WO2001087912A1

WO2001087912A1 - Polymorphic form of azithromycin dihydrate and preparation method thereof

Info

Publication number: WO2001087912A1
Application number: PCT/ES2001/000183
Authority: WO
Inventors: Ramon Asensio Rodriguez; Maria Del Carmen Cruzado Rodriguez; Luis Angel Diaz Tejo; José Ignacio BORREL BILBAO; Rosa Nomen Ribe; Julià SEMPERE CEBRIAN
Original assignee: Ercros Industrial, S.A.
Priority date: 2000-05-17
Filing date: 2001-05-11
Publication date: 2001-11-22
Also published as: AU5840901A; ES2162764A1; PT102565A; ES2162764B1

Abstract

The invention relates to a polymorphic form of azithromycin dihydrate (9-desoxo-9a-aza-9a-methyl-9a-homoerythromycin A) showing endothermy in differential scanning calorimetry (DSC) at 139° C, when recorded in an open aluminum crucible at a heating speed of 20° C/minute and showing an endothermy of 143, 7±0.5° C with a fusion heat of 54, 6±1.6 J/g when recorded in a capillary crucible at a heating speed of 10° C/minute. The invention also relates to a method for preparing said polymorphic form of azithromycin dihydrate. According to said method, hygroscopic azithromycin monohydrate is treated with acetone; water at 35-40° C is added; the mixture is then stirred at said temperature and crystals of said polymorph are optionally seeded; water is then added and the mixture is cooled at 5° C.

Description

D E S C R I P C I Ó N

Polymorphic form of azithromycin dihydrate, and its method of obtaining

Background of the invention

Azithromycin is the USAN generic name of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (formula 1), which is a compound derived from erythro icicin A which as it belongs to the group of macroli- antibiotics two. The structural difference between both compounds is the formal substitution of the carbonyl group in 9 of the erythromycin with a methylamino group. In this way, the formation of acetal compounds in the acidic stomach medium that lack antibiotic activity is avoided. In contrast, azithromycin is an excellent therapeutic agent for the treatment of skin and respiratory tract infections, as well as for the treatment of sexually transmitted diseases (Kirst, HA, Sides, GD, Antimicrob. Agents Chemother., 1989 , 33, 1419-1422.

This compound was described simultaneously by merely by S. Djokic and G. Kobrehel (Sour Pliva) in Belgian patent document BE 892,357 (and in equivalent document US-A-4,517,359) and by GM Bright and C. Gro-ton (Pfeizer Inc. ) in US-A-4,474,768. Both procedures end with a recrystallization of azithromycin in a water-ethanol mixture that allows the final compound to be obtained in the form of monohydrate. This crystalline form is extremely hygroscopic, difficult to prepare and with a poorly reproducible water content. It also presents problems during the formulation due to its ability to absorb varying amounts of water depending on the relative humidity to which it is subjected.

In this sense, D. J. M. Alien and K. M. Nepveux (Pfizer Inc.) describe in European patent document EP-A-298,650 azithromycin dihydrate as a new non-hygroscopic crystalline form suitable for the preparation of formulations for therapeutic use. The azithromycin dihydrate (Method B of said patent) is obtained by recrystallizing the hygroscopic azithromycin monohydrate from a tetrahydrofuran / hexane / water mixture (a minimum of two moles per mole of azithromycin). The characteristics of the dihydrate obtained according to said patent are the following:

The dihydrate melts at 126 ° C (heated stage, 10 ° C / minute); differential scanning calorimetry (DSC) (heating rate, 20 ° C / minute) shows an endotherm at 127 ° C; thermogravimetry (TGA) (heating rate, 30 ° C / minute) shows a weight loss of 1.8% at 100 ° C and 4.3% at 150 ° C. It also presents significant differences in the infrared (IR) spectrum in KBr tablet for azithromycin monohydrate as shown in the following table:

Finally, said document EP-A-298.650 describes the following behavior of azithromycin dihydrate against moisture: At relative humidity of 33% and 75% the water content remains essentially constant, at least 4 days, in the content theoretical 4.6%. At a relative humidity of 100% the moisture content rises to 5.2% and remains constant for the next three days.

Structural elucidation studies of azithromycin (Djokic, S., Kobrehel, G., J. Chem. Res. (S)., 1988, 132; and J. Chem. Res. (M), 1988, 1239) have allowed to characterize the two crystalline forms, monohydrate and dihydrate, of azithromycin.

