CN105012298A - Pharmaceutical composition containing spherical clopidogrel bisulfate I crystal form and preparation method of pharmaceutical composition - Google Patents
Pharmaceutical composition containing spherical clopidogrel bisulfate I crystal form and preparation method of pharmaceutical composition Download PDFInfo
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Abstract
The invention provides pharmaceutical composition containing spherical clopidogrel bisulfate I crystal form and a preparation method of the pharmaceutical composition. Direct powder compressing can be achieved favorably by the powder property of the pharmaceutical composition, and sticking during tablet compressing is avoided. The invention further provides a clopidogrel bisulfate tablet using direct powder compressing and a preparation method of the tablet. The tablet meets the requirements of clinical medication.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, especially, the present invention relates to a kind of pharmaceutical composition containing spherical bisulfate clopidogrel I crystal and preparation method thereof.
Background technology
Bisulfate clopidogrel (CAS:135046-48-9), the sulfate of clopidogrel, English name Clopidogrel Hydrogen Sulfate, chemistry is by name: (s)-α-(2-chlorphenyl)-6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H) acetate hydrogensulfate also.Bisulfate clopidogrel is a kind of anti-platelet aggregation agent.This product is developed by French pharmacy corporation Sanofi-Aventis company, and in 1998 first in UK and USA listing, bisulfate clopidogrel enters China in calendar year 2001, clinically for the atherosis thrombosis event of prevention of arterial.At present, domestic bisulfate clopidogrel formulation products mainly contains the Plavix (Plavix) of Sanofi-Aventis company and the Tai Jia of SHENZHEN SALUBRIS PHARMACEUTICALS CO., LTD.
The main crystal formation of bisulfate clopidogrel has I type and two kinds, II type, and wherein II type crystal formation is Thermodynamically stable crystal formation, and I type crystal formation is then thermodynamic instability crystal formation.
Current commercial sulfuric acid clopidogrel hydrogen formulation products many employings I type crystal, and I-type clopidogrel hydrogen sulfate crystal is for damp and hot instability, therefore conventional wet lay granulation-tabletting method and be not suitable in bisulfate clopidogrel preparation, at present conventional dry formulations technique prepares bisulfate clopidogrel preparation.
Known in this field, dry formulations technique is further divided into dry granulation-tablet forming technique and powder vertical compression technique.SHENZHEN SALUBRIS PHARMACEUTICALS CO., LTD once disclosed a kind of solid preparation dry granulation-tablet forming technique containing bisulfate clopidogrel at CN200610063151.7, and this technique can prepare the bisulfate clopidogrel oral formulations meeting Clinical practice.But dry granulation-tablet forming technique needs first mixed powder to be pressed into large stretch of rear pulverizing, granulate, and last tabletting, operation is many and loaded down with trivial details, the more important thing is dry granulation-tablet forming technique production capacity Shortcomings, cannot meet the growing market demand.
Powder vertical compression technique is that direct compression is prepared into oral tablet by the mixed powder containing effective ingredient without granulation process, and powder vertical compression technique has the advantages such as technique is simple, production capacity is large, is the developing direction of oral formulations preparation technology.It is reported, the oral solid formulation of European and American developed countries' significant proportion adopts the preparation of powder vertical compression technique.But this technique has higher requirement for the dry jet mixing pile of mixed powder, the not good powder body of mobility or compressibility is not suitable for adopting powder vertical compression technique.For bisulfate clopidogrel, many its I type crystalline formulation products of employing in the market, the crystallization of I type is thermodynamic instability crystal formation, although it has advantage in dissolubility, but because its conventional powder has very strong electrostatic more, compressibility is also bad, and mobility is not good on the one hand to make it, very easily sticking occurs thus causes production to carry out smoothly on the other hand in powder vertical compression technique.
