The present invention relates to a process for the preparation of a highly pure predominantly amorphous form of cefuroxime axetil in admixture with pharmaceutically acceptable excipients.
Cefuroxime axetil is 1-acetoxy ethyl ester of cefuroxime, a cephalosporin antibiotic with a broad spectrum of actvity against gram-positive and gram-negative microorganisms. US Patent No. 4,562,181 (Dec 31, 1985) disclosed cefuroxime axetil in a highly pure substantially amorphous form and described methods of spray drying, solvent precipitation and freeze-drying for preparing the amorphous proc1, ct from a solution thereof containing organic solvents. The preferred method involved spray drying. The product had a purity of atleast 95 %. The prior art also disclosed that the amorphous form had a higher bioavai1abi1ty than the crystalline form and had adequate chemical stability.
US Patent No. 4,820,833 (April 11, 1989) claimed a process for preparing a highly pure, substantially amorphous form of cefuroxime axetil which comprises preparing a highly pure solution of cefuroxime axetil and spray drying the said solution to recover highly pure substantially amorphous cefuroxime axetil.
US Patent No. 5,013,833 (May 7, 1991) claimed a process for the preparation of highly pure cefuroxime axetil in predominantly amorphous form by recovering cefuroxime axetil from a solution thereof containing organic solvents, by solvent precioitat ion.
US Patent No. 4,994,567 (Feb 19, 1991) claimed a process for the
preparation of highly pure cefuroxime axetil in predominantly
amorphous form wherein cefuroxime axetil is recovered from a
solution thereof by roller drying.
It is an object of the present invention to obtain a highly pure substantially amorphous form of cefuroxime axetil in admixture with pharmaceutical1y acceptable excipients without the use of organic solvents. This provides obvious benefits with respect to safety, health and environmental considerations. In the pharmaceutical industry, particularly, a lot of emphasis is laid to limit the residual solvents for the safety of patients. The liiftorphous product obtained would be at least as free of residual solvents as the starting crystalline material.

Accordingly the present invention provides a process for the preparation of a substantially amorphous form of cefuroxime axetii containing atleast 95 % amorphous cefuroxime axetii which process comprises mixing crystalline cefuroxime axe with atleast one pharmaceutical1y acceptable excipient selected from the group consisting of sodium lauryl sulphate, colloidal silica, talc, sodium chloride, starch, calcium carbonate and mixtures thereof in the ratio of 1 : 20 to 100 : 1 and subjecting said mixture to milling until said crystalline cefuroxime axetii is converted to substantially amorphous form.
The pharmaceutical1y acceptable excipients can be one or more of any known inert solid materials used in the formulation of dosage forms. Pharmaceutical excipients well known in the pharmaceutical art can be found listed in Pharmaceutical Excipients Handbook, FDA listing of inactive ingredients, and other sources of pharmaceutical literature. Examples of such excipients include sodium chloride, calcium carbonate, lactose starch, microcrystal1ine cellulose, colloidal silica, talc, sodium lauryl sulphate, and the like.
According to the present invention, cefuroxime axetil in a highly pure, substantially amorphous form having a chromatographic purity of at least 95% is obtained in admixture with pharmaceutically acceptable excipients.
In accordance with one aspect of the present invention, the mixture of crystalline cefuroxime axetil and excipient(s) is milled by grinding action between two surfaces of the mill. Such milling has been traditionally symbolic of pharmacy practice wherein medicaments were compounded using a pestle and mortar. According to the invention mills that work on substantially the same principle are used in the process. Examples of such mills include various makes of ball mills, roller mills, gyratory mills, and the like.
In a more preferred embodiment of the invention, a mill such as a Micros Super Fine Mill (Nara Machinery Co., Ltd, Japan). Depending on the size of the mill, the speed of rotation of the main shaft and the effective volume of the grinding chamber may vary. The effective volume of the grinding chamber may be in the range from 0.45 liters to 30 liters. For low capacity mills (Micros '0', capacity 0.45 liters; Micros 5, capacity 4.8 liters) the speed of rotation of the main shaft is typically in the range from about 500 rpm to 2000 rpm.
