EP1945615A2

EP1945615A2 - Preparation of dutasteride

Info

Publication number: EP1945615A2
Application number: EP06850136A
Authority: EP
Inventors: Srinivas Katkam; Satyanarayana Komati; Srinivasulu Gudipati; Jayaprakash Pitta; Nageswara Rao Challa; Ravinder Bucchikondla; Srinivasa Rao Mallina; Adolf Ceaser Goldwyn; Manoj Ramesh Kharkar; Sharat Pandurang Narsapur; Srinivasula Reddy Maddula; Ramamurthy Kasula; Arvind Mallinath Lali; Sandeep Bhaskar Kale; Abijar Joyebbhai Bhori
Original assignee: Dr Reddys Laboratories Ltd; Dr Reddys Laboratories Inc
Current assignee: Dr Reddys Laboratories Ltd; Dr Reddys Laboratories Inc
Priority date: 2005-11-10
Filing date: 2006-11-10
Publication date: 2008-07-23
Also published as: WO2007120263A2; WO2007120263A3

Abstract

Dutasteride having low concentrations of impurities, such as dihydrodutasteride and desmethyldutasteride, and processes for purifying dutasteride.

Description

PREPARATION OF DUTASTERIDE

INTRODUCTION TO THE INVENTION

The present invention relates to substantially pure dutasteride and an improved process for the preparation of dutasteride. More specifically, the invention provides a process for the preparation of substantially pure dutasteride, having low concentrations of impurities such as dihydrodutasteride and desmethyldutastehde. The present invention also provides an improved process for the preparation of a substantially pure crystalline Form Il of dutasteride. Dutasteride is chemically named (5α,17β)-N-{2,5 bis(trifluoromethyl) phenyl}-3-oxo-4-azaandrost-1 -ene-17-carboxamide and is represented by structural Formula I.

Formula I

Dutasteride is a synthetic 4-azasteroid compound that is a selective inhibitor of both the type 1 and type 2 isoforms of steroid 5α-reductase (5AR), an intracellular enzyme that converts testosterone to 5α-dihydrotestosterone (DHT), and is indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men. Pharmaceutical products containing dutasteride as the active ingredient are commercially available in the market as AVODART® from GlaxoSmithKline, in the form of soft gelatin capsules for oral administration and containing 0.5 mg of the active ingredient.

U.S. Patent No. 5,565,467 discloses dutasteride, pharmaceutical compositions comprising dutasteride and their use in the treatment of benign prostatic hyperplasia.

U.S. Patent Application Publication No. 2004/0077673 discloses crystalline Form Il and the amorphous form of dutasteride and processes for their preparation. It also discloses a process for the preparation of crystalline Form I of dutasteride.

U.S. Patent Application Publication No. 2005/0059692 discloses an alternative process for the preparation of dutasteride as depicted by Scheme 1

DDQ, BSTFA, Triflic acid

Toluene

Formula Il

I ) SOCI_2, Pyridine inToluene 2) Ammonia gas

Formula IV

Scheme 1

In brief, the process comprises oxidation of 3-oxo-4-aza-5α-androstane-

17β-carboxylic acid of Formula Il in the presence of 2,3-dichloro-5,6-dicyano-1 ,4- benzoquinone ("DDQ"), bis(trimethylsilyl)trifluoroacetamide ("BSTFA") and triflic acid in toluene to yield 3-oxo-4-aza-5α-androst-1 -ene-17β-carboxylic acid of Formula III. This compound on reaction with thionyl chloride and pyridine in toluene followed by reaction with ammonia gas yielded 3-oxo-4-aza-5α- androstane-17β-carboxamide of Formula IV. The compound of Formula IV on coupling with 2-iodo-1 ,4-bis(thfluoromethyl)benzene of Formula V in the presence of copper powder and potassium carbonate in xylene yields dutasteride of Formula I, which is then purified by recrystallization from tetrahydrofuran ("THF") and water in a ratio of 1 : 1. Dutasteride obtained as above is then converted into crystalline Form Il by a process comprising dissolving dutasteride in methanol followed by activated charcoal treatment and subsequent isolation from ethyl acetate after concentration of the methanol solution to about 90% of its initial volume.

Dutasteride prepared according to this process may be contaminated with several impurities. For example, during the oxidation of the compound of Formula II, a small quantity of the unreacted starting compound of Formula II, carried over into the compound of Formula III, may undergo the same course of reactions as that of compound of Formula III to yield the dihydro analogue of dutasteride of Formula Vl (herein after referred to as "dihydrodutastehde") as an impurity in dutasteride.

Formula Vl

Similarly, quantities of the compound of Formula Il may be over-oxidized resulting in the formation of a desmethyl impurity of Formula VII (herein after referred to as "desmethyldutasteride") through the same course of reactions as that of the compound of Formula III.

Formula VII Regulatory authorities worldwide require that drug manufacturers isolate, identify and characterize the impurities in their products. Moreover, it is required to control the levels of these impurities in the final drug compound obtained by the manufacturing process and to ensure that the impurity is present in the lowest possible levels, even if structure determination is not possible.

Providing substantially pure dutasteride free from these and other impurities and processes for preparing such pure dutasteride would be a significant contribution to the art.

SUMMARY OF THE INVENTION

The present invention relates to substantially pure dutasteride and processes for the preparation of such dutasteride. In an aspect, the dutasteride obtained according to the invention contains low amounts of the following impurities when analyzed by high performance liquid chromatography ("HPLC"): a) Dihydrodutasteride of Formula Vl; b) Desmethydutasteride of Formula VII; c) Unidentified impurity at 0.94 RRT; and d) Unidentified impurity at 0.97 RRT.

In another aspect the invention provides a purification process to remove the unidentified impurities at 0.94 RRT and 0.97 RRT from dutasteride.

In yet another aspect, the invention provides a purification process to remove the desmethyldutastehde impurity from dutasteride.

