CN102988319B - III crystal form pramipexole hydrochloride tablet and preparation method thereof - Google Patents
III crystal form pramipexole hydrochloride tablet and preparation method thereof Download PDFInfo
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- CN102988319B CN102988319B CN201210525806.3A CN201210525806A CN102988319B CN 102988319 B CN102988319 B CN 102988319B CN 201210525806 A CN201210525806 A CN 201210525806A CN 102988319 B CN102988319 B CN 102988319B
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Abstract
The invention discloses an III crystal form pramipexole hydrochloride tablet and a preparation method thereof. The preparation method comprises the following steps of smashing, mixing, dry granulating, total mixing and tabletting. The preparation method has the advantages that III crystal form published in brand-name drugs is adopted to feed, so that the crystal form stability of the product is guaranteed and the crystal form transformation is avoided; the solid state instability of pramipexole hydrochloride monohydrate in other wet production processes and the impurity degradation caused by light sensitivity can be avoided by adopting the dry granulating; and the stability of the product in the shelf life as well as the effectiveness and the safety of clinical application are guaranteed. The product produced by adopting the dry granulating process disclosed by the invention is similar to the brand-name drugs in the aspect of dissolution behavior.
Description
Technical field
The present invention relates to a kind of III crystal formation body of Pramipexole dihydrochloride tablet and preparation method thereof, belong to field of pharmaceutical preparations.
Background technology
Body of Pramipexole dihydrochloride, structural formula is as follows:
Be generally 1 hydrate, be used for the treatment of the parkinson disease that are common in old people.Parkinson disease belong to central nervous system degenerative disease, patient many at 60 years old with sequela.Main manifestations is that patient motion is slow, the trembling of the other parts of trick or health, and health has lost flexibility and harmony.
Because body of Pramipexole dihydrochloride solid is highly stable, prior art (US20080254118A1 for example; US20100252949A1; CN101505734A) adopt solvent dispersion method to ensure body of Pramipexole dihydrochloride uniformity of dosage units in product; but its solution state has heliosensitivity; under illumination condition, can degrade; thereby cause impurity level to raise; thereby adopt wet method preparation to adopt ratio of solvent need under lucifuge condition, in sparging fluidised bed granulator after body of Pramipexole dihydrochloride dissolving, granulate as water, can ensure like this uniformity of body of Pramipexole dihydrochloride content.Requirement for manufacturing condition just seems very harsh like this, has improved production cost.
CN102406626A discloses a kind of Pramipexole hydrochloride slow release tablet and preparation method thereof, be by pretreated body of Pramipexole dihydrochloride, ethyl cellulose premix, then mix in order in advance and add that magnesium stearate mixes, tabletting with pretreated, hydroxypropyl emthylcellulose, pregelatinized Starch.What the method adopted is the method for full pressed powder, because the material fluidity of full powdery material is poor, affects the hardness of tablet weight variation and tablet in tabletting process, increases the load of sheeting equipment simultaneously.
Summary of the invention
For deficiency of the prior art, the object of this invention is to provide a kind of method and formula thereof of dry process body of Pramipexole dihydrochloride conventional tablet.
Above-mentioned purpose of the present invention is achieved by the following technical solution:
A preparation method for III crystal formation body of Pramipexole dihydrochloride tablet, comprises the steps:
1, pulverize
III crystal formation body of Pramipexole dihydrochloride monohydrate is pulverized with mortar, crossed 200 mesh sieves; Corn starch, PEARLITOL 25C are crossed respectively to 100 sieves, discard caking;
2, mix
The body of Pramipexole dihydrochloride monohydrate raw material that step 1 is obtained, corn starch, PEARLITOL 25C, with after doubly measuring incremental method and tentatively mixing, are put in high efficient mixer and are mixed, and the detection level uniformity is carried out next step operation after qualified;
3, dry granulation
The material that step 2 is obtained is put in dry type extruding granulator and is carried out dry granulation, collects qualified granule, and bulky grain and fine powder are granulated again, until fine powder amount is less than total inventory 15%;
4, always mixed
The qualified granule of step 3 gained is placed in high efficient mixer, adds additional adjuvant always to mix;
5, tabletting
Calculate every sheet weight, tabletting in heavy ± 2.5% scope of sheet, adds step 4 gained material is carried out to tabletting.