According to the invention, the Micros Super Fine Mill is typically charged with a mixture of crystalline cefuroxime axetil and excipient(s) such that from about 10% to 30% of the effective volume of the grinding chamber is occupied. Examples of methods of transferring materials well known in the art include manual transfer, gravity feed, pneumatic (using high velocity air stream) conveying and vacuum transfer. Such methods, well known in the art, may be used with the process of this invention to charge the feed material into the grinding volume available between the bowl and the subshafts. For satisfactory operation of the Micros Super Fine Mill, the drug and the pharmaceutically acceptable excipient may be mixed in a wide range of ratios, for example, from 1:20 to 100:1, however, in preferred embodiments of the invention the ratio is from 24:1 to 2:1, more preferably from about 15:1 to 5:1. The pharmaceutically acceptable excipient acts as a diluent interposing itself between drug particles thus preventing the consolidation or bonding between drug particle surfaces.
The pharmaceutically acceptable excipients useful in the present invention include, but are not limited to, sodium lauryl sulphate, talc, colloidal silica, sodium chloride, calcium carbonate, starch and mixtures thereof. In more preferred embodiments the pharmaceutically acceptable excipient is selected from sodium lauryl sulphate, colloidal silica and mixtures thereof. In a more preferred embodiment of the invention the cefuroxime axetil is milled in the Micros Super Fine Mill together with sodium lauryl sulphate (10% w/w) and colloidal silica (2% w/w).
The period of milling using the Micros Super Fine Mill may vary depending on the size of the mill, the speed of rotation of the main shaft, the type and the quantity of material to be milled. The effects of these variables are well known in the art and the invention may be worked over a range of these variables. Typically the period of milling may range from about 15 min. to 300 min.
Generally, the drug and pharmaceutically acceptable excipient(s), in a ratio from 15:1 to 5:1, are milled together in a Micros '0' Super Fine Mill for about 120 min. with speed of rotation of the main shaft in the range from about 800 to 2000 rpm.
The drug and pharmaceutically acceptable excipient(s), in a ratio from 15:1 to 5:1, are milled ogcthcr in a Micros '5' Super Fine Mill for a period from about 90 to 240 min. with speed of -otation of the main shaft in the range from about 400 to 700 rpm.
According to preferred embodiments of the invention the crystalline cefuroxime axetil is milled by grinding action between surfaces such that the particle size of the particle in the milled material is reduced to less than 2um.
According to another aspect of the invention the mixture of crystalline cefuroxime axetil and excipicnt(s) is subjected to milling involving attrition of the particles of the said mixture by collisions with other particles of the mixture or with machine surfaces. An example of such a mill is a Nara Hybridization System, (Nara Machinery Co., Ltd., Tokyo, Japan).
According to the invention the Nara Hybridizing System is operated by milling a mixture of crystalline cefuroxime axetil and pharmaceutically acceptable excipients in ratios from about 1:7 to 3:2, more preferably from 1:4 to 1:1. In more preferred embodiments of the invention 3 parts of crystalline cefuroxime axetil together with 7 parts of starch are subjected to milling in a Nara Hybridization System. The period of milling may vary depending on the size of the mill, the velocity of the blades, the type and the quantity of material to be milled. The period of milling may typically range from about 30 min. to 240 min.
The present invention is illustrated by the following examples which are not intended to limit the effective scope of the claims.
Examples 1 to 9 illustrate the process of obtaining cefuroxime axetil in a highly pure substantially amorphous form by milling involving grinding of its mixture with pharmaceutically acceptable excipient(s) between two surfaces. Example 10 illustrates the process of obtaining cefuroxime axetil in an amorphous form by milling involving attrition of particles of the said mixture by collisions with other particles of the mixture or with machine surfaces.
EXAMPLE 1
1.4g of crystalline cefuroxime axetil S isomer and 0.6g of sodium chloride were subjected to grinding using an agate pestle and mortar for a period of 10 hrs. X-ray diffractions of crystalline cefuroxime axetil S isomer, sodium chloride and the milled sample are given in Figures 1, 2 and 3, of the accompanies respectively drawings. The XRD patterns show that the peaks characteristic of the crystalline form of cefuroxime axetil were either significantly decreased in intensity or absent. The XRD patterns thus demonstrate that cefuroxime axetil was converted to a predominantly amorphous form. The chromatographic purity was determined by HPLC and was found to be 99.31%.
