DESC:FORM 2

THE PATENTS ACT,
(39 OF 1970)
THE PATENT RULES, 2003.

COMPLETE SPECIFICATION
(SECTION 10 AND RULE 13)

AN IMPROVED PROCESS FOR THE PREPARATION OF CHLOROTHIAZIDE SODIUM MANNITOL PREMIX

Apicore Pharmaceuticals Private Limited,
Block No. 252-253, Opposite Jain Irrigation Company, Padra-Jambusar Highway, Taluka Padra, Village Dhobikuva, Vadodara-391440

The following specification particularly describes the invention and the manner in which it is to be performed.

AN IMPROVED PROCESS FOR THE PREPARATION OF CHLOROTHIAZIDE SODIUM MANNITOL PREMIX

FIELD OF THE INVENTION
The present invention relates to Chlorothiazide Sodium mannitol premix, and process for its preparation. The present invention further relates to an improved process for the preparation of substantially pure Chlorothiazide sodium.

BACKGROUND OF THE INVENTION
Chlorothiazide, chemically known as 6-chloro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide, represented by Formula I, has diuretic and antihypertensive activity.


Formula I
Chlorothiazide is marketed under the brand name DIURIL as an oral suspension. Chlorothiazide is also available as 250mg and 500mg tablets.
Chlorothiazide sodium is marketed under the brand name DIURIL as an injectable injection.
Chlorothiazide is a diuretic that prompts the body to eliminate excess fluid. Diuretics are an indispensable group of therapeutics used to regulate the excretion of water and salts by increasing the urinary flow. They act by diminishing sodium chloride reabsorption at different sites in the nephron thereby increasing urinary sodium chloride and water losses. The action of diuretics is based on the interference with the mechanism of ionic transport along the complete length of nephron. Chlorothiazide sodium is indicated as an adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis and corticosteroid and estrogen therapy. It is also useful in edema caused due to various forms of renal dysfunction such as nephrotic syndrome, acute glomerulonephritis and chronic renal failure. It is indicated in the management of hypertension either as sole therapeutic agent or to enhance the effectiveness of other anti-hypertensive drugs in more severe forms of hypertension. The mode of action of Chlorothiazide in hypertension most probably depends upon its ability to increase sodium excretion and reduce blood volume. The ability to induce negative fluid balance has made diuretics useful in the treatment of a variety of conditions, particularly edematous states and hypertension.
US2809194 (hereinafter referred to as US '194) discloses process for the preparation of Chlorothiazide sodium by dissolving the chlorothiazide in alcoholic sodium hydroxide and then evaporating in vacuo to yield Chlorothiazide sodium.
1514/MUM/2008 discloses a process for the preparation of Chlorothiazide sodium by dissolving chlorothiazide in methanol and then adding methanolic sodium hydroxide solution to obtain clear solution followed by concentrating at atmospheric pressure and precipitating by addition of ethyl acetate which is then filtered, washed, isolated and dried.
1515/MUM/2008 discloses process for purification of chlorothiazide sodium by treating chlorothiazide with sodium source in methanol to form chlorothiazide sodium methanol solvate and converting the solvate into chlorothiazide sodium.
The crystal structure of Chlorothiazide sodium dihydrate as an intramolecular self-assembly: (CTZ)3·(H2O)·Na(H2O)2Na·(H2O)·(CTZ)3, which has a triclinic crystal structure and a space group P-1 was reported in European Journal of Pharmaceutical Sciences (2010), 41(5), 603-611. The solubility of Chlorothiazide sodium dihydrate was determined to be 79.4±9.5 mg/ml, around 400-fold higher than that of Chlorothiazide.
