FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION
"PROCESS FOR PURIFICATION OF PROMETHAZINE HYDROCHLORIDE"
2. APPLICANT (S)
(a) NAME: WANBURY LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956
(c) ADDRESS: B- Wing, 10th Floor, BSEL Tech Park, Sector 30 A,
Plot no.39/5 & 39/5A, Opp. Vashi Railway Station, Navi Mumbai- 400 703, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field of invention:
The present invention relates to a process for preparing substantially highly pure Promethazine Hydrochloride which is free from its isomer impurity of Figure I by crystallization process.

Background of invention:
Promethazine HC1, a phenothiazine derivative, is designated chemically as N,N,α-
Trimethyl-10H-phenothiazine-10-ethanamine or (RS)-N,N-dimethyI-l-(10H-
phenothiazin-10-yl)propan-2-amine with the following structural Figure II,
Promethazine hydrochloride occurs as a white to faint yellow, practically odorless, crystalline powder which slowly oxidizes and turns blue on prolonged exposure to air. It is freely soluble in water and somewhat soluble in alcohol.
Promethazine hydrochloride, which belongs to phenothiazine class of compound, the first-generation H1 receptor antagonist is used medically as an antihistamine and antiemetic. It can also have strong sedative effects and in some countries and is prescribed for insomnia when benzodiazepines are contraindicated. It is a prescription drug in the United States but is available over the counter in the United Kingdom, Australia, Canada, Switzerland, and many other countries (brand names Phenergan,

Promethegan, Romergan, Fargan, Farganesse, Prothiazine, Avomine, Atosil, Receptozine, Lergigan).
Processes for the preparation of Promethazine hydrochloride or its derivatives described in the prior art is listed below:
US2530451 describes preparation of Promethazine and its derivatives by the action of 1-dimethylamino-2-chloropropane in xylene with phenothiazine using halogen-acid binding agent, preferably sodamide. The Promethazine base thus obtained was converted to its hydrochloride salt by treating with dry hydrochloric acid in acetone and ethyl acetate.
US2607773 discloses the process for preparation of derivatives of 10-dialkyl aminoalkyl-phenothiazine by reacting a dialkylamino alkyl halide with a complex of a grignard reagent with phenothiazine. The said patent further describes that when the methyl substituent on the carbon atom is a or p in relation to the halogen atom, isomerisation occurs during the process yielding two isomeric products. These two isomers are separated by converting the isomers to their hydrochlorides and further fractional crystallization from ethylene dichlorjde to obtain the required isomer.
US2687414 describes preparation of 10 -amino alkyl phenothiazine by condensation of phenothiazine with amino alkyl halide for example p-dimethyl aminopropyl chloride in presence of solid alkali metal hydroxide and ah inert hydrocarbon solvent. The base formed was converted to its hydrochloride by treating with alcoholic hydrogen chloride followed by recrystallization from isopropanol.q
US2769002 describes process for preparation of Promethazine hydrochloride which comprises cyclization in the presence of an acid binding agent, of a diphenylsulphide ortho-substituted in one ring by the group -NHZ (wherein Z is hydrogen or an amino alkyl group) and in the other ring by a halogen atom in an anhydrous solvent at elevated temperature.
GB680128 discloses the preparation of 10-dialkyl aminoalkyl-phenothiazine by reacting a dialkylaminoalkylhalide with a complex formed by reacting phenothiazine or a substituted phenothiazine with Grignard reagents in an inert solvent.

GB814512 relates to preparation of N,N dialkyl-sulfamoyl derivatives of 10-amino alkyl phenothiazines.
GB808050 describes process for preparation of acyl phenothiazine-10-carboxylic acid esters which comprises reacting the corresponding unsubstituted phenothiazine with phosgene, in an inert solvent, e.g. xylene, and reacting the resulting 10-carboxylic acid chloride with a basic alcohol, in boiling benzene.
Indian Application No. 1211/MUM/2006 describes preparation of Promethazine hydrochloride by condensation of phenothiazine with 2-Chloro-N,N-dimethyl propylamine and alkali in toluene solvent. The Promethazine base thus obtained was converted to its sulphate salt by treating with sulphuric acid. The sulphate salt is converted to its free base. The free base of sulphate is further treated with alcoholic hydrochloric acid to produce Promethazine hydrochloride,
The reported processes of the prior arts for the preparation of Promethazine HC1 suffer from drawbacks in that it employs the use of costly reactants, requires long hours for completion of the reaction, with low yields containing undesired isomer impurity.
Object of the Invention:
It is therefore the object of the present invention to provide a feasible and cost effective commercial process for preparation of Promethazine hydrochloride which is free from its isomer impurity (Figure-I) by solvent crystallization.
Summary of the invention:
The present invention discloses an improved process for the preparation of Promethazine hydrochloride of Figure II and its purification from the undesired isomer of Figure I.
In an aspect, the present invention involves condensation of hydrochloride salt of p-dimethyl amino isopropyl chloride with phenothiazine in aromatic hydrocarbon as a solvent and in presence of a condensation agent to obtain Promethazine base. Higher moles of condensation agent are used which reduces reaction time by 5-6 hours.

