WO 2016024243, New patent, Dr Reddy's Laboratories Ltd, Fidaxomicin
WO2016024243, FIDAXOMICIN POLYMORPHS AND PROCESSES FOR THEIR PREPARATION
DR. REDDY’S LABORATORIES LIMITED [IN/IN]; 8-2-337, Road No. 3, Banjara Hills, Telangana State, India Hyderabad 500034 (IN)
CHENNURU, Ramanaiah; (IN).
PEDDY, Vishweshwar; (IN).
RAMAKRISHNAN, Srividya; (IN)
PEDDY, Vishweshwar; (IN).
RAMAKRISHNAN, Srividya; (IN)
Aspects of the present application relate to crystalline forms of Fidaxomicin IV, V & VI and processes for their preparation. Further aspects relate to pharmaceutical compositions comprising these polymorphic forms of fidaxomicin
Fidaxomicin (also known as OPT-80 and PAR-101 ) is a novel antibiotic agent and the first representative of a new class of antibacterials called macrocycles. Fidaxomicin is a member of the tiacumicin family, which are complexes of 18-membered macrocyclic antibiotics naturally produced by a strain of Dactylosporangium aurantiacum isolated from a soil sample collected in Connecticut, USA. The major component of the tiacumicin complex is tiacumicin B. Optically pure R-tiacumicin B is the most active component of Fidaxomicin. The chiral center at C(19) of tiacumicinB affects biological activity, and R-tiacumicin B has an R-hydroxyl group attached at this position. The isomer displayed significantly higher activity than other tiacumicin B-related compounds and longer post-antibiotic activity.
As per WIPO publication number 2006085838, Fidaxomicin is an isomeric mixture of the configurationally distinct stereoisomers of tiacumicin B, composed of 70 to 100% of R-tiacumicin B and small quantities of related compounds, such as S-tiacumicin B and lipiarmycin A4. Fidaxomicin was produced by fermentation of the D aurantiacum subspecies hamdenensis (strain 718C-41 ). It has a narrow spectrum antibacterial profile mainly directed against Clostridium difficile and exerts a moderate activity against some other gram-positive species. Fidaxomicin is bactericidal and acts via inhibition of RNA synthesis by bacterial RNA polymerase at a distinct site from that of rifamycins. The drug product is poorly absorbed and exerts its activity in the gastrointestinal (Gl) tract, which is an advantage when used in the applied indication, treatment of C. difficile infection (CDI) (also known as C. difficile-associated disease or diarrhoea [CDAD]). Fidaxomicin is available as DIFICID oral tablet in US market. Its CAS chemical name is Oxacyclooctadeca-3,5,9, 13, 15-pentaen-2-one, 3-[[[6-deoxy-4-0-(3,5dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-0-methyl-P-D-manno pyranosyl]oxy]methyl]-12[[6-deoxy-5-C-methyl-4-0-(2-methyl-1 -oxopropyl)- -D-lyxo-hexo pyranosyl]oxy]-1 1 -ethyl-8-hydroxy-18-[(1 R)-1 -hydroxyethyl] -9,13,15-trimethyl-, (3E.5E, 8S.9E.1 1 S.12R.13E, 15E.18S)-. Structural formula (I) describes the absolute stereochemistry of fidaxomicin as determined by x-ray.
(I)
WIPO publication number 2004014295 discloses a process for preparation of Tiacumicins that comprises fermentation of Dactylosporangium aurantiacum NRRL18085 in suitable culture medium. It also provides process for isolation of tiacumicin from fermentation broth using techniques selected from the group consisting of: sieving and removing undesired material by eluting with at least one solvent or a solvent mixture; extraction with at least one solvent or a solvent mixture; Crystallization; chromatographic separation; High-Performance Liquid Chromatography (HPLC); MPLC; trituration; and extraction with saturated brine with at least one solvent or a solvent mixture. The product was isolated from /so-propyl alcohol (IPA) having a melting point of 166-169 °C.
U.S. Patent No. 7378508 B2 discloses polymorphic forms A and B of fidaxomicin, solid dosage forms of the two forms and composition thereof. As per the '508 patent form A is obtained from methanol water mixture and Form B is obtained from ethyl acetate.
J. Antibiotics, vol. 40(5), 575-588 (1987) discloses purification of Tiacumicins using suitable solvents wherein tiacumicin B exhibited a melting point of 143-145 °C.
PCT application WO2013170142A1 describes three crystalline forms of Fidaxomicn namely, Form-Z, Form-Z1 and Form-C. IN2650/CHE/2013 describes 6 crystalline polymorphic forms of Fidaxomicin namely, Forms I, Form la, Form II, Form Ha, Form III and Form Ilia).
The occurrence of different crystal forms, i.e., polymorphism, is a property of some compounds. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physico-chemical properties.
Polymorphs are different solid materials having the same molecular structure but different molecular arrangement in the crystal lattice, yet having distinct physico-chemical properties when compared to other polymorphs of the same molecular structure. The discovery of new polymorphs and solvates of a pharmaceutical active compound provides an opportunity to improve the performance of a drug product in terms of its bioavailability or release profile in vivo, or it may have improved stability or advantageous handling properties. Polymorphism is an unpredictable property of any given compound. This subject has been reviewed in recent articles, including A. Goho, "Tricky Business," Science News, August 21 , 2004. In general, one cannot predict whether there will be more than one form for a compound, how many forms will eventually be discovered, or how to prepare any previously unidentified form.