Chinese patent CN201180072203.6 discloses a kind of preparation method of spherical I-type clopidogrel hydrogen sulfate crystal, and adopts the powder vertical compression preparation of this spheroidal crystal.Its technique adopts 2-butanols/cyclohexane extraction system to prepare particle size distribution: d (0.1)=52.536 μm, d (0.5)=74.567 μm, the spheroidal crystal of d (0.9)=106.074 μm, this crystallization improves the mobility of bisulfate clopidogrel, and reduces the electrostatic effect of powder body.But, one of key technology factor of this technique is sulphuric acid-cyclohexane solution to be needed slowly to add in the cooling condition in dicyandiamide solution, because concentrated sulphuric acid and cyclohexane extraction do not dissolve each other, make easily to cause system local sulfuric acid concentration too high and gained crystallization is darkened adding in dicyandiamide solution process, affect crystalline quality; In addition, because this technique required time is longer, and there is the risk turning crystalline substance in the long response time on the one hand, also can reduce crystal bulk density because of the excessive irregular growth of crystal on the other hand.Above technological deficiency causes gained preparation to darken, and due to crystal bulk density too low, sticking phenomenon still cannot be avoided to occur.
Therefore, realize bisulfate clopidogrel powder vertical compression and remain the unsolved technical problem of prior art.
Summary of the invention
The object of the invention is to the shortcoming overcoming prior art, a kind of pharmaceutical composition containing spherical bisulfate clopidogrel I crystal is provided, its powder property is conducive to realizing powder vertical compression technique, and without sticking phenomenon in tableting processes, gained solid orally ingestible meets clinical application requirement.
Above-mentioned beneficial effect of the present invention is achieved through the following technical solutions.
A kind of pharmaceutical composition containing spherical bisulfate clopidogrel I crystal, comprise the bisulfate clopidogrel of spherical I crystal, filler, disintegrating agent and lubricant, it is characterized in that particle diameter 90 μm≤D90≤150 μm of described bisulfate clopidogrel, and bulk density is 0.7g/mL ~ 0.9g/mL, tap density is 0.8g/mL ~ 1.0g/mL.
One of key that above technical scheme realizes is the powder morphology of effective ingredient bisulfate clopidogrel, when particle diameter 90 μm≤D90≤150 μm of bisulfate clopidogrel, and bulk density is 0.7g/mL ~ 0.9g/mL, when tap density is 0.8g/mL ~ 1.0g/mL, its mobility is moderate, is applicable to using in powder vertical compression technique.Concrete, the particle diameter of bisulfate clopidogrel, bulk density and tap density need to meet above-mentioned scope simultaneously, and its dry jet mixing pile just can meet the requirement of mobility and compressibility simultaneously, just can realize powder vertical compression technique.More specifically, as well known to those skilled in the art, the particle diameter of medicament powder and bulk density, tap density, without necessary connection, even if the powder body that particle size range is close, also may correspond to distinct bulk density, tap density.For spherical bisulfate clopidogrel I crystal of the present invention, its actual particle shape can be the sphere that surface is full of gap, can be the sphere of surface in " Rrinaceus earopaeus " shape, also can be irregular ellipticity etc., it all can embody identical/close particle size range in the detection, and then be presented as similar mobility, but distinct bulk density and tap density can be presented as, also there is significant difference in its performance in actual production process, work as bulk density, when tap density is too small, vertical compression powder body and drift have relatively long time of contact at relatively high pressure, and stick to punch head surface when drift temperature is higher, show as after vertical compression technique carries out a period of time and occur " sticking " phenomenon, and bulk density, tap density excessive time, easily occur in vertical compression Studies of Process of Powder Mixing that mixing is uneven, the phenomenon of the easy layering of supplementary material, is unfavorable for the control of product quality.Preferably, the particle diameter of bisulfate clopidogrel is 100 μm≤D90≤120 μm; Preferred, the particle diameter of bisulfate clopidogrel is 100 μm≤D90≤120 μm, 60 μm≤D50≤90 μm, and bulk density is 0.72g/mL ~ 0.82g/mL, and tap density is 0.82g/mL ~ 0.92g/mL.
