CN107290445B - A method of lactic acid and ethyl alcohol acid content in detection microsphere for injection preparation - Google Patents
A method of lactic acid and ethyl alcohol acid content in detection microsphere for injection preparation Download PDFInfo
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- CN107290445B CN107290445B CN201710375553.9A CN201710375553A CN107290445B CN 107290445 B CN107290445 B CN 107290445B CN 201710375553 A CN201710375553 A CN 201710375553A CN 107290445 B CN107290445 B CN 107290445B
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- lactic acid
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- microsphere
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 title claims abstract description 58
- 239000004310 lactic acid Substances 0.000 title claims abstract description 29
- 235000014655 lactic acid Nutrition 0.000 title claims abstract description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000001514 detection method Methods 0.000 title claims abstract description 22
- 238000002347 injection Methods 0.000 title claims abstract description 18
- 239000007924 injection Substances 0.000 title claims abstract description 18
- 239000004005 microsphere Substances 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title claims abstract description 13
- 239000002253 acid Substances 0.000 title claims abstract description 11
- 235000019441 ethanol Nutrition 0.000 title claims abstract description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000000523 sample Substances 0.000 claims abstract description 21
- 239000000243 solution Substances 0.000 claims abstract description 21
- 238000012360 testing method Methods 0.000 claims abstract description 18
- 239000012488 sample solution Substances 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 7
- 239000013558 reference substance Substances 0.000 claims abstract description 5
- 238000010812 external standard method Methods 0.000 claims abstract description 4
- 239000007788 liquid Substances 0.000 claims abstract description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 8
- 229930182843 D-Lactic acid Natural products 0.000 claims description 4
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 claims description 4
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 4
- 239000012498 ultrapure water Substances 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 239000000284 extract Substances 0.000 abstract 1
- 239000012071 phase Substances 0.000 description 14
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 8
- 239000012086 standard solution Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 3
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 239000011806 microball Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The invention discloses a kind of methods of lactic acid and ethyl alcohol acid content in detection microsphere for injection preparation, include the following steps: the preparation of (1) microsphere for injection testing sample solution: precision weighs test sample 50mg, it is placed in 2mL centrifuge tube, 0.5mL methylene chloride vortex, which is added, to be made to dissolve 1min, again plus the rotation of the 0.5mL eddies of water extracts 1min, it is centrifuged in centrifuge afterwards, takes out centrifuge tube, taking upper layer aqueous is testing sample solution；(2) high performance liquid chromatography detection: taking testing sample solution and reference substance solution respectively, injects liquid chromatograph, and chromatogram is measured and recorded according to the testing conditions of setting, and gained peak area is calculated the content of lactic acid and glycolic in sample to be tested by external standard method.The present invention is quick, sensitive, effective.
Description
Technical field
The present invention relates to drug measurement techniques field, in particular to lactic acid and ethyl alcohol in a kind of detection microsphere for injection preparation
The method of acid content.
Background technique
Microsphere for injection often uses auxiliary material PLA/PLGA, belongs to polyester-based polymer polymer, production, storage or/and
Using and its manufacturing process of applied pharmaceutical formulation microsphere for injection in, ester bond eventually drops under the action of water and oxygen
Solution is lactic acid or/and glycolic, and lactic acid or/and glycolic can also accelerate the hydrolyzed of PLA/PLGA ester bond in acidic environment
Journey causes the stability of microballoon and slow release characteristic to change, and finally influence microballoon to influence the release characteristics of microballoon
Storage effect phase and clinical use effect, therefore detect in microsphere for injection the content of lactic acid and glycolic for microsphere for injection
Quality control important in inhibiting.There is presently no discovery detection having for lactic acid in microsphere for injection and ethyl alcohol acid content
Imitate analysis method.
Summary of the invention
The purpose of the present invention is to provide a kind of methods of lactic acid and ethyl alcohol acid content in detection microsphere for injection preparation, fastly
It is fast, sensitive, effective.
The technical solution adopted by the present invention to solve the technical problems is:
A method of lactic acid and ethyl alcohol acid content in detection microsphere for injection preparation include the following steps:
(1) preparation of microsphere for injection testing sample solution
Precision weighs test sample 50mg, is placed in 2mL centrifuge tube, and 0.5mL methylene chloride vortex, which is added, to be made to dissolve 1min, then
Add the 0.5mL eddies of water rotation extraction 1min, after be centrifuged in centrifuge, take out centrifuge tube, taking upper layer aqueous is testing sample solution；
(2) high performance liquid chromatography detection
Testing sample solution and reference substance solution are taken respectively, injects liquid chromatograph, are measured according to the testing conditions of setting
And chromatogram is recorded, gained peak area is calculated the content of lactic acid and glycolic in sample to be tested by external standard method.
The present invention first uses methylene chloride to handle test sample sample, can dissolve the jacket ingredients PLA/PLG of microballoon and shell
From to release lactic acid and glycolic therein, then water is extracted, and in this way can discharge detected material, and it is accurate to improve detection
Degree；PLA/PLGA is soluble in methylene chloride, and lactic acid and glycolic are soluble easily in water and do not dissolve in methylene chloride.
