CN105012298B - A kind of pharmaceutical composition and its preparation method containing spherical bisulfate clopidogrel I crystal - Google Patents
A kind of pharmaceutical composition and its preparation method containing spherical bisulfate clopidogrel I crystal Download PDFInfo
- Publication number
- CN105012298B CN105012298B CN201510424466.9A CN201510424466A CN105012298B CN 105012298 B CN105012298 B CN 105012298B CN 201510424466 A CN201510424466 A CN 201510424466A CN 105012298 B CN105012298 B CN 105012298B
- Authority
- CN
- China
- Prior art keywords
- clopidogrel
- bisulfate clopidogrel
- crystal
- pharmaceutical composition
- bisulfate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of pharmaceutical composition and its preparation method that contain spherical bisulfate clopidogrel I crystal, and its powder property is conducive to realizing the straight compression technology of powder, and rushes phenomenon without sticky in tableting processes. The present invention also provides the clopidogrel hydrogen sulfate tablet and its preparation method that a kind of powder directly presses, and described tablet meets the requirement of clinical application.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, especially, the present invention relates to a kind of pharmaceutical composition and its preparation method that contain spherical bisulfate clopidogrel I crystal.
Background technology
Bisulfate clopidogrel (CAS:135046-48-9), it is the vitriol of clopidogrel, English name ClopidogrelHydrogenSulfate, chemistry is by name: (s)-��-(2-chloro-phenyl-)-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 by the development of pharmacy corporation Sanofi-Aventis company of France, and in 1998 first in UK and USA listing, bisulfate clopidogrel entered China in 2001, for the atherosis thrombosis event of prevention of arterial on clinical. 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 brilliant type of bisulfate clopidogrel has I type and two kinds, II type, and wherein the brilliant type of II type is the brilliant type of Thermodynamically stable, and the brilliant type of I type is then the brilliant type of thermodynamic instability.
The many employing I N-type waferNs of current commercial sulfuric acid clopidogrel hydrogen formulation products, and I-type clopidogrel hydrogen sulfate crystal is for damp and hot instability, therefore the method for conventional wet granulation-compressing tablet and be not suitable in bisulfate clopidogrel preparation, conventional dry formulations technique prepares bisulfate clopidogrel preparation at present.
Known in this field, dry formulations technique is further divided into dry granulation-tablet forming technique and the straight compression technology of powder. 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 preparations meeting Clinical practice. But dry granulation-tablet forming technique needs mixed powder is first pressed into large stretch of rear pulverizing, whole grain, and last compressing tablet, 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 requirement.
The straight compression technology of powder is that direct compression is prepared into oral tablet by the mixed powder containing effective constituent without granulation process, and the straight compression technology of powder has the advantages such as technique is simple, production capacity is big, is the developing direction of oral preparations preparation technology. It is reported, the oral solid formulation of European and American developed countries' very vast scale adopts the preparation of powder straight compression technology. But, this technique has higher requirement for the dry jet mixing pile of mixed powder, and the not good powder body of mobility or compressibility is not suitable for adopting the straight compression technology of powder. For bisulfate clopidogrel, many its I type crystalline formulation products of employing in existing market, I type crystallization is the brilliant type of thermodynamic instability, although it has advantage in solvability, but owing to its conventional powder body has very strong electrostatic more, compressibility is not good yet so that mobility is not good on the one hand for it, in the straight compression technology of powder, sticky punching very easily occurs on the other hand thus causes production to carry out smoothly.
Chinese patent CN201180072203.6 discloses the preparation method of a kind of spherical I-type clopidogrel hydrogen sulfate crystal, and the powder adopting this spheroidal crystal directly suppresses agent. Its technique adopts 2-butanols/hexanaphthene system to prepare size distribution: d (0.1)=52.536 ��m, d (0.5)=74.567 ��m, the spheroidal crystal of d (0.9)=106.074 ��m, this crystallization improves the mobility of bisulfate clopidogrel, and reduces the electrostatic effect of powder body. But, one of gordian technique factor of this technique is sulfuric acid-cyclohexane solution to be needed slowly to add in the cooling condition in solvent system, owing to the vitriol oil and hexanaphthene do not dissolve each other, make solvent system process easily to cause system local sulfuric acid concentration too high and make gained crystallization color become dark adding, affect crystalline quality; In addition, owing to this technique required time is longer, and there is the risk turning brilliant in the excessively long reaction times 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 color to become dark, and due to crystal bulk density too low, sticky phenomenon of rushing still cannot be avoided to occur.