Another factor that above technical scheme realizes is the selection of prescription.Concrete, supplementary product consumption increase the probability being conducive to reducing sticking.If no special instructions, the effective ingredient consumption in invention formulation prescription is all in bisulfate clopidogrel.Described filler is any one or two or more mixture in silicified microcrystalline cellulose, microcrystalline Cellulose, Lactis Anhydrous, mannitol etc., preferred silicified microcrystalline cellulose, when the mass parts of bisulfate clopidogrel is 1, the consumption of described filler is 1.5 ~ 2.5 parts, preferably 1.9 ~ 2.4 parts; Described disintegrating agent is any one or two or more mixture in low-substituted hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose etc., preferred low-substituted hydroxypropyl methylcellulose, when the mass parts of bisulfate clopidogrel is 1, the consumption of described disintegrating agent is 0.05 ~ 0.5 part, preferably 0.1 ~ 0.3 part; Described lubricant is any one or two or more mixture in castor oil hydrogenated, micropowder silica gel, Glyceryl Behenate etc., preferred castor oil hydrogenated, when the mass parts of bisulfate clopidogrel is 1, the consumption of described lubricant is 0.05 ~ 0.5 part, preferably 0.1 ~ 0.3 part.
The spherical bisulfate clopidogrel I crystal that preparation prescription of the present invention uses meets the description of above-mentioned particle diameter and bulk density, an optimal technical scheme of the present invention, and spherical bisulfate clopidogrel I crystal used adopts following technique to prepare:
Prepare a method for spherical bisulfate clopidogrel I crystal, described method comprises following steps:
(1) clopidogrel free alkali is dissolved in 2-butanols, obtain the free base solution that concentration is 0.02 ~ 0.1g/mL, under 0 ~ 35 DEG C of temperature conditions, add the 2-butanol solution of 0.5 ~ 2.0mol/L sulphuric acid in 60min, the mol ratio adding sulphuric acid and clopidogrel free alkali is 0.8 ~ 1.1:1;
(2) keep step (1) temperature range, add with clopidogrel free alkali mass ratio be 1 ~ 10wt% bisulfate clopidogrel I crystal crystal seed after, keep temperature stir 4 ~ 8h;
(3) filter, wash and drying, obtain bisulfate clopidogrel I crystal sphaerocrystal.
The method sphaerocrystal product is that spherical growth mechanism obtains, adopt the method contribute to bisulfate clopidogrel in solution system fast nucleation, be grown to serve as the spherical of relatively fine and close, regular shape, gained bisulfate clopidogrel is spherical I type crystal, its bulk density and form etc. all meet follow-up preparation process requirement, and productive rate is also relatively high.
Described step (1) can realize under 0 ~ 35 DEG C of temperature range condition, and preferred operative temperature is 10 ~ 30 DEG C;
The mol ratio adding sulphuric acid and clopidogrel free alkali in described step (1) is 0.8 ~ 1.1:1, preferably 0.95 ~ 1.05:1; The purity of described clopidogrel free alkali preferably more than 95%.
In described step (1), due to the particularity of crystallization process, therefore sulphuric acid need add system after dilution, and the concentration of described sulphuric acid 2-butanol solution is 0.5 ~ 2.0mol/L, and preferably, the concentration of described sulphuric acid 2-butanol solution is 0.6 ~ 1.0mol/L; The concentration of described free base solution has certain influence to product, although improve concentration can improve yield to a certain extent, we find, too high concentration easily occurs to turn brilliant in crystallization process, and the bulk density of products obtained therefrom also has the trend of reduction; And too low concentration crystal nucleation and growth is slow, yield is low.Inventor finds, when the concentration of free base solution is 0.02 ~ 0.1g/mL, preferably during 0.040 ~ 0.065g/mL, is conducive to the generation of sphaerocrystal.
