FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
Process for the preparation of Type I, Type II and Type III crystalline Prulifloxacin.
2. APPLICANT (S)
(a) NAME : ELDER PHARMACEUTICALS LTD.
(b) NATIONALITY : INDIAN
(c) ADDRESS : Elder House, Plot No. C/9, Dalia Indl. Estate,
Off. New Link Road, Andheri (W),
Mumbai- 400 058, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in
which it is to be performed.




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controlling supersaturation concentration at the time of spontaneous nucleation or at the addition of Compound B seed crystals.
The process disclosed in EP1626051 requires very controlled condition of crystallization and change in the condition of supersaturation concentration results into contaminated type III with type I crystal form.
WO2008111018 describes the process for the preparation of type I, II and III crystal
form of Prulifloxacin. Preparation of type I, type II and type III crystals were carried
out from acetonitrile solution by following different crystallization temperature at
different cooling rate. Since type I, type II and type III crystals are isolated from the
same solvent at different crystallizing temperature, at industrial level there are
chances to get mixture of polymorph.
Hence there exists a need to improve the crystallization condition to isolate pure
polymorph and to develop industrially feasible process.
To isolate Type I, WO2008111018 teaches to cool the reaction mixture wherein the
solvent is present. The cooling is for longer periods.
According to WO2008111018, to isolate Type II, cooling to 0 - 10°C in 5-20
minutes is critical using monosolvent system. Whereas to obtain Type III crystals
WO2008111018 teaches the reaction mixture to be cooled to about 25 - 35°C.
It is surprisingly found that it is possible to get type I crystals without cooling the mixture containing larger quantities of solvents. Infact present invention teaches to distill substantial amount of solvent, to obtain Type I crystals. It was surprisingly noticed that making use of additional solvent /nonsolvent / cosolvent such as water provides Type II crystals, thereby eliminating the step of chilling to 0-10°C.
Novelty of present invention also resides in providing Type III crystals by quenching as described in example. It was surprisingly found that when obtained reaction mixture is chilled to a temperature of below 5°C and maintained for 2 hours, type III crystals are obtained which is in contrast to teachings of WO2008111018. Novelty of the present invention also resides in the ability of the process to provide three types of crystals without making use of seeding.
OBJECTIVE OF THE INVENTION
The object of the present invention is to develop industrially feasible process to
isolate pure crystalline form of Prulifloxacin.
Another object of the present invention is to provide simpler process to isolate pure
crystalline form of Prulifloxacin.
Yet another object of the invention is to provide a faster process to isolate pure
crystalline forms of Prulifloxacin.
Yet another object of the invention is to provide process to isolate Type I pure
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crystalline form of Prulifloxacin.
Yet another object of the invention is to provide process to isolate Type II pure
crystalline form of Prulifloxacin.
Yet another object of the invention is to provide process to isolate Type III pure
crystalline form of Prulifloxacin.
SUMMARY OF THE INVENTION
The invention relates to process for the preparation of pure type I, type II and type III
crystals of 6-fluoro-l-methyl-7-[4-[(5-methyl-2-oxo-l,3-dioxol-4-yl)methyl]-l-
piperazinyl]-4-oxo-lH?4H-[l,3]Thiazeto[3,2-a]quinoline-3-carboxylicacid.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention there is provided a novel industrially
feasible, simpler process for the preparation of type I crystals of Prulifloxacin which
comprises, a) dissolving Prulifloxacin in acetonitrile by heating to a reflux
temperature of solvent; b) distilling out substantial quantity of acetonitrile from the
reaction mixture obtained in step a) which can be directly used for recycling; c) cool
and filter the reaction mass obtained in step b); and d) isolating type I crystals of
Prulifloxacin.
In step a), Prulifloxacin is dissolved in acetonitrile by heating at a temperature of
75°C or more. The reaction mass obtained in step b) is cooled to 35°C and solid was
isolated and dried at 70 - 85°C.
In another aspect, a process for the preparation of type II crystals of Prulifloxacin is provided, which comprises, a) dissolving Prulifloxacin in acetonitrile by heating to a reflux temperature of solvent; b) adding water to the reaction mixture obtained in step a); c) cooling the reaction mixture obtained in step b); d) isolating the solid; and e) drying the solid to obtain type II crystals of Prulifloxacin.
