CN106806347A - A kind of new amoxicillin granules - Google Patents
A kind of new amoxicillin granules Download PDFInfo
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- CN106806347A CN106806347A CN201710048171.5A CN201710048171A CN106806347A CN 106806347 A CN106806347 A CN 106806347A CN 201710048171 A CN201710048171 A CN 201710048171A CN 106806347 A CN106806347 A CN 106806347A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
- C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
- C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
- C07D499/68—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with aromatic rings as additional substituents on the carbon chain
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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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
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- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/18—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The present invention relates to a kind of new amoxicillin granules and preparation method thereof, belong to pharmaceutical technology field.The new amoxicillin granules are prepared from by the component of following weight portion：Amoxicillin 125g~250g, sodium acid carbonate 6300g~10800g, Vicryl Rapide (34.7：65.3) 0.10g~0.50g, sodium carboxymethyl starch 120g~260g, sodium stearyl fumarate 130g~280g, mannitol 1500g~3250g, lactose 1520g~3090g, sucrose 13000g~26500g, starch 12500g~25800g, PVP K30 30g~56g, orange flavor 108g~220g, acesulfame potassium 116g~220g.Granule good stability of the present invention, so as to improve drug safety and validity, it is to avoid the incidence of adverse reaction.
Description
Technical field
The present invention relates to a kind of granule and preparation method thereof, more particularly to a kind of new amoxicillin granules and its preparation
Method, belongs to pharmaceutical technology field.
Background technology
Amoxicillin (Amoxicillin), also known as amoxycillin, its chemical name are (2S, 5R, 6R) -3,3- bis-
Methyl -6- [(R)-(-) -2- amino -2- (4- hydroxy phenyls) acetylamino] -7- oxo -4- thia -1- azabicyclos
[3.2.0] heptane -2- formic acid trihydrates, molecular formula is C16H19N3O5S·3H2O, molecular weight is 419.46.Amoxicillin
Proterties is off-white color or white powder, and in crystalloid, mildly bitter flavor, insoluble in ethanol, is slightly soluble in water, and its chemical structural formula is：
Amoxicillin is semi-synthetic penicillins antibiotic, is all had to gram positive bacteria and some gram-negative bacterias good
Antibacterial action.Antibacterial action is substantially better than ammonia benzyl mould rope, the base that its antibacterial activity plays a major role in vivo for Amoxicillin
This structure is the beta-lactam nucleus in 6-amino-penicillanic acid, can be combined with target site on bacterial inner membrane in specific manner, suppresses thin
The activity of the glutinous peptide synthetase of bacterium cell membrane, so that the synthesis of the glutinous peptide of block cell wall, makes the cell wall defective of bacterium, thalline expansion
Cracking.Amoxicillin is one of current widely used oral penicillin, and its preparation has capsule, tablet, granule, dispersion
Piece etc..
Amoxicillin granules in the market use traditional processing technology mostly, use wet granulation, and Amoxicillin
Raw material produces influence to damp and hot very sensitive, traditional wet granulation production technology to product quality, and content declines substantially, relevant
Especially macromolecule impurity increases notable to material, and product stability is poor.And there are some researches show Amoxicillin self-polymerization is formed
The mixture of different polymerization degree, is to trigger anaphylactoid main cause.Macromolecule impurity in control Wymox contains
Amount, is to reduce PCs allergic reaction, improve the fundamental way of drug safety.Thus presently commercially available Amoxicillin
Particle has that impurity is higher, stability.
Patent CN201010556659.7 is related to a kind of amoxicillin granules and its preparation technology, in the granule preparing process
Using low moisture, volatile binder solution and low temperature drying technology, it is to avoid influence of the humiture to product quality, product matter
Amount and stability are improved, but control to impurity or not ideal enough, can increase the generation of adverse drug reaction.
Therefore, clinically it is badly in need of developing a kind of more stable, safer amoxicillin granules product.
The content of the invention
Present invention aim at for the defect of prior art, there is provided a kind of new amoxicillin granules, the A Moxi
The active component of woods particle is a kind of Amoxicillin compound of the novel crystal forms different from prior art, and experiments prove that,
This kind of stability of the Amoxicillin compound of crystal formation is better than existing crystal formation, and impurity content is low, and medicine can be kept to put for a long time
Postpone content to decline seldom, be conducive to the steady in a long-term of preparation, so as to ensure that the security of medication.
