CN110376342A - The determination method of drugloading rate in solid dispersions preparation process - Google Patents
The determination method of drugloading rate in solid dispersions preparation process Download PDFInfo
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- 239000003814 drug Substances 0.000 claims abstract description 21
- 229940079593 drug Drugs 0.000 claims abstract description 13
- 238000000646 scanning calorimetry Methods 0.000 claims abstract description 4
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 claims description 22
- 229960004130 itraconazole Drugs 0.000 claims description 22
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- 238000001514 detection method Methods 0.000 claims description 4
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- 238000004090 dissolution Methods 0.000 description 14
- VHVPQPYKVGDNFY-ZPGVKDDISA-N itraconazole Chemical compound O=C1N(C(C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-ZPGVKDDISA-N 0.000 description 12
- 239000006069 physical mixture Substances 0.000 description 11
- 239000000523 sample Substances 0.000 description 11
- 230000008569 process Effects 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 238000012512 characterization method Methods 0.000 description 9
- 238000010586 diagram Methods 0.000 description 8
- 230000009477 glass transition Effects 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 238000001125 extrusion Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000012943 hotmelt Substances 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000003851 azoles Chemical class 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001757 thermogravimetry curve Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- BLSQLHNBWJLIBQ-OZXSUGGESA-N (2R,4S)-terconazole Chemical compound C1CN(C(C)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2N=CN=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 BLSQLHNBWJLIBQ-OZXSUGGESA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000009474 hot melt extrusion Methods 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000002798 spectrophotometry method Methods 0.000 description 2
- 229960000580 terconazole Drugs 0.000 description 2
- 238000002411 thermogravimetry Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
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- 229920002678 cellulose Polymers 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
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- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
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- 238000007922 dissolution test Methods 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
- 238000009778 extrusion testing Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- -1 hydroxypropyl Chemical group 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000016507 interphase Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000007500 overflow downdraw method Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
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- 230000001502 supplementing effect Effects 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
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- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
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- Food Science & Technology (AREA)
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- Analytical Chemistry (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of determination method of drugloading rate in solid dispersions preparation process, the phase transition peak occurred in certain temperature range using drugloading rate dispersed phase of the differentia scanning calorimetry to different proportion is as the distinguishing rule of drugloading rate best in solid dispersions preparation process.When the phase transition peak with drugloading rate increase and gradual change it is obvious when, show excessive drug and cannot be formed with auxiliary material uniform solid dispersion.Therefore when phase transition peak occurs, the auxiliary material under relevant temperature, which carries medicine ratio, can be used as the best drugloading rate of the auxiliary material combination.Beneficial effects of the present invention: can quickly and easily learn drugloading rate by this method, compare more convenient existing method, test period and number and reduce significantly, can be effectively reduced experimentation cost and save the time.
Description
Technical field
The present invention relates to a kind of methods that drugloading rate in solid dispersions is determined using phase transition peak, belong to biological medicine skill
Art field.
Background technique
Currently, in the marketed drugs for grinding new drug and 40% belonging to Biopharmaceutics Classification system (BCS) there are about 70%
Class orClass has that water-soluble, permeability and bioavilability are unable to meet demand in production process[1-2].Indissoluble
The property of property drug determines the highly difficult dissolution in vivo and in vitro of this substance and the low feature of bioavilability, present drug system
Agent mostly uses such as solvent method, nano-dispersed method, fusion method, hot-melt extruded technological means to handle it, and form solid
Dispersion is to guarantee that this kind of drug can satisfy dissolution and the requirement of bioavilability.Torching mark be earliest from plastics and
Food service industry develops, in recent years in pharmaceutical industry using increasingly extensive.With traditional solid dispersions preparation method phase
Than torching mark has many advantages, such as that organic solvent-free adds, repeatability is strong and can continuous production.
