydrochloride capsules preparation process preparation method of the invention is mixed by optimal control material
5min~40min, make in ranitidine hydrochloride capsules formulation process guarantee be uniformly mixed while, avoid hydrochloric acid thunder Buddhist nun
Issuable impurity increases when being externally exposed environment for a long time for fourth, turn yellow etc., reduce the need to environment temperature and humidity
Ask, at the same reduce magnesium stearate lubricant because incorporation time it is too long caused by cross lubrication influence capsule disintegration and dissolution wind
Danger effectively improves the feasibility of technique amplification industrialized production；
Material mixing in ranitidine hydrochloride capsules preparation process preparation method of the invention, granulation and granule materials
Drying carried out in same equipment, the optimization grain made parameters such as hydrojet speed, the operation cycle is 1h or so, is preferably shortened entire
In the Granulation time period of preparation process thereof, it is convenient to operate, and reduces individual drying process and drying equipment in the prior art,
Keep technical process operation simpler, significantly improves production efficiency, and equipment energy consumption is effectively reduced.
In conclusion prescription and technique of the present invention by optimization ranitidine hydrochloride capsules preparation, so that preparation method
Technique is smooth, and material is in uniform fine particles, effectively increases technique robustness and process controllability and feasibility；Simplify hydrochloric acid
The production process of Ranitidine Capsules shortens the production operation period, improves production efficiency；Granulation front and back material color with it is miscellaneous
Matter content situation is almost the same, and preparation impurity content is without dramatically increasing after preparation accelerates storage in 3 months and 6 months to place, significantly
Improve ranitidine hydrochloride capsules formulation products quality and drug safety.
The present invention also provides a kind of hydrochloric acid thunders that above-mentioned ranitidine hydrochloride capsules preparation process preparation method is prepared
Buddhist nun replaces fourth capsule preparations.
The present invention also provides a kind of hydrochloric acid thunders that above-mentioned ranitidine hydrochloride capsules preparation process preparation method is prepared
Buddhist nun is for fourth capsule preparations in preparation for treating or preventing the purposes in histamine H2-receptor related disease drug.
The ranitidine hydrochloride capsules that ranitidine hydrochloride capsules preparation process preparation method of the invention is prepared can
Preparation is used for: treatment hyperhydrochloria, heartburn, duodenal ulcer, benign gastric ulcer, postoperative ulcer, reflux esophagitis, on disappear
Change the histamine H2-receptors related disease such as gastrointestinal hemorrhage and zes.
In addition to being suitable for human treatment, the ranitidine hydrochloride capsules that preparation process of the invention is prepared are also suitable
For the veterinary treatment of companion animals, exotic animals and farm-animals including mammal, rodent etc., such as horse, dog
And cat.
Specific embodiment
The specific embodiment of form by the following examples makees further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
The preparation of the ranitidine hydrochloride capsules of the present invention of embodiment 1
Preparation process:
The ranitidine hydrochloride bulk pharmaceutical chemicals for weighing prescription dosage are placed in fluidized bed, by the starch slurry solution of 3% concentration with
Atomised form sprays into fluidized bed, atomizing pressure 0.3MPa, hydrojet speed 3g/kg/min, 25-30 DEG C of temperature of charge of control, right
Ranitidine hydrochloride is pelletized；Continue to carry out to moisture less than 3% dry materials with fluidized bed；Granule materials are crossed into 40 mesh
Sieve carries out whole grain, and even particle size is white to light yellow.Be added the sodium carboxymethyl starch of prescription dosage, silica and
It is filling to be prepared into the ranitidine hydrochloride capsules product that capsule 's content is 175mg after the auxiliary materials mixing such as magnesium stearate 10min.
The preparation of the ranitidine hydrochloride capsules of the present invention of embodiment 2
Preparation process:
The ranitidine hydrochloride and starch for weighing prescription dosage are mixed in fluidized bed and in fluidized states, make water fogging
It spraying into, atomizing pressure 0.2MPa, hydrojet speed 4g/kg/min are preheated and are controlled 30-35 DEG C of mixed material temperature and pelletize,
Material particle state to be mixed is good, is dried to moisture granule materials obtained not higher than 3%；Granule materials are crossed 40
Mesh screen carries out whole grain, and even particle size is white to light yellow.The croscarmellose sodium of addition prescription dosage,
It is filling to be prepared into the ranitidine hydrochloride glue that capsule 's content is 210mg after the auxiliary materials mixing such as talcum powder and magnesium stearate 15min
Capsule product.
