WO2005082330A2

WO2005082330A2 - Co-precipitated amorphous cefditoren pivoxil and dosage forms comprising the same

Info

Publication number: WO2005082330A2
Application number: PCT/IB2005/000419
Authority: WO
Inventors: Khalid Rafi; Sudhir Verma; Rajesh Bhaskar; Vinod Kumar Arora
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2004-02-19
Filing date: 2005-02-18
Publication date: 2005-09-09
Anticipated expiration: 2006-08-19
Also published as: WO2005082330A3

Abstract

The present invention relates to co-precipitated amorphous cefditoren pivoxil dosage forms and processes for their preparation. The process includes preparing a solution of crystalline cefditoren pivoxil in one or more solvents; dispersing one or more water insoluble carriers in the solution; and removing the solvent. The amorphous cefditoren pivoxil and one or more water insoluble carriers are co-precipitated from the solution.

Description

CO-PRECIPITATED AMORPHOUS CEFDITOREN PIVOXIL AND DOSAGE FORMS COMPRISING THE SAME Field of the Invention The field of the invention relates to co-precipitated amorphous cefditoren pivoxil dosage forms and processes for their preparation. Background of the Invention Cefditoren pivoxil, which is a pivaloxymethyl ester of cefditoren, is a third generation cephalosporin derivative belonging to the class of 3-(2-substituted vinyl) cephalosporin, which was first developed by Meiji Seika of Japan with the aim of producing active cephalosporins with potent and broad-spectrum activity (U.S. Patent No. 4,839,350). Cefditoren pivoxil is highly active, not only against a variety of gram-positive and gram-negative bacteria, but also against some resistant strains of bacteria. Chemically, cefditoren pivoxil is chemically known as [6R-[3(Z),6a,7b(Z)]]-7-[[(2-amino-4- thiazolyl)(methoxyimino)acetyl]amino]-3-[2-(4-methyl-5-thiazolyl)ethenyl]-8-oxo-5-thia- l-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, pivaloyloxy-methyl ester. 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 (U.S. Patent No. 6,294,669). Crystals of cefditoren pivoxil, however, have low solubility in water and thus have not been very suitable for oral administration. In general, for medicinal compounds which are sparingly soluble in water, the solubility or dissolution rate thereof is known to greatly affect the absorption of these compounds in vivo. Thus, many reports were presented on how to improve the water- solubility of such medicinal compounds, which are sparingly soluble in water. One of the reported proposals is a method in which a medicinal compound sparingly soluble in water is converted into an amorphous substance, thus to improve the solubility of the compound in water. It is known that an amoφhous substance generally has a higher solubility in water, as compared with that of the corresponding crystalline substance. Therefore, the conversion of crystalline form of cefditoren pivoxil into an amoφhous substance having higher water solubility is expected to improve its therapeutic efficacy and thus can be advantageously used. U.S. Patent No. 6,342,493 describes a process for preparing orally administrable compositions that include particles composed of a homogeneous mixture of a crystallographically stable, amoφhous, water soluble substance of cefditoren pivoxil and a water soluble high molecular weight polymer. The process involves mixing crystalline cefditoren pivoxil and a water soluble, high molecular weight polymer in an acidic solution followed by basification of the acidic solution to precipitate a yellow-colored powdery composition that contains amoφhous cefditoren pivoxil and high molecular weight polymer. Many technical problems are believed to exist in this process, such as the need for strict production controls and requirements to carry out the operation. WO 02/87588 discloses another method of conversion of crystalline cefditoren pivoxil to amoφhous form by grinding crystalline cefditoren pivoxil in the presence of a pharmaceutically acceptable organic polymeric compound. In the present invention we have found that amoφhous cefditoren pivoxil can be obtained by preparing a solution of crystalline cefditoren pivoxil in a solvent, optionally adding a wetting agent, dispersing a water insoluble carrier in this solution and removing the solvent. Summary of the Invention In one general aspect there is provided a process for preparing an amoφhous form of cefditoren pivoxil having a higher water-solubility. The process includes preparing a solution of crystalline cefditoren pivoxil in one or more solvents; dispersing one or more water insoluble carriers in the solution; and removing the solvent. The amoφhous cefditoren pivoxil and one or more water insoluble carriers are co-precipitated from the solution. 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; and chlorinated hydrocarbons, such as methylene chloride. The water insoluble carrier may be one or more of crospovidone, 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 crospovidone 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. Removing the solvent may include, for example, one or more of distillation, distillation under vacuum, evaporation, and spray drying. 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 process for preparing an amoφhous form of cefditoren pivoxil having a higher water-solubility. The process includes preparing a solution of crystalline cefditoren pivoxil in one or more solvents; adding one or more wetting agents; dispersing one or more water insoluble carriers in the solution; and removing the solvent. The amoφhous cefditoren pivoxil, one or more wetting agents, and one or more water insoluble carriers are co-precipitated from the solution. The wetting agent may be one or more of propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, poloxamers, polyethylene glycols and tweens. In another general aspect there is provided a pharmaceutical composition for oral administration that includes a co-precipitated mixture of amoφhous cefditoren pivoxil and one or more water insoluble carriers. Embodiments of the pharmaceutical composition may include one or more of the following features. The water insoluble carrier may be one or more of crospovidone, 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 crospovidone or colloidal silicon dioxide, or combinations thereof. In another general aspect there is provided a pharmaceutical composition for oral administration that includes a co-precipitated mixture of amoφhous cefditoren pivoxil, one or more wetting agents, and one or more water insoluble carriers. The wetting agent may be one or more of propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, poloxamers, polyethylene glycols and tweens. The pharmaceutical composition may further include one or more pharmaceutically inert excipients. The one or more pharmaceutically inert excipients may be one or more of fillers, buffering agents, binders, disintegrants, coloring agents, flavoring agents, lubricants, glidants, plasticizers, and preservatives. The pharmaceutical composition may be a solid dosage form and the solid dosage form comprises one or more of tablets, capsules, and powders, and, in particular, may be a tablet. The weight ratio of cefditoren pivoxil to water insoluble carrier may be from about 1:0.1 to about 1:2. 