DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
PROCESSES FOR THE PREPARATION OF LEVOCETIRIZINE ISOPROPYL ESTER AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

FIELD OF THE INVENTION
The present application relates to process for the preparation of Levocetirizine isopropyl ester and pharmaceutically acceptable salts thereof. The present application also relates solid state forms of pharmaceutically acceptable salts of Levocetirizine isopropyl ester and process for the preparation thereof.
BACKGROUND OF THE INVENTION
Levocetirizine dihydrochloride is the adopted name for a drug chemically described as (R)-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy] acetic acid dihydrochloride and is represented by structural Formula II.

Formula II
Levocetirizine dihydrochloride is a white, crystalline powder and is water soluble. It is used as an active and selective H1 -receptor antagonist and is marketed under the brand name as XYZAL® tablets in 5 mg strength.
U.S. Patents Nos. 4525358, 5478941, and 7381821, and Great Britain Patent Nos. 2225320 and 2225321 described various processes for the synthesis of cetirizine and its enantiomers.
Great Britain Patent No. 2225321 described a process for the preparation of cetirizine in the levorotatory or dextrorotatory form or a mixture of thereof comprising the hydrolysis of enantiomerically pure or racemic 2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)ethoxy)acetamide. Also, processes for preparing Levocetirizine and Dextrocetirizine from its racemic mixture or racemic intermediates were known in U.S. Patent No. 6977301, and International Application Publication Nos. WO 2005/073207 and WO 2006/094648.
The prodrug approach involves use of chemically modified inert compound which upon administration releases the active parent drug to elicit its therapeutic activity within the body. Since few decades, prodrug strategy has increasingly being developed to overcome undesired drug physicochemical properties. Generally, prodrugs consist of a promoiety that is removed by enzymatic or chemical reactions, while other prodrugs release their active drugs after molecular modification such as an oxidation or reduction reactions.
Organic Process Research & Development 2001, 5, 110-115 discloses process for the preparation of esters of Levocetirizine.
Although processes have been reported in the prior art for the preparation of esters of Levocetirizine, they suffer from one or more drawbacks. Hence, there is still a need for simple, cost effective and industrially viable process for the production of Levocetirizine isopropyl ester and its pharmaceutically acceptable salts.
Polymorphism is an important aspect of pharmaceutical drug in terms of its solubility and bioavailability. One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. Different crystalline forms of polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubility. The different solubility of the drug compound affects the bioavailability of drug at target site.
In the formulation of drug compositions, it is important for the drug substance to be in a form in which it can be conveniently handled and processed. This is of importance, not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of subsequent manufacture of pharmaceutical formulation comprising the active compound. Chemical stability, solid state stability and shelf life of the active ingredients are also very important factors. The drug substance and compositions containing it should be capable of being effectively stored over appreciable periods of time without exhibiting a significant change in the active component's physicochemical characteristics (e.g. its chemical composition, density, hygroscopicity and solubility). Moreover, it is also important to be able to provide drug in a form which is as pure as possible.
The inventors of present invention have found out an improved process for the preparation of Levocetirizine isopropyl ester and pharmaceutically acceptable salts thereof and solid state forms thereof.
Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods, and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation of Levocetirizine isopropyl ester of Formula I, comprising:

Formula I
treating, Levocetirizine or pharmaceutically acceptable salt thereof (Formula II) with isopropanol,

Formula II
to obtain compound of formula I.

In another aspect, the present invention provides pharmaceutically acceptable salts of Levocetirizine isopropyl ester.

In another aspect, the present invention provides a process for the preparation of pharmaceutically acceptable salts of Levocetirizine isopropyl ester, comprising steps of:
i) treating Levocetirizine isopropyl ester with suitable acid;
ii) isolating pharmaceutically acceptable salts of Levocetirizine isopropyl ester.

In another aspect, the present invention provides solid state forms of pharmaceutically acceptable salts of Levocetirizine isopropyl ester.

