CN115089551B - Tadalafil tablet and preparation method thereof - Google Patents
Tadalafil tablet and preparation method thereof Download PDFInfo
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- CN115089551B CN115089551B CN202210360815.5A CN202210360815A CN115089551B CN 115089551 B CN115089551 B CN 115089551B CN 202210360815 A CN202210360815 A CN 202210360815A CN 115089551 B CN115089551 B CN 115089551B
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- 229960000835 tadalafil Drugs 0.000 title claims abstract description 52
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 45
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims abstract description 108
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 88
- 239000008101 lactose Substances 0.000 claims abstract description 88
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 36
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 35
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 35
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 35
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 35
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims abstract description 29
- 229920002785 Croscarmellose sodium Polymers 0.000 claims abstract description 27
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 27
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 27
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229960001681 croscarmellose sodium Drugs 0.000 claims abstract description 24
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 24
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims abstract description 23
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims abstract description 23
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 18
- 239000007888 film coating Substances 0.000 claims abstract description 5
- 238000009501 film coating Methods 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims description 88
- 239000002245 particle Substances 0.000 claims description 73
- 239000007864 aqueous solution Substances 0.000 claims description 31
- 238000001035 drying Methods 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 26
- 239000008187 granular material Substances 0.000 claims description 21
- 239000000463 material Substances 0.000 claims description 19
- 239000007779 soft material Substances 0.000 claims description 18
- 238000000576 coating method Methods 0.000 claims description 17
- 239000011248 coating agent Substances 0.000 claims description 15
- 239000011812 mixed powder Substances 0.000 claims description 15
- 238000005303 weighing Methods 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 13
- 238000005520 cutting process Methods 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 abstract description 63
- 239000003814 drug Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 229940057948 magnesium stearate Drugs 0.000 abstract description 2
- 238000011835 investigation Methods 0.000 description 28
- 239000000843 powder Substances 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 239000000080 wetting agent Substances 0.000 description 16
- 238000002474 experimental method Methods 0.000 description 14
- 239000002609 medium Substances 0.000 description 14
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 14
- 229920000053 polysorbate 80 Polymers 0.000 description 14
- 239000000203 mixture Substances 0.000 description 12
- 239000002994 raw material Substances 0.000 description 12
- 230000008569 process Effects 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 238000009472 formulation Methods 0.000 description 8
- 238000005469 granulation Methods 0.000 description 8
- 230000003179 granulation Effects 0.000 description 8
- 208000010228 Erectile Dysfunction Diseases 0.000 description 7
- 201000001881 impotence Diseases 0.000 description 7
- 239000000853 adhesive Substances 0.000 description 6
- 230000001070 adhesive effect Effects 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000001186 cumulative effect Effects 0.000 description 6
- 238000009826 distribution Methods 0.000 description 6
- 238000011160 research Methods 0.000 description 5
- 238000001179 sorption measurement Methods 0.000 description 5
- 238000001694 spray drying Methods 0.000 description 5
- 230000008859 change Effects 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000005457 optimization Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 230000004584 weight gain Effects 0.000 description 4
- 235000019786 weight gain Nutrition 0.000 description 4
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 3
- 244000309466 calf Species 0.000 description 3
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 230000001502 supplementing effect Effects 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
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- 238000007689 inspection Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 101100296726 Caenorhabditis elegans pde-5 gene Proteins 0.000 description 1
- 101100189582 Dictyostelium discoideum pdeD gene Proteins 0.000 description 1
- 206010057672 Male sexual dysfunction Diseases 0.000 description 1
- 101150098694 PDE5A gene Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 102100029175 cGMP-specific 3',5'-cyclic phosphodiesterase Human genes 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 210000005226 corpus cavernosum Anatomy 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000000635 electron micrograph Methods 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000031864 metaphase Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000005453 pelletization Methods 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000031877 prophase Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000036259 sexual stimuli Effects 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Gynecology & Obstetrics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly discloses a tadalafil tablet and a preparation method thereof. The tadalafil tablet comprises the following components: tadalafil, lactose (315), croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, microcrystalline cellulose, magnesium stearate, and film coating premixes. The product of the invention has good stability and complete dissolution, and has better quality compared with the original ground medicine; the preparation method of the product of the invention is simple and easy to operate and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a tadalafil tablet and a preparation method thereof.
Background
Studies have shown that about half of individuals in men over 40 years old suffer from Erectile Dysfunction (ED), severely affecting their quality of life. Aiming at the pathogenesis of ED, expert scholars at home and abroad conduct intensive research from multiple angles. In particular, significant research results have been achieved at the level of the signal transduction pathway, and the NO-cGMP signal pathway has been demonstrated to be a critical pathway for the onset of ED. The research result is also applied to clinic, and has obvious clinical effects as selective inhibitors of type 5 phosphodiesterase (PDE 5) specific to cyclic guanosine monophosphate (cGMP), such as sildenafil and tadalafil for treating ED.
Tadalafil (Tadalafil) is a reversible, selective PDE5 inhibitor developed by gift companies to treat male Erectile Dysfunction (ED), which was approved by the FDA for marketing on 11/23 2003. The action mechanism is as follows: when there is a sexual stimulus that causes nitric oxide to be released locally from the corpora cavernosa, PDE5 is inhibited by tadalafil, which increases cGMP levels in the blood vessels of the penis and the cavernosa smooth muscle cells, resulting in relaxation of cavernosa smooth muscle, arterial blood inflow, penile congestion, rigidity, and erection. For example, in asexual stimulation, tadalafil does not act.
Tadalafil is a poorly soluble drug and U.S. patent No.6841167 discloses that its solubility in water at 25 ℃ is 2 μg/ml, so that it has a low dissolution rate and low bioavailability. Thus, the study of tadalafil and its improved bioavailability in related pharmaceutical formulations is particularly important for its wide clinical application in the treatment of male sexual dysfunction.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition containing tadalafil, and the tadalafil tablet has the advantages of small variation of total impurities and single impurity content and good dissolution.
Another object of the present invention is to provide a method for preparing tadalafil tablets as described above, which is simple to operate and suitable for industrial production.
In order to solve the technical problems, the invention provides the following technical scheme:
a tadalafil tablet comprising the following components: tadalafil, lactose (315), croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, microcrystalline cellulose, magnesium stearate, and film coating premixes.
Specifically, the tadalafil tablet comprises the following components in percentage by weight: 15-25 parts of tadalafil, 190-210 parts of lactose, 30-40 parts of lactose (315), 25-30 parts of croscarmellose sodium, 5-10 parts of hydroxypropyl cellulose, 0.5-1.0 part of sodium dodecyl sulfate, 55-60 parts of microcrystalline cellulose, 1.0-2.0 parts of magnesium stearate and 7.0-10 parts of film coating premix.