In a further aspect, the invention provides a purification process to remove the dihydrodutasteride impurity from dutasteride. In another aspect the invention provides an improved process for the preparation of crystalline Form Il of dutasteride comprising: a) providing a solution of dutasteride in a water-miscible solvent; b) optionally treating the solution with activated charcoal; and c) adding the solution to water for precipitation of the solid dutasteride. In another aspect the present invention provides a pharmaceutical composition comprising substantially pure dutasteride along with one or more pharmaceutically acceptable carriers, excipients or diluents. In a still further aspect the invention provides a process for the synthesis of desmethyldutastehde and its use as a reference standard in the analysis of dutasteride, such as by HPLC.

An embodiment of the invention relates to a process for removing desmethyldutastehde from dutasteride, comprising: providing a solution of crude dutasteride in a suitable solvent; optionally, removing undissolved material from the solution; adding an anti-solvent to the solution; and maintaining the reaction mass at reflux for a short duration followed by cooling.

Another embodiment of the invention relates to a process for purifying dutasteride, comprising contacting a solution comprising dutasteride with a hydrophobic polymer resin.

A further embodiment of the invention relates to a process for purifying dutasteride, comprising contacting a solution comprising dutasteride with a porous nonionic adsorbent for dutasteride.

In an embodiment, the invention includes substantially pure dutasteride.

In another embodiment, the invention includes dutasteride having crystalline Form II.

In a further embodiment, the invention includes a process for purifying dutasteride, comprising contacting a solution comprising dutasteride with a hydrophobic polymer resin.

In a still further embodiment, the invention includes a process for purifying dutasteride, comprising contacting a solution comprising dutasteride with a porous nonionic adsorbent for dutasteride.

In a yet further embodiment, the invention provides a process for preparing crystalline Form Il of dutasteride, comprising combining a dutasteride solution with water.

An embodiment of the invention includes a compound desmethyldutastehde having the structure:

In an embodiment, the invention provides a process for preparing desmethyldutastehde, comprising oxidizing dutasteride.

In another embodiment, the invention provides a process for purifying dutasteride, comprising treating a slurry of dutasteride in a solvent with hydrochloric acid, and separating dutasteride.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 A is an HPLC chromatogram showing the impurities at 0.94 and 0.97 RRT and their levels in dutasteride, before purification. Fig. 1 B is an HPLC chromatogram showing the levels of impurities at 0.94 and 0.97 RRT in dutasteride, after purification.

Fig. 2A is an HPLC chromatogram showing a dihydrodutasteride impurity level in dutasteride before purification

Fig. 2B is an HPLC chromatogram showing a dihydrodutasteride impurity level in dutasteride after purification

Fig. 3A is an HPLC chromatogram showing the presence of the desmethyl impurity in dutasteride.

Fig. 3B is an HPLC chromatogram showing the substantial absence of the desmethyl impurity in dutasteride. Fig. 4 is an HPLC chromatogram showing peaks for a number of impurities in dutasteride.

Fig. 5 is an X-ray powder diffraction ("XRPD") pattern of crystalline Form Il of dutasteride prepared according to Example 9. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to substantially pure dutasteride and to improved processes for the preparation of pure dutasteride. The dutasteride obtained from the processes of this invention contains low amounts of impurities. As used herein, the term "substantially pure" refers to dutasteride having no greater than about 0.5% by weight of total impurities. Frequently, the dutasteride of the invention will have no greater than about 0.2% by weight of total impurities. The impurity contents described herein relate only to the total of dutasteride and related compound impurities, as determined by high performance liquid chromatography ("HPLC"), and any residual solvent impurities. Any inorganic components of the product, such as moisture, will not be determined by HPLC, and therefore are not considered to be "impurities."

The term "RRT" as used herein is intended to indicate the relative retention time of the particular impurity against a pure dutasteride standard (assigned an RRT value of 1 ) during an HPLC analysis, an examples of useful HPLC analytical methods being described hereinbelow. A relative standard deviation that is equal to or less than 5% for a population of 6 injections is acceptable while referring to RRT values.

Two unidentified impurities observed by HPLC are referred to herein by their relative retention time (RRT) with respect to the dutasteride. They consistently appear in the described HPLC procedure at RRT of about 0.94 (herein referred to as the "0.94 RRT impurity") and about 0.97 (herein referred to as the "0.97 RRT impurity").

According to an embodiment of the invention, dutasteride having about 0.002% to about 0.15%, or to about 0.1 %, by weight of the desmethyldutasteride impurity, no greater than about 0.1 % by weight of the dihydrodutastehde impurity and no greater than about 0.1 % by weight of each of the 0.94 RRT impurity and the 0.97 RRT impurity, as determined by HPLC, is provided. Dutasteride is considered to be "substantially free" of a particular impurity if that impurity is present at concentrations no greater than about 0.1 percent by weight, as determined by HPLC.

In another aspect the invention provides a purification process to remove the impurities described as the 0.94 RRT and 0.97 RRT impurities, from dutasteride. The purification process comprises forming a slurry of the crude dutastehde in a mixture of a suitable organic solvent and an acid. Suitable acids that can be used in the process of purification are the hydrogen halides, including hydrochloric acid, hydrobromic acid and the like. Suitable solvents that can be used in the process of purification include nithles such as acetonithle, propionitrile and the like; chlorohydrocarbons such as dichloromethane, ethylene dichloride, chloroform and the like; acetates such as ethyl acetate, propyl acetate, butyl acetate and the like; and mixtures thereof.

Hydrochloric acid that can be used in this process can be in the form of a gas or a solution prepared by passing HCI gas into a solvent such as water, an alcohol, or an acetate, to dissolve HCI in the solvent. Such solutions include, without limitation, methanolic hydrochloride, isopropanolic hydrochloride, ethyl acetate hydrochloride, aqueous hydrochloric acid, and the like. The concentration of hydrochloric acid may range from about 10% to about 80% by w/v, or the amount of HCI that saturates the solvent.

Suitable temperatures for the purification may range from about 25-50 ⁰C or about 35-40 ⁰C. Any temperature can be chosen as long as the stability of the dutasteride is not compromised. Depending on the solvent used, dutastehde can have an enhanced solublility at temperatures above about 40 ⁰C, and higher temperatures generally promote impurity formation, so lower temperatures frequently will be used.