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 a co-precipitate of amoφhous cefditoren pivoxil and one or more water insoluble carriers, and one or more of pharmaceutically acceptable excipients. In another general aspect there is provided a co-precipitate of amoφhous cefditoren pivoxil and one or more water insoluble carriers. Embodiments of the co- precipitate may include any one or more of the following features or the features described above. For example, the weight ratio of cefditoren pivoxil to water insoluble carrier may be from about 1 :0.1 to about 1 :2. In another general aspect there is provided a co-precipitate of amoφhous cefditoren pivoxil, one or more wetting agents, and one or more water insoluble carriers. 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 'amoφhous' 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 amoφhous form can be confirmed by conventional powder X-ray diffractometry. Specifically, the crystalline cefditoren pivoxil exhibits shaφ diffraction peaks, whereas the co-precipitate of amoφhous cefditoren pivoxil and one or more water insoluble carriers according to the present invention does not substantially exhibit any X-ray diffraction peaks. In one embodiment, amoφhous cefditoren pivoxil may be prepared by a process that includes forming a solution of cefditoren pivoxil in one or more solvents, dispersing a water insoluble carrier into the solution, and removing the solvent by spray drying, thereby co-precipitating the amoφhous cefditoren pivoxil and water insoluble carriers. 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 solvent may be, for example, one or more of ketones, such as acetone; alcohols, such as methanol, ethanol, isopropyl alcohol; and chlorinated hydrocarbons, such as methylene chloride. Examples of water insoluble carrier may include one or more of crospovidone, 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 crospovidone, 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 wetting agents are the substances, usually surface-active agents, which reduce the surface tension of a liquid and thereby increase its adhesion to a solid surface. Due to poor dispersibility in solvents, the pharmaceutical composition containing cefditoren pivoxil may optionally include a wetting agent. The wetting agent wets the particles of cefditoren pivoxil such that when the solvent evaporates, the particles of cefditoren pivoxil which precipitate are tiny and do not aggregate. Examples of wetting agents may include one or more of propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, poloxamers, polyethylene glycols and tweens. The amoφhous cefditoren pivoxil prepared as generally described above may be further processed with one or more pharmaceutically inert excipients to prepare pharmaceutical compositions. 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. In one embodiment, the cefditoren pivoxil tablet may be prepared by blending a spray dried, co-precipitated mixture of cefditoren pivoxil and water insoluble carriers with diluents and disintegrants, mixing the blend with lubricant and glidants, directly compressing the mixed blend in a suitable tableting machine, and coating with one or more film forming polymers. In alternative embodiments, dry granulation and wet granulation techniques may be used for preparing cefditoren pivoxil tablets. Coating may be performed by applying one or more film forming polymers with or without other pharmaceutically inert excipients. This may be done as a solution or suspension using any conventional coating technique known in the prior art, such as spray coating in a conventional coating pan or fluidized bed processor, or dip coating. Suitable film forming polymers include one or more of ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, waxes, methacrylic acid polymers such as Eudragit® RL and RS, and mixtures thereof. The coating can also be performed using any commercially available ready to coat preparations such as opadry-AMB, opadry-white, opadry-clear, etc. Suitable solvents used for making a solution/suspension of film forming polymer include one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and mixtures thereof. In another embodiment, cefditoren pivoxil capsules may be prepared by blending the spray dried, co-precipitated mixture of cefditoren pivoxil and water insoluble carrier with other pharmaceutically inert excipients and filling into suitably sized hard gelatin capsules. The term "pharmaceutically inert excipient" as used herein includes one or more of fillers, buffering agents, binders, disintegrants, coloring agents, flavoring agents, lubricants, glidants, plasticizers and preservatives for pharmaceutical compositions. Suitable fillers may include one or more of corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, sorbitol, starch, starch pregelatinized, sucrose and mixtures thereof. Examples of buffering agents include one or more of sodium citrate, sodium tartarate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, and other sodium and potassium salts. Examples of binders include methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullutan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol or mixtures thereof. Examples of disintegrants include starch, croscarmellose sodium, crospovidone, sodium starch glycolate or mixtures thereof. Examples of lubricants and glidants include colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax and the like. The coloring agents of the present invention may be selected from any FDA approved colors for oral use. The amoφhous cefditoren pivoxil composition 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 coii, BranhameUa catarrhalis, Klebsiella, Proteus, and Haemophilus influenzae, and anaerobes such as Peptostreptococcus, Propionibacterium acnes, and Bacteriocides. Further, the composition according to the present invention is useful for the prophylaxis or therapy of diseases induced by gram-positive bacteria or gram-negative bacteria. The pharmaceutical composition according to the present invention may be used by any administration route so far as the high dissolvability of the amoφhous 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. The amoφhous Cefditoren pivoxil compositions according to the present invention may be administered in combination with other medicines, for example, other antibacterial agents. 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. Examples 1- 4: Amoφhous cefditoren pivoxil 1