Itraconazole (Itraconazole, ITZ) is to develop within U.S.'s Janssen Pharmaceutica 1992 a kind of triazole type listed to resist
Fungi-medicine has broad spectrum of activity and good Pharmacokinetic Characteristics.ITZ is white crystalline powder, is practically insoluble in water, micro-
It is dissolved in ethyl alcohol, is dissolved in methylene chloride, belongs to Biopharmaceutics Classification system (BCS)Class[3].The Yi Qukang of domestic listing at present
Azoles preparation is mainly based on 100mg specification capsule, and preparation method system is using solvent method dissolution Itraconazole and hydroxypropyl first
It is sprayed on capsule core surface after base cellulose (HPMC E5) and dresses up capsule.Currently, there has been no corresponding with U.S. FDA for China market
The tablet of specification (200mg) is on sale, and the product on sale on this international market is to be prepared using torching mark, therefore open
Hair 200mg specification tablet can be improved clinical application and select and fill a hole in the market.
It is to complete Itraconazole high bioavilability piece by the solid dispersions that torching mark prepares Itraconazole
The basis of agent, and in this process, it investigates the intermiscibility of bulk pharmaceutical chemicals, auxiliary material and plasticizer and determines suitable supplementary material proportion
It is the significant process for preparing stabilization of solid dispersion.Based on preformulation study, Yi Qu is prepared for using torching mark
Health azoles solid dispersions, using dissolution rate as inspection target, probe into extrusion process variation to molten by the variation of hot-melt extrusion process
The influence of out-degree is laid a good foundation further to prepare its imitation medicine using hot-melt extruded method.
[1]Kawabata Y, Wada K, Nakatani M, et al. Formulation design for
poorly water-soluble drugs based on biopharmaceutics classification system:
basic approaches and practical applications[J]. International Journal of
Pharmaceutics, 2011, 420(1):1-10.
[2]Dahan A, Miller J M, Amidon G L. Prediction of Solubility and
Permeability Class Membership: Provisional BCS Classification of the World’s
Top Oral Drugs[J]. Aaps Journal, 2009, 11(4):740-746.
[3]Zhong Y , Jing G , Tian B , et al. Supersaturation induced by
Itraconazole/Soluplus® micelles provided high GI absorption in vivo[J].
Asian Journal of Pharmaceutical Sciences, 2015, 11(2):255-264.。
Summary of the invention
In view of the prior art, there are drawbacks described above, and the purpose of the present invention is to provide in a kind of solid dispersions preparation process
The determination method of drugloading rate.
The purpose of the present invention will be realized through the following technical scheme:
The determination method of drugloading rate in solid dispersions preparation process, using differentia scanning calorimetry to the load of different proportion
The phase transition peak that dose dispersed phase occurs in certain temperature range is as best drugloading rate in solid dispersions preparation process
Distinguishing rule, when phase transition peak occurs, the ratio under relevant temperature is best drugloading rate, and the phase transition peak with
Drugloading rate increase and it is obvious.Excessive drug is shown with drugloading rate increase and when obvious gradual change when the phase transition peak
Uniform solid dispersion cannot be formed with auxiliary material.Therefore when phase transition peak occurs, the auxiliary material under relevant temperature carries medicine ratio and is
It can be used as the best drugloading rate of the auxiliary material combination.
Preferably, the solid dispersions are Itraconazole solid dispersions, and the temperature range is 74 DEG C -90 DEG C.
Preferably, include the following steps,
S1, insoluble drug is dissolved in different drugloading rate ratios by organic solvent, keeps its evenly dispersed to clarification；
S2, evenly dispersed solution is placed on to drying 0.5-3 hours in 40 DEG C -100 DEG C of drying box；
S3, it takes the sample after drying to be ground, and sample after grinding is placed on the drier that relative humidity is 20%-120%
It is 1-48 hours middle；
S4, the sample after placing in S3 is taken to carry out DSC detection, observation phase transition peak corresponding drugloading rate ratio when occurring, and with
This is as best drugloading rate.
