MOXIFLOXACIN
Bay-12-8039
US FDA:link
CAS 354812-41-2
186826-86-8 HYDROCHLORIDE
1-cyclopropyl-7-[(1S,6S)-2,8-diazabicyclo[4.3.0]non-8-yl]-6-fluoro-8-methoxy-4-oxo- quinoline-3-carboxylic acid
(4aS-Cis) -l-cyclopropyl-7- (2, 8- diazabicyclo [4.3.0] non-8-yl) -6-fluoro-8-methoxy-4-oxo-l, 4-dihydro-3- quinoline carboxylic acid
ALSO AS….
Vigamox, Avelox I.V., 151096-09-2, Moxifloxacin [INN:BAN], MXFX, CHEMBL32, Actira (*Hydrochloride*), Avelox (*Hydrochloride*)
Molecular Formula: C21H24FN3O4
Molecular Weight: 401.431363
Moxifloxacin is a synthetic fluoroquinolone antibiotic agent. Bayer AG developed the drug (initially called BAY 12-8039) and it is marketed worldwide (as the hydrochloride) under the brand name Avelox (in some countries also Avalox) for oral treatment
For the treatment of sinus and lung infections such as sinusitis, pneumonia, and secondary infections in chronic bronchitis. Also for the treatment of bacterial conjunctivitis (pinkeye).
http://www.fda.gov/ohrms/dockets/ac/99/slides/3558s1i/sld001.htm
Moxifloxacin and its salts are antibacterial agents, which were disclosed in EP 550,903. Moxifloxacin, chemically 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS, 7aS)-octahydro-6H-pyrrolo[3,4-b]pyridine-6-yl]-4-oxo-3-quinolinecarboxylic acid
Moxifloxacin is a fourth-generation synthetic fluoroquinolone antibacterial agent developed by Bayer AG (initially called BAY 12-8039). It is marketed worldwide (as the hydrochloride) under the brand names Avelox, Avalox, and Avelon for oral treatment. In most countries, the drug is also available in parenteral form for intravenous infusion. Moxifloxacin is also sold in an ophthalmic solution (eye drops) under the brand names Vigamox, Moxezafor the treatment of conjunctivitis (pink eye).
A United States patent application was submitted on 30 June 1989, for Avelox (moxifloxacin hydrochloride).[1] In 1999 Avelox was approved by theU.S. Food and Drug Administration (FDA) for use in the United States.[2]
In the United States, moxifloxacin is licensed for the treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, community acquired pneumonia, complicated and uncomplicated skin and skin structure infections, and complicated intra-abdominal infections.[3]
In the European Union, it is licensed for acute bacterial exacerbations of chronic bronchitis, non-severe community-acquired pneumonia, and acute bacterial sinusitis. Based on its investigation into reports of rare but severe cases of liver toxicity and skin reactions, the European Medicines Agency recommended in 2008 that the use of the oral (but not the IV) form of moxifloxacin be restricted to infections in which other antibacterial agents cannot be used or have failed.[4] In the US, the marketing approval does not contain these restrictions, though the label contains prominent warnings against skin reactions.MOXIFLOXACIN
Avelox (moxifloxacin) was launched in the United States in 1999 and is currently marketed in more than 80 countries worldwide. In the United States, Avelox is marketed by Bayer’s partner Merck.
In 2011 the FDA added two boxed warnings for this drug in reference to spontaneous tendon ruptures and the fact that moxifloxacin may cause worsening of myasthenia gravis symptoms, including muscle weakness and life-threatening breathing problems.[5]
Moxifloxacin is used to treat a number of infections including: respiratory tract infections, cellulitis, anthrax, intraabdominal infections, endocarditis,meningitis, and tuberculosis.[6]
The initial approval by the FDA (December 1999)[7] encompassed the following indications:
Acute Exacerbations of Chronic Bronchitis (AECB)
Acute Bacterial Sinusitis (ABS)
Community Acquired Pneumonia (CAP)
Additional indications were approved by the FDA as follows:
April 2001: Uncomplicated Skin and Skin Structure Infections (uSSSI)[8]
May 2004: Community Acquired Pneumonia caused by multi-drug resistant Streptococcus pneumoniae.[9]
June 2005: Complicated Skin and Skin Structure Infections (cSSSI)[10]
November 2005: Complicated Intra-Abdominal Infections (cIAI).[11]
The European Union requires that moxifloxacin only be prescribed when other antibiotics that have been initially recommended for treatment cannot be used or have failed.[12][13]
At the current time,[when?] there are no approved uses within the pediatric population for Oral and I.V. moxifloxacin. A significant number of drugs found within this class, including moxifloxacin, are not licensed by the FDA for use in children due to the risk of permanent injury to the musculoskeletal system.[14][15][16]
In ophthalmology, moxifloxacin is approved for the treatment of conjunctival infections caused by susceptible bacteria.[17]
Note: Moxifloxacin may be licensed for other uses, or restricted, by the various regulatory agencies worldwide
Marketing authorisations for the tablet and injectable forms of Moxifloxacin are held by Bayer, while Alcon (now a subsidiary of Novartis) produces ophthalmic solutions for treating conjunctivitis under the brand names of Moxeza, Vigamox, and Moxivig. Avelox generated sales of USD320 million in the first 9 months of 2013.