Therefore, it is achieved it is still the unresolved technical problem of prior art that bisulfate clopidogrel powder is directly pressed.
Summary of the invention
It is an object of the invention to overcome the shortcoming of prior art, a kind of pharmaceutical composition containing spherical bisulfate clopidogrel I crystal is provided, its powder property is conducive to realizing the straight compression technology of powder, and rushes phenomenon without sticky in tableting processes, and gained solid orally ingestible meets clinical application requirement.
The above-mentioned useful 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, weighting agent, disintegrating agent and lubricant, it is characterized in that particle diameter 90 ��m��D90��150 ��m 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 constituent bisulfate clopidogrel, when particle diameter 90 ��m��D90��150 ��m 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 in the straight compression technology of powder and uses. 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 the straight compression technology of powder. more specifically, as well known to those skilled in the art, the particle diameter of medicament powder and bulk density, tap density are without positive connection, even if the powder body that particle size range is close, it is also possible to correspond to completely different bulk density, tap density. for spherical bisulfate clopidogrel I crystal of the present invention, its actual particle form can be the globe that surface is full of gap, can be the globe of surface in " hedgehog " shape, can also be in irregular oval shape etc., it all can embody identical/close particle size range in the detection, and then it is presented as similar mobility, but completely different bulk density and tap density can be presented as, also there is obvious difference in its performance in actual production process, work as bulk density, vibration density is spent hour, straight powder compact and drift have relatively long duration of contact at relatively high pressure, and stick to punch head surface when drift temperature is higher, show as and " sticky punching " phenomenon occurs after straight compression technology carries out for some time, and bulk density, tap density excessive time, straight powder compact mixing process easily occurring, mixing is uneven, the phenomenon of the easy layering of supplementary material, is unfavorable for the control of quality product. preferably, the particle diameter of bisulfate clopidogrel is 100 ��m��D90��120 ��m, preferred, the particle diameter of bisulfate clopidogrel is 100 ��m��D90��120 ��m, 60 ��m��D50��90 ��m, 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, increasing of supplementary product consumption is conducive to reducing the sticky possibility rushed. If no special instructions, the effective ingredient consumption in preparation prescription of the present invention is all in bisulfate clopidogrel. Described weighting agent is any one or two or more mixture in silicified microcrystalline cellulose, Microcrystalline Cellulose, lactose hydrous, N.F,USP MANNITOL etc., preferred silicified microcrystalline cellulose, when the mass parts of bisulfate clopidogrel is 1, the consumption of described weighting agent is 1.5��2.5 parts, it is preferable that 1.9��2.4 parts; Described disintegrating agent is any one or two or more mixture in low-substituted hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, croscarmellose sodium 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, it is preferable that 0.1��0.3 part; Described lubricant is any one or two or more mixture in hydrogenated castor oil, micropowder silica gel, Glyceryl Behenate etc., preferred hydrogenated castor oil, when the mass parts of bisulfate clopidogrel is 1, the consumption of described lubricant is 0.05��0.5 part, it is preferable that 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:
Preparing 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 condition, adding the 2-butanol solution of 0.5��2.0mol/L sulfuric acid in 60min, the mol ratio adding sulfuric 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 quick nucleation, be grown to serve as relatively densification, regular shape spherical, gained bisulfate clopidogrel is spherical I N-type waferN, its bulk density and form etc. all meet follow-up preparation process requirement, and product rate is also relatively high.
Described step (1) can realize when 0��35 DEG C of temperature range, it is preferable that service temperature be 10��30 DEG C;
The mol ratio adding sulfuric acid and clopidogrel free alkali in described step (1) is 0.8��1.1:1, it is preferable that 0.95��1.05:1; The purity of described clopidogrel free alkali preferably more than 95%.
In described step (1), due to the singularity of crystallisation process, therefore sulfuric acid need to add system after dilution, and the concentration of described sulfuric acid 2-butanol solution is 0.5��2.0mol/L, it is preferable that, the concentration of described sulfuric acid 2-butanol solution is 0.6��1.0mol/L; Product is had certain influence by the concentration of described free base solution, although improving concentration can improve receipts rate to a certain extent, but it has been found that too high concentration easily occurs to turn brilliant in crystallisation 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, receipts rate is low. Contriver finds, when the concentration of free base solution is 0.02��0.1g/mL, it is preferable that 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, it has been found that, under the prerequisite that other conditions are constant, the brilliant time lengthening of the analysis in step (2) is tending towards obtaining bulk density product on the low side, and bulk density, tap density difference is relatively large; The analysis brilliant time shortens and then is tending towards obtaining the higher product of bulk density, and bulk density, tap density difference is relatively little.