Preferably, the tadalafil tablet comprises the following components in parts by weight: 20 parts of tadalafil, 198 parts of lactose, 35 parts of lactose (315), 28 parts of croscarmellose sodium, 8.05 parts of hydroxypropyl cellulose, 0.98 part of sodium dodecyl sulfate, 58.22 parts of microcrystalline cellulose, 1.75 parts of magnesium stearate and 8.75 parts of film coating premix.
The invention also claims a preparation method of the tadalafil tablet, which comprises the following steps:
s1, weighing lactose (315) with a prescription amount and tadalafil, and adding the lactose and tadalafil into a three-dimensional mixer to be uniformly mixed to obtain mixed powder;
s2, placing the mixed powder into a wet granulator, adding lactose, hydroxypropyl cellulose and croscarmellose sodium, and uniformly mixing;
s3, preparing an aqueous solution of sodium dodecyl sulfate, and adding the aqueous solution into a wet granulator to prepare a soft material;
s4, granulating by adopting a 20-mesh sieve of a swing granulator;
s5, drying particles by using a fluidized bed, controlling the moisture of the particles to be 0.5-2.5%, and taking out the particles;
s6, adopting a 20-mesh sieve of a swing granulator to carry out granule finishing;
s7, placing the particles, microcrystalline cellulose and magnesium stearate into a three-dimensional motion mixer, and uniformly mixing;
s8, tabletting: tabletting with hardness of 8-11 kg;
s9, coating liquid dosage: the weight is increased by 2-3% based on the solid.
Preferably, the mixing time in step S1 is 10min and the rotation speed is 250-350r/min.
Preferably, in step S2, the stirring speed is set to 140rpm, the cutting speed is 1800rpm, and the mixing is performed for 10min.
Preferably, in the step S3, the liquid adding time of the sodium dodecyl sulfate aqueous solution is controlled to be 0.5-1.5min; when preparing soft materials, setting stirring rotation speed at 140rpm, cutting rotation speed at 1800rpm, and stirring for 3-5min.
Preferably, in the step S5, the air inlet temperature is set to be 80 ℃, the air inlet temperature is controlled to be less than 90 ℃, and the material temperature is controlled to be less than 80 ℃.
Preferably, the frequency is set to 44.9-45.1Hz in step S7, and the mixing is carried out for 15-30min.
More preferably, in a specific embodiment, the preparation method comprises the steps of:
s1, weighing lactose (315) with a prescription amount and tadalafil, adding the lactose and tadalafil into a three-dimensional mixer, and mixing for 10min at a rotating speed of 250-350r/min to obtain mixed powder;
s2, placing the mixed powder into a wet granulator, adding lactose, hydroxypropyl cellulose and croscarmellose sodium, setting the stirring rotation speed to 140rpm, and setting the cutting rotation speed to 1800rpm, and mixing for 10min;
s3, preparing an aqueous solution of sodium dodecyl sulfate, and adding the aqueous solution into a wet granulator, wherein the liquid adding time is controlled to be 0.5-1.5min; preparing a soft material, setting the stirring rotation speed to be 140rpm, setting the cutting rotation speed to be 1800rpm, and stirring for 3-5min;
s4, granulating by adopting a 20-mesh sieve of a swing granulator;
s5, drying particles by adopting a fluidized bed, setting the air inlet temperature to be 80 ℃, controlling the air inlet temperature to be less than 90 ℃, controlling the material temperature to be less than 80 ℃, controlling the moisture of the particles to be 0.5-2.5%, and taking out;
s6, adopting a 20-mesh sieve of a swing granulator to carry out granule finishing;
s7, placing the particles, microcrystalline cellulose and magnesium stearate into a three-dimensional motion mixer, setting the frequency to be 44.9-45.1Hz, and mixing for 15-30min;
s8, tabletting: tabletting with hardness of 8-11 kg;
s9, coating liquid dosage: the weight is increased by 2-3% based on the solid.
Compared with the prior art, the invention has the following advantages and positive effects:
1. the product of the invention has good stability and complete dissolution.
2. The preparation process of the product is simple and feasible to operate, and is suitable for industrial production.
Drawings
FIG. 1 shows the results of examination of the particle size distribution of lactose of different types.
FIG. 2 is a lactose electron microscope of different model.
FIG. 3 is a comparison of dissolution curves of microcrystalline cellulose addition modes.
FIG. 4 is a comparison of dissolution curves of croscarmellose sodium in addition.
FIG. 5 is a comparison of dissolution curves for the manner in which the adhesive is added.
FIG. 6 shows the dissolution profile of the drying mode and the particle moisture investigation.
Fig. 7 is a dissolution profile for a granulation parameter study.
FIG. 8 shows a dissolution profile for a wet addition investigation.
FIG. 9 shows dissolution curves for mixing time and tablet hardness.
Fig. 10 is a prescription optimized dissolution profile.
Detailed Description
The present invention will be described in further detail with reference to the following examples, which are not intended to limit the present invention, but are merely illustrative of the present invention. The experimental methods used in the following examples are not specifically described, but the experimental methods in which specific conditions are not specified in the examples are generally carried out under conventional conditions, and the materials, reagents, etc. used in the following examples are commercially available unless otherwise specified.
Test example-initial prescription and Process design
Based on EMC literature information, the lactose dose in the recipe was 233mg, and the initial tablet core recipe was designed in combination with the example information in the patent filed by the original research company as shown in table 1 below.
Table 1 initial prescription design
The preparation process comprises the following steps:
(1) weighing the prescription amount of tadalafil and lactose (spraying) for dispersing and mixing uniformly;
(2) weighing lactose, hydroxypropyl cellulose and croscarmellose sodium with the prescription amount, placing into a wet mixing granulator, adding tadalafil and lactose (spraying) mixed powder, and uniformly mixing;
(3) preparing an aqueous solution of hydroxypropyl cellulose/sodium dodecyl sulfate as a wetting agent;
(4) adding a wetting agent into a wet mixing granulator to prepare a soft material, and granulating by adopting a swing granulator;
(5) drying the granules, finishing the granules by adopting a swinging granulator, and placing the granules in a mixer;
(6) weighing microcrystalline cellulose, externally added croscarmellose sodium and magnesium stearate according to the prescription amount, placing the microcrystalline cellulose, the externally added croscarmellose sodium and the magnesium stearate into a mixer, and mixing the materials;
(7) adjusting the weight and pressure of the tablet to carry out tabletting;
(8) coating parameters are adjusted to carry out coating.
1. Powder study of lactose (spray drying) of different models
According to the original grinding company patent, the preparation process firstly mixes the raw materials with spray-dried lactose, and then mixes the mixture with other materials for wet granulation. The reason for analyzing the premix addition of spray dried lactose was: 1) Because the particle size of the raw materials is smaller, large-particle lactose is adopted for dispersion, so that the mixing effect is improved; 2) Promoting the disintegration of the tablet.
