FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"A PROCESS FOR THE PREPARATION OF HYDROCHLOROTHIAZIDE"

We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Poacl, Ahmedabad-380015, Gujarat, India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Hydrochlorothiazide, particularly the present invention relates to process for the preparation of highly pure hydrochlorothiazide, avoiding the use of any organic solvent, a common diuretic used for the treatment of hypertension. BACKGROUND OF THE INVENTION
Hydrochlorothiazide, 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide 1,1 -dioxide, having formula I, sometimes abbreviated HCT, HCTZ, or HZT is a popular diuretic drug of the thiazide class that acts by inhibiting the kidney's ability to retain water. This reduces the volume of the blood, decreasing blood return to the heart and thus cardiac output and, by other mechanisms, is believed to lower peripheral vascular resistance. Hydrochlorothiazide is sold both as a generic drug and under a large number of brand names, including: Apo-Hydro, Aquazide H, Dichlotride, Hydrodiuril, HydroSaluric, Microzide, Oretic.
It acts by inhibiting the kidney's ability to retain water, and also acts on the kidney to reduce sodium (Na) reabsorption in the distal convoluted tubule. This reduces the osmotic pressure in the kidney, causing less water to be reabsorbed by the collecting ducts. Hydrochlorothiazide is used in combination with most of the antihypertensive daugs like fosinopril sodium, benazepril hydrochloride, bisoprolol fumarate, captopril, lisinopril, losartan potassium, valsartan, telmisartan, olmesartan rnedoxomil, candesartan cilexetil, eprosartan mesylate, etc.
methods available for the preparat suffer from the purity problem a
uses a process of preparation of mixture of 5-chloro-2,4-disulfamyl-aniline in anhydrous diethyleneglycol dimethylether, hydrogen chloride dissolved in ethyl acetate and paraformaldehyde. The product is reeryslallized from water. There is no sufficient information disclosed about yield and purity of Hydrrothiazide.
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US Patenl No. 3,025,292 disclosed a process for preparation of Hydrochlorothiazide by reducing 6-ehloro-7-sulfamyl-l,2,4-benzothiadizene-1,1- dioxide in presence of 5% ruthenium and obtained yield 83% but there is no any specification given about purity.

US Patent No. 3,043,840 discloses a purification process foi crude Hydrochlorothiazide by treatment of ammonia or water-soluble 1° or 2° amine and crystallization of the product from basic aqueous medium. The purity gained by this process is 97-98%. But the process is not economically viable in comparison.
US Patent No. 3,164,5S8 discloses a method for the preparation of Hydrochlorothiazide by reducing chlorothiazide (6-ehloro-7-sulfamyl-l,2,4-benzothiadiazine-1,1 -dioxide; in presence of ethanol and sodium hydroxide, formaldehyde, hydrochloric acid and ammonia, but there is no clarification about the purity and use of solvent may create problem regarding residual matter. The yield reported is 62.3 - 79%.

Werner et al. in J. Am. Chem. Soc. 82, 1161 (1960) has reported a process for preparation of Hydrochlorothiazide using 4-amino-6-chloro-m-benzcnedisulfonamide, paraformaldehyde, hydrogen chloride dissolved in ethyl acetate and dimethyl carbitol to gain a theoretical yield of 74?%. However ihey are using solvents so, process is not environmentally feasible and also the process is silent about the purity.

Journal of Pharmaceutical and Biomedical Analysis 26 (2001) 651-663 discloses the information regarding Isolation of a 2:1 hydrochlorothiazide-formaldehyde adduct impurity in hydrochlorothiazide drug substance by preparative chromatography and characterization by electrospray ionization LC-MS. In this regard the article discloses the proposed structure of the adduct impurity of hydrochlorothiazide.


WO2007026376 discloses a process for preparation of Hydrochlorothiazide treating of 4-amino-6-chloro-l, 3-benzenedisulfonamide with paraformaldehyde, which was added in portion and alcoholic inorganic acid (sulfuric acid or hydrochloric acid) to give crude Hydrochlorothiazide and purification of the crude Hydrochlorothiazide with acetone and water to gain 99.9% purity and single impurity is less than 0.1%. But this process is not environmentally feasible and economically viable as far as the use of organic solvents concern.
All the above processes result in the formation of two known impurities 4-amino-6-chloro-l,3-bcnzenesulfonamide and chlorothiazide impurity as well as a unknown recurring impurity, which is generally 2:1 Hydrochlorothiazide-formaldehyde adduct of parent drug substance.
The impurities of Hydrochlorothiazide are a major concern on human body. The toxicity is also unknown yet. Now it is very important to reach as much as good quality, improve purity and reduce the impurity below the threshold of ICH guidelines. It is now also