The slurry will be maintained for a time sufficient to provide the desired product purity, and this can be determined empirically using simple experiments with a particular starting dutasteride material. Usually it is necessary to maintain the slurry for at least about five minutes, and times in excess of about eight hours are not normally required.

Solid product isolation from the slurry can be carried out by using conventional techniques such as for example decantation, centrifugation, gravity filtration, vacuum filtration and other techniques known in the art for the separation of solids.

The wet solid is neutralized by forming a slurry with an aqueous inorganic base solution. Suitable inorganic bases that can be used include but are not limited to: hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate, and the like; and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; or mixtures thereof. Suitably the base can be added in solid form or it may be dissolved in the solvent and added in solution form. The wet solid thus obtained is dried using a suitable drying technique such as fluid bed drying, aerial drying, oven drying, rotational drying (Buchi drying) or other techniques known in the art. The drying can be conducted at temperatures of about 20-100 ⁰C, or about 60-70 ⁰C, with or without application of vacuum. Drying can optionally be carried out under inert atmosphere conditions. Drying will be conducted until a desired residual solvent content has been achieved.

In yet another embodiment, the invention provides a purification process to remove the desmethyldutastehde impurity from dutasteride. This process comprises: providing a solution of crude dutasteride in a suitable solvent; optionally, removing undissolved material from the solution; mixing the solution with water to form a suspension; maintaining the suspension at an elevated temperature to form a solution; and cooling to form a solid. The step of providing a solution of dutasteride may include dissolving crude dutasteride comprising the desmethyl impurity in a suitable organic solvent or mixture of solvents or obtaining an existing solution from a previous processing step.

The organic solvents that can be used in the dissolution of dutasteride include a single solvent or a mixture of water-miscible solvents. Examples of suitable solvents include ether solvents such as tetrahydrofuran, 1 ,4-dioxane and the like.

Suitable temperatures for the dissolution of crude dutasteride in the solvent may range from about 0 to 120 ⁰C or the reflux temperature of the solvent used. Any temperature can be chosen as long as the stability of the dutasteride is not compromised and a clear solution is obtained.

The solution thus formed is optionally filtered, such as through a bed of flux calcined diatomaceous earth (Hyflow), to remove undissolved material. Other means of filtration or other methods of removing undissolved matter from the solution are also acceptable.

The solution thus obtained is added to water for precipitation of the solid. The addition may also be performed in the reverse fashion, i.e., water may be added to the clear solution.

The suspension containing the precipitate thus formed is heated to a suitable temperature that may range from about 40-100 ⁰C, or the reflux temperature of the solvent used, for a time required to form a clear solution. The mass is then cooled to a temperature that may range from about 0-40 ⁰C, to form a solid.

Recovery of the product can be carried out by using conventional solid- liquid separation techniques such as decantation, centhfugation, gravity filtration, or vacuum filtration or other techniques known in the art for the separation of solids. The wet solid thus obtained can be dried using any suitable drying technique including fluid bed drying, aerial drying, oven drying, rotational drying (Buchi Rotavapor drying) or other techniques known in the art. The drying can be conducted at temperatures of about 20-100 ⁰C, or about 60-70 ⁰C, with or without application of vacuum. Drying can optionally be carried out under inert atmosphere conditions.

In another aspect, the invention provides a purification process to remove the dihydrodutasteride impurity from dutasteride, comprising: eluting dutasteride containing the dihydrodutasteride impurity that has been adsorbed on a support using a gradient elution technique. In one embodiment the present invention is directed to a purification process to remove dihydrodutasteride from dutasteride using silica gel, comprising the steps of: a) preparing a mixture of silica gel and dutasteride; b) feeding a mixture of silica gel and crude dutasteride into a silica gel packed chromatography column; c) eluting the column with a suitable solvent mixture; d) collecting the desired compound fractions from step c); and e) recovering the desired substantially pure dutasteride free from the dihydrodutasteride impurity The step of preparing a mixture of silica gel and dutasteride comprises providing a solution of crude dutasteride in a suitable solvent; mixing the solvent with a suitable quantity of silica gel; and evaporating the solvent to get a uniform mixture of silica gel and dutasteride. Suitable solvents that can be used to prepare crude dutasteride solution include but are not limited to any solvent or mixture of solvents in which the required components are soluble. Examples of such solvents include: alcohols like methanol, ethanol and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride and the like; ketones such as acetone, ethyl methyl ketone and the like; esters such as ethyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, and the like; hydrocarbons like toluene or xylene; and the like.

The dutasteride solution concentration may range from about 5% to about 30% depending upon the solvent used. Any concentration may be used as long as the dutasteride remains in solution.

The ratio of dutasteride to the silica that is used for adsorption can range from about 1 :2 to about 1 :10.

Solvent can be removed from the resultant suspension using any conventional methods of drying including distillation, spray drying, rotational evaporation (such as using a Buchi Rotovapor), agitated thin film drying-vertical (ATFD-V), spin-flash drying, fluid-bed drying, or other techniques known to those skilled in the art.

The silica gel used in the adsorption steps can be identical or different ones may be used. Selection of the silica gel depends upon the properties of the silica gel (pore size, grain size, surface area, polarity of the surface), type of material to be purified, level and nature of impurities present, type of medium, mobile phase.

According to one embodiment, the adsorption is mostly performed with a packed bed chromatographic column, which comprises filling the column with a suitable adsorbent and passing the liquid containing dutasteride and the impurities through the filled pre-equilibrated silica gel of particular mesh size or the ease and improved result. The packed silica gel column is equilibrated before loading the dutasteride with the mobile phase containing mixture of solvents of particular ratio. The proportion of organic solvents in the equilibrating mobile phase is in the range of 50 to 99 % v/v depending upon the polarity of organic solvents used. The said invention describes a suitable amount of the dutasteride containing liquid of the adsorbent silica gel filled into the column. The adsorbed silica gel column is washed with mobile phase of same or different composition as that of equilibration mobile phase followed by gradient elution to resolve the dutasteride from its related impurities.