Therefore, the powder engineering parameters of the raw materials and lactose with larger particles are firstly examined, and the examination items are as follows:
(1) Traits: visual inspection;
(2) Bulk density/tap density: measuring by using a tap density tester;
(3) Angle of repose: measuring by adopting an angle of repose measuring instrument;
(4) Particle size distribution: weighing a proper amount of materials, and sieving with 60 meshes, 80 meshes, 100 meshes, 120 meshes and 200 meshes. The particle size distribution was measured by weighing.
The results are shown in tables 2-3 and FIGS. 1-2.
TABLE 2 results of examination of the parameters of different types of lactose powder
Remarks: the karl index calculation formula is as follows: karl index= (tap density-bulk density)/tap density x 100%
TABLE 3 investigation of the particle size distribution of lactose of different types
| The ratio of% | ＞250μm | 180-250μm | 150-180μm | 125-150μm | 75-125μm | ＜75μm |
| Screen mesh number | > 60 mesh | 60-80 mesh | 80-100 mesh | 100-120 mesh | 120-200 meshes | Less than 200 meshes |
| Lactose Granulac 70 | 0.62 | 8.24 | 32.58 | 29.89 | 22.91 | 5.76 |
| Lactose Tablettose 80 | 17.67 | 20.74 | 29.00 | 5.82 | 15.96 | 10.81 |
| Lactose Flowlac100 | 0.76 | 25.47 | 45.36 | 2.55 | 11.12 | 14.75 |
| Lactose 315 | 2.78 | 19.06 | 32.35 | 4.52 | 21.80 | 19.50 |
Conclusion of experiment:
(1) From the karl index analysis, the raw material fluidity was poor, and therefore the angle of repose could not be measured. From the analysis of the karl index and angle of repose data, the different types of lactose flowability from high to low were lactose Flowlac100, lactose 315, lactose tabletose 80, lactose Granulac 70, respectively.
(2) From the particle size distribution results, the three types of lactose, flowlac100, tabletose 80 and 315, have more large particles and thus exhibit better flowability. Lactose grade 70 has a relatively high amount of fine powder and therefore has relatively poor flowability.
(3) From the electron micrograph, lactose Flowlac100 has a spherical shape, and thus has excellent fluidity. Three types of lactose, granulac 70, tabletose 80 and 315, exhibit irregular shapes, flowability depends on their particle size, and in combination with particle size distribution results, granulac 70 lactose has relatively poor flowability, and tabletose 80 and 315 have similar flowability.
2. Prescription investigation of lactose (spray drying) of different models
Combining with the examination of the powder parameters of different types of lactose, the four lactose fluidity ranges from high to low: flowlac100, 315, tabletose 80, granulac 70. Because Granulac 70 has poor fluidity and more powder, the powder is not easy to be dispersed and mixed with the raw materials uniformly. Thus, prescription studies were performed on the other three lactose models. The recipe is shown in Table 4.
Table 4 lactose prescriptions of different models
The preparation process comprises the following steps:
(1) weighing the prescription amount of tadalafil and lactose (spray drying), placing the mixture in a small mixer (two-dimensional mixer), mixing for 10min, and detecting the mixing uniformity;
(2) placing the powder into a wet granulator, adding lactose, hydroxypropyl cellulose and croscarmellose sodium with prescribed amount, and mixing with appropriate parameters;
(3) preparing an aqueous solution of HPC/SDS, adding the aqueous solution into a wet granulator, supplementing water, and preparing a soft material according to proper parameters;
(4) granulating with a 20-mesh sieve of a swing granulator;
(5) drying the particles by adopting an oven, and measuring the moisture;
(6) finishing grains by adopting a 20-mesh sieve of a swinging granulator;
(7) calculating the yield of the particles and the addition amount of the additional components, and placing the particles, the microcrystalline cellulose, the crosslinked sodium carboxymethylcellulose and the magnesium stearate into a three-dimensional motion mixer for mixing for 15min;
(8) tabletting with proper hardness;
after the tabletting is finished, the disintegration time of the reference preparation and the self-made product is measured, and the content uniformity of the self-made product is detected. The experimental results are shown in table 5.
TABLE 5 lactose prescriptions investigation results for different models
| Lot number | 18110901 | 18110902 | 18110903 |
| Lactose model | Tablettose 80 | Flowlac100 | 315 |
| Tablet weight g | 0.3510 | 0.3541 | 0.3506 |
| Hardness kg | 9.72 | 10.90 | 9.37 |
| Upon disintegrationLimiting min | 2.68 | 3.01 | 2.28 |
| Uniformity of mixing | 2.23 | 4.76 | 1.89 |
| Content uniformity | 6.87 | 6.78 | 6.86 |
The dissolution profile results are shown in table 6.
Dissolution conditions: the paddle method, 0.5% Tween 80+pH1.0 hydrochloric acid medium volume 1000ml, speed 50rpm, temperature 37 ℃.
TABLE 6 results of investigation of lactose 315 prescription dissolution curves
| Cumulative dissolution% | 0 | 5min | 10min | 15min | 30min | 45min | 60min | 90min | f2 |
| 18110903 | 0 | 40.21 | 57.17 | 67.18 | 80.26 | 87.31 | 89.66 | 90.72 | 64.3 |
| C852831 | 0 | 45.51 | 63.09 | 73.50 | 80.54 | 85.41 | 87.30 | 89.07 | — |
Conclusion of experiment:
from the experimental results, when the three types of lactose and tadalafil are mixed under the same conditions, the uniformity of mixing is from good to poor of 315, tablettose 80 and Flowlac100. The prepared tablet has no obvious difference in disintegration time and content uniformity. Lactose 315 was selected for subsequent study. The dissolution curve is fit with the reference preparation, the prescription dosage tried according to the patent literature and other documents is more proper, and the prescription dosage of each auxiliary material is not adjusted temporarily.
3. Investigation of microcrystalline cellulose addition mode
In the original patent, microcrystalline cellulose is added by an external addition method, and the internal addition method is examined, and the prescription is shown in table 7.
Table 7 microcrystalline cellulose addition protocol investigation recipe
The preparation process comprises the following steps:
(1) weighing the prescription amount of tadalafil and lactose (spray drying), placing in a three-dimensional mixer, and mixing for 10min;
(2) placing the powder into a wet granulator, adding lactose, hydroxypropyl cellulose, croscarmellose sodium and microcrystalline cellulose with prescribed amounts, and mixing with appropriate parameters;
(3) preparing an aqueous solution of HPC/SDS, adding the aqueous solution into a wet granulator, supplementing water, and preparing a soft material according to proper parameters;
(4) granulating with a 20-mesh sieve of a swing granulator;
(5) drying the particles by adopting an oven, and measuring the moisture;
(6) finishing grains by adopting a 20-mesh sieve of a swinging granulator;
(7) calculating the yield of the particles and the addition amount of the additional components, and placing the particles, the microcrystalline cellulose, the crosslinked sodium carboxymethylcellulose and the magnesium stearate into a three-dimensional motion mixer for mixing for 15min;
(8) and tabletting while keeping the main pressure unchanged.