In another aspect, the present invention provides a process for the preparation of solid state forms of pharmaceutically acceptable salts of Levocetirizine isopropyl ester, comprising steps of:
i) providing pharmaceutically acceptable salts of Levocetirizine isopropyl ester in one or more of suitable solvents;
ii) optionally, adding anti-solvent;
iii) isolating solid state forms of pharmaceutically acceptable salts of Levocetirizine isopropyl ester.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustration of a PXRD pattern of solid state form of Levocetirizine isopropyl ester tartrate salt.

Figure 2 is an illustration of a PXRD pattern of solid state form of Levocetirizine isopropyl ester citrate salt.
DETAILED DESCRIPTION OF THE INVENTION
While the specification concludes with the claims particularly pointing and distinctly claiming the invention, it is believed that the present invention will be better understood from the following description. All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25oC and normal pressure unless otherwise designated. All temperatures are in Degrees Celsius unless specified otherwise. The present invention can comprise (open ended) of the components of the present invention as well as other ingredients or elements described herein.
As used herein, "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
Terms such as "about," "generally," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
The “pharmaceutically acceptable salts” as used herein can be prepared from the free base forms of the compounds by reaction of the latter with pharmaceutically acceptable acid, followed by isolation of salt by conventional techniques, if required. A salt can be prepared in situ during the final isolation and purification of a compound or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
Suitable acids for forming acid addition salts of the compounds used in the present invention include, but are not limited to, acetic, benzoic, benzenesulfonic, hydrobromic, hydrochloric, citric, gluconic, glucuronic, glutamic, lactic, malic, maleic, oxalic, camphorsulphonic, methanesulfonic, palmoic, salicylic, stearic, succinic, sulfuric, tartaric and the like. The class of acids suitable for formation of pharmaceutically acceptable salts is well known to person having ordinary skills in the art, and are described, for example in Stahl, P. H., et al., “Handbook of Pharmaceutical Salts”, Wiley-VCH, Weinheim: Germany (2002), the contents of which are hereby incorporated herein by reference.
Representative salts include, but are not limited to, hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartarate, camphor sulphonate, naphthylate, mesylate, glucoheptonate, lactiobionate, laurylsulphonate salts, and the like. Pharmaceutically acceptable salts are well known to person having ordinary skills in the art, and are described, for example in Berge S. M., et al., “Pharmaceutical Salts,” J. Pharm. Sci., 66: 1-19, 1977, the contents of which are hereby incorporated herein by reference. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
The term "conventional techniques" as used herein includes but not limited to distillation, distillation under reduced pressure or vacuum, evaporation, solvent-antisolvent, spray drying, lyophilization or freeze drying.
The term "organic solvent" or "solvent" or “anti-solvent” as used herein includes but not limited to polar protic and aprotic solvents as well as non-polar solvents selected from water, hydrocarbons, ketones, alcohols, ethers, esters, halogenated solvents, dimethyl sulfoxide (DMSO) and dimethylformamide (DMF), pyridine, phenol, DMA, carbon disulphide, acetic acid, acetonitrile and mixtures thereof. Hydrocarbons include but not limited to such as benzene, toluene, xylene, pentane, hexane, heptane, cyclohexane and tetraline. Ketones include but not limited to such as acetone, methyl ethyl ketone, cyclohexanone and methyl isobutyl ketone. Alcohols include but not limited to such as methanol, ethanol, propanol, butanol, octanol, ethanediol, 1,2-propanediol and S-(+)-1,2- propanediol. Ethers include but not limited to such as diethyl ether, diisopropyl ether, dibutyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran and cyclopentyl methyl ether. Halogenated solvents include but not limited to such as chloroform, carbon tetrachloride, methylene chloride and 1,2-dichloroethane. Esters include but not limited to such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and n-propyl acetate.
The term "anti-solvent" as used herein refers to a solvent that, when combined with a solution of Levocetirizine isopropyl ester, reduces solubility of the Levocetirizine isopropyl ester in the solution, causing crystallization or precipitation in some instances spontaneously, and in other instances with additional steps, such as seeding, cooling, scratching and/or concentrating or other alternative techniques known to person having ordinary skill in the art
The term “solid state forms of pharmaceutically acceptable salts of Levocetirizine isopropyl ester” as used herein refers to pharmaceutically acceptable salt of Levocetirizine isopropyl ester being present in a crystalline form, an amorphous form, a solvate form, a hydrate form, an anhydrous form or a mixture thereof.
The term "anhydrous" as used herein refers to a compound which is substantially free of water, preferably less than about 5%, more preferably less than about 1%, most preferably zero percent, by weight of free or added water.
The term "hydrate" as used herein refers to a compound which is formed by the union of water with the parent compound. The term “solvate” as used herein refers to a compound which contains a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces.
The term “pharmaceutically acceptable excipient” as used herein includes vehicles, adjuvants, or diluents or other auxiliary substances, such as those conventional in the art, which are readily available to the public. For example, pharmaceutically acceptable excipients include pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like.
The starting material-Levocetirizine or pharmaceutically acceptable salt thereof was prepared according to process disclosed in prior arts and known to person having ordinary skills in the art.
In one embodiment, the present invention provides a process for the preparation of Levocetirizine isopropyl ester of Formula I, comprising:

Formula I
treating, Levocetirizine or pharmaceutically acceptable salt thereof (Formula II) with isopropanol,

Formula II
to obtain compound of formula I.
The compound of formula I can be isolated by techniques known to a person skilled in the art. For example, the compound of formula I can be isolated by distillation, distillation under reduced pressure or vacuum, evaporation, solvent-anti-solvent, spray drying, lyophilization or freeze drying.
Suitable temperatures for the reaction may be room temperature or ambient temperature, near about 60 °C, near about 80°C, or about the reflux temperature of solvent employed or any other suitable temperature. Suitable time for the reaction may be from about 30 minutes to about 10 hours, or longer.
In another embodiment, the present invention provides pharmaceutically acceptable salts of Levocetirizine isopropyl ester. In one preferred embodiment, the present invention provides hydrochloride, tartrate and citrate salts of Levocetirizine isopropyl ester.
In another embodiment, the present invention provides a process for the preparation of pharmaceutically acceptable salts of Levocetirizine isopropyl ester, comprising steps of:
i) treating Levocetirizine isopropyl ester with suitable acid;
ii) isolating pharmaceutically acceptable salts of Levocetirizine isopropyl ester.
The suitable source acid can be selected from, but are not limited to, hydrobromic, hydrochloric, citric, lactic, malic, maleic, oxalic, tartaric, or the like. Suitable temperatures for the reaction may be room temperature or ambient temperature, near about 60 °C, near about 80°C, or about the reflux temperature of solvent employed or any other suitable temperature. Suitable time for the reaction may be from about 30 minutes to about 10 hours, or longer.
The pharmaceutically acceptable salt of Levocetirizine isopropyl ester thus obtained can be isolated by techniques known to a person skilled in the art. For example, the pharmaceutically acceptable salt of Levocetirizine isopropyl ester can be isolated by distillation, distillation under reduced pressure or vacuum, evaporation, solvent-antisolvent, spray drying, lyophilization or freeze drying.
In another embodiment, the present invention provides solid state forms of pharmaceutically acceptable salts of Levocetirizine isopropyl ester. In one preferred embodiment, the present invention provides amorphous form of hydrochloride, tartrate and citrate salts of Levocetirizine isopropyl ester. In one preferred embodiment, the present invention provides crystalline form of hydrochloride, tartrate and citrate salts of Levocetirizine isopropyl ester.
In another embodiment, the present invention provides a process for the preparation of solid state forms of pharmaceutically acceptable salts of Levocetirizine isopropyl ester, comprising steps of:
i) providing pharmaceutically acceptable salts of Levocetirizine isopropyl ester in one or more of suitable solvents;
ii) optionally, adding anti-solvent;
iii) isolating solid state forms of pharmaceutically acceptable salts of Levocetirizine isopropyl ester.
The solvent or anti-solvent that can be employed include, but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, and n-butanol; organic acids like acetic acid, and propionic acid; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone, and n-butanone; halogenated solvents such as dichloromethane, ethylene dichloride, and chloroform; esters such as ethyl acetate, n-propyl acetate, and isopropyl acetate; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; ethers such as methyl tert butyl ether (MTBE), diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), dimethoxyethane (DME), diethoxyethane or mixture thereof; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), and dimethylacetamide (DMA); water or mixtures thereof.
Suitable times for preparation of solid state form will vary and can be from about 10 minutes to about 1 hour, to about 24 hours, or longer. Suitable temperatures for preparation of solid state form include from about -10°C to about 120°C or from about 10°C to about 60°C. Undissolved particles from a mixture can be removed suitably by filtration, centrifugation, decantation, or other techniques, such as passing the solution through paper, glass fiber, a particulate bed, or a membrane material. The solid state form of pharmaceutically acceptable salt of Levocetirizine isopropyl ester thus obtained can be isolated by techniques known to a person skilled in the art. For example, the pharmaceutically acceptable salt of Levocetirizine isopropyl ester can be isolated by distillation, distillation under reduced pressure or vacuum, evaporation, solvent-antisolvent, spray drying, lyophilization or freeze drying.