Described step (2) can keep the temperature range of step (1), carries out at 0-35 DEG C.Preferably, described step (2) adopt segmentation cooling, carry out in two steps: at 20 ~ 30 DEG C, be incubated 2-4h, after be cooled to 10-20 DEG C continue stirring and crystallizing.
In addition, we also find, under the prerequisite that other conditions are constant, the crystallize time lengthening in step (2) is tending towards obtaining bulk density product on the low side, and bulk density, tap density difference is relatively large; Crystallize time shorten is then tending towards obtaining the higher product of bulk density, and bulk density, tap density difference is relatively little.
Said method adopts the 3rd single kind solvent 2-butanols to be solvent, and relevant laws and regulations (as " chemicals residual solvent research guideline " etc.) are for the residual requirement with relative loose of the 3rd kind solvent; In addition, because this sphaerocrystal product is that spherical growth mechanism obtains, and be not the spherical coalescence mechanism in art methods, what therefore largely decrease to solvent in crystal growing process is coated, the solvent removal process making it follow-up is comparatively simple, and its dissolvent residual also relatively easily reaches the requirement of subsequent production technique.
The form of the bisulfate clopidogrel crystal used can be found out intuitively by observation procedure such as scanning electron microscope (SEM), the microscope etc. of routine.Also the conventional detection method in this area can be adopted to carry out for particle size distribution.
The X-ray powder diffractogram of spherical bisulfate clopidogrel I crystal of the present invention is 9.22 ± 0.02 ° at 2 θ, 10.90 ± 0.02 °, 11.58 ± 0.02 °, 13.84 ± 0.02 °, 14.40 ± 0.02 °, 14.82 ± 0.02 °, 15.54 ± 0.02 °, there is diffraction maximum in the position of 23.16 ± 0.02 °.The crystal formation of described sphaerocrystal can also adopt the detection method of this area routine, as methods such as differential scan calorimeter (DSC), fourier-transform infrareds (FT-IR), confirms further gained crystal formation.
The bisulfate clopidogrel sphaerocrystal that the method for the invention prepares meets follow-up preparation process requirement.Concrete, described sphaerocrystal reaches default object, namely improve liquidity and compressibility, can be embodied by particle diameter, bulk density and tap density, powder body bulk density adopts the detection method of this area routine such as graduated cylinder method to measure, and tap density also adopts the detection method of this area routine such as graduated cylinder hammering method to measure (from Ph.Eur2.9.34Bulk density and Tapped density).
Second object of the present invention is to provide a kind of preparation of the aforementioned pharmaceutical composition containing spherical bisulfate clopidogrel I crystal and employing powder vertical compression technique is pressed into the method containing spherical bisulfate clopidogrel I crystal solid orally ingestible further, and described method comprises following steps:
1) by the filler of crude drug and recipe quantity, the adjuvant such as disintegrating agent and lubricant mix homogeneously;
2) by step 1) gained mixes powder and carries out tabletting, obtains plain sheet.
For ensureing that tableting processes carries out smoothly, described step 2) in the hardness of tabletting should control at 5 ~ 9kgf.
Can look preparation needs, select to carry out coating to gained element sheet, described coating material and art for coating all defer to general knowledge known in this field, the preferred Opadry of preferred described coating material (Opadry).
The present invention has following advantage and beneficial effect relative to prior art:
1, provide a kind of pharmaceutical composition containing spherical bisulfate clopidogrel I crystal, its powder property is conducive to realizing powder vertical compression technique, and without sticking phenomenon in tableting processes, gained solid orally ingestible meets clinical application requirement;
2, provide a kind of preparation of the pharmaceutical composition containing spherical bisulfate clopidogrel I crystal and adopt powder vertical compression technique to be pressed into method containing spherical bisulfate clopidogrel I crystal solid orally ingestible further, the method can avoid the unfavorable factor such as sticking in powder vertical compression process, is conducive to suitability for industrialized production and prepares clopidogrel bisulfate solid oral formulations.
