WO2007026369A1 - A novel amorphous form of linezolid - Google Patents

A novel amorphous form of linezolid Download PDF

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Publication number
WO2007026369A1
WO2007026369A1 PCT/IN2005/000249 IN2005000249W WO2007026369A1 WO 2007026369 A1 WO2007026369 A1 WO 2007026369A1 IN 2005000249 W IN2005000249 W IN 2005000249W WO 2007026369 A1 WO2007026369 A1 WO 2007026369A1
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Prior art keywords
linezolid
amorphous
methyl
solvent
solvents
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PCT/IN2005/000249
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French (fr)
Inventor
Dodda Mohan Rao
Pingili Krishna Reddy
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Symed Labs Limited
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Priority to PCT/IN2005/000249 priority Critical patent/WO2007026369A1/en
Publication of WO2007026369A1 publication Critical patent/WO2007026369A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2

Definitions

  • the present invention relates to a novel amorphous form of linezolid, to processes for its preparation and to a pharmaceutical composition containing it.
  • Linezolid chemically N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo- 5-oxazolidinyl]methyl]acetamide is an antibacterial agent.
  • Linezolid is represented by the following structure:
  • 6,559,305 claims crystalline form Il characterized by IR spectrum having bands at 3364, 1748, 1675, 1537, 1517, 1445, 1410, 1401, 1358, 1329, 1287, 1274, 1253, 1237, 1221 , 1145, 1130, 1123, 1116, 1078, 1066, 1049, 907, 852 and 758 cnrT 1 and powder X-ray diffraction spectrum having 2-theta values at 7.10, 9.54, 13.88, 14.23, 16.18, 16.79, 17.69, 19.41, 19.69, 19.93, 21.61 , 22.39, 22.84, 23.52, 24.16, 25.28, 26.66, 27.01 and 27.77 degrees.
  • Linezolid form III is characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 7.6, 9.6, 13.6, 14.9, 18.2, 18.9, 21.2, 22.3, 25.6, 26.9, 27.9 and 29.9 degrees and by IR spectrum having main bands at about 3338, 1741 , 1662, 1544, 1517, 1471, 1452, 1425, 1400, 1381, 1334, 1273, 1255, 1228, 1213, 1197, 1176, 1116, 1082, 1051 , 937, 923, 904, 869, 825 and 756 crrT 1 .
  • Amorphous form of linezolid has not been reported in the prior art.
  • Amorphous forms of pharmaceutical products are usually known to have better dissolution properties than their crystalline forms. It can be formulated to a pharmaceutical composition having good dissolution properties. So, there is a need for stable amorphous form of linezolid for better pharmaceutical preparations.
  • the object of the present invention is to provide a stable, consistently reproducible amorphous form of linezolid; processes for preparing it; and to a pharmaceutical composition containing it.
  • a novel amorphous form of linezolid is characterized by having broad x-ray powder diffraction spectrum as ih figure 1.
  • Amorphous linezolid is further characterized by IR spectrum in potassium bromide pellet having main absorption bands at about 3338, 3282, 3084, 1741 ,
  • a process for preparation of amorphous linezolid which comprises spray drying or vacuum drying a solution of linezolid in a solvent.
  • linezolid is obtained by dissolving linezolid in a solvent.
  • linezolid used in the preparation of above solution is in the form of crystalline form Il or crystalline form III and more preferably being crystalline form 111.
  • Linezolid required in the process may also be obtained as a part of synthesizing linezolid.
  • Linezolid may be synthesized by a process described in the prior art and the reaction mass obtained in the synthesis may optionally be washed with, for example, water before using the process of the invention.
  • Preferable solvent is selected from alcoholic solvents such as methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butyl alcohol; ketonic solvents such as acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone; ether solvents such as diethyl ether, diisopropyl ether and tert-butyl methyl ether; chlorinated hydrocarbon solvents such as methylene chloride, ethylene chloride and chloroform; hydrocarbon solvents such as toluene and xylene; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, tert-butyl acetate, ethyl formate and methyj formate; acetonitrile; tetrahydrofuran; dimethylformamide
  • More preferable solvent is selected from acetonitrile, methanol and acetone. Most preferable solvent is acetonitrile.
  • Linezolid used as starting material may be obtained by processes described in the art, for example by the processes described in U.S. Patent No. 6,559,305 and PCT Publication No. WO 2005/035530 Al
  • a pharmaceutical composition comprising amorphous linezolid and a pharmaceutically acceptable excipient.
  • Preferable pharmaceutical composition of amorphous linezolid is a solid oral dosage form.
  • FIG. 1 is a X-ray powder diffraction spectrum of amorphous linezo ⁇ d.
  • X-Ray powder diffraction spectrum was measured on a Bruker axs D8 advance X-ray powder diffractometer having a Copper-K ⁇ radiation.
  • Approximately 1 gm of sample was gently flattened on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.03 degrees two-theta per step and a step time of 0.5 seconds.
  • the sample was simply placed on the sample holder.
  • the sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
  • Linezolid form III (10 gm) is dissolved in acetonitrile (600 ml) at ambient temperature and then the solution is subjected to spray drying to give 9.6 gm of amorphous linezolid.
  • Example 2
  • Linezolid form Il (10 gm) is dissolved in methanol (400 ml) at ambient temperature and then the solution is subjected to vacuum drying to give 9.5 gm of amorphous linezolid.
  • Example 3 Example 1 is repeated using linezolid form Il instead of linezolid form III to give 9.3 gm of amorphous linezolid.

