DESC:FIELD OF INVENTION
The present invention relates to the field of pharmaceuticals and chemistry; more particularly, the invention relates to a process for synthesis of solid form of Levocetirizine and Cetirizine base.

BACKGROUND OF THE INVENTION
Levocetirizine (2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]piperazin-1-yl]ethoxy]acetic acid) and Cetirizine (2-[2-[4-[(4-chlorophenyl)-phenylmethyl]piperazin-1-yl]ethoxy]acetic acid) base and are chemically represented by the formula I and II respectively.

Formula I

Formula II

Hydrochloride salts of Levocetirizine and Cetirizine are, over-the-counter antihistamines used to relieve allergy symptoms such as watery eyes, runny nose, itching eyes/nose, sneezing, itching and hives, by selectively blocking H1 receptors or histamine. Levocetirizine is the R-enantiomer of cetirizine and is known to be less sedating and more potent than cetirizine. The US FDA approved Levocetirizine under the brand name XYZAL and it was first marketed in the US by Sanofi Aventis US LLC as levocetirizine dihydrochloride salt form in 2007.
From a pharmaceutical standpoint, levocetirizine and cetirizine are classified under BCS class III drug, thus the chemical and physical parameters of the drug play a pivotal role in the solubility, product yield, purity, stability, storage, dosage, formulation and subsequent bioavailability of the drug. Purity and stability of the compounds is highly sort after on the commercial scale as they effect efficacy and efficiency of the drug and can lead to degradation of the drug with more serious complications and side effects. Even more so the stability parameters for a solid powder form of the levocetirizine and cetirizine base need to be strictly controlled in order to meet ICH and regulatory guidelines.
A solid form of the drugs has a significant effect during the downstream processing during formulation as they do affect the entire manufacturing process on commercial scale. The physical properties such as the stability of the solid form are also essential as this avoids clumping and aggregation of the drug that may affect the dispersion and bioavailability over a long period of time.
There appears to be various disclosures in the public domain that cover the synthesis of the salt form of levocetirizine and cetirizine and however there is an unmet need for the preparation of a solid form of levocetirizine and cetirizine base which may effect in formulation, stability and increased shelf life, and although the process are known to be used widely, they are not feasible while yielding the solid form on a commercial scale that is essential for formulation of the drug.
The inventors of the present invention surprisingly found that their process yielded in solid form of levocetirizine and cetirizine base, and it has found to be economical and commercially scalable.

OBJECT OF INVENTION
The object of the present invention is to prepare a solid form of Levocetirizine and Cetirizine base that is commercially scalable, versatile and economical in nature.
Another objective of the present invention is to yield a solid premix form of Levocetirizine and Cetirizine base and the use of the said base and premix products as mentioned above in pharmaceutical formulation such as tablets, capsules, syrups and solutions.
SUMMARY OF INVENTION
The present invention relates to preparation of solid form of Levocetirizine base (Formula I) and Cetirizine base (Formula II).
An embodiment of the present invention provides a solid form of levocetirizine base (Formula I) by reacting levocetirizine dihydrochloride in the presence of a solvent and base and can be manufactured on a commercial scale.
An additional embodiment of the present invention, the solvent used for the preparation of solid form of levocetirizine base (Formula I) by reacting levocetirizine dihydrochloride in the presence of a solvent, wherein the solvent maybe selected from the group comprising of organic or inorganic solvents such as hydrocarbons, alcohols, ethers, chlorinated solvents, ketones and aqueous solutions. The preferable solvents of the present invention selected individually or in combination of solvents Methylene chloride, n-Heptane and Ethyl acetate.
In an additional embodiment of the present invention, the base used for the preparation of solid form of levocetirizine base (Formula I) by reacting levocetirizine dihydrochloride in the presence of a solvent, wherein the base is selected from the group comprising of organic base such as Triethylamine (TEA), Pyridine and N,N-Diisopropylethylamine (DIPEA) or strong Arrhenius Bases such as the hydroxides of alkali metals and alkaline earth metals. Preferable base is selected from Potassium hydroxide (KOH), Sodium hydroxide (NaOH), and Lithium hydroxide (LiOH).
An added embodiment of the present invention provides for a solid form of levocetirizine base (Formula I) with the XRPD as described in Figure 1.
Another embodiment of the present invention provides of a solid form of levocetirizine base (Formula I) with the PSD as described in Figure 2.
An additional embodiment of the present invention provides of a solid form of levocetirizine base (Formula I) according to conditions specified by ICH.
An embodiment of the present invention provides the process for synthesizing solid premix forms of levocetirizine base (Formula I) with a polymer. Wherein the polymers used maybe selected from the group comprising of Microcrystalline cellulose (MCC), Lactose, Polyvinylpyrrolidone (PVP), Hydroxyethyl cellulose (HEC, HMHEC), Hydroxypropyl cellulose (HPC), Prosolv HD, and Silicon dioxide.
An embodiment of the present invention provides the process for synthesizing solid premix forms of levocetirizine base (Formula I) with a polymer in the ratio that ranges from 1:1 to 1:1.25 w/w, Wherein the polymers used maybe selected from the group comprising of Microcrystalline cellulose (MCC), Lactose, Polyvinylpyrrolidone (PVP), Hydroxyethyl cellulose (HEC, HMHEC), Hydroxypropyl cellulose (HPC), Prosolv HD and Silicon dioxide.
In an added embodiment of the present invention, the process for synthesizing solid premix forms of levocetirizine base (Formula I), comprises the use of methods of Freeze drying, Spray drying, Solvent evaporation, Trituration, Dry mixing, or Melt trituration.
In another alternative embodiment of the present invention, the process is a continuous process at a commercial scale that is both economical and safe to the environment.
In a final embodiment of the present invention, the process yields a product that is used in pharmaceutical formulation.