The present invention develops targetedly specific inspection for the detection of lactic acid and ethyl alcohol acid content in microsphere for injection preparation
Survey method is quick, sensitive, effective.
Preferably, the parameter being centrifuged in step (1) are as follows: 8000rmp, 10min.
Preferably, reference substance solution is D/L lactic acid in step (2), glycolic standard items add ultrapure water to be made into.
Preferably, high performance liquid chromatography detection condition in step (2) are as follows:
Chromatographic column is C18Column, Detection wavelength 210nm, 30 DEG C of column temperature, sample volume 100 μ L, flow velocity 0.5mL/min；
Mobile phase is 0.1vol% phosphate aqueous solution-acetonitrile, and wherein mobile phase A is 0.1vol% phosphoric acid solution, Mobile phase B
For acetonitrile, gradient elution program: 0~12min is 100% mobile phase A, and 12~13min mobile phase A is down to 50%, Mobile phase B liter
To 50%, 13~18min keeps mobile phase A 50%, Mobile phase B 50%.
Preferably, the 0.1vol% phosphoric acid solution 1mol/L sodium hydroxide solution tune pH to 2.5 as mobile phase A.
0.1vol% phosphoric acid solution 1mol/L sodium hydroxide solution tune pH to 2.5, the buffer system that can be formed in this way, the peak shape of appearance
It is good, it detects more accurate.
The beneficial effects of the present invention are: detection method is with strong points, it is quick, sensitive, accurate.
Detailed description of the invention
Fig. 1 is blank solution typical case's chromatogram.
Fig. 2 is glycolic lactate standard solution typical case's chromatogram；Glycolic 4ug/ml, lactic acid 4ug/ml.Respectively with respect to sample
The 40ppm of product concentration.
Fig. 3 is glycolic lactic acid LOQ solution typical case's chromatogram；Glycolic 0.2ug/ml, the 2ppm of relative sample concentration.
Lactic acid 0.27ug/ml, the 2.7ppm of relative sample concentration.
Fig. 4 is test solution typical case's chromatogram.
Specific embodiment
Below by specific embodiment, technical scheme of the present invention will be further explained in detail.
In the present invention, if not refering in particular to, used raw material and equipment etc. are commercially available or commonly used in the art.
Method in following embodiments is unless otherwise instructed the conventional method of this field.
Embodiment:
One, instrument and material
High performance liquid chromatograph (Waters, e2695/2489), assay balance (Mei Tele, XP205 type), vortex instrument
(IKA, Vortex genius3), centrifuge (Sigma, 3K15), pH meter (Mei Tele, FE20/plus).
Phosphoric acid (AR, Shanghai Ling Feng), sodium hydroxide (AR, Hangzhou Xiaoshan chemistry), acetonitrile (HPLC, TEDIA), methylene chloride
(HPLC, α Cygni friend), ultrapure water (18.2M Ω .cm, Millipore Direct-8).
Standard reagent D/L lactic acid (TGI, > 85%), glycolic (aladdin, 98%).
Two, method and result
The preparation of 2.1 standard solutions
Take D/L lactic acid, glycolic standard items appropriate respectively, accurately weighed, it is standby that addition ultrapure water is made into 1mg/ml stock solution
Required concentration is diluted to when with, use.
2.2 chromatographic condition
Chromatographic column is C18 column (250 × 4.6mm, 5um Waters Atlantis T3), and mobile phase is 0.1% phosphoric acid water
Solution-acetonitrile, wherein mobile phase A is 0.1% phosphoric acid solution (1mol/L sodium hydroxide solution tune pH to 2.5), and Mobile phase B is second
Nitrile, gradient elution:
| Time | Mobile phase | %A | %B | |
| 1 | 0.00 | 0.50 | 100.0 | 0.0 |
| 2 | 12.00 | 0.50 | 100.0 | 0.0 |
| 3 | 13.00 | 0.50 | 50.0 | 50.0 |
| 4 | 18.00 | 0.50 | 50.0 | 50.0 |
| 5 | 19.00 | 0.50 | 100.0 | 0.0 |
| 6 | 40.00 | 0.50 | 100.0 | 0.0 |
Detection wavelength is 210nm, 30 DEG C of column temperature, sample volume 100 μ L, flow velocity 0.5mL/min, runing time 40min.
2.3 standard chromatograms are shown in Fig. 2-3, and peak shape is good and Fig. 1 is shown in the enough height of sensitivity, blank control.
2.4 precisions weigh test sample, about 50mg, are placed in 2mL centrifuge tube, and 0.5mL methylene chloride vortex, which is added, to be made to dissolve
1min, then plus 0.5ml eddies of water rotation extraction 1min, after be centrifuged 10min under 8000rmp in centrifuge, it is simultaneously careful to take out centrifuge tube
Upper layer aqueous 250ul is taken, is placed in liquid-phase inlet bottle, sample introduction 100ul.