In the present invention, in the uniformity of control blend step and dry granulation step, granular size has remarkable effect for controlling body of Pramipexole dihydrochloride uniformity of dosage units in tablet.Generally speaking, in the present invention, in blend step, the weight of each component is III crystal formation body of Pramipexole dihydrochloride monohydrate: PEARLITOL 25C: corn starch=0.1-1mg:50-150 mg:20-100 mg, be preferably 0.25-1mg:50-130 mg:30-80 mg, more preferably 0.25mg:61mg:40 mg or 1mg:122mg:80mg; Doubly amount increases progressively control for 1:1 ~ 1:2, and incorporation time is controlled in 45 minutes to 1 hour, preferably controls the RSD of the uniformity of III crystal formation body of Pramipexole dihydrochloride monohydrate in material within the scope of 1.0%-5.0%.
Further, in the present invention, the qualified granule described in step 3 refers to granule between 20 orders and 100 eye mesh screens, is preferably 24 to 80 orders; Extruding granulator parameter is controlled as pre-pinch roller: 15-20Hz, binder: 30-50Hz, charging: 10-15Hz, oil pressure pressure: 6-7Mpa; General dry granulation just can be controlled in triplicate fine powder amount and be less than total inventory 15%.
As preferably, in the present invention, the additional adjuvant that always mixed step adds is silicon dioxide, magnesium stearate, and addition is silica volume=35g * yield, magnesium stearate amount=40g * yield; Described yield is that yield=reality obtains quantity/inventory * 100%.General preferred formula is III crystal formation body of Pramipexole dihydrochloride monohydrate: silicon dioxide: magnesium stearate=0.1-1.0 mg:1-5 mg:1-5 mg, be preferably 0.25mg-1.0:1.5-3mg:2-4mg, more preferably 0.25mg:1.75mg:2mg or 1 mg:3 mg:4 mg.Total mixed 15-30 minute that is mixed into, is preferably 20 minutes; Acquiescence rotating speed 10-15 rev/min, preferably 12 revs/min; Control in the material that total mixed step obtains III crystal formation body of Pramipexole dihydrochloride content and be 0.450%-0.490% (1mg) or 0.220%-0.250%(0.25mg), moisture is 1.0% ~ 5.0%.
Generally speaking, in the present invention, the requirement of tabletting step: ￠ 5.5mm(0.125mg), ￠ 6mm(0.25mg) and ￠ 8mm(1.0mg) punching of shallow arc; Hardness requirement: 4-5kg.Within every 15 minutes, extract 10, the weight of weighed every slice, thin piece, should all meet tablet weight variation scope respectively, measures respectively the hardness of 4 slice, thin pieces simultaneously again, should be all up to specification.Detect at any time outward appearance, should be complete bright and clean, neat in edge, sheet type is consistent, foreign, loose sheet, sliver, chooses defective work.
beneficial effect of the present invention is:
1. adopt and brand medicine (Sen Fuluo
?) the III crystal formation announced feeds intake, and ensures the stable crystal form of product, do not have the conversion of crystal formation;
2. adopt dry granulation can avoid the solid-state unstability of body of Pramipexole dihydrochloride monohydrate under other wet process techniques; Avoid heliosensitivity to produce impurity degraded.Ensure that product is in the stability of shelf life and the effectiveness of clinical application and safety;
3. adopt product and the brand medicine (Sen Fuluo of dry granulation explained hereafter
?) stripping behavior be similar (50≤f
2≤ 100).
Accompanying drawing explanation
Fig. 1 is 0.25mg specification tablet and commercially available product stripping curve comparison diagram in pH6.8 buffer in the present invention.