EXAMPLE 2
30g of crystalline cefuroxime axetil S isomer with a particle size, 10-300 um, and bulk density, 0.391g/cc, together with 3g of sodium lauryl sulphate (SLS) was placed in the bowl of a Micros '0' Super Fine Mill. Cold water was circulated through the outer jacket. The mill was operated with main shaft rotation set at 1000 rpm for 120 min. The inner temperature was maintained in the range from 19-24 °C. The process details are given in Table 1 herein. The milling proceeded smoothly during the run with the powder blend exhibiting good flow within the milling chamber. Samples of the material were examined by scanning electron microscopy and by X-ray diffraction crystallography. The particle size was found to be reduced to less than 2 um. The X-ray diffraction of the milled material is given in Figure 4 of the accompany drawings. The XRD pattern show that the peaks characteristic of the crystalline form of cefuroxime axetil were cither significantly decreased in intensity or absent. The XRD pattern thus demonstrates that
cefuroxime axetil was converted to a predominantly amorphous form. The total impurities (related substances) as determined by HPLC were found to be 1.129 % m/m.
EXAMPLES 3-9
The crystalline cefuroxime axetil S isomer with a particle size, 10-300 jam, and bulk density 0.391g/cc, a mixture of crystalline ot-f uocime axetil S isomer with crystalline cefuroxime axetil R isomer with a particle size 5-50 µm, and bulk density 0.221g/cc and the crystalline cefuroxime axetil RS racemic mixture were tested for conversion from the crystalline form to an amorphous form in different trials. The process details are given in Table 1. The feed material consisted of cefuroxime axetil together with sodium lauryl sulphate or cefuroxime axetil together with sodium lauryl sulphate and colloidal silica (Aerosil 200). Samples of the material were withdrawn at various timesfor X-ray diffraction crystallography using a XRG 3000 diffractometer and for scanning electron photomicrography. X-ray diffraction patterns of the samples are given in Figures 5 to 11 of the accompanying drawings Peaks characteristic of the crystalline form of the corresponding isomer of cefuroxime axetil were either significantly decreased in intensity or absent. The XRD patterns thus demonstrate that as milling was continued, the degree of crystal 1inity progressively decreased until cefuroxime axetil was converted into a predomi¬nantly amorphous form. The total impurities (related substances) as determined by HPLC are given in Table 1 herein.
EXAMPLE 10
30 g of crystalline cefuroxime axetil RS racemic mixture and 70 g of potato starch were processed in a Nara Hybridization System NHS - 1 (Nara Machinery Co. Ltd., Japan), for 1 hr with the outer edges of the blades rotating at 80 ms""' . The inner surface of the hybridization chamber was cooled by water circulation through the outer jacket.The XRD pattern of the sample collected after 30 min, of milling is given in Figure 12 of the accompanying drawing The XRD pattern confirms the conversion of cefuroxime axetil into a substantially form. The total impurities (related substances) as determined by HPLC were found to be 2.803 % m/m.
The resultant substantially amorphous cefuroxime axetil admixed with one or more pharmaceutical1y acceptable excipients prepared by the process of the present invention, is not a mere admixture but has properties different from the sum total properties of the crystalline cefuroxime axetil and the said pharmaceutical1y acceptable excipient(s).
TABLE 1(Table Removed)

We claim :
1. A process for the preparation of a substantially amorphous form of Cefuroxime axetil containing at least 95 % of amorphous Cefuroxime axetil which process comprises mixing crystalline Cefuroxime axetil with at lease one pharmaceutically acceptable excipient selected from the the group consisting of sodium lauryl sulphate, colloidal silica, talc, sodium chloride, starch, calcium carbonate and mixtures thereof in the ratio of 1 : 20 to 100 : 1 and subjecting said mixture to milling until said crystalline Cefuroxime axetil is converted to substantially amorphous form.
2. A process as claimed in claim 1 wherein the milling involves grinding of the said mixture between two surfaces of the mi 11.
3. A process as claimed in claim 2 wherein the particle size of particles in the milled material is reduced to less than 2 AJm.
4. A process as claimed in claim 1 wherein the milling involves attrition of the particles of the said mixture by collisions with other particles of the mixture or with machine surfaces.
5. A process for the preparation of a substantially amorphous form of Cefuroxime axetil substantial 1 as herein described and illustrated by the examples herein.