1312/MUM/2010 discloses Chlorothiazide sodium polymorphic forms I-IV. Chlorothiazide sodium obtained by following the process disclosed in US2809194 patent has been designated as Chlorothiazide sodium Form I in this patent application. A parenteral composition comprising a therapeutically effective amount of Chlorothiazide sodium, a pharmaceutically acceptable tonicity agent and a pharmaceutically acceptable pH adjusting agent has also been disclosed in this patent application. Chlorothiazide sodium injection disclosed in this patent application is provided as a lyophilized product which can be reconstituted by dissolving the lyophilized product in a suitable solvent such as physiological saline, aqueous solution of 5% Dextrose or distilled water for injection. Preferred tonicity agent which has been exemplified in this patent application is mannitol.
Amorphous microparticles of Chlorothiazide sodium obtained by spray drying from water, methanol (MeOH) and mixture of MeOH and butyl acetate (BA) was reported in Journal of Pharmacy and Pharmacology (2012), 64(11), 1570-1582 and Journal of Pharmacy and Pharmacology (2012), 64(11), 1583-1591.
74/MUM/2013 discloses Chlorothiazide sodium dihydrate injection which is a stable ready to use injectable phamaceutical composition comprising chlorothiazide sodium dihydrate.
Prior art processes for the preparation of Chlorothiazide sodium especially lyophilisation suffers from serious drawbacks, such as
1) Lengthy and complex manufacturing process
2) Higher overall production cost as preparation of sterile chlorothiazide sodium lyophilized powder requires "Lyophilizer" which is an expensive technique at commercial scale and therefore sterile chlorothiazide sodium lyophilized powder is an expensive dosage form.
3) Limited Batch size and purities
4) Degradation of chlorothiazide sodium sterile lyophilized white powder after reconstitution with water.
5) Challenges during development phase
1. Requires optimization of the lyophilisation Cycle for the cake formation
2. Need of maintaining batch to batch uniformity in the cake
3. Problem of cake melting back and blowing out of vial.
6) Presence of Base Degrade Impurity: Lyophilization involves use of water as solvent which generates base degrade impurity in initial samples which can go on increasing with time.
Accordingly, there is a need in the art to develop simple, highly pure, stable, non-expensive and commercially viable form of chlorothiazide sodium. The present invention describes stable and highly pure chlorothiazide sodium mannitol premix and provides industrial process for its preparation.
The present invention further provides improved process for the preparation of substantially pure Chlorothiazide sodium which is used for the preparation of chlorothiazide sodium mannitol premix.
The advantages of the present invention in comparison with prior art are
1) A process yields more stable crystalline form of Chlorothiazide sodium by crystallization in aseptic conditions.
2) Process requires less infrastructure, reduced energy consumption and shorter amount of time to produce a batch.
3) Process is much more cost effective and commercially viable.
4) Handling procedure is simple which involves minimal exposure of API to tedious manufacturing steps.
5) Apicore process is carried out under non-aqueous condition which quench/minimize the formation of base degrade impurity.
6) Chlorothiazide sodium dihydrate polymorph which is used for formulating Chlorothiazide sodium mannitol premix is thermally and kinetically most stable polymorph in which water is tightly associated (hydrogen bonded) with chlorothiazide sodium molecule. Free/surficial water is the main reason for formation of base degrade impurity which is completely avoided/controlled in dihydrate polymorph. The compound A and Acid degrade impurity also remain well within the limit.