Propylene glycol was dissolved in acetone. Cefditoren pivoxil was added to the solution formed and crospovidone was dispersed in it. The solvent was removed to obtain the amoφhous cefditoren pivoxil.

Amoφhous cefditoren pivoxil 2

Hydroxypropyl cellulose was dissolved in acetone. Cefditoren pivoxil was added to the solution formed and colloidal silicon dioxide was dispersed in it. The solvent was removed to obtain the amoφhous cefditoren pivoxil.

Amoφhous cefditoren pivoxil 3

Cefditoren pivoxil was dissolved in acetone and colloidal silicon dioxide was dispersed in it. The solvent was removed to obtain the amoφhous cefditoren pivoxil. Amoφhous Cefditoren pivoxil 4

Hydroxypropyl methylcellulose was dissolved in a mixture of dichloromethane and isopropyl alcohol. Cefditoren pivoxil was added to the solution formed and colloidal silicon dioxide was dispersed in it. The solvent was removed to obtain the amoφhous cefditoren pivoxil. Example 5:

Tablets containing amoφhous cefditoren pivoxil 1

1. Amoφhous Cefditoren pivoxil 1 and mannitol were granulated with a solution of hydroxypropylcellulose in water. 2. The wet granules were dried in a fluid bed drier, passed through a screen and then subjected to sizing. 3. Crosscarmellose sodium and magnesium stearate were passed through a screen, blended with the blend of step 2 and the total mixture was compressed into tablets. 4. The tablets were coated with the coating composition in the coating pan. Example 6:

Tablets containing amoφhous cefditoren pivoxil 2

1. Amoφhous cefditoren pivoxil 2, sodium lauryl sulphate and mannitol were granulated with a solution of polyvinyl pyrrolidone in water. 2. The wet granules were dried in a fluid bed drier, passed through a screen and then subjected to sizing. 3. Crospovidone and magnesium stearate were passed through a screen, blended with the blend of step 2 and the total mixture was compressed into tablets. 4. The tablets were coated with the coating composition in the coating pan. Example 7: Tablets containing amoφhous cefditoren pivoxil 3