Recently, M. S. Bayod, and J. M. Fernández (As- tur-Phar a, S. A.) describe in the European patent document EP-A-827,965 the obtaining of azithromycin dihydrate by crystallization of acetone / water.

None of the aforementioned patents refers to different polymorphic forms of azithromycin dihydrate. As is well known, the different crystalline structures in which it can be called polymorphs are called The same chemical substance may occur.

The detection and characterization of polymorphic forms of drugs has aroused great interest on the part of pharmaceutical companies and has led to the granting of numerous patents on polymorphic forms. By way of example, we can mention the cases of fa otidine, ranitidine or diflunisal among others (Borka, L., Haleblian, J. K., Acta Pharm. Juices!, 1990, 40, 71-94).

Description of the invention

The object of the present invention is a new polymorphic form of azithromycin dihydrate, thermodynamically more stable, perfectly characterizable and reproducible by recrystallization of hygroscopic azithromycin monohydrate from an acetone-water mixture.

The recrystallization process starts from azithromycin monohydrate, obtained by means of the Djokic and Kobrehel synthesis procedure mentioned above, which is dissolved in acetone and stirred for 30-40 minutes at a temperature of 18-25 ° C. Active carbon is added and stirring is maintained for 15 minutes, then filtered. The resulting solution is heated with stirring to 35-40 ° C and a first fraction of distilled water is added over a period of 30-40 minutes. Stirring is maintained for 2 h during which the formation of an abundant precipitate is observed. A second fraction of water is added for 2 h while maintaining the temperature between 35-40 ° C. After the addition, stirring is maintained for 8 h. Finally the mixture is cooled to 5 ° C, temperature at which Hold for 1 h. The resulting azithromycin dihydrate is filtered, washed with water and dried in a stream of air at 35-40 ° C.

In order to demonstrate the different nature of the dihydrate obtained by this crystallization methodology with respect to the dihydrate obtained by the Alien and Nepveux method (Pfizer Inc.), described in European patent EP-A-298,650 cited above, the Methods A and B of crystallization contained therein. Samples are identified throughout the study as follows:

AZI.PA Azithromycin dihydrate obtained according to method A of EP-A-298,650

AZI.PB Azithromycin dihydrate obtained according to method B of patent EP-A-298,650

AZI.F Azithromycin polymorph dihydrate object of the present invention To study these samples both differential scanning calorimetry (DSC) and thermogravimetry (TGA) have been used.

The DSC allows to detect specific heat changes and enthalpic changes of the samples against temperature or time, while the TGA also studies its mass losses as a function of temperature or time. Experiments carried out by means of a temperature sweep (heating or cooling at constant speed) are called dynamic registers and those performed at constant temperature isothermal.

All studies of polymorphism by thermal analysis They are usually used by DSC and are based on the different melting temperatures of polymorphic or transition forms between crystalline forms.

When the studied samples of hydrates are treated, it is expected that during their heating they lose water, either progressively, or at defined temperatures. This loss is directly recorded in TGA, while in DSC the endothermic phenomenon associated with evaporation is observed. The loss of the crystallization water causes the loss of the initial crystalline form, usually leading to an anhydrous form, which may or may not recrystallize. If the release of the crystallization water is avoided by application of external pressure, it is possible to register the melting point of the hydrated form.

The study has allowed to obtain the following results:

The theoretical water content of azithromycin hydrates and the results of the analyzes by the Karl-Fisher method are shown in the following table.

Theoretical (% water) Karl-Fisher (% water)

AZI PA 4, 6 5.1

AZI PB 4, 6 3.4

AZI F 4, 6 4 _ ^ _ 9

Thermogravimetry (TGA)

The records are carried out in an instrument

Mettler-Toledo Star ^e , TG50 with a nitrogen sweep 200 ml / minute dry and standard 100 μl alumina crucible without lid, in a temperature range of 30 to 1000 ° C and with a heating rate of 30 ° C / minute. The main results are shown in Table 1 and in Figure 1, specifically intended to represent thermogravimetry records in standard alumina crucible without lid at 30 ° C / minute.

Table 1 Thermogravimetry records in standard alumina crucible without lid at 30 ° C / minute.