The compounds at any stage of the process of the present invention may be recovered from a suspension/solution using any of techniques such as decantation, filtration by gravity or by suction, centrifugation, slow evaporation, or the like, or any other suitable techniques. The reaction can be efficiently completed at room temperature or ambient temperature or if required reaction mass can be heated to elevated temperatures or up to about the reflux temperatures, and maintained for about 10 minutes to about 5 hours or longer.
The resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, about 1 to about 15 hours, or longer.
In an embodiment, Levocetirizine isopropyl ester and its pharmaceutically acceptable salts of present invention has average particle size of particles between 1 to 100 µm, less than 90 µm, less than 80 µm, less than 60 µm, less than 50 µm, less than 40 µm, less than 30 µm, less than 20 µm, less than 10 µm, less than 5 µm or any other suitable particle sizes. In another embodiment, Levocetirizine isopropyl ester and its pharmaceutically acceptable salts of present invention may have particle size distribution: D10 of particles smaller than 20 µm, smaller than 15 µm, smaller than 10 µm, or smaller than 5 µm; D50 of particles smaller than 100 µm, smaller than 90 µm, smaller than 80 µm, smaller than 70 µm, smaller than 60 µm, smaller than 50 µm, smaller than 40 µm, smaller than 30 µm, smaller than 20 µm, smaller than 10 µm; D90 of particles smaller than 200 µm, smaller than 175 µm, smaller than 150 µm, smaller than 140 µm, smaller than 130 µm, smaller than 120 µm, smaller than 110 µm, smaller than 100 µm, smaller than 90 µm, smaller than 80 µm, smaller than 70 µm, smaller than 60 µm, smaller than 50 µm, smaller than 40 µm, smaller than 30 µm, smaller than 20 µm, smaller than 10 µm.
Particle size distributions of Levocetirizine isopropyl ester and its pharmaceutically acceptable salts particles may be measured using any techniques known in the art. For example, particle size distributions of Levocetirizine isopropyl ester and its pharmaceutically acceptable salts particles may be measured using microscopy or light scattering equipment, such as, for example, a Malvern Master Size 2000 from Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom. As referred herein, the term “D10” in the context of the present invention is 10% of the particles by volume are smaller than the D10 value and 90% particles by volume are larger than the D10 value. “D50” in the context of the present invention is 50% of the particles by volume are smaller than the D50 value and 50% particles by volume are larger than the D50 value. “D90” in the context of the present invention is 90% of the particles by volume are smaller than the D90 value and 10% particles by volume are larger than the D90 value.
In another embodiment, the present invention provides pharmaceutical compositions comprising Levocetirizine isopropyl ester and its pharmaceutically acceptable salts alone or in combination with other drugs. Further the present invention provides a process of preparing a pharmaceutical composition comprising Levocetirizine isopropyl ester and its pharmaceutically acceptable salts alone or in combination with other drugs. Conveniently various pharmaceutically acceptable excipients can be employed in a process according to the present invention.
The compound of this application is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. PXRD data reported herein was obtained using CuK? radiation, having the wavelength 1.5406 Å and were obtained using a PANalytical X’Pert PRO instruments. For a discussion of these techniques see J. Haleblain, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblain and W. McCrone, J. Pharm. Sci. 1969 58:911-929.
Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ± 0.2o. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2o. Accordingly, the present application includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2o. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2? ± 0.2o) of 7.9o" means "having a diffraction peak at a diffraction angle (2?) of 7.7o ?to 8.1o”. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art. The relative intensities of the PXRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments can vary by plus or minus about 0.2 degree. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not).
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.
Examples
Example 1: Preparation of Levocetirizine isopropyl ester:

