DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

A PROCESS FOR PARTICLE SIZE REDUCTION OF HYDROCHLOROTHIAZIDE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the nature of this invention and the manner in which is to be performed:
FIELD OF THE INVENTION

The present invention relates to a process for reducing nitrosamine impurity while reducing the particle size of Hydrochlorothiazide.

BACKGROUND OF THE INVENTION

Hydrochlorothiazide of Formula I is chemically known as 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.

Formula I

Hydrochlorothiazide 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.

A number of methods for the synthesis of Hydrochlorothiazide have been reported. US Patent no. 3,163,645 of Ciba describes a process for the preparation of Hydrochlorothiazide by heating a mixture of 5-Chloro-2,4-disulfamyl aniline in anhydrous diethyleneglycol dimethyl ether, hydrochloride dissolved in ethyl acetate and paraformaldehyde which is depicted in scheme-I. The product is recrystallized from water.

In other method, 5-chloro-2,4-disulfamyl-aniline 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.

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

The process involves reacting 4,6-dichloro-benzene-1,3-disulfonic acid dichloride 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 describes a process for the preparation of Hydrochlorothiazide which is depicted in the scheme-III.

In pharmaceutical industry, particle characterization of powder materials has become one of the crucial aspects in drug product development and quality control of solid oral dosage forms. The particle size distribution (PSD) of the drug substance may have significant effects on final drug product performance (e.g., dissolution, bioavailability, content uniformity, stability, etc.). Furthermore, the PSDs of both drug substance and excipients can affect drug product manufacturability (e.g., flowability, blend uniformity, compactibility, etc.), which, ultimately, can impact safety, efficacy, and quality of the drug product. The PSDs of pharmaceutical powders have profound influence on almost every step of manufacturing processes for solid oral dosage forms, including pre-mixing/mixing, granulation, drying, milling, blending, coating, encapsulation, and compression. Therefore, the impact of particle sizes of pharmaceutical powders on drug product manufacturability and performance should be evaluated at different pharmaceutical development phases for each specific drug application.

Hydrochlorothiazide drug substance was found to contain traces of nitrosamine impurity. It was identified that nitrosamine impurities are potent genotoxic agents in several animal species and some are classified as probable or possible human carcinogens by the International Agency for Research on Cancer (IARC).

As per the guidelines issued by the FDA and other regulatory authorities, although nitrosamine impurities have been found in only some drug products, batches of those drugs have been recalled when there were unacceptable levels of these impurities. Nitrosamine impurities may exist in APIs and drug products due to vulnerable processes and materials that may produce nitrosamine impurities.
The FDA guideline recommends control of any known mutagenic carcinogen, such as nitroso-compounds, at or below a level such that there would be a negligible human cancer risk associated with the exposure to potentially mutagenic impurities.

Various conventional methods used for the particle size reduction of Hydrochlorothiazide resulted in an increase in nitrosamine impurity. The inventors of the present invention have surprisingly found a method for controlling the nitrosamine content in Hydrochlorothiazide during the particle size reduction.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to control the nitrosamine impurity formed during particle size reduction of Hydrochlorothiazide utilizing purification and colloidal milling.

SUMMARY OF THE INVENTION

The present invention describes a process for the particle size reduction of Hydrochlorothiazide with reduced nitrosamine impurity which comprises:
(1) Suspending Hydrochlorothiazide in a solvent or a mixture of solvents;
(2) Cooling the reaction mixture and passing through colloidal mill; and
(3) Filtering the suspension and isolating Hydrochlorothiazide.

In another embodiment, the present invention further describes a process for particle size reduction of Hydrochlorothiazide with reduced nitrosamine impurity content which comprises:
(1) Suspending Hydrochlorothiazide in a solvent or a mixture of solvents thereof;
(2) Heating the reaction mixture to reflux;
(3) Treating the solution from step (2) with activated carbon and filtering the reaction mass;
(4) Cooling the filtrate to ambient temperature;
(5) Further cooling the reaction mass to 0-5°C and maintaining for 1-2 hrs.;
(6) Filtering the reaction mass and washing with a precooled solvent or a mixture of solvents thereof;
(7) Suspending the wet material in a solvent or a mixture of solvents thereof at ambient temperature;
(8) Stirring the suspension at 0-5°C and passing through the colloidal mill;
(9) Filtering the suspension and washing with precooled solvent mixture;
10) Drying the wet material at 70-80°C under vacuum.

