CN1753901A - Macrolide solvates - Google Patents
Macrolide solvates Download PDFInfo
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- CN1753901A CN1753901A CN 01819472 CN01819472A CN1753901A CN 1753901 A CN1753901 A CN 1753901A CN 01819472 CN01819472 CN 01819472 CN 01819472 A CN01819472 A CN 01819472A CN 1753901 A CN1753901 A CN 1753901A
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- azythromycin
- water
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Abstract
Azithromycin in the form of a monohydrate comprising from 4.0 % to 6.5 % of water, a process for its preparation and its use in pharmaceutical compositions.
Description
The present invention relates to the solvate of macrolides compound, i.e. the solvate of Azythromycin and similar compound.Azythromycin (9-deoxidation-9 α-azepine-9 Alpha-Methyl-9 α-Erythromycin A) is a kind of well-known antiseptic-germicide, and it is as the Merck index the 12nd edition (1996), addresses in 157 pages (946) and can be according to known method preparation.Can obtain the Azythromycin of solvate forms, for example hydrate such as monohydrate form or for example Azythromycin of dihydrate form.The Azythromycin of known monohydrate form is when being placed in normal air humidity conditions potentially unstable of following time and may containing degraded product, and also may contain high-load residual solvent according to the monohydrate of the prepared Azythromycin of known method (for example precipitating from ethanolic soln by water) except instability.Therefore at present commercially available Azythromycin is the Azythromycin of dihydrate form, known its under normal air humidity conditions, be stable.
We surprisingly find: can obtain stable, the Azythromycin of the monohydrate form of crystallization shape for example.
On the one hand, the invention provides the Azythromycin of the monohydrate form of moisture 4.0% to 6.5% (w/w).
The Azythromycin of the monohydrate form of moisture 4.0% to 6.5% (w/w) is called as " Azythromycin of the present invention " hereinafter.
Azythromycin of the present invention contains 4.0% to 6.5% water.In the Azythromycin of the composite form of forming by 1 mole of Azythromycin and 1 mole of water, the calculating content of water is about 2.35% (w/w), is not to mean that necessarily the crystallized form of Azythromycin is different with the crystallized form of the Azythromycin of monohydrate form but water content is not equal to the Azythromycin/water complex of 2.35% (w/w).We find: the X-powder diffraction pattern according to disclosed Azythromycin monohydrate among Fig. 2 of the Fig. 2 of the X-powder diffraction pattern of Azythromycin of the present invention and EP941999 and EP984020 conforms to, and obviously is different from the X-powder diffraction pattern of disclosed azithromycin dihydrate among Fig. 4 of the Fig. 1 of EP941999 and EP984020.Azythromycin of the present invention comes down to crystallization shape, and can be under normal operation, under for example normal air, the humidity condition, for example even at elevated temperatures, at least 2 weeks, for example reached for 6 week or longer times, for example in the time in 2 to 6 weeks, keep its X-powder diffraction pattern, promptly keep its crystalline structure.
Can further limit Azythromycin of the present invention according to the azithromycin degradation product of its low levels.For example, we find: when Azythromycin sample of the present invention being positioned over for example normal air of normal condition, humidity condition (as 70% to 80%, 75% humidity for example) following time, for example in the temperature that raises as (for example 35 ℃-45 ℃ of the temperature that are higher than room temperature, for example 40 ℃) under, in 2 to 6 weeks (for example 6 all in) and even longer time in, in fact the degraded of Azythromycin does not take place in the described sample; For example we find: under 40 ℃ the temperature, in humidity is 75% environment, the degraded of Azythromycin of the present invention is lower than 2.0% in 6 weeks, even be lower than 1.0% even be lower than 0.5%, i.e. (pact) 0.1%, and under same condition, water content is that the Azythromycin of 2.8% to 3.6% monohydrate form has demonstrated 2.5% degraded in 2 weeks, and described degraded increases in 4 weeks gradually, is almost 7% in 6 weeks.
On the other hand, the invention provides the Azythromycin of monohydrate form, it is characterized in that: when its sample being placed for example normal air of normal condition, humidity condition (ambient moisture) following time as 75%, for example the temperature that raises as 40 ℃ under, in at least 2 weeks (for example in 2 weeks, 4 all in addition 6 all in), the degraded of Azythromycin is lower than 2%, even is lower than 1.5%, for example 0.05% to 1.0%, for example 0.05% to 0.5%.
In the sample of Azythromycin of the present invention, under these conditions in the percentage range of the degraded of the Azythromycin of Fa Shenging (in commercially available Azythromycin form) degraded product of being in that pharmacopeia allows.
