CN104367551B - A kind of Aprepitant compound and preparation method thereof - Google Patents
A kind of Aprepitant compound and preparation method thereof Download PDFInfo
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Abstract
The invention provides a kind of Aprepitant compound, the compound by following weight percent match into being grouped into：Aprepitant 30% 70%, monose 20% 60%, suspending agent 10% 50%.The formation for acting as helping Aprepitant nanocrystal of monose in compound of the present invention；The acting as of suspending agent avoids local uneven caused by the sedimentation of suspension in wet grinding and spray-drying process.Obtained Aprepitant compound of the invention drastically increases Aprepitant solubility, is favorably improved the bioavilability of Aprepitant, there is larger clinical value.The inventive method is easy, is suitable for industrialized production.
Description
Technical field
The present invention relates to pharmaceutical preparation, and in particular to Aprepitant compound of a kind of highly dissoluble and preparation method thereof.
Background technology
Aprepitant is U.S. FDA in first neurokinin nk 1 receptor retarding agent of approval listing in 2003.It is former
The exploitation producer of product is ground for United States Merck company, is mainly used in the prevention of postoperative vomiting, and use vomiting after chemotherapeutic
Prevention and control.Its chemical entitled 5- [[(2R, 3S) -2- [(R) -1- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3- (4-
Fluorophenyl) morpholinyl] methyl] -1 hydrogen -1,2,4- triazoles -3（2 hydrogen）-one, molecular formula is C23H21F7N4O3.Its structural formula is such as
Under：
Aprepitant is almost insoluble in water, the Log P under the conditions of pH7.0（P is Determination of oil-water partition coefficient）It is 4.8, because
This, according to Biopharmaceutics Classification, it belongs to the 4th class medicine, i.e. low-solubility hypotonicity medicine.Such medicine is often difficult
The product of clinical efficacy is formed with, its reason is that medicine is difficult to be absorbed by organisms, and internal release rate is too fast, bioavilability
Difference.
For the property of the low-solubility hypotonicity of Aprepitant, industry professional has carried out many grinding
Study carefully, and achieved certain achievement.The former triturate of Merck ＆ Co., Inc.'s listing is prepared by the technology for employing wet grinding, its
Patented technology is disclosed in WO2003049718 first, describes to grind Aprepitant particle diameter using wet grinding device in the patent
Less than 1000 nanometers are ground to, and the surface stabilizers such as lauryl sodium sulfate are added when it grinds to maintain its effective grain size,
With this, by reducing the particle diameter of Aprepitant, solubility is improve, and then improve bioavilability.
Personnel of the present invention is carried out for the purposes of solving the problems, such as the low-solubility hypotonicity of above-mentioned Aprepitant
Substantial amounts of research, has groped number of ways.In research process, personnel are it has surprisingly been found that Aprepitant and monosaccharide for invention
After combinations of substances, under certain process conditions, the compound of Aprepitant is prepared into, makes the solubility property of the compound significantly
Improve, can further study new preparation.
The content of the invention
The technical problems to be solved by the invention are to overcome above-mentioned weak point, and it is molten that research and design improves Aprepitant
Xie Du, improves the preparation and preparation method of its bioavilability.
The invention provides a kind of compound of Aprepitant.
Aprepitant compound of the present invention is made up of Aprepitant, monose and suspending agent.
Aprepitant compound of the present invention by following weight percent match into being grouped into：
Aprepitant 30%-70%, monose 20%-60%, suspending agent 10%-50%.
In compound of the present invention, monose is selected from one or more in glucose, sucrose or fructose；Suspending agent is selected from
Sodium carboxymethylcellulose, Hydroxypropyl methylcellulose, hydroxyethyl cellulose, poloxamer or PVP.
The formation for acting as helping Aprepitant nanocrystal of monose in compound of the present invention；The acting as of suspending agent is kept away
Part is uneven caused by exempting from the sedimentation of suspension in wet grinding and spray-drying process.
It is a further object of the present invention to provide the preparation method of described Aprepitant compound.