Accompanying drawing explanation
Fig. 1 embodiment 1 gained bisulfate clopidogrel XRPD spectrogram
Fig. 2 embodiment 1 gained bisulfate clopidogrel DSC spectrogram
Fig. 3 embodiment 1 gained bisulfate clopidogrel microphotograph
Fig. 4 comparative example 1 gained bisulfate clopidogrel microphotograph
Detailed description of the invention
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but working of an invention mode is not limited thereto.
Embodiment 1
Get clopidogrel hydrogenesulphate 760g (purity is greater than 99.0%) to be scattered in the mixed liquor of 10L dichloromethane and 5L water, add solid sodium bicarbonate to aqueous phase pH>7.Leave standstill separatory, get organic facies and wash with water (1L × 2), anhydrous magnesium sulfate dewaters to solution and clarifies.
Organic facies filtration, vacuum are revolved to steam and no longer changed to quality, residue is dissolved in the 2-butanols of 10.5L, solution is incubated at 25 DEG C.100mL concentrated sulphuric acid (181g) is scattered in and added in system in 1 hour in the 2-butanols of 2.5L, 10g I crystal crystal seed is scattered in the 2-butanols of 1L and pours in the lump.Be incubated 2.5h at 25 DEG C, be cooled to 15 DEG C and continue insulation 4h, sucking filtration, filter cake ethyl acetate is washed, 40 DEG C of vacuum drying 1.0h, obtains product 610g (2-butanols remains <0.2%).
As shown in Figure 1, as shown in Figure 2, microphotograph as shown in Figure 3 for DSC spectrogram for products obtained therefrom XRPD spectrogram.
Embodiment 2
Get clopidogrel hydrogenesulphate 760g (purity is greater than 99.0%) to be scattered in the mixed liquor of 10L dichloromethane and 5L water, add solid sodium bicarbonate to aqueous phase pH>7.Leave standstill separatory, get organic facies and wash with water (1L × 2), anhydrous magnesium sulfate dewaters to solution and clarifies.
Organic facies filtration, vacuum are revolved to steam and no longer changed to quality, residue is dissolved in the 2-butanols of 10.5L, solution is incubated at 25 DEG C.100mL concentrated sulphuric acid (181g) is scattered in and added in system in 1 hour in the 2-butanols of 2.5L, 10g I crystal crystal seed is scattered in the 2-butanols of 1L and pours in the lump.Be incubated 2.5h at 25 DEG C, be cooled to 15 DEG C and continue insulation 2h, sucking filtration, filter cake ethyl acetate is washed, 40 DEG C of vacuum drying 1.0h, obtains product 560g (2-butanols remains <0.2%).
Comparative example 1
Get clopidogrel hydrogenesulphate 760g (purity is greater than 99.0%) to be scattered in the mixed liquor of 10L dichloromethane and 5L water, add solid sodium bicarbonate to aqueous phase pH>7.Leave standstill separatory, get organic facies and wash with water (1L × 2), anhydrous magnesium sulfate dewaters to solution and clarifies.
Organic facies filtration, vacuum are revolved to steam and no longer changed to quality, residue is dissolved in the 2-butanols of 10.5L, solution is incubated at 25 DEG C.100mL concentrated sulphuric acid (181g) is scattered in and added in system in 1 hour in the 2-butanols of 2.5L, 10g I crystal crystal seed is scattered in the 2-butanols of 1L and pours in the lump.Be incubated 2.5h at 25 DEG C, be cooled to 15 DEG C and continue insulation 8h, sucking filtration, filter cake ethyl acetate is washed, 40 DEG C of vacuum drying 1.0h, obtains product 660g (2-butanols remains <0.2%).
Because the crystallize time is partially long, from microphotograph (as shown in Figure 4) although can find out that particle shape is spherical, its surface blur, illustrate that its surface is covered by tiny burr, macro manifestations is that bulk density, tap density are relatively little.
