CN108456144A - A kind of small particle is crystalline Pregabalin, composition and its preparation process - Google Patents
A kind of small particle is crystalline Pregabalin, composition and its preparation process Download PDFInfo
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- CN108456144A CN108456144A CN201711069860.0A CN201711069860A CN108456144A CN 108456144 A CN108456144 A CN 108456144A CN 201711069860 A CN201711069860 A CN 201711069860A CN 108456144 A CN108456144 A CN 108456144A
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- pregabalin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
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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 crystalline Pregabalins of small particle, composition and preparation method thereof.The present invention provides a kind of crystalline pregabaline particles of small particle, D (50) is less than 50 μm, and purity is higher than 98%, can meet the needs of different dosage forms.The present invention also provides a kind of pregabalin compositions, including the crystalline pregabaline particles of small particle and diluent or carrier, the composition disintegration is fast, and dissolution is fast, and bioavilability is high, and hardness is higher, and friability is small.The present invention also provides a kind of solution to crystallize the method for preparing small particle pregabaline particles, and this method includes to add to Pregabalin crude product solution is counter in poor solvent, easy to operate it is not necessary that crystal seed is added, and high income, purity are high.
Description
Technical field
The invention belongs to field of medicaments, a kind of crystalline Pregabalin of small particle, composition and its preparation are more particularly related to
Technique.
Background technology
Pregabalin is a kind of novel γ-aminobutyric acid (GABA) receptor antagonist, chemical name (S) -3- aminomethyls -5-
Methyl is sour.The diseases such as partial seizure, anxiety disorder, the nerve pain of primary treatment adult patients.In clinical application side
Face, Pregabalin have many advantages, such as that dosage is low, curative effect is strong, toxic side effect is few, it has also become one of best-selling drug in the whole world.
It is wanted as the development of various quick-releases, controlled formulation technique proposes higher quality to the grain graininess of bulk pharmaceutical chemicals
It asks.It is considered that only insoluble drug just has the problem of dissolution rate, but Recent study proves, soluble drug (such as Puri
Bahrain) can also be brought because of the formula and technique of preparation, the particle size of drug and the otherness of particle diameter distribution to production process and
Important, the different influence of drug quality.
The D (50) of Pregabalin commercial product is at 50 μm or more, the prior art reports small particle Pregabalin
Preparation method, the little particle Pregabalin product and preparation method thereof such as CN104649919A report D (50) at 100-300 μm,
This method need to be added crystal seed, the grain size that the quality of crystal seed plays crystalline product quality very crucial effect, and obtains need into
The grinding of one step, crushing could meet the needs of ordinary preparation, quick releasing formulation, controlled release preparation.It crushes, be repeatedly sieved using multiple
Method, not only efficiency is low, time-consuming for this method, but also inconvenient, is difficult to realize industrialization, can not carry out technique amplification.
Therefore a kind of Pregabalin product of smaller particle is provided and preparation method is simpler, good product quality, easy industrialized production
It is assistant officer's technical barrier to be solved.
Invention content
Summary of the invention
First aspect present invention provides the crystalline Pregabalin that a kind of grain size is small, purity is high, to meet opening for different dosage forms
Hair demand.
Second aspect of the present invention provides a kind of pregabalin composition, including the crystalline Pregabalin of small particle and diluent or
Carrier, the composition disintegration is fast, and dissolution is fast, and bioavilability is high, and hardness is higher, and friability is small.
Third aspect present invention provides a kind of method that solution crystallization prepares small particle Pregabalin product, and this method includes
Committed step adds to Pregabalin crude product solution is counter in poor solvent, and it is not necessary that crystal seed is added, easy to operate, high income, pure
Degree is high.
Term defines
The invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in as claim is fixed
In the scope of the invention of justice.Those skilled in the art will appreciate that many and similar or equivalent method and material described herein
It can be used in the practice present invention.The present invention is not limited to method described herein and material.In document, patent and the class combined
One or more or contradict in the case of (include but not limited to defined in term, terms different from the application like material
Using, described technology etc.), it is subject to the application.
It will further be appreciated that certain features of the present invention, are clearly visible, are carried out in multiple independent embodiments
Description, but can also in combination be provided in single embodiment.Conversely, the various features of the present invention, for brevity,
It is described, but can also be provided individually or with any suitable sub-portfolio in single embodiment.
Unless otherwise stated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's
It is generally understood identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference
It is bright.