The experimental results are shown in table 8 and fig. 3.
Dissolution conditions: the paddle method, 0.5% Tween 80+pH1.0 hydrochloric acid medium volume 1000ml, speed 50rpm, temperature 37 ℃.
Table 8 microcrystalline cellulose addition mode investigation results
Remarks: 18110903 the preparation process is shown in 3.2.P.2.2.1.6 lactose (spray drying) prescription investigation of different types.
Conclusion of experiment:
after internal addition, the compressibility of the microcrystalline cellulose is increased, the disintegration is slowed down, and the earlier dissolution period is slower than that of the reference preparation, so that the microcrystalline cellulose is added in an external form later. The 18110903 batches are similar to the reference preparation, so the dosage of the prescription is not adjusted, and the addition modes of the disintegrating agent and the adhesive are examined.
4. Inspection of the adding mode of croscarmellose sodium
In the original patent, the disintegrating agent adopts an internal and external adding mode, and the dissolution condition of the internal and external adding mode is examined. The recipe is shown in Table 9.
Table 9 sodium croscarmellose addition mode investigation recipe
The preparation process comprises the following steps:
(1) weighing the prescription amount of lactose (315), placing the lactose into a three-dimensional mixer, mixing for 5min, and adding the prescription amount of tadalafil into the lactose, and mixing for 10min;
(2) placing the powder into a wet granulator according to a prescription adding mode, adding the prescription amount of lactose, hydroxypropyl cellulose and croscarmellose sodium (added according to prescription requirements), and mixing with proper parameters;
(3) preparing an aqueous solution of HPC/SDS, adding the aqueous solution into a wet granulator, supplementing water, and preparing a soft material according to proper parameters;
(4) granulating with a 20-mesh sieve of a swing granulator;
(5) drying the particles by adopting an oven, and measuring the moisture;
(6) finishing grains by adopting a 20-mesh sieve of a swinging granulator;
(7) calculating the yield of the particles and the addition amount of the additional components according to the addition mode of the prescription, and placing the particles, the croscarmellose sodium, the microcrystalline cellulose and the magnesium stearate into a three-dimensional motion mixer for mixing for 15min;
(8) tabletting with proper hardness;
the experimental results are shown in table 10 and fig. 4.
Dissolution conditions: the paddle method, 0.5% Tween 80+pH1.0 hydrochloric acid medium volume 1000ml, speed 50rpm, temperature 37 ℃.
Table 10 examination of results of sodium croscarmellose addition mode
Conclusion of experiment:
the f2 values of 18110903, 19010701 and 19010801 in-line mode are all greater than 50 compared to the reference formulation dissolution. 19010801, the tentative cross-linked sodium carboxymethylcellulose is in the form of an intragranular addition.
5. Investigation of the manner of adding hydroxypropyl cellulose
The adding mode of the hydroxypropyl cellulose in the original grinding patent is internal addition and wetting agent addition, and whether all internal addition has great influence on dissolution is examined. The prescription is shown in table 11.
Table 11 adhesive addition mode investigation recipe
The preparation process comprises the following steps:
(1) weighing the prescription amount of lactose (315), placing the lactose into a three-dimensional mixer, mixing for 5min, and adding the prescription amount of tadalafil into the lactose, and mixing for 10min;
(2) placing the powder into a wet granulator, adding lactose, croscarmellose sodium and hydroxypropyl cellulose with prescribed amounts, and mixing with appropriate parameters;
(3) preparing an aqueous solution of SDS, adding the aqueous solution into a wet granulator, and preparing a soft material according to proper parameters;
(4) granulating with a 20-mesh sieve of a swing granulator;
(5) drying the particles by adopting an oven, and measuring the moisture;
(6) finishing grains by adopting a 20-mesh sieve of a swinging granulator;
(7) calculating the yield of the particles and the addition amount of the additional components, and placing the particles, the microcrystalline cellulose and the magnesium stearate into a three-dimensional motion mixer for mixing for 15min;
(8) tabletting with proper hardness;
the experimental results are shown in table 12 and fig. 5.
Dissolution conditions: the paddle method, 0.5% Tween 80+pH1.0 hydrochloric acid medium volume 1000ml, speed 50rpm, temperature 37 ℃.
Table 12 investigation of the adhesive addition mode results
Conclusion of experiment:
from the experimental results, the 19011601 batch of adhesive is added in an internal mode, and the 19010801 batch of adhesive is added in an internal mode and the wetting agent is added in an internal mode, so that f2 meets the requirements compared with the reference preparation. The tentative hydroxypropylcellulose is in the form of intraparticle addition.
6. Microcrystalline cellulose model investigation
And (3) examining by combining with the microcrystalline cellulose adding mode, and determining that the microcrystalline cellulose is added in an additional mode. The microcrystalline cellulose type powder selected in the previous study is more, and the fluidity is reduced when the microcrystalline cellulose type powder is mixed with particles. Therefore, the microcrystalline cellulose model was examined for the overall powder mix morphology. The experimental results are shown in table 13.
TABLE 13 results of investigation of microcrystalline cellulose type
| Lot number | 19011601 Total mixed powder | 19012101 Total mixed powder |
| Microcrystalline cellulose model | CG-1 | SH-102 |
| Bulk Density g/ml | 0.524 | 0.520 |
| Tap density g/ml | 0.649 | 0.622 |
| Calf index% | 19.30 | 16.36 |
| Angle of repose alpha ° | 36.87 | 33.42 |
In summary, microcrystalline cellulose CG-1 has no obvious difference with SH-102, but the flowability of the SH-102 model is better. And in the prior patent application, the microcrystalline cellulose model is definitely 102. Therefore, SH-102 model was selected for subsequent study.
7. Preliminary prescription determination
In summary, the prepared tablets meet the requirements of all indexes. Therefore, the usage amount of the components with smaller proportion of the hydroxypropyl cellulose, the sodium dodecyl sulfate and the magnesium stearate is not examined. The results are detailed in the following prescription, and are amplified primarily, and detailed in table 14.
Table 14 preliminary prescription determination
And the preliminary influencing factors are examined, the conditions are high temperature 60 ℃, high humidity 92.5% RH and illumination 4500Lux, and the standing time is 30 days. The experimental results are shown in table 15.
TABLE 15 Primary prescription determination influencing factor results
Remarks: the related substances are counted by the impurity G, and other impurities are not detected.
After the sample is placed by the influencing factors, the content and related substances have no obvious change.