1. Amoφhous cefditoren pivoxil 3, mannitol, sodium polyphosphate and intragranular croscarmellose sodium were granulated with a solution of hydroxypropylcellulose in water. 2. The wet granules were dried in a fluid bed drier, passed through a screen and then subjected to sizing. 3. The extragranular croscarmellose sodium and magnesium stearate were passed through a screen, blended with the blend of step 2 and the total mixture was compressed into tablets. 4. The tablets were coated with the coating composition in the coating pan. Example 8: Tables containing amorphous cefditoren pivoxil 4

1. Amoφhous cefditoren pivoxil 4, mannitol, sodium polyphosphate and intragranular croscarmellose sodium were granulated with a solution of hydroxypropyl methylcellulose in water. 2. The wet granules were dried in a fluid bed drier, passed through a screen and then subjected to sizing. 3. The extragranular croscarmellose sodium and magnesium stearate were passed through a screen, blended with the blend of step 2 and the total mixture was compressed into tablets. 4. The tablets were coated with the coating composition in the coating pan. In vitro dissolution study:

In vitro release of cefditoren pivoxil from tablets as per composition of Example 5, 6, 7 and 8 were studied in 900 ml water, using USP Dissolution Apparatus (Paddle Type II), at 50 φm. The results are listed in Table 1.

Table 1 : In vitro release of Cefditoren pivoxil from tablets

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

Claims

WE CLAIM:

1. A pharmaceutical composition comprising: a co-precipitated mixture of amoφhous cefditoren pivoxil and one or more water insoluble carriers.

2. The amoφhous cefditoren pivoxil according to claim 1, wherein the water insoluble carrier comprises one or more of crospovidone, colloidal silicon dioxide, microcrystalline cellulose, cross-linked sodium carboxymethylcellulose, methylcellulose, starch, carboxymethylcellulose calcium, calcium carbonate and dibasic calcium phosphate and combinations thereof.

3. The amoφhous cefditoren pivoxil according to claim 1, wherein the composition further comprises one or more pharmaceutically inert excipients.

4. The pharmaceutical composition according to claim 3, wherein the one or more pharmaceutically inert excipients comprise one or more of fillers, buffering agents, binders, disintegrants, coloring agents, flavoring agents, lubricants, glidants, plasticizers and preservatives.

5. The pharmaceutical composition according to claim 4, wherein the filler comprises one or more of mannitol, corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, sorbitol, starch, starch pregelatinized, sucrose, and mixtures thereof.

6. The pharmaceutical composition according to claim 4, wherein the buffering agent comprises one or more of sodium citrate, sodium tartarate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, and other sodium and potassium salts.

7. The pharmaceutical composition according to claim 4, wherein the binder comprises one or more of methyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate or propylene glycol.pharmaceutical composition according to claim 1, wherein a ratio of cefditoren pivoxil to water insoluble carrier is from about 1 :0.1 to about 1 :2.

8. The pharmaceutical composition according to claim 4 wherein the disintegrant comprises one or more of croscarmellose sodium, calcium carboxymethyl cellulose, colloidal silicon dioxide, starch, crospovidone or sodium starch glycolate.

9. The pharmaceutical composition according to claim 4 wherein the lubricant comprises one or more of colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax and mixtures thereof.

10. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a solid dosage form.

11. The The pharmaceutical composition of claim 10, wherein the solid dosage form comprises one or more tablets, capsules, and powders.

12. The pharmaceutical composition according to claim 11, wherein the solid dosage form comprises a tablet.

13. The pharmaceutical composition according to claim 12, wherein the tablet is further coated with one or more functional and/or non-functional layers.

14. The pharmaceutical composition according to claim 13, wherein the coating is with one or more film forming agents and are selected from ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl methyl phthalate, cellulose acetate, cellulose acetate trimelliatate, cellulose acetate phthalate; Waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit ® RL and RS; and mixture thereof.

15. The pharmaceutical according to claim 1, wherein a ratio of cefditoren pivoxil to water insoluble carrier is from about 1 :0.1 to about 1 :2.

16. The pharmaceutical composition according to claim 1, further comprising one or more wetting agents.

17. The pharmaceutical composition according to claim 16, wherein the wetting agent comprises one or more of propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, poloxamers, polyethylene glycols and tweens.

