Field of Invention

The present invention relates to a stable pharmaceutical composition of ethacrynic acid wherein the composition is substantially free of dimer (II) also known as impurity C in the formulation. Specifically, the present invention relates to a stable pharmaceutical composition of ethacrynic acid having a lower degradation rate of ethacrynic acid and lower content of impurity C in the composition.

Background of Invention

Ethacrynic acid is a phenoxyacetic acid that has a rapid diuretic action. Ethacrynic acid is currently marketed as Edecrin ^® by Merck & Co. It was developed as a loop ("high-ceiling") diuretic and was found to be effective in the treatment of fluid retention but at relatively high dose for the treatment of hypertension.

US Patent No. 3,255,241 describes ethacrynic acid as an unsaturated ketone derivative of an aryloxyacetic acid. It is chemically designated as [2, 3- dichloro-4-(2-methylene-l-oxobutyl) phenoxy] acetic acid and is represented as structural formula I.

(I)

Edecrin ^® is indicated for treatment of edema when an agent with greater diuretic potential than the commonly employed diuretics is required. Edecrin ^® is also administered through intravenous injectable route in the form of ethacrynic sodium salt which is indicated when a rapid onset of diuresis is desired, e.g., in acute pulmonary edema, or when gastrointestinal absorption is impaired or oral medication is not practicable.

Ethacrynic acid is a small molecule, which is prone to Diels-Alder type of condensation process, a dimerization reaction and produces a dimer (II) known as impurity C in the pharmaceutical formulation.

European pharmacopoeia has identified three degradation impurities of ethacrynic acid, and Impurity C is identified as one of the impurity. Of the three reported degradation impurities, impurity C has major concern in pharmaceutical formulations due to its effect on the stability of formulation during long period of time as well as regulatory compliance aspect. Impurity C is chemically known as (4-(2-(4-(carboxymethoxy)-2, 3-dichlorobenzoyl)-2, 5-diethyl-3, 4-dihydro-2H- pyran-6-yl)-2, 3-dichlorophenoxy) acetic acid and is represented by following chemical structure.

Impurity C

Cohen 1971 article discloses ethacrynic acid as a potent saluretic agent and mentions that ethacrynic acid undergoes a Diels-Alder type of condensation to produce a dimer (II) known as impurity C in pharmacopoeia report. It discloses that dimerization occurs under a variety of conditions and the principle pathway for the compound is in pharmaceutical dosage form. Cohen article also discloses structure of dimer II which was formed using a combined reaction of ethacrynic acid with sodium sulfite. It further discloses that α,β-unsaturated aryl ketone moiety is essential for optimum biological activity and any alteration of this grouping, such as saturation of the double bond or reduction of the ketone to the corresponding alcohol, resulted in a marked diminution in diuretic activity. The α,β-unsaturated ketone group is quite reactive chemically.

Cohen et al. 1985 article discloses ethacrynic acid as a phenoxyacetic acid compound with rapid diuretic action. It discloses that the principal route of degradation of ethacrynic acid in tablets and lyophilized injections formulation by a Diels-Alder type of condensation reaction which leads to the formation of a dimer, [4- [2- [4-(carboxymethoxy)-2,3-dichlorobenzoyl] - 3,4-dihydro-2,5- diethyl-ZH-pyran-6-yl] -2,3-dichlorophenoxy] - acetic acid known as impurity C in European pharmacopoeia report.

Wang et al. 2009 article discloses that ethacrynic acid as a small molecule, which provides an example of a dimerization reaction where the reaction is likely to be diffusion controlled in the solid state.

From the aforementioned prior art, it is known that ethacrynic acid is susceptible to dimerization reaction in the pharmaceutical formulation which leads to the formation of dimer (II) known as impurity C. Impurity C effects the stability of pharmaceutical dosage form during shelf-life of the formulation. The impurity C also presents major hurdles with regulatory compliance because higher amount of impurity C leads to instability of formulation as well as produces toxicity. Therefore, there is a need to develop pharmaceutical formulations which overcome issues associated with the formation of impurity C in ethacrynic acid formulation as well as maintain the minimal level of impurity C in the formulation during shelf-life of the formulation.