DETAILED DESCRIPTION OF THE INVENTION

In pharmaceutical research and development, various drug substances are found to be poorly water-soluble. Therefore, solubility enhancement, a key factor for higher bioavailability is a major challenge in pharmaceutical industries.

Particle size reduction is one such method that increases the surface area of the pharmaceutical compounds and subsequently leads to a higher dissolution rate and bioavailability.

There are several conventional processes such as milling, high-pressure homogenization and spray drying which are widely used for particle size reduction. Non-conventional processes such as liquid anti-solvent crystallization, super critical anti solvent process, rapid expansion of super critical solutions, particles from gas saturated solutions, and pulsed laser ablation are emerging potential alternatives.

During the particle size reduction of Hydrochlorothiazide by conventional process of micronization, it is observed that the Hydrochlorothiazide nitrosamine impurity of Formula II has increased significantly.

Formula II

During the particle size reduction of Hydrochlorothiazide by conventional process of micronization, it is observed that the nitrosamine impurity (II) has increased significantly. The present invention provides a process for reducing particle size and nitrosamine impurity (II) in Hydrochlorothiazide.

The present invention describes a new scalable process to control the particle size of chemical product and particularly a product of pharmaceutical interest i.e., Hydrochlorothiazide with high precision. The invention addresses unwanted consequences of size reduction process, particularly an increase in the nitrosamine impurity.

A study on the nitrosamine impurity was done in several batches of the commercially prepared Hydrochlorothiazide. The nitrosamine impurity observed in the commercially prepared process is as shown in Table -1.
Table-1
S. No. Batch No. N-Nitroso Hydrochlorothiazide content in Hydrochlorothiazide-Tech (ppm)
1 2008102506 (Plain) 0.127
2 2008102507 (Plain) 0.118
3 2008106751 (Plain) 0.070
The Hydrochlorothiazide thus obtained from the commercial process was subjected to micronization process for particle size reduction. During this process, it was observed that there is a substantial increase in nitrosamine impurity content.

The nitrosamine impurity content observed in batches after micronization of Hydrochlorothiazide drug substance is as shown in Table-2 below.
Table-2
S. No. Batch No. N-Nitroso Hydrochlorothiazide content in Hydrochlorothiazide-Tech (ppm)
1 2108106845(MG) 1.299
2 2108106553(MG) 1.059
3 2108106554(MG) 1.401

In view of this disadvantage, it was necessary to find an alternative solution to control the nitrosamine impurity during the particle size reduction.

The inventors of the present application have developed a process of purification and particle size reduction.

In one embodiment, the present invention provides a process for the particle size reduction of Hydrochlorothiazide with reduced nitrosamine impurity content which comprises:
(1) Suspending Hydrochlorothiazide in a solvent or a mixture of solvents thereof;
(2) Heating the reaction mixture to reflux;
(3) Treating the solution from step (2) with activated carbon and filtering the reaction mass;
(4) Cooling the filtrate to ambient temperature;
(5) Further cooling the reaction mass to 0-5°C and maintaining for 1-2 hrs.
(6) Filtering the reaction mass and washing with a precooled solvent or a mixture of solvents thereof;
(7) Suspending the wet material in a solvent or a mixture thereof at ambient temperature;
(8) Stirring the suspension at 0-5°C and passing through the colloidal mill;
(9) Filtering the suspension and washing with precooled solvent mixture;
10) Drying the wet material at 70-80°C under vacuum.

In another embodiment, the solvent used in the present invention comprises of esters selected from ethyl acetate, and isopropyl acetate; alcohols selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol; ketones selected from acetone, methyl ethyl ketone, and methyl isobutyl ketone; water and/or mixtures thereof.