To realize the object of the invention, using following technical scheme：
The present invention provides a kind of new amoxicillin granules, the new amoxicillin granules by following weight portion component system
It is standby to form：Amoxicillin 125g~250g, sodium acid carbonate 6300g~10800g, Vicryl Rapide (34.7：65.3)
0.10g~0.50g, sodium carboxymethyl starch 120g~260g, sodium stearyl fumarate 130g~280g, mannitol 1500g~
3250g, lactose 1520g~3090g, sucrose 13000g~26500g, starch 12500g~25800g, PVP K30 30g~
56g, orange flavor 108g~220g, acesulfame potassium 116g~220g；
Wherein, the Amoxicillin is the Amoxicillin of novel crystal forms, as shown in formula (I)：
Using in the X-ray powder diffraction collection that Cu-Ka radionetric surveys are obtained 2 θ be 11.62 ± 0.1 °, 16.29 ± 0.1 °,
17.51 ± 0.1 °, 20.04 ± 0.1 °, 20.80 ± 0.1 °, 22.32 ± 0.1 °, 23.01 ± 0.1 °, show at 27.56 ± 0.1 °
Characteristic peak.
A kind of above-mentioned new amoxicillin granules, the Differential Scanning Calorimetry of the Amoxicillin of the novel crystal forms is 163
DEG C -168 DEG C have an endothermic peak.
A kind of above-mentioned new amoxicillin granules, the Amoxicillin of the novel crystal forms is obtained using Cu-Ka radionetric surveys
In X-ray powder diffraction collection 2 θ be 5.78 ± 0.1 °, 11.82 ± 0.1 °, 12.57 ± 0.1 °, 13.78 ± 0.1 °,
15.73±0.1°、16.84±0.1°、18.81±0.1°、19.28±0.1°、23.44±0.1°、24.69±0.1°、25.08
± 0.1 °, 27.80 ± 0.1 °, 28.82 ± 0.1 °, 33.06 ± 0.1 °, show characteristic peak at 33.71 ± 0.1 °.
A kind of above-mentioned new amoxicillin granules, the Differential Scanning Calorimetry of the Amoxicillin of the novel crystal forms exists
There is endothermic peak at 166.50 ± 2 DEG C.
According to foregoing new amoxicillin granules, wherein, the preparation method of the Amoxicillin of the novel crystal forms include with
Lower step：
Amoxicillin crude product is added in the mixed solvent of the methyl alcohol with 1-METHYLPYRROLIDONE of certain proportioning, be heated to back
Stream dissolving, then to adding absolute ethyl alcohol in solution and then forming mixed solvent system, then cooling down crystallization, filters, washing,
Vacuum drying, obtains the Amoxicillin of novel crystal forms.
Above-mentioned new amoxicillin granules, the Amoxicillin crude product and methyl alcohol and the weight g of 1-METHYLPYRROLIDONE：Body
Product ml：The ratio between volume ml is 10：65~75：12~16.
Above-mentioned new amoxicillin granules, methyl alcohol, 1-METHYLPYRROLIDONE and absolute ethyl alcohol in the mixed solvent system
Volume ml ratios be 65~75：12~16：6~10.
Above-mentioned new amoxicillin granules, described cooling down crystallization, its temperature is reduced to 0~15 DEG C.
Above-mentioned new amoxicillin granules, described washing, the solvent that it is used is petroleum ether.
Above-mentioned new amoxicillin granules, described vacuum drying, it dries 40~55 DEG C used of temperature.
Present invention also offers a kind of preparation method of above-mentioned new amoxicillin granules, comprise the following steps：
The above-mentioned novel crystal forms Amoxicillin raw materials of compound medicine of recipe quantity is crossed into 100 mesh sieves, auxiliary material crosses 40 mesh sieves, standby；Press
Prescription weight proportion weighs the Amoxicillin of recipe quantity, the sodium acid carbonate of 56% recipe quantity, the glycolide third of 47% recipe quantity and hands over
Ester copolymer (34.7：65.3) with the sodium stearyl fumarate of 40% recipe quantity, it is well mixed, dry granulation is made fine grained；Plus
Enter the sodium carboxymethyl starch of recipe quantity and the sodium acid carbonate and Vicryl Rapide (34.7 of remaining recipe quantity：65.3),
Well mixed, dry granulation is made particle；By in above-mentioned particle sodium stearyl fumarate again with remaining recipe quantity, prescription other
After auxiliary materials and mixing, pack is obtained final product.