The method comprises the following steps：
（1）Wet grinding mill is connected into water-cooling system respectively, the Agitation Tank of jacketed and agitating paddle is connected into water-cooling system,
Cold water temperature is 7 DEG C -10 DEG C；
（2）Take and be placed in Agitation Tank equivalent to the purified water of 5-20 times of raw material Aprepitant weight, stirring is opened, by A Rui
Smooth and suspending agent is slowly added into Agitation Tank, is added while stirring, forms uniform suspension, maintains stirring, standby；
（3）The discharging opening of above-mentioned Agitation Tank is connected the charging aperture of wet grinding mill with pipeline, by going out for wet grinding mill
Material mouth connects the charging aperture of Agitation Tank with pipeline, opens grinder, and grinding chamber internal rotor rotates to form negative pressure, by Aprepitant
Suspension is suctioned out from Agitation Tank discharging opening, is entered in wet grinding mill by the charging aperture of wet grinding mill, of short duration grinding 1-2 points
Zhong Hou, the suspension of Aprepitant is returned in Agitation Tank by the discharging opening of wet grinding mill, is thusly-formed circulation, grinding administration
Speed is 1-10L/ minutes, and grinding bead particle diameter is 0.1-0.5 millimeters；
（4）After circulation is formed, monose is slowly added into Agitation Tank, is added in circulation, after the completion of addition, maintain to follow
Ring grinding state；
（5）Sampled during circular grinding, the particle diameter of particle in suspension is determined with laser particle analyzer, work as test result
When the grain diameter of display more than 90% is less than 600 nanometers（Laser particle analyzer programming count is calculated）, stop grinding, A Rui is obtained
The suspension of smooth compound；
（6）By the suspension of Aprepitant compound using spray drying, temperature is 60 DEG C -80 DEG C, and centrifugal atomizing disk is frequently
Rate is 40, and spray drying is obtained the compound of Aprepitant after terminating.
In the wet grinding stage of preparation method of the present invention, the concentration of monose is maintained and faced in Aprepitant suspension
Boundary's saturated concentration state.In 7 DEG C -10 DEG C of low temperature wet method process of lapping, due to the water-insoluble of Aprepitant, monose is with Ah
Auspicious smooth for nucleus is slowly formed Aprepitant complex crystallization.Due to the effect of wet grinding, slightly larger complex crystallization
Be ground it is broken, and Nano grade crystallization then be easier maintain.In whole crystallization and the broken motion process of grinding, when
When the grain diameter of crystallization more than 90% is less than 600 nanometers, the mixed of Aprepitant compound of the present invention is formed
Suspension.
In the wet grinding stage of preparation method of the present invention, temperature maintains 7 DEG C -10 DEG C.Found in research process, this temperature
When spending, preferred monose, including the critical saturated concentration of glucose, sucrose or fructose under the conditions of the formula rate of 20%-60%
It is to dissolve 0.04g-0.2g in every 1g purified waters.
The spray-drying stage of preparation method of the present invention, the suspension of Aprepitant compound is atomized into small by centrifugal pan
In the drying chamber that the form of 10 microns of droplets is sprayed onto spray dryer, moisture rapid evaporation is satiated so as to form the high of monose
And solution, under 60 DEG C -80 DEG C of product temperature control, monose rapidly forms crystallization and is wrapped in nano level Aprepitant
The compound of Aprepitant is formd in crystallization.
The Aprepitant compound that preparation method of the present invention is obtained can use routine techniques side well known in the art
Method is prepared into such as capsule, tablet, powder, granule, Oral Dry Suspensions formulation.
By comparative test, 15 minutes in 37 DEG C of 0.1%SLS aqueous solution of the Aprepitant bulk drug that the present invention is used
Solubility is 0.36 mcg/ml.The compound of the Aprepitant obtained in the present invention presses the second method of Chinese Pharmacopoeia 2005 editions
Paddle method, is dissolution medium with 37 DEG C of 900ml 0.1%SLS aqueous solution, and rotating speed is 100 turns per minute, detection.Input amount is with A Rui
It is smooth to be calculated as 80 milligrams, as a result show that its 15 minutes burst sizes reach more than 80%, it is micro- that the dissolving solubility of 15 minutes reaches 71
Grams per milliliter, drastically increases solubility, improves the bioavilability of Aprepitant.