Abstract

The present invention relates to a novel amorphous form of linezolid, to processes for its preparation and to a pharmaceutical composition containing it.

Description

A NOVEL AMORPHOUS FORM OF LINEZOLID
FIELD OF THE INVENTION
The present invention relates to a novel amorphous form of linezolid, to processes for its preparation and to a pharmaceutical composition containing it.
BACKGROUND OF THE INVENTION
Linezolid, chemically N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo- 5-oxazolidinyl]methyl]acetamide is an antibacterial agent. Linezolid is represented by the following structure:
Figure imgf000002_0001
Linezolid and related compounds, processes for their preparation and their therapeutic uses were disclosed in U.S. Patent No. 5,688,792. Processes for preparation of linezolid were also described in U.S. Patent No. 5,837,870, PCT Publication No. WO 99/24393, PCT Application No. PCT/IN04/00105, PCT Application No. PCT/IN04/00218, J. Med. Chem. 39(3), 673-679, 1996 and Tetrahedron Lett., 40(26), 4855, 1999.
Linezolid is known to exhibit polymorphism and three crystalline forms are so far known. U.S. Patent No. 6,559,305 and U.S. Patent No. 6,444,813 addressed that the product obtained by the process described by J. Med. Chem. 39(3), 673-679, 1996 is form I and is characterized by having melting point of 181.5 - 182.50C and by^lR spectrum having bands at 3284, 3092, 1753, 1728, 1649, 1565, 1519, 1447, 1435 cnrϊ1. U.S. Patent No. 6,559,305 claims crystalline form Il characterized by IR spectrum having bands at 3364, 1748, 1675, 1537, 1517, 1445, 1410, 1401, 1358, 1329, 1287, 1274, 1253, 1237, 1221 , 1145, 1130, 1123, 1116, 1078, 1066, 1049, 907, 852 and 758 cnrT1 and powder X-ray diffraction spectrum having 2-theta values at 7.10, 9.54, 13.88, 14.23, 16.18, 16.79, 17.69, 19.41, 19.69, 19.93, 21.61 , 22.39, 22.84, 23.52, 24.16, 25.28, 26.66, 27.01 and 27.77 degrees.
PCT Publication No. WO 2005/035530 A1 claims Linezolid form III is characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 7.6, 9.6, 13.6, 14.9, 18.2, 18.9, 21.2, 22.3, 25.6, 26.9, 27.9 and 29.9 degrees and by IR spectrum having main bands at about 3338, 1741 , 1662, 1544, 1517, 1471, 1452, 1425, 1400, 1381, 1334, 1273, 1255, 1228, 1213, 1197, 1176, 1116, 1082, 1051 , 937, 923, 904, 869, 825 and 756 crrT1. Amorphous form of linezolid has not been reported in the prior art.
Amorphous forms of pharmaceutical products are usually known to have better dissolution properties than their crystalline forms. It can be formulated to a pharmaceutical composition having good dissolution properties. So, there is a need for stable amorphous form of linezolid for better pharmaceutical preparations.
The existence of amorphous form of linezolid has now been discovered. We have also found-that linezolid in amorphous form has higher bioavailability than when in crystalline form and that the amorphous form of linezolid has adequate chemical stability upon storage and therefore can be used in pharmaceutical formulation. . ..
The object of the present invention is to provide a stable, consistently reproducible amorphous form of linezolid; processes for preparing it; and to a pharmaceutical composition containing it.
DETAILED DESCRIPTION OF THE INVENTION
According to one aspect of the present invention, there is provided a novel amorphous form of linezolid. The amorphous linezolid is characterized by having broad x-ray powder diffraction spectrum as ih figure 1.