Moxifloxacin is available in three distinct administration forms. Formulated as a salt, Moxifloxacin hydrochloride is sold as an oral 400 mg film-coated tablet and as an injectable solution for infusion by Bayer; although in the US it is distributed by Merck Sharp and Dohme under license from Bayer.
Alcon has formulated Moxifloxacin hydrochloride as a 0.5% ophthalmic solution under license from Bayer. Moxifloxacin was first discovered in 1988 and received the first market authorisation eleven years later in 1999 in the US.
Moxifloxacin hydrochloride is a synthetic broad-spectrum antibacterial agent. The active moiety, moxifloxacin has been shown to be clinically active against most strains of microorganisms such as aerobic gram-positive microorganisms including staphylococcus aureus, streptococcus pneumonia (penicillin-susceptible strains) and streptococcus pyogenes, aerobic gram-negative microorganisms including haemophilus influenza hemophilus parainfluenzae, klebisiella pneumonia. Moxifloxacin is commercially available under the brand name of AVELOX® marketed by Bayer pharms.
VIGAMOX® (moxifloxacin hydrochloride ophthalmic solution) 0.5% is a sterile solution for topical ophthalmic use. Moxifloxacin hydrochloride is an 8-methoxy fluoroquinolone anti-infective, with a diazabicyclononyl ring at the C7 position.
http://images.rxlist.com/images/rxlist/vigamox1.gif” width=”286″ height=”171″ />
C21H24FN304•HC1 Mol Wt 437.9
Chemical Name: l-Cyclopropyl-6-fluoro-l,4-dihydro-8-methoxy-7-[(4aS,7aS)-octahydro-6H-pyrrolol[3,4-b]pyridin-6-yl]-4-oxo-3-quinolinecarboxylic acid, monohydrochloride. Moxifloxacin hydrochloride is a slightly yellow to yellow crystalline powder. Each mL of VIGAMOX® solution contains 5.45 mg moxifloxacin hydrochloride, equivalent to 5 mg moxifloxacin base.
Contains: Active: Moxifloxacin 0.5% (5 mg/mL); Inactives: Boric acid, sodium chloride, and purified water. May also contain hydrochloric acid/sodium hydroxide to adjust pH to approximately 6.8.
VIGAMOX® solution is an isotonic solution with an osmolality of approximately 290 mOsm/kg.
Market Considerations
Amongst the US approvals, Dr. Reddy’s, Teva, Torrent, and Aurobindo have received tentative approvals for the 400 mg oral tablet formulation. Akorn, Teva and Apotex have received tentative approvals for a Moxifloxacin hydrochloride ophthalmic solution. No 180 day period of exclusivity has been awarded since all patents were found to be valid.
In the UK, Teva, Rivopharm, and Double-E Pharma have received marketing authorisations for the 400 mg Moxifloxacin tablets, while Noridem has received a market authorisation for the equivalent 400mg/250ml solution for infusion. A similar trend of generic competition, for tablets and infusions, following molecule patent expiry is expected throughout Europe. Currently no generic market authorisations for ophthalmic formulations have been granted in major European countries. However, Sandoz and Hexal have gained market authorisations in some European markets for the ophthalmic dosage form following Novartis’ acquisition of Alcon.
In Canada the only generic manufacturer holding a marketing authorisation is Sandoz, however, this was granted as a New Drug Submission rather than as an ANDS. Following patent expiries from mid-2014, the European and North American markets are likely to have significant competition if the numbers of companies filing litigation, ANDS, ANDAs and the like in the northern hemisphere is anything to go by.
MOXIFLOXACIN
History
Moxifloxacin was first patented (United States patent) in 1991 by Bayer A.G., and again in 1997.[47] Avelox was subsequently approved by the U.S. Food and Drug Administration (FDA) for use in the United States in 1999 to treat specific bacterial infections.[2] Ranking 140th within the top 200 prescribed drugs in the United States for 2007[48] moxifloxacin, in the same manner asciprofloxacin, has proven to be a blockbuster drug for Bayer A. G., generating billions of dollars in additional revenue. In 2007 alone, Avelox generated sales of $697.3 million dollars worldwide.[26]
Moxifloxacin is also manufactured by Alcon as Vigamox.[citation needed]
Patent
A United States patent application was made on 30 June 1989, for Avelox (moxifloxacin hydrochloride),(Bayer A.G. being the assignee), which was subsequently approved on 5 February 1991. This patent was scheduled to expire on 30 June 2009. However, this patent was extended for an additional two and one half years on 16 September 2004, and as such is not expected to expire until 2012.[49] Moxifloxacin was subsequently (ten years later) approved by the U.S. Food and Drug Administration (FDA) for use in the United States in 1999. There have been at least four additional United States patents filed regarding moxifloxacin hydrochloride since the 1989 United States application,[47][50] as well as patents outside of the USA.