Sample Typical lost mass

(%) (° C)

AZI.PA 5.3 (5.3) 110

80.9 255

5.8 420

10.3 570

AZI.PB 5.8 (5.8) 100

82.5 255

11.0 555

AZI.F 5.0 (4.7) 110

80.6 255

5.4 410

11.8 565

In the records of AZI. PA (5154), AZI.PB (5156), AZI.F (5153) the initial part is analyzed again (Figure 2), first jump, corresponding to the loss of water. In Figure 2, representative of the initial zone of the thermogravimetry records, it is possible to observe the difficulty of evaluating this loss, which, on the one hand, is superimposed on the initial transitory heating (weight gain) and, on the other, The baseline at the end of the loss is not horizontal. The initial rise is eliminated due to the stabilization of the balance and a corrected value is obtained, which is indicated in parentheses in Table 1. Table 2 shows the comparison of this value with that obtained by Karl-Fisher. The theoretical value of water content of azithromycin dihydrate is 4.6%.

Table 2

Karl-Fisher (% TGA (% water) water)

AZI.PA 5.1 5.3

AZI.PB 3.4 5.7

AZI.F 4.9 4.7 These results show that the value in water content of AZI.PB is lower than the theoretical when determined by Karl-Fisher but higher than the theoretical when determined by TGA. This result shows that AZI.PB is not a stable dihydrate.

Differential scanning calorimetry DSC

The temperature and rate of water loss depends on the temperature and the partial pressure of the water vapor on the sample. Therefore, there is a great influence of the conditions of registration on the results obtained. Consequently, it has been necessary to establish the appropriate registration conditions in DSC for the samples to be studied. Different tests have been tested which include: - At atmospheric pressure registers in standard aluminum crucible with the lid perforated at 10 ° C / minute with a dry nitrogen sweep at 100 ml / minute. - Atmospheric pressure records in standard crucible of aluminum with the lid perforated at 20 ° C / minute with a dry nitrogen scan at 100 ml / minute (shown in Figure 3).

Records under 30 bar of dry nitrogen pressure (represented in Figure 4).

Registers in capillary crucible (represented in Figure 5).

All records made at atmospheric pressure with standard aluminum crucible with perforated lid have been made on a Mettler-Toledo Star ^e instrument, DSC821 and have wide, slightly resolved peaks. The best results are obtained with a heating rate of 20 ° C / minute (Figure 3). This fact is typical of phenomena associated with the loss of volatiles.

The atmospheric pressure recording with standard aluminum crucible with a perforated lid at 20 ° C / minute of the sample indicated as AZI.PA presents the endotherm of fixation at 129 ° C, a value compatible with the 127 ° C described in AZI. PA, while AZI.F, according to the present invention, the present invention, presents it at 139 ° C.

The records obtained under 30 bar of nitrogen pressure (Figure 4 and Table 3) have been performed on a Mettler-Toledo Star ^e instrument, DSC27HP. They have a better resolution than those made at atmospheric pressure and would already allow in principle to differentiate between the different crystalline forms. The AZI.F form, object of the present invention, also has the melting peak above 140 ° C, while that obtained according to Example A described in European Patent EP-A-298,650 ci- All previously done at a clearly lower temperature.

Table 3

DSC records made at 10 ° C / minute in standard open aluminum crucible, under 30 bar of nitrogen

ΔH Typical Sample (J / g) (° C)

AZI.PA 85.1 135.9

AZI.PB 61.4 100.8

AZI.F 84.5 141.7

The records in the closed flame capillary crucible make it possible to clearly differentiate between the crystalline forms and rule out possible mixtures between them. A Mettler-Toledo Star ⁸ , DSC821 instrument with a scanning speed of 10 ° C / minute and a modification of the crucible design proposed by Whiting et al. (Whiting, L., Labean, M. and Eadie, S .; Thermochimica Acta, 136 (1988), 231-245) with the characteristics shown in Figure 5, and which are the following: the constituent material of the support it is gold, and its thickness is 0.2 itira; - the constituent material of the capillary is glass, and its thickness is 0.15 mm; The measurements are: a = 5.6 mm b = 2.3 mm c = 9-11 mm d = 1.8 mm The results are presented in Table 4 and Figure 6.

Table 4 DSC records made in capillary crucible

ΔH Typical Sample (J / g) (° ^c )

AZI.PA 134.8 139.3

AZI.PB 13.3 110.5

25.9 120.5

23.9 143.8

AZI.F 67.7 142.4

Said records show that the azithromycin dihydrate object of the present invention (AZI.F) has an endotherm that is located, in all types of records tested, at a temperature higher than that of the azithromycin dihydrate obtained according to procedure A described by DJM Alien and KM Nepveux (Pfizer Inc.) in European Patent EP-A-298,650 (AZI.PA). The above records show the anomalous behavior of the AZI.PB sample obtained according to procedure B of said patent.

