Technical Field of the Invention
The invention relates to an amorphous form of Cefditoren pivoxil, which has improved solubility; and a process for the preparation of amorphous Cefditoren pivoxil.
Background of the Invention
'Cefditoren' is the generic name of a cepham compound {chemical name: 7-[2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (syn-isomer, cis-isomer)}. Cefditoren synthesis is disclosed in U.S. Pat. Nos. 4,839,350 and 4,918,068; and an injectable Cefditoren preparation is disclosed in U.S. Pat. No. 5,595,986. Cefditoren pivoxil, synthesized by forming a pivaloyloxymethyl (pivoxil) ester with cefditoren at the carboxylic acid moiety, exhibits better oral absorption and is quickly hydrolyzed to cefditoren by enzymatic esterases upon absorption.
Cefditoren exhibits a broad antibacterial spectrum relatively having low toxicity and is very useful for the therapy and prophylaxis of diseases induced by gram-positive and gram-negative bacteria. Cefditoren pivoxyl is, by itself, antibacterially inactive but is useful as a pro-drug which is administrable orally and can be converted into the antibacterially active Cefditoren in the digestive tubes of mammals, with cleaving the ester-forming pivaloyloxymethyl group therefrom.
Crystals of Cefditoren pivoxil are known to have high purity, high heat stability and in addition satisfactory stability even when stored under high humidity conditions (US patent No. 6,294,669). However crystals of Cefditoren pivoxil, have low solubility in water and thus have not been very suitable for oral administration. Low-solubility or dissolution rate drugs often show poor bioavailability or irregular absorption, the degree of irregularity being affected by factors such as dose level, fed state of the patient, and form of the drug.
Over the years, compositions and methods have been developed to achieve improved solubility of such poorly or sparingly soluble drugs. Amorphous substances are generally known to have smaller energy necessary for dissolution, than the corresponding crystalline substances. Therefore, the conversion of crystalline form of Cefditoren pivoxil sparingly soluble in water to an amorphous substance having high water solubility leads to the expectation of improved usefulness of Cefditoren pivoxil in the therapy of diseases.

US Appl. No 2003/0060451 discloses the method of preventing the premature de-esterification
of pro-drug esters and enhancing the oral bioavailability by formulating the prodrug ester i.'c;
cefditoren pivoxil in a non-emulsified formulation with lecithin. ;
One of the reported methods involves the conversion of a medicinal compound sparingly soluble in water into an amorphous substance, thus to improve the solubility of the compound in water. Conversion of crystalline form of Cefditoren pivoxil to amorphous substance leads to high water solubility and improves the usefulness of Cefditoren pivoxil in the therapy of disease.
US Patents No's 6,342,493 and 6,486,149 disclose the conversion of crystalline Cefditoren pivoxil to amorphous form. In this method the crystalline Cefditoren pivoxil is dissolved in an acidic aqueous solution containing a water-soluble polymeric additive, the acidic aqueous solution is then neutralized to coprecipitate Cefditoren pivoxil together with the water-soluble polymeric additive, and the precipitate is then collected, washed and dried. According to this method a yellow colored powdery composition comprising solid particles of an intimate mixture of an amorphous form of Cefditoren pivoxil having a high level of dissolvability in water and high heat stability with the water-soluble polymeric additive (0.5 to 5%) can be provided. This method however involves many steps and thus requires process control and relatively lot of time.
EP 0629404 discloses a pharmaceutical composition comprising cefditoren pivoxil and a wate'i: soluble polymer like hydroxypropylcellulose. This preparation showed improved wettability, dispersibility and absorbability without increasing its bitterness. Improved dispersibility and absorbability was also shown by composition containing cefditoren pivoxil and B-cyclodextrin along with an ionic surfactant in a pharmaceutically acceptable carrier (EP 0339465).
US Appl. No. 2006/0051411 discloses a pharmaceutical composition comprising amorphous cefditoren pivoxil and a sugar ester fatty acid, which is obtainable by mixing or wet-granulating particles containing amorphous cefditoren pivoxil with the sugar ester fatty acid while
amorphous cefditoren pivoxil maintains its particle state.
'
WO 02/87588 discloses another method of conversion of crystalline cefditoren pivoxil to amorphous form by grinding crystalline cefditoren pivoxil in the presence of a pharmaceutically acceptable organic polymeric compound.

