WO2000077017A1

WO2000077017A1 - Novel amorphous form of clarithromycin

Info

Publication number: WO2000077017A1
Application number: PCT/IB2000/000762
Authority: WO
Inventors: Naresh Kumar; Mohammad Salman; Kiran Kumar Gangakhedkar
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 1999-06-11
Filing date: 2000-06-07
Publication date: 2000-12-21
Anticipated expiration: 2001-12-11
Also published as: AU4942800A

Abstract

This invention relates to novel amorphous form of 6-0-methylerythromycin A (Clarithromycin), to a process for the preparation thereof and to a composition containing it.

Description

NOVEL AMORPHOUS FORM OF CLARITHROMYCIN

FIELD OF THE INVENTION

This invention relates to novel amorphous form of 6-0-methylerythro-

mcyin A (Clarithromycin), to a process for the preparation thereof and to a

composition containing it.

BACKGROUND OF THE INVENTION

6-0-methylerythromycin A (Clarithromycin) is a second generation

semi-synthetic macrolide antibiotic which exhibits excellent antibacterial

activity against gram-positive bacteria, some gram-negative bacteria,

anaerobic bacteria, Mycoplasma, and Chlamydia. Furthermore, it has greater stability at physiologic pH which renders it as a superior alternative to its

parent compound, erythromycin. Clarithromycin is a useful therapy for

infections of the upper and lower respiratory tract, for infections due to

Chlamydia, Mycoplasma, and legionella, for infections of soft tissue, and for the eradication of H. Pylori (when used in combination with acid suppressing

agents).

It is well known that different morphs of biologically active compounds,

which exist in the solid state, could potentially have quite different absorption profile in vivo and consequently different pharmacokinetic profile. Two distinctly different forms of Clarithromycin (Forms I and II) have been described in two U.S. patents, Nos. 5,838,986 and 5,844,105. Furthermore, these U.S. patents describe that these two forms have very different intrinsic dissolution rates; Form-I showed three-times faster intrinsic dissolution rate as compared with Form-ll. The present invention describes an amorphous form of Clarithromycin which has an even better intrinsic dissolution and methods of preparing such a Clarithromycin in this, hitherto unknown, solid form which would be essentially free of any crystallinity.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, there is provided clarithromycin in an amorphous form.

Clarithromycin in an amorphous form is prepared by an efficient process which is a further aspect of the present invention and which comprises dissolving crystalline clarithromycin (Form I or Form II) in a solvent followed by recovering amorphous form from its solution by spray drying or by grinding action between the two surfaces.

The amorphous clarithromycin thus obtained may be formulated with one or more pharmaceutical carriers or excipients.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an infrared spectrum showing peaks characteristic of amorphous clarithromycin. Figure 2 is an X-ray powder diffraction (XRD) pattern of amorphous clarithromycin.

Figure 3 is an infrared spectrum showing peaks characteristic of crystalline Form I of clarithromycin obtained per U.S. Patent No. 5,838,986.

Figure 4 is an infrared spectrum showing peaks characteristic of crystalline Form II of clarithromycin obtained per U.S. Patent No. 5,844,105.

Figure 5 is an XRD pattern showing peaks characteristic of crystalline form I of clarithromycin obtained per U.S. Patent No. 5,838,986.

Figure 6 is an XRD pattern showing peaks characteristic of crystalline form II of clarithromycin obtained per U.S. Patent No. 5,844,105.

DETAILED DESCRIPTION OF THE INVENTION

Clarithromycin in new amorphous form is obtained by a process which comprises dissolving crystalline clarithromycin (Form-I or Form-ll) in a solvent followed by recovering amorphous form of clarithromycin from the solution thereof by spray drying or by grinding action between two surfaces.

The term "solvent" includes ketones, chlorinated solvents, ethers, esters, alcohols, or mixture(s) thereof. Preferably, the solvent may be selected from the group consisting of acetone, dichloromethane, chloroform, tetrahydrofuran, 1 ,4-dioxane, ethyl acetate, methanol, ethanol or mixtures thereof. In a preferred embodiment of the invention, clarithromycin is recovered from the solution in an amorphous form using a spray drying technique. The mini-spray Dryer (Model: Buchi 190, Switzerland) which operates on the principle of nozzle spraying in a parallel - flow, i.e. the sprayed product and the drying gas flow in the same direction. The drying gas can be air or inert gases such as nitrogen, argon, or carbon dioxide. Nitrogen is preferred in this case.