Additional regulatory history
6/12/2002 Changes made to minimize the impact of warnings concerning adverse reactions.[51]
26 June 2003 New Zealand Pharmacovigilance warns of moxifloxacin induced respiratory insufficiency.[52]
10/6/2003 Changes made to minimize the impact of post marketing reports as well as the risk of tendon injuries.[53]
29 December 2008 Addition of numerous adverse reactions associated with the use of moxifloxacin.[54]
27 April 2009 Issuance of a Medication Guide and revisions to include new safety information including the addition of the Black Box Warning to the Medication Guide. The FDA had determined that Moxifloxacin poses a serious and significant public health concern, requiring the distribution of a Medication Guide.[55]
24 June 2009 Updating of the carton and container labels to include a statement to let dispensers know that a Medication Guide must be dispensed with the product.(emphasis added)[56]
Patent related
Country
Patent Number
Approved
Expires (estimated)
Canada
1340114
1998-11-03
2015-11-03
Canada
2342211
2009-05-26
2019-09-29
United States
4990517
1994-12-08
2011-12-08
United States
6548079
2000-07-25
2020-07-25
As indicated by the Key Patent Indicator (Fig. 2), patents in the families with priority DE3824072A, 15/07/1988 (‘072), and DE4200414A, 10/01/1992, (‘414) provide protection for the Moxifloxacin molecule and are considered to be the main constraint to generic entry. As patents in the ‘414 family have expired or were never granted, the only remaining constraint to generic entry is the ‘072 family. The term of the Australian patent of this family have been extended to 19 June 2014 while the Canadian member will enjoy the longer term of 17 years from grant, expiring in November 2015.
Supplementary protection certificates (SPCs) have been granted in France, Germany, Spain and the UK, and will expire in June 2014. Given that there are less than 2 years until these SPCs expire, and that as yet no applications for paediatric extension of the SPCs have been published in Europe, they are unlikely to be extended by 6 months on the basis of the approved Paediatric Investigation Plans.
The US member, 4,990,517 (‘517), protecting the general structure of the Moxifloxacin molecule, expired in June 2012, after enjoying 6 month paediatric extension on top of a 901 day s156 extension. However, the absence of generics on the US market is due to Bayer securing a divisional patent, 5,607,942 (‘942). This patent claims the Moxifloxacin molecule specifically and is due to expire in September 2014, after being awarded a 6 month paediatric extension.
Members of the ‘072 family from both Canada and the US have been the subject of litigation after generic manufacturers identified these patents in paragraph IV filings, and the equivalent in Canada, as early as 2006. After filing an infringement suit in the US against Teva in relation to US ‘517, US ‘942, Bayer enjoyed a satisfying validification of their patents when Teva agreed that it would be infringing two of the patents, while the third was decided by the court to be equally valid.
In Canada, Novopharm, Cobalt, Apotex, Mylan and Apotex have also all tested the litigation waters relating to the equivalent patent with no success noted so far.
A third patent family that promises to be a constraint for generic ophthalmic formulations is Alcon’s 1998 patent, US10250498P (Fig. 2), which identifies an ophthalmic formulation of Moxifloxacin and its use in the treatment and prevention of eye infections. Patents in this family are set to expire in August 2019. US members 6,716,830 (‘830) and 7,671,070 (‘070) have been awarded a 6 month paediatric extension, extending their expiration until March 2020. The validity of US ‘830 was upheld following Teva filing paragraph IV certifications to manufacture generic Vigamox. Teva has since appealed this ruling.
In addition, Alcon has filed patent infringement suits against Watson, Lupin and Apotex in relation to US ‘070 after they submitted Abbreviated New Drug Applications (ANDAs)with paragraph IV filings in preparation for commercialisation of a Moxeza/Vigamox generic equivalent. There has been no outcome from these suits to date. In addition, applications for Orders of Prohibition against Cobalt, Apotex and Teva have also been noted for the equivalent Canadian patent following the filing of Abbreviated New Drug Submissions (ANDS) by these companies.
The equivalent European patent 1,117,401 was revoked following opposition by Teva filed in the European patent office. Its divisional patents, 1,384,478 (granted) and 2,301,541 (accepted) have restricted claims to the use of Moxifloxacin in the topical treatment of ophthalmic infections caused by P. aeruginosa and H. influenza, respectively. This may provide a prepared generic competitor an opportunity to launch their Moxifloxacin ophthalmic equivalent in Europe soon after the expiry of patents protecting the molecule, subject to legal review of the remaining claims of the patent.
Alcon have secured additional protection for their Moxeza ophthalmic formulation by way of patents in the family with priority US5987708P (09/06/2008). Patent claims specify ratios of Moxifloxacin to inactive ingredients and additional inactive ingredients and therefore generic competitors are likely to circumvent the patent by reformulation. Lupin has filed paragraph IV certifications to US8450311, which is currently subject of a patent infringement suit.
Families with priorities DE19546249A (12/12/1995), DE19751948A (24/11/1997), DE19855758A (10/11/1998) and US36433499A (30/07/1999) are not considered to be a constraint to generic entry because the protected technologies are likely to be circumvented.