The present invention overcomes the formation of impurity C based on a co-relationship between moisture content of pharmaceutical formulations with the degradation rate of ethacrynic acid and impurity generation level over a shelf-life of the formulation. The present invention has identified the impact of moisture content on impurity C generation in pharmaceutical formulation and has observed that when moisture content of pharmaceutical formulation is kept to certain desired level, it reduces the generation of impurity C in the final formulation. Therefore, by developing an ethacrynic acid formulation with a desired moisture level, it reduces the rate of degradation of ethacrynic acid, lowers the formation of dimer (I I) impurity C and also reduces the total impurity level content in the final formulation resulting in a stable pharmaceutical composition of ethacrynic acid.

Summary of the Invention

The present invention relates to a stable pharmaceutical composition of ethacrynic acid which is substantially free of impurity C.

Specifically, the present invention relates to a stable pharmaceutical composition comprising ethacrynic acid and one or more pharmaceutically acceptable excipients wherein the composition contains impurity C in an amount of less than about 2% by weight of ethacrynic acid.

Further, the present invention contains a stable pharmaceutical composition of ethacrynic acid having a lower level of impurity C which has been achieved by maintaining the moisture content in an appropriate amount in the finished dosage form.

Detail Description of Invention

The present invention relates to a stabilized pharmaceutical composition comprising an ethacrynic acid and a process of preparing the stabilized pharmaceutical composition.

The term "ethacrynic acid" refers to ethacrynic acid as a preferred active pharmaceutical ingredient (API) and it may include pharmaceutically acceptable derivative, pro-drug, salt, polymorph, or isomer of that recited API . The term "impurity C" refers to degradation impurity of ethacrynic acid chemically known as [4- [2- [4-(carboxymethoxy)-2,3-dichlorobenzoyl] - 3,4- dihydro-2,5-diethyl-ZH-pyran-6-yl] -2,3-dichlorophenoxy] - acetic acid.

The term "substantially free" refers in the present invention in context of Impurity C and relates to an amount of impurity present in the active pharmaceutical ingredient during formulation. It may include an amount of less than about 2% by weight of API, preferably less than about 1.8% by weight of API, more preferably less than about 1% by weight of API or even may not be present in API during formulation. Further, the term "substantially free" and "minimal level" is interchangeable in the present invention.

The term "about" refers to any value which lies within the defined range by present inventors from a variation of up to ±10% of the claimed value.

The term "intragranular" refers to being or occurring within granules of the composition i.e. granules comprising pharmaceutically acceptable active ingredient, a first pharmaceutically acceptable excipient component selected from the group consisting of a binder, a disintegrant, a diluent, a glidant and/or a solvent. All these elements fall under an intragranular part of composition.

The term "extragranular" refers to the addition of pharmaceutically acceptable component to a material following granulation i.e. an extra-granular fraction comprising a second pharmaceutically acceptable excipient component, wherein said second pharmaceutically acceptable excipient component is selected from the group consisting of a disintegrant, a diluent, a lubricant, a glidant and/or the like.

The term "loss-on-drying" refers to an evaporated amount of water, solvent and volatile materials in a sample, expressed as a percentage (%) based on the weight of sample before drying when the sample is dried under heating condition. The term loss-on-drying reciprocally deals with stability of the final formulation. Ethacrynic acid (Formula 1) and its sodium salt formulations have been sold in the USA under the proprietary name of Edecrin ^® . It is indicated for treatment of edema when an agent with greater diuretic potential than those commonly employed is required.

Ethacrynic acid is a small molecule, which provides an example of a dimerization reaction where the reaction is likely to be diffusion controlled in the solid state.

The α,β-unsaturated aryl ketone moiety is essential for optimum biological activity. Any alteration of this grouping, such as saturation of the double bond or reduction of the ketone to the corresponding alcohol, resulted in a marked diminution in diuretic activity. The α,β-unsaturated ketone group is quite reactive chemically.

A first aspect of the present invention relates to a stable pharmaceutical composition of ethacrynic acid together with one or more pharmaceutically acceptable carriers or excipients wherein the pharmaceutical composition is substantially free of impurity C.

European pharmacopoeia has identified three degradation impurities of ethacrynic acid of which Impurity C is identified as one of the impurity. Of the three reported degradation impurities, impurity C has major concern in pharmaceutical formulations due to its effect on the stability of formulation during long period of storage as well as regulatory compliance aspect.