There is document report, preparation stability can be improved by changing crystal formation, the crystal formation currently for Amoxicillin there has been
Certain research, such as patent CN201610060313.5 provide the capsule that a kind of novel crystal forms Amoxicillin compound is prepared
Agent stability is more preferably, safe and effective for medication.
In field of crystals, certain compound whether there is crystal form, there is how many kinds of crystal form and which kind of be present
Crystal form is not it is contemplated that therefore, the invention of compound crystal or its preparation carry not predictability, certain novel crystal forms
Acquisition generally requires dependence experimental result and is determined.The present inventor passes through many experiments, by the tight of crystallization processes parameter
Lattice are controlled, and unexpectedly obtain the novel crystal forms Amoxicillins different from prior art.Can be seen by embodiment of the present invention 1-3
Go out, the preparation-obtained new Amoxicillin good fluidity of the present invention can more meet the requirement of pharmaceutics, be more suitable for preparing respectively
Plant pharmaceutical preparation.Be can be seen that by embodiment of the present invention 5-7 and be added into addition by novel crystal forms Amoxicillin of the present invention
New stabilizer auxiliary material Vicryl Rapide (34.7：And its granule stability for preparing of ratio of adjuvant 65.3)
It is good, so as to improve drug safety and validity, it is to avoid the incidence of adverse reaction.
Brief description of the drawings
The X-ray powder diffraction collection of the Amoxicillin of novel crystal forms described in Fig. 1 embodiment of the present invention 1
The DSC spectrograms of the Amoxicillin of novel crystal forms described in Fig. 2 embodiment of the present invention 1
Specific embodiment
The present invention is described in further detail below by specific embodiment, but is only intended to help and understand this hair
It is bright, professional and technical personnel in the field is realized or using the present invention, any limitation is not constituted to the present invention.
Embodiment 1 prepares the Amoxicillin of novel crystal forms of the present invention
Amoxicillin crude product 1000g is added in 25L there-necked flasks, plus methyl alcohol 7000mL and 1-METHYLPYRROLIDONE
1400mL, stirs, is heated to backflow dissolving, then to 800mL absolute ethyl alcohols are added in solution, then slow cooling is cooled to 5 DEG C,
Stirring and crystallizing, filtering, petroleum ether, 50 DEG C of vacuum drying obtain the Amoxicillin 977g of novel crystal forms, yield 97.7%.
The X-ray powder diffraction figure of the Amoxicillin of the novel crystal forms is (precision is ± 0.1 °) in the θ of angle of reflection 2：5.78°、
11.62°、11.82°、12.57°、13.78°、15.73°、16.29°、16.84°、17.51°、18.81°、19.28°、20.04°、
20.80°、22.32°、23.01°、23.44°、24.69°、25.08°、27.56°、27.80°、28.82°、33.06°、33.71°
There is characteristic absorption peak at place, as shown in Figure 1.
Its DSC collection of illustrative plates has endothermic peak (precision is ± 2 DEG C) near 166.50 DEG C, as shown in Figure 2.
Embodiment 2 prepares the Amoxicillin of novel crystal forms of the present invention
Amoxicillin crude product 1000g is added in 25L there-necked flasks, plus methyl alcohol 6500mL and 1-METHYLPYRROLIDONE
1200mL, stirs, is heated to backflow dissolving, then to 600mL absolute ethyl alcohols are added in solution, then slow cooling is cooled to 15
DEG C, stirring and crystallizing, filtering, petroleum ether, 40 DEG C of vacuum drying obtain the Amoxicillin 936g of novel crystal forms, yield 93.6%.
Embodiment 3 prepares the Amoxicillin of novel crystal forms of the present invention
Amoxicillin crude product 1000g is added in 25L there-necked flasks, plus methyl alcohol 7500mL and 1-METHYLPYRROLIDONE
1600mL, stirs, is heated to backflow dissolving, then to 1000mL absolute ethyl alcohols are added in solution, then slow cooling is cooled to 0
DEG C, stirring and crystallizing, filtering, petroleum ether, 55 DEG C of vacuum drying obtain the Amoxicillin 959g of novel crystal forms, yield 95.9%.
