Title of Invention

NEBIVOLOL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS, PROCESS FOR PREPARATION AND PHARMACEUTICAL COMPOSITIONS OF NEBIVOLOL

Abstract ABSTRACT NEBIVOLOL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS. PROCESS FOR PREPARATION AND PHARMACEUTICAL COMPOSITIONS OF NEBIVOLOL The present invention provides an improved process for the synthesis of nebivolol or its pharmaceutical^ acceptable salts, more particularly hydrochloride salt of formula (I). The present invention further provides a new Form T1 of nebivolol and its pharmaceutically acceptable salts. The present invention also provides pharmaceutical compositions and process for the preparation of a solid oral dosage form of nebivolol hydrochloride of formula (I), without the use of wetting agent, and optionally using binder and /or disintegrant. 2 AUG 2005
Full Text

FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
1. Title of the invention. -
NEBIVOLOL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS, PROCESS FOR PREPARATION AND PHARMACEUTICAL COMPOSITIONS OF NEBIVOLOL

2. Applicant(s)
(a) NAME :
(b) NATIONALITY
(c) ADDRESS :

TORRENT PHARMACEUTICALS LIMITED
An Indian Company
Torrent Research Center, P.O. Bhat-382 428,
Dist. Gandhinagar, State of Gujarat, India

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

GRANTED

29-10-2007
2 AUG 2007
ORIGIGNAL
811/MUM/2004
30-7-2004


FIELD OF THE INVENTION
The present invention relates to an improved process for the synthesis of pharmaceutically active 2,2'-iminobisethanol derivative i.e., 2H-1-benzopyran-2-methanol, a, a' -iminobis (methylene)] bis [6-fluoro-3,4-dihydro-, [2R*[R*[R*(S*)]]J] i.e., nebivolol or its pharmaceutically acceptable salts, more particularly hydrochloride salt (I).

(i)
Nebivolol is useful in the treatment and prevention of coronary vascular disorders.
The present invention also relates to pharmaceutical compositions and process for the preparation of a solid oral dosage form of nebivolol hydrochloride of formula (I), without the use of wetting agent, and optionally using binder and /or disintegrant.
The present invention further provides a new polymorphic form of nebivolol hydrochloride. BACKGROUND OF THE INVENTION
Beta-blockers are used for the treatment of high blood pressure, control of angina, arrhythmia, post myocardial infection, heart failure, migraine or essential tremor.
Nebivolol is a highly selective beta-1 blocker and has been found to be useful for the management of hypertension. Hypertension (high blood pressure) is a significant health risk affecting more than 500 million people across the world and needs long-term therapy for its management.
Chemically nebivolol is 2,2'-iminobisethanol derivative i.e., 2H-1-benzopyran-2-methanol, oc,oc'-[iminobis (methylene)] bis[6-fluoro-3,4-dihydro-, [2R*[R*[R*(S*)]]]]. EP 744 946 B1 discloses nebivolol to be a mixture of equal

amounts of 2 enantiomers having respectively the SRRR- and the RSSS-configuration.
Methods for preparation of nebivolol are disclosed in EP-0145067 and EP-0334429. EP 0145067 B1 describes a process for the conversion of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (VI) into isomeric mixtures of 6-fluoro-3, 4-dihydro-2-oxiranyl-2H-1-benzopyran (VII). This reaction entails the use of sodium hydride as the base, which is extremely hazardous. Further, purity of the product, i.e., 6-fluoro-3, 4-dihydro-2-oxiranyl-2H-1-benzopyran (VII) obtained by using sodium hydride is low and is found to be around 62-65 %, which is unacceptable. The mixture of oxiranes represented by the formula (VII) are separated by column chromatography as shown in Scheme (I) to obtain A-isomer of (VII) (i.e., Vll-A) from the first fraction and B-isomer of (VII) (i.e., Vll-B) from the second fraction.

The A-isomer of (VII) is then treated with benzylamine to obtain the benzylated A-isomer of (VII) (i.e., Intermediate I), which is reacted with the B-isomer in presence of oxalic acid to obtain the oxalate salt of benzylated nebivolol (Vlll-a), as shown in Scheme - II.
Furthermore, the oxalate salt (Vlll-a) as obtained has to be treated with an alkali to obtain the free benzylated nebivolol base (VIII).