In step a), Prulifloxacin is dissolved in acetonitrile by heating at temperature of 75°C or more and water is added at 75 - 80°C. The reaction mixture obtained in step b) is cooled to 35 - 0°C and the resulted solid was isolated and dried at 70 - 80°C.
In a further aspect, a process for the preparation of type III crystals of Prulifloxacin is discussed, which involves a) dissolving Prulifloxacin in acetonitrile by heating to a reflux temperature of solvent; b) quenching the reaction mass obtained in step a) in separately chilled acetonitrile; c) chilling the reaction mixture obtained in step b); d) isolating the solid; and e) drying the solid to obtain type III crystals of Prulifloxacin.
In step a), Prulifloxacin is dissolved in acetonitrile by heating at a temperature of 75°C or more. In a separate reactor, acetonitrile is cooled to below 5°C and to this chilled acetonitrile, above reaction mass is added and the reaction mixture obtained
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from step b) is chilled to below 5°C and maintained for 2 hours. Solid isolated is dried at 75 - 85°C to remove solvent.
Prulifloxacin used for the experiments is prepared according to the description of US5086049. Also for the preparation of type I, type II and type III solid, any crystalline form of Prulifloxacin can be used.
Hereunder, the present invention is explained in more detail with the following examples, However this illustration does not limit the scope of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1 represents XRPD of type I Prulifloxacin Fig 2 represents XRPD of type II Prulifloxacin Fig 3 represents XRPD of type III Prulifloxacin
EXAMPLES
Example 1: Type I crystals of Prulifloxacin
Prulifloxacin 10 gm was dissolved in acetonitrile 750 ml at reflux temperature and maintained for 30 minutes with stirring. The acetonitrile was distilled out without stirring. The reaction mass was cooled to room temperature Product was isolated by filtration. The obtained product was dried at 80 - 85°C to get type I crystals of Prulifloxacin 9.6 gm.
Example 2: Type II crystals of Prulifloxacin
Prulifloxacin 10 gm was dissolved in acetonitrile 750 ml at reflux temperature of solvent and maintained for 30 minutes. Water 250 ml was added slowly to the reaction mixture and maintained for 15 minutes. The reaction mixture was cooled to room temperature and maintained for 1 hour. Product was isolated by filtration and suck dry. The obtained product was dried at 80 - 85°C to get type II crystals of Prulifloxacin 5 gm.
Example 3: Type HI crystals of Prulifloxacin
Prulifloxacin 10 gm was dissolved in acetonitrile 750 ml at reflux temperature of solvent and maintained for 30 minutes. In another flask, acetonitrile 250 ml was charged and chilled to 0 - 5°C and quenched the above reaction mixture in the chilled acetonitrile. The obtained reaction mixture is chilled to a temperature of 0°C
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- 5°C and maintained for 2 hours. The reaction mixture was filtered and suck dried. The solid was dried under vacuum at 80 - 85°C for 24 hours to get type III crystals of Prulifloxacin 8 gm.
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We claim,
1. A process for the preparation of type I crystals of Prulifloxacin, the process
comprising:
a) dissolving Prulifloxacin in acetonitrile by heating to a reflux temperature of solvent;
b) distilling out a substantial amount of acetonitrile from the reaction mixture;
c) cooling and filtering the reaction mass; and
d) isolating type I crystals of Prulifloxacin.

2. A process to prepare type I crystal of Prulifloxacin as claimed in claim 1, distilling out acetonitrile.
3. A process for the preparation of type II crystals of Prulifloxacin, the process comprising:

a) dissolving Prulifloxacin in acetonitrile by heating to a reflux temperature of solvent;
b) adding water to the reaction mixture obtained in step a);
c) cooling the reaction mixture obtained in step b);
d) isolating the solid; and
e) drying the solid to obtain type II crystals of Prulifloxacin.

4. A process to prepare type II crystals of Prulifloxacin as claimed in claim 3, from mixture of acetonitrile and water.
5. A process for the preparation of type III crystals of Prulifloxacin, the process comprising:

a) dissolving Prulifloxacin in acetonitrile by heating to a reflux temperature of solvent;
b) quenching the reaction mass obtained in step a) in separately chilled acetonitrile;
c) chilling the reaction mixture obtained in step b);

d) isolating the solid; and
e) drying the solid to obtain type III crystals of Prulifloxacin.
6. A process to prepare type III crystal of Prulifloxacin as claimed in claim 5, by
quenching solution of Prulifloxacin in cooled acetonitrile.
DATE AND SIGNATURE
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