subject to cure environment by invention of such a method of production, which is environmentally feasible and also economically viable.
Thus there is a need to have an economical, environmentally feasible and industrial viable process for the synthesis of Hydrochlorothiazide having purity greater than 99.9%, single impurity level less than 0.05% and yield over S7%. OBJECTS OF THE INVENTION
It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.
It is another object of the invention is to provide a process for the preparation of Hydrochlorothiazide having high purity.
It is an also object of the present invention is to provide a process for the preparation of Hydrochlorothiazide having total impurity not more than 0.1% and individual impurity level less than 0.05% in better yield.
It is yet another object of the invention is to provide an economically viable and industrially applicable process for the preparation of Hydrochlorothiazide.
It is a further object of the invention is to provide crystalline form of Hydrochlorothiazide characterized by x-ray powder diffration pattern, infrared spectrometry, differential scanning calorimetry and thermal gravimetric analysis. BRIEF DISCRIPTION OF THE DRAWINGS FIG. I: X-ray powder diffraction pattern of Hydrochlorothiazide FIG. II: Infrared Spectrometry of Hydrochlorothiazide FIG. Ill: Differential Scanning Calorimetry analysis of Hydrochlorothiazide FIG. IV: HPLC chromatograph for the purity of Hydrochlorothiazide
SUMMARY OF THE INVENTION
According to the first aspect of the present invention, there is provided a the preparation of the 6-chloro-3,4-dihydro-2H-l,2,4-benzolhiadiazine-7-sulfonsumde 1,1-dioxide (hydrochlorothiazide) of formula (1),

which comprises of:
(a) reacting 5-chloroaniline-2,4-disulfonamide of formula (2) with paraformaldehyde and
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base at suitable temperature to obtain the 6-ehloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide of formula (3);
(b) treatment of 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide 1,1 -dioxide of formula (3) with base in water to adjust the pH atleast 10; and
(c) isolating 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide of formula (1) by addition of mineral acid.

According to (he further aspect of the present invention, there is provided a process for the preparation of the 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide of formula (3),

which comprises of:
(a) reacting 5-chloroaniline-2,4-disulfonamide of formula (2) with paraformaldehyde and a base at suitable temperature in water;
(b) maintaining for 2 hours;
(c) heating the reaction mixture about 80°C to 150°C;
(d) maintaining for 20hrs;
(e) cooling the reaction mixture; and
(0 filtering and washing with water to isolate formula (1).
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According to the further more aspect of the present invention, there is provided a process for the preparation of the substantially pure 6-ehloro-3,4-dihydro-2H-I,2,4-benzothiadiazine-7-sulfonaniide 1,1-dioxide of formula (1)

which comprises of:
(a) treating 6-chIoro-3,4-dihydro-2I-I-l,2s4-henzothiadiazine-7-sulfonaniide 1,1-dioxide of formula (3) with a base in water at an ambient temperature;
(b) stir the reaction mixture to obtain clear solution;
(c) filtering and washing with water;
(d) treating with mineral acid to isolate the 6-ehlor-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide of formula (1);
(e) treating wet cake with a mixture of water and mineral acid;
(f) heating the reaction mixture;
(g) maintaining the reaction temperature;
(h) cooling the reaction mixture;
(i) filtering and washing with water to gel 6-7 pH of the filtrate; and (j) isolating substantially pure hydrochlorothiazide of formula (1).
According to another aspect of the present invention, there is provided a crystalline hydrochlorothiazide prepared by the above process characterized by atleasl one of the following properties,
a) X-ray powder diffraction pattern having characteristics at 16.6, 19.1, 20.S, 28.8 ±0.2 (20); and/or
b) X-ray powder diffraction patter substantially as depicted in FIG. I: and/or
c) FTIR spectra substantially as depicted in FIG. II; and/or
d) Differential Scanning Calorimelry analysis of Hydrochlorothiazide as depicted in FIG.III; and/or
e) purity of atleasl 99.7% by HPT.C as depicted in FIG. IV.
DETAILED DISCRETION OF THE INVENTION
The term "Substantially pure" herein the specification means hydrochlorothiazide of formula (1) having purity not less than 99.0% by area percentage of HPLC, preferably not less than 99.5%, most preferably 99.9% by area percentage of HPLC.