The chromatography apparatus comprises a chromatography column having a column housing defining a bed space to contain in use a bed of particulate chromatography medium, through which in use a process liquid containing components to be separated is passed to separate the components chromatographically resulting in the desired purity of the components.

The crude dutasteride sample for the loading to the chromatographic column is prepared by dissolving a suitable quantity of crude dutasteride in the equilibrating mobile phase. The concentration of dutasteride in the loading sample is in the range of 0.01 to 25 % w/v, or 2 to 15 % w/v.

The mobile phase for regenerating the column can be properly selected depending upon the types and amounts of impurities, and the type of adsorbent silica gel used in the process. The suitable organic solvents that can be used as a mobile phase for elution and separation of dutasteride from its related impurities such as dihydrodutasteride include but are not limited to hydrocarbons such as n-heptane, n-hexane, and the like in combination with esters such as ethyl acetate, n-propyl acetate, isopropyl acetate and the like with out limitation and in any proportions. The pure form of dustasteride can be collected with or without applying an external pressure to enhance the liquid flow rates, such as using inert gas pressures. The inert gases that can be used include nitrogen, argon and the like.

In one embodiment of the present invention, the column used for purification of the dutasteride sample can be regenerated to enable reuse of the column thereby resulting in a more economic process. In the process of the present invention the mobile phase for regenerating the column can be properly selected depending upon the types and amounts of impurities, and the type of the adsorbent silica gel used in the process. For example, alcohols such as methanol, ethanol, isopropanol, can be used. Other organic solvents are selected from the group of solvents mentioned above in a suitable concentration.

In another embodiment the present invention is directed to a purification process to remove the dihydrodutasteride impurity from dutasteride using a resin. The process comprises bringing a liquid containing dutasteride and its impurities into contact with a hydrophobic natural or synthetic polymer-based resin, such as for example a) a divinylbenzene-styrene copolymer; b) a copolymer of divinylbenzene, styrene and other derivatives of these having aliphatic and/or aromatic moieties comprising from 2 to 18 carbon atoms, or having substituted halogen atoms chlorine, fluorine or bromine; c) a copolymer of divinylbenzene and styrene with surface grafted moieties that are aliphatic or aromatic containing two or more carbon atoms and/or having substituted halogen atoms chlorine, fluorine or bromine; d) based on one or a combination of natural polymers, derivatized or as such from for example, agarose, dextran or cellulose; or e) based on a polymethacrylate matrix, or its combination with other acrylate polymers, prepared by cross-linking of monomers, with or without grafted moieties that are aliphatic or aromatic containing two or more carbon atoms with or without substituted halogen atoms chlorine, fluorine or bromine.

The interacting group may be the part of the base matrix or may be grafted onto the matrix by known activation chemistry to give the desired characteristics to the resin.

In the adsorption step of the process according to the invention any known macroreticular (pore size: 10^~8 to 10^~6 m, grain size (or particle size): at least 10^~5 m, specific surface area: at least 200 m²/g) non-ionic adsorption resin, e.g. DIAION HP-20, HP-21 , HP-2 MG, HP20SS, or SEPABEADS SP207, SP825, SP700, SP207SS, SP850, SP20SS (Mitsubishi, Japan), SOURCE 5 RPC, 15 RPC, Phenyl Sepharose 6 FF, HP, high substitution, Butyl and Octyl Sepharose 4FF (GE Biosciences) or Amberlite XAD-2, XAD-4, XAD-7, XAD-8 or XAD-9 (products of Rohm and Haas, U.S.A.), can be employed with good results.

The resins used in the adsorption steps can be identical or different ones may be used. Selection of resin depends upon the properties of the resin (pore size, grain size, surface area, polarity of the surface and solubility index), type of material to be purified, level and nature of impurities present, type of medium used for sample preparation, mobile phase and chromatographic conditions like temperature, flow rate, gradient volume.

In the present invention the term "gradient volume" means the volume of mobile phase in which the final strength of the eluting mobile phase is achieved.

In the gradient elution chromatography, if carried out under optimally selected conditions, a purified dutastehde should be obtained, which is essentially devoid of most of impurities including dihydrodutasteride. In the experiments the presence of dihydrodutasteride and other impurities can be determined by quantitative techniques such as high performance liquid chromatography (HPLC).

According to one embodiment, the adsorption is mostly performed with a packed bed chromatographic column, which comprises filling the column with a suitable adsorbent and passing the liquid containing dutastehde and the impurities through the filled pre-equilibrated resin layer or the ease and improved result The packed column is equilibrated before loading the dutastehde with the mobile phase containing 1 to 50 % v/v of water in organic solvent. The proportion of organic solvent in the equilibrating mobile phase is in the range of 50 to 99 % v/v depending upon the type of organic solvent.

The invention utilizes a suitable amount (for example about 1 to about 50 % v/v of the dutastehde containing liquid) of the adsorbent filled into the column. In an embodiment, the feed is pumped into the column at the rate of 50 to 500 cm/hour linear flow velocity or more preferably 100 to 300 cm/hour linear flow velocity and the elution fraction corresponding to the pure dutasteride is collected. The adsorbed resin column is washed with mobile phase of same or different composition as that of equilibration mobile phase followed by gradient elution to resolve the dutasteride from impurities.

According to one embodiment, the dutasteride is resolved from dihydrodutasteride not only by the stepwise or linear gradient of mobile phases but also by the isocratic elution with mobile phase. If gradient elution is used the gradient volume may be 0.5 to 10 column volumes, or 1 to 5 column volumes or 1.5 to 2.5 column volumes.

The mobile phase can contain organic modifiers such as but not limited to: alcohols such as methanol, ethanol, isopropanol, butanol and the like; nithles such as acetonitrile and the like; chlorinated hydrocarbons such as chloroform, dichloromethane and the like; toluene; esters such as butyl acetate, ethyl acetate and the like, ketones such as acetone, methyl ethyl ketone and the like; and any suitable combination of one or more than one of these solvents. Water may also be combined with these solvents to adjust the polarity as required. Other solvents may also be used as required without limitation.