Fig. 2 is 0.25mg specification tablet and commercially available product stripping curve comparison diagram in pH4.5 buffer in the present invention.
Fig. 3 is 0.25mg specification tablet and commercially available product stripping curve comparison diagram in 0.1mol/L hydrochloric acid solution in the present invention.
Fig. 4 is 0.25mg specification tablet and commercially available product stripping curve comparison diagram in water in the present invention.
Fig. 5 is 1.0mg specification tablet and commercially available product stripping curve comparison diagram in pH6.8 buffer in the present invention.
Fig. 6 is 1.0mg specification tablet and commercially available product stripping curve comparison diagram in pH4.5 buffer in the present invention.
Fig. 7 is 1.0mg specification tablet and commercially available product stripping curve comparison diagram in 0.1mol/L hydrochloric acid solution in the present invention.
Fig. 8 is 1.0mg specification tablet and commercially available product stripping curve comparison diagram in water in the present invention.
Fig. 9 is bibliographical information III crystal formation pramipexole PXRD collection of illustrative plates.
Figure 10 is the III crystal formation pramipexole XRD figure spectrum that the present invention adopts.
The specific embodiment
prescription:
| Prescription | Body of Pramipexole dihydrochloride | Mannitol | Corn starch | Magnesium stearate | Silicon dioxide |
| 1 | 0.15 mg | 50.0 mg | 20.0 mg | 1.0 mg | 1.0 mg |
| 2 | 0.15 mg | 55.0 mg | 30.0 mg | 1.0 mg | 1.5 mg |
| 3 | 0.25 mg | 61.0 mg | 40.0 mg | 2.0 mg | 1.75 mg |
| 4 | 0.25 mg | 80.0 mg | 60.0 mg | 2.0 mg | 2.0 mg |
| 5 | 0.25 mg | 100.0 mg | 70.0 mg | 2.0 mg | 2.0 mg |
| 6 | 1.0 mg | 122.0 mg | 80.0 mg | 4.0 mg | 3.0 mg |
| 7 | 1.0 mg | 130.0 mg | 90.0 mg | 4.0 mg | 4.0 mg |
| 8 | 1.0 mg | 150.0 mg | 100.0 mg | 5.0 mg | 5.0 mg |
embodiment 1
1. by prescription 1, mannitol, corn starch, magnesium stearate, silicon dioxide are crossed to 100 mesh sieves; III crystal formation body of Pramipexole dihydrochloride monohydrate is crossed 200 mesh sieves.
2. by the prescription of design, took respectively each 50,000 amounts of adjuvant of 100 mesh sieves.By weighing complete III crystal formation body of Pramipexole dihydrochloride monohydrate raw material, corn starch, PEARLITOL 25C with after doubly measuring incremental method and tentatively mixing, put in high efficient mixer, to mix 45 minutes, the detection level uniformity, carries out next step operation after qualified.
3. after end to be mixed, the material mixing is put in dry type extruding granulator and carried out dry granulation.(pre-pinch roller: 15-20Hz, binder: 30-50Hz, charging: 10-15Hz, oil pressure pressure: 6-7Mpa).In pelletization, reinforced in hopper at any time.According to practical situation, regulate oil pressure pressure.Collecting granule between 24 orders and 80 eye mesh screens, is qualified granule, and bulky grain and fine powder are granulated again.Until fine powder amount is less than total inventory 15% under 80 eye mesh screens, approximately in triplicate.
N gained fine powder amount of fine powder percentage ratio=the/(for the first time qualified granule heavy+for the second time qualified granule heavy+for the third time qualified granule heavy+... + the n time qualified granule be heavy+the n time gained fine powder amount) * 100%.
4. all qualified granules are placed in high efficient mixer, add additional adjuvant, silicon dioxide, magnesium stearate are always mixed, mix 20 minutes, and 12 revs/min of acquiescence rotating speeds, intermediate samples, and detects its content, moisture.Weigh, stick material card, hang up sign board to be tested, send into intermediate station.