Generic equivalents
In 2007, the U.S. District Court for the District of Delaware held that two Bayer patents on Avelox (moxifloxacin hydrochloride) are valid and enforceable, and infringed by Dr. Reddy’s ANDA for a generic version of Avelox.[70][71] The district court sided with Bayer, citing the Federal Circuit’s prior decision in Takeda v. Alphapharm[72] as “affirming the district court’s finding that defendant failed to prove a prima facie case of obviousness where the prior art disclosed a broad selection of compounds, any one of which could have been selected as a lead compound for further investigation, and defendant did not prove that the prior art would have led to the selection of the particular compound singled out by defendant.” According to Bayer’s press release[70] announcing the court’s decision, it was noted that Teva had also challenged the validity of the same Bayer patents at issue in the Dr. Reddy’s case. Within Bayer’s first quarter 2008 stockholder’s newsletter[73]
Bayer stated that they had reached an agreement with Teva Pharmaceuticals USA, Inc., the adverse party, to settle their patent litigation with regard to the two Bayer patents. Under the settlement terms agreed upon, Teva would obtain a license to sell its generic moxifloxacin tablet product in the U.S. shortly before the second of the two Bayer patents expires in March 2014.
Economic impact: adverse reactions:
The advocacy group Public Citizen has lobbied for increasing safety warnings and for the removal of some fluoroquinolone drugs from clinical practice.[74][75][76][77][78][79][80][81]
US5607942
3-5-1997
7-(1-pyrrolidinyl)-3-quinolone- and – naphthyridone-carboxylic acid derivatives as antibacterial agents and feed additives
WO0032196
6-9-2000
INHIBITORS OF MULTIDRUG TRANSPORTERS INHIBITORS OF MULTIDRUG TRANSPORTERS
WO0027398
5-19-2000
PHARMACEUTICAL MOXIFLOXACIN PREPARATION
WO0025765
5-12-2000
AQUEOUS DRUG FORMULATION FOR ORAL APPLICATION AQUEOUS DRUG FORMULATION FOR ORAL APPLICATION
WO0018386
4-7-2000
ANTIBIOTIC COMPOSITIONS FOR TREATMENT OF THE EYE, EAR AND NOSE ANTIBIOTIC COMPOSITIONS FOR TREATMENT OF THE EYE, EAR AND NOSE
WO0018388
4-7-2000
ANTIBIOTIC COMPOSITIONS FOR TREATMENT OF THE EYE, EAR AND NOSE ANTIBIOTIC COMPOSITIONS FOR TREATMENT OF THE EYE, EAR AND NOSE
WO0018404
4-7-2000
ANTIBIOTIC COMPOSITIONS FOR TREATMENT OF THE EYE, EAR AND NOSE
EP0971691
1-20-2000
COMBINATION PREPARATION FOR ORALLY ADMINISTERED ANTIBIOTICS
WO9964037
12-17-1999
NOVEL THERAPEUTIC AGENTS THAT MODULATE ENZYMATIC PROCESSES
WO9915172
4-2-1999
MEDICAMENT FORMULATION WITH A CONTROLLED RELEASE OF AN ACTIVE AGENT
WO9836732
8-28-1998
COMBINATION PREPARATION FOR ORALLY ADMINISTERED ANTIBIOTICS COMBINATION PREPARATION FOR ORALLY ADMINISTERED ANTIBIOTICS
US2006252789
11-10-2006
Amorphous moxifloxacin hydrochloride
US7115744
10-4-2006
Method for producing 8-methoxy-quinolinecarboxylic acids
US2005152975
7-15-2005
Pharmaceutical composition
US6916484
7-13-2005
Aqueous pharmaceutical composition containing moxifloxacin or salts thereof
US6897315
5-25-2005
Method for producing 8-methoxy-quinolinecarboxylic acids
US2004022848
2-6-2004
Medicinal composition
US6566523
5-21-2003
Method for the enantiomer separation of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane
WO0071541
11-31-2000
OPTICALLY ACTIVE QUINOLINE CARBOXYLIC ACID DERIVATIVES HAVING 7-PYRROLIDINE SUBSTITUTES CAUSING OPTICAL ACTIVITY AND A PROCESS FOR PREPARING THEREOF
WO0068229
11-17-2000
ANTIBACTERIAL OPTICALLY PURE BENZOQUINOLIZINE CARBOXYLIC ACIDS, PROCESSES, COMPOSITIONS AND METHODS OF TREATMENT (S)-BENZOQUINOLIZINE CARBOXYLIC ACIDS AND THEIR USE AS ANTIBACTERIAL AGENTS
WO0050007
8-32-2000
COMPOSITIONS AND METHODS FOR IMPROVED DELIVERY OF HYDROPHOBIC THERAPEUTIC AGENTS
US2010152414
6-18-2010
MULTI-ARM POLYMER PRODRUGS
US2010087409
4-9-2010
COMPOSITION COMPRISING AN ANTIBIOTIC AND A CORTICOSTEROID
US7563805
7-22-2009
Tri-, tetra-substituted-3-aminopyrrolidine derivative
US2009170893
7-3-2009
NOVEL HYDRATE FORM
US2009074704
3-20-2009
Multi-Arm Polymer Prodrugs
US2009018169
1-16-2009
Sulfonamide Derivatives for the Treatment of Bacterial Infections
US2008287396
11-21-2008
Phosphonated Fluoroquinolones, Antibacterial Analogs Thereof, and Methods for the Prevention and Treatment of Bone and Joint Infections
US2008194612
8-15-2008
Multi-arm polymer prodrugs
US2007196504
8-24-2007
PHARMACEUTICAL COMPOSITION
US2007148235
6-29-2007
PHARMACEUTICAL COMPOSITION
US8211910
7-4-2012
TRI-, TETRA-SUBSTITUTED-3-AMINOPYRROLIDINE DERIVATIVE
US8198451
6-13-2012
Process for the Synthesis of Moxifloxacin Hydrochloride
US2011293717
12-2-2011
COMPACTED MOXIFLOXACIN
US8034817
10-12-2011
Treatment of bacterial diseases of the respiratory organs
US2011224249
9-16-2011
Novel Hydrate Form
US2011212990
9-2-2011
NOVEL POLYMORPH OF MOXIFLOXACIN HYDROCHLORIDE
US2011159049
6-31-2011
PHARMACEUTICAL COMPOSITION
US2011137036
6-10-2011
SYNTHESIS OF (4aS,7aS)-OCTAHYDRO-1H-PYRROLO[3,4-b]PYRIDINE
US2010190933
7-30-2010
MULTI-ARM POLYMER PRODRUGS
US7744861
6-30-2010
Multi-arm polymer prodrugs
DESCRIPTION
Moxifloxacin is a therapeutic agent that shows a broad spectrum antibacterial action. Moxifloxacin is the international non-proprietary name (INN) for 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4-oxo-3-quinolinecarboxylic acid.