2.5 testing result
Fig. 2 is glycolic lactate standard solution typical case's chromatogram；Glycolic 4ug/ml, lactic acid 4ug/ml.Respectively with respect to sample
The 40ppm of product concentration, the retention time of glycolic are 7.832min, and the retention time of lactic acid is 13.051min.The two and solvent
Peak separation is good, and standard solution repeats sample introduction 6 times, and the RSD of response factor obtained by glycolic is 0.41%, response obtained by glycolic
The RSD of the factor is 0.39%, and sample introduction precision is good.
Calculating the content of glycolic and lactic acid in microball preparation by external standard method is respectively 5.41ppm and 93.89ppm, mark-on
The content of glycolic and lactic acid is respectively 84.11ppm and 178.49ppm in solution, and the rate of recovery reaches 97.71% He
100.51%, show that glycolic and lactic acid content detection method disclosed by the invention is accurate, reliable.
Fig. 3 is glycolic lactic acid LOQ solution typical case's chromatogram；Glycolic 0.2ug/ml, the 2ppm of relative sample concentration.
Lactic acid 0.27ug/ml, the 2.7ppm of relative sample concentration.Fig. 4 is test solution typical case's chromatogram.
Above-mentioned embodiment is only a preferred solution of the present invention, not the present invention is made in any form
Limitation, there are also other variations and modifications on the premise of not exceeding the technical scheme recorded in the claims.
Claims (3)
1. a kind of method of lactic acid and ethyl alcohol acid content in detection microsphere for injection preparation, which comprises the steps of:
(1) preparation of microsphere for injection testing sample solution
Precision weighs test sample 50mg, is placed in 2mL centrifuge tube, and 0.5mL methylene chloride, which is added, and is vortexed makes to dissolve 1min, then plus
The 0.5ml eddies of water rotation extraction 1min, after be centrifuged in centrifuge, take out centrifuge tube, taking upper layer aqueous is testing sample solution；
(2) high performance liquid chromatography detection
Testing sample solution and reference substance solution are taken respectively, are injected liquid chromatograph, are measured and remember according to the testing conditions of setting
Chromatogram is recorded, gained peak area is calculated the content of lactic acid and glycolic in sample to be tested by external standard method；
High performance liquid chromatography detection condition are as follows:
Chromatographic column be C18 column, Detection wavelength 210nm, 30 DEG C of column temperature, sample volume 100 μ L, flow velocity 0.5mL/min；
Mobile phase is 0.1vol% phosphate aqueous solution-acetonitrile, and wherein mobile phase A is 0.1vol% phosphoric acid solution, and Mobile phase B is second
Nitrile, gradient elution program: 0~12min is 100% mobile phase A, and 12~13min mobile phase A is down to 50%, and Mobile phase B rises to
50%, 13~18min keep mobile phase A 50%, Mobile phase B 50%；
Wherein, as the 0.1vol% phosphoric acid solution of mobile phase A 1mol/L sodium hydroxide solution tune pH to 2.5.
2. the method for lactic acid and ethyl alcohol acid content, special in a kind of detection microsphere for injection preparation according to claim 1
Sign is, the parameter being centrifuged in step (1) are as follows: 8000rmp, 10min.
3. the method for lactic acid and ethyl alcohol acid content, special in a kind of detection microsphere for injection preparation according to claim 1
Sign is that reference substance solution is D/L lactic acid in step (2), glycolic standard items add ultrapure water to be made into.
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| CN110426481A (en) * | 2019-09-16 | 2019-11-08 | 亚太星原农牧科技海安有限公司 | The method of lactic acid content and the measurement extracting method of prepare liquid in a kind of measurement fermented bean dregs |
| CN112824893B (en) * | 2019-11-21 | 2023-09-26 | 浙江圣兆药物科技股份有限公司 | Method for detecting glycolide and lactide monomers in microspheres |
| CN115097037B (en) * | 2022-06-22 | 2024-03-29 | 华润双鹤药业股份有限公司 | Method for detecting lactic acid in pentazocine injection |
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| WO2012019295A1 (en) * | 2010-08-13 | 2012-02-16 | Tony Antakly | Bioactive compounds in camel urine and milk |
| WO2017015488A1 (en) * | 2015-07-22 | 2017-01-26 | Temple University-Of The Commonwealth System Of Higher Education | Soy-derived bioactive peptides for use in compositions and methods for wound healing, tissue engineering, and regenerative medicine |
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| WO2012019295A1 (en) * | 2010-08-13 | 2012-02-16 | Tony Antakly | Bioactive compounds in camel urine and milk |
| WO2017015488A1 (en) * | 2015-07-22 | 2017-01-26 | Temple University-Of The Commonwealth System Of Higher Education | Soy-derived bioactive peptides for use in compositions and methods for wound healing, tissue engineering, and regenerative medicine |
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