Further, since the alkyl side chain substituted to the phenothiazine ring is asymmetric branched chain, isomerisation can take place during the course of the reaction resulting in the production of two isomeric products.
In an aspect, Promethazine base obtained in the condensation step contains isomer impurity of 20-30%. The isomer impurity is controlled by preparation of Promethazine hydrochloride. Accordingly, Promethazine base is washed with water and ethyl acetate to get the clear solution, followed by addition of alcoholic hydrochloride to yield crude Promethazine hydrochloride at 25-30°C with the isomer impurity reduced to in the range of 1-10%.
In a preferred aspect of the invention, crude Promethazine hydrochloride is subjected to fractional crystallization wherein, the crude product is heated with aliphatic hydrocarbon/aromatic hydrocarbon/substituted aromatic hydrocarbon and alcohol at 40-45°C, to obtain Promethazine hydrochloride tech with an isomer impurity in the range of 0.1-0.8%.
In another preferred aspect, Promethazine hydrochloride tech having isomer impurity in the range of 0.1-0.8% is further purified by treating Promethazine hydrochloride tech with an alcohol selected from C1-C4 alcohol at reflux temperature followed by addition of 0.1-20% alcoholic hydrochloride or cone, hydrochloric acid. The reaction mass is then filtered through hyflo and further washed with alcohol, cooled the reaction mass, dried to give pure Promethazine hydrochloride having isomer impurity less than 0.05% to absent.
Alternately, Promethazine hydrochloride can be dried at 40-80°C under vacuum (650 -700 mm / Hg) to yield pure product.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the appended examples and claims.
Detailed description of the invention:
The present invention relates to an improved process for the preparation of Promethazine hydrochloride of Figure II, of valuable therapeutic property and is particularly concerned with the purification of the required derivative from its undesired isomer of Figure I.

In an embodiment, the present invention relates to condensation of hydrochloride salt of β-dimethyl amino isopropyl chloride with phenothiazine in aromatic hydrocarbon as a solvent and in presence of a condensation agent to obtain Promethazine base.
Ordinarily, amines having aromatic substitution are weak bases, or even are acidic in nature; consequently do not undergo substitution with amino alky halides easily. It thus becomes necessary to carry out the condensation reaction in presence of a strong and safe condensation agent. Sodamide used previously are highly reactive, expensive and difficult to handle. In the present invention, the condensation agents used are selected from powdered alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, alkali metal carbonates such as potassium carbonate, sodium carbonate which are cheap, safe and readily available. Powdered potassium hydroxide is most preferred.
In an embodiment, higher moles of potassium hydroxide are used in order to reduce the reaction time as compared to the earlier reported processes (Indian Application No.l211/MUM/2006). Accordingly, about.5-7 moles of the condensation agent is used which reduces reaction time by 5-6 hours.
The condensation reaction is conveniently and efficiently carried out in aromatic hydrocarbon such as toluene, xylene etc as. a solvent. The reaction is preferably carried out at the reflux temperature of the solvent.
Further, since the alkyl side chain substituted to the phenothiazine ring is asymmetric branched chain, isomerisation can take place during the course of the reaction resulting in the production of two isomeric products.
The mechanism of the formation of isomer impurity during the course of the reaction is given below:


Promethazine base obtained in the condensation step contains isomer impurity of 20-30%. The isomer impurity is controlled by preparation of Promethazine hydrochloride. Accordingly, Promethazine base is washed with water and ethyl acetate to get the clear solution, followed by addition of alcoholic hydrochloride to yield crude Promethazine hydrochloride at 25-30°C with the isomer impurity reduced to in the range of l-10%.The said alcoholic hydrochloride used is methanolic hydrochloride or isopropyl hydrochloride.
According to a preferred feature of the present invention, crude Promethazine hydrochloride is subjected to fractional crystallization wherein, the crude product is heated with aliphatic hydrocarbon/aromatic hydrocarbon/substituted aromatic hydrocarbon and alcohol at 40-45°C, to obtain Promethazine hydrochloride tech with an isomer impurity in the range of 0.1-0.8%.
The aliphatic hydrocarbon/aromatic hydrocarbon/substituted aromatic hydrocarbon are selected from n-hexane, cyclohexane, toluene, o, m, p-xylene,.o, m, p -chiorotoluene etc. The alcohol is selected from C1-C4 straight or branched chain alcohol such as methanol, ethanol, isopropanol, butanol etc. The aliphatic hydrocarbon/aromatic hydrocarbon/substituted aromatic hydrocarbon and C1-C4 alcohol may be used as a mixture of different percentage of alcohol with hydrocarbon solvents.
In another preferred feature of the present invention, Promethazine hydrochloride tech having isomer impurity in the range of 0.1-0.8% is further purified by treating Promethazine hydrochloride tech with an alcohol selected from C1-C4 alcohol at reflux