The preparation of the ranitidine hydrochloride capsules of the present invention of embodiment 3
Preparation process:
The ranitidine hydrochloride bulk pharmaceutical chemicals and lactose for weighing recipe quantity are mixed in fluidized bed, by the povidone of 8% concentration
Aqueous solution atomization sprays into fluidized bed, and atomizing pressure 0.5MPa, hydrojet speed 0.2g/kg/min are preheated and controlled temperature of charge
It pelletizes after 35-40 DEG C, continues to be not higher than 3% to granule materials drying to moisture in fluidized bed；Granule materials are crossed into 40 mesh
After sieve carries out whole grain, even particle size is white to light yellow.Recipe quantity low-substituted hydroxypropyl cellulose, dioxy is added
It is filling to be prepared into the ranitidine hydrochloride capsules that capsule 's content is 280mg after the auxiliary materials mixing such as SiClx and magnesium stearate 30min
Product.
The preparation of the ranitidine hydrochloride capsules of the present invention of embodiment 4
Preparation process:
The ranitidine hydrochloride bulk pharmaceutical chemicals and microcrystalline cellulose for weighing recipe quantity are mixed in fluidized bed, by 3% concentration hydroxyl
The atomization of third methylated cellulose aqueous solution sprays into fluidized bed, and atomizing pressure 0.5MPa, hydrojet speed 0.5g/kg/min, preheating is simultaneously
It pelletizes after 40-45 DEG C of temperature of charge of control, granule materials drying to moisture is not higher than after material particle state is good
3%；Even particle size, white to light yellow after whole grain.Prescription dosage croscarmellose sodium, silica is added
It is filling to be prepared into the ranitidine hydrochloride capsules product that capsule 's content is 240mg with the auxiliary materials mixing such as magnesium stearate 35min.
The preparation of the ranitidine hydrochloride capsules of the present invention of embodiment 5
Preparation process:
The ranitidine hydrochloride bulk pharmaceutical chemicals and lactose for weighing recipe quantity are mixed in fluidized bed, by the carboxymethyl of 15% concentration
The atomization of sodium cellulosate aqueous solution sprays into fluidized bed, and atomizing pressure 0.2MPa, hydrojet speed 1g/kg/min are preheated and controlled object
It pelletizes after 35-40 DEG C of material temperature degree, continues to be not higher than 3% to granule materials drying to moisture in fluidized bed；By granule materials
After crossing 40 mesh screens progress whole grain, even particle size is white to light yellow.Recipe quantity low substituted hydroxy-propyl fiber is added
It is filling to be prepared into the hydrochloric acid thunder Buddhist nun that capsule 's content is 320mg after the auxiliary materials mixing 30min such as element, silica and magnesium stearate
For fourth capsule product.
The preparation of the ranitidine hydrochloride capsules of the present invention of embodiment 6
Preparation process:
The ranitidine hydrochloride bulk pharmaceutical chemicals and lactose for weighing recipe quantity are mixed in fluidized bed, by the povidone of 8% concentration
Aqueous solution atomization sprays into fluidized bed, and atomizing pressure 0.4MPa, hydrojet speed 4g/kg/min are preheated and controlled temperature of charge 35-
It pelletizes after 40 DEG C, continues to be not higher than 3% to granule materials drying to moisture in fluidized bed；By granule materials and silica
After carrying out crushing and pelletizing, even particle size is white to light yellow.Recipe quantity low-substituted hydroxypropyl cellulose, tristearin is added
It is filling to be prepared into the ranitidine hydrochloride capsules product that capsule 's content is 280mg after the auxiliary materials mixing such as sour magnesium 30min.
