TR 700, TR 701FA, Tedizolid phosphate

“TR-700”

5R)-3-{3-Fluoro-4-[6-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)-pyridin-3-yl]-phenyl}-5-hydroxymethyl-1,3-oxazolidin-2-one

Trius Therapeutics, Inc.

US Patent Publication No. 20070155798, which is hereby incorporated by reference in its entirety, recently disclosed a series of potently anti-bacterial oxazolidinones including

wherein R═H, PO(OH)₂, and PO(ONa)₂.

(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate, CAS 856867-55-5

DISODIUM SALT

CAS 856867-39-5

• C₁₇ H₁₆ F N₆ O₆ P . 2 Na
• 2-​Oxazolidinone, 3-​[3-​fluoro-​4-​[6-​(2-​methyl-​2H-​tetrazol-​5-​yl)​-​3-​pyridinyl]​phenyl]​-​5-​[(phosphonooxy)​methyl]​-​, sodium salt (1:2)​, (5R)​-
• • DA 7218, Tedizolid phosphate disodium salt

In addition, improved methods of making the free acid are disclosed in U.S. patent application Ser. No. 12/577,089, which is assigned to Trius Therapeutics, Inc., and which is incorporated herein by reference

crystalline (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate 1 (R═PO(OH)₂), was more stable and non-hygroscopic than the salt forms that were tested. In addition, unlike typical crystallizations, where the crystallization conditions, such as the solvent and temperature conditions, determine the particular crystalline form, the same crystalline form of 1 (R═PO(OH)₂) was produced using many solvent and crystallization conditions. Therefore, this crystalline form was very stable, was made reproducibly, and ideal for commercial production because it reduced the chances that other polymorphs would form contaminating impurities during production. However, in all preliminary testing, the free acid crystallized as fine particles, making filtering and processing difficult.

To overcome difficulties in filtering and processing crystalline (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate 1 (R═PO(OH)₂), processes described herein result in significantly reduced filtering time, avoid more toxic solvents, and significantly increased ease of preparing dosage forms such as tablets. It has been found that implementing various processes can control the particle size distribution of the resulting material, which is useful for making the crystalline form, and for commercial production and pharmaceutical use. Surprisingly, the process for increasing the particle size reduces the amount of the dimer impurity, in comparison to the process for making the free acid disclosed in U.S. patent application Ser. No. 12/577,089. Thus, various methods of making and using the crystalline form are also provided.

In addition, by using methods of making the free acid disclosed in U.S. patent application Ser. No. 12/577,089, which is assigned to the same assignee as in the present application, and by using the crystallization methods described herein, a crystalline free acid having at least 96% purity by weight may be formed that comprises a compound having the following formula:

(hereinafter “the chloro impurity”), i.e., (R)-5-(chloromethyl)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl)oxazolidin-2-one in an amount less than 1%.

Similarly, by using methods of making the free acid disclosed in U.S. patent application Ser. No. 12/577,089, which is assigned to the same assignee as in the present application, and by using the crystallization methods described herein, a crystalline free acid having at least 96% purity by weight may be formed that comprises a compound having the following formula:

(hereinafter “TR-700”), i.e., 5R)-3-{3-Fluoro-4-[6-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)-pyridin-3-yl]-phenyl}-5-hydroxymethyl-1,3-oxazolidin-2-one, in an amount less than 1%.

The crystalline free acid may have one or more of the attributes described herein.

In some aspects, a purified crystalline (R)-3-(4-(2-(2-methyltetrazol-5-yl)-pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate, i.e., the free acid, has a purity of at least about 96% by weight. In some embodiments, the crystalline free acid has a median volume diameter of at least about 1.0 μm.

BRIEF DESCRIPTION OF THE DRAWINGS……http://www.google.com/patents/US8426389

FIG. 1 the FT-Raman spectrum of crystalline 1 (R═PO(OH)₂).

FIG. 2 shows the X-ray powder pattern of crystalline 1 (R═PO(OH)₂).

http://www.google.com/patents/US8426389

FIG. 3 shows the differential scanning calorimetry (DSC) thermogram of crystalline 1 (R═PO(OH)₂).

http://www.google.com/patents/US8426389

FIG. 4 shows the ¹H NMR spectrum of 1 (R═PO(OH)₂).

FIG. 5 depicts the TG-FTIR diagram of crystalline 1 (R═PO(OH)₂).

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FIG. 6 is a diagram showing the dynamic vapor sorption (DVS) behavior of crystalline 1 (R═PO(OH)₂).

FIG. 7 is a manufacturing process schematic for 1 (R═PO(OH)₂) (TR-701 FA) in a tablet dosage form.

FIG. 8 is a manufacturing process schematic for 1 (R═PO(OH)₂) (TR-701 FA) Compounding Solution for Lyophilization.

FIG. 9 is a manufacturing process schematic for 1 (R═PO(OH)₂) (TR-701 FA) for Injection, 200 mg/vial: sterile filtering, filling, and lyophilization.

FIG. 10 is a representative particle size distribution of crystalline free acid without regard to controlling particle size distribution as also described herein.

FIG. 11 is a representative particle size distribution of crystalline free acid made using laboratory processes to control particle size described herein.

FIG. 12 is a representative particle size distribution of crystalline free acid made using scaled up manufacturing processes to control particle size described herein.

These impurities include

i.e., 5R)-3-{3-Fluoro-4-[6-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)-pyridin-3-yl]-phenyl}-5-hydroxymethyl-1,3-oxazolidin-2-one (“TR-700”) and/or

i.e., (R)-5-(chloromethyl)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl)oxazolidin-2-one (“chloro impurity”).