Preferably, the insoluble drug is Itraconazole.
Preferably, DSC heating rate is 10 DEG C/min in the S4.
Beneficial effects of the present invention: drugloading rate can quickly and easily be learnt by this method, compare existing method more
Convenient and cost is greatly reduced.
Below just in conjunction with the embodiments, the embodiment of the present invention is described in further detail, so that the technology of the present invention
Scheme is more readily understood, grasps.
Detailed description of the invention
Fig. 1: the DSC detection curve figure after heating up for the first time after 75 % RH, 24 h in the embodiment of the present invention.
Fig. 2: the DSC detection curve figure in the embodiment of the present invention after 75 % RH, 24 h after second of heating.
Fig. 3: the TGA curve synoptic diagram of different samples in the embodiment of the present invention.
The DSC curve schematic diagram that Fig. 4: ITZ raw material measures under nitrogen atmosphere.
Fig. 5: the E5 DSC curve schematic diagram measured under nitrogen atmosphere.
The DSC curve schematic diagram that Fig. 6: 5% PG PM is measured under nitrogen atmosphere.
The DSC curve schematic diagram that Fig. 7: 10% PG PM is measured under nitrogen atmosphere.
Fig. 8: the TGA curve synoptic diagram of different extrudates.
Fig. 9: the DSC curve schematic diagram of different extrudates.
The XRD spectrum of Figure 10: ITZ raw material and each extrudate.
Figure 11: difference squeezes out the dissolution curve schematic diagram of formula, wherein n=3.
Specific embodiment
Method of the invention is illustrated below by specific embodiment, so that technical solution of the present invention is easier to manage
Solution is grasped, but the present invention is not limited thereto.Experimental method described in following embodiments is unless otherwise specified conventional side
Method；The reagent and material commercially obtain unless otherwise specified.
Present invention discloses a kind of determination method of drugloading rate in solid dispersions preparation process, to prepare her in embodiment
For triaconazole solid dispersions.As a result, it has been found that being existed using drugloading rate dispersed phase of the differentia scanning calorimetry to different proportion
The phase transition peak occurred in certain temperature range can be used as the differentiation of best drugloading rate in solid dispersions preparation process according to
According to.And when phase transition peak occurs, the ratio under relevant temperature is best drugloading rate, and the phase transition peak increases with drugloading rate
Add and obvious.
The preparation of Itraconazole solid dispersions and its selection of auxiliary material
Test material and equipment
Itraconazole (lot number: A-10511611011, Shouguang Citroen zx pharmacy)；Hydroxypropyl methyl cellulose (lot number: PD441808,
DOW Chemical)；Propylene glycol (PG, Guangzhou Mei Yi Biotechnology Co., Ltd)；(Haake Minilab matches silent fly to hot-melt extruded machine
Generation that Co., Ltd)；Thermogravimetric analyzer (Discovery TGA, water generation company, the U.S.)；Differential scanning calorimeter
(Discovery DSC, water generation company, the U.S.)；Intelligent digestion instrument (Distek 7100, Xinghe Instrument Ltd.)；Automatically
Sampler (Distek 4300, Xinghe Instrument Ltd.)；(Distek S-3100, Xinghe instrument have ultraviolet specrophotometer
Limit company)；X-ray powder diffraction instrument (D8 Advance, Brooker dalton company, the U.S.)；Other reagents are that analysis is pure.
Test method
By preformulation study, the thermogravimetric analysis (TGA, centainly to rise of the physical mixture of supplementary material and various ratios is specified
The method that varies with temperature of determination of heating rate substance weight of temperature), (DSC includes glass transition to differential scanning calorimetric analysis
The features such as temperature, fusing point, enthalpy), and extrusion test is carried out using this parameters in series as the process parameters of hot-melt extruded, and to crowded
Out object carry out include TGA, DSC, XRD and dissolution rate etc. characterization, to obtain uniform, in stable condition ideal solid
Dispersion.