According to one embodiment of the present invention, a stable pharmaceutical composition of ethacrynic acid and one or more pharmaceutically acceptable excipients is described wherein the pharmaceutical composition is substantially free of impurity C.

According to another embodiment of the present invention, a stable pharmaceutical composition of ethacrynic acid and one or more pharmaceutically acceptable excipients is described wherein said pharmaceutical composition contains impurity C in an amount of less than about 2% by weight of ethacrynic acid. Preferably, impurity C is present in an amount range of about 0.01% to about 2.0% by weight of ethacrynic acid, more preferably of about 0.04% to about 1.8% by weight of ethacrynic acid.

The present invention pharmaceutical composition contains ethacrynic acid in an amount of about 5% to about 25% by weight of composition, preferably of about 10% to about 22% by weight of composition and more preferably of about 15% to about 20% by weight of composition.

According to another embodiment of the present invention, a stable pharmaceutical composition of ethacrynic acid and one or more pharmaceutically acceptable excipients is described wherein said pharmaceutical composition contains moisture content in a range of about 1% to about 5% by weight of composition. Preferably, the pharmaceutical composition contains moisture content in a range of about 1.2% to about 2% by weight of composition.

According to another embodiment of the present invention, a stable pharmaceutical composition of ethacrynic acid and one or more pharmaceutically acceptable excipients is described wherein one or more pharmaceutically acceptable excipients are selected from group consisting of: diluents, binders, disintegrants, glidants, lubricants, and mixtures thereof.

Examples of diluents that may be suitable for use in the present invention include inorganic phosphates like dibasic calcium phosphate, or sugars or sugar analogues and derivatives thereof, I n particular lactose, such as lactose monohydrate or water-free lactose, dextrose, sorbitol, mannitol, saccharose, maltodextrin, isomalt, or celluloses like microcrystalline cellulose or powdered celluloses or the like. The diluents may be present in an amount of about 10% to about 80% by weight of composition, preferably of about 40% to about 70% by weight of composition.

Examples of binders that may be suitable for use in the present invention include polyvinylpyrrolidone (PVP), starch, cellulose derivatives like hydroxypropylmethyl cellulose, sucrose, lactose, xylitol, sorbitol, maltitol, water, alcohol or polyethelyne glycol or the like. According to the present invention, preferable binder are Lactose, polyvinylpyrrolidone (plasdone k29/32), and polyethelyne glycol. The binders may be present in an amount of about 50% to about 90% by weight of composition, preferably of about 60% to about 70% by weight of composition.

Examples of disintegrants that may be suitable for use in the present invention includesodium starch glycolate, alginates, pregelatinized starch, croscarmellose and cross-linked PVP like collidone and crospovidone or the like. According to the present invention, a preferable disintegrant is pregelatinized starch. The disintegrants may be present in an amount of about 1% to about 10% by weight of composition, preferably of about 4% to about 8% by weight of composition.

Examples of glidants that may be suitable for use in the present invention include silicon dioxide, talc, magnesium stearate or the like. Preferred glidants are talc and magnesium stearate. The preferred amount of glidant is of about 0.1% to about 10% by weight of composition.

Examples of lubricants that may be suitable for use in the present invention include fatty acids or fatty acid derivatives, such as alkali and earth alkali salts of stearic, lauric and/or palmitic acid. A preferred lubricant is magnesium stearate. The preferred amount of lubricants is about 0.1% to about 2% by weight of composition.

In a preferred embodiment the composition comprising of about 18% w/w of ethacrynic acid, about 68% w/w of lactose monohydrate, about 10% w/w of pregelatinized starch, about 2% w/w of talc and about 1% w/w of magnesium stearate.

The composition of the present invention conveniently may be in unit dosage form and may be prepared by any methods known in the art of pharmacy. I n particular, the pharmaceutical composition of the present invention can be obtained by a known conventional methods like dry granulation, wet granulation, direct compression, roller compaction, fluidized bed granulation, rapid mixture granulation, solvent evaporation, hot-melt extrusion or the like.