The mobile phase used may also contain as required ion-pairing agents or polarity modifiers such as but not limited to phosphoric acid, acetic acid, pentane sulphonic acid, thfluoroacetic acid, tetrahydrofuran, triethylamine and any suitable combination of one or more than one thereof. The concentration of ion-pairing agent in the mobile phase ranges from 0.001 % v/v to 2.5% v/v depending upon the type of ion-pairing agent selected. Other ion pairing agents or polarity modifiers that are useful in the invention include citrate buffer, phosphate buffer, acetate buffer, phosphate-citrate buffer, hexane sulphonic acid, heptane sulphonic acid and the like. Other polarity modifiers or ion-pairing agents may also be used without limitation.

The mobile phase may contain about 1 % v/v to about 50% v/v of water. If water is used in the mobile phase then the mobile phases used in the gradient chromatography should be miscible with each other.

The crude dutasteride sample for the loading to the chromatographic column is prepared by dissolving a suitable quantity of crude dutasteride in the equilibrating mobile phase. The concentration of dutasteride in the loading sample is in the range of 0.01 to 25 % w/v or more specifically is in the range of 2 to 15 % w/v.

In one embodiment of the present invention, the column used for purification of the dutasteride sample can be regenerated to enable reuse of the column, thereby resulting in a more economic process. In the process of the present invention the mobile phase for regenerating the column can be properly selected depending upon the types and amounts of impurities, and the type of the adsorbent resin used in the process. For example, alcohols such as methanol, ethanol, isopropanol, can be used. Other organic solvents are selected from the group of solvents mentioned above in a suitable concentration.

Dutasteride obtained according this aspect of the invention is substantially pure and contains the dihydrodutastehde impurity at less than about 0.1 %, or less than about 0.05%, or less than about 0.01 %, by weight. In a further aspect, the invention provides an improved process for the preparation of crystalline Form Il of dutasteride comprising: a) providing a solution of dutasteride in a water-miscible solvent; b) optionally treating the solution with activated charcoal; c) adding the solution to water for precipitation of the solid; d) isolating and drying the solid.

The step of providing a solution of dutasteride may include dissolving any form of dutasteride in a suitable organic solvent or obtaining an existing solution from a previous processing step. The organic solvents that can be used in the dissolution of dutasteride include solvents or mixtures of solvents, which are miscible with water. Examples include alcohols such as methanol, ethanol, isopropyl alcohol, isobutyl alcohol, tertiary butyl alcohol and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and the like; and nitriles such as acetonitrile, propionitrile and the like.

Any polymorphic form of dutasteride or amorphous form or mixtures thereof may be used in the preparation of the dutasteride crystalline Form Il of the present invention. Whatever the form of the dutasteride used, the process of the present invention yields the desired crystalline Form Il of the present invention.

The suitable temperatures for the dissolution of dutasteride in the solvent may range from 0 to 120 ⁰C or reflux temperature of the solvent used or 25-35 ⁰C. Any temperature can be chosen as long as the stability of the dutasteride is not compromised and a clear solution is obtained. The solution thus formed is optionally treated with activated charcoal to enhance the color of the compound and can be filtered, such as through a flux calcined diatomaceous earth (Hyflow) bed to remove the charcoal. Any other filtration medium or solid-liquid separation technique can be used.

The solution thus obtained is added to water for solid precipitation. Optionally, a small quantity of crystalline Form Il of dutasteride as a seed may be added to the water before the dutasteride solution is added. The quantity of seed material frequently will range from 1-4%, or 2-3%, by weight, or larger amounts can be added. The addition may also be performed in the reverse fashion, i.e., water containing the seed crystals can be added to the dutasteride solution. The solid isolation of step d) can be carried out by using conventional techniques, such as decantation, centrifugation, gravity filtration, or vacuum filtration or other techniques known in the art for the separation of solids.

The wet solid thus obtained can be dried using suitable drying technique including fluid bed drying, aerial drying, oven drying, rotational drying (Buchi drying) or other techniques known in the art. The drying can be conducted at temperatures of about 20-100 ⁰C, or about 60-70 ⁰C, with or without application of vacuum. Drying can also optionally be carried out under inert atmosphere conditions. The crystalline Form Il of dutasteride is characterized by its XRPD pattern.

All X-ray powder diffraction information herein was obtained using a Bruker Axe, D8 Advance Powder X-ray Diffractometer with a Cu K alpha-1 radiation source. Crystalline Form Il of dutasteride has an XRPD pattern substantially in accordance with Fig. 5. Dutasteride prepared in this process contains residual solvents at concentrations equal to or less than the requirement of ICH guidelines when analyzed by gas chromatography. For example dutasteride prepared according to this process can contain any of the residual solvents: acetone at less than about 5000 ppm, or less than about 1000 ppm, or less than about 50 ppm; methanol at less than about 3000 ppm, or less than about 1000 ppm, or less than about 50 ppm; acetonitrile at less than about 410 ppm, or less than about 200 ppm, or less than about 50 ppm; toluene at less than about 890 ppm, or less than about 200 ppm, or less than about 50 ppm; dichloromethane at less than about 600 ppm, or less than about 300 ppm, or less than about 50 ppm; ethyl acetate at less than about 5000 ppm, or less than about 1000 ppm, or less than about 50 ppm; THF at less than about 720 ppm, or less than about 100 ppm, or less than about 50 ppm; n-heptane at less than about 5000 ppm, or less than about 1000 ppm, or less than about 50 ppm; pyridine at less than about 200 ppm, or less than about 100 ppm, or less than about 10 ppm; and o-xylene at less than about 2170 ppm, or less than about 1000 ppm, or less than about 50 ppm.

In a still further aspect the invention provides a process for the synthesis of the desmethyldutasteride impurity of Formula VII,

Formula VII comprising oxidation of dutasteride of Formula I

Formula I in the presence of a suitable oxidizing agent in a suitable organic solvent.