Formula I
Isopropanol (100 mL) was charged into a reactor at 25-35 °C under nitrogen atmosphere. Levocetirizine dihydrochloride (10 g) was added to the reactor at 25-35 °C and the reaction mixture was heated to 75-85 °C with stirring for 19-22 h. The reaction mixture was cooled to a temperature below 50 °C and the solvent was evaporated under reduced pressure below 50 °C. Ethyl acetate (80 mL) was charged into the residue and saturated solution of sodium bicarbonate (100 mL) was added into the reaction mass. The reaction mixture was stirred for 1-2 h at 25-35°C. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution (50 mL), followed by saturated sodium chloride solution (50 mL). The solvent was evaporated under reduced pressure below 50 °C to get title compound (8 g) as brown colored residue [Purity by HPLC analysis 98.78%; Levocetirizine content 0.84%; Yield: 94%].

Example 2: Preparation of Levocetirizine isopropyl ester:

Formula I
Isopropanol (100 mL) was charged into a reactor at 25-35 °C under nitrogen atmosphere. Levocetirizine dihydrochloride (10 g) and conc. sulphuric acid (1 mL) were added to the reactor at 25-35 °C and the reaction mixture was heated to 75-85 °C with stirring for 19-22 h. The reaction mixture was cooled to a temperature below 50 °C and the solvent was evaporated under reduced pressure below 50 °C. Ethyl acetate (80 mL) was charged into the residue and saturated solution of sodium bicarbonate (100 mL) was added into the reaction mass. The reaction mixture was stirred for 1-2 h at 25-35°C. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution (50 mL), followed by saturated sodium chloride solution (50 mL). The solvent was evaporated under reduced pressure below 50 °C to get title compound (7.3 g) as brown colored residue [Purity by HPLC analysis 96%; Yield: 86%].

Example 3: Preparation of Levocetirizine isopropyl ester:

Formula I
Isopropanol (100 mL) was charged into a reactor at 25-35 °C under nitrogen atmosphere. Levocetirizine dihydrochloride (10 g) and titanium isopropoxide (10 mL) were added to the reactor at 25-35 °C and the reaction mixture was heated to 50-60 °C with stirring for 50-60 h. The reaction mixture was cooled to a temperature below 50 °C and the solvent was evaporated under reduced pressure below 50 °C. Ethyl acetate (80 mL) was charged into the residue and saturated solution of sodium bicarbonate (100 mL) was added into the reaction mass. The reaction mixture was stirred for 1-2 h at 25-35°C. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution (50 mL), followed by saturated sodium chloride solution (50 mL). The solvent was evaporated under reduced pressure below 50 °C to get title compound (6.9 g) as brown colored residue [Purity by HPLC analysis 95%; Yield: 82%].