Aforesaid method adopts the 3rd single kind solvent 2-butanols to be solvent, and relevant laws and regulations (such as the governing principle of research " chemicals residual solvent " etc.) have the requirement of relative loose for the residual of the 3rd kind solvent; In addition, owing to this sphaerocrystal product is that spherical growth mechanism obtains, and it is not the spherical coalescence mechanism in art methods, what therefore very big degree decreased in crystal growing process solvent 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. The detection method that this area can also be adopted conventional for size distribution carries out.
The X-ray powdery diffractometry spectrogram of spherical bisulfate clopidogrel I crystal of the present invention is 9.22 �� 0.02 �� at 2 ��, 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 peak in the position of 23.16 �� 0.02 ��. The brilliant type of described sphaerocrystal can also adopt the detection method of this area routine, such as methods such as differential scan calorimeter (DSC), fourier-transform infrareds (FT-IR), is confirmed further by the brilliant type of gained.
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 embody 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 to measure (fromPh.Eur2.9.34BulkdensityandTappeddensity) as graduated cylinder knocks method.
2nd object of the present invention is to provide the preparation of a kind of aforementioned pharmaceutical composition containing spherical bisulfate clopidogrel I crystal and adopts the straight compression technology of powder to be pressed into the method containing spherical bisulfate clopidogrel I crystal solid orally ingestible further, and described method comprises following steps:
1) by the weighting agent of bulk drug and recipe quantity, the auxiliary material such as disintegrating agent and lubricant mixes;
2) by step 1) the mixed powder of gained carries out compressing tablet, obtains element sheet.
For ensureing that tableting processes carries out smoothly, described step 2) in the hardness of compressing tablet should control at 5��9kgf.
Preparation needs can be looked, select to gained element sheet carry out dressing, described coating material and art for coating all defer to general knowledge known in this field, it is preferable that the preferred Ou Badai of described coating material (Opadry).
The present invention has following advantage and useful effect relative to prior art:
1, providing a kind of pharmaceutical composition containing spherical bisulfate clopidogrel I crystal, its powder property is conducive to realizing the straight compression technology of powder, and rushes phenomenon without sticky in tableting processes, and gained solid orally ingestible meets clinical application requirement;
2, the preparation of a kind of pharmaceutical composition containing spherical bisulfate clopidogrel I crystal is provided and adopts the straight compression technology of powder to be pressed into the method containing spherical bisulfate clopidogrel I crystal solid orally ingestible further, the method can avoid powder directly to press through in journey the unfavorable factors such as sticky punching, is conducive to suitability for industrialized production to prepare clopidogrel bisulfate solid oral preparations.
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
Embodiment
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but the enforcement mode of invention is not limited to this.
Embodiment 1
Get SR-25990C 760g (purity is greater than 99.0%) to be scattered in the mixed solution of 10L methylene dichloride and 5L water, add solid sodium bicarbonate to aqueous phase pH > 7. Leaving standstill separatory, get organic phase and wash with water (1L �� 2), anhydrous magnesium sulfate removes water and clarifies to solution.
Organic phase filtration, vacuum are revolved to steam and no longer changed to quality, residuum is dissolved in the 2-butanols of 10.5L, solution is incubated at 25 DEG C. Be scattered in the 2-butanols of 2.5L by the 100mL vitriol oil (181g) added in system in 1 hour, is scattered in the 2-butanols of 1L by brilliant for 10gI type crystal seed and pours in the lump. Being incubated 2.5h at 25 DEG C, be cooled to 15 DEG C and continue insulation 4h, take out filter, filter cake ethyl acetate is washed, 40 DEG C of vacuum drying 1.0h, obtains product 610g (2-butanols residual < 0.2%).
As shown in Figure 1, as shown in Figure 2, microphotograph is as shown in Figure 3 for DSC spectrogram for products obtained therefrom XRPD spectrogram.
Embodiment 2
Get SR-25990C 760g (purity is greater than 99.0%) to be scattered in the mixed solution of 10L methylene dichloride and 5L water, add solid sodium bicarbonate to aqueous phase pH > 7. Leaving standstill separatory, get organic phase and wash with water (1L �� 2), anhydrous magnesium sulfate removes water and clarifies to solution.