Can further limit Azythromycin of the present invention according to its stable water content.For example we find: when the sample with Azythromycin of the present invention is positioned over for example normal air of normal condition, humidity condition (as 70% to 80%, 75% humidity for example) following time, for example in the temperature that raises as (for example 35 ℃ to 45 ℃ of the temperature that are higher than room temperature, for example 40 ℃) under, in 6 weeks (for example 4 to 6 week in) and even longer time in, the water content in the described sample is in fact less than increase (for example water content remains unchanged basically); For example we find: under 40 ℃ the temperature, in humidity is 75% environment, the water content of Azythromycin of the present invention keeps identical with the water content in 0 week in all basically in 4 weeks even 6.
On the other hand, the invention provides the Azythromycin of monohydrate form, it is characterized in that: when its sample being placed for example normal air of normal condition, humidity condition (ambient moisture) following time as 75%, for example in the temperature that raises as (for example 35 ℃ to 45 ℃ of the temperature that are higher than room temperature, for example 40 ℃) under, the water content the when water content in the described sample keeps with 0 week in the time in 4 weeks (for example 4 to 6 weeks) is basic identical.
Can obtain Azythromycin of the present invention according to for example following mode: can for example use any type of Azythromycin as raw material, for example form of free alkali form, salt (for example form of hydrochloride such as dihydrochloride, acetate) and/or solvate forms (for example water content is not equal to 4.0% to 6.5% monohydrate form, anhydrous form or dihydrate form), the form of preferably salt.For example be dissolved in the solvent or form (for example by acid being added in the Azythromycin in the solvent), can prepare the solution of Azythromycin in solvent of salt form by in solvent, the free form of Azythromycin being converted into its salt by Azythromycin with salt form." solution " comprises the suspension that has wherein dissolved part (as salt form) Azythromycin at least.Suitable acid comprises organic acid (for example formic acid or acetate) and mineral acid (for example hydrochloric acid, Hydrogen bromide, nitric acid or sulfuric acid), preferred hydrochloric acid or sulfuric acid.Solvent comprises the solvent of the Azythromycin that is suitable for the dissolved salt form, for example comprises aqueous solvent.Aqueous solvent comprises the mixture of water or water and organic solvent (for example one or more organic solvents), described organic solvent is for example water miscibility and water-immiscible organic solvent, as alcohols (for example methyl alcohol, ethanol, Virahol), ketone (as acetone, methyl iso-butyl ketone (MIBK)), the alkyl carboxylic ester (C of formic acid or acetate for example
1-4) alkyl carboxylic ester (for example methyl acetate, ethyl acetate, acetate isopropyl esters, butylacetate), aromatic hydrocarbon based (as toluene, dimethylbenzene), ethers (as tetrahydrofuran (THF), methyl tertiary butyl ether), chlorinated hydrocarbon (as methylene dichloride) and amides such as monoalkyl and dialkyl amide class (for example N-methylformamide, N, N-N,N-DIMETHYLACETAMIDE, N, dinethylformamide).The mixture of described aqueous solvent preferably water or water and one or more alcohols, ketone, alkyl acetate, for example water or aqueous solvent are as water or contain the water of the organic solvent of 0.5% to 20% (v/v) (as 1% to 15% (v/v)).An advantage of the present invention is: can use the water that does not contain organic solvent.
The method according to this invention, the appropriate reaction conditions of the solution of the Azythromycin of preparation salt form for example comprises:
(i) temperature, Azythromycin is non-degradable under this temperature, for example comprises the temperature range of-20 ℃ to 90 ℃ as 0 ℃ to 70 ℃,
(ii) suitable pressure, barometric point and be higher or lower than the pressure of barometric point for example,
(iii) suitable dilution degree, for example dilution range of the Azythromycin of every liter of solvent 1g to 500g raw material form.
As needs, can by for example filter, activated carbon treatment randomly carries out purifying to remove impurity with the solution of Azythromycin in solvent of the salt form that obtains.The pH value of solution that can be by for example adding the Azythromycin that alkali will (for example purifying) salt form in the solution of Azythromycin in solvent of salt form is adjusted to and can makes Azythromycin with the pH value that free form exists, and comprises for example about 8.0 to 13.0, the pH value as 9.0 to 12.0, for example 10.0 to 11.0." solution " of the Azythromycin of free form comprises having part Azythromycin dissolved suspension at least.Suitable alkali comprises the alkali that is suitable for regulating the pH value, for example oxyhydroxide, carbonate, supercarbonate and the organic bases of mineral alkali such as ammonia or basic metal (as sodium, potassium), alkaline-earth metal (as calcium, magnesium) and ammonium such as amine (for example alkylamine) and for example mixture of above-described each alkali.Preferred alkali is for example sodium hydroxide or ammonia of oxyhydroxide, preferably in the aqueous solution.Can be from solution the Azythromycin of free form and stable crystallization shape monohydrate form be precipitated out, and can be according to for example being similar to conventional method (for example by centrifugal or filtration) with its separation; And can be in suitable temperature (for example comprise 20 ℃ to 80 ℃ temperature range in), for example be dried until water content at normal atmosphere or under vacuum and reach 4.0% to 6.5%.Can obtain crystallization shape Azythromycin moisture 4.0% to 6.5%, the monohydrate form.