The term "ambient temperature" herein the specification means any temperature of about less than 35°C. Preferably the reaction is cooled to the room temperature in the range of 15°C to 35°C. Furthermore, the temperature in the range of 0°C to 35°C can be considered as ambient temperature as the scope of this invention
According to the first embodiment of the present invention, there is provided a process for the preparation of the 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide (hydrochlorothiazide) of formula (1),

which comprises of:
(a) reacting 5-chloroaniline-2,4-disulfonamide of formula (2) with paraformaldehyde and
base at suitable temperature to obtain the 6-chloro-3,4-dihydro-2H-l,2,4-
benzothiacdiazine-7-sulfonamide 1,1 -dioxide of formula (3);

(b) treating 6-chloro-3,4-dihydro-2H-l,2.4-benzothiadiazine-7-sulfonamide 1,1-dioxide of
formula (3) with base in water to adjust the pH atleast 10; and

(c) isolating 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-3ulfonamide 1,1 -dioxide of formula (1) by addition of mineral acid.
As in step (a) reaction of 5-chIoroaniline-2,4-disuIfonamkle of formula (2) with paraformaldehyde and base can be selected from the group of alkali metal hydroxide, carbonates, bicarbonales i.e. sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate or bicarbonales etc, preferably sodium hydroxide at suitable temperature preferably 75°C 10 S0°C for 2 hrs, then raising the temperature at about 99°C to 103°C maintained for 20 hrs to obtain the 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonarnide 1,1 -dioxide of formula (3).
As in step (b) treatment of 6-chloro-3,4-dihydro-2H-],2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide of formula (3) with base can be selected from the group of alkali metal

nydroxide, carbonates, bicaibonates i.e. sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate or bicaibonates etc, preferably sodium hydroxide in water to adjust the pH atleast 10; and
As in step (c) isolation of 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide of formula (1) by addition of mineral acid can be selected from sulphuric acid, nitric acid, hydrochloric acid, phosphoric acid, preferably sulphuric acid.
According to the further embodiment of the present invention, there is provided a process for the preparation of the 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-suifonamide 1,1-dioxide of formula (3),

which compriscs of:
(a) reacting 5-chloroaniline-2,4-disulfonamide of formula (2) with paraformaldehyde and a base at suitable temperature in water;
(b) maintaining for 2 hours;
(c) heating the reaction mixture about 80°C to 150°C;
(d) maintaining for 20hrs;

(e) cooling the reaction mixture; and
(f) filtering and washing with water to isolate formula (1).
As in step (a) reaction of 5 - chloroaniline-2,4-disulfonamide of formula (2) with paraformaldehyde and a base can be selected from the group of alkali metal hydroxide, carbonates, bicaibonates i.e. sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate or bicaibonates etc, preferably sodium hydroxide at suitable temperature preferably 75°C to 80°C in water. The reaction mixture is maintained for 2 hours in step (b). According to step (c), heating the reaction mixture about 80°C to 150°C preferably 99°C to 103°C and as in step (e) cooling the reaction mixture at about 25°C to 35°C.
According to the further more embodiment of the present invention, there is provided a process for the preparation of the substantially pure 6-chloro-3,4-dihydro-2H-l,2,4-benzolhiadiazine-7-sulfonamide 1,1-dioxide of formula (1)
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which comprises of:
(a) treating 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide 1,1 -dioxide of formula (3) with a base in water at an ambient temperature;
(b) stir the reaction mixture to obtain clear solution;
(c) filtering and washing with water;
(d) treating with mineral acid to isolate the 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide of formula (1);
(e) treating wet cake with a mixture of water and mineral acid;
(f) heating and maintaining;
(g) cooling;
(h) filtering and washing with water to get 6-7 pH of the filtrate;
(i) optionally repeating the steps (a) to (h); and
(j) isolating substantially pure hydrochlorothiazide of formula (1).
As in step (a) treating 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide of formula (3; with a base can be selected from the group of alkali metal hydroxide, carbonates, bicarbonates i.e. sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate or bicarbonates etc, preferably sodium hydroxide in water at an ambient temperature. As in step (d) treating with mineral acid can be selected from sulphuric acid, nitric acid, hydrochloric acid, phosphoric acid and the like, preferably sulphuric acid to isolate the 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide of formula (1). As in step (e) treating wet cake with a mixture of water and mineral acid can be selected from sulphuric acid, nitric acid, hydrochloric acid, phosphoric acid and the like, preferably sulphuric acid. As in step (f) heating the reaction mixture preferably at 99°C to 103°C. As in step (f) maintaining the reaction temperature preferably for 20hrs. As in step (g) cooling the reaction mixture preferably 25°C to 35°C.
According to another aspect of the present invention, there is provided a crystalline hydrochlorothiazide prepared by the above process characterized by atleast one of the following properties, a) X-ray powder diffraction pattern having characteristics at 16.6, 19.1, 20.8, 28.78 ±0.2 (20);
and/or
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b) X-ray powder diffraction patter substantially as depicted in FIG. I; and/or
c) FTIR spectra substantially as depicted in FIG. II; and/or
d) Differential Scanning Calorimetry analysis of Hydrochlorothiazide as depicted in FIG.III; and/or
e) purity of atleast 99.9% by HPLC as depicted in FIG. IV.
According to the present invention, the process for the preparation of hydrochlorothiazide can be illustrated by below mentioned scheme, which should not be considered as limiting the scope of the invention.