The preparation of the ranitidine hydrochloride capsules of the present invention of embodiment 7
Preparation process:
The ranitidine hydrochloride bulk pharmaceutical chemicals and lactose for weighing recipe quantity are mixed in fluidized bed, by the carboxymethyl of 15% concentration
The atomization of sodium cellulosate aqueous solution sprays into fluidized bed, and atomizing pressure 0.2MPa, hydrojet speed 0.8g/kg/min are preheated and controlled
It pelletizes after 35-40 DEG C of temperature of charge, continues to be not higher than 3% to granule materials drying to moisture in fluidized bed；By particulate matter
After material carries out crushing and pelletizing, even particle size is white to light yellow.Recipe quantity low-substituted hydroxypropyl cellulose, two is added
It is filling to be prepared into the ranitidine hydrochloride glue that capsule 's content is 320mg after the auxiliary materials mixing such as silica and magnesium stearate 30min
Capsule product.
The preparation of the ranitidine hydrochloride capsules of the present invention of embodiment 8
Preparation process:
The ranitidine hydrochloride bulk pharmaceutical chemicals and microcrystalline cellulose for weighing recipe quantity are mixed in fluidized bed, by 10% concentration
The atomization of povidone aqueous solution sprays into fluidized bed, and atomizing pressure 0.3MPa, hydrojet speed 3g/kg/min are preheated and controlled material
It pelletizes after 45-50 DEG C of temperature, continues to be not higher than 3% to granule materials drying to moisture in fluidized bed；By granule materials into
It went after 40 mesh screen whole grains, even particle size is white to light yellow.Addition recipe quantity croscarmellose sodium,
It is filling to be prepared into the ranitidine hydrochloride that capsule 's content is 320mg after the auxiliary materials mixing such as silica and magnesium stearate 30min
Capsule product.
The preparation of the ranitidine hydrochloride capsules of the present invention of embodiment 9
Preparation process:
The ranitidine hydrochloride bulk pharmaceutical chemicals and lactose for weighing recipe quantity are mixed in fluidized bed, by the povidone of 8% concentration
Aqueous solution atomization sprays into fluidized bed, and atomizing pressure 0.2MPa, hydrojet speed 1g/kg/min are preheated and controlled temperature of charge 25-
It pelletizes after 30 DEG C, continues to be not higher than 3% to granule materials drying to moisture in fluidized bed；Granule materials crush whole
After grain, even particle size is white to light yellow.Recipe quantity low-substituted hydroxypropyl cellulose, silica, stearic acid is added
It is filling to be prepared into the ranitidine hydrochloride capsules product that capsule 's content is 280mg after the auxiliary materials mixing such as magnesium 30min.
The preparation of the ranitidine hydrochloride capsules of the present invention of embodiment 10
Preparation process:
The ranitidine hydrochloride bulk pharmaceutical chemicals and lactose for weighing recipe quantity are mixed in fluidized bed, by the povidone of 15% concentration
Aqueous solution atomization sprays into fluidized bed, and atomizing pressure 0.2MPa, hydrojet speed 0.5g/kg/min are preheated and controlled temperature of charge
It pelletizes after 20-25 DEG C, continues to be not higher than 3% to granule materials drying to moisture in fluidized bed；By particle and silica
After carrying out crushing and pelletizing, even particle size is white to light yellow.Recipe quantity croscarmellose sodium and tristearin is added
It is filling to be prepared into the ranitidine hydrochloride capsules product that capsule 's content is 320mg after the auxiliary materials mixing such as sour magnesium 30min.
Comparative example 1
The preparation of ranitidine hydrochloride capsules is carried out to the prescription of the embodiment of the present invention 2 using existing process of preparing.
Preparation process:
The ranitidine hydrochloride of prescription dosage and starch are added into wet granulator, aqueous solution is added dropwise to wet process system
Softwood processed in grain machine, softwood are crossed after 30 mesh Shai Zhi wet granulars with oven drying to moisture less than 3%.Granule materials are crossed into 40 meshes
Whole grain is carried out, after the auxiliary materials mixing 15min such as croscarmellose sodium, talcum powder and the magnesium stearate of prescription dosage are added,
It is filling to be prepared into the ranitidine hydrochloride capsules product that capsule 's content is 210mg.
Comparative example 2
Ranitidine hydrochloride granulation, material screening temperature parameter are carried out to the prescription of the embodiment of the present invention 11.