Suitable oxidizing agents include: a combination of 2,3-dichloro-5,6- dicyano-1 ,4-benzoquinone (DDQ) and bis(trimethylsilyl) trifluoroacetamide (BSFTA); benzene selenic anhydride; and the like. Suitable organic solvents include, but are not limited to, members from the classes of: alcohols such as methanol, ethanol, isopropyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, methyl tertiarybutyl ether, tetrahydrofuran, 1 ,4-dioxane and the like; hydrocarbons such as toluene, xylene and the like; nitriles such as acetonitrile, propionitrile and the like; or mixtures of any two or more thereof in various proportions. Regulatory authorities require declarations that the active agent is acceptable for administration to humans and that the particular formulation, which is to be marketed, is free from impurities at the time of release and has an appropriate shelf life. While submitting these declarations, drug manufacturers must include analytical records to demonstrate that impurities are absent from the drug at the time of manufacture, or are present only at a negligible level, and that the storage stability, i.e., shelf-life of the drug is acceptable.

These details are usually obtained by testing the drug against an external standard, or reference marker, which is a pure sample of a potential impurity or a potential degradation product. Desmethyldutastehde is useful as a reference marker compound in identifying the purity of the dutasteride.

Impurities in dutasteride can be analyzed by HPLC, such as is performed using a Zorbax SB Ciβ column (250 cm^χ4.6 mm, 5 μm particle size) with the following parameters:

Detector Variable wavelength UV-detector Wavelength 210 nm Injection volume 10 μl Flow rate 1 ml/minute Run time 60 minutes Mobile phase A 0.01 M KH₂PO₄ in water and pH adjusted to 3.0 with dilute

H₃PO₄

Mobile phase B Acetonithle and water in the ratio of 9:1 by volume Gradient program

A sample chromatogram showing results for a blend of known impurities and dutasteride is provided in Fig. 4. In this and the other chromatograms of the figures, "AU" is absorbance units from the detector and "RT" is the retention time at the highest point of a peak. From the information on a chromatogram, the relative retention time ("RRT") can be calculated for a peak by dividing its RT by the RT for dutasteride. Use of RRT values reduces the confusion that might be introduced by variations in the actual retention times that are frequently observed from repeated analyses of a sample.

To prepare a standard for analysis, 60 mg of pure dutasteride are dissolved in a solvent ("Mobile phase B" above) and the solution is diluted to 100 ml_. A 5 mL aliquot of this first solution is diluted to 100 ml_ with the solvent, and then a further dilution is made by taking a 1 ml_ aliquot of the second solution and diluting to 50 ml_; this final dilution is injected into the chromatograph. For analyzing an unknown sample, a 10 mg portion is dissolved in the solvent and diluted to 50 ml_. Using the above-described conditions, a desmethyl dutasteride impurity content about 0.0013% by weight can be detected in a sample.

In a still further aspect, the present invention provides a pharmaceutical composition comprising substantially pure dutasteride along with one or more pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutical composition comprising substantially pure dutasteride along with one or more pharmaceutically acceptable carriers of this invention may further formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared by direct blending, dry granulation or wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.

Pharmaceutically acceptable excipients that find use in the present invention include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodexthns, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

In the compositions of present invention dutasteride is a useful active ingredient in the range of 0.5 mg to 50 mg, or 1 mg to 25 mg, per dosage form unit.

Certain specific aspects and embodiments of the invention described herein are further described in the following examples. These examples are provided solely for the purpose of illustrating those particular aspects and embodiments, and should not be construed as limiting the scope of the invention.

EXAMPLE 1 Purification of dutasteride containing impurities at 0.94 RRT and 0.97 RRT.

2 g of crude dutasteride (containing 0.007% of the impurity at 0.94 RRT and 0.16% of the impurity at 0.97 RRT) was charged into a clean dry round- bottom flask containing 20 ml of acetonitrile and heated to about 40 ⁰C. The mixture was stirred at 40 ⁰C for 10 minutes and then 2 ml of 36 % aqueous hydrochloric acid was added. The contents were cooled to about 30 ⁰C and stirred for about 1 hour. The solid was filtered and washed with 4 ml of acetonitrile. The solid was dried at about 65 ⁰C for about 16 hours to afford 1.8 g of pure dutasteride.

Figs. 1 A and 1 B are HPLC chromatograms showing the 0.94 and 0.97 RRT impurities contents before and after the purification, respectively. The determined impurities were present in the indicated amounts: Fig. 1A

EXAMPLE 2

Purification to remove the dihydrodutastehde impurity by column chromatography on silica gel.

A clean and dry, vertical, gravity chromatography column was filled with 60 g of silica gel with a particle size of about 100-200 μm and irrigated with 200 ml of n-heptane to make a packed bed height of 170 cm. 5 g of crude dutasteride was dissolved in 50 ml of dichloromethane and the solution was mixed with 30 g of silica gel having a particle size of 100-200 μm and then the solvent was evaporated. The blend of dutasteride and silica gel was loaded onto the column. The bound dutasteride was then eluted by gradient elution using a 1 :1 mixture of ethyl acetate and n-heptane. The equilibration, elution and regeneration were monitored using thin layer chromatography. The peak fractions containing dutasteride were collected and distilled to dryness at about 60-70 ⁰C under a reduced pressure of about 600-700 mm Hg and the solid separated was collected by scraping the flask to provide 4.4 g of purified title compound having a dihydrodutasteride content below the limit of detection of about 0.003%. Figs. 2A and 2B are HPLC chromatograms showing the dihydrodutastehde impurity contents before and after the purification, respectively. The determined impurities were present in the indicated amounts:

Fig. 2A

EXAMPLES 3-5 Purification to remove dihydrodutasteride impurity by column chromatography using a resin column with gradient elution.