The process of the present invention will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be constructed as limit to the scope of the claims in any manner. Example 1: Preparation of hydrochlorothiazide (Technical)

1050 mL water, 100 gm (0.350 mole) 5-chloroaniline-2,4-disulfonamide, 28 mL formaldehyde solution (35-37%) and dilute NaOH solution (0.7 gm NaOH + 20 mL water) ware charged into 2.0 liters RBF equipped with stirrer, thermometer and condenser. The reaction mixture was heated to get 70°C to 80°C temperature. Then the reaction mass was maintained at 75°C to 80°C. The reaction mixture was maintained at reflux temperature for 20.0 hrs. Then content was cooled to 25°C to 35°C slowly in 2-3 hrs followed by stirring for
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1.0 hrs. The product was filtered and washed the wet cake with 3x100 mL water. The product was dried at 60°C to 65°C for 8-10 hrs, yielded in 95 gm. Example 2: Process for the purification of hydrochlorothiazide

100 gm of hydrochlorothiazide (technical) and 1500 mL RO water was charged in 3.0 Liters RBF, stirred for the ambient temperature followed by the addition of NaOH solution slowly at ambient temperature with in 30-45 min. The reaction mixture was stirred for 15 min at 25°C to 35°C followed by treatment with activated chai'coal. The solution was filtered and washed with 100 mL of RO water. The solution was recharged in RBF followed by the slow addition of the dilute sulfuric acid solution (20 mL cone, sulfuric acid and SO mL RO water) at 25°C to 35°C within 30-45 min. It was stirred for 01 hrs and subsequently filtered and washed with 200 mL of RO water. Obtained wet cake. 1000 mL of RO water, 15 mL of concentrated sulfuric acid was charged in 2.0 Liters RBF equipped with stirrer, thermometer and water circulating condenser. The reaction mass was heated to get reflux temperature at about 99°C-103°C. Then it was maintained for 02 hrs at reflux temperature followed by natural cooling to 40°C-45°C in 3-4 hrs, further cooled to 25°C-35°C. The mixture was stir for 01 hr at 25°C-35°C temperature. The reaction mass was filtered and washed with water. The wet cake was obtained. Optionally, the purification process can be repeated as herein above to obtain the purity greater than 99.90% if initial purification results in purity less than 99.90%.
HPLC purity: - 99.97%e Dimer Impurity: - Not Detected
Benzothiadiazine related compound-A: - Not Detected Chlorothiazide: - Not Detected 5-Chlorohydrochlorothiazide: - Not Detected Unk Impurity: - 0.03% and Total Impurity:- 0.03%.
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We claims:
1. A process for the preparation of the 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide 1,1 -dioxide of formula (1),

which comprises of:
(a; reacting 5--choroaniline-2,4-disulfonamide of formula (2) with paraformaldehyde and
base at suitable temperature to obtain the 6-ehloro-3,4-dihydro-2H-l,2,4-
benzothiadiazine-7-sulfonamide 1,1 -dioxide of formula (3);

(b; treating 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide of formula (3) with base in water to adjust the pH atleast 10; and