On the other hand, the invention provides the method for the Azythromycin of preparation moisture 4.0% to 6.5% monohydrate form, said method comprising the steps of:
(i) the pH value of the solution of the Azythromycin of adjusting salt form, solvent wherein is selected from the mixture of water or water and organic solvent,
(ii) separate the monohydrate form Azythromycin and
(iii) make it dry to obtain the Azythromycin of moisture 4.0% to 6.5% monohydrate form.
When only making water, can obtain to be substantially free of the Azythromycin of the present invention of organic solvent as solvent." be substantially free of " amount that refers to organic solvent, comprise with analytical procedure detect less than the amount of organic solvent to the amount of organic solvent that can detected 0.5% (w/w) with analytical procedure, the amount of described organic solvent is in the defined pharmaceutical cpd of European Pharmacopoeia for example in the suitable content range of low-toxic solvent (the 3rd kind solvent).
On the other hand, the invention provides the Azythromycin of the crystallization shape monohydrate form that is substantially free of organic solvent.
Azythromycin of the present invention can be used for preparing and comprises the pharmaceutical composition of Azythromycin as activeconstituents.
On the other hand, the invention provides pharmaceutical composition, described pharmaceutical composition comprises, for example be made up of Azythromycin of the present invention and at least a pharmaceutical carrier or thinner basically.
Compare with the known pharmaceutical composition (for example present commercially available pharmaceutical composition) that comprises azithromycin dihydrate, pharmaceutical composition of the present invention can contain the Azythromycin of same concentrations and can be used for identical indication with identical dosage range.
Embodiment
In following examples, all temperature are centigradetemperature and without overcorrection.X-powder diffraction pattern according to the Azythromycin of the monohydrate form that following examples obtained conforms to the X-powder diffraction pattern of the Azythromycin of monohydrate form.When under normal air humidity conditions, preserving for 6 weeks at elevated temperatures, kept its crystallinity and X-powder diffraction pattern thereof and be substantially free of degraded product according to the Azythromycin of the monohydrate form that following examples obtained.
Measure water-content (%w/w) with Ka Er-Fischer's method.
Embodiment
Adding HCl in the suspension of 20g Azythromycin in 83ml water dissolves until suspension.Resulting solution is filtered removing insoluble microparticle, and under about 55 ℃ temperature, resulting filtrate is dropwise joined in the 103ml water, regulate the pH value to 10-11 by adding 20% NaOH simultaneously.Leach solid precipitation, washing and drying reach 4.0 to 6.5% until water content.Obtain the Azythromycin monohydrate of 18.4g crystallized form.Water content: 6.0%
Under room temperature and normal air humidity conditions, the water content after 2 days is 6.3%.
Under room temperature and normal air humidity conditions, the water content after 13 days is 6.3%.
The X-powder diffraction pattern of the Azythromycin of disclosed monohydrate form conforms among the 1st day, the 2nd day Fig. 2 with the Fig. 2 of the X-powder diffraction pattern of the Azythromycin that was obtained in the 13rd day and for example EP941999 and EP984020.
Stability and comparative example
Be 75% in relative humidity, temperature is that the sample of the Azythromycin of the monohydrate form with moisture 5.3% and moisture 2.8% placed for 6 weeks in 40 ℃ the environment.Measure the tire degraded of (content), Azythromycin and the water content of sample of Azythromycin in the 0th week, the 2nd week, the 4th week and the 6th week.Measure tiring and degrading of Azythromycin (in anhydrous Azythromycin) by HPLC.Measure water content with Ka Er-Fischer's method.Obtain
The experimental result of the Azythromycin of moisture 5.3% the shown in-following table 1,
The experimental result of the Azythromycin of moisture 2.8% the shown in-following table 2:
Table 1
| Week | (%) tires | Degraded (%) | Moisture (%) |
| 0 | 99.8 | - | 5.3 |
| 2 | 98.9 | 0.1 | 5.3 |
| 4 | 99.5 | 0.1 | 5.3 |
| 6 | 99.5 | 0.1 | 5.3 |
Table 2
| Week | (%) tires | Degraded (%) | Moisture (%) |
| 0 | 99.7 | - | 2.8 |
| 2 | Unmatchful photograph | 2.5 | 2.8 |
| 4 | Unmatchful photograph | 6.1 | 3.3 |
| 6 | 91.6 | 6.6 | 3.6 |
In table 1 and the table 2
In the 0th week and the 6th week, the X-powder diffraction pattern of the Azythromycin of the monohydrate form among Fig. 2 of the X-powder diffraction pattern of the crystallization shape Azythromycin demonstration in two samples and the Fig. 2 of EP941999 and EP984020 is consistent.