Embodiment 3
The form of Malvern-3000 Particle Size Analyzer to embodiment 1 ~ 2, the spherical bisulfate clopidogrel I crystal of comparative example 1 gained is adopted to detect, graduated cylinder method is adopted to detect bulk density, adopt graduated cylinder hammering method to detect (from Ph.Eur 2.9.34Bulk density and Tapped density) tap density, testing result is as shown in the table:
| Embodiment | D50(μm) | D90(μm) | Bulk density (g/mL) | Tap density (g/mL) |
| Embodiment 1 | 78.67 | 109.10 | 0.78 | 0.86 |
| Embodiment 2 | 73.18 | 114.06 | 0.73 | 0.82 |
| Comparative example 1 | 77.41 | 117.61 | 0.62 | 0.72 |
The diameter of particle of embodiment 1,2 and comparative example 1 is close as can be seen from the above table, but due to the crystallize overlong time of comparative example 1, its sphaerocrystal is covered by tiny burr, shows as bulk density, tap density is starkly lower than embodiment 1 and embodiment 2.
By to technology controlling and process such as crystallize times, particle diameter can be obtained similar, the powder body that bulk density, tap density are different.
Embodiment 4
Respectively with embodiment 1,2 and the spherical bisulfate clopidogrel I crystal of comparative example 1 gained for raw material, adopt following prescription and technique to prepare label, as follows
Preparation process:
(1) filler of crude drug and recipe quantity, the adjuvant such as disintegrating agent and lubricant mixing 10min;
(2) according to average hardness in 5 ~ 9kgf compressed cores, investigate label outward appearance in pressing process, observe its whether sticking;
(3) by outward appearance and the qualified label of hardness, Opadry coating in coating pan is used, coating weight gain about 3%.
In tableting processes, adopt the group of embodiment 1 and embodiment 2 raw material to carry out smoothly, gained tablet uniformity also meets the requirement of " Chinese Pharmacopoeia " (2010 editions).
And for comparative example 1 group, namely sticking phenomenon occurs its 8min after tabletting starts, cause gained tablet appearance defective, do not meet the requirement of Chinese Pharmacopoeia.
Embodiment 5
Respectively with embodiment 1,2 and the spherical bisulfate clopidogrel I crystal of comparative example 1 gained for raw material, adopt following prescription and technique to prepare label, as follows
Preparation process:
(1) filler of crude drug and recipe quantity, the adjuvant such as disintegrating agent and lubricant mixing 10min;
(2) according to average hardness in 5 ~ 9kgf compressed cores, investigate label outward appearance in pressing process, observe its whether sticking;
(3) by outward appearance and the qualified label of hardness, Opadry coating in coating pan is used, coating weight gain about 3%.
In tableting processes, adopt the group of embodiment 1 and embodiment 2 raw material to carry out smoothly, gained tablet uniformity also meets the requirement of " Chinese Pharmacopoeia " (2010 editions).
And for comparative example 1 group, owing to increasing compared with the use of embodiment 4 prescription filler and lubricant, reduce the probability of sticking to a certain extent, but still there is sticking phenomenon in its 30min after tabletting starts, cause gained tablet appearance defective, do not meet the requirement of Chinese Pharmacopoeia.
By to technology controlling and process such as crystallize times, particle diameter can be obtained similar, the powder body that bulk density, tap density are different.Find in the further screening of the prescription to crude drug bulk density, tap density, Technological adaptability, when crude drug bulk density is lower than 0.7g/mL, when tap density is lower than 0.8g/mL, and bulk density, tap density are lower, its easier sticking, prescription, technique adapt to also relatively poorer; Too high bulk density, tap density are then presented as and not easily realize former, that adjuvant is even, stable mixing.
Learnt by further amplification test research, the powder vertical compression technique of aforementioned employing embodiment 1-2 raw material shows as the consistent effect of scale when large-scale production, crude drug and the preparation process of known correspondence are equally applicable to large-scale production.