Organic phase filtration, vacuum are revolved to steam and no longer changed to quality, residuum is dissolved in the 2-butanols of 10.5L, solution is incubated at 25 DEG C. Be scattered in the 2-butanols of 2.5L by the 100mL vitriol oil (181g) added in system in 1 hour, is scattered in the 2-butanols of 1L by brilliant for 10gI type crystal seed and pours in the lump. Being incubated 2.5h at 25 DEG C, be cooled to 15 DEG C and continue insulation 2h, take out filter, filter cake ethyl acetate is washed, 40 DEG C of vacuum drying 1.0h, obtains product 560g (2-butanols residual < 0.2%).
Comparative example 1
Get SR-25990C 760g (purity is greater than 99.0%) to be scattered in the mixed solution of 10L methylene dichloride and 5L water, add solid sodium bicarbonate to aqueous phase pH > 7. Leaving standstill separatory, get organic phase and wash with water (1L �� 2), anhydrous magnesium sulfate removes water and clarifies to solution.
Organic phase filtration, vacuum are revolved to steam and no longer changed to quality, residuum is dissolved in the 2-butanols of 10.5L, solution is incubated at 25 DEG C. Be scattered in the 2-butanols of 2.5L by the 100mL vitriol oil (181g) added in system in 1 hour, is scattered in the 2-butanols of 1L by brilliant for 10gI type crystal seed and pours in the lump. Being incubated 2.5h at 25 DEG C, be cooled to 15 DEG C and continue insulation 8h, take out filter, filter cake ethyl acetate is washed, 40 DEG C of vacuum drying 1.0h, obtains product 660g (2-butanols residual < 0.2%).
Partially long owing to analysing the brilliant time, from microphotograph (as shown in Figure 4) although can find out that particle form is spherical, but its surface blur, illustrating that its surface is covered by tiny burr, macro manifestations is that bulk density, tap density are relatively little.
Embodiment 3
Malvern-3000 particle-size analyzer is adopted the form of embodiment 1��2, the spherical bisulfate clopidogrel I crystal of comparative example 1 gained to be detected, graduated cylinder method is adopted to be detected by bulk density, adopting graduated cylinder to knock method tap density to be detected (fromPh.Eur2.9.34BulkdensityandTappeddensity), detected result is as shown in the table:
| Embodiment | D50(��m) | D90(��m) | 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 the brilliant overlong time of analysis due to comparative example 1, its sphaerocrystal is covered by tiny burr, shows as bulk density, tap density is significantly lower than embodiment 1 and embodiment 2.
By to technology controlling and process such as analysis brilliant times, it is possible to obtain particle diameter similar, the powder body that bulk density, tap density are different.
Embodiment 4
Respectively taking the spherical bisulfate clopidogrel I crystal of embodiment 1,2 and comparative example 1 gained as raw material, following prescription and technique is adopted to prepare sheet core, as follows
Preparation process:
(1) weighting agent of bulk drug and recipe quantity, the auxiliary material mixing 10min such as disintegrating agent and lubricant;
(2) according to average hardness in 5��9kgf compressed cores, pressing process is investigated sheet core outward appearance, observe its whether sticky punching;
(3) by sheet core qualified to outward appearance and hardness, it may also be useful to Ou Badai is dressing in coating pan, dressing weightening finish about 3%.
In tableting processes, adopting 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 its 8min after compressing tablet starts occurs sticky to rush phenomenon, cause gained tablet appearance defective, do not meet the requirement of Chinese Pharmacopoeia.
Embodiment 5
Respectively taking the spherical bisulfate clopidogrel I crystal of embodiment 1,2 and comparative example 1 gained as raw material, following prescription and technique is adopted to prepare sheet core, as follows
Preparation process:
(1) weighting agent of bulk drug and recipe quantity, the auxiliary material mixing 10min such as disintegrating agent and lubricant;
(2) according to average hardness in 5��9kgf compressed cores, pressing process is investigated sheet core outward appearance, observe its whether sticky punching;
(3) by sheet core qualified to outward appearance and hardness, it may also be useful to Ou Badai is dressing in coating pan, dressing weightening finish about 3%.
In tableting processes, adopting 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 the use of relatively embodiment 4 prescription weighting agent and lubricant increases, reduce the possibility of sticky punching to a certain extent, but its 30min after compressing tablet starts still occurs sticky to rush phenomenon, cause gained tablet appearance defective, do not meet the requirement of Chinese Pharmacopoeia.