The structure of moxifloxacin corresponds to formula (I):
Racemic moxifloxacin was firstly described in EP-A-350733 and, particularly, moxifloxacin having a (S,S)-configuration is described inEP-A-550903 .
In experimental example 19 of EP-A-550903 and example Z19 of EP-A-591808 , a method for preparing and isolating moxifloxacin base is described. The same method is described in patent document EP-A-592868 ). These published patent applications neither describe nor suggest the possible existence of a crystalline form of moxifloxacin base. In WO-A-2008059521 it is disclosed that by performing the mentioned examples an acetonitrile solvated form of moxifloxacin with low purity is obtained, and so the obtained solvate form can not be used as such in pharmaceutical formulations. In the above mentioned examples, the obtained moxifloxacin base crude is purified and isolated by chromatography using methylene chloride/methanol/17% aqueous ammonia as the solvent system. The purification process disclosed in said documents has been reproduced by the authors of the present invention, but only an amorphous form of moxifloxacin was obtained. This process for the purification and isolation of moxifloxacin base is complex and difficult to perform on industrial scale due to the need for purifying the product by column chromatography.
WO-A-9926940 discloses a process for the preparation of moxifloxacin from a difluoro precursor comprising the step of adjusting the pH to 6.8- 7.0. However, the reproduction of this example shows that at this pH moxifloxacin hydrochloride or a mixture of moxifloxacin hydrochloride and moxifloxacin base is obtained, since the X-ray diffractogram of the isolated compound corresponds with the hydrochloride moxifloxacin. This fact has also been confirmed by the reproduction of the subsequent crystallization described in the international patent application of the previous compound in ethanol/water. The behaviour of this solid was very different regarding its solubility in respect what was described in the international patent application.
WO-A-2004091619 and WO-A-2007010555 disclose the preparation of moxifloxacin base as a solid. Nevertheless, they do not describe nor suggest the preparation of a crystalline form of moxifloxacin base. The authors of the present invention have proved that the X-ray diffractogram of the product obtained by reproducing the reference example disclosed in WO-A-2004091619 , based on a pH adjustment to 7.0-7.2, corresponds to the X-ray diffractogram of the monohydrate of moxifloxacin hydrochloride disclosed in US 5849752 . Similarly, by reproducing the reference example of WO-A-2007010555 , also for obtaining moxifloxacin base but based on a pH adjustment to 5.0-6.0, it is neither expected to obtain moxifloxacin base due to the adjustment of the solution within a range of acidic pH values.
[0008]
WO-A-2008059521 discloses a process for the preparation of a crystalline form of moxifloxacin base, designated as Form I, by recrystallization in a ketosolvent, such as acetone. This form is characterized by its X-ray diffraction pattern corresponding to a hemihydrate. The best yield obtained is a 78.2% starting from moxifloxacin hydrochloride in example 18. This crystalline form has a tendency to occlude solvent molecules within the crystalline network in amounts very superiors to the allowed ones by for Guidelines Residual Solvents (CPMP/ICH/283/95) and can be difficult to impossible to remove by drying, what forces to carry out laborious treatments, either physical, or chemical to reach allowed solvent levels. The presence of any non-aqueous solvents in amounts over the allowed ones would not make this crystalline form suitable for the preparation of pharmaceutical formulations.
The existence of polymorphs is unpredictable and there is no a priori established procedure to prepare an unknown polymorph. The difference in the physical properties of different morphological forms results from the orientation and intermolecular interactions of adjacent molecules are complexes in the bulk solid. Furthermore, the different solid forms of a pharmaceutically active ingredient can have different characteristics, and offer certain advantages in methods of manufacture and also in pharmacology. Thus, the discovery of new solid forms can contribute to clear improvements in the efficiency of methods of production and/or improvements in the characteristics of the pharmaceutical formulations of the active ingredients, since some forms are more adequate for one type of formulation, and other forms for other different formulations.