Embodiment 4 prepares Vicryl Rapide of the present invention (PLGA)
Glycolide (GA) and L- lactides (LLA) are put into there-necked flask according to constant weight ratio, catalyst is added
Stannous octoate (the 0.78% of glycolide monomer quality) and initiator dodecanol (the 0.33% of glycolide monomer quality), take out true
It is empty to be heated to 185 DEG C under agitation to 10Pa, 6h is reacted, stop stirring, maintain vacuum to be incubated 8h, it is then naturally cold
But room temperature is arrived.With a small amount of dichloromethane dissolved product, then settled with the absolute ethyl alcohols of 12 times of amounts of liquor capacity, suction filtration, instead
Carry out again 3 times, last gained copolymer product 45 DEG C of drying under reduced pressure 3h in vacuum drying chamber, obtain the PLGA of different ratio into
Product.
Embodiment 5 prepares amoxicillin granules (specification of the present invention：0.25g)
Prescription：
Preparation method：
100 mesh sieves are crossed into the Amoxicillin prepared in embodiment 1, auxiliary material crosses 40 mesh sieves, standby；Claim by prescription weight proportion
Take sodium acid carbonate, the Vicryl Rapide (34.7 of 47% recipe quantity of Amoxicillin and 56% recipe quantity：65.3) and
The sodium stearyl fumarate of 40% recipe quantity, is well mixed, and dry granulation is made fine grained；Add the CMS of recipe quantity
The sodium acid carbonate and Vicryl Rapide (34.7 of sodium and remaining recipe quantity：65.3), it is well mixed, dry granulation, system
Into particle；After other auxiliary materials and mixings in above-mentioned particle sodium stearyl fumarate again with remaining recipe quantity, prescription, pack is obtained final product.
Embodiment 6 prepares amoxicillin granules (specification of the present invention：0.25g)
Prescription：
Preparation method：
100 mesh sieves are crossed into the Amoxicillin prepared in embodiment 2, auxiliary material crosses 40 mesh sieves, standby；Claim by prescription weight proportion
Take sodium acid carbonate, the Vicryl Rapide (34.7 of 47% recipe quantity of Amoxicillin and 56% recipe quantity：65.3) and
The sodium stearyl fumarate of 40% recipe quantity, is well mixed, and dry granulation is made fine grained；Add the CMS of recipe quantity
The sodium acid carbonate and Vicryl Rapide (34.7 of sodium and remaining recipe quantity：65.3), it is well mixed, dry granulation, system
Into particle；After other auxiliary materials and mixings in above-mentioned particle sodium stearyl fumarate again with remaining recipe quantity, prescription, pack is obtained final product.
Embodiment 7 prepares amoxicillin granules (specification of the present invention：0.125g)
Prescription：
Preparation method：
100 mesh sieves are crossed into the Amoxicillin prepared in embodiment 3, auxiliary material crosses 40 mesh sieves, standby；Claim by prescription weight proportion
Take sodium acid carbonate, the Vicryl Rapide (34.7 of 47% recipe quantity of Amoxicillin and 56% recipe quantity：65.3) and
The sodium stearyl fumarate of 40% recipe quantity, is well mixed, and dry granulation is made fine grained；Add the CMS of recipe quantity
The sodium acid carbonate and Vicryl Rapide (34.7 of sodium and remaining recipe quantity：65.3), it is well mixed, dry granulation, system
Into particle；After other auxiliary materials and mixings in above-mentioned particle sodium stearyl fumarate again with remaining recipe quantity, prescription, pack is obtained final product.
Product prepared by the present invention, its mobility, stability are significantly increased compared with commercially available product.
The mobility of test example 1 compares
Comparative example A of the present invention is the A Moxi prepared according to method in patent CN201610060313.5 embodiments 1
Woods material sample.
Angle of repose is the most easy method for checking powder fluidity quality, and angle of repose is smaller, illustrates that frictional force is smaller, is flowed
Dynamic property is better.This experiment determines the new crystalline substance prepared by embodiment 1, embodiment 2 and embodiment 3 using injection method (fixed funnel method)
The angle of repose of the Amoxicillin material sample, comparative example A and Amoxicillin raw material commercially available product 1, commercially available product 2 and commercially available product 3 of type.Will
Testing sample pours into funnel, make its lightly, equably fall into disc centre, a cone is formed, when material is oblique from powder
Stop charging when freely being fallen in edge disk border, angle of repose is determined with protractor, measurement result is shown in Table 1.Result display is originally
The prepared product mobility of invention is more preferable, better than comparative example A and commercially available product.