Judge the method for supplementary material compatibility (drugloading rate)
There are many method for determining drugloading rate, and common membrane process is by the way that insoluble drug and carrier to be dissolved in organic solvent simultaneously
Situation is precipitated according to it and stable case makes the compatibility relation (drugloading rate) between supplementary material.Glass transition temperature (Tg)
It can usually be used to join type, adding proportion, the degree of saturation of Drug loadings and the extrusion temperature etc. between supplementary material
Number is judged.
And the method that this test uses are as follows: press 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% and 90%(w/w) nine
Kind drugloading rate weighing is uniformly mixed so as to obtain physical mixture, makes it with methylene chloride and alcohol mixed solvent (80/20, v/v) dissolution
It is even to be dispersed to clarification, it is placed on drying 1 hour in 80 DEG C of drying boxes, takes sample after drying, grinding.Sample after grinding is placed on
In 75% relative humidity (RH) drier, detects for DSC after 24 h and set heating → cooling → secondary temperature elevation circulation journey
Sequence sets DSC temperature rate as 10 DEG C/min, and circulation temperature program is 20 DEG C → 200 DEG C → -30 DEG C → 200 DEG C.
Measurement result is as Figure 1-Figure 2.Wherein, Fig. 1 the result shows that, it is molten to occur Itraconazole since 50% drugloading rate
Point peak.According to fig. 2 the results show that belonging to 74 DEG C and 90 DEG C of Itraconazole during secondary temperature elevation under 50% to 90% drugloading rate
Under phase transition peak occur, wherein the phase transition peak at 74 DEG C is relatively small, be easy to be covered by glass transition temperature curve, 90
Phase transition peak at DEG C is relatively unambiguous, and all gradually obvious with drugloading rate increase.
The phenomenon that this phase transition peak becomes larger with drugloading rate increase is since those are in the Yi Qu of unformed state
Health azoles raw material causes the molecular structure of extra drug that the change of configuration has occurred (with phase transition peak since concentration increases
It is characterized), these change the molecule after structure can not form uniform solid dispersions with carrier molecule again, and with this condition
Occur carrying the state of medicine saturation.Its intrinsic phase transition peak that this conclusion solid dispersions in secondary temperature elevation are shown
Feature has obtained further confirmation, and the Itraconazole for illustrating that those disperse in the carrier at relatively high temperatures has started analysis again
Process out.According to the above results, this test has selected 40% drugloading rate as the parameter of subsequent hot melt extrusion step, and to extrusion
The characterization that object has carried out following various aspects is confirmed.
Using the characterization for the 40% drugloading rate extrudate that phase transition peak is judged
Characterization of the TGA to physical mixed
TGA is used to determine the degradation temperature (T of polymerd) and moisture content.About 5-8mg sample is taken to be placed in TGA platinum hanging basket,
It is suspended in high accuracy balance, measures its heat decomposition curve in a nitrogen atmosphere.TGA heating rate is set as 10 DEG C/min, temperature
Spending range is 20 → 400 DEG C, to determine the weight-loss curve of each sample.
TGA to Itraconazole raw material and each physical mixture (PM) is analysis shows ITZ bulk pharmaceutical chemicals divide at 350 DEG C or more
Solution, each mixture that difference carries medicine ratio are stablized within the scope of 250 DEG C, as shown in figure 3, this temperature can be used as hot-melt extruded operation temperature
The upper limit of degree.Itraconazole raw material is practically free of moisture, and the moisture content of E5 is in 3% or so, 5% propylene glycol and 10% propylene glycol
Physical mixed (referred to as 5% PG PM and 10% PG PM) shows as two sections of weightlessness, respectively corresponds moisture and the volatilization of PG, until
TGA curve tends to the volatilization completion that level shows moisture and PG at a temperature of this at 150 DEG C.This result explanation is high when hot-melt extruded
PG volatilization can be made complete in 150 DEG C of extrusion temperatures.