Scheme- II

Thus, as can be seen from Scheme II, the reaction between lntermediate-1 and (Vll-B) involves purification by column chromatography, and subsequent treatment with oxalic acid to form the oxalate salt. Treatment with oxalic acid

results in the separation of the undesired (RSRR + SRSS) diastereomers from the desired (RSSS + SRRR) isomers, due to a difference in solubilities between the desired and the undesired isomers. Further, the oxalic acid salt has to be converted to the free benzylated nebivolol base by treatment with an alkali. The multiple steps in the process make it cumbersome and lead to increase in utilities and in the manufacturing time cycle of the active pharmaceutical ingredient. Moreover the purity of the free benzylated nebivolol base is also found to be relatively low.
EP 334429 B1 discloses a process for the preparation of specifically the RSSS isomer of nebivolol independently. The said process for the independent preparation of RSSS nebivolol involves the use of hazardous reagents like thionyl chloride, sodium hydride and di-isobutyl aluminium hydride (DIBAL), expensive optically active reagents like (+)-1,2,3,4,4a,9,10,10a-octahydro-1,4a-dimethyl-7-(1 -methylethyl-1 -phenathrenemethanamine[(+)-dehydroabiethylamine] and utilities like column chromatography and low temperatures. The processes also involve a large number of steps thereby increasing in utilities, manpower and time required to complete the production cycle, rendering the process commercially expensive.
Furthermore, EP 744946B1 describes a process for obtaining nebivolol hydrochloride from a mixture containing the desired (RSSS + SRRR) nebivolol base contaminated by the undesired (RSRR + SRSS) diastereomers, using ethanol as both the reaction as well as the recrystallization solvent. The major disadvantage of the said process is that it uses impure nebivolol base as the starting material containing different isomeric impurities, and thereby results in a very low yield (6.6 %) of the desired isomers (having the SRRR- and the RSSS-configuration) of nebivolol hydrochloride. Moreover, ethanol is a solvent that can be used only in controlled quantities due to stringent regulatory requirements, and therefore its use on an industrial scale is limited.
Thus, there exists a need for developing a method for the synthesis of the desired diastereomeric mixture of higher purity with the reduction of undesirable

isomeric impurities and eliminating the use of hazardous sodium hydride, while at the same time reducing the process steps in the synthesis of nebivolol.
It has been surprisingly found that the process of synthesizing nebivolol in accordance with the process of the present invention not only increases the purity of the desired diastereomeric mixture in a minimum number of process steps but also eliminates the use of hazardous chemicals in the process.
Nebivolol is mainly used for the treatment and prevention of coronary vascular disorders. It is taken once or twice a day as per the requirement of the patient.
EP 0744946 discloses pharmaceutical compositions of nebivolol where the drug is in micronized form and with the addition of one or more wetting agents specifically polysorbates as an adjuvant. This patent emphasizes the need of micronization and further wetting as the oral administration of nebivolol hydrochloride is impeded by the poor dissolution when in a normal crystalline form. In order to achieve a good dissolution the active ingredient has to be sufficiently wetted.
The micronization of nebivolol hydrochloride as required in EP 0744946 B1 for preparing pharmaceutical compositions unjustifiably increases the time cycle for the manufacturing process. It also requires undue utilities like milling and sifting, which increases the cost of preparing the final product. It is further demonstrated that on comparison of dissolution of tablets comprising crystalline versus micronized nebivolol, the dissolution rate of the tablet comprising crystalline nebivolol (Example 6 of EP 744946) is less than 50 % after 45 minutes.
EP 0145067 B1 provides pharmaceutical composition of derivatives of 2,2'-iminobisethanol for various dosage forms i.e. oral drops, injectable solution, oral solution, film coated tablets and the like. The use of sodium dodecyl sulfate is disclosed in EP 0145067 B1 in the preparation of film-coated tablet. Sodium dodecyl sulfate, i.e., sodium lauryl sulfate, (Wade, A. and Weller P.J., Handbook of Pharmaceutical Excipients, 2nd ed., 1994, page 448) is a wetting agent in the core of the composition (film coated tablet).


WO 2002/087508 discloses nitrosated and nitrosylated nebivolol and its metabolites and pharmaceutical composition using the same. It is disclosed that the bio-availability of the composition can be enhanced by micronization of the formulation using conventional techniques such as grinding, milling, spray drying and the like in the presence of suitable excipients or agents such as phospholipids or surfactants.
Thus, the existing literature reveals that attempts to use the natural crystalline form of nebivolol have resulted in poor dissolution rate and poor bioavailability. Attempts for combining the crystalline form with a wetting agent are also largely unsuccessful. For achieving appropriate dissolution rate or bioavailability of nebivolol hydrochloride, micronized nebivolol is needed. The micronization process is both cost extensive and time consuming, and requires the use of wetting agent.
Wetting agent is a surfactant, a substance capable of reducing the surface tension of a liquid in which it is dissolved. The effect of surfactant over the intestinal membrane is more complex. It has been shown that most surfactants interact with the absorbing membranes (Bermejo, D.M. and Ruiz-Garcia, A., Business Briefing: Pharmatech 2003; pages 1-7). Permeability enhancement and local damage are closely related sequelae of the interaction of surfactants with the intestinal wall (Swenson, E.S., Milisen, W.B., Curatolo, W., Pharm. Res. 1994 Aug; 11(8), pages 1132-42). Ingested surfactants may facilitate penetration or absorption of potentially toxic or pathogenic compounds, which in turn may result in adverse effects on the other organs (Lieberman, H.A., Rieger, M.M. and Banker, G.S., Eds., Pharmaceutical Dosage Forms: Disperse Systems, 2nd ed, Vol. 1, page 261). The surfactant can facilitate their own entry and that of other material into the body, which thus enters in to the systemic circulation (Lieberman, H.A., Rieger, M.M. and Banker, G.S., Eds., Pharmaceutical Dosage Forms: Disperse Systems, 2nd ed., Vol. 1, page 264).
Polysorbate 60 or 80 affects the integrity of intestinal mucosa (Lieberman, H.A., Rieger, M.M. and Banker, G.S., Eds., Pharmaceutical Dosage Forms:

Disperse Systems, 2nd ed., Vol. 1, page 261), Polysorbate 80 may increase the
absorption of fat-soluble substances
(www.lactose.co.uk/milkallergy/foodadditives400.html).
Management of hypertension being a long term therapy, use of wetting
agents in the formulation of nebivolol need to be judiciously avoided. Large
doses of polysorbate 80 as a wetting agent in pharmaceutical formulations
produces abdominal spasms, diarrhea
(http://www.jtbker.com/msds/englishhtm1/t7683.htm). Further, polysorbate 80
containing pharmaceutical compositions have found to cause allergy in various
patients (http://www.hci.utah.edu/patientdocs/hci/drugd/docetaxel.htm).
Polysorbate 20 and polysorbate 40 should also be avoided in formulations as
they are banned in certain countries
(http://www.lactose.co.uk/milkallergy/foodadditives400.html).
Thus there is a long felt need to have compositions of nebivolol that are safe and efficacious at the same time being cost and time effective for manufacturing.
The present inventors have surprisingly found that pharmaceutical compositions of the present invention prepared using nebivolol as the active ingredient and without using wetting agent, exhibited excellent dissolution characteristics that were also found to be comparable with respect to the marketed formulation.
It was further surprisingly found that nebivolol hydrochloride could be formulated not only without the use of wetting agent but optionally without using binder or disintegrant without retarding the dissolution characteristics of the drug. OBJECTS OF THE INVENTION
It is thus an object of the present invention to provide for an improved process for the synthesis of pharmaceutically active 2,2'iminobisethanol derivative i.e. 2H-1-benzopy ran-2-methanol, a, a'-iminobis (methylene)] bis[6-fluoro-3,4-dihydro-, [2R*[R*[R*(S*)]]j] i.e. nebivolol base or its hydrochloride salt of formula (I) above .

Another object of the present invention is to provide a simple and economical process for synthesis of nebivolol base or its hydrochloride salt that involves minimum number of process steps and does not utilize hazardous chemicals in the synthesis.
Yet another object of the present invention is to provide pharmaceutical compositions comprising nebivolol hydrochloride active ingredient and one or more adjuvants, without incorporating wetting agent, to achieve desired dissolution profile.
A further object of the present invention is to provide process to manufacture solid dosage form as tablets or capsules in a simple and cost effective manner.
Yet another object of the present invention is the preparation of a solid dosage form of nebivolol hydrochloride, and one or more adjuvants, without the use of wetting agent optionally without using binder and optionally without using disintegrant.
Another object of the present invention is to provide a novel polymorphic form of nebivolol and its pharmaceutically acceptable salts in particular hydrochloride salt and its process of preparation.
Another object of the present invention is to provide use of the pharmaceutical composition of nebivolol hydrochloride of the instant invention prepared without using wetting agent for the treatment of hypertension. SUMMARY OF THE INVENTION
Thus according to a first aspect of the present invention there is provided an improved process for the synthesis of pharmaceutically active 2,2'iminobisethanol derivative i.e. 2H-1-benzopyran-2-methanol, ct.cf-iminobis (methylene)] bis[6-fluoro-3,4-dihydro-, [2R*[R*[R*(S*)]]]] i.e., nebivolol or its hydro halide more particularly nebivolol hydrochloride salt, as shown in Figure (I),


wherein
- 6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (VI) is converted to isomeric mixture of oxiranes represented by formula (VII), in presence of potassium tertiary butoxide as a base, and
- the reaction between the benzylated A-isomer of (VII) (i.e., Intermediate I) and the B-isomer (VII-B) and isolation of the reaction product is carried out in presence of an organic solvent in controlled time and temperature conditions, leading to the formation of the free benzylated nebivolol base (IX).
According to second aspect of the present invention, there is provided nebivolol synthesized by the process of the present invention.
According to another aspect of the present invention, there are provided pharmaceutical compositions of nebivolol comprising nebivolol or its pharmaceutically acceptable salts formulated without using wetting agents.
Further, the present invention also provides a solid dosage form of nebivolol hydrochloride, and one or more adjuvants, without the use of wetting agent, optionally without using binder and / or disintegrant and a process for preparation of the same.
According to yet another aspect of the present invention, there are provided a process for manufacturing the pharmaceutical composition of the present invention
In yet another aspect of the present invention, there is provided a novel polymorphic form of nebivolol and its pharmaceutically acceptable salts.
In another embodiment of the invention, the preferred specific surface area of the nebivolol hydrochloride is 0.2 x 103 m2/ kg to 1.95 x 103 m2/ kg.