To a 1 cm x 200 cm glass column, resin beads with a particle size of 63- 150 μm (chemically modified brominated styrenic polymeric bead type resin, available from Mitsubishi Chemical Corporation, Tokyo, Japan under the trademark SEPABEADS SP207SS), were filled and irrigated with methanol to produce a packed bed height of 170 cm. The column was then equilibrated in a mixture of mobile phase A (90% v/v methanol, 10% water containing 0.1 % v/v of phosphoric acid) and mobile phase B (90 % v/v acetonithle, 10% water containing 0.1 % v/v of phosphoric acid) in a ratio and at a linear flow rate as given in Table 1. Crude dutasteride having a dihydrodutasteride content of 0.022% was dissolved in the equilibrating mobile phase and the sample was loaded onto the column at a linear flow velocity of 50 cm/hour followed by washing with one column volume of the equilibrating mobile phase. The bound dutasteride was then eluted by gradient elution using 2.5 column volumes of eluant in the form of a gradient as given in Table 1 at a linear flow velocity of 150 cm/hour. The equilibration, loading, elution and regeneration were monitored using a UV detector set at a wavelength of 210 nm. The peak fraction corresponding to dutastehde was collected and analyzed by HPLC.

Table 1 : Chromatographic Conditions.

HPLC purity and dihydrodutastehde content in the products along with yield is shown in Table 2

Table 2: Analysis results.

EXAMPLE 6 Purification to remove dihydrodutasteride impurity by column chromatography using a resin column.

A 5 cm x 300 cm glass column was packed with resin beads having a particle size of 63-150 μm (chemically modified brominated styrenic polymeric bead type resin, available from Mitsubishi Chemical Corporation, Tokyo, Japan under the trade name SEPABEADS SP207SS), by irrigating in methanol to make a packed bed height of 270 cm. The column was then equilibrated with a 85:15 mixture of mobile phase A (90% v/v methanol containing 0.1 % v/v of phosphoric acid) to mobile phase B (90% v/v acetonitrile containing 0.1 % v/v of phosphoric acid) at 150 cm/hr linear flow rate. Crude dutasteride (8 g) was dissolved in 400 ml of equilibrating mobile phase and the sample was loaded to the column at a 30 cm/hr linear flow velocity followed by washing with 0.25 column volumes of the equilibrating mobile phase. The bound dutasteride was then eluted by gradient elution using 1.8 column volumes gradient from 15% mobile phase B to 30% mobile phase B at a 150 cm/hr linear flow rate. The equilibration, loading, elution and regeneration were monitored using a UV detector set at a wavelength of 210 nm. The peak fraction corresponding to dutasteride was collected and analyzed by HPLC.

The HPLC purity of dutasteride obtained was 99.22%, the dihydrodutasteride content was below 0.003%, and the yield was 85%.

EXAMPLE 7 Regeneration of resin beds.

The columns packed with resin beads were subjected to a regeneration process by washing with 100% acetonitrile until the HPLC chromatogram of the eluted solvent fraction was identical to the original solvent feed being used.

EXAMPLE 8

Purification of dutasteride containing desmethyl impurity.

10 g of crude dutasteride was charged into a clean dry round-bottom flask containing 75 ml of tetrahydrofuran at 28 ⁰C. The contents were heated to reflux and stirred for about 30 minutes at reflux. The mixture was cooled to 28 ⁰C and the undissolved solid was removed by filtration through a cloth. The filtrate was charged into a flask and heated to reflux. 75 ml of water was added to the solution during reflux and stirred for 15 minutes. The reaction mass was cooled to 30 ⁰C and the solid isolated by filtration. The solid was dried in an oven at about 70 ⁰C for about 6 hours to get 8.8 g of dry solid. The dry solid obtained above was charged into a 250 ml clean dry round- bottom flask containing a mixture of THF (75 ml) and water (75 ml). The contents were heated to reflux and stirred for about 25 minutes at reflux. The contents were cooled to 28 ⁰C and stirred for about 50 minutes. The solid was filtered and washed with a mixture of THF (5 ml) and water (5 ml). The solid was dried at 70- 71 ⁰C for about 6 hours to get 6.8 g of purified dutasteride.

Figs. 3A and 3B are HPLC chromatograms showing the desmethyldutastehde impurity contents before and after the purification, respectively. The determined impurities were present in the indicated amounts:

Fig. 3A

Fig. 3B

EXAMPLE 9

Preparation of dutasteride crystalline Form Il using methanol and water.

750 g of dutasteride was charged into a clean dry reactor containing 6 L of methanol and stirred for about 10 minutes. The reaction mass was heated to about 52 ⁰C to obtain a solution. 40 g of activated charcoal was charged to the solution and the resulting suspension was stirred for about 15 minutes. The suspension was filtered through a flux-calcined diatomaceous earth ("Hyflow") bed and washed with 1.5 L of methanol. The filtrate was again filtered through a 0.45 micron filter paper and then was added to a mixture of water (11.25 L) and 15 g of pure dutasteride crystalline Form Il under stirring, at about 26 ⁰C over about 1 hour, 40 minutes. The mass was stirred further for about 30 minutes. The separated solid was centrifuged and washed with 1.5 L of water. The solid obtained was dried at 65-70° C under vacuum of about 650 mm Hg for about 15 hours to yield 620 g of the title compound. Purity by HPLC: 99.85%. Desmethyldutasteride content: 0.09%. Dihydrodutasteride content: less than 0.003%.

Unidentified impurity content: each less than 0.02%.

Residual solvents methanol (LOD: 15 ppm), acetone (LOD: 18 ppm), toluene (LOD: 6 ppm), dichloromethane (LOD: 50 ppm), ethyl acetate (LOD: 25 ppm), tetrahydrofuran (LOD: 20 ppm), n-heptane (LOD: 16 ppm), pyridine (LOD: 35 ppm), o-xylene (LOD: 8 ppm), acetonithle (LOD: 20 ppm), if present were below the limits of detection ("LOD").

Moisture content: 1.6% w/w.

Fig. 5 is the XRPD pattern of the compound prepared in this example, where the vertical axis is intensity and the horizontal axis is the 2Θ angle, in degrees.