By to technology controlling and process such as analysis brilliant times, it is possible to obtain particle diameter similar, the powder body that bulk density, tap density are different. The further screening of the prescription to bulk drug bulk density, tap density, Technological adaptability finds, when bulk drug bulk density is lower than 0.7g/mL, when tap density is lower than 0.8g/mL, and bulk density, tap density are more low, it is sticky punching more easily, and prescription, technique adapt to also relatively more poor; Too high bulk density, tap density are then presented as and not easily realize mixing former, that auxiliary material is even, stable.
Being learnt by the research of further amplification test, the straight compression technology of powder of aforementioned employing embodiment 1-2 raw material shows as the consistent effect of scale when scale operation, it is seen that corresponding bulk drug and preparation process are equally applicable to large-scale production.
Embodiment 6
Adopting " Chinese Pharmacopoeia " (2010 editions) annex XC dissolution determination method first method basket method to detect adopting embodiment 1 and embodiment 2 bulk drug gained powder directly to suppress agent in embodiment 4 and embodiment 5 respectively, gained result is as follows:
It may be seen that the dissolution rate adopting clopidogrel hydrogen sulfate tablet prepared by embodiment 1 and embodiment 2 raw material meets clinical application relevant regulations.
Further the stability (such as Acceleration study, long storage experiment etc.) of gained tablet is being detected, it has been found that gained tablet all meets clinical application relevant regulations.
Above-described embodiment is that the present invention preferably implements mode; but embodiments of the present invention are not restricted to the described embodiments; the change done under the spirit of other any the present invention of not deviating from and principle, modification, replacement, combination, simplification; all should be the substitute mode of equivalence, it is included within protection scope of the present invention.
Claims (8)
1. one kind contains the pharmaceutical composition of spherical bisulfate clopidogrel I crystal, comprise the bisulfate clopidogrel of spherical I crystal, weighting agent, disintegrating agent and lubricant, it is characterized in that the particle diameter of described bisulfate clopidogrel is 90 ��m��D90��150 ��m, and bulk density is 0.7g/mL��0.9g/mL, tap density is 0.8g/mL��1.0g/mL, and the bisulfate clopidogrel of described spherical I crystal is adopted and prepared 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 condition, adding the 2-butanol solution of 0.5��2.0mol/L sulfuric acid in 60min, the mol ratio adding sulfuric 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.
2. pharmaceutical composition according to claim 1, it is characterised in that particle diameter 100 ��m��D90��120 ��m of described bisulfate clopidogrel.
3. pharmaceutical composition according to claim 2, it is characterised in that particle diameter 60 ��m��D50��90 ��m of described bisulfate clopidogrel, and bulk density is 0.72g/mL��0.82g/mL, tap density is 0.82g/mL��0.92g/mL.
4. pharmaceutical composition according to claim 1-3 any one, it is characterized in that described weighting agent is silicified microcrystalline cellulose, Microcrystalline Cellulose, lactose hydrous, any one or two or more mixture in N.F,USP MANNITOL, described disintegrating agent is low-substituted hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, any one or two or more mixture in croscarmellose sodium, described lubricant is hydrogenated castor oil, 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 weighting agent 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. pharmaceutical composition according to claim 4, it is characterized in that when the mass parts of bisulfate clopidogrel is 1, the consumption of described weighting agent 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. pharmaceutical composition according to claim 1, it is characterized in that the temperature of described step (1) is 10��30 DEG C, the mol ratio adding sulfuric acid and clopidogrel free alkali in described step (1) is 0.95��1.05:1, in described step (1), the concentration of described sulfuric 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.
7. the straight die mould tablet of bisulfate clopidogrel, it is characterised in that use the pharmaceutical composition described in claim 1-6 any one to prepare.