Term "comprising" or " comprising " are open language, that is, include the content specified by the present invention, but it is not precluded
Content in terms of him.
In the context of the present invention, wordings such as " about " or " about " whether or not using, all numbers being disclosed that
Word is approximation.The numerical value of each number is possible to the conjunction that will appear 10% difference below or those skilled in the art think
The difference of reason, such as 1%, 2%, 3%, 4% or 5% difference.
Term " D (10) " refers to that the cumulative particle sizes volume percentile of Pregabalin reaches grain corresponding when 10%
Diameter, term " D (50) " refer to that the cumulative particle sizes volume percentile of Pregabalin reaches grain size corresponding when 50%, term
" D (90) " refer to that the cumulative particle sizes volume percentile of Pregabalin reaches grain size corresponding when 90%.
Unless otherwise stated, Particle Size Determination Method of the invention is measured according to following laser scattering method：
Instrument：Scirocco 2000 (A) laser particle analyzer
Detection operation：" configuration " → " attachment " is clicked, proper pressure and air-flow (such as 3.5bar, 70%) are adjusted, is clicked
" air-flow " purges entire pipeline, waits for 30s, clicks " stopping " and exits；" measurement " → " manual " is clicked again, observes background shading
Degree ensures obscurity >=70.0%；Otherwise, sample inlet pool and measuring cell are cleaned, then purges entire pipeline, until obscurity range is full
Foot requires.
It takes in appropriate (single sample amount) to the sample tray of test sample, runs correlation SOP (setting of according to the form below instrument parameter),
Horizontal survey 3 times, takes average result.
| Project | Parameter |
| Injector | Scirocco 2000(A) |
| Pattern | Universal model (enhancing) |
| Particle refractive index | 1.520 |
| Granule absorbance | 0.1 |
| Dispersant refractive index | 1.000 |
| Obscurity | 0.5%~6.0% |
| Disperse air pressure | 3.0bar |
| Sample rate | 50% |
| Sample time of measuring | 12s |
| Background time of measuring | 12s |
Detailed description of the invention
The present invention provides a kind of crystalline Pregabalin of small particle, the crystalline pregabaline particles D (50) is less than 50 μm,
More preferable D (50) is less than 10 μm.
Crystalline pregabaline particles D (90) described in some embodiments of the invention is less than 50 μm, and more preferable D (90) is less than 30
μm。
Crystalline Pregabalin purity described in some embodiments of the invention is more than 98%, more preferably above 99%.
The small particle of the present invention, grain size can meet different doses in normal distribution, high-purity crystalline Pregabalin
The demand of type.
Second aspect of the present invention provides pregabalin composition, the composition include the crystalline Pregabalin and
Medicinal diluent or carrier.
According to some embodiments of the invention, the composition can further include disintegrant and/or lubricant.
Drug content is more uniformly distributed after composition of the present invention has small grain size product mix, the tablet method of double differences obtained
Different small, disintegration is fast, and dissolution is fast, and bioavilability is high, and hardness is higher, and friability is small, reduces in coating process because hardness is low
And the advantages such as abrasion generated.
Third aspect present invention provides a kind of small particle pregabaline particles preparation method, and the preparation method includes will be general
Auspicious Bahrain's crude product is dissolved in good solvent, and it is counter add in poor solvent, stirring precipitates crystal, filtering, be dried to obtain Puri bar
Forestry products.
The temperature of poor solvent described in some embodiments of the invention is -10 DEG C -20 DEG C, more preferably -5 DEG C -5 DEG C.
The rotating speed 50-500rpm stirred described in some embodiments of the invention, more preferably 200~400rpm.
Good solvent described in some embodiments of the invention is selected from ethyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, sec-butyl alcohol
One or more mixed solvents with water.
Poor solvent described in some embodiments of the invention is selected from methyl acetate, ethyl acetate, Ethyl formate, formic acid fourth
Ester, n-butyl acetate, isopropyl acetate, dimethyl carbonate, acetone, butanone, N-Methyl pyrrolidone, acetonitrile, 1,4- dioxies six
Ring, tetrahydrofuran, toluene, n-hexane, hexamethylene, pentane, normal heptane, ether, isopropyl ether, glycol dimethyl ether, methyl- tert
At least one of butyl ether, dimethyl sulfoxide, N,N-dimethylformamide.