Embodiment 6
Adopt " Chinese Pharmacopoeia " (2010 editions) annex XC dissolution determination method first method basket method respectively to adopting embodiment 1 and embodiment 2 crude drug gained powder vertical compression preparation to detect in embodiment 4 and embodiment 5, acquired results is as follows:
Can find out, the dissolution of the clopidogrel hydrogen sulfate tablet adopting embodiment 1 and embodiment 2 raw material to prepare meets clinical application relevant regulations.
Detecting the stability (as Acceleration study, long storage experiment etc.) of gained tablet further, find that gained tablet all meets clinical application relevant regulations.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (9)
1. the pharmaceutical composition containing spherical bisulfate clopidogrel I crystal, comprise the bisulfate clopidogrel of spherical I crystal, filler, disintegrating agent and lubricant, it is characterized in that the particle diameter of described bisulfate clopidogrel is 90 μm≤D90≤150 μm, and bulk density is 0.7g/mL ~ 0.9g/mL, tap density is 0.8g/mL ~ 1.0g/mL.
2. pharmaceutical composition according to claim 1, is characterized in that particle diameter 100 μm≤D90≤120 μm of described bisulfate clopidogrel.
3. the pharmaceutical composition according to claim 1 or 2 any one, it is characterized in that particle diameter 60 μm≤D50≤90 μm of described bisulfate clopidogrel, and bulk density is 0.72g/mL ~ 0.82g/mL, tap density is 0.82g/mL ~ 0.92g/mL.
4. the pharmaceutical composition according to claim 1-3 any one, it is characterized in that described filler is silicified microcrystalline cellulose, microcrystalline Cellulose, Lactis Anhydrous, any one or two or more mixture in mannitol, described disintegrating agent is low-substituted hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, any one or two or more mixture in cross-linking sodium carboxymethyl cellulose, described lubricant is castor oil hydrogenated, micropowder silica gel, any one or two or more mixture in Glyceryl Behenate etc., when the mass parts of bisulfate clopidogrel is 1, the consumption of described filler is 1.5 ~ 2.5 parts, the consumption of described disintegrating agent is 0.05 ~ 0.5 part, the consumption of described lubricant is 0.05 ~ 0.5 part.
5. the pharmaceutical composition according to claim 1-4 any one, it is characterized in that when the mass parts of bisulfate clopidogrel is 1, the consumption of described filler is 1.9 ~ 2.4 parts, and the consumption of described disintegrating agent is 0.1 ~ 0.3 part, and the consumption of described lubricant is 0.1 ~ 0.3 part.
6. the pharmaceutical composition according to claim 1-5 any one, is characterized in that the bisulfate clopidogrel of described spherical I crystal is adopted and prepares with the following method:
(1) clopidogrel free alkali is dissolved in 2-butanols, obtain the free base solution that concentration is 0.02 ~ 0.1g/mL, under 0 ~ 35 DEG C of temperature conditions, add the 2-butanol solution of 0.5 ~ 2.0mol/L sulphuric acid in 60min, the mol ratio adding sulphuric acid and clopidogrel free alkali is 0.8 ~ 1.1:1;
(2) keep step (1) temperature range, add with clopidogrel free alkali mass ratio be 1 ~ 10wt% bisulfate clopidogrel I crystal crystal seed after, keep temperature stir 4 ~ 8h;
(3) filter, wash and drying, obtain bisulfate clopidogrel I crystal sphaerocrystal.
7. pharmaceutical composition according to claim 6, it is characterized in that the temperature of described step (1) is 10 ~ 30 DEG C, the mol ratio adding sulphuric acid and clopidogrel free alkali in described step (1) is 0.95 ~ 1.05:1, in described step (1), the concentration of described sulphuric acid 2-butanol solution is 0.6 ~ 1.0mol/L, and the concentration of described free base solution is 0.040 ~ 0.065g/mL; Described step (2) adopt segmentation cooling, carry out in two steps: at 20 ~ 30 DEG C, be incubated 2-4h, after be cooled to 10-20 DEG C continue stirring and crystallizing, the purity more than 95% of described clopidogrel free alkali.
