Field of the invention

The present invention relates to an improved process for the preparation of Hydrochlorothiazide of formula (I) having purity of at least 99.9% and OVI content below detectable limit. The present invention further provides a new polymorphic form of Hydrochlorothiazide.

Background of the invention

The chemical name of Hydrochlorothiazide is 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide and formula is C7H8ClN3O4S2 and molecular weight is 297.74.

Hydrochlrothiazide is used as Diuretic. It is generally used in combination with antihypertensive drugs such as Irbesartan, Valsartan, Candesartan Cilexetil, Olmesartan, Telmisartan, Catopril, Enalapril, Fosinopril, Lisinopril, Quinapril, moexipril, Benazepril, Propranolol, Metoprolol Tartarate, Bisoprolol, Methyldopa and Hydralazine. It is also used in combination with other diuretic drugs such as Amiloride and Triamterene. Hydrochlorothiazide is used to treat high blood pressure and fluid retention caused by various conditions, including heart disease.

US patent no. 3,163,645 discloses a process for the preparation of Hydrochlorothiazide which is depicted in the scheme-I.

Scheme-I

The process involves reacting 5-chloro-2,4-disulfamyl-aniline (II) or its salt with aldehyde such as formaldehyde in the absence or presence of a base and a solvent. The base is alkali metal hydroxide and the solvent is selected from THF, dioxane, diethylene glycol, methanol and water or mixtures thereof.

In other method, 5-chloro-2,4-disulfamyl-aniline (II) is reacted with paraformaldehyde in the presence of a mineral acid and a solvent. The mineral acid is selected from hydrochloric acid, hydrobromic acid and sulfuric acid. Hydrochlorothiazide obtained is recrystallized from water. However, the yield obtained by this process is only 46.3% which makes the process less attractive at an industrial scale. Moreover repeating this experiment, it is found that it results in the formation of dimer impurity along with Hydrochlorothiazide which is difficult to remove by conventional purification methods.

This patent also discloses a preparation of an alkali metal salt of Hydrochlorothiazide, a process for converting it to a free compound by treating it with mineral acid and then converting the free compound to an alkali metal salt. But this patent does not disclose any purification process involving acid/base treatment.

US patent no. 3,227,710 discloses a process for the preparation of Hydrochlorothiazide which is depicted in the scheme-II.

Scheme-II

The process involves reacting 4,6-dichloro-benzene-1,3-disulfonic acid dichloride (III) with 30% aq. formaldehyde in the presence of saturated alcoholic ammonia solution at 150°C. The solvent is distilled off and residue obtained is acidified with dil. HCl. The oily reaction product crystallizes on standing in a refrigerator. The product is further charcoalized in 60% ethanol and then recrystallized from the same solvent. This patent discloses purification by crystallization and charcoalization methods but is silent on the purity and yield.

US patent no. 3,267,095 discloses a process for the preparation of Hydrochlorothiazide which is depicted in the scheme-III.

Scheme-III

The process involves reacting 5-chloro-aniline 2,4-disulfonyl chloride (IV) with paraformaldehyde in the presence of HCl gas in diethyleneglycol diethylether to give an intermediate which is further reacted with an anhydrous ammonia to give solid product which is further purified by recrystallization from aqueous methanol to give pure Hydrochlorothiazide. This patent is silent about the purity and yield.

US patent no. 3,340,150 discloses a process for preparation of Hydrochlorothiazide in which 5-chloro-2,4-disulfamyl-aniline (II) is reacted with paraformaldehyde in the presence of HCl in diethyleneglycol diethylether to give Hydrochlorothiazide which is crystallized from diethyleneglycol diethylether/water and recrystallized from water. However, the yield obtained by this process is only 46.3% which is very low for industrial application.

The content of undesired impurity in the final product is always a cause of concern with respect to Food and Drug Authorities (FDA) requirement. Therefore, it is required to have the undesired impurity content well below the level specified in the International Conference on Harmonization (ICH) guideline as per regulatory authority. Particularly with respect to the known impurity the acceptable limit 0.15%. Therefore it is extremely important to control the level of dimer impurity to comply with the regulatory requirement.

Therefore, there is a need to develop an easy to operate, industrially feasible, eco-friendly and yet cost effective process for preparing Hydrochlorothiazide and still this process ensure the formation of dimeric impurity to a level less than 0.10%. The present invention addresses these needs.