Example 4: Preparation of Levocetirizine isopropyl ester:

Formula I
Isopropanol (100 mL) was charged into a reactor at 25-35 °C under nitrogen atmosphere. Levocetirizine dihydrochloride (10 g), thionyl chloride (1 mL) and catalytic amount of dimethyl fumarate were added to the reactor at 25-35 °C and the reaction mixture was heated to 40-50 °C with stirring for 15-17 h. The reaction mixture was cooled to a temperature below 50 °C and the solvent was evaporated under reduced pressure below 50 °C. Ethyl acetate (80 mL) was charged into the residue and saturated solution of sodium bicarbonate (100 mL) was added into the reaction mass. The reaction mixture was stirred for 1-2 h at 25-35°C. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution (50 mL), followed by saturated sodium chloride solution (50 mL). The solvent was evaporated under reduced pressure below 50 °C to get title compound (6.2 g) as brown colored residue [Purity by HPLC analysis 95%; Yield: 73%].

Example 5: Preparation of Levocetirizine isopropyl ester hydrochloride salt:

Formula I-HCl salt
Levocetirizine isopropyl ester (10 g) and n-hexane (100 mL) were charged into the reactor at 25-35 °C. The reaction mixture was cooled to -5 °C - 0 °C. HCl gas (generated from solid sodium chloride and conc. H2SO4) was charged into the reaction mixture for 45-60 min at -5°C to 0°C. n-hexane (50 mL) was added to reaction mixture and the reaction mass was warmed to 20-25 °C. The solid obtained was filtered under N2 atmosphere. The wet cake was washed with n-hexane (50 mL) and dried under reduced pressure below 40 °C for 3-4 h to obtain title compound (9.9 g) as an off-white colored solid. [Purity by HPLC analysis 99.3%; Yield: 85%; Water content by KF: 4.12% (w/w)]

The following process was used to obtain enrichment of HCl content in Levocetirizine isopropyl ester hydrochloride salt:
Levocetirizine isopropyl ester (10 g) and n-hexane (150 mL) were charged into the reactor at 25-35 °C. The reaction mixture was cooled to -5 °C - 0 °C. HCl gas (generated from solid sodium chloride and conc. H2SO4) was charged into the reaction mixture for 60-90 min at -5°C to 0°C. The reaction mass was warmed to 20-25 °C. The solid obtained was filtered under N2 atmosphere. The wet cake was washed with n-hexane (50 mL) and dried under reduced pressure below 40 °C for 3-4 h to obtain title compound (9.9 g) as an off-white colored solid. [Purity by HPLC analysis 99.2%; Yield: 86%; Water content by KF: 4.0% (w/w)]

Example 6: Preparation of Levocetirizine isopropyl ester hydrochloride salt:

Formula I-HCl salt

Levocetirizine isopropyl ester (5 g) and n-hexane (50 mL) were charged into the reactor at 25-35 °C. The reaction mixture was cooled to -5 °C - 0 °C. HCl gas (generated from solid sodium chloride and conc. H2SO4) was charged into the reaction mixture for 45-60 min at -5°C to 0°C. n-hexane (25 mL) was added to reaction mixture and the reaction mass was warmed to 20-25 °C. The solid obtained was filtered under N2 atmosphere. The wet cake was washed with n-hexane (25 mL) and dried under reduced pressure below 40 °C for 3-4 h to obtain title compound (4.7 g) as an off-white colored solid. [Purity by HPLC analysis 99.5%; Yield: 82%].