Preparation process:
The ranitidine hydrochloride bulk pharmaceutical chemicals and microcrystalline cellulose for weighing recipe quantity are mixed in fluidized bed, by 3% concentration hydroxyl
The atomization of third methylated cellulose aqueous solution sprays into fluidized bed, 15-18 DEG C of temperature of charge is controlled, to ranitidine hydrochloride system
Grain.
Particle obtained is in yellow and aggregation is agglomerating, is unfavorable for dry and whole grain.
Comparative example 3
Ranitidine hydrochloride granulation, material screening temperature parameter are carried out to the prescription of the embodiment of the present invention 1.
Preparation process:
The ranitidine hydrochloride bulk pharmaceutical chemicals for weighing prescription dosage are placed in fluidized bed, by the starch slurry solution of 3-5% concentration
It is sprayed into fluidized bed with atomised form, controls 60-65 DEG C of temperature of charge, pelletize to ranitidine hydrochloride.
Even particle distribution obtained, but turned yellow in hot conditions, influence product characteristics.
Comparative example 4
Ranitidine hydrochloride granulation is carried out to the prescription of the embodiment of the present invention 1, screens atomizing pressure.
Preparation process:
The ranitidine hydrochloride bulk pharmaceutical chemicals for weighing prescription dosage are placed in fluidized bed, by the starch slurry solution of 3-5% concentration
It is sprayed into fluidized bed with atomised form, controls 25-30 DEG C of temperature of charge, atomizing pressure 0.05MPa, ranitidine hydrochloride is carried out
Granulation.
Particle obtained is in yellow and aggregation is agglomerating, is unfavorable for dry and whole grain.
Comparative example 5
Ranitidine hydrochloride granulation is carried out to the prescription of the embodiment of the present invention 1, screens atomizing pressure.
Preparation process:
The ranitidine hydrochloride bulk pharmaceutical chemicals for weighing prescription dosage are placed in fluidized bed, by the starch slurry solution of 3-5% concentration
It is sprayed into fluidized bed with atomised form, controls 25-30 DEG C of temperature of charge, atomizing pressure 0.7MPa, ranitidine hydrochloride is carried out
Granulation.
Particle obtained is largely adhered to fluidized bed inner wall, is unfavorable for drying, and will cause yield reduction.
Comparative example 6
Ranitidine hydrochloride granulation is carried out to the prescription of the embodiment of the present invention 1, screens adhesive hydrojet speed.
Preparation process:
The ranitidine hydrochloride bulk pharmaceutical chemicals for weighing prescription dosage are placed in fluidized bed, by the starch slurry solution of 3-5% concentration
It is sprayed into fluidized bed with atomised form, controls 25-30 DEG C of temperature of charge, hydrojet speed 0.1g/kg/min, to ranitidine hydrochloride
It pelletizes.
Granulation time is up to 2 hours, and the low efficiency that particle is formed, production efficiency reduces, and causes unnecessary time and energy
Source waste.
Comparative example 7
Ranitidine hydrochloride granulation is carried out to the prescription of the embodiment of the present invention 1, screens adhesive hydrojet speed.
Preparation process:
The ranitidine hydrochloride bulk pharmaceutical chemicals for weighing prescription dosage are placed in fluidized bed, by the starch slurry solution of 3-5% concentration
With atomised form spray into fluidized bed in, control 25-30 DEG C of temperature of charge, hydrojet speed 6g/kg/min, to ranitidine hydrochloride into
Row granulation.
Particle obtained is in yellow and aggregation is agglomerating, is unfavorable for dry and whole grain.
Ranitidine hydrochloride capsules product prepared by preparation method of the present invention and comparison are compared below by way of testing inspection
The correlated quality parameter of ranitidine hydrochloride capsules product prepared by example 1, to prove beneficial effects of the present invention.
Impurity determination method:
Using octadecylsilane chemically bonded silica chromatographic column, mobile phase A is phosphate buffer and acetonitrile (phosphate-buffered
Liquid: acetonitrile=98:2) system, Mobile phase B be phosphate buffer and acetonitrile (phosphate buffer: acetonitrile=78:22) system,
Detection wavelength is 230nm, and flow velocity is 1.0ml per minute, and column temperature is 30 DEG C.