(cj isolating 6-ehloro-3,4-dihydro-2H-l,2.4-ben20thiadiazine-7-sulfonamide 1.1 -dioxide of formula (1) by addition of mineral acid.
2. A process as claimed in claim 1(a), wherein base can be selected from the group of alkali metal hydroxide, carbonates, bicarbonates i.e. sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate or bicarbonales etc, preferably sodium hydroxide.
3. A process as claimed in claim 1(a), wherein suitable temperature is preferably 75°C to 80°C for the suitable period of time.
4. A process as claimed in claim 3, wherein reaction is carried out for about 2 hrs.
5. A process as claimed in claim 1(b), wherein base can be selected from the group of alkali metal hydroxide, carbonates, bicarbonales i.e. sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate or bicarbonales etc, preferably sodium hydroxide in water to adjust the pH atleast 10, preferably 10 to 12.
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o. A process as claimed in claim 1(c), wherein mineral acid can be selected from sulphuric acid, nitric acid, hydrochloric acid, phosphorie acid, preferably sulphuric acid.
7. A process for the preparation of the 6-chloro-3;4-dihydro-2H-1.2,4-benzothiadiazine-7-
sulfonamide 1,1-dioxide of formula (3),

which comprises of:
(a) reacting 5-chloroaniline-2,4-disulfonamide of formula (2) with paraformaldehyde and a base at suitable temperature in water;
(b) maintaining for 2 hours;
(c) heating the reaction mixture about 80°C to 150°C;
(d) maintaining for 20hrs;
(e) cooling the reaction mixture; and
(f) filtering and washing with water to isolate formula (1).
8. A process according to claim 7(a), wherein base can be selected from the group of alkali metal hydroxide, carbonates, bicarbonates i.e. sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate or bicarbonates etc, preferably sodium hydroxide at suitable temperature with maintaining for a period of time.
9. A process as claimed in claim 8, wherein suitable temperature is preferably 75°C to S0°C.
10. A process according lo claim 7(b), wherein maintenance of reaction mixture is preferably 2 hrs.
11. A process as claimed in claim 7(c), wherein heating at about 80°C to 150°C preferably 99°C to l03°C.
12. A process as claimed in claim 7(e), wherein cooling at about 25°C to 35°C.
13. A process for the preparation of the substantially pure 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide 1,1 -dioxide of formula (1)

which comprises of:
(a) treating 6-chloro-3,4-dihydro-2H-l,2,4-benzolhiadiazine-7-sulfonarnide 1,1 -dioxide of formula (3) with a base in water at an ambient temperature;
(b) stirring the reaction mixture to obtain clear solution;
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(c) filtering and washing with water;
(d) treating with mineral acid to isolate the 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide of formula (1);
(e) treating wet cake with a mixture of water and mineral acid;
(f) heating and maintaining;
(g) cooling;
(h) filtering and washing with water to get 6-7 pH of the filtrate;
(i) optionally repeating the steps (a) to (h); and .
(j) isolating substantially pure hydrochlorothiazide of formula (1).
14. A process as claimed in claim 13(a), wherein base can be selected from the group of alkali metal hydroxide, carbonates, biearbonates i.e. sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate or biearbonates etc, preferably sodium hydroxide.
15. A process as claimed in claim 13(a), wherein reaction is cairied out preferably at ambient temperature.
16. A process as claimed in claim 13(d), wherein mineral acid can be selected from sulphuric acid, nitric acid, hydrochloric acid, phosphoric acid, preferably sulphuric acid.
17. A process as claimed in claim 13(e), vvheiein mineral acid can be selected from sulphuric acid, nitric acid, hydrochloric acid, phosphoric acid, preferably sulphuric acid.
18. A process as claimed in claim 13(f), wherein temperature is preferably at 99°C to 103°C.
19. A process according to claim 13(f), wherein maintenance of the reaction temperature preferably for 20hrs.
20. A process as claimed in claim 13(g), wherein cooling at about 25°C to 35°C.
21 A process as claimed in claim 1, 7 and 13 for the preparation of a crystalline
hydrochlorothiazide characterized by atleast one of the following properties,
a) X-ray powder diffraction pattern having characteristics at 16.6, 19.1, 20.8, 28.8 ±0.2 (20); and/or
b) X-ray powder diffraction patter substantially as depicted in FIG. I: and/or
c) FTIR spectra substantially as depicted in FIG. II; and/or
d) Differential Scanning Calorimetry analysis as depicted in FIG III; and/or
e) purity of alleast 99.9% by HPLC as depicted in FIG. IV.
Dated this the 27th day of May 2008

H. SUBRAMANIAM
Of Subramaniam, Nataraj & Associates
Attorneys for the Applicants
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