DRAWINGS:
Figure 1: Describes the XRPD of Levocetirizine base.
Figure 2: Describes the PDS of Levocetirizine base.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to preparation of solid form of Levocetirizine base (Formula I) and Cetirizine base (Formula II).
An embodiment of the present invention provides for a process for synthesizing solid form of levocetirizine base (Formula I) by reacting levocetirizine dihydrochloride in the presence of a solvent and base and can be manufactured on a commercial scale.
In another embodiment, the present invention provides for a process for synthesizing solid form of cetirizine base (Formula II) by reacting cetirizine dihydrochloride in the presence of a solvent and base and can be manufactured on a commercial scale.
In an additional embodiment of the present invention, the solvent used maybe selected from the group comprising of organic or inorganic solvents such as hydrocarbons, alcohols, ethers, chlorinated solvents, ketones and aqueous solutions. Wherein the inorganic solvent maybe selected from the group comprising of water, aqueous solutions containing special additives (surfactants, detergents, pH buffers, inhibitors), liquid anhydrous Ammonia (NH3), concentrated sulfuric acid (H2SO4), sulfuryl chloride fluoride (SO2ClF), etc. Wherein the organic solvent maybe selected from the group comprising of ester solvents such as ethyl acetate, isopropyl acetate, butyl acetate; halogenated solvents such as methylene chloride, ethylene chloride, chloroform, chlorobenzene; nitrile solvents such as acetonitrile; alcoholic solvents such as methanol, ethanol, isopropanol, n-butanol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; ether solvents such as diethyl ether, diisopropylether, tetrahydrofuran and/or hydrocarbon solvents such as methyl cyclohexane, toluene, cyclohexane, n-hexane, n-heptane. Preferable selected individually or in combination of solvents Methylene chloride, n-Heptane and Ethyl acetate.
In an additional embodiment of the present invention, the base used maybe selected from the group comprising of organic base such as Triethylamine (TEA), Pyridine and N,N-Diisopropylethylamine (DIPEA) or strong Arrhenius Bases selected from hydroxides of alkali metals and alkaline earth metals such as Potassium hydroxide (KOH), Sodium hydroxide (NaOH), Barium hydroxide (Ba(OH)2), Caesium hydroxide (CsOH), Strontium hydroxide (Sr(OH)2), Calcium hydroxide (Ca(OH)2), Lithium hydroxide (LiOH), Rubidium hydroxide (RbOH). Preferable selected from Potassium hydroxide (KOH), Sodium hydroxide (NaOH), and Lithium hydroxide (LiOH).
Another embodiment of the present invention provides for a solid form of levocetirizine base (Formula I) with the XRPD as described in Figure 1.
Another embodiment of the present invention provides of a solid form of levocetirizine base (Formula I) with the PSD as described in Figure 2.
An additional embodiment of the present invention provides of a solid form of levocetirizine base (Formula I) is solid according to storage conditions specified by ICH.
An embodiment of the present invention provides the process for synthesizing solid premix forms of levocetirizine base (Formula I) with a polymer. Wherein the polymers used maybe selected from the group comprising of Microcrystalline cellulose (MCC), Lactose, Polyvinylpyrrolidone (PVP), Hydroxyethyl cellulose (HEC, HMHEC), Hydroxypropyl cellulose (HPC), Prosolv HD, and Silicon dioxide.
In an additional embodiment of the present invention, the process for synthesizing solid levocetirizine premix wherein the preparation comprises of levocetirizine to polymer in the ratio that ranges from 1:1 to 1:1.25 w/w.
In an added embodiment of the present invention, the process for synthesizing solid premix powder forms of levocetirizine base (Formula I), comprises the use of methods of Freeze drying, Spray drying, Solvent evaporation, Trituration, Dry mixing, or Melt.
In another alternative embodiment of the present invention, the process is a continuous process at a commercial scale that is both economical and safe to the environment.
In a final embodiment of the present invention, the process yields a product that is used in pharmaceutical formulation.
Without being limited by theory, the process according to the present invention may be advantageously used to prepare the solid powder forms of Levocetirizine base and Cetirizine base. The proposed preparations of the solid form of Levocetirizine base and Cetirizine base was an unmet need and the successful preparation of the same prevents the disadvantages of the prior art. It is envisaged that by providing the solid forms of product and may control the impurity content of the product is during the preparation, thereby contributing to the overall efficacy of the product.
The foregoing embodiments and advantages are merely exemplary and are not to be construed as limiting the scope of the present invention. The description of the exemplary embodiments of the present invention is intended to be illustrative and not to limit the scope of the invention. Various modifications, alterations and variations, which are apparent to a person skilled in the art, are intended to fall within the scope of the invention.
From the foregoing it will be understood that the embodiments of the present invention described above are well suited to provide the advantages set forth, and since many possible embodiments may be made of the various features of this invention, all without departing from the scope of the invention, it is to be understood that all matter hereinbefore set forth or shown in the description and synthetic schemes is to be interpreted as illustrative and that in certain instances some of the features may be used without a corresponding use of other features, all without departing from the scope of the invention.
The present invention is further described below by way of example, but not to limit the invention thus described in the embodiments. Experimental methods are without specific conditions in the examples below and may be altered in accordance with conventional methods and conditions, according to the product specification or selection.