5. after intermediate assay is qualified, according to testing result, calculate every sheet weight, tabletting in heavy ± 2.5% scope of sheet, rotary tablet machine is adjusted, and adds material to carry out tabletting, requires: ￠ 6mm(0.25mg) and ￠ 8mm(1.0mg) shallow arc rushes; Hardness requirement: 4-5kg.Within every 15 minutes, extract 10, the weight of weighed every slice, thin piece, should all meet tablet weight variation scope respectively, measures respectively the hardness of 4 slice, thin pieces simultaneously again, should be all up to specification.Detect at any time outward appearance, should be complete bright and clean, neat in edge, sheet type is consistent, foreign, loose sheet, sliver, chooses defective work.Tabletting finishes, and pick test weighs, and fills in material card, puts intermediate station and stores.
embodiment 2
In the film-making of prescription 2-8 ratio, concrete operations reference example 1.
embodiment 3
Body of Pramipexole dihydrochloride is easily molten in water, in import quality standard (JX20070241), adopt citron salt/phosphate buffer (PH6.8) 500ml as solvent, use oar method, 50 revs/min of rotating speeds, the term harmonization of the body of Pramipexole dihydrochloride sheet dissolving-out method that the method and FDA stripping data base announce.The present invention adopts four kinds of solvents (in Table 1) condition to investigate the similarity (50≤f of the stripping behavior of definite embodiment 1-2 and commercially available product
2≤ 100) whether meet the requirements.
Four kinds of solvent conditions of table 1
By body of Pramipexole dihydrochloride sheet in embodiment (lot number: 100602, specification: 0.25mg; Lot number: 100601, specification: 1.0mg) with body of Pramipexole dihydrochloride sheet commercially available product (Sen Fuluo; Lot number: 002448; Specification: 1.0mg; Lot number: 004381; Specification: 0.25mg) carry out stripping curve research in four kinds of dissolution mediums and draw stripping curve and calculate stripping similarity (f
2).The results are shown in Table 2-9.
Table 2
pH6.8 citrate/phosphate-buffered liquid medium (1.0mg specification)
Table 3 pH6.8 citrate/phosphate-buffered liquid medium (0.25mg specification)
Table 4 pH4.5 acetate salt buffer liquid medium (1.0mg specification)
Table 5 pH4.5 acetate salt buffer liquid medium (0.25mg specification)
Table 6 0.1mol/L hydrochloric acid solution medium (1.0mg specification)
Table 7 0.1mol/L hydrochloric acid solution medium (0.25mg specification)
Table 8 aqueous medium (1.0mg specification)
Table 9
aqueous medium (0.25mg specification)
Claims (12)
1. a preparation method for III crystal formation body of Pramipexole dihydrochloride tablet, comprises the steps:
1, pulverize
III crystal formation body of Pramipexole dihydrochloride monohydrate is pulverized with mortar, crossed 200 mesh sieves; Corn starch, PEARLITOL 25C are crossed respectively to 100 sieves, discard caking;
2, mix
The III crystal formation body of Pramipexole dihydrochloride monohydrate raw material that step 1 is obtained, corn starch, PEARLITOL 25C, with after doubly measuring incremental method and tentatively mixing, are put in high efficient mixer and are mixed, and the detection level uniformity is carried out next step operation after qualified;
3, dry granulation
The material that step 2 is obtained is put in dry type extruding granulator and is carried out dry granulation, collects qualified granule, and bulky grain and fine powder are granulated again, until fine powder amount is less than total inventory 15%;
4, always mixed
The qualified granule of step 3 gained is placed in high efficient mixer, adds additional adjuvant always to mix;
5, tabletting
Calculate every sheet weight, tabletting in heavy ± 2.5% scope of sheet, adds step 4 gained material is carried out to tabletting.
2. the method for claim 1, wherein doubly measures to increase progressively described in step 2 and controls as 1:1 ~ 1:2, and incorporation time is controlled in 45 minutes to 1 hour, preferably controls the RSD of the uniformity within the scope of 1%-5%.