Example 7: Preparation of Levocetirizine isopropyl ester hydrochloride salt:

Formula I-HCl salt
Levocetirizine isopropyl ester (8 g) and n-hexane (100 mL) were charged into the reactor at 25-35 °C. The reaction mixture was cooled to -5 °C - 0 °C. HCl gas (generated from solid sodium chloride and conc. H2SO4) was charged into the reaction mixture for 45-60 min at -5°C to 0°C. n-hexane (50 mL) was added to reaction mixture and the reaction mass was warmed to 20-25 °C. The solid obtained was filtered under N2 atmosphere. The wet cake was triturated with methyl tert-butyl ether (50 mL) and dried under reduced pressure below 40 °C for 3-4 h to obtain title compound (7.7 g) as an off-white colored solid. [Yield: 91%].

Example 8: Preparation of Levocetirizine isopropyl ester hydrochloride salt:

Formula I-HCl salt
Levocetirizine isopropyl ester (8 g) and ethyl acetate (100 mL) were charged into the reactor at 25-35 °C. The reaction mixture was cooled to -5 °C - 0 °C. HCl gas (generated from solid sodium chloride and conc. H2SO4) was charged into the reaction mixture for 45-60 min at -5°C to 0°C. n-hexane (50 mL) was added to reaction mixture and the reaction mass was warmed to 20-25 °C. The solid obtained was filtered under N2 atmosphere. The wet cake was washed with n-hexane (50 mL) and dried under reduced pressure below 40 °C for 3-4 h to obtain title compound (7.2 g) as an off-white colored solid. [Purity by HPLC analysis 98.1%; Yield: 85.5%].

Example 9: Preparation of Levocetirizine isopropyl ester hydrochloride salt:

Formula I-HCl salt
Levocetirizine isopropyl ester dihydrochloride (7.5 g) and acetaone (75 mL) were charged into the reactor at 25-35 °C. The reaction mixture was cooled to -5 °C - 0 °C. The solid obtained was filtered under N2 atmosphere. The wet cake was washed with acetone (50 mL) and dried under reduced pressure for 3-4 h to obtain title compound (4 g) as an off-white colored solid. [Purity by HPLC analysis 99.1%; Yield: 53%].

Example 10: Preparation of Levocetirizine isopropyl ester tartrate salt:

Formula I-tartrate salt
Levocetirizine isopropyl ester (12 g) and tetrahydrofuran (60 mL) were charged into the reactor at 25-35 °C. L-tartaric acid (4.2 g) was charged into the reaction mixture at 25-35°C and the reaction mass was stirred at 25-35 °C for 1-2 h. The reaction mixture was transferred to another reactor containing pre-cooled solvent mixture of methyl tert-butyl ether (50 mL) and n-hexane (280 mL) at -12°C to -10 °C and stirred for 30-50 min at -12°C to -10 °C. The reaction mixture was filtered at 0 °C to -5 °C and n-hexane (50 mL) was charged into the residue. The reaction mixture was filtered at 0 °C to -5 °C and the residue was dried under reduced pressure below 50 °C for 6-7 h to obtain title compound (15.3 g) as an off-white colored solid. [Purity by HPLC analysis 99.2%; Yield: 94.4%]. PXRD pattern of solid state form of Levocetirizine isopropyl ester tartrate salt obtained by present invention is illustrated by Figure 1.

Example 11: Preparation of Levocetirizine isopropyl ester tartrate salt:

Formula I-tartrate salt
Levocetirizine isopropyl ester (12 g) and tetrahydrofuran (60 mL) were charged into the reactor at 25-35 °C. L-tartaric acid (4.2 g) was charged into the reaction mixture at 25-35°C and the reaction mass was stirred at 25-35 °C for 1-2 h. The reaction mixture was transferred to another reactor containing pre-cooled solvent mixture of diethyl ether (280 mL) at -12°C to -10 °C and stirred for 30-50 min at -12°C to -10 °C. The reaction mixture was filtered at 0 °C to -5 °C and the residue was dried under reduced pressure below 50 °C for 6-7 h to obtain title compound (13.9 g) as an off-white colored solid. [Purity by HPLC analysis 99.1%; Yield: 85.8%].