Aprepitant compound of the invention obtained overcomes the relatively low problem of Aprepitant solubility, be favorably improved Ah
Auspicious smooth bioavilability, there is larger clinical value.The inventive method is easy, is suitable for industrialized production.
Brief description of the drawings
D90 in the embodiment 6 of accompanying drawing 1 determines change of size figure
Ordinate：D90 particle size values（Micron）, abscissa：Time（Point）
Dissolution rate release profiles in the embodiment 8 of accompanying drawing 2
Ordinate：Burst size %, abscissa：Time（Point）
The square dissolution rate release profiles for representing embodiment 7 in figure
Figure intermediate cam shape represents the dissolution rate release profiles of embodiment 6
Specific embodiment
All material used below is commercially available acquisition.
Embodiment 1 prepares Aprepitant compound
Aprepitant, sucrose and suspending agent Hydroxypropyl methylcellulose and poloxamer are carried out into wet grinding.
Formula：
| Title | Amount（Gram） | Percentage by weight |
| Aprepitant | 250 | 44.64 |
| Hydroxypropyl methylcellulose E5 | 54 | 9.64 |
| Poloxamer F127 | 6 | 1.07 |
| Sucrose | 250 | 44.65 |
| 2500 | -- | |
| Solid is amounted to | 560 | 100.00 |
*：Removed in technical process
Prepare：
By wet grinding mill ECM-AP 05 and Agitation Tank（Jacketed and agitating paddle）Upper water-cooling system is connected respectively, it is cold
Coolant-temperature gage is 10 DEG C.Aprepitant, poloxamer F127 and Hydroxypropyl methylcellulose E5 are mixed into homogeneous solid mixture.Separately take
Purified water is placed in Agitation Tank, opens stirring, and Aprepitant, poloxamer F127 and Hydroxypropyl methylcellulose E5 are slowly added into
State in Agitation Tank, add while stirring, form uniform suspension, maintain stirring, it is standby.The discharging opening of Agitation Tank is used
Pipeline connects the charging aperture of wet grinding mill, and the discharging opening of wet grinding mill is connected the charging aperture of Agitation Tank with pipeline, opens
Grinder, grinding chamber internal rotor rotates to form negative pressure, the suspension of Aprepitant is suctioned out from Agitation Tank discharging opening, by wet method
The charging aperture of grinder enters in wet grinding mill, and after of short duration grinding 2 minutes, the suspension of Aprepitant passes through wet grinding mill
Discharging opening return to Agitation Tank, be thusly-formed circulation, grinding injection speed is 3L/ minute, grinding bead particle diameter is 0.3 millimeter.
Sampled during circular grinding, the grain of particle in suspension is determined with laser particle analyzer BetterSize2000
Footpath, measurement result is as follows：
After grinding reaches 110 minutes, grinding terminates, and above-mentioned suspension is spray-dried using spray dryer LPG-10,
Temperature is 60-80 degree, and centrifugal atomizing disk frequency is 40, and suspension has all been sprayed, and Aprepitant is obtained after the completion of spray drying
540 grams of compound.
Above-mentioned compound is pressed the second method paddle method of Chinese Pharmacopoeia 2005 editions, with 37 degrees Celsius of 900ml0.1%SLS aqueous solution
It is dissolution medium, rotating speed is 100 turns per minute, detection.Input amount is calculated as 80 milligrams with Aprepitant, and dissolution result is as follows：
| 10 minutes | 15 minutes | 30 minutes | |
| Dissolution rate（%） | 77 | 87 | 90 |
Embodiment 2
Aprepitant, fructose and suspending agent sodium carboxymethylcellulose are carried out into wet grinding.