Amorphous linezolid is further characterized by IR spectrum in potassium bromide pellet having main absorption bands at about 3338, 3282, 3084, 1741 ,
1662, 1546, 1517, 1471 , 1446, 1425, 1379, 1334,. 1303, 1273, 1255, 1228,
1215, 1197, 1176, 1145, 1116, 1080, 1051, 939, 923, 902, 869, 823, 804, 752 and 661 cm"1. According to another aspect of the present invention, a process is provided for preparation of amorphous linezolid, which comprises spray drying or vacuum drying a solution of linezolid in a solvent.
The solution of linezolid is obtained by dissolving linezolid in a solvent. Preferably linezolid used in the preparation of above solution is in the form of crystalline form Il or crystalline form III and more preferably being crystalline form 111.
The solution of linezolid required in the process may also be obtained as a part of synthesizing linezolid. Linezolid may be synthesized by a process described in the prior art and the reaction mass obtained in the synthesis may optionally be washed with, for example, water before using the process of the invention.
Preferable solvent is selected from alcoholic solvents such as methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butyl alcohol; ketonic solvents such as acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone; ether solvents such as diethyl ether, diisopropyl ether and tert-butyl methyl ether; chlorinated hydrocarbon solvents such as methylene chloride, ethylene chloride and chloroform; hydrocarbon solvents such as toluene and xylene; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, tert-butyl acetate, ethyl formate and methyj formate; acetonitrile; tetrahydrofuran; dimethylformamide, dimethylsulfoxide; 1 ,4- dioxane; water; acetic acid; acetic anhydride and a mixture thereof. More preferable solvent is selected from acetonitrile, methanol and acetone. Most preferable solvent is acetonitrile. Linezolid used as starting material may be obtained by processes described in the art, for example by the processes described in U.S. Patent No. 6,559,305 and PCT Publication No. WO 2005/035530 Al
According to another aspect of the present invention there is provided a pharmaceutical composition comprising amorphous linezolid and a pharmaceutically acceptable excipient.
Preferable pharmaceutical composition of amorphous linezolid is a solid oral dosage form.
. BRIEF DESCRIPTION OF THE DRAWING Figure 1 is a X-ray powder diffraction spectrum of amorphous linezoϋd. X-Ray powder diffraction spectrum was measured on a Bruker axs D8 advance X-ray powder diffractometer having a Copper-Kα radiation. Approximately 1 gm of sample was gently flattened on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.03 degrees two-theta per step and a step time of 0.5 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitations on the scope or spirit of the invention.
Example 1
Linezolid form III (10 gm) is dissolved in acetonitrile (600 ml) at ambient temperature and then the solution is subjected to spray drying to give 9.6 gm of amorphous linezolid. Example 2
Linezolid form Il (10 gm) is dissolved in methanol (400 ml) at ambient temperature and then the solution is subjected to vacuum drying to give 9.5 gm of amorphous linezolid.
Example 3 Example 1 is repeated using linezolid form Il instead of linezolid form III to give 9.3 gm of amorphous linezolid.