The research work was directed by the present inventors towards not only improving yield and purity, but also to reduce the content of dimer and trimer impurity in Hydrochlorothiazide. The present inventors observed that when 5-chloro-2,4-disulfamyl aniline is reacted with paraformaldehyde in the presence of acid or base, dimer impurity is generated in the reaction along with the formation of Hydrochlorothiazide, which is difficult to remove by conventional purification method. The present inventors reacted 5-chloro-2,4-disulfamyl aniline with paraformaldehyde in the absence of acid or base. They found that the generation of dimer impurity is low. The present inventors also directed their research work towards developing a purification process in which dimer and trimer impurities are removed. Surprisingly, a novel process for purification of Hydrochlorothiazide was found in which the said impurities are considerably reduced to comply the regulatory needs. The present inventors also found that the Hydrochlorothiazide obtained by process of present invention followed by the purification is having purity of at least 99.9% and OVI (organic volatile impurity) content below detectable limit. The present inventors further provided a new polymorphic form of Hydrochlorothiazide.
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Summary of the invention:
It is therefore an object of the present invention to provide an improved process for preparing Hydrochlorothiazide.

Another object of the present invention is to provide an improved process for preparing highly pure Hydrochlorothiazide.

Another object of the present invention is to provide an improved process which is simple and easy to handle at an industrial scale.

Another object of the present invention is to provide a process for purification of Hydrochlorothiazide to give purity of at least 99.5%.

Another object of the present invention is to provide Hydrochlorothiazide having dimer content less than 0.10%.

Another object of the present invention is to provide Hydrochlorothiazide having trimer content less than 0.05%.

Another object of the present invention is to provide Hydrochlorothiazide having purity of at least 99.9% and OVI content below detectable limit.

Yet, another object of the present invention is to provide a new polymorphic form of Hydrochlorothiazide.

Accordingly, in one aspect, the present invention provides an improved process of preparation of Hydrochlorothiazide (I)

comprising a step of reacting 5-chloro-2,4-disulfamyl aniline (II)

with formaldehyde in the absence of an acid or base in a solvent to obtain Hydrochlorothiazide (I).

In another aspect of the present invention provides a process for preparation of Hydrochlorothiazide having purity of at least 99.5% comprising steps of:
(i) stirring an impure Hydrochlorothiazide (I) with a mixture of liq. Ammonia: water (1:1);
(ii) adding a base solution;
(iii) adding an activated charcoal;
(iv) adjusting pH to about 4 to about 10 with a mineral acid;
(v) isolating pure Hydrochlorothiazide.

Further, the present invention provides a new polymorphic form of Hydrochlorothiazide.

Brief description of the drawings
FIG. 1 shows the X-ray powder diffraction pattern of new polymorphic form of Hydrochlorothiazide (I).

Detailed description of the invention:

The present invention provides an improved process of preparation of Hydrochlorothiazide (I)

comprising a step of reacting 5-chloro-2,4-disulfamyl aniline (II)

with formaldehyde in the absence of an acid or base in a solvent to obtain Hydrochlorothiazide (I).

The synthetic reaction scheme of the present invention is as shown in scheme-IV

Scheme-IV

In the process of present invention, 5-chloro-2,4-disulfamyl aniline (II) is reacted with formaldehyde in the absence of an acid or base and in the presence of a solvent at reflux temperature for 1 to 2 hours. The formaldehyde can be used in a form of polymer such as paraformaldehyde or trioxane or as an acetal, such as dimethoxymethane or diethoxymethane. The solvent is selected from alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, butanol, sec-butanol; acetates such as ethyl acetate, butyl acetate; nitriles such as acetonitrile, chlorinated solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride; ethers such as THF, diethyl ether, methyl ethyl ether, 1,4-dioxane, polar aprotic solvents such as DMF, dimethyl acetamide, DMSO and other solvents such as water, carbon disulfide, sulfolane and the like or mixtures thereof. After completion of reaction, the reaction mixture is cooled to about 15°C to about 30°C. The solid is filtered, washed with water and suck dried. The solid obtained can be dried in hot air oven or can also be taken as such for purification step.

The dimer content in Hydrochlorothiazide prepared by above method is 0.47% whereas trimer content is not detected

The advantage of the present invention can be easily understood by analyzing the data of purity and yield depicted in the following table.

Table-I

Prior art method (using sulfuric acid) Present invention method (in the absence of acid or base)
Purity HCTZ content 98.88% 99.16%
Dimer content 0.77% 0.47%
Trimer content 0.07% Not detected
Yield 86% 92%

Wherein
HCTZ represents Hydrochlorothiazide
The present invention further provides a process for preparation of Hydrochlorothiazide having purity of at least 99.5% comprising steps of:
(i) stirring an impure Hydrochlorothiazide (I) with a mixture of liq. Ammonia: water (1:1);
(ii) adding a base solution;
(iii) adding an activated charcoal;
(iv) adjusting pH to about 4 to about 10 with a mineral acid;
(v) isolating pure Hydrochlorothiazide.