Development of test example two production Process
1. Mixed mode investigation
Because the particle size of the dabrafil raw material is small, the static electricity is large, and the dabrafil raw material is not easy to be uniformly mixed with other materials, and the premixing mode is examined. The scheme is as follows: 1. mixing spray-dried lactose and tadalafil in a wet mixing granulator, and adding common lactose and other materials in batches; 2. placing the materials together in a wet mixing granulator for mixing; 3. after the spray-dried lactose and tadalafil are mixed in a three-dimensional mixer, other materials are placed in a wet mixing granulator for mixing. The prescription design is shown in table 16.
Table 16 premix mode investigation recipe
The preparation process comprises the following steps:
(1) 19012301, putting tadalafil and lactose (315) into a wet mixing granulator, and putting 19030801 into a three-dimensional mixer for premixing;
(2) 19012301, adding other materials in batches, 19030801, placing all the materials in the particles in a wet mixing granulator, taking 19030401, mixing the raw materials with lactose spray, and placing the mixture with the other materials in the wet mixing granulator for mixing;
(3) preparing an aqueous solution of SDS, adding the aqueous solution into a wet granulator, and preparing a soft material according to proper parameters;
(4) granulating with a 20-mesh sieve of a swing granulator;
(5) drying the particles by adopting an oven, and measuring the moisture;
(6) finishing grains by adopting a 20-mesh sieve of a swinging granulator;
(7) calculating the yield of the particles and the addition amount of the additional components, and placing the particles, the microcrystalline cellulose and the magnesium stearate into a three-dimensional motion mixer for mixing for 15min;
(8) tabletting is carried out with proper hardness.
The experimental results are shown in table 17.
Table 17 premix run test results
Conclusion of experiment:
experimental results show that 19030401 batches of tadalafil and lactose (315) are uniformly dispersed after being premixed by a three-dimensional mixer, so that the adsorption degree of raw materials on the surface of equipment is reduced. The prepared tablet has the content and content uniformity meeting the requirements; 19012301 when tadalafil and lactose (315) are premixed by a wet mixing granulator, the adsorption degree is deepened easily due to severe mixing degree, the mixing is required to be cleaned in time, the production operation is inconvenient, the content uniformity of the prepared tablets meets the requirements, but the content of the individual tablets does not meet the requirements, and the general mixing effect is indicated; 19030801 the batch is directly mixed by adopting a wet mixing granulator, the adsorption degree is general, the adsorption degree needs to be cleaned in time, and the prepared tablets have relatively poor content and content uniformity which meet the requirements although the mixing time is prolonged.
In summary, the premixing mode is selected from the steps of dispersing and premixing tadalafil and lactose (315) in a three-dimensional mixer. And then other materials are placed in a wet mixing granulator for mixing. In order to further reduce the adsorption degree, lactose (315) is firstly mixed for a period of time during premixing, and then tadalafil raw materials are added for premixing; during mixing, other auxiliary materials are placed in a wet mixing granulator for mixing for a period of time, and then the tadalafil and the premixed powder of the lactose spray are added for mixing.
2. Drying mode and particle moisture investigation
In the previous studies, the wet granules were dried in an oven. In order to reduce the drying time, the fluidized drying mode was examined, and at the same time, the particle moisture was examined. The prescription is shown in table 18.
Table 18 drying mode and granule moisture investigation recipe
The preparation process comprises the following steps:
(1) weighing the prescription amount of lactose (315), and adding tadalafil into a three-dimensional mixer to mix for 10min;
(2) placing the powder into a wet granulator, adding common lactose, hydroxypropyl cellulose and croscarmellose sodium, and mixing with appropriate parameters;
(3) preparing an aqueous solution of SDS, adding the aqueous solution into a wet granulator, and preparing a soft material according to proper parameters;
(4) granulating with a 20-mesh sieve of a swing granulator;
(5) drying the particles by adopting a fluidized bed, and taking out the particles when the moisture of the particles is 2% -3%, 1% -2% and less than 1%;
(6) adopting a 20-mesh sieve of a swinging granulator to carry out granule finishing;
(7) calculating the yield of the particles and the addition amount of the additional components, and placing the particles, the microcrystalline cellulose and the magnesium stearate into a three-dimensional motion mixer for mixing for 15min;
(8) measuring the bulk density/tap density, repose angle and fine powder rate of the total mixed powder;
(9) tabletting with proper hardness; the dissolution curve of the tablet is detected, the influence factors are placed, and the change of related substances is inspected.
The experimental results are shown in tables 19-21 and FIG. 6.
Table 19 drying method and results of examination of particle moisture content-1
Table 20 drying method and results of examination of particle moisture content-2
Dissolution profile results:
dissolution conditions: the paddle method, 0.5% Tween 80+pH1.0 hydrochloric acid medium volume 1000ml, speed 50rpm, temperature 37 ℃.
Table 21 drying method and results of examination of particle moisture-3
| Cumulative dissolution% | 0 | 5min | 10min | 15min | 30min | 45min | 60min | 90min | f2 |
| C852831 | 0 | 45.51 | 63.09 | 73.50 | 80.54 | 85.41 | 87.30 | 89.07 | — |
| 19030501-1 | 0 | 40.95 | 61.02 | 70.26 | 82.8 | 88.12 | 91.32 | 94.62 | 73.8 |
| 19030501-2 | 0 | 46.47 | 62.95 | 71.96 | 83.08 | 88.63 | 92.08 | 95.87 | 86.6 |
| 19030501-3 | 0 | 38.79 | 58.37 | 68.49 | 80.86 | 86.9 | 90.83 | 93.53 | 65.4 |
Conclusion of experiment:
the method of boiling drying is feasible, and the prepared total mixed powder has good fluidity and meets the tabletting requirement. The dissolution curve of the prepared tablet is f2 qualified compared with that of a reference preparation.
The particle moisture of the reference preparation is detected to be 1-2%, and the particle moisture is inspected to be within the range of not more than 2.5%, so that the dissolution curve is well matched with the reference preparation, and the requirements are met. Through the influence factor experiment, the content of the tablet and related substances have no obvious change. Thus, the suggested particle moisture range is not more than 2.5%.
3. Examination of the pelletization Process
During wet granulation, stirring, shearing speed, time and wetting agent addition mode have certain influence on the soft material, so that the granule properties and dissolution after tabletting are influenced. Because of the amplifying effect from the laboratory to the production plant, the granulation parameters are examined in the laboratory stage at the extreme, i.e. the soft mass is prepared by the relaxing parameters and the soft mass is prepared by the severe parameters. Thus, the trend of the influence of the granulation parameters on dissolution was analyzed. The prescription is shown in table 22.
Table 22 examination of the formulation of the granulation process
The preparation process comprises the following steps:
(1) the prescribed amount of lactose (315) and tadalafil are weighed into a three-dimensional mixer and mixed for 10 minutes.