8. a bisulfate clopidogrel vertical compression matrix agent, is characterized in that using the pharmaceutical composition described in claim 1-7 any one to prepare.
9. prepare a method for bisulfate clopidogrel vertical compression matrix agent described in claim 8, it is characterized in that described method comprises following steps:
1) by the filler of crude drug and recipe quantity, the adjuvant such as disintegrating agent and lubricant mix homogeneously;
2) by step 1) gained mixes powder and carries out tabletting, obtains plain sheet,
Described step 2) in the Hardness Control of tabletting at 5 ~ 9kgf.
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| CN201610225348.XA CN105748419B (en) | 2015-07-17 | 2015-07-17 | A kind of pharmaceutical composition and preparation method thereof containing spherical bisulfate clopidogrel I crystal |
| CN201510424466.9A CN105012298B (en) | 2015-07-17 | 2015-07-17 | A kind of pharmaceutical composition and its preparation method containing spherical bisulfate clopidogrel I crystal |
| PCT/CN2016/089889 WO2016161988A2 (en) | 2015-07-17 | 2016-07-13 | Pharmaceutical composition containing spherical clopidogrel bisulphate crystalline form i, and preparation method for pharmaceutical composition |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016161988A3 (en) * | 2015-07-17 | 2016-11-24 | 深圳信立泰药业股份有限公司 | Pharmaceutical composition containing spherical clopidogrel bisulphate crystalline form i, and preparation method for pharmaceutical composition |
| WO2016161989A3 (en) * | 2015-07-21 | 2016-12-01 | 深圳信立泰药业股份有限公司 | Preparation method for clopidogrel bisulphate crystalline form i spherical crystals |
| CN109096302A (en) * | 2018-07-27 | 2018-12-28 | 天津大学 | Spherical bisulfate clopidogrel II crystal form and preparation method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103408567A (en) * | 2013-07-18 | 2013-11-27 | 浙江普洛医药科技有限公司 | Method for preparing crystalline form I of clopidogrel bisulfate |
| CN103717207A (en) * | 2011-07-12 | 2014-04-09 | 三进制药株式会社 | Spherical particles of clopidogrel bisulfate, pharmaceutical composition including same, and method for manufacturing same |
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| CN105012298B (en) * | 2015-07-17 | 2016-06-01 | 深圳信立泰药业股份有限公司 | A kind of pharmaceutical composition and its preparation method containing spherical bisulfate clopidogrel I crystal |
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| CN103717207A (en) * | 2011-07-12 | 2014-04-09 | 三进制药株式会社 | Spherical particles of clopidogrel bisulfate, pharmaceutical composition including same, and method for manufacturing same |
| CN103408567A (en) * | 2013-07-18 | 2013-11-27 | 浙江普洛医药科技有限公司 | Method for preparing crystalline form I of clopidogrel bisulfate |
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| WO2016161988A3 (en) * | 2015-07-17 | 2016-11-24 | 深圳信立泰药业股份有限公司 | Pharmaceutical composition containing spherical clopidogrel bisulphate crystalline form i, and preparation method for pharmaceutical composition |
| WO2016161989A3 (en) * | 2015-07-21 | 2016-12-01 | 深圳信立泰药业股份有限公司 | Preparation method for clopidogrel bisulphate crystalline form i spherical crystals |
| CN109096302A (en) * | 2018-07-27 | 2018-12-28 | 天津大学 | Spherical bisulfate clopidogrel II crystal form and preparation method |
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| Publication number | Publication date |
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| CN105012298B (en) | 2016-06-01 |
| WO2016161988A3 (en) | 2016-11-24 |
| WO2016161988A2 (en) | 2016-10-13 |
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