To the characterization of physical mixed
DSC is for determining glass transition temperature (Tg), melting temperature (Tm) of polymer etc..This test takes about 3-5mg to squeeze out
Object sample is placed in DSC alumina crucible, the plasticizer (5% PG PM and 10% PG PM) of various concentration in sealed crucible,
Remaining sample is in crucible of uncapping, same to measure its thermal change curve in a nitrogen atmosphere using identical blank crucible as reference.If
Determining DSC temperature rate is 10 DEG C/min, and circulation temperature program is 20 DEG C → 200 DEG C → -30 DEG C → 200 DEG C, measures her respectively
Fusing point of triaconazole during 20 DEG C → 200 DEG C of first time heating, cooling 200 DEG C → -30 DEG C and -30 DEG C of secondary temperature elevation →
Glass transition temperature and phase transition during 200 DEG C.
Fig. 4 the result shows that, extrudate fusing point about at 168.9 DEG C, send out in cyclic process at 58.7 DEG C by glass transition temperature
There is the feature endothermic peak for belonging to Itraconazole itself when cooling now and secondary temperature elevation at 74 DEG C and 90 DEG C, this endothermic peak may
Transformation with the nematic interphase of Itraconazole glassy state is related (claiming phase transition peak).Fig. 5 statistics indicate that E5 glass transition
For temperature about at 144 DEG C, the presence of endothermic peak may be related with its intermolecular well-regulated arrangement.Fig. 6 and Fig. 7 illustrate different proportion
The addition of PG significantly reduces the glass transition temperature and fusing point of Itraconazole.
To the characterization of extrudate
TGA analysis is carried out to each solid dispersion under 40% drugloading rate, Fig. 8 is the result shows that directly extrude the solid with secondary extrusion
Dispersion is practically free of moisture, the solid of 5% PG and 10% PG be dispersed in 100 DEG C to 150 DEG C within the temperature range of weightless process
It is similar with the TGA process of its physical mixture.According to TGA tracing analysis, PG can volatilize completely at 150 DEG C, Ke Nengshou
The shear ability of Minilab extruder and the influence in path and lacking exhaust apparatus reason causes PG that cannot effectively be discharged.
To the characterization of extrudate
Fig. 9's the result shows that, do not occur endothermic peak in ITZ fusing point position, illustrate that extrudate exists in the form of unformed.In conjunction with
Fig. 4-Fig. 7 is it is found that endothermic peak is related with the volatilization of PG within the scope of 80 DEG C to 160 DEG C.
Characterization of the ray powder diffraction to extrudate
ITZ and each solid dispersion powder are scanned using XRD.Operating condition: Cu target, pipe press 40 kV, 40 mA of Guan Liu,
Scanning 2 θ angular ranges is 3~60 °, scanning speed: 6 ° of min- 1.As shown in Figure 10, ITZ crystal diffraction in each extrudate is special
It levies peak to disappear, illustrates that ITZ is dispersed in carrier E5 in the form of unformed, it is consistent with DSC result.
In Vitro Dissolution test result
Precision weighs 25mg ITZ bulk pharmaceutical chemicals, is placed in 500 ml volumetric flasks addition proper amount of methanol ultrasound and makes it dissolve, is situated between with dissolution
Matter constant volume simultaneously shakes up, and makees stock solution preservation.Precision weighs 0.5,1.0,2.0,3.0,4.0,5.0,6.0 ml in 10 ml capacity
Bottle, is diluted to scale with dissolution medium, being configured to concentration is respectively 2.5,5.0,10.0,15.0,20.0,25.0,30.0
ug.ml-1Series standard solution absorption value is measured, medium is blank control at 255 nm using ultraviolet spectrophotometry.