(2) Placing the powder into a wet granulator, adding common lactose, hydroxypropyl cellulose and croscarmellose sodium, and mixing with appropriate parameters;
(3) preparing an aqueous solution of SDS, adding the aqueous solution into a wet granulator, and preparing a soft material according to set parameters;
(4) granulating with a 20-mesh sieve of a swing granulator;
(5) drying the particles by using a fluidized bed, wherein the moisture of the particles is required to be 0.5-2.5%, and taking out;
(6) adopting a 20-mesh sieve of a swinging granulator to carry out granule finishing;
(7) calculating the yield of the particles and the addition amount of the additional components, and placing the particles and the addition amount of the additional components in a three-dimensional motion mixer for mixing for 15min;
(8) measuring the bulk density/tap density, repose angle and fine powder rate of the total mixed powder;
(9) tabletting with proper hardness; the tablets were tested for dissolution profile.
The experimental results are shown in tables 23-24 and FIG. 7.
Table 23 granulation parameter investigation results-1
| Lot number | 19031301 | 19031302 |
| Degree of granulation | Moderating | Severe intensity |
| Particle moisture% | 1.45 | 1.63 |
| Bulk Density g/ml | 0.547 | 0.504 |
| Tap density g/ml | 0.641 | 0.602 |
| Calf index% | 14.63 | 16.29 |
| Angle of repose degree | 34.99 | 36.50 |
| 80 mesh sieve fines ratio% | 72.2 | 69.2 |
Dissolution profile results:
dissolution conditions: the paddle method, 0.5% Tween 80+pH1.0 hydrochloric acid medium volume 1000ml, speed 50rpm, temperature 37 ℃.
Table 24 granulation parameter investigation results-2
| Cumulative dissolution% | 0 | 5min | 10min | 15min | 30min | 45min | 60min | 90min | f2 |
| C852831 | 0 | 45.51 | 63.09 | 73.50 | 80.54 | 85.41 | 87.30 | 89.07 | — |
| 19031301 | 0 | 43.98 | 58.07 | 66.18 | 76.61 | 82.36 | 86.14 | 90.46 | 65.0 |
| 19031302 | 0 | 37.02 | 54.92 | 64.68 | 76.06 | 83 | 86.16 | 89.77 | 55.5 |
Conclusion of experiment:
under the condition that the wetting agent is suitable, the granule properties prepared by different granulating parameters are not obviously different, the dissolution curves of the pressed tablets are not obviously different, and f2 meets the requirements compared with the reference preparation. Therefore, the granulating parameter has less influence on the dissolution curve under the condition that the addition amount of the wetting agent is proper.
4. Inspection of the amount of wetting agent added
The amount of wetting agent added affects the granule properties and thus tablet dissolution. We examined the different wetting agent addition under the appropriate granulation parameters. The recipe is shown in Table 25.
Table 25 wetting agent addition investigation recipe
The preparation process comprises the following steps:
(1) the prescribed amount of lactose (315) and tadalafil are weighed into a three-dimensional mixer and mixed for 10 minutes.
(2) Placing the powder into a wet granulator, adding common lactose, hydroxypropyl cellulose and croscarmellose sodium, and mixing with appropriate parameters;
(3) preparing an aqueous solution of SDS, adding the aqueous solution into a wet granulator, and preparing a soft material according to set parameters;
(4) granulating with a 20-mesh sieve of a swing granulator;
(5) drying the particles by using a fluidized bed, wherein the moisture of the particles is required to be 0.5-2.5%, and taking out;
(6) adopting a 20-mesh sieve of a swinging granulator to carry out granule finishing;
(7) calculating the yield of the particles and the addition amount of the additional components, and placing the particles and the addition amount of the additional components in a three-dimensional motion mixer for mixing for 15min;
(8) measuring the bulk density/tap density, repose angle and fine powder rate of the total mixed powder;
(9) tabletting with proper hardness; the tablets were tested for dissolution profile.
The experimental results are shown in tables 26-27 and FIG. 8.
Table 26 wetting agent addition investigation results-1
| Lot number | 19031801 | 19031802-2 | 19032701-2 |
| Particle moisture% | 1.45 | 0.64 | 1.05 |
| Bulk Density g/ml | 0.476 | 0.532 | 0.562 |
| Tap density g/ml | 0.579 | 0.634 | 0.650 |
| Calf index% | 17.84 | 16.13 | 13.54 |
| Angle of repose degree | 34.99 | 34.22 | 33.82 |
| 80 mesh sieve fines ratio% | 50.8％ | 67.9％ | 78.3％ |
Dissolution profile results:
dissolution conditions: the paddle method, 0.5% Tween 80+pH1.0 hydrochloric acid medium volume 1000ml, speed 50rpm, temperature 37 ℃.
Table 27 wetting agent addition investigation results-2
| Cumulative dissolution% | 0 | 5min | 10min | 15min | 30min | 45min | 60min | 90min | f2 |
| C852831 | 0 | 45.51 | 63.09 | 73.5 | 80.54 | 85.41 | 87.3 | 89.07 | — |
| 19031801 | 0 | 43.23 | 57.04 | 64.16 | 74.06 | 78.35 | 82.53 | 83.38 | 59.0 |
| 19031802-2 | 0 | 39.97 | 58.54 | 66.91 | 80.36 | 85.81 | 90 | 94.29 | 65.2 |
| 19032701-2 | 0 | 41.08 | 56.87 | 69.21 | 83.14 | 88.91 | 92.83 | 96.42 | 66.5 |
Conclusion of experiment:
the addition amount of the wetting agent is reduced, the prepared intermediate fine powder is increased, but the fluidity of the intermediate is not affected. The dissolution curve is basically consistent with that of the reference preparation, and f2 meets the requirements. However, the excessive addition results in a decrease in the dissolution end point, probably due to the excessive wetting agent, and the existence of partially harder granules after granulating and drying, and the raw materials in the hard granules cannot be released during the dissolution test, thereby resulting in a decrease in the dissolution end point. Thus, in the laboratory batch range, suitable wetting agents are added in an amount ranging from 23 to 28% of the ingredients in the granule.
5. Mixing time and tablet hardness investigation
The raw material occupation of the tadalafil tablet is smaller, so that the mixing time is verified and inspected. The mixing time and the total mixing time during wet granulation are mainly verified. In addition, the tablet content uniformity is monitored to meet the requirement in the middle and front stages in the tabletting process.
The hardness range of the tablet was examined, and the hardness, friability and dissolution profile of the tablet were monitored. The prescription is shown in table 28.
Table 28 mixing time and tablet hardness study recipe
The preparation process comprises the following steps:
(1) the prescribed amount of lactose (315) and tadalafil are weighed into a three-dimensional mixer and mixed for 10 minutes.