DETAILED DESCRIPTION
The present invention accordingly provides for an improved process for
the preparation of 2H-1-benzopyran-2-methanol, a, a'
[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-, [2R*[R*[R*(S*)]]]] i.e. nebivolol of formula (IX) or its pharmaceutically acceptable salts like the hydrochloride salt as shown in formula (I).

Nebivolol is prepared according to the present invention by the synthetic route shown in Scheme III given below:


The reaction steps in the present invention for the preparation of nebivolol starting from compound (II) according to Scheme III above are now described hereunder:

5-Fluoro-2-hydroxyacetophenone (II) was treated with potassium tertiary butoxide and diethyl oxalate to give 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid (III) according to Reaction 1 as given below by a known process (JP 2218675).

6-Fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid (III) was reacted with 10% palladium on carbon in acetic acid as solvent under hydrogen atmosphere to give 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (IV) as shown in Reaction - 2 given below by a known process (US 4,654,362).

6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (IV) is converted into the amide (V-A) using amine RR'NH and acid activating agent as indicated in Reaction 3(a),


wherein, R and R' are independently H, alkyl or phenyl, optionally joined together with or without a heteroatom such as O, N or S. Alkyl is straight chain or branched C1to C6 alkyl.
In the Reaction 3 (a) of formation of amide (V-A) from acid (IV), the amine RR'NH can be selected from the group of primary or secondary amines. The primary amine is selected from aliphatic or aromatic primary amine, whereas the secondary amine is selected from cyclic secondary amines or non-cyclic secondary amines, wherein substitution on nitrogen is independently aliphatic or aromatic or combination thereof.
Preferably, secondary amines can be used. More preferably, secondary amines, which are cyclic amines are used.
The amines can be selected from the group comprising of dimethylamine, diethylamine, N-methylphenylamine, pyrrolidine, piperidine, N,0-dimethylhydroxylamine and morpholine. The preferred amine is piperidine.
The activating agent according to Reaction-3 (a) is selected from the group comprising of thionyl chloride, ethylchloroformate, acetic anhydride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, dicyclohexylcarbodiimide, N,N'- carbonyldiimidazole and chlorosaccharin. The preferred activating agents are thionyl chloride and ethylchloroformate.
In a preferred embodiment, 6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (IV) was converted into 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid piperidine amide (V) using thionyl chloride and piperidine in toluene as solvent, as indicated in Reaction - 3 below.


The reduction of amide (V-A) to give 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde of Formula (VI) is carried out by using an alkoxy metallic hydride wherein, alkoxy group is substituted or unsubstituted -0(C1-C4)alkyl, and substitution if any, by -0(C1-C4)alkyl and, metallic part contains metal selected from the group comprising of Li or Na.

The alkoxy metallic hydride reducing agent is selected from the group comprising of sodium bis (2-methoxyethoxy)aluminium hydride, lithium diethoxyaluminium dihydride and lithium tri-terf-butoxy aluminium hydride.
The preferred reducing agent is sodium bis (2-methoxyethoxy) aluminium hydride.
6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid piperidine amide (V) was reduced by using vitride i.e. Sodium bis (2-methoxyethoxy)aluminium hydride in toluene to give 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (VI) as given below in Reaction - 4.

Reaction - 4
6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (VI) was reacted with trimethyl sulfoxonium iodide in presence of base, potassium tertiary butoxide and solvent dimethyl sulfoxide to give isomeric mixture of oxiranes


represented by formula (VII), which may be optionally distilled, as indicated in Reaction-5.