temperature followed by addition of 0.1-20% alcoholic hydrochloride or cone. hydrochloric acid. The reaction mass is then filtered through hyflo and further washed with alcohol, cooled the reaction mass, dried to give pure Promethazine hydrochloride having isomer impurity less than 0.05% to absent.
In an embodiment, the use of alcoholic hydrogen chloride in the crystallization/purification process prevents Promethazine hydrochloride from oxidation and avoids formation of blue colour thus increasing its pharmacodynamic property.
The detailed process of the present invention along with a schematic representation is given below:

Accordingly, in an embodiment, the first step comprises condensation of phenothiazine dissolved in aromatic hydrocarbon and in presence of powder sodium or potassium hydroxide as a condensing agent, with hydrochloride salt of β-dimethyl amino isopropyl chloride at 25-35°C. The reaction mass is then heated to reflux (105-115°C) and maintained at reflux for 5-6 hours to obtain Promethazine hydrochloride having isomer impurity 20-30%. The reaction mass is cooled to 25-35°C, washed with water, then washed the organic layer with 10% sodium chloride solution. This is followed by distilling out the organic layer under vacuum (720-750mm/Hg) at 50-55°C till thick residue is obtained To the cooled reaction mass is further added ethyl acetate at 25-35°C followed by slow addition of alcoholic hydrochloride maintaining the pH of the reaction

mass less than 1.5 at the same temperature. The reaction mass is further cooled to 0-5°C, filtered and washed with chilled ethyl acetate, dried under vacuum at 50-55°C to yield Promethazine hydrochloride having isomer impurity 1-10%.
In a preferred embodiment, to the crude Promethazine hydrochloride obtained above are added C1-C4 alcohol and aliphatic hydrocarbon/aromatic hydrocarbon/substituted aromatic hydrocarbon. The reaction mass is heated to 40-45°C followed by addition of toluene at the same temperature and maintained for 1. hour. The reaction mass is then cooled to 25-30°C and further cooled to 10-15°C. Filtered the mass, washed the wet cake with toluene, dried under vacuum at 50-55°C, to yield Promethazine hydrochloride tech having isomer impurity 0.1-0.8%.
In another preferred embodiment, Promethazine hydrochloride tech is treated with alcohol selected from C1-C4 and heated at reflux temperature. To the reaction mass is then added activated carbon 2.5% and stirred for 30min at reflux temperature followed by addition of 0.1-20% alcoholic hydrochloride or cone, hydrochloric acid. The reaction mass is then filtered through hyflo and washed the wet cake with hot alcohol. Cooled the reaction mass to 25-35 °C, further cooled to 15-20°C and maintained for two hours. Filtered the mass and washed the wet cake with chilled alcohol, dried under vacuum at 50-55°C to yield Promethazine hydrochloride having isomer impurity less than 0.05% to absent.
In an alternate embodiment, pure Promethazine hydrochloride is dried at 40-80°C under vacuum (650 - 700 mm / Hg).
Pure Promethazine hydrochloride obtained by the process of the present invention may be thereafter incorporated in a pharmaceutical composition along with suitable pharmaceutical excipients and made into dosage forms such as tablet, capsules etc.
Further details of the process of the present invention will be apparent from the examples presented below. Examples presented are purely illustrative and are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description.