The angle of repose measurement result of table 1
| Sample | Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative example A | Commercially available product 1 | Commercially available product 2 | Commercially available product 3 |
| Angle of repose | 16.2 | 19.5 | 17.8 | 20.8 | 47.1 | 48.6 | 50.9 |
The stabilizer auxiliary material of test example 2 is screened
Using the Amoxicillin of novel crystal forms as active component, using the PLGA of different ratio as stabilizer auxiliary material, prepare Ah
Amdinocillin particle.
Preparation method：100 mesh sieves are crossed into the Amoxicillin prepared in embodiment 1, auxiliary material crosses 40 mesh sieves, standby；By prescription
Weight proportion is weighed at the sodium acid carbonate of Amoxicillin and 56% recipe quantity, the PLGA and 40% of certain proportioning of 47% recipe quantity
The sodium stearyl fumarate of side's amount, is well mixed, and dry granulation is made fine grained；Add the sodium carboxymethyl starch of recipe quantity and remain
The PLGA of the sodium acid carbonate of remaining recipe quantity and certain proportioning, is well mixed, and dry granulation is made particle；By above-mentioned particle again with
After interior other auxiliary materials and mixings of the sodium stearyl fumarate of remaining recipe quantity, prescription, pack is obtained final product.
Then the amoxicillin granules for preparing are carried out with the accelerated test of 3 months, accelerated test condition is temperature 40 ± 2
DEG C, relative humidity 75 ± 5%, carry out quality testing analysis after off-test, melting, content and equal about the detection method of thing
It is official method (Chinese Pharmacopoeia version two in 2015), the results are shown in Table 2.
The stabilizer auxiliary material screening test of table 2
From table 2, compared by accelerating 3 months test datas, stabilizer auxiliary material Vicryl Rapide is optimal
Proportioning be 34.7：65.3, the optimal stability of the amoxicillin granules as prepared by it.
The raw material study on the stability of test example 3
Comparative example A of the present invention is the A Moxi prepared according to method in patent CN201610060313.5 embodiments 1
Woods material sample.
The Amoxicillin material sample of the novel crystal forms prepared by the embodiment of the present invention 1, embodiment 2 and embodiment 3 and contrast
Example A, Amoxicillin raw material commercially available product 1, commercially available product 2 and commercially available product 3 carry out quality testing analysis, and detection method is official method
(Chinese Pharmacopoeia version two in 2015), the results are shown in Table 3.
Chinese Pharmacopoeia has been expressly recited the quality standard of Amoxicillin raw material for 2015 in version two, it is desirable to which content must not be lacked
In 95.0%, acidity pH value is 3.5-5.5, and relevant thing list is miscellaneous to cannot be greater than 1.0%, relevant thing it is total it is miscellaneous cannot be greater than 3.0%, Ah
Amdinocillin polymer (abbreviation polymer) must not cross 0.15%, and moisture is 12.0%-15.0%, and residue on ignition must not cross 1.0%.
The Amoxicillin material quality detection and analysis of table 3
From table 3：Compared with comparative example A, commercially available product 1, commercially available product 2, commercially available product 3, the embodiment of the present invention 1, embodiment 2
Amoxicillin material sample content with the novel crystal forms prepared by embodiment 3 is higher, and relevant thing is lower.Particularly embodiment 1 contains
Amount up to 99.99%, and the content of commercially available product 1, commercially available product 2, commercially available product 3 is less than 96%, relevant thing and polymer data
Also there are obvious gap, the Amoxicillin raw material of the novel crystal forms prepared by every data display embodiment 1, embodiment 2 and embodiment 3
Sample quality is more preferable.
The preparation stability of test example 4 is investigated
Comparative example of the present invention 1 is Ah not prepared according to the method in patent CN201010556659.7 embodiments 1
XiLin particulate samples.
Comparative example of the present invention 2 is the material sample prepared according to the method in patent CN201610060313.5 embodiments 1
The amoxicillin granules sample for being prepared by method in the embodiment of the present invention 5 again.
Amoxicillin granules sample and comparative example 1, contrast prepared by the embodiment of the present invention 5, embodiment 6 and embodiment 7
Example 2, amoxicillin granules commercially available product A carry out accelerated test, accelerated test condition be 40 ± 2 DEG C of temperature, relative humidity 75 ±
Under conditions of 5%, place 3 months.Melting, content and the detection method about thing are official method (Chinese Pharmacopoeia 2015
Year version two), the results are shown in Table 4.