Thus, the present invention avoids the use of sodium hydride as base in the above reaction. Due to the said change of the above base, the purity of the reaction product, i.e., oxirane (VII) is substantially higher. The purity of the oxirane obtained by using potassium tertiary butoxide as base is above 75 % before product distillation , compared to a purity of 60-65 % of the product before product distillation obtained in our hand by using sodium hydride base, as per the procedure described in EP 0145067 B1. The process of the present invention affords the advantage of both avoiding the use of hazardous sodium hydride as well as improving the purity of the oxirane.
The mixture of oxiranes was separated by column chromatography to elute firstly pure fraction (A-isomer i.e. Vll-A), i.e. (A)-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran of EP 0 145 067. Further, upon elution the second fraction (B-isomer i.e. VII - B), i.e. (B)-6-fluoro-3, 4-dihydro-2-oxiranyl-2H-1-benzopyran of EP 0 145 067 was obtained.
The chromatographic separation of two isomers A and B was carried out (EP 0 145 067) (Scheme -1) using silica gel as the stationary phase whereas the eluant is the mixture of hexanes and ethyl acetate. If the loading material is in higher quantity, the purification by column chromatography can be done simultaneously on multiple columns (more than one column). The column chromatography yielded Isomer-A in the beginning, followed by Isomer-B. Based on the purity of the fractions from the column, they can be mixed together and used for further reaction.
16


(A)-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (VII-A) was reacted with benzylamine in isopropyl alcohol to give (A)-6-fluoro-3,4-dihydro-alpha-[[(phenylmethyl)amino]-methyl]-2H-1-benzopyran-2-methanol (Intermediate I), by a known process (US 4,654,362), as indicated in Reaction-6.

(A)-6-Fluorodihydro-a-[[(phenylmethyl)amino]-methyl]-2H-1-benzopyran-2-methanol (Intermediate-I) was reacted with (B)-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (Vll-B) in presence of an organic solvent and isolated at a temperature of -5 to -25°C, and maintaining the reaction mass at the temperature of isolation for more than 2 hours to give benzylated nebivolol as shown in the following Reaction - 7.


(vm)
Reaction - 7
In the present invention, the reaction between the benzylated A-isomer of (VII) (i.e.,. Intermediate I) and the B-isomer (Vll-B) was carried out in an organic solvent and isolated at a temperature of -5 to -25°C leading directly to the formation of the free benzylated nebivolol base (IX) containing only the desired isomers (having SRRR- and RSSS-configuration). It has been observed surprisingly in the present invention, that the isolation when carried out a low temperature, particularly at a temperature of -5 to -25°C yields substantially pure desired stereoisomers, (HPLC purity > 90.0%) which can be further optionally purified in alcoholic solvent such as methanol, ethanol to get desired stereoisomer in highly pure form (HPLC purity >98.5%) , as compared to the process described in the prior art, wherein the desired isomers are obtained with considerably less purity (HPLC purity
The organic solvent as used in Reaction-7 is selected from the group comprising of alcohols, esters, ketones and acetonitrile.
In one embodiment of the invention, the alcohol is selected from the group comprising of methanol, ethanol, isopropyl alcohol, n-propyl alcohol, n-butanol, isobutanol. In a preferred embodiment, the alcohol used is methanol. In another embodiment, the esters are selected from the group comprising of ethyl acetate, n-butyl acetate. In a further embodiment, the ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone (MIBK).
The isolation is carried out a temperature range of-5 to -25°C , preferably at a range of -10 to -20°C, and more preferably at a range of -10 to -15°C.
The reaction mass is maintained at the temperature of isolation for a period of 2 - 40 hours, preferably for a period of 4 - 30 hours, more preferably for a period of 8 - 20 hours, and most preferably for a period of 10-15 hours.
Thus, the process of the present invention has the following advantages:
(i) Avoids the use of column chromatography,
(ii) Avoids preparation of oxalate salt and recrystallization steps thereof, and,
(iii) Avoids subsequent conversion of the oxalate salt to free benzylated nebivolol base by treatment with an alkali.
Therefore, compared to prior art processes, the process of the present invention leads to a decrease in the number of process steps, thereby making it more economical and time effective.
Further, the hydrogenation reaction was carried out using 10 % palladium on carbon for debenzylation reaction of the benzylated nebivolol base (VIM) to give nebivolol base (IX), by a known process (US 4,654,362) as given in the following Reaction 8.



Nebivolol may be converted into its pharmaceutical^ acceptable acid
addition salt forms by treatment with appropriate acids. Appropriate acids are, for
example, inorganic acids, such as hydrohalic acid, e.g., hydrochloric,
hydrobromic, sulfuric acid, nitric acid, phosphoric acid; or organic acids, for
example, acetic, propanoic, hydroxy acetic, 2-hydroxypropanoic, 2-oxopropanoic,
ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-
hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-
propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methybenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic acids. In a preferred embodiment, the acid addition salt is hydrochloride.
Nebivolol base (IX) was converted into nebivolol hydrochloride (I) using an organic solvent and hydrochloric acid (Reaction 9). It was observed in the present invention that the preparation of nebivolol hydrochloride in alcohols / esters / ketones gives near quantitative yield of the product compared to other


organic solvents. The present process for the conversion of nebivolol base to nebivolol hydrochloride salt in the presence of alcohol as solvent leads to product with near quantitative yields. Thus, by the process of the present invention, nebivolol hydrochloride containing only the desired isomeric mixture can be prepared in high yield.

