CN104211738B - Impurity, its preparation method and application thereof in a kind of idarubicin - Google Patents
Impurity, its preparation method and application thereof in a kind of idarubicin Download PDFInfo
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- CN104211738B CN104211738B CN201410404020.5A CN201410404020A CN104211738B CN 104211738 B CN104211738 B CN 104211738B CN 201410404020 A CN201410404020 A CN 201410404020A CN 104211738 B CN104211738 B CN 104211738B
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Abstract
The present invention relates to pharmaceutical analysis and field of pharmaceutical preparations, impurity (I), its preparation method and the application as impurity reference substance thereof being specifically related in a kind of idarubicin.Research finds, after idarubicin makes preparation with the adjuvant containing lactose, can produce a kind of impurity, i.e. formula (I) compound, and the idarubicin impurity of formula I structure can be used in the detection of the idarubicin quality of the pharmaceutical preparations as impurity reference substance.
Description
Technical field
The present invention relates to pharmaceutical analysis and field of pharmaceutical preparations, be specifically related to the impurity in a kind of idarubicin, it prepares
Method and the application as impurity reference substance thereof.
Background technology
Idarubicin is a kind of DNA intercalator, acts on topoisomerase II, thus suppresses nucleic acid to synthesize.This compound
Having highly lipophilic, compared with doxorubicin and daunorubicin, the absorption of medicine is increased by cell.Compared with daunorubicin, she
Reach more more effective to murine leukemia and lymphoma than star has wider array of Antitumor test, vein or oral medication.Idarubicin structure
As follows
The commercial formulations of idarubicin is that Idarubicin Hydrochloride (trade name: Zavedos, Zavedos) is by brightness at present
Auspicious company is in global marketing, including China.
Summary of the invention
Idarubicin preparation is being carried out discovery in quality research, is having a unknown impuritie.Further study show that, when her
Reaching after making preparation than star with the adjuvant containing lactose, can produce a kind of impurity, this impurity is a kind of noval chemical compound, and structure is such as
Under:
Fig. 1 is Idarubicin Hydrochloride (Zavedos, Zavedos) impurity change comparison diagram in stability study,
Lower surface curve does good the HPLC chromatogram measured immediately after only reaching purchase, and upper noodles curve is that at 105 DEG C, Zavedos heats 2 hours
HPLC chromatogram.Under visible high temperature in addition to increasing idarubicin ketone impurity (about 14 minutes), also add a unknown miscellaneous
Matter.
Contrast test:
Weighing idarubicin hydrochloride 1g, mannitol 10g, the 400ml that adds water is configured to solution, filter, be distributed into hydrochloric she
Reach and prop up than star 5mg/, lyophilization, obtain orange-yellow lyophilizing block, be lactose-free Idarubicin Hydrochloride, use
Make below against product.
Take commercially available Idarubicin Hydrochloride (Zavedos, Zavedos) (5mg, containing lactose 50mg) and reference substance prepares
Lactose-free Idarubicin Hydrochloride, each 10,105 DEG C of high-temperature heatings, after 2 hours, are separately added into solvent (every
The 1.44g Han sodium lauryl sulphate in 1000ml, phosphatase 11 ml, N, N-dimethyl octylame 1ml, regulate with 2M sodium hydroxide solution
PH value is to 4.0) make contents melting in right amount, solution is transferred to completely in same 50ml measuring bottle, every bottle is with solvent by several times
Washing, washing liquid is transferred in measuring bottle in the lump, with solvent dilution to scale, shakes up, and filters, takes subsequent filtrate as need testing solution.
Detecting by liquid phase process in embodiment 1, result is shown in Fig. 4.Being arranged above reference substance sample, lower section is Zavedos, it is seen that at Zavedos
In sample, hence it is evident that increase an impurity, it is the formula I structure idarubicin impurity of the present invention, and lactose-free reference substance
Without this impurity in sample, demonstrate again that, the degradation impurity of this impurity not idarubicin, but idarubicin occurs with lactose
The impurity that compatibility produces.Prompting idarubicin preparation should avoid direct contact with lactose.
The idarubicin impurity of formula I structure can also be prepared by the following method and obtain: take idarubicin and lactose exists
Lower alcohol reacts and get final product.The preferred methanol of described lower alcohol, ethanol, propanol, isopropanol, butanol, propylene glycol, glycerol etc., enter one
Walk preferred methanol.The preferred back flow reaction of reaction condition.Preferably 24～48 hours response time.
Reaction equation is as follows:
Possible reaction mechanism: idarubicin contains primary amine groups, lactose is reducing sugar, containing activity hemiacetal hydroxyl, both
At high temperature occurring Mei Lade (Maillard) to react, idarubicin sloughs a molecule with lactose condensation, obtains formula I structure
Idarubicin impurity.
The idarubicin impurity of formula I structure can also be its pharmaceutical salts or its hydrate.
Owing to idarubicin can belong to raw material and the incompatibility of adjuvant in preparation with lactose generation Maillard reaction.