EXPERIMENTAL PROCEDURES
Example 1: Synthesis of Levocetirizine Base (Formula I):

To 1200.0 mL of water in a clean RBF, 200 g of Levocetirizine dihydrochloride was added and stirred at 25-35ºC. The pH of reaction mass was adjusted to 4.5 to 5.0 with potassium hydroxide solution and the resultant product was extracted with 1500.0 mL of methylene chloride. The organic layer was washed with 1500 mL of water while constantly maintaining the pH at 4.5 to 5.0. The resultant organic layer was dried in the presence of sodium sulfate and transferred to a RBF and activated carbon was added and stirred for 30-40 min at 25-35ºC. The resultant mixture was filtered through hyflo bed and washed with 1500.0 mL of methylene chloride. The methylene chloride solvent was distilled using Rota vapor at below 50 ºC. The solvent methylene chloride was distilled at below 50 ºC using Rota vapor. The residue formed was further co-distilled with 600 mL n-Heptane. To the product formed in RB-Flask, 1200.0 mL n-Heptane was charged and stirred for 2 hrs at 25-35 ºC. The final product was filtered, washed with n-Heptane and dried for 12 h at 40-45ºC under vacuum to yield 210.0 g which is a solid form of Levocetrizine base.

Example 2: Synthesis of Levocetirizine Base (Formula I):

To 1200.0 mL of water in a clean RBF, 200 g of Levocetirizine dihydrochloride was added and stirred at 25-35ºC. The pH of reaction mass was adjusted to 4.5 to 5.0 with potassium hydroxide solution and the resultant product was extracted with 1500.0 mL of methylene chloride. The organic layer was washed with 1500 mL of water while constantly maintaining the pH at 4.5 to 5.0. The resultant organic layer was dried in the presence of sodium sulfate and transferred to a RBF and activated carbon was added and stirred for 30-40 min at 25-35ºC. The resultant mixture was filtered through hyflo bed and washed with 1500.0 mL of methylene chloride. The methylene chloride solvent was distilled using Rota vapor at below 50 ºC. The solvent methylene chloride was distilled at below 50 ºC using Rota vapor. The residue formed was further co-distilled with 600 mL Ethyl acetate. To the product formed in RB-Flask, 1200.0 mL Ethyl acetate was charged and stirred for 2 hrs at 25-35 ºC. The final product was filtered, washed with Ethyl acetate and dried for 12 h at 40-45 ºC under vacuum to yield 160.0 g which is a solid form of Levocetrizine base.

Example 3:
Preparation of Levocetirizine Premix with microcrystalline cellulose (MCC):
To the slurry of Levocetirizine base as formed in example 1or 2 (before drying), microcrystalline cellulose is added in the ratio of 1:1 to 1:1.25 w/w and the resulting mass was further stirred for 60 minutes at 20 to 25°C, filtered the reaction mass and concentrated filtrate in rotavapor apparatus under vacuum at 45 to 55°C to get solid. Then dried the obtained solid in rotavapor apparatus under vacuum at 60°C to yield Levocetirizine premix with microcrystalline cellulose.