In particular, the azithromycin dihydrate object of the present invention has the endotherm at 143.7 ± 0.5 ° C with a heat of fusion of 54.6 + 1.6 J / g, when recorded in a capillary crucible with a velocity of heating of 10 ° C / minute. Under these conditions, azithromycin dihydrate obtained according to procedure A described by DJM Alien and KM Nepveux (Pfizer Inc.) in European Patent EP-A-298,650 (AZI.PA) presents an endotherm at 139 ° C with a heat of fusion of 135 J / g.

To demonstrate the repeatability of the crystallization process, samples from different batches are recorded in capillary crucible and at 10 ° C / minute with the results of Table 5.

Table 5

DSC records of the repeatability tests of the crystallization method No. Or- ΔH Tpico

Sample den (J / g) (° C)

AZ016 5794 53.4 143.9

AZ017 5795 55.0 143.4

AZ019 5792 54.8 143.0

AZ020 5793 55.1 143.7

Consequently, it can be concluded that the process of recrystallization of the azithromycin described in this patent repeatedly renders a dihydrated polymorphic form different from that claimed in European Patent EP-A-298,650. In addition, the polymorphic form of azithromycin dihydrate object of this invention turns out to be the thermodynamically more stable, since the endotherm is produced at a higher temperature.

Said higher thermodynamic stability is also reflected in the greater stability of the azithromycin dihydrate object of the present invention against moisture. Indeed, as explained above, The water content of azithromycin dihydrate obtained according to European Patent EP-A-298,650 is essentially constant at relative humidity of 33% and 75%, at least 4 days, in the theoretical content of 4.6%. At a relative humidity of 100% the moisture content rises to 5.2% and remains constant for the next three days. For its part, the azithromycin dihydrate object of the present invention maintains the humidity between 4.0 and 5.0% for at least 64 days under forced conditions of 70% humidity. In conditions of relative humidity of 95% it remains stable for at least 21 days.

Experimental part Azithromycin dihydrate AZI.PA and AZI.PB samples have been obtained following procedures A and B of European Patent EP-A-298,650 by D. J. M. Alien and K. M. Nepveux (Pfizer Inc.).

AZI.F

In a 1 1 glass flask, 290 ml of acetone are introduced and 165 g of crude azithromycin monohydrate are added. The mixture is stirred for 30-4 minutes at 18-25 ° C until complete dissolution. Then 1 g of activated carbon is added and stirred for 15 minutes. The solution is then filtered and the activated carbon is washed with 30 ml of acetone. The filtrate is heated with stirring at 35-40 ° C and then 72 ml of distilled water is added for 30-40 minutes maintaining the temperature. It is then left for 2 h with stirring during which an abundant precipitate appears (said precipitation can be favored by seeded with azithromycin dihydrate from a previous operation). Subsequently, a new addition of 480 ml of water is made for 2 h keeping the mixture at 35-40 ° C. Finally, the resulting mixture is left for 8 h at said temperature. The resulting mixture is slowly cooled to 5 ° C and maintained at this temperature for 1 h. It is then filtered and the resulting solid is washed with 300 ml of distilled water. The solid is dried at 35-40 ° C in an oven with an air flow to constant weight. 115 g of azithromycin dihydrate are obtained. Said polymorphic form has an endotherm at 139 ° C when registered in an open aluminum crucible with a heating rate of 20 ° C / minute. The IR spectrum recorded in KBr is shown in Figure 7.

Claims

1. Polymorphic form of azithromycin dihydrate (9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A) characterized by presenting an endotherm in differential scanning calorimetry (DSC) at 139 ° C, when recorded in open crucible of aluminum with a heating rate of 20 ° C / minute, and presents it at 143.7 ± 0.5 ° C with a heat of fusion of 54.6 ± 1.6 J / g, when recorded in a capillary crucible with a heating rate of 10 ° C / minute.

2. Method for obtaining the polymorphic form of azithromizine dihydrate of claim 1, characterized in that according to it, azithromycin monohydrate is treated with acetone followed by the addition of water at 35-40 ° C, after stirring at said temperature with seeding optional crystals of said polymorph and subsequent addition of water followed by cooling to 5 ° C.