There remains a need for additional polymorphic forms of fidaxomicin and for processes to prepare polymorphic forms in an environmentally-friendly, cost-effective, and industrially applicable manner.
G.V. Prasad, chairman, Dr Reddy's Laboratories
EXAMPLES
Example 1 : Preparation of fidaxomicin Form IV:
Fidaxomicin (0.5 g) and a mixture of 1 ,4-Dioxane (10 mL), THF (10 ml) and water (20mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:
Starting temperature: 25 °C;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 25 °C over a period of 2 hours;
Temperature maintained at 25 °C for 6 hours.
After completion of temperature cycling process, the slurry was filtered under suction, followed by drying in air tray dryer (ATD) at 40°C to a constant weight to produce crystalline fidaxomicin form-IV.
Example 2: Preparation of fidaxomicin Form V:
Fidaxomicin (1 g) and a mixture of propylene glycol (10 mL) and water (20mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:
Starting temperature is 25 °C;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 25 °C over a period of 2 hours;
Temperature maintained at 25 °C for 6 hours.
After completion of temperature cycling process, the slurry was filtered under suction, followed by drying in air tray dryer (ATD) at 40°C to a constant weight to produce crystalline fidaxomicin form-V.
Example 3: Preparation of fidaxomicin Form VI:
Fidaxomicin (0.5 mg) and MIBK (10 mL) were charged in Easy max reactor (Mettler Toledo) and the mixture was heated to 80°C. n-heptane (20 mL) was added to the solution at the same temperature. The mixture was stirred for 1 hour. The reaction mass was then cooled to 25°C. Solid formed was filtered at 25°C and dried at 40°C in air tray dryer (ATD) to a constant weight to produce crystalline fidaxomicin form VI.
Example 4: Preparation of fidaxomicin Form V:
Fidaxomicin (500 mg) and a mixture of R-propylene glycol (5 mL) and water (15 mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:
Starting temperature is 25 °C;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 25 °C over a period of 2 hours;
Temperature maintained at 25 °C for 2 hours.
After completion of temperature cycling process, the slurry was filtered and dried at 25°C to produce crystalline fidaxomicin form-V.
Example 5: Preparation of fidaxomicin Form V:
Fidaxomicin (1 g) and a mixture of S-propylene glycol (3 ml_) and water (30 mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:
Starting temperature is 25 °C;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 25 °C over a period of 2 hours;
Temperature maintained at 25 °C for 2 hours.
After completion of temperature cycling process, the slurry was filtered and dried at 25°C to produce crystalline fidaxomicin form-V.
Example 6: Preparation of fidaxomicin Form V:
Fidaxomicin (40 g) and a mixture of propylene glycol (400 mL) and water (1600 mL) were charged in Chem glass reactor. The reactor was set to temperature cycle with following parameters:
Starting temperature is 25 °C;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 25 °C over a period of 2 hours;
Temperature maintained at 25 °C for 6 hours.
After completion of temperature cycling process, the slurry was filtered under suction, followed by drying in air tray dryer (ATD) at 40°C to a constant weight to produce crystalline fidaxomicin form-V.
The 10-member board at pharmaceutical major Dr Reddy's thrives on diversity. Liberally sprinkled with gray hairs, who are never quite impressed with powerpoint presentations, "they want information to be pre-loaded so that the following discussions (at the board level) are fruitful," says Satish Reddy, Chairman, Dr Reddy's. That said, the company has now equipped its board members with a customized application (that runs on their tablets) to manage board agenda and related processes.
see at
Dr. Reddy's Laboratories Managing Director and Chief Operating Officer Satish Reddy addressing
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| Systematic (IUPAC) name | |
|---|---|
| 3-(((6-Deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl)oxy)-methyl)-12(R)-[(6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl)oxy]-11(S)-ethyl-8(S)-hydroxy-18(S)-(1(R)-hydroxyethyl)-9,13,15-trimethyloxacyclooctadeca-3,5,9,13,15-pentaene-2-one | |
| Clinical data | |
| Trade names | Dificid, Dificlir |
| Licence data | US FDA:link |
| Pregnancy category | |
| Legal status | |
| Routes of administration | Oral |
| Pharmacokinetic data | |
| Bioavailability | Minimal systemic absorption[1] |
| Biological half-life | 11.7 ± 4.80 hours[1] |
| Excretion | Urine (<1%), faeces (92%)[1] |
| Identifiers | |
| CAS Number | 873857-62-6  |
| ATC code | A07AA12 |
| PubChem | CID 11528171 |
| ChemSpider | 8209640  |
| UNII | Z5N076G8YQ |
| KEGG | D09394 |
| ChEBI | CHEBI:68590 |
| ChEMBL | CHEMBL1255800 |
| Synonyms | Clostomicin B1, lipiarmicin, lipiarmycin, lipiarmycin A3, OPT 80, PAR 01, PAR 101, tiacumicin B |
| Chemical data | |
| Formula | C52H74Cl2O18 |
| Molar mass | 1058.04 g/mol |
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