Formula：
| Title | Amount（Gram） | Percentage by weight |
| Aprepitant | 300 | 30.00 |
| Sodium carboxymethylcellulose | 500 | 50.00 |
| Fructose | 200 | 20.00 |
| 5000 | -- | |
| Solid is amounted to | 1000 | 100.00 |
*：Removed in technical process
Prepare：
By wet grinding mill ECM-AP 05 and Agitation Tank（Jacketed and agitating paddle）Water-cooling system in connection, cold water temperature
Spend is 8 degree.Aprepitant and sodium carboxymethylcellulose are mixed into homogeneous solid mixture.Weigh a certain amount of purified water and put and match somebody with somebody
In flow container, stirring is opened, Aprepitant and sodium carboxymethylcellulose is slowly added into above-mentioned Agitation Tank, added while stirring,
Uniform suspension is formed, stirring is maintained, it is standby.Above-mentioned Agitation Tank and wet grinding mill are connected with pipeline, opening is ground
Grinding machine, grinding injection speed is 3L/ minutes, and grinding bead particle diameter is 0.5 millimeter.After grinding starts, slowly added in Agitation Tank
The fructose of recipe quantity, circular grinding is maintained after adding.Sampled during circular grinding, use laser particle analyzer
BetterSize2000 determines the particle diameter of particle in suspension, and measurement result is as follows：
| Particle diameter distribution（um） | Initially | 30 minutes | 60 minutes | 90 minutes | 120 minutes | 150 minutes |
| d10 | 85.2 | 0.56 | 0.20 | 0.17 | 0.12 | 0.12 |
| d50 | 214 | 0.89 | 0.37 | 0.28 | 0.25 | 0.22 |
| d90 | 934 | 3.26 | 0.99 | 0.77 | 0.60 | 0.52 |
After grinding reaches 150 minutes, grinding terminates, and above-mentioned suspension is spray-dried using spray dryer LPG-10,
Temperature is 60-80 degree, and centrifugal atomizing disk frequency is 40, and 980 grams of the compound of Aprepitant is obtained after the completion of drying.
Above-mentioned compound is pressed the second method paddle method of Chinese Pharmacopoeia 2005 editions, with 37 degrees Celsius of 900ml0.1%SLS aqueous solution
It is dissolution medium, rotating speed is 100 turns per minute, detection.Input amount is calculated as 80 milligrams with Aprepitant, and dissolution result is as follows：
| 10 minutes | 15 minutes | 30 minutes | |
| Dissolution rate（%） | 64 | 80 | 83 |
Embodiment 3
Aprepitant, glucose and suspending agent hydroxyethyl cellulose are carried out into wet grinding.
Formula：
| Title | Amount（Gram） | Percentage by weight |
| Aprepitant | 300 | 30.00 |
| Hydroxyethyl cellulose | 100 | 10.00 |
| Glucose | 600 | 60.00 |
| 3000 | -- | |
| Solid is amounted to | 1000 | 100.00 |
*：Removed in technical process
Prepare：
By wet grinding mill ECM-AP 05 and Agitation Tank（Jacketed and agitating paddle）Water-cooling system in connection, cold water temperature
Spend is 7 degree.Aprepitant and hydroxyethyl cellulose are mixed into homogeneous solid mixture.A certain amount of purified water is weighed to put with liquid
In tank, stirring is opened, Aprepitant and hydroxyethyl cellulose are slowly added into above-mentioned Agitation Tank, added while stirring, formed
Uniform suspension, maintains stirring, standby.Above-mentioned Agitation Tank and wet grinding mill are connected with pipeline, grinder is opened,
Grinding injection speed is 4L/ minutes, and grinding bead particle diameter is 0.1 millimeter.After grinding starts, slowly to adding recipe quantity in Agitation Tank
Glucose, maintain circular grinding after adding.Sampled during circular grinding, surveyed with laser particle analyzer BetterSize2000
Determine the particle diameter of particle in suspension, measurement result is as follows：
| Particle diameter distribution（um） | Initially | 30 minutes | 60 minutes | 90 minutes | 120 minutes | 150 minutes |
| d10 | 77.8 | 1.20 | 0.50 | 0.33 | 0.24 | 0.20 |
| d50 | 198 | 5.87 | 0.86 | 0.56 | 0.43 | 0.32 |
| d90 | 897 | 10.26 | 1.24 | 0.86 | 0.77 | 0.59 |
After grinding reaches 150 minutes, grinding terminates, and above-mentioned suspension is spray-dried using spray dryer LPG-10,
Temperature is 60-80 degree, and centrifugal atomizing disk frequency is 40, and 983 grams of the compound of Aprepitant is obtained after the completion of drying.