Example 12: Preparation of Levocetirizine isopropyl ester citrate salt:

Formula I-citrate salt
Levocetirizine isopropyl ester (2 g) and citric acid (0.9 g) were charged into the reactor at 25-35 °C. Tetrahydrofuran (8 mL) was added into the reaction mixture and the reaction mixture was stirred for 10-15 minutes to obtain a clear solution. Diethyl ether (65 mL) was charged into the reaction mixture and the reaction mass was stirred at 25-35 °C for 10-15 minutes. The reaction mixture was filtered and the residue was dried under reduced pressure at 25-35 °C for 3-4 h to obtain title compound (2.3 g) as an off-white colored solid. [Purity by HPLC analysis 98.5%; Water content: 2.4%; Yield: 81.2%]. PXRD pattern of solid state form of Levocetirizine isopropyl ester citrate salt obtained by present invention is illustrated by Figure 2.

Example 13: Preparation of Levocetirizine isopropyl ester citrate salt:

Formula I-citrate salt
Levocetirizine isopropyl ester (2 g) and citric acid (0.9 g) were charged into the reactor at 25-35 °C. Tetrahydrofuran (8 mL) was added into the reaction mixture and the reaction mixture was stirred for 10-15 minutes to obtain a clear solution. Diethyl ether (50 mL) was charged into the reaction mixture and the reaction mass was stirred at 25-35 °C for 10-15 minutes. The reaction mixture was filtered and the residue was dried under reduced pressure at 25-35 °C for 3-4 h to obtain title compound (2.1 g) as an off-white colored solid. [Purity by HPLC analysis 99.2%; Yield: 74.1%].

Example 14: Preparation of Levocetirizine isopropyl ester:

Formula I-HCl salt
Isopropanol (100 mL) was charged into a reactor at 25-35 °C. Levocetirizine dihydrochloride (10 g), was added to the reactor at 25-35 °C and the reaction mixture was heated to 70-90 °C with stirring for 15-18 h. The reaction mixture was cooled to a temperature below 50 °C and the solvent was evaporated under reduced pressure below 50 °C. The reaction mass was cooled to 25-35 °C. n-heptane (150 mL) was charged and the reaction mixture was stirred for 2-4 h at 0-5°C. The solid was filtered under nitrogen atmosphere and the residue was washed with n-heptane (30 mL). The material was unloaded and dried at 45-55oC for 4-6 hrs to get title compound (5.9 g). [Purity by HPLC analysis 98.3%; Yield: 83%].
,CLAIMS:Claims:
1. A process for the preparation of Levocetirizine isopropyl ester of Formula I, comprising:

Formula I
treating, Levocetirizine or pharmaceutically acceptable salt thereof (Formula II) with isopropanol,

Formula II
to obtain compound of formula I.

2. Levocetirizine isopropyl ester and pharmaceutically acceptable salts thereof.

3. The Levocetirizine isopropyl ester pharmaceutically acceptable salts as claimed in claim-2, wherein the pharmaceutically acceptable salts are selected from group consisting of: hydrochloride, tartrate and citrate.

4. A process for the preparation of pharmaceutically acceptable salts of Levocetirizine isopropyl ester, comprising steps of:
i) treating Levocetirizine isopropyl ester with suitable acid;
ii) isolating pharmaceutically acceptable salts of Levocetirizine isopropyl ester.
5. A process for the preparation of solid state forms of pharmaceutically acceptable salts of Levocetirizine isopropyl ester, comprising steps of:
i) providing pharmaceutically acceptable salts of Levocetirizine isopropyl ester in one or more of suitable solvents;
ii) optionally, adding anti-solvent;
iii) isolating solid state forms of pharmaceutically acceptable salts of Levocetirizine isopropyl ester.