Small particle pregabaline particles preparation method of the present invention includes committed step by the solution of Pregabalin crude product
It is counter to add to poor solvent process, and it is not necessary that crystal seed is added, it is simpler with operating, acquisition pregabaline particles grain size smaller,
Particle diameter distribution is in advantages such as normal distribution, high income, purity height.
Description of the drawings
Fig. 1 disclose the product that the crystalline Pregabalin of small particle in some embodiments of the present invention and crystallisation by cooling obtain,
Commercial product particle diameter distribution comparison diagram.
Fig. 2 discloses two kinds of tablet stripping curves of Pregabalin containing small particle or big grain size Pregabalin.
Fig. 3 discloses the XRD spectrum of the crystalline Pregabalin of the present invention.
Fig. 4 discloses the grain size distribution of the crystalline Pregabalin of small particle of one embodiment.
Specific implementation mode
In order to make those skilled in the art more fully understand technical scheme of the present invention, it is non-that some are disclosed further below
Limiting embodiment, the present invention is described in further detail.
Reagent used in the present invention can be bought or can described method system through the invention from the market
It is standby and obtain.
In the present invention, μm refer to micron, rpm refers to rev/min, and min refers to minute, and mL or ml refer to milliliter, and g refers to gram, " 0.06N
HCl " refers to 0.06 mol/L hydrochloric acid,
Embodiment 1
Measure crystalline Pregabalin product and crystallisation by cooling product, the commercially available production of the present invention respectively according to laser scattering method
The grain size of product, the results are shown in Figure 1.
From fig. 1, it can be seen that the crystalline Pregabalin grain size D90 of small particle of the present invention is less than (15 μm), hence it is evident that be less than cooling knot
Product cut size (100 μm) and commercial product grain size (200 μm) prepared by crystallization.And the crystalline Pregabalin diameter of small particle of the present invention
Particle diameter distribution is substantially in normal distribution.
Embodiment 2
Respectively by the Pregabalin 5.0g or commercially available Pregabalins 5.0g of small particle and microcrystalline cellulose 16.3g, mannitol
16.3g、
Tablet is made in crospovidone XL-10 2.0g, magnesium stearate 0.4g.Preparation process：By microcrystalline cellulose, sweet dew
Alcohol, magnesium stearate cross 80 mesh sieve, respectively after mixing with the Pregabalin of two kinds of grain sizes, magnesium stearate are added, are uniformly mixed
Afterwards 100 tablets are suppressed using suitable for punch die.
(1), the dissolution rate measurement method of tablet made from two kinds of grain sizes：
The release profiles of tablet made from two kinds of grain sizes are illustrated in fig. 2 shown below.As can be seen from Figure 2, small particle (D (50) of the present invention
At 10 μm or less) tablet just basically reach maximum stripping quantity in 10min or so, and (commercial product D's big grain size (50) exists
50 μm or more) tablet just basically reach maximum stripping quantity in 30min.It can be seen that small particle product is preparing quick-effective preparation production
Product have apparent advantage when for alleviating acute forms pain.
(2), disintegration time limited
In addition disintegration time limited of two kinds of tablets in pure water is also measured, measurement side see the table below：
| Dissolution medium | Pure water |
| Dissolution medium temperature | 37±0.5℃ |
| Medium volume | 900mL±10mL |
| Tablet number | N=6 |
Experimental result：The disintegration time limited of small particle tablet is 32 seconds, and the disintegration time limited of big grain size product is 60 seconds.
(3), hardness
Measure the hardness of two kinds of tablets (two kinds of tablets are to suppress to come under same pressure)：It is small
The hardness of grain size tablet is 76N, and the hardness of big grain size product is 60N.
(4), friability
Measure the friability of two kinds of tablets：The friability of small particle tablet is 0.084%, big grain size product
Friability be 0.216%.
It follows that drug content is more uniformly distributed after small grain size product mix, disintegration is fast, and dissolution is fast, and bioavilability is high,
And hardness is higher, friability is small, reduces in coating process because of the abrasion that hardness is low and generates, improves the dissolving out capability of drug.
Embodiment 3
The preparation needs of current general small particle product are by repeatedly crushing, being repeatedly sieved, this process is not only imitated
Rate is low, time-consuming, and inconvenient, is difficult to realize industrialization, can not carry out technique amplification.Test process technology personnel hair
Existing, pregabaline particles can introduce a unknown impuritie (single miscellaneous content ＞ 0.45%) after mechanical crushing 2min, cause Puri
Bahrain's purity declines.