18. A process for preparing an amoφhous cefditoren pivoxil comprising cefditoren pivoxil, and a water insoluble carrier, the process comprising: a) preparing a solution of cefditoren pivoxil by dissolving crystalline cefditoren pivoxil in one or more solvents; b) dispersing one or more water insoluble carriers in the solution; and c) removing the solvent, whereby the amoφhous cefditoren pivoxil and one or more water insoluble carriers are co-precipitated from the solution.

19. The process according to claim 18, wherein the solution is prepared in an organic solvent comprising one or more of acetone, ethanol, isopropyl alcohol, methylene chloride and mixtures thereof.

20. The process according to claim 18, wherein the water insoluble carrier comprises one or more of crospovidone, colloidal silicon dioxide, microcrystalline cellulose, cross- linked sodium carboxymethylcellulose, methylcellulose, starch, carboxymethylcellulose calcium, calcium carbonate and dibasic calcium phosphate and combinations thereof.

21. The process according to claim 20, wherein the water insoluble carrier comprises one or more of crospovidone, colloidal silicon dioxide, and combinations thereof.

22. The process according to claim 18, wherein the weight ratio of cefditoren pivoxil to water insoluble carrier is from about 1 :0.1 to about 1 :2.

23. The process according to claims 18, wherein the solvent is removed by one or more of distillation, distillation under vacuum, evaporation or spray drying.

24. The process according to claim 23, wherein the solvent is removed by spray drying.

25. The process according to claim 18, further comprising processing the co- precipitate of amoφhous cefditoren pivoxil and one or more water insoluble carriers with one or more pharmaceutically inert excipients.

26. The process according to claim 25, wherein the pharmaceutically inert excipient comprises one or more diluents, binders, disintegrants, coloring agents, flavoring agents, stabilizers, surfactants, lubricants, glidants, plasticizers, and preservatives.

27. The process according to claim 25, further comprising forming one or more of a tablet, a capsule, and a powder.

28. A process for preparing an amoφhous cefditoren pivoxil comprising cefditoren pivoxil, a wetting agent and a water insoluble carrier, the process comprising: a) preparing a solution of cefditoren pivoxil by dissolving crystalline cefditoren pivoxil in one or more solvents; b) adding one or more wetting agents; c) dispersing one or more water insoluble carriers in the solution; and removing the solvent, whereby the amoφhous cefditoren pivoxil, one or more wetting agents and one or more water insoluble carriers are co-precipitated from the solution.

29. The process according to claim 28, wherein the wetting agent comprises one or more of propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, poloxamers, polyethylene glycols and tweens.

30. The process according to claim 28, further comprising processing the co- precipitate of amoφhous cefditoren pivoxil, one or more wetting agents and one or more water insoluble carriers with one or more pharmaceutically inert excipients.

31. The process according to claim 30, wherein the pharmaceutically inert excipient comprises one or more diluents, binders, disintegrants, coloring agents, flavoring agents, stabilizers, surfactants, lubricants, glidants, plasticizers, and preservatives.

32. The process according to claim 31 , further comprising forming one or more of a tablet, a capsule, and a powder.

33. A method for the treatment of bacterial infections in a mammal, the method comprising administering a pharmaceutical composition comprising a co-precipitate of amoφhous cefditoren pivoxil and one or more water insoluble carriers, and one or more pharmaceutically inert excipients.

34. The method according to claim 33, wherein the water insoluble carrier comprises one or more of crospovidone, colloidal silicon dioxide, and combinations thereof.

35. The method according to claim 34, wherein the weight ratio of cefditoren pivoxil to water insoluble carrier is from about 1 :0.1 to about 1 :2.

36. A method for the treatment of bacterial infections in a mammal, the method comprising administering a pharmaceutical composition comprising a co-precipitate of amoφhous cefditoren pivoxil, one or more watting agents and one or more water insoluble carriers, and one or more pharmaceutically inert excipients.

37. A co-precipitate of amoφhous cefditoren pivoxil and one or more water insoluble carriers.

38. The co-precipitate of claim 37, wherein the weight ratio of cefditoren pivoxil to water insoluble carrier is from about 1 :0.1 to about 1 :2.

39. A co-precipitate of amoφhous cefditoren pivoxil, one or more wetting agents and one or more water insoluble carriers.

40. The co-precipitate of claim 39, wherein the weight ratio of cefditoren pivoxil to water insoluble carrier is from about 1 :0.1 to about 1 :2.