Method of preparing form II crystals of clarithromycin

Details Method of preparing form II crystals of clarithromycin Method of preparing form II crystals of clarithromycin

2000-10-20

2002-09-03

Peselev, Elli (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S018500

Reexamination Certificate

active

06444796

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a method of preparing pure Form II crystals of clarithromycin in a high yield; and crystalline clarithromycin formate used therein.
BACKGROUND OF THE INVENTION
Clarithromycin, 6-O-methylerythromycin A, is a semisynthetic macrolide antibiotic of formula (I) which exhibits strong antibacterial activity toward a wide range of bacteria inclusive of gram positive bacteria, some gram negative bacteria, anaerobic bacteria, Mycoplasma, Chlamidia and
Helicobacter pylori
, and because of its high stability in the acidic environment of the stomach, it can be orally administered to treat respiratory organ diseases, and also to prevent recurrence of ulcer when used in a combination with other medicines:
It has been discovered that clarithromycin exists in at least three distinct crystalline forms, “Form 0”, “Form I” and “Form II”, as described in International Publication Nos. WO 98-04573, WO 98-04574 and WO 98-31699. The crystal forms can be identified by infrared spectroscopy, differential scanning calorimetly and powder X-ray diffraction spectrophotometry. Form II, which is thermodynamically more stable than Form I, is used in the drug formulations currently on the market, and Form 0 is a solvate having an incorporated crystallizing solvent molecule.
Form II crystals clarithromycin have been typically prepared by any of three methods, as summarized in the schematic drawing of FIG.
3
:
Method 1) is to heat Form 0 or Form I crystals under a vacuum at a temperature ranging from 70 to 110° C. for a prolonged period of time to prepare Form II crystals (see International Publication Nos. WO 98-04573 and WO 98-31699), but this method has the problem of low productivity and high cost.
Alternatively, in Method 2), Form II crystals may be obtained by recrystallizing Form I crystals from chloroform/isopropyl ether (1:2) (see Merck Index 12th ed., pp. 395). In addition, in Method 3), Form II crystals may be obtained by recrystallizing Form I crystals from an organic solvent such as alkanol (except ethanol and isopropanol); hydrocarbon; ketone; carboxyl ester (except isopropyl acetate); ether; substituted or non-substituted benzene; an aprotic polar solvent; amine; a water-miscible organic solvent or a mixture of a water-miscible alkanol and water; a mixture of methanol and hydrocarbon, alkanol, ketone, carboxyl ester, ether or substituted or non-substituted benzene; a mixture of hydrocarbon and ketone, carboxyl ester, ether or substituted or non-substituted benzene, or a mixture of said organic solvent and water (see International Publication Nos. WO 98-04574).
However, Methods 2) and 3) have a problem in that because the conversion step of Form I to Form II does not enhance the clarithromycin purity, Form I crystals having an pharmaceutically allowable purity must be prepared in advance from crude clarithromycin, at the expense of reduced clarithromycin yield and high manufacturing cost. Further, Method 3) employs a hot-filter during the recrystallization step, but hot-filtration is not suitable for mass-production.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of the present invention to provide a high yield process for preparing Form II crystals of clarithromycin of a high purity.
In accordance with one aspect of the present invention, there is provided a method of preparing Form II crystals of clarithromycin of formula (I) comprising the steps of: (a) treating clarithromycin with formic acid in an organic solvent to give crystalline clarithromycin formate of formula (II) and (b) neutralizing the clarithromycin formate with a base in a mixture of water and a water-miscible organic solvent:


REFERENCES:
patent: 5274085 (1993-12-01), Amano et al.
patent: 5844105 (1998-12-01), Liu et al.

Affiliated with

Also associated with

Rating

Method of preparing form II crystals of clarithromycin does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Method of preparing form II crystals of clarithromycin, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method of preparing form II crystals of clarithromycin will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2873931