And the present invention develops a kind of method that solution crystallization prepares small particle Pregabalin, the crystallinity of obtained particle
High (as shown in the XRD diagram of Fig. 3), without further crushing, while technique improves purity and yield again, it will be apparent that shortens entire
The time of process and improve production capacity.
Embodiment 4
It weighs 2.0g Pregabalin crude products and is dissolved in 7.5mL ethyl alcohol and 12mL purified water in the mixed solvents, it is counter in 15min to drip
It is dry to be filtered after the rotating speed stirring 4h of 300rpm into 20mL n,N-Dimethylformamide (0 DEG C), obtain small particle product, D
(50)=5.4 μm, D (90)=12.7 μm, yield 91%, purity 99.90%.After testing, particle size distribution figure and Fig. 4 basic one
It causes.
Embodiment 5
It weighs 5.0g Pregabalin crude products and is dissolved in 25mL sec-butyl alcohols and 25mL purified water in the mixed solvents, it is anti-in 20min
It drops in 50mL dimethyl sulfoxides (20 DEG C), it is dry to be filtered after the rotating speed of 300rpm stirring 2h, obtain small particle product, D (50)=
6.4 μm, D (90)=21.3 μm, yield 92%, purity 99.86%.After testing, particle size distribution figure and Fig. 4 are almost the same.
Embodiment 6
It weighs 20.0g Pregabalin products and is dissolved in 100mL n-butanols and 100mL purified water in the mixed solvents, in 30min
It is counter to drop in 200mL n-butyl acetates (0 DEG C), it is dry to be filtered after the stirring 3h of 400rpm, obtain small particle product, D (50)=
8.7 μm, D (90)=26.0 μm, yield 89%, purity 99.91%.After testing, particle size distribution figure and Fig. 4 are almost the same.
Embodiment 7
It weighs 20.0g Pregabalin products and is dissolved in the 80mL tert-butyl alcohols and 80mL purified water in the mixed solvents, it is anti-in 25min
It drops in 160mL acetone (0 DEG C), it is dry to be filtered after the rotating speed stirring 1h of 300rpm, obtain small particle product, D (50)=7.6 μ
M, D (90)=22.4 μm, yield 90%, purity 99.88%.After testing, particle size distribution figure and Fig. 4 are almost the same.
Embodiment 8
It weighs 20.0g Pregabalin products and is dissolved in 80mL n-butanols and 80mL purified water in the mixed solvents, it is anti-in 50min
It drops in 200mL normal heptanes (5 DEG C), it is dry to be filtered after the rotating speed of 500rpm stirring 4h, obtain small particle product, D (50)=
5.5 μm, D (90)=12.5 μm, yield 92%, purity 99.93%.After testing, particle size distribution figure and Fig. 4 are almost the same.
In conclusion the D (50) of crystalline pregabaline particles of the present invention is less than 50 μm, more even up to D (50) is small
In 10 μm, purity is 99% or more.Pregabalin composition of the present invention, including crystalline pregabaline particles of small particle and dilute
Agent or carrier are released, the composition disintegration is fast, and dissolution is fast, and bioavilability is high, and hardness is higher, and friability is small.It is of the present invention
The method that a kind of crystallization of solution prepares small particle pregabaline particles, this method include committed step by Pregabalin crude product solution
It is counter to drop in poor solvent, and it is not necessary that crystal seed is added, easy to operate, high income, purity are high.
The method of the present invention is described by preferred embodiment, related personnel can obviously hold within the present invention,
Method described herein and application are modified or are suitably changed and combined in spirit and scope, to realize and apply the present invention
Technology.Those skilled in the art can use for reference present disclosure, be suitably modified technological parameter realization.In particular, it should be pointed out that institute
There are similar replacement and change apparent to those skilled in the art, they are considered as being included in the present invention
It is interior.
Claims (12)
1. a kind of crystalline Pregabalin, which is characterized in that crystalline 50 μm of Pregabalin D (50) ＜.
2. crystalline Pregabalin according to claim 1, which is characterized in that crystalline 10 μm of Pregabalin D (50) ＜.
3. according to any one of the claim 1-2 crystalline Pregabalins, which is characterized in that the crystalline Pregabalin D (90)
50 μm of ＜.
4. according to any one of the claim 1-2 crystalline Pregabalins, which is characterized in that the crystalline Pregabalin D (90)
30 μm of ＜.
5. crystalline Pregabalin according to claim 1, which is characterized in that the purity of the crystalline Pregabalin is more than
98%.