Above-mentioned compound is pressed the second method paddle method of Chinese Pharmacopoeia, with 37 degrees Celsius of 900ml 0.1%SLS aqueous solution as molten
Go out medium, rotating speed is 100 turns per minute, detection.Input amount is calculated as 80 milligrams with Aprepitant, and dissolution result is as follows：
| 10 minutes | 15 minutes | 30 minutes | |
| Dissolution rate（%） | 71 | 82 | 84 |
Embodiment 4
Aprepitant, glucose, fructose and suspending agent PVP, poloxamer are carried out into wet grinding.
Formula：
| Title | Amount（Gram） | Percentage by weight |
| Aprepitant | 700 | 70.00 |
| PVP | 50 | 5.00 |
| Poloxamer | 50 | 5.00 |
| Glucose | 50 | 5.00 |
| Fructose | 150 | 15.00 |
| 4000 | -- | |
| Solid is amounted to | 1000 | 100.00 |
*：Removed in technical process
Prepare：
By wet grinding mill ECM-AP 05 and Agitation Tank（Jacketed and agitating paddle）Water-cooling system in connection, cold water temperature
Spend is 10 degree.Aprepitant, PVP and poloxamer are mixed into homogeneous solid mixture.A certain amount of purified water is weighed to put
In Agitation Tank, stirring is opened, the mixture of Aprepitant, PVP and poloxamer is slowly added into above-mentioned Agitation Tank, side
Stirring side adds, and forms uniform suspension, maintains stirring, standby.By above-mentioned Agitation Tank and wet grinding mill pipeline
Connection, opens grinder, and grinding injection speed is 10L/ minutes, and grinding bead particle diameter is 0.3 millimeter.Grinding start after, slowly to
The glucose and fructose of recipe quantity are added in Agitation Tank, circular grinding is maintained after adding.During circular grinding sample, with swash
Light particle size analyzer BetterSize2000 determines the particle diameter of particle in suspension, and measurement result is as follows：
| Particle diameter distribution（um） | Initially | 30 minutes | 60 minutes | 90 minutes |
| d10 | 79.8 | 0.61 | 0.33 | 0.11 |
| d50 | 201 | 0.83 | 0.56 | 0.31 |
| d90 | 937 | 1.09 | 0.77 | 0.52 |
After grinding reaches 90 minutes, grinding terminates, and above-mentioned suspension is spray-dried using spray dryer LPG-10, produces
Product temperature degree is 60-80 degree, and centrifugal atomizing disk frequency is 40, and 965 grams of the compound of Aprepitant is obtained after the completion of drying.
Above-mentioned compound is pressed the second method paddle method of Chinese Pharmacopoeia, is dissolution with 37 degrees Celsius of 900ml0.1%SLS aqueous solution
Medium, rotating speed is 100 turns per minute, detection.Input amount is calculated as 80 milligrams with Aprepitant, and dissolution result is as follows：
| 10 minutes | 15 minutes | 30 minutes | |
| Dissolution rate（%） | 61 | 81 | 82 |
Embodiment 5
Aprepitant, sucrose and suspending agent Hydroxypropyl methylcellulose and poloxamer are carried out into wet grinding.