All the above methods, however, involves many steps and thus requires process control and
relatively lot of time. Therefore, the above methods are not necessarily satisfactory from the viewpoint of production efficiency.
Further, in order to satisfy safety concerns, the regulatory agencies generally require a manufacturing specification that sets the maximum amount of each identified impurity as well as the maximum amount for all remaining unidentified impurities. Once approved, each batch or lot of the pharmaceutical product is tested to ensure that the specification is met. Further, stability testing is performed on the pharmaceutical product in order to show that the composition does not substantially or materially change over time; i.e. over its indicated shelf-life. It is important that before the administration of a pharmaceutical product to a patient it does not deviate from its approved specification in a way that might detract from its safety or efficacy.
Accordingly, pharmaceuticals are tested for purity both during manufacture and subsequently
during its shelf-life. Typically, the product is tested by comparing certain analytical results with
those of a standard reference result. For impurity detection, this normally means assaying the
pharmaceutical product and comparing the result to the result obtained for a substantially puro
form of the suspected impurity in the same assay. •
In the present invention we have found that amorphous Cefditoren pivoxil with minimal quantity of impurity can be obtained by a simplest technique, by homogenizing water insoluble carrier and crystalline Cefditoren pivoxil in a solvent and removing the solvent.
Summary of the Invention
The object of present invention is to provide an amorphous Cefditoren pivoxil, which has related substances (RS) profile less than 2% w/w, and also a process for the preparation of the same. .;•
It is one of the aspects to provide a process for preparing an amorphous Cefditoren pivoxil. comprising the steps of:
(i) homogenizing one or more water insoluble carriers in a solvent,
(ii) preparing a solution of crystalline Cefditoren pivoxil in solvent,
(iii) adding solution of step (i) to solution of step (ii), and
(iv) removing the solvent,

wherein the total related substances present in the amorphous Cefditoren pivoxil is less than 2'.0
% w/w.
Embodiments of the process may include one or more of the following features. For example, the solution may be prepared in an organic solvent and may include one or more of ketones. such as acetone; alcohols, such as methanol, ethanol, isopropyl alcohol; chlorinated hydrocarbons, such as methylene chloride; and more particularly, the solvent is methylene chloride.
The water insoluble carrier may be one or more of cross-linked polyvinyl pyrrolidone, colloidal
silicon dioxide, microcrystalline cellulose, cross-linked sodium carboxymethylcellulose, starch,
carboxymethylcellulose calcium, calcium carbonate, dibasic calcium phosphate, and
combinations thereof and, in particular, the water insoluble carrier may be cross-linked
polyvinyl pyrrolidone or colloidal silicon dioxide, or combinations thereof. The weight ratio of
Cefditoren pivoxil to water insoluble carrier may be from about 1:0.1 to about 1:2. ,•
Embodiments involving removing the solvent may include, for example, one or more of spray drying, distillation, distillation under vacuum and evaporation.
It is another one of the aspects to provide a process for preparing an amorphous Cefditoren pivoxil, comprising the steps of:
(i) homogenizing one or more water insoluble carriers in methylene chloride,
(ii) preparing a solution of crystalline Cefditoren pivoxil in methylene chloride,
(iii) adding solution of step (i) to solution of step (ii), and
(iv) removing the solvent,
wherein the total related substances present in the amorphous Cefditoren pivoxil is less than 2.0 % w/w.
In another general aspect there is provided a process for preparing stable amorphous Cefditoren
pivoxil. ;r
The process may further include processing the mixture with one or more pharmaceutically inert excipients. The pharmaceutically inert excipients may be one or more of fillers, buffering agents, binders, disintegrants, coloring agents, flavoring agents, lubricants, glidants, plasticizers.

and preservatives. The process may further include forming one or more of a tablet, a capsule, and a powder.
In another general aspect there is provided a method for the treatment of bacterial infections in a mammal. The method includes administering a pharmaceutical composition that includes amorphous Cefditoren pivoxil and one or more water insoluble carriers, and one or more of pharmaceutically acceptable excipients.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and claims.
Detailed description of the Invention
The term 'amorphous' as used herein means a solid state in which Cefditoren pivoxil molecules gather together with a pharmaceutically acceptable organic polymeric compound without forming crystals having a regular special configuration, more specifically, a solid state in which the amorphous form can be confirmed by conventional powder X-ray diffractometry Specifically, the crystalline Cefditoren pivoxil exhibits sharp diffraction peaks, whereas the amorphous Cefditoren pivoxil and one or more water insoluble carriers according to the present invention does not substantially exhibit any X-ray diffraction peaks.
The amorphous Cefditoren pivoxil can be prepared by any of the methods known in the art for preparing amorphous Cefditoren pivoxil and also by methods described in our co-pending Indian Patent Application No's. 236/DEL/2004 and 207/DEL/2005, which is incorporated herein entirety. Each of these methods gives rise to producing different types of impurities in the end product, due to their different manufacturing process involved. Impurities in Pharmaceuticals are the unwanted chemicals that remain with the active pharmaceutical ingredients (APIs), or develop during formulation. The presence of these unwanted chemical even in small amounts may influence the efficacy, safety and stability of the pharmaceutical products.
Worldwide, regulatory agencies and international organizations like International Conference (In Harmonization (ICH), has started giving important critical attention on impurities and has published various guidelines on identification and monitoring of impurities, and allowed permissible levels of impurities should be present in the final APIs or formulations. Mostly