Moxifloxacin Hydrochloride namely (4aS-Cis) -l-cyclopropyl-7- (2, 8- diazabicyclo [4.3.0] non-8-yl) -6-fluoro-8-methoxy-4-oxo-l, 4-dihydro-3- quinoline carboxylic acidhydrochloride has the formula
Moxifloxacin Hydrochloride
Moxifloxacin is a fluoroquinolone broad spectrum antibacterial particularly against Gram-positive bacteria significantly better than those of Sparfloxacin and Ciprofloxacin that was disclosed in EP No 350,733 and EP No 550,903. Moxifloxacin has activity against Gram- negative and Gram-positive organisms, including Streptococcus pneumonia, Staphylococcus aureus, Pseudomonas aeruginosa, particularly against the respiratory disease-causing pathogens like Mycoplasma pneumonia, Mycobacterium tuberculosis, Chlamydia pneumoniae and the activity shown to be unaffected by B-lactamases .
US Patent No 5,157,117 discloses (l-cyclopropyl-6, 7-difluoro-8-methoxy- 4-oxo-l, 4-dihydro-3-quinoline carboxylic acid-O3, 04)bis (acyloxy-O) borate and process for its preparation by reacting ethyl-1- cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-l, -dihydro-3-quinoline carboxylate with Boric acid and acetic anhydride in presence of zinc chloride and its conversion to Gatifloxacin hydrochloride.
WO 2005/012285 discloses the process for the preparation of moxifloxacin hydrochloride using a novel intermediate namely (4aS-Cis)-(1-cyclopropyl-7-(2,8-diazabicyclo[4,3,0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-O3,O4)bis(acycloxy-O)borate.
Hydrates of Moxifloxacin hydrochloride known are the anhydrous and monohydrate. US Patent No. 5,849,752 discloses the monohydrate of Moxifloxacin hydrochloride and its preparation by treating the anhydrous crystalline form with ethanol/ water mixtures.
The prior art disclosed in European Patent No’s EP 350,733, EP 550,903 and EP 657,448 discloses the preparation of Moxifloxacin hydrochloride involving the condensation of l-cyclopropyl-6, 7-difluoro-8-methoxy-4- oxo-1, 4-dihydro-3-quinoline carboxylic acid or its esters with (S,S) 2,8-Diaza bicyclo [4.3.0] nonane in presence of a base and its conversion to hydrochloride at higher temperatures leading to the desired Moxifloxacin along with its positional isomer namely (4aS-Cis)-l- cyclopropyl-6- (2, 8-diazabicyclo [4.3.0] non-8-yl) -7-fluoro-8-methoxy-4- oxo-1, 4-dihydro-3-quinoline carboxylic acid as a major impurity. As the impurity and the Moxifloxacin are positional isomers they are difficult to separate. Purification of Moxifloxacin to remove this isomer results in lower yields thereby increasing the product cost. Similarly methods described in the prior art involves the preparation of Moxifloxacin and then its conversion to its hydrochloride thereby incorporating an additional step in the manufacturing process also leading to lowering of yields.
Moxifloxacin and its pharmacologically acceptable salts are disclosed in European patents EP 350733, EP 550903 and EP 657,448. The disclosed process for the preparation of moxifloxacin hydrochloride comprises of condensing l-cyclopropyl-6,7- difluoro-8-methoxy-4-oxo-l,4-dihydro-3-quinoline carboxylic acid or its esters with (S,S)2,8-diazobicyclo[4.3.0]nonane, in presence of a base at high temperature followed by conversion into hydrochloride salt .
This process not only produces desired moxifloxacin hydrochloride but also its positional isomer namely l-cyclopropyl-7-fluoro- 1,4- dihydro -8- methoxy -6- (4aS,7aS)- octahydro- 6H -pyrrolo [3,4-b] pyridine-6-yl] -4- oxo-quinolinecarboxylic acid as a major impurity which is difficult to separate. The purification of moxifloaxcin to remove this isomer results in lower yields thereby increasing the product cost.
The International publication WO 2005/012285 discloses an improved process for the preparation of moxifloxacin hydrochloride incorporated herein by reference. The disclosed process involves the preparation of moxifloxacin hydrochloride from the ethyl 1 -cyclopropyl-6,7-difluoro-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolme carboxylate through a novel intermediate (4aS-cis)-l-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8- yl)-6-fluoro-8-methoxy-4-oxo- 1 ,4-dihydro-3 -quinolinecarboxylicacid-03,04)bis(acyloxy -0)-borate.
US patent application 6897315 discloses a process for the preparation of 8-methoxy-3-quinoline carboxylic acid especially moxifloxacin incorporated herein by reference. The disclosed process involves the preparation of moxifloxacin from 8-halo moxifloxacin derivative using methanol and potassium tertiary butoxide. US patent 5639886 discloses one-pot process for the preparation of 3-quinoline carboxylic acid derivatives including moxifloxacin.
WO 2004 091619 claims anhydrous crystalline form-Ill of moxifloxacin hydrochloride and WO 2004/039804 claims amorphous form of moxifloxacin hydrochloride. US Pat.No.5, 849,752 discloses specific crystalline forms of anhydrous moxifloxacin mono hydrochloride and monohydrated moxifloxacin mono hydrochloride. Anhydrous moxifloxacin mono hydrochloride disclosed in US Pat. No.5, 849,752 has been designated as “Form-I” and the hydrated form as “Form-II” in US Pat. No.7,230,006. It also discloses a novel crystalline Form-Ill of anhydrous moxifloxacin mono hydrochloride.