Formula：
| Title | Amount（Gram） | Percentage by weight |
| Aprepitant | 250 | 43.86 |
| Hydroxypropyl methylcellulose E5 | 60 | 10.53 |
| Poloxamer F127 | 10 | 1.75 |
| Sucrose | 250 | 43.86 |
| 2500 | -- | |
| Solid is amounted to | 570 | 100.00 |
*：Removed in technical process
Prepare：
By wet grinding mill ECM-AP 05 and Agitation Tank（Jacketed and agitating paddle）Water-cooling system in connection, cold water temperature
Spend is 9 degree.Aprepitant, poloxamer F127 and Hydroxypropyl methylcellulose E5 are mixed into homogeneous solid mixture.Weigh certain
The purified water of amount is put in Agitation Tank, opens stirring, and Aprepitant, poloxamer F127 and Hydroxypropyl methylcellulose E5 are slowly added into
In above-mentioned Agitation Tank, add while stirring, form uniform suspension, maintain stirring, it is standby.By above-mentioned Agitation Tank and wet
Method grinder is connected with pipeline, opens grinder, and grinding injection speed is 7L/ minutes, and grinding bead particle diameter is 0.3 millimeter.Grinding
After beginning, slowly to the sucrose that recipe quantity is added in Agitation Tank, circular grinding is maintained after adding.Taken during circular grinding
Sample, the particle diameter of particle in suspension is determined with laser particle analyzer BetterSize2000, and measurement result is as follows：
| Particle diameter distribution（um） | Initially | 30 minutes | 60 minutes | 90 minutes | 120 minutes | 180 minutes |
| d10 | 95.2 | 0.23 | 0.15 | 0.13 | 0.11 | 0.11 |
| d50 | 264 | 0.41 | 0.25 | 0.22 | 0.20 | 0.19 |
| d90 | 997 | 0.98 | 0.62 | 0.53 | 0.42 | 0.29 |
After grinding reaches 180 minutes, grinding terminates, and above-mentioned suspension is spray-dried using spray dryer LPG-10,
Temperature is 60-80 degree, and centrifugal atomizing disk frequency is 40, and 546 grams of the compound of Aprepitant is obtained after the completion of drying.
Above-mentioned compound is filling into capsule by terms of Aprepitant 80 milligrams/UD.Capsule filling machine model
IN-CAP, filling material total amount is 342 grams, and the filling amount of UD is 183 milligrams, and filling grain number is 1860.
It is dissolution medium with 37 degrees Celsius of 900ml0.1%SLS aqueous solution by the second method paddle method of Chinese Pharmacopoeia, rotating speed is
100 turns per minute, detect the dissolution rate of above-mentioned capsule.Dissolution result is as follows：
| 10 minutes | 15 minutes | 30 minutes | |
| Dissolution rate（%） | 77 | 86 | 94 |
Embodiment 6
Aprepitant, sucrose and suspending agent Hydroxypropyl methylcellulose are carried out into wet grinding, and comparative example is compared,
Investigate the effect that monose is added.
Formula：
| Title | Amount（Gram） | Percentage by weight |
| Aprepitant | 125 | 50.00 |
| Hydroxypropyl methylcellulose E5 | 25 | 10.00 |
| Sucrose | 100 | 40.00 |
| 850 | -- | |
| Solid is amounted to | 250 | 100.00 |
*：Removed in technical process
Prepare：
By wet grinding mill ECM-AP 05 and Agitation Tank（Jacketed and agitating paddle）Water-cooling system in connection, cold water temperature
Spend is 7 degree.Aprepitant and Hydroxypropyl methylcellulose E5 are mixed into homogeneous solid mixture.Weigh a certain amount of purified water and put and match somebody with somebody
In flow container, stirring is opened, Aprepitant and Hydroxypropyl methylcellulose E5 is slowly added into above-mentioned Agitation Tank, added while stirring,
Uniform suspension is formed, stirring is maintained, it is standby.Above-mentioned Agitation Tank and wet grinding mill are connected with pipeline, opening is ground
Grinding machine, grinding injection speed is 1L/ minutes, and grinding bead particle diameter is 0.3 millimeter.After grinding starts, slowly added in Agitation Tank
Sucrose, maintain circular grinding after adding.Sampled during circular grinding, determined with laser particle analyzer BetterSize2000
The particle diameter of particle in suspension, measurement result is as follows：
| Particle diameter distribution（um） | Initially | 30 minutes | 50 minutes | 70 minutes | 90 minutes | 110 minutes |
| d10 | 87.5 | 0.33 | 0.17 | 0.16 | 0.13 | 0.13 |
| d50 | 242 | 0.64 | 0.33 | 0.27 | 0.25 | 0.24 |
| d90 | 950 | 2.95 | 0.97 | 0.65 | 0.60 | 0.58 |
Under the prescription for adding sucrose, when being ground to 70 minutes, particle diameter basically reaches minimum value, extension over time,
Agglomeration in particle, minimum grain size when can maintain 70 minutes there is no.As can be seen here, sucrose in process of lapping to A Rui
Smooth nano microcrystalline has good protective effect, it is to avoid the reunion crystallization of Aprepitant.
