Background of the Invention 6-O-methylerythromycin A (clarithromycin) is a second-generation semi-synthetic erythromycin A derivative belonging to the class of macrolide antibiotics having Formula I.

FORMULAI It exhibits excellent antibacterial activity against gram-positive bacteria, some gram-negative bacteria, anaerobic bacteria, mycoplasma and chlamydia. Furthermore, it has a greater stability at physiological pH levels, which renders it superior to its parent compound, erythromycin. Clarithromycin is a useful therapy for infections of the upper and lower respiratory tract, chlamydia, mycoplasma, legionella, infections of soft tissues, and for the eradication of H. Pylori (when used in combination with acid suppressing agents).

The synthesis of clarithromycin has been extensively studied. There are several processes reported in U. S. Patent Nos. 4,331, 803; 4,672, 109; 4, 680, 386; 4,670, 549; 4,990, 602; 6,342, 590 and 6,617, 436, which describe the preparation of clarithromycin from erythromycin A. After obtaining clarithromycin by following these processes, the crude product is purified through the use of organic solvents, preferably ethanol.

U. S. Patent No. 4,990, 602 describes a process for the preparation of clarithromycin by methylation of the erythromycin oxime derivative of Formula II with methyl iodide, followed by the deprotection of the protecting groups and deoximation of the resulting 6- O-methylerythromycin A-oxime. The crude clarithromycin obtained is then crystallized from the ethanol.

Clarithromycin exists in several polymorphic forms each having different stability levels and physical properties. These polymorphic forms include Form I, II, IV, hydrated form, anhydrous form, solvated Form 0, amorphous form, and the like. All the polymorphic forms have characteristic infrared absorption spectra, powdered X-ray diffraction patterns and differential scanning calorimetric profiles. The various forms of clarithromycin may be converted into each other.

It is a well-known fact that among various forms of clarithromycin, Form II is the most stable polymorphic form. The current marketed formulations include Form II clarithromycin. The processes disclosed involve heating wet clarithromycin to obtain clarithromycin Form II.

However, the use of a vacuum for drying a product has several limitations, such as, special drying assembly, increased utility cost, loss of material, contamination of the product with impurities during leakage and the maintenance of pumps in order to maintain an efficient vacuum. These problems are pronounced when higher quantities of material are to be dried on a commercial scale. Breakdown of a vacuum system may also lead to an indefinite loss of vital production time resulting in decreased productivity.

Summary of the Invention In one general aspect there is provided a process for forming Form II clarithromycin. The process includes obtaining wet clarithromycin and, in a first heating step, heating the wet clarithromycin at a temperature between about 55°C and about 65°C.

In a second heating step, the clarithromycin is heated at a temperature between about 90°C and about 110°C.

Embodiments of the process may include one or more of the following features.

For example, a vacuum may be applied when the wet clarithromycin is between about 55°C and about 65°C and in particular, when the wet clarithromycin is heated between 57°C and 63°C. The vacuum may be eliminated if the temperature is above about 65°C.

A flow of nitrogen may be applied to the clarithromycin when the temperature is between about 55°C and about 65°C and in particular when the temperature is between 57°C and 63°C. A flow of nitrogen may also be applied to the clarithromycin when the temperature is between 90°C and 110°C.

In the first heating step, the wet clarithromycin may be heated for about 30 minutes or it may be heated between about 5 and about 10 hours. After the first heating step, the clarithromycin may be converted to Form I.

In the second heating step, the clarithromycin may be heated for between about 15 hours and about 20 hours in a rotary dryer.

Embodiments may include one or more of the following features. The Form II clarithromycin may be combined with one or more pharmaceutically acceptable excipients to form a dosage form.

The dosage form may be a tablet or capsule.

In a second general aspect there is provided a process of forming Form II clarithromycin. The process includes obtaining wet clarithromycin and heating the wet clarithromycin at between about 90°C and about 110°C under the flow of nitrogen.

A vacuum is not supplied to the wet clarithromycin during heating. The wet clarithromycin may be heated for about 15 hours in a rotary dryer.

In another general aspect there is provided a dosage form which includes the clarithromycin produced by the above processes.

In another general aspect there is provided a method of treating a condition for which antibiotics are indicated. The method includes administering a dosage form which includes the clarithromycin produced by any of the above processes.

The details of various embodiments of the invention are set forth in the description below. Other features and advantages of the invention will be apparent from the description and the claims.

Detailed Description of the Invention The inventors have now surprisingly found that when clarithromycin, solvated Form 0 or Form I, is dried in a nitrogen atmosphere at a temperature from about 75°C to about 115°C without vacuum, Form II clarithromycin is produced. The present inventors have also found that the quality of clarithromycin remains unaffected when it is dried at temperature of about 75°C to about 115°C in nitrogen atmosphere without using a vacuum.

The inventors have sought to develop methods to produce Form II clarithromycin from Form I, and to understand the factors that control this conversion. For example, factors that have influence on the conversion or relevant related conversions include temperature, presence or absence of a vacuum, environment, sequence of steps and duration of the various operations described herein.