SUMMARY OF THE INVENTION
One aspect of the present invention is to provide Chlorothiazide sodium mannitol premix.
Another aspect of the present invention provides a method for preparing a sterile chlorothiazide sodium mannitol premix that includes the steps of slurring Chlorothiazide sodium and mannitol in suitable solvent; Isolation of Chlorothiazide sodium mannitol premix.
Further aspect of the present invention provides a method for the preparation of substantially pure Chlorothiazide sodium.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrative a characteristic X-ray powder diffraction pattern of Chlorothiazide sodium dihydrate
Figure 2 illustrative a characteristic X-ray powder diffraction pattern of Chlorothiazide sodium mannitol premix.

DETAILED DESCRIPTION OF THE INVENTION
As used herein the term “substantially pure” refers to the Chlorothiazide sodium having purity greater than 99.50% by high performance liquid chromatography (HPLC) or preferably greater than 99.60% by HPLC or more preferably greater than 99.70% by HPLC.
In the first embodiment, the present invention provides Chlorothiazide sodium mannitol premix.
In the preferred embodiment, obtained Chlorothiazide sodium mannitol premix is sterile.
In the second embodiment, the present invention provides an industrial process for preparing Chlorothiazide sodium mannitol premix, comprising the steps of:
(a) Slurring Chlorothiazide sodium and mannitol in a suitable solvent;
(b) Isolation of Chlorothiazide sodium mannitol premix.
In the preferred embodiment, both Chlorothiazide sodium and mannitol used in step (a) are sterile.
Chlorothiazide sodium which can be used in step (a) for the preparation of Chlorothiazide sodium mannitol premix includes various forms of Chlorothiazide sodium such as anhydrous form, monohydrate form, dihydrate form, amorphous form or any other polymorphic form of Chlorothiazide sodium.
In a preferred embodiment, Chlorothiazide sodium which can be used in step (a) is sterile Chlorothiazide sodium monohydrate form or dihydrate form.
Suitable solvents which can be used in step (a) includes ether selected from diethylether, diisopropyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran or 1,4-dioxane; preferably methyl tert-butyl ether (MTBE).
Sterile mannitol which can be used in step (a) for the preparation of Chlorothiazide sodium mannitol premix is obtained by dissolving D-Mannitol in water by heating the reaction mixture at 70-80?, stirring for 2-3 hours followed by aseptic filtration.
Suitable temperature at which step (a) is carried out is typically 20-40oC, preferably 20-30oC.
Suitable techniques which can be used in step (b) for isolation of Chlorothiazide sodium mannitol premix are filtration, micron filter, centrifugation, decantation, or any other techniques known in the art. The solution can be filtered by passing through paper, or other membrane material, or a clarifying agent such as celite.
The resulting Chlorothiazide sodium mannitol premix may optionally be further dried. Drying can be carried out in a 15-tray dryer, vacuum oven, air oven, buchi®, rotavapor®, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, gravity oven, or the like. Preferably, drying can be carried out at temperatures of 50-80? till water content is below 5%.
In a preferred embodiment of the invention, Chlorothiazide sodium mannitol premix is having purity greater than 99.5% by HPLC, preferably greater 99.60% by HPLC or more preferably greater than about 99.70% by HPLC.
Another embodiment of the present invention provides substantially pure Chlorothiazide sodium dihydrate characterized by X-ray diffraction pattern as shown in Fig. 1. Chlorothiazide sodium dihydrate polymorph is thermally and kinetically most stable polymorph in which water is tightly associated (hydrogen bonded) with chlorothiazide sodium molecule. Free/surficial water is the main reason for formation of base degrade impurity which is completely avoided/controlled in dihydrate polymorph.
Further embodiment of the present invention provides a process for preparation of substantially pure Chlorothiazide sodium comprising:
(a) treating Chlorothiazide with a suitable alkaline medium to get a solution;
(b) optionally adding an anti-solvent to the solution obtained in step a); and
(c) isolating substantially pure Chlorothiazide sodium.
In a preferred embodiment, substantially pure Chlorothiazide sodium obtained in step (c) is in sterile form.
In a further preferred embodiment, substantially pure Chlorothiazide sodium obtained in step (c) is sterile Chlorothiazide sodium monohydrate or dihydrate.