See accompanying drawing 1
Embodiment 7（Comparative example）
Aprepitant and suspending agent Hydroxypropyl methylcellulose are carried out into wet grinding, monose is added without, as a comparison embodiment.
Formula：
| Title | Amount（Gram） | Percentage by weight |
| Aprepitant | 125 | 83.33 |
| Hydroxypropyl methylcellulose E5 | 25 | 16.67 |
| 850 | -- | |
| Solid is amounted to | 150 | 100.00 |
*：Removed in technical process
Prepare：
By wet grinding mill ECM-AP05 and Agitation Tank（Jacketed and agitating paddle）Upper water-cooling system, cold water are connected respectively
Temperature is 7 DEG C.Aprepitant and Hydroxypropyl methylcellulose E5 are mixed into homogeneous solid mixture.Separately taking purified water is placed in Agitation Tank
In, stirring is opened, Aprepitant and Hydroxypropyl methylcellulose E5 are slowly added into above-mentioned Agitation Tank, add while stirring, formed
Uniform suspension, maintains stirring, standby.Above-mentioned Agitation Tank and wet grinding mill are connected with pipeline, grinder is opened,
The suspension of Aprepitant is inhaled into wet grinding mill from Agitation Tank, and after of short duration grinding, grinding injection speed is 1L/ points
Clock, grinding bead particle diameter is 0.3 millimeter.In returning to Agitation Tank by another pipeline again, circulation is thusly-formed, in circular grinding mistake
Sampled in journey, the particle diameter of particle in suspension is determined with laser particle analyzer BetterSize2000, measurement result is as follows：
| Particle diameter distribution（um） | Initially | 30 minutes | 50 minutes | 70 minutes | 90 minutes |
| d10 | 86.5 | 0.30 | 0.18 | 0.16 | 0.15 |
| d50 | 235 | 0.60 | 0.36 | 0.30 | 0.30 |
| d90 | 924 | 2.90 | 0.90 | 0.80 | 1.90 |
Under the prescription for being added without monose, when being ground to 70 minutes, particle diameter reaches minimum value, extension over time, Ah
Auspicious smooth generation is reunited and is crystallized, and particle diameter increases, and cannot return to the particle diameter state of minimum.
Embodiment 8
The Aprepitant suspension for respectively obtaining above-described embodiment 6 and embodiment 7 is sprayed using spray dryer LPG-10
Mist is dried, and product temperature is 60-80 degree, and centrifugal atomizing disk frequency is 40, and the compound of Aprepitant is obtained after the completion of drying.Point
The Aprepitant compound for not obtaining above-mentioned two embodiment 6 and embodiment 7 by Chinese Pharmacopoeia 2005 editions the second method paddle method,
It is dissolution medium with 37 degrees Celsius of 900ml0.1%SLS aqueous solution, rotating speed is 100 turns per minute, detection.Input amount is with A Rui
Smooth to be calculated as 80 milligrams, dissolution result is as follows：
| Dissolution rate（%） | 10 minutes | 15 minutes | 30 minutes |
| Embodiment 7 | 63 | 74 | 70 |
| Embodiment 6 | 79 | 85 | 89 |
Dissolution results show, embodiment 7 is substantially better than in the Aprepitant solubility property of embodiment 6.The product of embodiment 7
Product occur in that the state of solubility reduction in process in leaching, and embodiment 6 is produced without similar phenomenon, sees accompanying drawing 2.