Product to be measured is taken, mobile phase A is added to be used as product to be tested solution in right amount, takes the mobile phase with product to be tested solution same volume
A is reference substance solution；Product to be tested solution and reference substance solution are detected using liquid chromatograph, record chromatogram.It is to be measured
After product solution chromatogram deducts reference substance solution chromatogram, impurity content in product to be tested is read to obtain.
Test example 1
According to above-mentioned method for detecting impurities, to the ranitidine hydrochloride capsules being prepared by present invention process preparation method
The largest single impurity of ranitidine hydrochloride capsules product prepared by product and comparative example 1 and total miscellaneous content and appearance carry out detection and
Observation, the results are shown in Table 1.
Table 1
| Character | Largest single impurity (%) | Total miscellaneous (%) | |
| Embodiment 1 | White is to pale yellow coloured particles | 0.043 | 0.17 |
| Embodiment 2 | White is to pale yellow coloured particles | 0.045 | 0.18 |
| Embodiment 3 | White is to pale yellow coloured particles | 0.05 | 0.18 |
| Embodiment 4 | White is to pale yellow coloured particles | 0.05 | 0.17 |
| Comparative example 1 | Yellow particle | 0.071 | 0.35 |
1 test data of table shows that the maximum of the ranitidine hydrochloride capsules product of process of preparing preparation of the present invention is single
Miscellaneous content between 0.04~0.05%, total miscellaneous content between 0.17~0.18%, the list substantially less than in comparative example 1 it is miscellaneous and
Total miscellaneous content.Test example 2
It prepared by ranitidine hydrochloride capsules product and comparative example 1 that aforementioned present invention preparation process is prepared
Ranitidine hydrochloride capsules product is carried out at a temperature of 40 DEG C after placing storage 3 months, to ranitidine hydrochloride capsules product
Largest single impurity and total miscellaneous content are detected, and the results are shown in Table 2.
Table 2
| Character | Largest single impurity (%) | Total miscellaneous (%) | |
| Embodiment 1 | White is to pale yellow coloured particles | 0.046 | 0.32 |
| Embodiment 2 | White is to pale yellow coloured particles | 0.072 | 0.34 |
| Embodiment 3 | White is to pale yellow coloured particles | 0.078 | 0.35 |
| Embodiment 4 | White is to pale yellow coloured particles | 0.069 | 0.35 |
| Comparative example 1 | Yellow particle | 0.10 | 0.66 |
2 test data of table shows that the ranitidine hydrochloride capsules product of present invention process preparation method preparation is placing 3
After month, largest single impurity content is 0.08% hereinafter, always miscellaneous content is 0.35% hereinafter, relative to the list miscellaneous 0.1% in comparative example 1
With total miscellaneous 0.66% content, the impurity content of the ranitidine hydrochloride capsules product of present invention process preparation method preparation is significant
It reduces.
Test example 3:
It prepared by ranitidine hydrochloride capsules product and comparative example 1 that aforementioned present invention preparation process is prepared
Ranitidine hydrochloride capsules product is carried out at a temperature of 40 DEG C after placing storage 6 months, to ranitidine hydrochloride capsules product
Largest single impurity and total miscellaneous content are detected, and the results are shown in Table 3.
Table 3
| Character | Largest single impurity (%) | Total miscellaneous (%) | |
| Embodiment 1 | White is to pale yellow coloured particles | 0.051 | 0.32 |
| Embodiment 2 | White is to pale yellow coloured particles | 0.069 | 0.35 |
| Embodiment 3 | White is to pale yellow coloured particles | 0.077 | 0.34 |
| Embodiment 4 | White is to pale yellow coloured particles | 0.072 | 0.36 |
| Comparative example 1 | Yellow particle | 0.15 | 0.87 |
3 test data of table shows that the ranitidine hydrochloride capsules product of present invention process preparation method preparation is placing 6
After month, largest single impurity content is 0.08% hereinafter, always miscellaneous content is 0.36% hereinafter, miscellaneous relative to the list in comparative example 1
The impurity of 0.15% and total miscellaneous 0.87% content, the ranitidine hydrochloride capsules product of present invention process preparation method preparation contains
Amount significantly reduces.