Examples:
Examplel: Preparation of Promethazine Hydrochloride crude
Toluene (7.5 vol) and phenothiazine (1.0 mol) was stirred for 15 - 20 min at 25 - 35°C. Potassium hydroxide powder (6.0mol) was then added to the mixture and stirred the reaction mass for 15 - 20 min at 25 - 35°C.This was followed by addition of hydrochloride salt of p-dimethylaminoisopropyl chloride (1.5moI) and stirred the reaction mass for 15 - 20 min at 25 - 35°C Heated the reaction mass to reflux (105 - 115 °C) and maintained the reaction mass at reflux for 5 - 6 hrs and collect water, to obtain Promethazine base having isomer impurity 20-30%.Cooled the reaction to 25 - 35°C. Washed the reaction mass with water (7.5 vol) and further washed with 5.0 volume water twice. Further, washed the organic layer with 10% sodium chloride solution. Distilled out organic layer under vacuum (720 - 750 mm/Hg) at 50 - 55 °C till thick residue. Cooled the reaction mass to 25 - 35 °C. Added ethyl acetate (3.0 vol) at 25-30°C and stirred the mass at 25-35°C to get the clear solution. Then added slowly, alcoholic hydrochloric acid to maintain pH of reaction mass less than 1.5 at 25 - 30°C for 30 min. Cooled the mass to 0 - 5°C and maintained the reaction mass for 2 hrs. Filtered the mass and washed the wet cake with chilled ethyl acetate. Suck dried and further dried the solid under vacuum at 50 - 55°C for 10 hrs. Yield: 50-60% having isomer impurity 1-10%.
Example 2: Preparation of Promethazine HC1 Tech
To 1.0 mol of crude promethazine hydrochloride (example 1) was added isopropyl alcohol (IPA) (0.5 to 2.0 mol) and toluene (0.5 to 2.0 mol). Heated reaction mass to 40-45°C and maintained for 1.0 hr. Added toluene (5.0 vol) in 1.0 hr at 40-45°C and maintained for 1.0 hr. Cooled the reaction mass to 25-30°C in 1.0 hr. Cooled the mass to 10 - 15°C and maintained for 1.0 hr. Filtered the mass and washed the wet cake with Toluene. Suck dried and dried the solid under vacuum at 5.0 - 55 °C for 8 hrs. Yield 78 -90%, having isomer impurity 0.1 to 0.8%.
Example 3: Preparation of Pure Promethazine HCl
To 1.0 mol of Promethazine HCl tech (example 2) was added IPA (11 vol). Heated the reaction mass at reflux temperature and further added activated carbon 2.5%, stirred for 30 min at reflux with addition of 0.1- 20% alcoholic hydrochloric acid. Filtered the

reaction mass through hyflo and washed hyflow wet cake with hot IPA. Cooled the reaction mass to 25 - 35°C and further cooled to 15 - 20°C and maintained for 2 hrs. Filtered the mass and washed the wet cake with 10-15°C IPA. Suck dried and dried the product under vacuum (650 - 700 mm / Hg) at 50 - 55°C for 10 hrs. Yield: 80 to 95 % having isomer impurity less than 0.05%.

We Claim,
1. The cost effective purification process for purifying Promethazine hydrochloride
from its undesired isomer, comprising the steps of:
(a) Converting Promethazine base having undesired impurity to its
hydrochloride which involves extracting said base in ethyl acetate
followed by reacting with 2.0-8.0% alcoholic hydrogen chloride to obtain
crude Promethazine hydrochloride;
(b) Crystallizing crude Promethazine hydrochloride of step (a)from C1-C4
alcohol and aliphatic hydrocarbon/aromatic hydrocarbon/substituted
aromatic hydrocarbon at 40-45°C to obtain Promethazine hydrochloride
tech and
(c) Recrystallizing Promethazine hydrochloride tech of step (b) from C1-C4
alcohol at reflux temperature followed by addition of 0.1-20% alcoholic
hydrochloride or concentrated hydrochloric acid and dried to obtain pure
Promethazine hydrochloride.
2. The process according to claiml, wherein the aliphatic hydrocarbon/aromatic hydrocarbon/substituted aromatic hydrocarbon is selected from n-hexane, cyclohexane, toluene, o, m, p-xylene, o, m, p -chlorotoluene, etc.
3. The process according to claiml,wherein the-Cl-C4 alcohol is straight or branched such as methanol, ethanol, isopropanol etc.
4. The process according to claims .1,2 and 3, wherein the C1-C4 alcohol and the aliphatic hydrocarbon/aromatic hydrocarbon/substituted aromatic hydrocarbon may be used as a mixture of different percentage of alcohol with hydrocarbon solvents in step (b).
5. The process according to claim 1, wherein the said alcoholic hydrochloride is methanolic hydrochloride or isopropyl hydrochloride.
6. The process according to claim 1, wherein the drying of pure Promethazine hydrochloride of step (c) is carried out at 40-80°C under vacuum of 650 - 700 mm/Hg.
7. The process according to claim 1, wherein the isomer content in crude Promethazine hydrochloride of step (a) is 1 -10%.
8. The process according to claim 1, wherein the isomer content in Promethazine hydrochloride tech of step (b) is 0.1 -0.8%.

9. The process according to claim 1, wherein the pure Promethazine hydrochloride is substantially pure having less than 0.05% of the undesired isomer.
10. The process according to claim 1, wherein Promethazine base used in step(a) is prepared by reacting phenothiazine with hydrochloride salt of p-dimethylaminoisopropyl chloride in aromatic hydrocarbon and in presence of 5 -7 mole of condensation agent.