(2) Placing the powder into a wet granulator, adding common lactose, hydroxypropyl cellulose and croscarmellose sodium, and mixing with appropriate parameters for 5min;
(3) preparing an aqueous solution of SDS, adding the aqueous solution into a wet granulator, and preparing a soft material according to set parameters;
(4) granulating with a 20-mesh sieve of a swing granulator;
(5) drying the particles by using a fluidized bed, wherein the moisture of the particles is required to be 0.5-2.5%, and taking out;
(6) adopting a 20-mesh sieve of a swinging granulator to carry out granule finishing;
(7) calculating granule yield and additive component addition amount, placing into three-dimensional motion mixer, mixing for 15 and 20min
(8) Tabletting with hardness of 6-8kg and hardness of 8-11kg respectively; and monitoring tablet weight and hardness process at the early, middle and later stages of 8-11kg tabletting, and taking the early and later stages of tablets for content uniformity detection. And taking tablets with different hardness to carry out dissolution curve detection.
The experimental results are shown in tables 29-32 and FIG. 9.
Table 29 mixing time and tablet hardness test results-1
Table 30 mixing time and tablet hardness test results-2
| Lot number | 19032701-1 | 19032701-2 prophase | 19032701-2 metaphase | 19032701-2 late stage |
| Tablet weight average value g | 0.3497 | 0.3514 | 0.3501 | 0.3537 |
| Tablet weight RSD% | 0.40 | 0.27 | 0.30 | 0.50 |
| Hardness mean value kg | 7.44 | 9.78 | 9.95 | 10.52 |
| Hardness RSD% | 4.43 | 2.26 | 2.31 | 3.06 |
| Friability% | 0.27 | / | 0.15 | / |
Remarks: 19032701-2, the tablet weights and the hardness of the tablet at the front, middle and later stages have no obvious difference, so that the friability detection is only carried out at the middle stage.
Table 31 mixing time and tablet hardness test results-3
Dissolution profile results:
dissolution conditions: the paddle method, 0.5% Tween 80+pH1.0 hydrochloric acid medium volume 1000ml, speed 50rpm, temperature 37 ℃.
Table 32 mixing time and tablet hardness test results-4
| Cumulative dissolution% | 0 | 5min | 10min | 15min | 30min | 45min | 60min | 90min | f2 |
| 19032701-1 | 0 | 36.81 | 55.40 | 67.21 | 80.40 | 86.76 | 90.54 | 94.58 | 61.0 |
| 19032701-2 | 0 | 41.08 | 56.87 | 69.21 | 83.14 | 88.91 | 92.83 | 96.42 | 66.5 |
| C852831 | 0 | 45.51 | 63.09 | 73.50 | 80.54 | 85.41 | 87.30 | 89.07 | / |
Remarks: 19032701-2, the tablet weights at the front, middle and later stages have no obvious difference in hardness, and the content uniformity meets the requirements. Thus, the samples were mixed as 19032701-2 batches.
Conclusion of experiment:
mixing time in laboratory stage is 5min, total mixing is 15min, and mixing powder can be uniformly mixed. In the tabletting process, the tablet weight, hardness and content uniformity are stable and meet the requirements. 8-11kg of tablet hardness dissolution, and f2 is similar to that of a reference preparation and meets the requirements.
In summary, the mixing time in the tentative laboratory stage is 5min, the total mixing time is 15min, and the tablet hardness is controlled to be 8-11kg. The prepared tablet index meets the requirements.
6. Prescription optimization and coating investigation
In the research, the dissolution in a Tween 80 medium (1000 ml,50 rpm) with pH of 1.0 and 0.5% of hydrochloric acid is slower than that of a reference preparation for 5min, and the initial determined prescription disintegrating agent is added with 6.4% for optimizing the prescription, so that the dosage and the adding mode of the disintegrating agent are subjected to fine adjustment investigation. In the first scheme, 5 percent of disintegrating agent and 3 percent of disintegrating agent are added; scheme two increases the disintegrant loading to 8%. At the same time, the coating weight gain of 2-3% was examined, and the prescription is shown in Table 33.
Table 33 prescription optimization
The preparation process comprises the following steps:
(1) the prescribed amount of lactose (315) and tadalafil are weighed into a three-dimensional mixer and mixed for 10 minutes.
(2) Placing the powder into a wet granulator, adding common lactose, hydroxypropyl cellulose and croscarmellose sodium, and mixing with appropriate parameters for 5min;
(3) preparing an aqueous solution of SDS, adding the aqueous solution into a wet granulator, and preparing a soft material according to set parameters;
(4) granulating with a 20-mesh sieve of a swing granulator;
(5) drying the particles by using a fluidized bed, wherein the moisture of the particles is required to be 0.5-2.5%, and taking out;
(6) adopting a 20-mesh sieve of a swinging granulator to carry out granule finishing;
(7) calculating granule yield and additive component addition amount, placing into three-dimensional motion mixer, and mixing for 15min
(8) Tabletting with hardness of 8-11 kg;
(9) during coating, the air inlet temperature is set to 80 ℃, the material temperature is kept at 50-60 ℃, the coating weight is increased to 2-3%, and the proper rotating speed is adjusted during the coating process to carry out coating. After coating, the dissolution profile was examined.
The experimental results are shown in tables 34-35 and FIG. 10.
Table 34 recipe process optimization results-1
| Lot number | 19041201 | 19041601 |
| Particle moisture% | 1.05 | 1.65 |
| Tablet weight g | 0.3511 | 0.3565 |
| Hardness kg | 10.09 | 9.83 |
| Coating weight gain% | 2.31 | 2.34 |
Dissolution profile results:
dissolution conditions: the paddle method, 0.5% Tween 80+pH1.0 hydrochloric acid medium volume 1000ml, speed 50rpm, temperature 37 ℃.
Table 35 recipe Process optimization results-2
| Cumulative dissolution% | 0 | 5min | 10min | 15min | 30min | 45min | 60min | 90min | f2 |
| 19041201 | 0 | 35.23 | 53.47 | 65.14 | 79.60 | 86.36 | 90.81 | 95.28 | 54.2 |
| 19041601 | 0 | 46.30 | 63.32 | 70.46 | 84.23 | 87.73 | 91.69 | 95.02 | 79.0 |
| C852831 | 0 | 45.51 | 63.09 | 73.50 | 80.54 | 85.41 | 87.30 | 89.07 | — |
Remarks: the 19041201 batches in the experimental records examine different contents, and the dissolution data in the table correspond to 19041201-1 batches in the experimental records.
Conclusion of experiment:
the disintegrant is added internally, the dosage is 8% and the dissolution is better fitted with the reference preparation, the adding mode is consistent with the initially determined prescription, and the dosage is slightly increased. The coating weight gain is 2-3% and is consistent with the reference preparation, and f2 meets the requirement. Thus, the suggested coating weight gain is 2-3%. The coatings were subsequently further validated by laboratory scale-up.