Reaction - 9
The solvents for conversion into nebivolol hydrochloride or even further purification can be selected from the group consisting of alcohols, esters, ketones, halogenated solvents, acetonitrile and water or mixtures thereof. In one embodiment of the invention, the alcohol used for the conversion can be selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like. In another embodiment, the ester can be selected from the group comprising of ethyl acetate, n-butyl acetate and the like. In yet another embodiment, the ketone can be selected from acetone or methyl isobutyl ketone (MIBK). In another embodiment, halogenated solvents such as methylene dichloride, can be used for conversion of nebivolol base into nebivolol hydrochloride.
21

Also, nebivolol hydrochloride can be prepared by reacting nebivolol base and alcoholic hydrogen chloride such as methanolic HCI, ethanolic HCI, n-propanolic HCI, isopropanolic HCI, n-butanolic HCI.
Also, the same can be achieved by passing HCI gas through the solution of nebivolol base, wherein the solvent used can be as mentioned above. Nebivolol hydrochloride Form T1
The present invention also provides a novel amorphous form of nebivolol and its pharmaceutical^ acceptable salts designated as Form T1.
Polymorphism is the occurrence of distinct crystalline forms of a single compound, and have the same molecular formula, but each polymorph may have distinct physical properties. A single compound may give rise to a variety of polymorphic forms, whose physical properties may be distinct and different, such as different solubility profiles, different melting point temperatures and different x-ray diffraction peaks. Due to differing solubility profiles of polymorphs, the identification of pharmaceutical polymorphs is essential for preparing pharmaceutical dosage forms with predictable solubility profiles.
The term "amorphous" as used herein denotes a physical state, which is not crystalline and may be verified by X-ray diffraction, infrared spectroscopy and other means including but not limited to observation with a polarized light microscope and differential scanning calorimetry.
The term "pharmaceutically acceptable salt" as used herein refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenylsubstituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate,

o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate,
phenylbutyrate, beta -hydroxybutyrate, chloride, cinnamate, citrate, formate,
fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate,
mesylate, nitrate, oxalate, phthalate, phosphate, monohydro genphosphate,
dihydrogenphosphate, metaphosphate, pyrophosphate, propionate,
phenylpropionate, salicylate, succinate, sulfate, bisulfate, pyrosulfate, sulfite,
bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate,
chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate,
methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like. A preferred salt is the hydrochloride salt.
In one particularly preferred embodiment, the invention provides the hydrochloride salt of nebivolol, in an amorphous form.
The said amorphous form can be obtained by techniques such as spray drying. Freeze drying and the like.
In a preferred embodiment the said form is obtained by conventional spray drying technique using a LabPlant SPD-005® spray drier. Nebivolol hydrochloride is dissolved in alcohol such as methanol under heating to obtain a clear solution or adjust pH below 2.0 of nebivolol base solution/suspension in alcohol using aqueous HCI / Alcoholic HCI / HCI gas, which is then spray dried for a period of 2 to 5 hours, and further isolating nebivolol hydrochloride FormTI.
The term "isolating" comprises filtration, drying, or any other techniques known to the person skilled in art. The alcohol used for the preparation of Nebivolol hydrochloride Form T1 is selected from the group comprises of methanol, ethanol, propanol, isopropanol, n-butanol ,and the like and its mixtures thereof.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS Fig. 1: This figure indicates X-ray diffraction pattern of partially amorphous Form T1 of nebivolol hydrochloride obtained according to the present invention. Fig. 2: This figure indicates X-ray diffraction pattern of the crystalline form of nebivolol hydrochloride obtained by reported process (EP0145067).

Fig. 3: This figure indicates comparative and superimposed X-ray diffraction
pattern of form T1 and crystalline form of nebivolol hydrochloride obtained
according to present invention.
Fig. 4: This photograph is a microscopic image of crystalline nebivolol
hydrochloride taken using AXIOLAB microscope.
Fig. 5: This photograph is a microscopic image of spray dried nebivolol
hydrochloride taken using AXIOLAB microscope.
Fig. 6: Mean plasma concentration time curve of nebivolol test v/s reference
formulation.
Characterization of nebivolol hydrochloride Form T1
The Form T1 of nebivolol hydrochloride of formula (I) is characterized by the following data:
Nebivolol hydrochloride Form T1 is characterized by powder X-ray diffraction (XRPD) pattern as depicted in Fig 1, and can be differentiated from the crystalline form by X-ray powder diffraction angles (26, degrees), d-values, and relative intensities, as set out in Table 1 given below:





The Form T1 of nebivolol hydrochloride is differentiated from the crystalline form with the following differentiation:
Absence of the peaks at about 11.67 ± 0.2, 16.54 ± 0.2, 22.75± 0.2, 25.41 ± 0.2, 29.81± 0.2, 31.56± 0.2, 32.09± 0.2 degrees two-theta. Conspicuous presence of the peaks at 5.4330 ± 0.2, 11.1544 ± 0.2 & 19.7730 ± 0.2 degrees two-theta. Pharmaceutical composition
The present invention also provides a process for preparation of solid dosage form preferably tablet or capsule of nebivolol hydrochloride (I) and one or more adjuvants, without the use of wetting agent. Further the present invention also provides the solid dosage form of nebivolol hydrochloride, and one or more adjuvants, without the use of wetting agent, optionally without using binder and optionally without using disintegrant and process for preparation of the same.
Pharmaceutical composition according to the present invention is preferably in the form of a tablet or capsule. The active ingredient used in the present pharmaceutical composition is nebivolol hydrochloride, which may be optionally sieved through mesh # 100.
The solid dosage form tablet or capsule of the present invention is prepared using active ingredient i.e,. nebivolol hydrochloride and pharmaceutically acceptable excipients selected from the group comprising of diluents, disintegrants, binders, lubricants, glidants and other pharmaceutically acceptable excipients or adjuvants but not wetting agent.
Diluents can be selected from the group comprising of lactose, starch, dibasic calcium phosphate anhydrous, tribasic calcium phosphate, kaolin, sucrose, mannitol, precipitated calcium carbonate, sorbitol, maltodextrin, cellulose derivatives including powdered cellulose, micro crystalline cellulose and other materials known to one of ordinary skill in the art.
Binders can be selected from the group comprising of polyvinylpyrrolidone or hydroxypropylmethylcellulose, acacia, alginic acid, hydroxy propyl cellulose, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin,

liquid glucose, methylcellulose, pregelatinized starch and other materials known to one of ordinary skill in the art.
Disintegrants can be selected from the group comprising of starch, sodium starch glycolate or croscarmellose sodium, crospovidone, alginic acid, carboxymethyl cellulose sodium, Guar gum and other materials known to one of ordinary skill in the art.
Lubricants can be selected from the group comprising of stearic acid, polyethylene glycol, magnesium stearate, calcium stearate, talc, zinc stearate, hydrogenated castor oil, silica, colloidal silica, cornstarch, calcium silicate, magnesium silicate, silicon hydrogel and other materials known to one of ordinary skill in the art.
Glidants can be selected from the group comprising of colloidal silicon dioxide, colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, colloidal silicon, silicon hydrogel and other materials known to one of ordinary skill in the art.
Other pharmaceutical solvents are selected from the group comprising of methanol, acetone and purified water.
The preferred specific surface area of the nebivolol hydrochloride according to the present invention is between 0.2 x 10 3 m2/ kg and 1.95 x 10 3 m2/ kg.
The composition of the present invention comprises the ingredients in the following proportion. Quantity of nebivolol or its pharmaceutically acceptable salt can be based upon the requirement of human dosage.


The solid dosage form of the present invention containing nebivolol or its pharmaceutical^ acceptable salt is prepared according to the following steps:
(I) a. Prepare powder blend by passing lactose, starch and croscarmellose sodium through mesh # 60 and further mixing it.
b. Prepare the solution of nebivolol or its pharmaceutically acceptable salt
and hydroxypropyl methylcellulose or povidone in methanol or a
suitable solvent and water.
c. Adsorb the solution from above step (b) onto the dry mix diluents of step 1
(a).
d. Dry the resultant of step (c) above and granulate with water.
e. Dry the wet granules at 60 ° C and sieve the dried granules though #30
mesh
f. Lubricate the granules of step (e) with croscarmellose sodium, colloidal
silicon dioxide, microcrystalline cellulose and magnesium stearate and
mix in a blender.


g. Compress the granules obtained in step (IV) into tablets or fill the granules into capsules.
OR
(I) Nebivolol or its pharmaceuticaly acceptable salt, lactose, starch and croscarmellose sodium are passed through mesh # 60 and mix it properly.
(II) Prepare binder solution using hydroxy propyl methylcellulose or povidone in aqueous or non-aqueous granulating solvents.
(III) Granulate the powder mixture of step (l)-c OR (I') with a binder solution prepared in step II in a high speed mixer and dry the granules in a fluid bed dryer.
(IV) Lubricate the granules of step (III) with croscarmellose sodium, colloidal silicon dioxide, microcrystalline cellulose and magnesium stearate and mix in a cage blender.
(V) Compress the granules obtained in step (IV) into tablets or fill the granules into capsules.
Thus, by using the above simple and less expensive method, dissolution achieved is at least 75 % in 45 minutes without the use of wetting agent as shown in the relevant examples.
Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
The details of the invention, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary illustrations. The examples are merely illustrative and do not limit the teaching of this invention and it would be obvious that various modifications or changes in the procedural steps