Claims

We claim:
1. Amorphous form of linezolid.
2. A process for the preparation of amorphous linezolid as claimed in claim 1 , which comprises spray drying or vacuum drying a solution of linezolid in a solvent.
3. The process as claimed in claim 2, wherein the solution of linezolid is obtained by dissolving linezolid in a solvent.
4. The process as claimed in claim 3, wherein the linezolid used is in the form of crystalline form Il or crystalline form III.
5. The process as claimed in claim 4, wherein the linezolid used is in the form of crystalline form III.
6. The process as claimed in claim 2, wherein the solution of linezolid is obtained as a part of synthesizing linezolid.
7. The process as claimed in claim 2, wherein the solvent is selected from alcoholic solvents such as methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butyl alcohol; ketonic solvents such as acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone; ether solvents such as diethyl ether, diisopropyl ether and tert-butyl methyl ether; chlorinated hydrocarbon solvents, such as methylene chloride, ethylene chloride and chloroform; hydrocarbon solvents such as toluene and xylene; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n- butyl acetate, tert-butyl acetate, ethyl formate and methyl formate; acetonitrile; tetrahydrofuran; dimethylformamide, dimethylsulfoxide; 1,4- dioxane; water; acetic acid; acetic anhydride and a mixture thereof.
8. The process as claimed in claim 7, wherein the solvent is acetonitrile, methanol or acetone.
9. The process as claimed in claim 8, wherein the solvent is acetonitrile.
10. A pharmaceutical composition comprising amorphous linezolid of claim 1 and a pharmaceutically acceptable excipient.
11. The pharmaceutical composition as claimed in claim 10, wherein the pharmaceutical composition of amorphous linezolid is a solid oral dosage form.
PCT/IN2005/000249 2005-08-29 2005-08-29 A novel amorphous form of linezolid WO2007026369A1 (en)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2033960A2 (en) 2007-09-04 2009-03-11 Dipharma Francis S.r.l. Linezolid crystalline hydrate form and linezolid salts
WO2009140466A2 (en) * 2008-05-14 2009-11-19 Dr. Reddy's Laboratories Ltd. Linezolid co-crystals
WO2011051384A1 (en) 2009-10-28 2011-05-05 Synthon Bv Process for making crystalline form a of linezolid
WO2012019632A1 (en) 2010-08-11 2012-02-16 Synthon B.V. Process for making linezolid
WO2012119653A1 (en) 2011-03-09 2012-09-13 Synthon Bv Process for making crystalline form a of linezolid
EP2690100A1 (en) 2010-08-11 2014-01-29 Synhton B.V. Process for making linezolid
WO2014071990A1 (en) 2012-11-09 2014-05-15 Synthon Bv Process for making linezolid
WO2014118809A1 (en) 2013-01-29 2014-08-07 Actavis Group Ptc Ehf. Pharmaceutical composition with linezolid
WO2015068121A1 (en) 2013-11-06 2015-05-14 Unimark Remedies Ltd. Process for preparation of crystalline form i of linezolid and its compositions
WO2019097242A1 (en) 2017-11-16 2019-05-23 Persica Pharmaceuticals Ltd. Linezolid formulations
WO2023062080A1 (en) 2021-10-12 2023-04-20 Persica Pharmaceuticals Ltd. Low back pain treatment

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6559305B1 (en) * 2000-02-02 2003-05-06 Pharmacia & Upjohn Company Linezolid—crystal form II
CN1615878A (en) * 2004-09-01 2005-05-18 魏雪纹 Linwzolid powder injection and preparing method

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6559305B1 (en) * 2000-02-02 2003-05-06 Pharmacia & Upjohn Company Linezolid—crystal form II
CN1615878A (en) * 2004-09-01 2005-05-18 魏雪纹 Linwzolid powder injection and preparing method

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2033960A2 (en) 2007-09-04 2009-03-11 Dipharma Francis S.r.l. Linezolid crystalline hydrate form and linezolid salts
US7989618B2 (en) 2007-09-04 2011-08-02 Dipharma Francis S.R.L. Linezolid crystalline hydrate form and linezolid salts
WO2009140466A2 (en) * 2008-05-14 2009-11-19 Dr. Reddy's Laboratories Ltd. Linezolid co-crystals
WO2009140466A3 (en) * 2008-05-14 2010-03-04 Dr. Reddy's Laboratories Ltd. Linezolid co-crystals
WO2011051384A1 (en) 2009-10-28 2011-05-05 Synthon Bv Process for making crystalline form a of linezolid
WO2011050865A1 (en) 2009-10-28 2011-05-05 Synthon B.V. Process for making crystalline form a of linezolid
WO2012019632A1 (en) 2010-08-11 2012-02-16 Synthon B.V. Process for making linezolid
WO2012019862A1 (en) 2010-08-11 2012-02-16 Synthon B.V. Process for making linezolid
EP2690100A1 (en) 2010-08-11 2014-01-29 Synhton B.V. Process for making linezolid
WO2012119653A1 (en) 2011-03-09 2012-09-13 Synthon Bv Process for making crystalline form a of linezolid
WO2014071990A1 (en) 2012-11-09 2014-05-15 Synthon Bv Process for making linezolid
WO2014118809A1 (en) 2013-01-29 2014-08-07 Actavis Group Ptc Ehf. Pharmaceutical composition with linezolid
WO2015068121A1 (en) 2013-11-06 2015-05-14 Unimark Remedies Ltd. Process for preparation of crystalline form i of linezolid and its compositions
WO2019097242A1 (en) 2017-11-16 2019-05-23 Persica Pharmaceuticals Ltd. Linezolid formulations
WO2023062080A1 (en) 2021-10-12 2023-04-20 Persica Pharmaceuticals Ltd. Low back pain treatment

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