In order to get the conversion of wet clarithromycin to Form I, the temperature is maintained between a range of about 55°C and about 65°C and in particular at a temperature between a range of 57°C and 63°C. The temperature range is sustained for between about 5 hours and about 10 hours in the presence of a vacuum. Additionally, a nitrogen flow is applied to the clarithromyin during this first heating step. After these steps, Form I of clarithromycin is present.

The conversion of Form I to Form II clarithromycin is accomplished through a second heating step. The temperature is maintained from between about 90°C to about 110°C. This temperature range is sustained for between about 15 hours and about 20 hours in the absence of a vacuum in a rotary dryer. A nitrogen flow is applied to the clarithromycin during this second heating step. At the conclusion of this heating step, Form II clarithromycin is present.

The Form II clarithromycin prepared in the above processes may be formulated into a pharmaceutical dosage form. This dosage form may contain one or more phannaceutically inert excipients. The pharmaceutically inert excipients as used herein include one or more of diluents, binders, disintegrants, coloring agents, flavoring agents, stabilizers, lubricants/glidants, and plasticizers.

Examples of diluents include one or more of calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose-microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol,

lactose, mannitol, sorbitol, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like, and combinations thereof.

Examples of binders include one or more of methylcellulose, hydroxypropyl cellulose, HPMC, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like, and combinations thereof.

Examples of disintegrants include one or more of microcrystalline cellulose, croscarmellose sodium, and the like, and combinations thereof.

Examples of lubricants and glidants include one or more of colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like, and combinations thereof.

Examples of plasticizers include one or more of polyethylene glycol, triethyl citrate, triacetin, diethyl phthalate, dibutyl sebacate and the like and combinations thereof.

Examples of stabilizers include antioxidants, buffers, acids and the like and combinations thereof. Examples of coloring agents include any FDA approved colors for oral use.

The dosage form may be formulated into tablets, capsules, or any other suitable dosage form.

The dosage form can be used for the treatment of any condition for which antibiotics are indicated. This includes, but is not limited to, the treatment of gram- positive bacteria, gram-negative bacteria, anaerobic bacteria, mycoplasma, legionella and soft tissue infections.

EXAMPLE 1 PREPARATION OF WET CLARITHROMYCIN Erythromycin A (250 kg) is reacted at about 68°C to about 72°C with hydroxylamine hydrochloride (118 kg) in the presence of triethylamine (86 kg) in methanol. The reaction is worked up and the product is extracted in methylene chloride.

This layer is taken for the next reaction.

Moisture from the methylene chloride layer is removed by azeotropic distillation and reacted with 2-methoxypropene (71 kg) and hexamethyldisilazane (82.5 kg) in the presence of pyridinium hydrobromide. To this mixture, potassium hydroxide (18. 75kg) and methyl iodide (40.5 kg) are added. After the reaction is over, it is worked up and treated with sodium bisulfite and formic acid in denatured spirit at about 82°C-84°C. The crude clarithromycin is obtained by a work up of the reaction mixture.

The crude clarithromycin is heated to dissolve in ethanol and crystallized at about 42° to about 44°C. The product is dried and recrystallized again using alcohol to obtain the wet clarithromycin.

EXAMPLE 2 PREPARATION OF FORM II CLARITHROMYCIN FROM WET CLARITHROMYCIN The wet clarithromycin obtained in Example 1 was dried under nitrogen flow at about 90°C to about 110°C (bath temperature) in a rotary dryer for about 15 hours. Form II clarithromycin was obtained which was characterized by IR and XRD. The XRD was found to be consistent with that known in the prior art for Form II clarithromycin.

EXAMPLE 3 PREPARATION OF FORM II CLARITHROMYCIN FROM WET CLARITHROMYCIN The wet clarithromycin obtained in Example 1 was dried under a vacuum at 55°C- 60°C for 30 minutes. The vacuum was removed and the product was dried under the nitrogen flow at about 90°C-110°C (bath temperature) in a rotary dryer for about 15 to about 20 hours. Form II clarithromycin was obtained which was characterized by IR and

XRD. The XRD was found to be consistent with that known in the prior art for Form II clarithromycin.

EXAMPLE 4 PREPARATION OF FORM I CLARITHROMYCIN FROM WET CLARITHROMYCIN The wet clarithromycin obtained in Example 1 was dried at 55°C-65°C under a nitrogen atmosphere for about 5 to about 10 hours. Crystals of Form I clarithromycin were characterized by XRD and IR. The XRD was found to be consistent with that known in the prior art for Form I clarithromycin.

EXAMPLE 5 PREPARATION OF FORM II CLARITHROMYCIN FROM FORM I CLARITHROMYCIN Form I clarithromycin was dried under nitrogen flow at 90°C-110°C (bath temperature) in a rotary dryer for about 15 to about 20 hours. Form II clarithromycin was obtained which was characterized by IR and XRD. The XRD was found to be consistent with that known in the prior art for Form II clarithromycin.

While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention.

Accordingly, it is not intended that the invention be limited, except as by the appended claims.