3. method as claimed in claim 1 or 2, wherein the qualified granule described in step 3 refers to granule between 20 to 100 eye mesh screens; Extruding granulator parameter is controlled as pre-pinch roller: 15-20Hz, binder: 30-50Hz, charging: 10-15Hz, oil pressure pressure: 6-7Mpa; Preferred 1-3 time of the number of times that granulation is controlled again.
4. method as claimed in claim 3, wherein the qualified granule described in step 3 refers to granule between 24 to 80 eye mesh screens.
5. the method as described in claim 1-2,4 any one, the additional adjuvant that wherein step 4 adds is silicon dioxide, magnesium stearate, addition is silica volume=35g * yield, magnesium stearate amount=40g * yield; Described yield is that yield=reality obtains quantity/inventory * 100%.
6. the method as described in claim 1-2,4 any one, wherein the incorporation time of step 4 is 15-30 minute; Acquiescence rotating speed 10-15 rev/min; In the material that the total mixed step of control obtains, body of Pramipexole dihydrochloride content is the every 1mg of 0.450%-0.490% or the every 0.25mg of 0.220%-0.250%, and moisture is 1.0% ~ 5.0%.
7. the method as described in claim 6 any one, wherein the incorporation time of step 4 is for being 20 minutes; 12 revs/min of acquiescence rotating speeds.
8. the method as described in claim 1-2,4,6 any one, wherein the requirement of step 5 tabletting step: 0.125mg is that ￠ 5.5mm, 0.25mg are that ￠ 6mm and 1.0mg are the shallow arc punching of ￠ 8mm; Hardness requirement: 4-5kg.
9. an III crystal formation body of Pramipexole dihydrochloride tablet, comprises following component:
III crystal formation body of Pramipexole dihydrochloride monohydrate 0.1-1mg
PEARLITOL 25C 50-150 mg
Corn starch 20-100 mg
Silica 1-5 mg
Magnesium stearate 1-5 mg;
Described tablet is prepared by claim 1-8 any one method.
10. tablet as claimed in claim 9, comprises following component:
III crystal formation body of Pramipexole dihydrochloride monohydrate 0.25-1mg
PEARLITOL 25C 50-130 mg
Corn starch 30-80mg
Silica 1 .5-3mg
Magnesium stearate 2-4mg.
11. the tablet as described in claim 9 or 10, comprises following component:
III crystal formation body of Pramipexole dihydrochloride monohydrate 0.25mg
PEARLITOL 25C 61mg
Corn starch 40mg
Silica 1 .75mg
Magnesium stearate 2mg.
12. the tablet as described in claim 9 or 10, comprises following component:
III crystal formation body of Pramipexole dihydrochloride monohydrate 1mg
PEARLITOL 25C 122mg
Corn starch 80mg
Silicon dioxide 3mg
Magnesium stearate 4mg.
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| CN201210525806.3A CN102988319B (en) | 2012-12-10 | 2012-12-10 | III crystal form pramipexole hydrochloride tablet and preparation method thereof |
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| CN102988319B true CN102988319B (en) | 2014-10-08 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101884626A (en) * | 2004-08-13 | 2010-11-17 | 贝林格尔.英格海姆国际有限公司 | The prolongation release tablet, the Preparation Method And The Use that comprise pramipexole or its officinal salt |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101884626A (en) * | 2004-08-13 | 2010-11-17 | 贝林格尔.英格海姆国际有限公司 | The prolongation release tablet, the Preparation Method And The Use that comprise pramipexole or its officinal salt |
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Address after: 88 building B7, No. 501 South Garden Road, Chengdu hi tech Zone, Sichuan 610041, China Patentee after: CHENGDU XINJIE HI-TECH DEVELOPMENT CO., LTD. Address before: 88 building B7, No. 501 South Garden Road, Chengdu hi tech Zone, Sichuan 610041, China Patentee before: Chengdu Xinjie Hi-Tech Development Co., Ltd. |