In another embodiment the crystalline clarithromycin is milled by grinding action between two surfaces till the time we get amorphous clarithromycin essentially free of any crystallinity. Such milling can be carried out by using a traditional technique of compounding using a pestle and mortar or by milling machines that essentially work on the same principle. Examples of such milling machines include various makes of ball mills, roller mills, gyratory mills, and the like.

Amorphous clarithromycin prepared according to the process of the present invention may be characterized by its infra-red spectrum (Figure 1) and by its X-ray powder diffraction pattern (Figure 2). The infra-red spectrum (Figure 1) obtained for the sample, prepared by the process of the present invention, is different from the infra-red spectra of crystalline forms (I and II) (Figure 3 and Figure 4) of Clarithromycin. X-ray powder diffraction patterns of the newly prepared form also gave a plain halo (Figure 2) and show no peaks which are characteristic of the crystalline forms I and II of Clarithromycin (Figure 5 and Figure 6), thus demonstrating the amorphous nature of the product.

The present invention is illustrated by the following examples which are not intended to limit the effective scope of the claims.

EXAMPLE 1

Preparation of amorphous clarithromycin by Spray Drying using

crystalline clarithromycin.

Crystalline Clarithromycin (50 g) was dissolved in acetone (1200 ml) at

25-30^δC. The clear solution thus obtained was subjected to spray drying in mini-Spray Dryer (Buchi Model 190) at an inlet temperature of 71 °C and outlet temperature of 58 °C with a feed rate of 15 ml per minute.

Clarithromycin (40 g) in an amorphous form was thus isolated.

X-ray powder diffraction pattern (Figure 2), shows a plain halo thus demonstrating the amorphous nature of the product. Infrared spectrum in KBr (Figure 1), is different from the IR spectra for Forms-I and II, as shown in

Figure 3 and Figure 4.

EXAMPLE 2

The process of Example 1 was repeated with crystalline clarithromycin (100 g) using dichloromethane (600 ml) instead of acetone to give amorphous clarithromycin (83 g) IR (KBr) and X-ray crystallography confirmed that the material was amorphous. EXAMPLE 3

10g of crystalline clarithromycin was subjected to grinding using an agate pestle and mortar for a period of 10 hours to get amorphous clarithromycin essentially free of crystallinity. IR (KBr) spectrum and X-ray crystallo- graphy examination confirmed the amorphous nature of the product.

Claims

WE CLAIM:

1. An amorphous form of clarithromycin essentially free of any crystallinity.

2. A pharmaceutical composition containing a therapeutically effective amount of compound of claim 1 with one or more pharmaceutical carriers or excipients.

3. A process for the preparation of clarithromycin in an amorphous form which comprises dissolving crystalline clarithromycin in a solvent and recovering amorphous form of clarithromycin from said solution by spray drying.

4. The process of claim 3 wherein the solvent is selected from the group consisting of ketones, chlorinated solvents, ethers, esters, alcohols and mixtures thereof.

5. The process of claim 4 wherein the solvent is selected from the group consisting of acetone, dichloromethane, chloroform, tetrahydrofuran, 1- 4-dioxane ethylacetate , methanol, ethanol and mixtures thereof.

6. The process of claim 5 wherein the preferred solvent is selected from the group consisting of acetone, dichloromethane, chloroform, methanol and ethanol.

7. A process for preparing amorphous clarithromycin by subjecting the crystalline clarithromycin to milling until said crystalline clarithromycin is converted to amorphous form essentially free of crystallinity.

8. The process of claim 7 wherein said milling comprises grinding crystalline clarithromycin between two surfaces.

9. The process of claim 7 wherein said milling comprises reducing the size of the particles by collisions among said particles and with machine surface to get amorphous clarithromycin essentially free of crystallinity.