Chinese Pharmacopoeia has been expressly recited the quality standard of amoxicillin granules for 2015 in version two, it is desirable to which content is
90.0%-110.0%, relevant thing list is miscellaneous to cannot be greater than 1.0%, and relevant thing is always miscellaneous to cannot be greater than 5.0%.
The accelerated test of table 4
From table 4：Compared with commercially available product A, comparative example 1, comparative example 2, the A Moxi prepared by embodiment of the present invention 5-7
Woods particulate samples content is higher, and relevant thing is lower.By after 3 months accelerated tests, the Amoxicillin prepared by embodiment 5-7
Grain sample size reduces slower, and more than 103%, relevant thing increases slower content, and relevant thing list is miscellaneous 0.30%
Hereinafter, relevant thing is total miscellaneous below 3.0%, and it is qualified that melting is checked；And comparative example 1 and comparative example 2 also comply with quality
Standard, but content declines and relevant thing increases all quickly, and content is respectively 92.6% and 96.1%, and relevant thing list is miscellaneous to be respectively
0.77% and 0.59%, about thing total miscellaneous respectively 4.87% and 3.99%, it is qualified that melting is checked；And commercially available product A exists
When accelerating 2 months, just there is situation off quality, content is 81.4%, it is 2.16% that relevant thing list is miscellaneous, relevant thing is total
Miscellaneous is 9.15%, and melting checks also unqualified.By the way that after 3 months accelerated tests, the relevant thing list of commercially available product A is miscellaneous about real
Apply the amoxicillin granules sample prepared by a 5-7 25 times, and total miscellaneous about 9 times of relevant thing, content is less than half, the above
Result shows that the stability of the amoxicillin granules sample prepared by embodiment of the present invention 5-7 is drastically lifted.
As can be seen here, the amoxicillin granules product that the present invention is provided, due to having used the specific crystalline substance of preparation of the present invention
Vicryl Rapide (34.7 has been used in the Amoxicillin of type form and prescription：, and glycolide lactide 65.3)
Copolymer (34.7：65.3) Nei Jia and added weight ratio are 47:53 so that the relevant thing of amoxicillin granules of the present invention contains
Amount is lower, and active constituent content is higher, and preparation stability is greatly improved, and is that clinical practice is carried with obvious effect
More preferable selection is supplied.
The above is only the preferred embodiment of the present invention, be not intended to limit the invention, come for those skilled in the art
Say, under the premise without departing from the principles of the invention, some improvement, retouching, the equivalent that can also be made should be included in this
Within the protection domain of invention.
Claims (6)
1. a kind of new amoxicillin granules, the new amoxicillin granules are prepared from by the component of following weight portion：A Mo
XiLin 125g~250g, sodium acid carbonate 6300g~10800g, weight ratio are 34.7：65.3 Vicryl Rapide
0.10g~0.50g, sodium carboxymethyl starch 120g~260g, sodium stearyl fumarate 130g~280g, mannitol 1500g~
3250g, lactose 1520g~3090g, sucrose 13000g~26500g, starch 12500g~25800g, PVP K30 30g~
56g, orange flavor 108g~220g, acesulfame potassium 116g~220g；
Wherein, the Amoxicillin is the Amoxicillin of novel crystal forms, as shown in formula (I), the X- obtained using Cu-Ka radionetric surveys
In ray powder diffraction 2 θ be 11.62 ± 0.1 °, 16.29 ± 0.1 °, 17.51 ± 0.1 °, 20.04 ± 0.1 °, 20.80
± 0.1 °, 22.32 ± 0.1 °, 23.01 ± 0.1 °, show characteristic peak at 27.56 ± 0.1 °；The Amoxicillin of the novel crystal forms
Differential Scanning Calorimetry has an endothermic peak at 163 DEG C -168 DEG C.
2. new amoxicillin granules according to claim 1, it is characterised in that the Amoxicillin of the novel crystal forms, make
In the X-ray powder diffraction collection obtained with Cu-Ka radionetric surveys 2 θ be 5.78 ± 0.1 °, 11.82 ± 0.1 °, 12.57 ±
0.1°、13.78±0.1°、15.73±0.1°、16.84±0.1°、18.81±0.1°、19.28±0.1°、23.44±0.1°、
24.69 ± 0.1 °, 25.08 ± 0.1 °, 27.80 ± 0.1 °, 28.82 ± 0.1 °, 33.06 ± 0.1 °, show at 33.71 ± 0.1 °
Characteristic peak；The Differential Scanning Calorimetry of the Amoxicillin of the novel crystal forms has endothermic peak at 166.50 ± 2 DEG C.