In another embodiment of the present invention, the treatment of Chlorothiazide with a suitable alkaline medium in the step (a) is carried out at a temperature of 0-10°C, preferably at a temperature of 0-5°C.
The alkaline medium used in step (a) is preferably selected from sodium hydroxide or sodium alkoxide in a suitable solvent. Suitable solvent used in step (a) is selected from water or polar protic solvents such as methanol, ethanol, n-propanol, isopropanol or mixture thereof; preferably methanol.
In a further embodiment of the present invention, Chlorothiazide sodium obtained after step (c) is Chlorothiazide sodium monohydrate when step (a) is carried out in presence of molecular sieves.
In a preferred embodiment of the invention, solution obtained in step (a) is aseptically filtered and further washed with suitable solvent before addition of anti-solvent in step (b).
In the further preferred embodiment of the invention, solution obtained in step (a) is aseptically filtered by passing the solution through 0.22-micron filter.
In another embodiment of the invention, addition of anti-solvent in step (b) is carried out at a temperature of 0-10°C, preferably at a temperature of 0-5°C.
In a further embodiment of the invention, anti-solvent which is added in step (b) is selected from hydrocarbon, chlorinated hydrocarbon, ether, nitrile or ketone. Preferably, Hydrocarbon is selected from hexane, heptane or toluene, preferably toluene; chlorinated hydrocarbon is methylene dichloride (MDC); ether is selected from diethyl ether, di-isopropyl ether, methyl tert-butyl ether, tetrahydrofuran or 1,4-dioxane, preferably methyl tert-butyl ether (MTBE); nitrile used is acetonitrile; and ketone is selected from acetone, ethyl methyl ketone or 2-butanone.
In the preferred embodiment of the invention, anti-solvent which is added in step (b) is methyl tert-butyl ether (MTBE).
In a preferred embodiment of the invention, Chlorothiazide is dissolved in an alkaline medium preferably in a methanolic solution of sodium hydroxide at a temperature of about 0-10°C, preferably at a temperature of about 0-5°C, followed by addition of an anti-solvent to obtain substantially pure Chlorothiazide sodium dihydrate which is isolated by filtration, washed with MTBE, suck dried well and further dried in vacuum oven at 80-1000C for 24-48 hours till water content is below 5%.
In another preferred embodiment of the invention, Chlorothiazide is dissolved in an alkaline medium preferably in a methanolic solution of sodium hydroxide at a temperature of about 0-10°C in presence of molecular sieves, preferably at a temperature of about 0-5°C, followed by addition of an anti-solvent to obtain substantially pure Chlorothiazide sodium monohydrate which is isolated by filtration, washed with MTBE and further dried in vacuum oven at 80? for 2-4h.
In a further preferred embodiment of the invention, Chlorothiazide sodium obtained in step (c) is having purity greater than 99.5% by HPLC, more preferably greater 99.60% by HPLC or most preferably greater than about 99.70% by HPLC.

# Commercial advantages of the present invention
Preparations Cost per kg raw material materials Lyophilization cost Overall cost
Marketed preparation $11000 $30000 $41000
Present invention $1800 $2500 $ 20000

Preparations Impurity limit Solvents used Purity
Marketed preparation 1.5% Water lower
Present invention 0.5% Methanol higher

Preparations Yield Overall processing time Lyophilization/Drying time
Prior arts 99% Upto 5 hrs 36-48hrs
Present invention 99% 1hr to 2 hr 12-24hrs

Certain specific aspects and embodiments of the present invention will be explained in more 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 present application in any manner.

Examples
Example 1: Preparation of sterile Chlorothiazide sodium dihydrate from Chlorothiazide.
Methanol (10V) was charged in round bottom flask. Sodium Hydroxide was then charged in round bottom flask and stirred to dissolve it completely. The solution was then cooled to 0-5?. Chlorothiazide (5gm) was charged in round bottom flask and stirred for 60 min. The Solution was filtered (0.22 micron) and washed with methanol (0.5V). Methyl tertiary butyl ether (MTBE) (20V) was then added slowly in methanolic solution at 0-5?. Slurry was stirred for 5-8 hours. The solid was filtered, washed with MTBE (2V) and suck dried well. The material was unloaded and dihydrate form further dried in vacuum oven at 80-100? for 24-48h till water content below 5%.
Yield: 4.9 gm (85-98%); Purity: 99.88%
Example 2: Preparation of sterile Chlorothiazide sodium monohydrate from Chlorothiazide.
Methanol (10V) was charged in round bottom flask. Activated molecular sieves was added. Sodium Hydroxide was then charged in round bottom flask and stirred to dissolve it completely. The solution was then cooled to 0-5?. Chlorothiazide (5gm) was charged in round bottom flask and stirred for 60 min. The Solution was filtered through celite and followed by (0.22 micron), washed with methanol (0.5V). Methyl tertiary butyl ether (MTBE) (20V) was then added in methanolic solution at 0-5?. Slurry was stirred for 5-8 hours. The solid was filtered, washed with MTBE (2V) and suck dried well. The material was unloaded and observed water content without drying is below 5%. Material further dried in vacuum oven at 80? for 2-4h.
Yield: 4.8gm (85-98%); Purity: 99.79%
Example 3: Preparation of Chlorothiazide Sodium Mannitol premix from Chlorothiazide sodium monohydrate/dihydrate (Sterile).
MTBE (10V) was charged in round bottom flask. Sterile Chlorothiazide sodium (10.78gm) and sterile D-mannitol (5.0gm) were then charged. The slurry was obtained at 20-30? which was stirred for 5 hours. The obtained solid was filtered, washed with MTBE (2-4V) and suck dried well. The material was unloaded, and further dried in vacuum oven at 80? till water content below 5% is achieved.
Yield: 14.9 gm (~99%); Purity: 99.82%
Stability Study of Chlorothiazide Sodium Mannitol premix was carried out for the period of three months under the conditions tabulated in Table 1 given below and the Chlorothiazide Sodium Mannitol premix obtained according to the present invention was found to be stable without substantial change in water content, purity, and pH of composition as a function of time.
Table 1: Stability Study of Chlorothiazide Sodium Mannitol premix
Storage Condition
Water Content HPLC Purity (%) pH
At 25± 2?/ 60 ± 5% RH
Initial 3.5% 99.82 9.8
1 months 3.8% 99.75 9.9
2 months 3.9% 99.78 9.7
3 months 3.7% 99.76 9.9
At 40± 2?/ 75 ± 5% RH
Initial 3.5% 99.82 9.8
1 months 4.0 % 99.60 9.5
2 months 3.7% 99.62 9.8
3 months 3.8% 99.71 9.7