US patent US 5,480,879 discloses the melting range of moxifloxacin in example part as 203-208°C and does not speaks about polymorphism of moxifloxacin. Experiment executed as per the procedure given in example Zl 9 of US 5,480,879 and resulted in acetonitrile solvated form of moxifloxacin with low purity and the obtained solvated form can not used for formulations
U.S. Pat. No. 5,849, 752 (“the ‘752 patent”), incorporated by reference, described two crystalline forms of moxifloxacin hydrochloride namely, anhydrous moxifloxacin hydrochloride and monohydrated moxifloxacin hydrochloride. For convenience, the anhydrous crystalline form described in the 752 patent is designated as “Form I”, and the hydrated form as “Form II”. According to U.S. Pat. No. ‘752’, moxifloxacin hydrochloride monohydrate Form II was obtained by stirring a suspension of the anhydrous moxifloxacin hydrochloride in aqueous media until hydration. Moxifloxacin hydrochloride monohydrate of ‘752’ was also prepared by crystallizing moxifloxacin hydrochloride from a media having a water content which is stoichiometrically sufficient but limited to 10%.
WO patent application publication No. 04/091619 disclosed anhydrous Form III of moxifloxacin hydrochloride.
WO patent application publication No. 04/039804 disclosed amorphous form of moxifloxacin hydrochloride.
WO 2005/054240 disclosed two novel crystalline forms which were designated as Form A and Form B of moxifloxacin hydrochloride.
WO patent application publication No. 07/010555 disclosed two crystalline forms which were Form X and Form Y of moxifloxacin hydrochloride. According to WO Publication No. 2007/010555, Form Y was obtained by crystallization of moxifloxacin hydrochloride from the mixture of methanol and water in the ratio of about 8:1 by volume.
WO patent application publication No. 07/148137 disclosed hydrate form of moxifloxacin hydrochloride. According to WO Publication No. 2007/148137, moxifloxacin hydrochloride monohydrate was obtained by crystallization moxifloxacin hydrochloride by humidification of moxifloxacin hydrochloride at 50-90% relative humidity at 25-60° C. for 8 to 24 hours.
WO patent application publication No. 08/028959 disclosed crystalline form of moxifloxacin hydrochloride. According to WO Publication No. 2008/028959, moxifloxacin hydrochloride was obtained by dissolving moxifloxacin hydrochloride in a mixture of methanol and water and adding acetone and recovering moxifloxacin hydrochloride crystalline form.
WO patent application publication No. 08/059521 disclosed process for the preparation of anhydrous crystalline form I of moxifloxacin hydrochloride.
WO patent application publication No. 08/095964 disclosed crystalline form of moxifloxacin base.
……………………
SYNTHESIS
Drugs Fut 1997,22(2),109
36th Intersci Conf Antimicrob Agents Chemother (Sept 15-18, New Orleans) 1996,Abst. F1.
The anhydrization of pyridine-2,3-dicarboxylic acid (I) with acetic anhydride gives the corresponding anhydride (II), which by treatment with benzylamine (III) is converted into the benzylimide (IV). The hydrogenation of (IV) with H2 over Pd/C yields 8-benzyl-2,8-diazabicyclo[4.3.0]nonane-7,9-dione (V), which is further hydrogenated with LiAlH4, affording (?-cis-8-benzyl-2,8-diazabicyclo[4.3.0]nonane (VI) (1). The optical resolution of (VI) by separation of the cis-(R,R)-isomer as crystalline L-(+)-tartrate and further purification of the cis-(S,S)-isomer (VII) as the D-(-)-tartrate affords enantiomerically pure (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane (VII). The debenzylation of (VII) by hydrogenolysis with H2 over Pd/C gives (S,S)-2,8-diazabicyclo[4.3.0]nonane (VIII), which is condensed with 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (IX) in basic medium and finally salified with HCl. The 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (IX) has been obtained as follows: The reaction of 2,4,5-trifluoro-3-methoxybenzoyl chloride (X) with malonic acid monoethyl ester monopotassium salt (XI) by means of triethylamine gives 2-(2,4,5-trifluoro-3-methoxybenzoyl)acetic acid ethyl ester (XII), which is condensed with triethyl orthoformate yielding the corresponding ethoxymethylene derivative (XIII). The reaction of (XIII) with cyclopropylamine affords the cyclopropylaminomethylene derivative (XIV), which is finally cyclized to (IX) by means of NaF in DMF.
………………………..
J Label Compd Radiopharm 2000,43(8),795
The condensation of 2,4,5-trifluoro-3-methoxybenzoyl chloride (I) with 14C-labeled diethyl malonate (II) by means of MgCl2 and TEA gives the benzoylmalonate (III), which is monodecarboxylated with TsOH in refluxing water, yielding the benzoylacetate (IV). The reaction of (IV) with triethyl orthoformate and Ac2O at 140 C affords the benzoylacrylate (V), which is treated with cyclopropylamine (VI) in cyclohexane to provide ethyl 3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)acrylate (VII). The cyclization of (VII) by means of K2CO3 in hot N-methylpyrrolidone gives the quinolone carboxylate (VIII), which is hydrolyzed with NaOH in hot methanol, affording the carboxylic acid (IX). Finally, this compound is condensed with (S,S)-2,8-diazabicyclo[4.3.0]octane (X) by means of 1,4-diazabicyclo[2.2.2]octane (DABCO) in refluxing acetonitrile.