Claims (3)
1. a kind of method for preparing Aprepitant compound, it is characterised in that
Described Aprepitant compound by following weight percent match into being grouped into：
Aprepitant 30%-70%, monose 20%-60%, suspending agent 10%-50%；
Described monose is selected from one or more in glucose or fructose；Suspending agent is selected from sodium carboxymethylcellulose, hydroxypropyl first
Cellulose, polyoxyethylene, hydroxypropyl cellulose, hydroxyethyl cellulose, poloxamer or PVP；
Preparation method comprises the following steps：
(1) wet grinding mill is connected into water-cooling system respectively, the Agitation Tank of jacketed and agitating paddle is connected into water-cooling system, cold water
Temperature is 7 DEG C -10 DEG C；
(2) take and be placed in Agitation Tank equivalent to the purified water of 5-20 times of raw material Aprepitant weight, stirring is opened, by Aprepitant
It is slowly added into Agitation Tank with suspending agent, is added while stirring, form uniform suspension, maintains stirring, it is standby；
(3) discharging opening of above-mentioned Agitation Tank is connected the charging aperture of wet grinding mill with pipeline, by the discharging opening of wet grinding mill
The charging aperture of Agitation Tank is connected with pipeline, grinder is opened, grinding chamber internal rotor rotates to form negative pressure, by the suspension of Aprepitant
Liquid is suctioned out from Agitation Tank discharging opening, is entered in wet grinding mill by the charging aperture of wet grinding mill, of short duration grinding 1-2 minutes
Afterwards, during the suspension of Aprepitant returns to Agitation Tank by the discharging opening of wet grinding mill, it is thusly-formed circulation；
(4) after circulation is formed, monose is slowly added into Agitation Tank, is added in circulation, after the completion of addition, maintain circulation to grind
Mill state；
(5) sampled during circular grinding, the particle diameter of particle in suspension is determined with laser particle analyzer, when test result shows
When more than 90% grain diameter is less than 600 nanometers, stop grinding, the suspension of Aprepitant compound is obtained；
(6) by the suspension of Aprepitant compound using spray drying, temperature is 60 DEG C -80 DEG C, and centrifugal atomizing disk frequency is
40, spray drying is obtained the compound of Aprepitant after terminating.
2. a kind of method for preparing Aprepitant compound according to claim 1, it is characterised in that step (3) grind to
Medicine speed is 1-10L/ minutes, and grinding bead particle diameter is 0.1-0.5 millimeters.
3. a kind of method for preparing Aprepitant compound according to claim 1, it is characterised in that described Aprepitant
Compound is prepared into capsule, tablet, powder, granule or Oral Dry Suspensions.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310357043.0A CN104367551B (en) | 2013-08-15 | 2013-08-15 | A kind of Aprepitant compound and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310357043.0A CN104367551B (en) | 2013-08-15 | 2013-08-15 | A kind of Aprepitant compound and preparation method thereof |
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Address after: 201210 Shanghai Pudong New Area China (Shanghai) free trade test area No. 1999 Zhang Heng Road No. 7 Patentee after: Shanghai Double Star Thai Pharmaceutical Technology Co., Ltd. Address before: 201203 Shanghai city Pudong New Area Bing Road No. 306 building 3 floor No. 1 Patentee before: SHANGHAI SUNTECH PHARMACEUTICAL CO., LTD. |
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Effective date of registration: 20210408 Address after: 201210 building 7, 1999 zhangheng Road, China (Shanghai) pilot Free Trade Zone, Pudong New Area, Shanghai Patentee after: SHANGHAI FOSUN XINGTAI PHARMA TECHNOLOGY Co.,Ltd. Patentee after: JIANGSU WANBANG BIOPHARMACEUTICAL GROUP Co.,Ltd. Address before: 201210 building 7, 1999 zhangheng Road, China (Shanghai) pilot Free Trade Zone, Pudong New Area, Shanghai Patentee before: SHANGHAI FOSUN XINGTAI PHARMA TECHNOLOGY Co.,Ltd. |