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 may be interpreted as mere illustrative of the invention and not in a limiting sense.

Dated this: 05th May 2022

Signature:
Dr. VURE PRASAD
Patent Agent Reg. No.: IN/PA-1636
Vice President Head - Global IP,
RK Pharma Group
APICORE Pharma limited
,CLAIMS:I/ We claim
1. Chlorothiazide sodium mannitol premix.
2. A process for preparing Chlorothiazide sodium mannitol premix, comprising the steps of
(a) Slurring Chlorothiazide sodium and mannitol in a suitable solvent;
(b) Isolation of Chlorothiazide sodium mannitol premix.
3. The process as claimed in claim 2, wherein suitable solvent used in step (a) is selected from ether selected from diethylether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran or 1,4-dioxane, preferably methyl tert-butyl ether (MTBE).
4. The process as claimed in claim 2, wherein Chlorothiazide sodium mannitol premix is isolated by filtration, micron filter, centrifugation, decantation or any other isolation technique.
5. A process for preparation of substantially pure Chlorothiazide sodium comprising the steps of:
(a) treating Chlorothiazide with a suitable alkaline medium in a suitable solvent to get a solution.
(b) optionally adding an anti-solvent to the solution obtained in step a); and
(c) isolating substantially pure Chlorothiazide sodium.
6. The process as claimed in claim 5, wherein the alkaline medium used in step (a) is selected from sodium hydroxide or sodium alkoxide in a suitable solvent and suitable solvent used in step (a) is selected from water or polar protic solvents such as methanol, ethanol, n-propanol, isopropanol or mixture thereof, preferably methanol.
7. The process as claimed in claim 5, wherein anti-solvent used in the step (b) is selected from hydrocarbon such as hexane, heptane or toluene; chlorinated hydrocarbon such as methylene dichloride (MDC); ether such as diethyl ether, di-isopropyl ether, methyl tert-butyl ether, tetrahydrofuran or 1,4-dioxane; nitrile such as acetonitrile; or ketone such as acetone, ethyl methyl ketone or 2-butanone; preferably methyl tert-butyl ether.
8. The process as claimed in claim 5, wherein step (a) and step (b) reactions are carried out at a temperature ranging from 0-10°C, preferably at a temperature ranging from 0-5°C.
9. The process as claimed in claim 5, wherein solution obtained in step (a) is aseptically filtered and further washed with suitable solvent before addition of anti-solvent in step (b)
10. The process as claimed in claim 5, wherein substantially pure Chlorothiazide sodium obtained in the step (c) is sterile Chlorothiazide sodium monohydrate or dihydrate, and further mixed with mannitol in a suitable solvent and isolated as Chlorothiazide sodium mannitol premix.
Dated this: 05th May, 2022

Signature:
Dr. VURE PRASAD
Patent Agent Reg. No.: IN/PA-1636
Vice President Head - Global IP,
RK Pharma Group
APICORE Pharma limited