7. Prescription process determination
In summary, the prescription and process are determined as follows:
table 36 recipe process determination
The preparation process comprises the following steps:
(1) weighing lactose (315) and tadalafil according to the prescription, adding into a three-dimensional mixer, and mixing for 10min at the rotating speed of 250-350r/min to obtain mixed powder;
(2) placing the mixed powder into a wet granulator, adding lactose, hydroxypropyl cellulose and croscarmellose sodium, setting stirring rotation speed to 140rpm, cutting rotation speed to 1800rpm, and mixing for 10min;
(3) preparing an aqueous solution of sodium dodecyl sulfate, and adding the aqueous solution into a wet granulator, wherein the liquid adding time is controlled to be 0.5-1.5min; preparing a soft material, setting the stirring rotation speed to be 140rpm, setting the cutting rotation speed to be 1800rpm, and stirring for 3-5min;
(4) granulating with a 20-mesh sieve of a swing granulator;
(5) drying the particles by using a fluidized bed, setting the air inlet temperature to be 80 ℃, controlling the air inlet temperature to be less than 90 ℃, controlling the material temperature to be less than 80 ℃, controlling the moisture of the particles to be 0.5-2.5%, and taking out;
(6) finishing grains by adopting a 20-mesh sieve of a swinging granulator;
(7) calculating the yield of the particles and the addition amount of the additional components, placing the particles, the microcrystalline cellulose and the magnesium stearate into a three-dimensional motion mixer, setting the frequency to be 44.9-45.1Hz, and mixing for 15-30min;
(8) tabletting: tabletting with hardness of 8-11 kg;
(9) the coating liquid is used in the following amount: the weight is increased by 2-3% based on the solid.
Examples
The present example was prepared according to the prescription procedure identified in table 36 above, with samples of different batches (200901, 200902, 200903) compared to the reference formulation quality information as follows:
1. examples three batches of samples and reference formulation information summary
Table 37 summary of sample and reference formulation information for the examples
2. Example three batches of samples and reference formulation quality information comparison
Table 38 comparison of sample and reference formulation quality information for examples
In addition, comparison of dissolution information of the example samples with that of the reference formulation was also performed. Respectively adding hydrochloric acid with pH value of 1.0 and 0.5% Tween 80 medium; (2) 0.5% tween 80+ph4.5 acetate medium; (3) 0.5% tween 80+ aqueous medium; (4) dissolution comparison in pH6.8 phosphate+0.5% Tween 80 medium. The dissolution method comprises the following steps: the paddle method, medium volume 1000ml, dissolution speed 50rpm, temperature 37 ℃. The comprehensive results show that the self-product and the reference preparation have no obvious difference.
In addition, stability studies were also performed. The reference preparation and the sample of the example are inspected under the conditions of influencing factors (high temperature 60+/-2 ℃,30 days; high humidity 25+/-2 ℃, 92.5+/-5% RH,30 days; illumination 4500+/-500 Lux, ultraviolet 85uW,10 days), acceleration test (40+/-2 ℃, 75+/-5% RH,1/2/3/6 months), long-term test (25+/-2 ℃, 60+/-5% RH,3/6 months), and the comprehensive result shows that the key quality attribute of the product and the reference preparation has no obvious change.
In conclusion, the product of the invention has good stability and complete dissolution; the preparation process is simple and easy to operate, and is suitable for industrial production.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.
Claims (6)
1. The preparation method of the tadalafil tablet is characterized by comprising the following components in parts by weight: 20 parts of tadalafil, 198 parts of lactose, 35 parts of lactose 315, 28 parts of croscarmellose sodium, 8.05 parts of hydroxypropyl cellulose, 0.98 part of sodium dodecyl sulfate, 58.22 parts of microcrystalline cellulose, 1.75 parts of magnesium stearate and 8.75 parts of film coating premix;
the preparation method comprises the following steps:
s1, weighing a prescription amount of lactose 315 and adding tadalafil into a three-dimensional mixer to be uniformly mixed to obtain mixed powder;
s2, placing the mixed powder into a wet granulator, adding lactose, hydroxypropyl cellulose and croscarmellose sodium, and uniformly mixing;
s3, preparing an aqueous solution of sodium dodecyl sulfate, and adding the aqueous solution into a wet granulator to prepare a soft material;
s4, granulating by adopting a 20-mesh sieve of a swing granulator;
s5, drying particles by using a fluidized bed, controlling the moisture of the particles to be 0.5-2.5%, and taking out the particles;
s6, adopting a 20-mesh sieve of a swing granulator to carry out granule finishing;
s7, placing the particles, microcrystalline cellulose and magnesium stearate into a three-dimensional motion mixer, and uniformly mixing;
s8, tabletting: tabletting with hardness of 8-11 kg;
s9, coating liquid dosage: the weight is increased by 2-3% based on the solid.
2. The method according to claim 1, wherein the mixing time in step S1 is 10min and the rotation speed is 250-350r/min.
3. The preparation method according to claim 1, wherein the stirring speed is set to 140rpm, the cutting speed is set to 1800rpm, and the mixing is performed for 10 minutes in step S2.
4. The preparation method according to claim 1, wherein the adding time of the sodium dodecyl sulfate aqueous solution is controlled to be 0.5-1.5min in the step S3; when preparing soft materials, setting stirring rotation speed at 140rpm, cutting rotation speed at 1800rpm, and stirring for 3-5min.
5. The method according to claim 1, wherein the inlet air temperature is set to 80 ℃ and the inlet air temperature is controlled to be less than 90 ℃ and the material temperature is controlled to be less than 80 ℃ during the drying in the step S5.
6. The preparation method according to claim 1, wherein the frequency is set to 44.9-45.1Hz in step S7, and the mixing is performed for 15-30min.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011048553A2 (en) * | 2009-10-22 | 2011-04-28 | Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi | Pharmaceutical compositions of pde-5 inhibitors and dapoxetine |
| WO2014167579A2 (en) * | 2013-03-28 | 2014-10-16 | Astron Research Limited | Stable pharmaceutical compositions of tadalafil |
| KR20190038441A (en) * | 2017-09-29 | 2019-04-08 | 한미약품 주식회사 | Solid formulation containing tadalafil with improved productivity and uniformity and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011048553A2 (en) * | 2009-10-22 | 2011-04-28 | Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi | Pharmaceutical compositions of pde-5 inhibitors and dapoxetine |
| WO2014167579A2 (en) * | 2013-03-28 | 2014-10-16 | Astron Research Limited | Stable pharmaceutical compositions of tadalafil |
| KR20190038441A (en) * | 2017-09-29 | 2019-04-08 | 한미약품 주식회사 | Solid formulation containing tadalafil with improved productivity and uniformity and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| 粉末直接压片工艺的进展;黄朝霞;《现代食品与药品杂志》;第17卷(第05期);第31-36段 * |
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