“Impure Hydrochlorothiazide” means Hydrochlorothiazide having dimer impurity of about 2.0% and traceable amount of trimer impurity. Isolation of the solid can be done by filtration, decantation or centrifugation methods. Isolation is preferably done by filtration.

In the process of present invention, the purification can be achieved by stirring impure Hydrochlorothiazide with a mixture of liq. Ammonia: water (1:1). A base solution is added to get clear solution. The base solution is generally taken as 50% aqueous solution. The base is selected from a group of alkali metal hydroxide, alkoxide such as methoxide, ethoxide. The examples of a base includes but not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert butoxide, sodium tert butoxide and the like or mixtures thereof. An activated charcoal is added to the reaction mixture, stirred well and filtered through hyflobed. The pH of the filtrate is adjusted to about 4 to about 10 by adding mineral acid such as 5N hydrochloric acid or hydrobromic acid. The resulting solid is filtered, washed with water and suck dried. The solid product is dried in hot air oven at about 60°C to about 65°C for about 12 to 14 hours to give pure Hydrochlorothiazide.

Hydrochlorothiazide purified by above process is having purity of at least 99.5%. Hydrochlorothiazide purified by above process has dimer content less than 0.10% and trimer content less than 0.05%.

More surprisingly, Hydrochlorothiazide as prepared by the present invention comprising the steps of preparation of crude as mentioned hereinabove and further purifying the obtained crude by the purification of present invention is having purity of at least 99.9% and OVI content below detectable limit. Further, it does not contain detectable amount of dimer and trimer impurity.

The advantage of the present invention can be easily understood by analyzing the data of purity and yield depicted in the following table.
Table-II
Purification by Prior art method (using NaOH/ HCl) Purification by Present invention
(using NH3/ aq. NaOH/ HCl)
Purification of crude as obtained by prior art method Purification of crude as obtained by present invention
Purity SM content 0.14% 0.04% Not detected
HCTZ content 97.30% 99.84% Not detected
Dimer content 1.86% 0.08% Not detected
Yield 93% 95%

Wherein
SM represents 5-chloro-2,4-disulfamyl aniline; and
HCTZ represents Hydrochlorothiazide

As depicted in the Table-II, when the crude as obtained by the process of present invention is subject to the purification of present invention, the purified Hydrochlorothiazide obtained is extremely pure having purity of at least 99.9% and OVI content below detectable limit. Further, it does not contain detectable amount of dimer and trimer impurity.

The invention further provides a new polymorphic form of Hydrochlorothiazide. The new polymorphic form is characterized by its X-ray powder diffraction pattern as shown, for example, in FIG. 1. A polymorphic form of Hydrochlorothiazide is characterized by X-ray diffraction pattern having peaks at about 12.8, 16.5, 18.6, 19.0, 20.8, 21.3, 24.5, 27.8, 28.7, 33.3, 34.1 and 37.3+0.2° 2?.

This new polymorphic form of Hydrochlorothiazide is obtained by following the above mentioned process methods.

The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims.

Example-1
(a) Preparation of Hydrochlorothiazide
5-chloro-2,4-disulfamyl aniline (25 g) was heated with paraformaldehyde (2.98 g) in water at reflux temperature for 1 to 2 hours. The reaction mixture was cooled to 15°C to 30°C. The precipitated solid was filtered and washed with water (50mlx2) and suck dried. The product hydrochlorothiazide is obtained as white wet cake. The solid is dried in hot air oven to give Hydrochlorothiazide (24.0g)
Yield: 92%
Dimer content: 0.47%
Purity (by HPLC): ~99.0%

(b) Purification of Hydrochlorothiazide
Hydrochlorothiazide wet cake (33.0 g) obtained in step (a) was suspended in a mixture of liq. Ammonia: water (1:1) (125 ml). 50% sodium hydroxide solution was added to the reaction mixture to get clear solution. Activated carbon (0.5 g) was added and stirred for 15 to 20 min at 20°C to 25°C. The reaction mixture was filtered through hyflobed. The pH of filtrate was adjusted to about 4 to about 10 by adding 5N HCl (140 ml). Resulting solid was filtered, washed with water (50 ml) and suck dried. The solid was dried in hot-air oven at about 60°C to about 65°C for 12 to 14 hours to give pure Hydrochlorothiazide as white crystalline (20.0g).
Yield: 80.0%
Purity (by HPLC): 99.9%
Dimer content: Not detected
Trimer content: Not detected
X-ray diffraction pattern: 12.8, 16.5, 18.6, 19.0, 20.8, 21.3, 24.5, 27.8, 28.7, 33.3, 34.1 and 37.3+0.2° 2?.