The most in the formulation in order to avoid incompatibility, produce impurity, it should avoid lactose use in idarubicin preparation or
Idarubicin is avoided directly to contact with lactose.
The idarubicin impurity of formula I structure can be used in the detection of the idarubicin quality of the pharmaceutical preparations as impurity reference substance.Can
In idarubicin preparation, impurity comparison positions, qualitatively or quantitatively uses.
Present invention discover that, identify and be prepared for a new impurity of idarubicin, the fall of this impurity not idarubicin
Hydrolysis products, but the impurity produced with the supplementary product compatibility in preparation, it is fixed that this impurity can be used for impurity comparison in idarubicin preparation
Position, qualitatively or quantitatively use, also prompting containing the preparation of idarubicin time avoid directly using lactose.
Accompanying drawing explanation
Fig. 1 is impurity change comparison diagram in Zavedos stability study, and lower surface curve does good after only reaching purchase and measures immediately
HPLC chromatogram, upper noodles curve is that at 105 DEG C, Zavedos heats the HPLC chromatogram of 2 hours.
Fig. 2 is free from reference substance and the Zavedos sample stability comparison diagram of lactose
Fig. 3 is the HPLC figure of the idarubicin impurity reactant liquor of embodiment 1 preparation.
Fig. 4 is the mass spectrum of the idarubicin impurity of embodiment 1 preparation.
Detailed description of the invention
Embodiment 1
Weigh idarubicin hydrochloride 1g, lactose 10g, put in reaction bulb, add methanol 100ml, back flow reaction 24 hours.Filter
Crossing, a small amount of methanol washs, and dries.Taking out and be carried out as follows liquid phase test on a small quantity, remainder divides with 200 mesh silicagel columns
From, eluent is acetate-methanol sodium (6:4), collects target component.It is evaporated faint yellow solid 0.31g, mass spectrometric measurement condition
As follows, m/z:821.56.
Liquid-phase condition:
Test according to high performance liquid chromatography (Chinese Pharmacopoeia two annex V D of version in 2010), be bonded by octadecylsilane
Silica gel is filler；Mobile phase A is: 0.05M sodium dihydrogen phosphate-oxolane (80:20) is (containing dodecane in every 1000ml
Base sodium sulfate 1.44g, phosphatase 11 ml, N, N-dimethyl octylame 1ml, with 2M sodium hydroxide solution regulation pH value to 4.0), flow phase
B is: 0.05M sodium dihydrogen phosphate-oxolane (40:60) (1.44g Han sodium lauryl sulphate, phosphoric acid in every 1000ml
1ml, N, N-dimethyl octylame 1ml, with 2M sodium hydroxide solution regulation pH value to 4.0)；Column temperature 35 DEG C, flow velocity is 1.0ml/
Min, linear gradient elution；Detection wavelength is 254nm.
Liquid Detection result is shown in Fig. 3, idarubicin lactose condensation substance, idarubicin, idarubicin respectively 8.5,16.5,
Within 28 minutes, going out peak, idarubicin lactose condensation substance peak area is much larger than idarubicin and the peak area of idarubicin ketone, it is seen that produce
In thing, major part is idarubicin lactose condensation substance.
Mass Spectrometry Conditions: electron spray ionisation source (ESI), cation detects, and ionization voltage is 4.7KV；Electrospray interface is dried
Gas (nitrogen) flow velocity is 280L/hr, and ion source temperature is 170 DEG C.Direct injected, Q1MS full scan pattern, m/z sweep limits:
200～1000.Mass spectrum such as Fig. 4, belongs to as follows.
Visible reaction certain time after, generate the unknown compound that molecular weight is about 821, through resolve to idarubicin with
The condensation substance of lactose, formula (I) compound the most of the present invention.
Claims (5)
1. the compound or pharmaceutically acceptable salt thereof of formula I:
2. the compound or pharmaceutically acceptable salt thereof of claim 1, described pharmaceutical salts is the hydrochlorate of formula (I) compound.
3. the preparation method of the compound or pharmaceutically acceptable salt thereof of claim 1, including: darubicin and lactose react in lower alcohol
Obtaining, described lower alcohol is selected from methanol, ethanol, normal propyl alcohol, isopropanol, butanol, propylene glycol or glycerol.
4. the preparation method of claim 3, wherein lower alcohol is ethanol.
5. the compound or pharmaceutically acceptable salt thereof of claim 1 is used for the use during the darubicin quality of the pharmaceutical preparations detects as impurity reference substance
On the way.
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| CN104211738B true CN104211738B (en) | 2016-09-28 |
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| CN107669693B (en) * | 2017-09-22 | 2020-03-31 | 南京正大天晴制药有限公司 | Stable and safe idarubicin pharmaceutical composition and preparation method thereof |
| CN112305088B (en) * | 2019-07-26 | 2022-07-05 | 南京正大天晴制药有限公司 | Analysis method of 4-demethoxydaunorubicin related substances for injection |
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| CN100379749C (en) * | 2003-05-21 | 2008-04-09 | 獀洛克斯股份有限公司 | Method of preparing 4-R-substituted 4-demethoxydaunorubicin |
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