EXAMPLES 10-15 Preparation of dutastehde crystalline Form Il using water miscible solvents and water.

5 g of dutasteride and a water miscible solvent were charged into a 4-neck round bottom flask at about 26 ⁰C and stirred for about 5 minutes to obtain a solution. 0.25 g of activated charcoal was charged to the solution and the resulting suspension was stirred for about 10 minutes. The reaction suspension was filtered through a flux-calcined diatomaceous earth ("Hyflow") bed and washed with 20 ml of water miscible solvent. The filtrate was added to a mixture of water and 0.2 g of pure dutasteride crystalline Form Il seed crystals under stirring at about 26 ⁰C for about 30 minutes and was stirred further for about 15 minutes. The separated solid was filtered and washed with 20 ml of water. The solid obtained was dried at 68-70 ⁰C under vacuum for about 4 hours to yield the title compound as shown in Table 3.

Table 3: Preparation of dutasteride Form Il in water miscible solvents.

EXAMPLE 16 Preparation of desmethyldutasteride (Formula VII).

10.5 g of 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone (DDQ) and 180 ml of toluene were charged into a clean and dry round bottom flask equipped with a Dean-Stark apparatus followed by heating to about 110° C. The suspension was stirred for about 1 hour. The suspension was cooled to about 55° C and 12 g of dutasteride and 23.3 g of bis(thmethylsilyl) trifluoroacetamide (BSTFA) were charged to this suspension. The resultant suspension was heated to about 105° C and was stirred for about 24 hours. The suspension was then cooled to about 80° C and washed with a 10% w/v sodium sulphite solution (2*60 ml). The resultant reaction mass was washed with water (2*50 ml) and the final clear organic layer was dried on anhydrous sodium sulphate. The solvent was distilled completely from the organic layer at about 60° C under vacuum to obtain a residue. A mixture of petroleum ether (105 ml) and ethyl acetate (45 ml) was charged to the residue and the mixture was stirred for about 5 hours. The separated solid was filtered and was dried at about 70° C for about 6 hours to afford 1.3 g of the title compound as a solid.

The solid obtained was purified by flash chromatography on a silica gel column by eluting with a mixture of petroleum ether and ethyl acetate (9:1 ).

Fractions were collected and the solvent was distilled completely at about 60° C under vacuum to afford 0.9 g of the title compound with purity by HPLC of 93.8 %.

EXAMPLE 17 Determination of impurities in AVODART-

Two AVODART^® 0.5 mg capsules (Batch No. RP048926A) were dissolved in a solvent ("Solution B" below) and diluted to 5 mL. The solution was analyzed to determine certain impurity contents in the dutasteride drug substance. The HPLC analysis conditions are described in Table 4. Table 4

Claims

CLAIMS:

1. Substantially pure dutasteride.

2. The dutasteride of claim 1 , prepared by a process comprising recrystallizing dutasteride from a mixture of water and tetrahydrofuran.

3. Dutasteride, containing about 0.002 to about 0.15 percent by weight of a compound having the formula:

4. The dutasteride of claim 3, containing about 0.002 to about 0.1 percent by weight of the compound.

5. The dutasteride of claim 3, prepared by a process comprising: providing a solution of crude dutasteride in a suitable solvent; optionally, removing undissolved material from the solution; mixing the solution with water to form a suspension; maintaining the suspension at an elevated temperature to form a solution; and cooling to form a solid.

6. Dutasteride, being substantially free of a compound having the formula:

7. The dutasteride of claim 6, prepared by a process comprising contacting a solution comprising dutasteride with a hydrophobic polymer resin or a porous nonionic adsorbent for dutasteride.

8. The dutasteride of claim 7, wherein a hydrophobic polymer resin is: a) a divinylbenzene-styrene copolymer; b) a copolymer of divinylbenzene and styrene, and derivatives thereof having aliphatic and/or aromatic moieties comprising from 2 to 18 carbon atoms, or having substituted halogen atoms chlorine, fluorine or bromine; c) a copolymer of divinylbenzene and styrene with surface grafted moieties that contain two or more carbon atoms and are aliphatic or aromatic, optionally substituted with one or more halogen atoms; d) based on one or a combination of optionally dehvatized natural polymers; or e) based on a polymethacrylate matrix, or its combination with other acrylate polymers, prepared by cross-linking of monomers, with or without grafted moieties that are aliphatic or aromatic containing two or more carbon atoms with or without halogen atom substitution.

9. The dutasteride of claim 7, wherein a porous nonionic adsorbent comprises silica gel.

10. Dutasteride having crystalline Form II.

11. The dutasteride of claim 10, prepared by a process comprising combining a dutasteride solution in a water-miscible solvent, with water.

12. The dutasteride of claim 10, prepared by a process comprising combining a dutasteride solution with water and seed crystals of dutasteride Form II.

13. The dutasteride of claim 10, wherein a dutasteride solution comprises a solvent comprising an alcohol.

14. The dutasteride of claim 10, wherein a dutasteride solution comprises a solvent comprising a ketone.

15. The dutasteride of claim 10, wherein a dutasteride solution comprises a solvent comprising a nitrile.

16. A process for purifying dutasteride, comprising contacting a solution comprising dutasteride with a hydrophobic polymer resin.

17. A process for purifying dutasteride, comprising contacting a solution comprising dutasteride with a porous nonionic adsorbent for dutasteride.

18. A process for preparing crystalline Form Il of dutasteride, comprising combining a dutasteride solution with water.

19. A compound desmethyldutasteride having the structure:

20. A process for preparing the compound of claim 19, comprising oxidizing dutasteride.

21. The process of claim 20, wherein dutasteride is oxidized using a combination of 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone and bis(trimethylsilyl) trifluoroacetamide.

22. A process for purifying dutasteride, comprising treating a slurry of dutasteride in a solvent with an acid, and separating dutasteride.

23. The process of claim 22, wherein a solvent comprises acetonitrile.

24. The process of claim 22, further comprising neutralizing residual acid in separated dutasteride by forming a slurry in an aqueous base.