impurities originate due to side reactions of the manufacturing process and are generally structurally related to the drug substance, and this class of impurities called 'related substances'.
However, the related substances (RS) present in the final product have a greater impact on their stability. Amorphous Cefditoren pivoxil containing lesser RS profile proved to have greater
\ :
stability over longer duration of time.
The amorphous Cefditoren pivoxil prepared by the present invention has lesser RS profile compared to other exciting prior art methods. The total related substances present in the amorphous Cefditoren pivoxil of the present invention is less than 2.0% w/w.
In one embodiment, the amorphous Cefditoren pivoxil may be prepared by a process including steps of:
(i) homogenizing one or more water insoluble carriers in a solvent, '
(ii) preparing a solution of crystalline Cefditoren pivoxil in a solvent,
(iii) adding solution of step (i) to solution of step (ii), and
(iv) removing the solvent
The water insoluble carrier used may include one or more of cross-linked polyvinyl pyrrolidone. colloidal silicon dioxide, microcrystalline cellulose, cross-linked sodium carboxymethylcellulose, starch, carboxymethylcellulose calcium, calcium carbonate and dibasic calcium phosphate, and combinations thereof. More particularly, the water insoluble carrier is cross-linked polyvinyl pyrrolidone or colloidal silicon dioxide, or combinations thereof.
The weight ratio of cefditoren pivoxil to water insoluble carrier may vary from about 1:0.1 to
about 1:2. ;
The solvents used in the process comprise one or more of ketones, such as acetone; alcohols, such as methanol, ethanol, isopropyl alcohol; chlorinated hydrocarbons, such as methylene chloride. The total RS profile was significantly better with the use of methylene chloride as the solvent.

The spray dryer used for drying the solution may be any of the conventional spray driers known in the art including nozzle type, disc type or jet type. Based on the selection of spray dryer, the various process parameters may be varied.
The amorphous Cefditoren pivoxil of the present invention may be used as a bulk powder for the manufacture of a pharmaceutical composition comprising the amorphous Cefditoren pivoxil and pharmaceutically acceptable excipients.
The amorphous Cefditoren pivoxil according to the present invention may be used as antibacterial agents. Bacteria referred to herein include for example gram-positive bacteria such as staphylococcus and streptococcus, gram-negative bacteria such as Escherchia coli, Branhamella catarrhalis, Klebsiella, Proteus, and Haemophilus influenzae, and anaerobes such as Peptostreptococcus, Propiombacterium acnes, and Bacteriocides.
Further, it can be useful for the prophylaxis or therapy of diseases induced by gram-positive bacteria or gram-negative bacteria.
The amorphous Cefditoren pivoxil prepared as generally described above may be further processed with one or more pharmaceutically inert excipients to prepare pharmaceutical compositions.
The pharmaceutical composition according to the present invention may be used by any administration route so far as the high dissolvability of the amorphous Cefditoren pivoxil can be utilized, for example by oral administration, intraoral administration, parenteral administration, topical administration, or rectal administration. The pharmaceutical composition according to the present invention is particularly administered orally. Further, the pharmaceutical composition according to the present invention can be used as antibacterial agents.
The term "pharmaceutical composition" includes solid dosage forms such as one or more of tablets, capsules, and powders that are formulated by conventional methods of admixture such as one or more of blending, filling, and granulation. Of course, other formulation methods also may be used. The dosage form may be optionally coated with one or more film forming polymers.

The following examples illustrate various aspects of the present inventions. These examples are for illustration only and do not limit the scope of the inventions.
Preparation of Amorphous Cefditoren pivoxil
Example 1:

Colloidal silicon dioxide was homogenized in about 1/1 On of the solvent for one hour. To remaining quantity of solvent Crystalline Cefditoren pivoxil was dissolved and homogenized with carrier mixture for 20 minutes. The mixture was spray dried in the following conditions:
a. Inlet temperature (°C): 70-80
b. Outlet temperature: (°C): 50-55
c. Nozzle Diameter (mm): 1
d. Atomizing pressure (mm Hg): 35-40
e. Atmospheric condition: Under air
The spray dried amorphous Cefditoren pivoxil was dried at 60°C under vacuum for 4 hours. Example 2:

Colloidal silicon dioxide was homogenized in about 1/10th of the solvent for one hour. To remaining quantity of solvent Crystalline Cefditoren pivoxil was dissolved and homogenized with carrier mixture for 20 minutes. The mixture was spray dried in the following conditions:
a. Inlet temperature (°C): 70-80

b. Outlet temperature: ( C):

50-55

-9-

phi His ('eldiloreu pi\ oxil \\as dried al 60'(' under \ aeiium lor -I hours
Quantity
lal siikV'ii dioxide \\as homoL'em/ed in about 1 ••' 1 0 ' ol the solvent lor one hour. !>• )!n: .|n.iiiiii\ o['sol\i:nl ('r\ sia line Cefdiloren pi\o\il \\as dissoved and homoL!eni/e'.! i; i ier m i \ini"e h >r ^( i mi miles. I lie mixture \\as spra\ di'ietl in the lol lo\\ IIIL; eondilions:


00- 00 50-55 0.75
d \[oM!i/m" prevMire ( mm I In): 35-40
\lnii >\p lene eondilion: I hider air
('eldiioren pi\ oxil \vas dnei at 60 (' under \ aemini lor 4 hours.


Quanlity
45 y 6.5 u 5000 ml

>n ilioNide \\as lioinogem/ed in about I. 10 ' of the solxenl lor one hour. I* liiix ol M'hcnl ( r\sla me ('elditoren pi\o\il \\as dissoxed and homoueni/e \iure lor Mi miniiles. I he mixture \\as spray dried in the lolkm iny eondilions:

d. Atomizing pressure (mm Hg): 35-40
c. Atmospheric condition: Under air
The spray dried amorphous Cefditoren pivoxil was dried at 60°C under vacuum for 4 hours.
The amorphous Cefditoren pivoxil prepared as per Examples 1-4 were studied for their related substance (RS) profile, in comparison with the Crystalline Cefditoren pivoxil sample. Thp results of this study are provided in Table 1.

Table 1:

Comparative Related substances (RS) profile:

Table remove

Residual solvent (ppm)
.rying 3441 ND 291 421 -
viim 1809 ND 245 260 -
Note: ND - Not Detected.
ll is evident from the above table, that the total related substance (RS) present in the Example 2 (prepared using Methylene chloride) is less than 2% w/w, compared to other examples.

WE CLAIM:
1. A process for preparing an amorphous Cefditoren pivoxil, comprising the steps of: (i) homogenizing one or more water insoluble carriers in methylene chloride, (ii) preparing a solution of crystalline Cefditoren pivoxil in methylene chloride, (iii) adding solution of step (i) to solution of step (ii), and (iv) removing the solvent,
wherein the total related substances present in the amorphous Cefditoren pivoxil is lest than 2.0 % w/w.
2. The process according to claim 1 wherein the water insoluble carrier comprises one or more of cross-linked polyvinyl pyrrolidone, colloidal silicon dioxide, microcrystalline cellulose, cross-linked sodium carboxymethylcellulose, methylcellulose, starch, carboxymethylcellulose calcium, calcium carbonate and dibasic calcium phosphate and combinations thereof.
3. The process according to claim 1 wherein the weight ratio of Cefditoren pivoxil to water
insoluble carrier is in the range of 1:0.1 to 1:2.
4. The process according to claim 1 wherein the solvent is removed by one or more of
spray drying, distillation, distillation under vacuum and evaporation.
5. A pharmaceutical composition for oral administration comprising amorphous Cefditoren
composition according to any one of the preceding claims and one or more
pharmaceutically acceptable excipients. :
6. The pharmaceutical composition according to claim 5 wherein the one or more
pharmaceutically acceptable excipients comprise one or more of fillers, buffering agents,
binders, disintegrants, coloring agents, flavoring agents, lubricants, glidants, plasticizers,
and preservatives.

7. The pharmaceutical composition according to claim 5 wherein the pharmaceutica'
composition is one or more tablets, capsules, and powders.
8. The pharmaceutical composition according to any one of the preceding claims wherein
the amorphous cefditoren pivoxil is prepared by the process comprising the steps of:
(i) homogenizing colloidal silicon dioxide in methylene chloride,
(ii) preparing a solution of crystalline Cefditoren pivoxil in methylene chloride,
(iii) adding solution of step (i) to solution of step (ii),
(iv) homogenizing the mixture of step (iii), and
(v) spray drying the mixture to remove the solvent.
9. A medicament for the treatment of bacterial infections comprising amorphous Cefditorer;
pivoxil of claim 1.
10. An amorphous Cefditoren pivoxil prepared by a process substantially as described and illustrated herein.