6. a kind of composition, which is characterized in that the composition include any one of the claim 1-5 crystalline Pregabalin with
And medicinal diluent or carrier.
7. composition according to claim 6, which is characterized in that the composition also further contains disintegrant, lubricant.
8. a kind of method preparing the crystalline Pregabalin as described in claim any one of 1-5, which is characterized in that the method packet
It includes：Pregabalin crude product is dissolved in good solvent, and it is counter add in poor solvent, stirring precipitates crystal, filtering, be dried to obtain
Pregabalin product.
9. method according to claim 8, which is characterized in that the temperature of the poor solvent is -10-20 DEG C.
10. method according to claim 8, which is characterized in that the range of speeds of the stirring is 50-500rpm.
11. according to any one of claim 8-10 the methods, which is characterized in that the good solvent be selected from ethyl alcohol, isopropanol,
N-butanol, the tert-butyl alcohol, sec-butyl alcohol one or more and water mixed solvent.
12. according to any one of claim 8-10 the methods, which is characterized in that the poor solvent be selected from methyl acetate,
Ethyl acetate, Ethyl formate, butyl formate, n-butyl acetate, isopropyl acetate, dimethyl carbonate, acetone, butanone, N- methyl
It is pyrrolidones, acetonitrile, 1,4- dioxane, tetrahydrofuran, toluene, n-hexane, hexamethylene, pentane, normal heptane, ether, different
At least one of propyl ether, glycol dimethyl ether, methyl tertiary butyl ether(MTBE), dimethyl sulfoxide, N,N-dimethylformamide.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109115661A (en) * | 2018-09-27 | 2019-01-01 | 湖北省宏源药业科技股份有限公司 | A method of for measuring azithromycin drug partial size and size distribution |
| CN110922356A (en) * | 2019-12-03 | 2020-03-27 | 宁波南大光电材料有限公司 | Preparation method of electronic grade high-purity 8-hydroxyquinoline aluminum |
| CN111170879A (en) * | 2020-01-21 | 2020-05-19 | 石药集团中奇制药技术（石家庄）有限公司 | Small-particle-size pregabalin and preparation method thereof |
| CN113717069A (en) * | 2021-09-29 | 2021-11-30 | 浙江华海药业股份有限公司 | Crystallization method of pregabalin |
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| CN1962612A (en) * | 2006-11-23 | 2007-05-16 | 重庆医药工业研究院有限责任公司 | Novel pregabalin crystal form and preparing method thereof |
| CN102089273A (en) * | 2008-04-04 | 2011-06-08 | 基因里克斯(英国)有限公司 | Novel process |
| CN104649919A (en) * | 2015-02-10 | 2015-05-27 | 浙江华海药业股份有限公司 | Preparation method of small-particle pregabalin |
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- 2017-11-03 CN CN201711069860.0A patent/CN108456144A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1962612A (en) * | 2006-11-23 | 2007-05-16 | 重庆医药工业研究院有限责任公司 | Novel pregabalin crystal form and preparing method thereof |
| CN102089273A (en) * | 2008-04-04 | 2011-06-08 | 基因里克斯(英国)有限公司 | Novel process |
| CN104649919A (en) * | 2015-02-10 | 2015-05-27 | 浙江华海药业股份有限公司 | Preparation method of small-particle pregabalin |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109115661A (en) * | 2018-09-27 | 2019-01-01 | 湖北省宏源药业科技股份有限公司 | A method of for measuring azithromycin drug partial size and size distribution |
| CN110922356A (en) * | 2019-12-03 | 2020-03-27 | 宁波南大光电材料有限公司 | Preparation method of electronic grade high-purity 8-hydroxyquinoline aluminum |
| CN111170879A (en) * | 2020-01-21 | 2020-05-19 | 石药集团中奇制药技术（石家庄）有限公司 | Small-particle-size pregabalin and preparation method thereof |
| CN111170879B (en) * | 2020-01-21 | 2023-07-14 | 石药集团中奇制药技术（石家庄）有限公司 | Small-granularity pregabalin and preparation method thereof |
| CN113717069A (en) * | 2021-09-29 | 2021-11-30 | 浙江华海药业股份有限公司 | Crystallization method of pregabalin |
| CN113717069B (en) * | 2021-09-29 | 2024-09-17 | 浙江华海药业股份有限公司 | Crystallization method of pregabalin |
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Application publication date: 20180828 |