" (%) tires " in table 1 and table 2 down shown in the time period accordingly the percentage ratio of tiring of Azythromycin in each sample.
" degraded (%) " in table 1 and table 2 down shown in the time period accordingly the degraded percentage ratio of Azythromycin in each sample.
" moisture (%) " in table 1 and table 2 down shown in the time period accordingly the per cent moisture of Azythromycin in each sample.
Claims (5)
1. the Azythromycin of moisture 4.0% to 6.5% monohydrate form.
2. the Azythromycin of monohydrate form is characterized in that: when its sample being positioned at elevated temperatures normal humidity condition following time, the degraded of Azythromycin is lower than 2% in its sample at least 2 weeks.
3. the Azythromycin of monohydrate form is characterized in that: when with its sample at elevated temperatures when normal humidity condition placed for 4 weeks down, the water content in the described sample is identical with the water content in the 0th week basically.
4. pharmaceutical composition, it comprises each described Azythromycin and at least a pharmaceutical carrier or thinner in the claim 1 to 3.
5. prepare the method for the Azythromycin of moisture 4.0% to 6.5% monohydrate form, described method comprises the steps:
(i) the pH value of the solution of the Azythromycin of adjusting salt form, solvent wherein is selected from the mixture of water or water and organic solvent,
(ii) separate the monohydrate form Azythromycin and
(iii) carry out dry to obtain the Azythromycin of moisture 4.0% to 6.5% monohydrate form.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US25311900P | 2000-11-27 | 2000-11-27 | |
| US60/253,119 | 2000-11-27 | ||
| GB0031355.1 | 2000-12-21 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1753901A true CN1753901A (en) | 2006-03-29 |
| CN100341886C CN100341886C (en) | 2007-10-10 |
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ID=36680255
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB018194729A Expired - Fee Related CN100341886C (en) | 2000-11-27 | 2001-11-26 | Macrolide solvates |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN100341886C (en) |
| RU (1) | RU2279439C2 (en) |
| UA (1) | UA76967C2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101418026B (en) * | 2008-10-09 | 2011-05-18 | 南京工业大学 | Azithromycin crystallization process with controllable crystal form and granularity |
| CN114699386A (en) * | 2022-04-14 | 2022-07-05 | 深圳职业技术学院 | Azithromycin composition and preparation method thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT102006B (en) * | 1997-05-19 | 2000-06-30 | Hovione Sociedade Quimica S A | NEW AZITROMYCIN PREPARATION PROCESS |
| SK282427B6 (en) * | 1997-06-11 | 2002-01-07 | Abbott Laboratories | Solid pharmaceutical composition with controlled release |
| PT102130A (en) * | 1998-03-13 | 1999-09-30 | Hovione Sociedade Quimica S A | METHOD FOR PREPARING AZITHROMYCY DIHYDRATE |
| CA2245398C (en) * | 1998-08-21 | 2002-01-29 | Apotex Inc. | Azithromycin monohydrate isopropanol clathrate and methods for the manufacture thereof |
| CZ20011886A3 (en) * | 1998-11-30 | 2001-10-17 | Teva Pharmaceutical Industries Ltd. | Azithromycin ethanolate, process of its preparation and pharmaceutical preparations containing thereof |
-
2001
- 2001-11-26 UA UA2003054704A patent/UA76967C2/en unknown
- 2001-11-26 CN CNB018194729A patent/CN100341886C/en not_active Expired - Fee Related
- 2001-11-26 RU RU2003117480/04A patent/RU2279439C2/en not_active IP Right Cessation
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101418026B (en) * | 2008-10-09 | 2011-05-18 | 南京工业大学 | Azithromycin crystallization process with controllable crystal form and granularity |
| CN114699386A (en) * | 2022-04-14 | 2022-07-05 | 深圳职业技术学院 | Azithromycin composition and preparation method thereof |
| CN114699386B (en) * | 2022-04-14 | 2023-05-23 | 深圳职业技术学院 | Azithromycin composition and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| UA76967C2 (en) | 2006-10-16 |
| RU2279439C2 (en) | 2006-07-10 |
| CN100341886C (en) | 2007-10-10 |
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Granted publication date: 20071010 Termination date: 20151126 |