8. prepare the method for the straight die mould tablet of bisulfate clopidogrel described in claim 7 for one kind, it is characterised in that described method comprises following steps:
1) by the weighting agent of bulk drug and recipe quantity, the auxiliary material such as disintegrating agent and lubricant mixes;
2) by step 1) the mixed powder of gained carries out compressing tablet, obtains element sheet,
Described step 2) in the Hardness Control of compressing tablet at 5��9kgf.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610225348.XA Division CN105748419B (en) | 2015-07-17 | 2015-07-17 | A kind of pharmaceutical composition and preparation method thereof containing spherical bisulfate clopidogrel I crystal |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105012298A CN105012298A (en) | 2015-11-04 |
| CN105012298B true CN105012298B (en) | 2016-06-01 |
Family
ID=54402852
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510424466.9A Active CN105012298B (en) | 2015-07-17 | 2015-07-17 | A kind of pharmaceutical composition and its preparation method containing spherical bisulfate clopidogrel I crystal |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN105012298B (en) |
| WO (1) | WO2016161988A2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105061459B (en) * | 2015-07-21 | 2016-08-24 | 深圳信立泰药业股份有限公司 | A kind of preparation method of bisulfate clopidogrel I crystal spheroidal crystal |
| 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 |
|---|---|---|---|---|
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2015
- 2015-07-17 CN CN201510424466.9A patent/CN105012298B/en active Active
-
2016
- 2016-07-13 WO PCT/CN2016/089889 patent/WO2016161988A2/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 硫酸氢氯吡格雷片处方和制备工艺研究;高原等;《中国药学杂志》;20110131;第46卷(第02期);117-123 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105012298A (en) | 2015-11-04 |
| WO2016161988A2 (en) | 2016-10-13 |
| WO2016161988A3 (en) | 2016-11-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105061459B (en) | A kind of preparation method of bisulfate clopidogrel I crystal spheroidal crystal | |
| CN105012298B (en) | A kind of pharmaceutical composition and its preparation method containing spherical bisulfate clopidogrel I crystal | |
| WO2017020841A1 (en) | Pharmaceutical composition containing lcz696 and preparation method thereof | |
| CN102429880B (en) | Dasatinib tablet | |
| CN104817571B (en) | A kind of method preparing spherical bisulfate clopidogrel I crystal | |
| CN109512789B (en) | High-purity granular xylitol capable of being directly tabletted and preparation method thereof | |
| CN105106166A (en) | Cefalexin tablet and preparation method thereof | |
| CN104829622B (en) | A kind of sildenafil citrate compound and pharmaceutical composition thereof | |
| CN102382034A (en) | Synthetic method of N-amino-3-azabicyclo[3,3,0]octane hydrochloride | |
| CN105748419B (en) | A kind of pharmaceutical composition and preparation method thereof containing spherical bisulfate clopidogrel I crystal | |
| CN109438467B (en) | Preparation method of clopidogrel hydrogen sulfate type II spherical crystal | |
| CN106138009A (en) | Roxithromycin capsules and preparation technology thereof | |
| KR101710922B1 (en) | Method for preparing crystalline form I of Clopidogrel hydrogen sulfate | |
| CN104721828A (en) | Medicinal composition for improving stability of crystal medicines, and preparation method thereof | |
| CN102988297A (en) | Roflumilast solid dispersion and medicinal composition containing same | |
| CN102366412B (en) | Preparation method of tolvaptan tablet | |
| CN107684549A (en) | A kind of Valsartan tablet and preparation method thereof | |
| WO2016011783A1 (en) | Method for preparing spherical clopidogrel hydrogen sulfate polymorph i | |
| CN105496979A (en) | Rasagiline tablet | |
| CA2949155C (en) | Allisartan isoproxil polymorph, its preparation method and pharmaceutical | |
| CN105412027A (en) | Preparation method of dronedarone hydrochloride tablets | |
| CN104546772A (en) | Cetirizine hydrochloride tablet | |
| CN104257617A (en) | Itopride hydrochloride oral preparation | |
| CN102813634B (en) | Hydrotalcite tablet and its preparation method | |
| CN106344532A (en) | Preparation method of cobamamide tablets |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: Area A, 4th Floor, Digital Peninsula, No. 2, Hongliu Road, Fubao Community, Fubao Street, Futian District, Shenzhen, Guangdong, 518017 Patentee after: SHENZHEN SALUBRIS PHARMACEUTICALS Co.,Ltd. Patentee after: SHANDONG SALUBRIS PHARMACEUTICALS Co.,Ltd. Patentee after: HUIZHOU XINLITAI PHARMACEUTICAL Co.,Ltd. Address before: 518040 37th floor, chegongmiao Lvjing Plaza, 6009 Shennan Avenue, Futian District, Shenzhen City, Guangdong Province Patentee before: SHENZHEN SALUBRIS PHARMACEUTICALS Co.,Ltd. Patentee before: SHANDONG SALUBRIS PHARMACEUTICALS Co.,Ltd. Patentee before: HUIZHOU XINLITAI PHARMACEUTICAL Co.,Ltd. |