According to another embodiment of the present invention, the pharmaceutical composition is prepared by a process comprising the steps of:

(a) preparing a dry mixture of ethacrynic acid and one or more pharmaceutical excipients; (b) granulating the dry mixture of ethacrynic acid and one or more pharmaceutical excipients with extragranular excipients to form a blend; (c) compressing and/or filling the blend to form the pharmaceutical composition and optionally coating the pharmaceutical composition.

A second aspect of the present invention provides a process for the preparation of the pharmaceutical composition of the present invention, wherein the process comprises the steps of:

(a) forming a blend of: ethacrynic acid, one or more: diluents, binders, and disintegrants, and lubricants;

(b) compacting the blend to obtain granules or flakes;

(c) lubricating the granules or flakes using one or more additional lubricants to form lubricated granules; and

(d) compressing the lubricated granules into tablets or filling into capsules.

The composition of the present invention may be in the form of minitablets, granules, pellets, tablets, capsules, or the like. The pharmaceutical composition of the present invention may further be film-coated using techniques known in the art such as spray coating in a conventional coating pan or a fluidized bed processor or dip coating. Alternatively, coating may also be performed using the hot melt technique. The film coat comprises film-forming polymers, one or more pharmaceutically acceptable excipients and pharmaceutically acceptable solvents.

The pharmaceutical composition of the present invention can be used as diuretic in the treatment of edema, acute pulmonary edema, hypertension or the like.

The present invention addresses the problems associated with the principal route of degradation of ethacrynic acid in conventional tablets and lyophilized injections formulations by Diels-Alder type condensation process which leads to the formation of a dimer, [4- [2- [4-(carboxymethoxy)-2,3- dichlorobenzoyl] - 3,4-dihydro-2,5-diethyl-ZH-pyran-6-yl] -2,3-dichlorophenoxy] - acetic acid known as "Impurity C".

The present invention has found an approach for solving this problem by preparing a stable pharmaceutical composition of ethacrynic acid having a lower level of impurity C which has been achieved by maintaining the moisture content in an appropriate amount in the finished dosage form.

The present invention is illustrated below by reference to the following examples.

However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention. Example 1

Procedure:

18.52% w/w of ethacrynic acid was co-sifted with 68.48%w/w of lactose monohydrate and 3.00%w/w of pregelatinized starch to form a blend, and the blend was dry mixed in rapid mixture granulator. It was granulated by addition of purified water.

The granules were dried in a fluidized bed drier at three different LOD (loss on drying) contents of granules as: i) Less than 1% (Batch 1A)

ii) At 1.24% (Batch IB)

iii) At 1.99% (Batch 1C)

LOD content was measured using following technique: A pooled sample of dried granules from different locations was taken and granules were crushed in mortar and pestle. Required quantity of crushed granules was transferred in a halogen moisture analyzer and the LOD of the dried granules was checked at 105 °C. All these three different batches dried granules were sifted and sized the oversize granules in an oscillating granulator. It was followed by co sifting with 7%w/w pre-gelatinized starch and 2% w/w talc.

The granules were lubricated with 1.0% magnesium stearate and finally the lubricated granules were compressed into tablet compression machine.

Example 2:

Formulations prepared by the wet granulation technique as mentioned in example 1. I n order to evaluate this, batches with different moisture content were prepared and subjected to accelerated stability conditions RH). The samples were withdrawn at a defined period and analyzed for detecting the levels of Impurity C by a validated HPLC method.

The result data obtained are as depicted below at initial time level:

From the above result, it was found that the amount of moisture in the dried granules impacts the level of impurity C in the finished formulation.

Example 3:

Formulations prepared by the wet granulation technique as mentioned in example 1 and with measured impurity as per example 2, were placed under the accelerated stability studies (40^C ± 2^C/75% ± 5% RH) and the level of impurity C at the 3 months and 6 months interval were analyzed using HPLC technique. The results obtained are as mentioned below:

The results indicate that as the moisture content level of dried granules increases, the levels of Impurity C in the finished formulations decreases during stability, which is due to decreased rate of degradation of ethacrynic acid by dimerization process. Thus, moisture content has stabilizing effect on ethacrynic acid and a correct level is critical to achieve a stable solid oral formulation of ethacrynic acid. The present invention shows that as there is higher moisture content in range from 1.2% to 2%. This makes the granules wet which ultimately leads to lower rate of degradation of the ethacrynic acid and results in formation of stable pharmaceutical composition of ethacrynic acid.