Example 4:
Preparation of Levocetirizine Premix with Lactose:
To the slurry of Levocetirizine base as formed in example 1or 2 (before drying), Lactose anhydrous is accurately weighed and added in the ratio of 1:1 to 1:1.25 w/w, the resulting mass was further stirred for 60 minutes at 20 to 25°C, and triturated in a clean and dry mortar with a small volume of ethyl acetate to make a thick slurry. The mass was uniformly mixed and dried at in a rotavapor apparatus under vacuum at 60°C to yield Levocetirizine premix with Lactose.

Example 5:
Preparation of Levocetirizine Premix with polyvinylpyrrolidone (PVP):
To the slurry of Levocetirizine base as formed in example 1or 2 (before drying), polyvinylpyrrolidone accurately weighed and added in the ratio of 1:1 to 1:1.25 w/w, resultant mass is triturated in a clean and dry mortar with a small volume of ethyl acetate to make a thick slurry. The mass was uniformly mixed and dried at 60°C for 3 hours to yield Levocetirizine premix with polyvinylpyrrolidone (PVP).

Example 7:
Preparation of Levocetirizine Premix with hydroxyethyl cellulose (HEC, HMHEC):
To the slurry of Levocetirizine base as formed in example 1or 2 (before drying), hydroxyethyl cellulose is accurately weighed and added in the ratio of 1:1 to 1:1.25 w/w, resultant mass is dissolved in acetone and the solid premix powder is Spray drying at 45-55°C to yield Levocetirizine premix with hydroxyethyl cellulose (HEC, HMHEC).

Example 8:
Preparation of Levocetirizine Premix with hydroxypropyl cellulose (HPC):
To the slurry of Levocetirizine base as formed in example 1or 2 (before drying), hydroxypropyl cellulose is accurately weighed and added in the ratio of 1:1 to 1:1.25 w/w, resultant mass is dissolved in acetone and the solid premix powder is Spray drying at 45-55°C to yield Levocetirizine premix with hydroxypropyl cellulose (HPC).

Example 9:
Preparation of Levocetirizine Premix with Prosolv HD:
To the slurry of Levocetirizine base as formed in example 1or 2 (before drying), Prosolv HD is accurately weighed and added in the ratio of 1:1 to 1:1.25 w/w, resultant mass is triturated in a clean and dry mortar with a small volume of methylene chloride solvent to make a thick slurry. The mass was uniformly mixed and dried at 35-45°C for 1-2 hours to yield Levocetirizine premix with Prosolv HD.

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense. ,CLAIMS:We Claim:
1. A process for the preparation of solid form of Levocetirizine base comprises of
a) Dissolving levocetirizine dihydrochloride in a solvent,
b) Adding a base,
c) Isolating Levocetirizine base.

2. The process according to claim 1, wherein the Particle Size Distribution (PSD), D10 is within 2-5 µm, D50 is within 10-15 µm or D90 is within 20-500 µm.

3. The process according to claim 1, wherein the base is selected from the group comprising of organic base selected from Triethylamine (TEA), Pyridine and N,N-Diisopropylethylamine (DIPEA) or strong Arrhenius Bases selected from hydroxides of alkali metals and alkaline earth metals

4. The process according to claim 3, wherein the base is selected Potassium hydroxide (KOH), Sodium hydroxide (NaOH), and Lithium hydroxide (LiOH).

5. The process according to claim 1, wherein the solvent is selected from the group comprising of organic or inorganic solvents such as hydrocarbons, alcohols, ethers, chlorinated solvents, ketones and aqueous solutions.

6. The process according to claim 5, wherein the solvents is selected individually Methylene chloride, n-Heptane and Ethyl acetate or mixture thereof.

7. The process for the preparation of solid premix powder forms of Levocetirizine base, wherein the methods used is selected from Freeze drying, Spray drying, Solvent evaporation, Trituration, Dry mixing, or Melt trituration.

8. The process according to claim 5, wherein Levocetirizine base with a polymer in the ratio that ranges from 1:1 to 1:1.25 w/w, with the polymers are selected from the group comprising of Microcrystalline cellulose (MCC), Lactose, Polyvinylpyrrolidone (PVP), Hydroxyethyl cellulose (HEC, HMHEC), Hydroxypropyl cellulose (HPC), Prosolv HD, and Silicon dioxide.

9. A pharmaceutical formulation according to claims 5 and 6, wherein the compound used is a solid premix powder forms of Levocetirizine base.