…………………….
……………………
EP1651630A1
The reaction scheme is given below: Stage-I
Acetic anhydride
Ethyl-l-cyclopropyl-6, 7- ( l-cyclopropyl-6, 7-difluoro-l, 4- difluoro-1, 4-dihydro-8- dihydro-8- methoxy-4-oxo-3- methoxy-4-oxo-3-quinoline quinoline carboxylic acid-03, 04) carboxylate . Bis ( acetate-O) -borate (Borate complex)
Stage-II
Triet yl amine
Acetonitrile
l-cyclo propyl-6, 7-difluoro- [S, S] -2, 8-diazabicyclo- (1- cyclo propyl-6, fluoro-7 (2, 8- 1, 4-dihydro-8- methoxy-4-oxo [4 ,3.0]nonane Diazabicyclo-nonane) 1,4- -3-quinoline carboxylic acid- dihydro-8-methoxy-4-oxo-3 03,04)Bis ( acetate-O) -borate- quinoline carboxylic acid- (Borate complex) (03,04) bis (acetate-O) -borate itage-III
(1- cyclo propyl-6, fluoro- (2, 8- Moxifloxacin HCI pseudohydrate Diazabicyclo-nonane) 1,4- dihydro-8-methoxy-4-oxo-3 -quinolinecarboxylicacid- (O^O4) bis (acetate-O) -borate
Stage-TV
Moxifloxacin HCI pseudohydrate Moxifloxacin HCI monohydrate
EXAMPLE – I
Stage-1: Preparation of l-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo- l,4-dihydro-3-quinoline carboxylic acid-O3,O*)bis (acyloxy-O)borate
Acetic anhydride (175 g) is heated to 70°C and boric acid (30 g) is slowly added lot wise in a temperature range of 70°C to 90°C. The temperature is then raised, maintained under reflux for 1 hr followed by cooling to about 70°C. Ethyl-l-cyclopropyl-6, 7-difluoro-8-methoxy-4- oxo-1, 4-dihydro-3-quinoline carboxylate (100 g) is added under stirring. The temperature is then raised and maintained for 1 hr in the range of 100°C to 105°C. The reaction mass is cooled to 0°C, chilled water (400 ml) is added slowly followed by cold water (600 ml) at temperature 0°C to 5°C and maintained for 2 hrs at 0°C to 5°C. The product which is a boron acetate complex is filtered, washed with water (500 ml) and dried at 55°C to 60°C under vacuum to constant weight. The dry wt is 130.0 g corresponding to yield of 95.2%.
Stage-2: Preparation of (4aS-Cis) -l-Cyclopropyl-7- (2, 8-diazabicyclo [4.3.0]non-8-yl) -6-fluoro-8-methoxy-4-oxo-l , 4-dihydro-3-quinoline carboxylicacid-03,0*)bis (acyloxy-O)borate
The boron acetate complex (130 g) prepared in stage 1 is suspended in acetonitrile (650 ml), and [S, S] -2, 8-diazabicyclo [4.3.0] nonane (47 g) and triethyl amine (72.9 g) are added. The temperature is raised to reflux and maintained for 1 hr. at reflux, followed by cooling to about 40°C. The solvent is removed under vacuum at temperature below 40°C, and n-hexane (200 ml) is added. After maintaining the reaction mass for 1 hr at room temperature the product is isolated by filtration followed by washing of the wet cake with n-hexane . The product is dried at about 45°C to about 50°C to constant weight.
Dry wt of the novel intermediate is 117.0 g corresponding to yield of 71.5%.
Elemental analysis: C: 56.42%, H: 5.62%, N: 7.76% and the calculated values for the intermediate, formula C25H29BFN308C: 56.6%, H: 5.47%, N: 7.92%
IR Spectrum (KBr, cm-1) : 3415, 3332, 2936, 1718, 1630, 1573, 1526, 1445, 1273, 1042, 935, 860, 798, 682
^ NMR (200 MHz, CDC13, ppm) : 9.00 (1H), 7.82 (1H), 4.12 (4H), 3.57 (3H), 3.43 (4H), 3.07 (2H) , 2.75 (2H), 2.4 (1H),’ 2.1 (6H), 1.84 (2H) , 1.6 (1H), 1.31 (2H)
Mass Spectrum (MJ : 530.3 [M+H] , 470.2 [M+ - CH3COOH] , 428.2 [M+- (CH3CO)20, 100%], 402.2, 388.2
Stage -3: Preparation of Moxifloxacin Hydrochloride pseudohydrate
The intermediate (117 g) prepared stage-2 is dissolved in ethanol (600 ml) by stirring for about 30 min. at room temperature and the insolubles if any are filtered off. pH of the filtrate is adjusted to about 0.5 by addition of hydrochloric acid at room temperature and maintained for 2 hrs. The reaction mass is cooled, and maintained for two hrs, at about