Example 4:

Edecrin ^® marketed RLD formulation were analyzed with HPLC technique for impurity C level at initial, 3M and 6M time interval at 25^C ± 2^C/60% RH ± 5% RH condition as well as at initial, 1M, 2M and 3M at 40^C ±2^C/75% ±5% RH accelerated stability study condition. The results obtained are as mentioned below:

Comparative example 1:

The impurity C level detected into three different batches (1A, IB, 1C) of the present invention developed at three different LOD levels (as mentioned in example 2 & 3) were directly compared with the RLD formulation impurity C level (as mentioned in example 4) for accelerated stability conditions 40^C ±2^C/75% ±5% RH data at Initial & 3M time interval.

From the above result, it is concluded that as the moisture content increases in the formulation, amount of impurity C decreases which ultimately increases the stability of the formulation.

In the following clauses, further aspects, embodiments and features of the invention are described.

1. A stable pharmaceutical composition comprising ethacrynic acid and one or more pharmaceutically acceptable excipients wherein the said composition is substantially free of impurity C.

2. The pharmaceutical composition according to clause 1, wherein ethacrynic acid is present in an amount from about 5% to about 25% by weight of composition.

3. The pharmaceutical composition according to clause 2, wherein ethacrynic acid is present in an amount from about 10% to about 22% by weight of composition.

4. The pharmaceutical composition according to clause 3, wherein ethacrynic acid is present in an amount from about 15% to about 20% by weight of composition. The pharmaceutical composition according to any of the preceding clauses, wherein the said pharmaceutical composition contains impurity C in a range from about 0.01% to about 2.0% by weight of ethacrynic acid. The pharmaceutical composition according to clause 5, wherein the said pharmaceutical composition contains impurity C in a range from about 0.04% to about 1.8% by weight of ethacrynic acid. The pharmaceutical composition according to any of the preceding clauses, wherein the level of impurity C is determined within 24 hours after preparation of the pharmaceutical composition. The pharmaceutical composition according to any of clauses 1 to 6, wherein the level of impurity C is determined using HPLC after three months storage at 40 ^Q C ± 25C and 75% ± 5% relative humidity ( H). The pharmaceutical composition according to any of clauses 1 to 6, wherein the level of impurity C is determined using HPLC after six months storage at 40 ^Q C ± 25C and 75% ± 5% relative humidity (RH). The pharmaceutical composition according to any of the preceding clauses, wherein the one or more pharmaceutically acceptable excipients are selected from group consisting of diluents, binders, disintegrants, glidants, lubricants, or mixtures thereof. The pharmaceutical composition according to any of the preceding clauses, wherein the said pharmaceutical composition contains moisture content in a range from about 1% to about 5% by weight of composition, in particular the said pharmaceutical composition contains moisture content in a range from about 1.2% to about 2% by weight of composition The pharmaceutical composition according to any of the preceding clauses, wherein the said pharmaceutical composition is present in the form of tablets, capsules, pellets, sachets or a like thereof. The pharmaceutical composition according to any of the preceding clauses, wherein the said pharmaceutical composition is prepared by a process comprising the steps of:

(a) preparing dry mixture of ethacrynic acid and one or more pharmaceutical excipients;

(b) granulating said dry mixture of ethacrynic acid and one or more

pharmaceutical excipients with extragranular excipients; and

(c) compressing/filling the blend to form a composition and optionally coating the said composition. The pharmaceutical composition according to clause 13, wherein the step (b) comprises drying a granulated mixture of ethacrynic acid and one or more pharmaceutical excipients to moisture content of 5.0% by weight or less, in particular 2.0% by weight or less. The pharmaceutical composition according to clause 1, wherein the said pharmaceutical composition comprises about 18% w/w of Ethacrynic acid, about 68% w/w of lactose monohydrate, about 10% w/w of pregelatinized starch, about 2% w/w of talc and about 1% w/w of magnesium stearate. A granule consisting of the pharmaceutical composition according to any of clauses 1-11. The granule according to clause 16, wherein the granule comprises about 20% w/w of Ethacrynic acid, about 76% w/w of lactose monohydrate, and about 3% w/w of pregelatinized starch

A tablet or capsule comprising a plurality of granules according to clause 16 or 17.