1~table of consolidated statement 3 statistics indicate that, relative to comparative example 1, present invention process preparation method preparation hydrochloric acid thunder Buddhist nun replace
The appearance character of fourth capsule product is white to pale yellow coloured particles, appearance character after storage is placed 3~6 months at a temperature of 40 DEG C
It is unchanged；The ranitidine hydrochloride capsules product of present invention process preparation method preparation, which is shown, has lower impurity content, and
And the impurity content after placing is lower.Show the ranitidine hydrochloride capsules product stability of present invention process preparation method preparation
It is good, the drug toxicity in the use process of ranitidine hydrochloride is advantageously reduced, drug safety is improved.
Claims (13)
1. a kind of preparation process of ranitidine hydrochloride capsules preparation, it is characterized in that: mainly containing comprising following weight percentage
The supplementary material of amount:
Mainly include following step:
Step 1: taking ranitidine hydrochloride, the filler mixing of above-mentioned formula ratio, make mixture at fluidized state；
Step 2: after mixed material preheating in step 1, atomization sprays into binder solution, while carrying out particle of pelletizing to obtain to material
Material；
Step 3: granule materials in step 2 are dried；
Step 4: for the particle preparation after will be dry in step 3 at hybrid particles, described the step of preparing hybrid particles includes whole grain
And disintegrating agent, the mixed uniformly operation of lubricant is added；
Step 5: it is filling to get ranitidine hydrochloride capsules that the hybrid particles in step 4 being subjected to capsule filling；
Wherein, step 1 is completed in same equipment to step 3, is preferably completed in a fluidized bed.
2. the preparation process of ranitidine hydrochloride capsules preparation as described in claim 1, characterized in that the step 4
The mode of middle whole grain includes sieving whole grain and crushing and pelletizing.
3. the preparation process of ranitidine hydrochloride capsules preparation as claimed in claim 1 or 2, characterized in that the step
The step of preparing hybrid particles in rapid 4 are as follows: the particle after will be dry in step 3 carries out sieving whole grain, then with disintegrating agent, lubrication
Agent is uniformly mixed to obtain hybrid particles.
4. the preparation process of ranitidine hydrochloride capsules preparation as claimed in claim 1 or 2, characterized in that the step
The step of preparing hybrid particles in rapid 4 are as follows: carry out whole grain after the particle and mix lubricant after will be dry in step 3, then again
Hybrid particles are uniformly made with disintegrating agent, mix lubricant.
5. the preparation process of ranitidine hydrochloride capsules preparation as described in any one of Claims 1 to 4, it is characterized in that: filling out
The weight percentage for filling agent, adhesive and disintegrating agent is not all 0, and preferably adhesive and disintegrating agent is not all 0, is most preferably disintegrated
Agent is not 0.
6. the preparation process of ranitidine hydrochloride capsules preparation as described in any one of Claims 1 to 5, it is characterized in that: filling out
It fills agent and is selected from one of starch, sucrose, dextrin, calcium sulfate, microcrystalline cellulose, lactose or a variety of；Adhesive be selected from starch slurry,
One of povidone (PVP), sodium carboxymethylcellulose, hypromellose, water are a variety of；Disintegrating agent is selected from starch, carboxylic
Methyl starch sodium, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, crospovidone, in croscarmellose sodium
It is one or more；Lubricant be selected from stearic acid, magnesium stearate, calcium stearate, lauryl sodium sulfate, talcum powder, superfine silica gel powder,
One of silica is a variety of；
Or, one of filler preferred starch, microcrystalline cellulose, lactose or a variety of；One in adhesive preferred starch slurry, water
Kind is a variety of；The preferred sodium carboxymethyl starch of disintegrating agent, crospovidone, croscarmellose sodium, low substituted hydroxy-propyl are fine
Tie up one of element or a variety of；One of the preferred magnesium stearate of lubricant, silica, talcum powder are a variety of.