3. a kind of new amoxicillin granules according to claim 1 and 2, it is characterised in that Ah not of the novel crystal forms
The preparation method in XiLin is comprised the following steps：
Amoxicillin crude product is added in the mixed solvent of the methyl alcohol with 1-METHYLPYRROLIDONE of certain proportioning, be heated to backflow molten
Solution, then to adding absolute ethyl alcohol in solution and then forming mixed solvent system, then cooling down crystallization, filtering, wash, vacuum
Dry, obtain the Amoxicillin of novel crystal forms.
4. a kind of new amoxicillin granules according to claim 3, it is characterised in that the Amoxicillin crude product and first
The weight g of alcohol and 1-METHYLPYRROLIDONE：Volume ml：The ratio between volume ml is 10：65~75：12~16；The mixed solvent body
The volume ml ratios of methyl alcohol, 1-METHYLPYRROLIDONE and absolute ethyl alcohol are 65~75 in system：12~16：6~10；Described cooling is cold
But crystallization, its temperature is reduced to 0~15 DEG C；Described washing, the solvent that it is used is petroleum ether；Described vacuum drying, it is done
Dry 40~55 DEG C used of temperature.
5. a kind of new amoxicillin granules according to claim 1, it is characterised in that the weight ratio is 34.7：
The preparation method of 65.3 Vicryl Rapide is comprised the following steps：
By glycolide and L- lactides according to 34.7：65.3 weight ratio is put into there-necked flask, adds glycolide quality
0.78% octoate catalyst stannous and the initiator dodecanol of glycolide quality 0.33%, are evacuated to 10Pa, in stirring
Under the conditions of be heated to 185 DEG C, react 6h, stop stirring, maintain vacuum insulation 8h, then naturally cool to room temperature；With a small amount of
Dichloromethane dissolved product, then settled with the absolute ethyl alcohol of 12 times of amounts of liquor capacity, suction filtration is repeated 3 times, last institute
Copolymer product 45 DEG C of drying under reduced pressure 3h in vacuum drying chamber are obtained, it is 34.7 to obtain weight ratio：65.3 glycolide lactide is total to
Polymers.
6. a kind of method of new amoxicillin granules as claimed in claim 1 or 2 is prepared, it is characterised in that including as follows
Step：
Recipe quantity novel crystal forms Amoxicillin raw materials of compound medicine is crossed into 100 mesh sieves, auxiliary material crosses 40 mesh sieves, standby；By prescription weight
It is 34.7 that proportioning weighs the Amoxicillin of recipe quantity, the sodium acid carbonate of 56% recipe quantity, the weight ratio of 47% recipe quantity：65.3
The sodium stearyl fumarate of Vicryl Rapide and 40% recipe quantity, is well mixed, and dry granulation is made fine grained；Plus
It is 34.7 to enter the sodium carboxymethyl starch of recipe quantity and the sodium acid carbonate and weight ratio of remaining recipe quantity：65.3 glycolide lactide
Copolymer, is well mixed, and dry granulation is made particle；By above-mentioned particle sodium stearyl fumarate, prescription again with remaining recipe quantity
After interior other auxiliary materials and mixings, pack is obtained final product.
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| CN108969488A (en) * | 2018-07-30 | 2018-12-11 | 石药集团中诺药业（石家庄）有限公司 | A kind of amoxicillin granules that quality is stable |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105884798A (en) * | 2016-01-28 | 2016-08-24 | 石药集团中诺药业（石家庄）有限公司 | Novel amoxicillin compound |
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| CN105884798A (en) * | 2016-01-28 | 2016-08-24 | 石药集团中诺药业（石家庄）有限公司 | Novel amoxicillin compound |
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|---|---|---|---|---|
| CN108969488A (en) * | 2018-07-30 | 2018-12-11 | 石药集团中诺药业（石家庄）有限公司 | A kind of amoxicillin granules that quality is stable |
| CN108969488B (en) * | 2018-07-30 | 2021-05-25 | 石药集团中诺药业（石家庄）有限公司 | Amoxicillin granules |
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Application publication date: 20170609 |