In another embodiment of the present invention the Hydrochlorothiazide suspended in a solvent or mixture of solvents thereof is passed through the colloidal mill while maintaining the temperature below 20°C.

In another embodiment, the present invention describes a process for the particle size reduction of Hydrochlorothiazide with reduced nitrosamine impurity content which comprises:
(1) Suspending Hydrochlorothiazide in methanol and water;
(2) Heating the reaction mixture to reflux;
(3) Treating the solution from step (2) with activated carbon and filtering the reaction mass;
(4) Cooling the filtrate to ambient temperature;
(5) Further cooling the reaction mass to 0-5°C and maintaining for 1-2 hrs.
(6) Filtering the reaction mass and washing with a precooled methanol-water mixture;
(7) Suspending the wet material in a mixture of methanol-water at ambient temperature;
(8) Stirring the suspension at 0-5°C and passing through the colloidal mill;
(9) Filtering the suspension and washing with precooled methanol-water mixture;
10) Drying the wet material at 70-80°C under vacuum.

In another embodiment, the present invention provides a process for particle size reduction of Hydrochlorothiazide to achieve d(0.9) < 70µm.

The nitrosamine impurity content observed in batches after colloidal milling of Hydrochlorothiazide is as shown in Table-3 below.

Table-3
S.No Batch No. Nitrosamine Impurity present in input batch
(Batch. No. 2208101777)
(ppm) Nitrosamine
Impurity of the output
(ppm) PSD (µm)
d(0.1) d(0.5) d(0.9)
1 HCTS0122011 0.144ppm ND 4 15.45 53.72
2 HCTS0122019 0.144ppm ND 3.51 13.39 40.99
3 HCTS0122020 0.144ppm ND 3.35 12.34 38.05

EXAMPLE:

A stirred suspension of 200g of Hydrochlorothiazide in a mixture of 1680ml of methanol and 1120ml of water was heated to reflux to get a clear solution. To this solution, 5g of activated carbon was added and refluxed for 30min. The reaction mass was passed through a celite filter bed and washed with methanol (120ml) and water (80ml). The collected filtrate was cooled to 20-30°C as the precipitation begins. The reaction mass was further cooled to 0-5°C and stirred for 1hr at 0-5°C. The reaction mass was then filtered and washed with precooled methanol (120ml) and water (80ml). The wet material (~180g) was suspended in methanol (600ml) and water (400ml) and stirred for 10±5 min at 20-30°C, it was then cooled to 0-5°C and passed through colloidal mill until desired particle size was obtained. Once the desired particle size (d(0.9)< 70µm) was obtained the suspension was maintained at 0-5°C for 30±5 min. It was then filtered and washed with precooled methanol (120ml) and water (80ml). The above material was dried under vacuum at 70-80°C till LOD was 0.5%w/w.

Yield: 170g (85%);
Nitrosamine impurity: Not detected. ,CLAIMS:WE CLAIM:
1. A process for the particle size reduction and purification of Hydrochlorothiazide comprising:
(i) Suspending Hydrochlorothiazide in a solvent or a mixture of solvents;
(ii) Cooling the reaction mixture and passing through colloidal mill; and
(iii) Filtering the suspension and isolating Hydrochlorothiazide.

2. The process as claimed in claim 1 wherein the solvent in step (i) comprises of esters selected from ethyl acetate, and isopropyl acetate; alcohols selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol; ketones selected from acetone, methyl ethyl ketone, and methyl isobutyl ketone; water and/or mixtures thereof.

3. The process as claimed in claim 1, step (i), wherein the reaction mixture is heated to a reflux temperature.

4. The process as claimed in claim 1, step (ii), wherein the reaction mixture is cooled between 0 to 20°C, more preferably 0-5°C, before passing through the colloidal mill.

5. The process, as claimed in claim 1, wherein the particle size obtained is d(0.9) < 70µm.