7. the preparation process of ranitidine hydrochloride capsules preparation as described in claim any one of 1-6, it is characterized in that: step
The time that ranitidine hydrochloride, filler mix in 1 is 10-40min；The temperature that material preheats in step 2 is 20 DEG C~50 DEG C,
It is preferred that 25 DEG C~50 DEG C, more preferable 25 DEG C~45 DEG C；The concentration for spraying into adhesive is 0-15% (w/w), preferably 0.05-15%
(w/w), more preferable 3-8% (w/w), most preferably 5% (w/w)；Material is dried to material moisture not higher than 3% in step 3；
Or, the time that ranitidine hydrochloride, filler mix in step 1 is 10-40min；The temperature of material preheating is in step 2
25 DEG C~45 DEG C；The concentration for spraying into adhesive is 0.05-15% (w/w)；Material is dried not high to material moisture in step 3
In 3%；It is preferred that the concentration for spraying into adhesive is 3-8% (w/w)；The concentration of more preferable adhesive is 5% (w/w)；
Or, the time that ranitidine hydrochloride, filler mix in step 1 is 10-40min；The temperature of material preheating is in step 2
20 DEG C~50 DEG C, preferably 25 DEG C~50 DEG C, more preferable 25 DEG C~45 DEG C；The concentration for spraying into adhesive is 0-15% (w/w), preferably
0.05-15% (w/w), more preferable 3-8% (w/w), most preferably 5% (w/w)；Hydrojet speed is 0.2-5g/kg/min；Atomization
Pressure is 0.1~0.6MPa；Material is dried to material moisture not higher than 3% in step 3.
8. the preparation process of ranitidine hydrochloride capsules preparation as described in claim any one of 1-7, it is characterized in that: step
The mesh number being sieved in 4 is 40 meshes, particle and disintegrating agent, mix lubricant time be 5min~40min.
9. the preparation process of ranitidine hydrochloride capsules preparation as described in claim any one of 1-8, it is characterized in that: hydrochloric acid
The weight percentage of ranitidine is 80-97%；The weight percentage of filler is 0-29.5%；The weight hundred of adhesive
Dividing content is 0-5.0%；The weight percentage of disintegrating agent is 0.5-2.0%；The weight percentage of lubricant is 0.5-
3.5%；
Or, the weight percentage of ranitidine hydrochloride is 80-97%；The weight percentage of filler is 0-18%；Bonding
The weight percentage of agent is 0-5.0%；The weight percentage of disintegrating agent is 0.5-2.0%；The weight percent of lubricant contains
Amount is 0.5-3.5%.
10. the preparation process of ranitidine hydrochloride capsules preparation as described in claim any one of 1-9, it is characterized in that: salt
The weight percentage of sour ranitidine is 90-97%；The weight percentage of filler is 0-15%；The weight hundred of adhesive
Dividing content is 0.5-5.0%；The weight percentage of disintegrating agent is 0.5-1.5%；The weight percentage of lubricant is 2-
3.5%；
Or, the weight percentage of ranitidine hydrochloride is 90-97%；The weight percentage of filler is 0-7%；Adhesive
Weight percentage be 0.5-5.0%；The weight percentage of disintegrating agent is 0.5-1.5%；The weight percent of lubricant contains
Amount is 2-3.5%.
11. the preparation process of ranitidine hydrochloride capsules preparation as described in claim any one of 1-10, it is characterised in that
The preparation includes the supplementary material of following weight percent: ranitidine hydrochloride 94-97%, starch or povidone or carboxymethyl
Sodium cellulosate 0.5-2%, sodium carboxymethyl starch 0.5-2%, silica 1-2%, magnesium stearate 0.5-2%.
Or, ranitidine hydrochloride 94-97%, starch or povidone or sodium carboxymethylcellulose 0.5-2%, sodium carboxymethyl starch
0.5-1%, silica 1 .5-2%, magnesium stearate 0.5-1%.
What 12. a kind of preparation process of any one of claim 1-11 ranitidine hydrochloride capsules preparation was prepared
Ranitidine hydrochloride capsules.
13. ranitidine hydrochloride capsules as claimed in claim 12 are in preparation for the use in histamine H2-receptor related disease drug
On the way.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111202718A (en) * | 2020-02-25 | 2020-05-29 | 北京鑫开元医药科技有限公司 | Ranitidine hydrochloride capsule and preparation method thereof |
| 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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| 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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