Obtain calibration curve equation: A=0.0295C-0.0093(r=0.999), the range of linearity: 2.5~30 ug.ml-1。
Precision weighs physical mixed and extrudate powder appropriate (being equivalent to 20 mg of ITZ bulk pharmaceutical chemicals) carries out dissolution determination,
Method: USP II (paddle method), test temperature (37 ± 0.5) DEG C, 75 RPM of revolving speed, medium 0.1 N HCL, 900 ml of volume, point
5 ml(of sample is not taken respectively in 5,15,30,45,60,75 and 90 min while supplementing the fresh dissolution medium of 5 ml), 0.45 μm of filter
Film filtering detects absorbance using ultraviolet spectrophotometry at 255 nm wavelength, calculates ITZ dissolution rate.
It is shown according to dissolution result such as Figure 11,10%PG squeezes out > 5%PG extrusion bis- extrusion > of > and directly extrudes > physics
Mixing, the physical mixed of PG are not effectively improved dissolution, and accumulative dissolution is squeezed out under the conditions of 10%PG most preferably can reach 93%.
To sum up, physics is carried out in the auxiliary material matched with various concentration according to discovery Itraconazole during preformulation study to mix
Merging carries out circulation elevated temperature test process, it was found that two unique phase transition peaks.Wherein, the phase transition peak at 74 DEG C because by
The influence of Tg step and it is unobvious, the phase transition peak at 90 DEG C is relatively obvious.This phase transition peak gradually becomes with drugloading rate increase
Big phenomenon is ostensibly due to the performance that phase transition occurs in the carrier for the unformed Itraconazole that those fail dissolution part, and
Show that solid dispersions have reached the state for carrying medicine saturation with this condition.This conclusion is showed when DSC heats up for the first time
Fusing point peak out is confirmed.Because Itraconazole itself is not easy to recrystallize under unformed state, so, directly surveyed with DSC
The method for determining fusing point not can determine that drugloading rate.Accordingly, it is believed that it is compatible that the phase transition peak at 90 DEG C can be used as confirmation supplementary material
Property and solubility (drugloading rate) innovation judgment method, using 40% drugloading rate selected by this method various characterizations test
The result shows that this processing does not show the precipitation phenomenon of bulk pharmaceutical chemicals and shows preferably to dissolve out result.
Still there are many specific embodiments by the present invention.All all skills formed using equivalent replacement or equivalent transformation
Art scheme, all falls within the scope of protection of present invention.
Claims (5)
1. the determination method of drugloading rate in solid dispersions preparation process, it is characterised in that: utilize differentia scanning calorimetry
The phase transition peak occurred in certain temperature range to the drugloading rate dispersed phase of different proportion was prepared as solid dispersions
The distinguishing rule of best drugloading rate in journey, when phase transition peak occurs, the ratio under relevant temperature is best drugloading rate, and institute
It is obvious with drugloading rate increase to state phase transition peak.
2. the determination method of drugloading rate in solid dispersions preparation process according to claim 1, it is characterised in that: described
Solid dispersions are Itraconazole solid dispersions, and the temperature range is 74 DEG C -90 DEG C.
3. the determination method of drugloading rate in solid dispersions preparation process according to claim 2, it is characterised in that: including
Following steps,
S1, insoluble drug is dissolved in different drugloading rate ratios by organic solvent, keeps its evenly dispersed to clarification；
S2, evenly dispersed solution is placed on to drying 0.5-3 hours in 40 DEG C -100 DEG C of drying box；
S3, it takes the sample after drying to be ground, and sample after grinding is placed on the drier that relative humidity is 20%-120%
It is 1-48 hours middle；
S4, the sample after placing in S3 is taken to carry out DSC detection, observation phase transition peak corresponding drugloading rate ratio when occurring, and with
This is as best drugloading rate.
4. the determination method of drugloading rate in solid dispersions preparation process according to claim 3, it is characterised in that: described
Insoluble drug is Itraconazole.
5. the determination method of drugloading rate in solid dispersions preparation process according to claim 3, it is characterised in that: described
DSC heating rate is 10 DEG C/min in S4.
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