as well as compositions by those skilled in the art without departing from the scope of the invention and shall be consequently encompassed within the ambit and spirit of this approach and scope thereof.
EXAMPLES
Example 1
Preparation of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid
piperidine amide (V)
120 ml of toluene and 0.8 ml of dimethyl formamide were added to 40 g of 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxylic acid (IV) under stirring at room temperature. Thionyl chloride (32 g) was added and the reaction mixture heated to 60 -70° C and maintained for 30 min. Thionyl chloride and toluene were distilled out under reduced pressure. To the reaction mixture, 160 ml of toluene was further added and cooled. To this, 88 ml of piperidine was slowly added at room temperature and stirred for 30 min. The reaction mixture was acidified using dilute HCI. The aqueous layer was extracted with toluene and the combined organic layers washed with dilute HCI followed by water. The organic solvent was removed under reduced pressure to obtain 40 g of the title compound as a solid.
Alternatively, the following procedure can as well be used. To 100 g of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (IV), 1500 ml of methylene chloride and 70 g of triethylamine were added at 20° to 40°C. The reaction mixture was cooled to 0° to -5°C and 57 g of ethylchloroformate was slowly added over a period of 30 to 45 minutes. The reaction mixture was maintained at 0° to -5° C for 1 h. Subsequently, 55 g of piperidine was added over a period of 30 to 45 minutes, while maintaining the temperature at 0° to -5° C. The reaction mixture was maintained at 0° to 5°C for 1.5 h. till completion of the reaction. 1 lit of water was added at 0° to 5° C and the pH adjusted to 2.0 with concentrated hydrochloric acid at 15° to 20° C. Stirred for 0.5 hr and the layers were separated. The methylene chloride layer was washed with 2 lit of water, and then distilled out the methylene chloride completely under vacuum at the temperature up to 45°C. 200 ml of hexane was added and distilled out completely. Again 200 ml of


hexane was added and stirred at 20° to 40° C for 0.5 h and cooled to 0° - 5° C.
Maintained at 0° - 5°C for 1 h, filtered and washed with 100 ml of chilled hexane
at 0° - 5° C to give 110 g dry weight (dried at 55° to 60° C in hot air oven for 6
hours) of the title compound as a solid.
Example 2
Preparation of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (VI)
To 40 g of amide (V) was added 400 ml of toluene. To it, vitride solution (mixture of 44 g vitride in toluene) was slowly added at 10 to 15°C. Methanol was added to the reaction mixture which was then acidified using dilute HCI. The reaction mixture was extracted with toluene and concentrated under reduced pressure to provide 26 g of the title compound. Example 3 Preparation of 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (VII)
To 234 ml of dimethyl sulfoxide was added 32 g of trimethyl sulfoxonium iodide. To it, potassium tertiary butoxide (16 g) was added and stirred for 1 h at 20-40°C. The reaction mixture was cooled and to it was added a solution of the compound obtained in Example 2 in dimethyl sulfoxide (26 ml.) while maintaining the temperature between 20° - 40°C for 1.5 hr. The reaction mixture was quenched in cold water. The aqueous layer was extracted with ethyl acetate, washed with water, concentrated under reduced pressure followed by product distillation to give 19.6 g of 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (VII) in the form of a mixture of A and B as an oil.
The mixture of isomer A (Vll-A) and isomer B (Vll-B) were separated by column chromatography using silica gel as the stationary phase and a mixture of hexane and ethyl acetate as eluant. 6.75 g of the mixture of isomers A and B was eluted with a mixture of hexane : ethyl acetate (in the ratio 97 : 3), till Isomer A separates out completely. The column is further eluted with a mixture of hexane : ethyl acetate (in the ratio 90 : 10), to get Isomer B. The eluates of Isomer A and Isomer B were evaporated to get respectively 2.6 g of isomer A (Vll-A) as an oil and 1.4 g of isomer B (Vll-B). % Purity obtained : 78-82 %


Example 4
Preparation of (A)-6-fluorodihydro-a-[[(phenylmethyl) amino]-methyl]-2H-1-
benzopyran-2-methanol (Intermediate -1).
10.65 g of isomer A (Vll-A) was added to 31.9575 ml of isopropyl alcohol followed by addition of 7.13 g. of benzylamine. The reaction mixture was heated to reflux for 2 hr and chilled to 0 - 5° C. The solid was filtered and purified with isopropyl alcohol (27 ml) to give 8.52 g of the title compound. Example 5 Preparation of benzylated nebivolol base (VIII)
10 g of Isomer B (Vll-B) and 14.70 g of A amine (Intermediate - I) were added to 50 ml of methanol and heated to 65-70°C. The reaction mass was maintained at the same temperature for 15 h. The mass was then cooled to 50-55° C, to which 30 ml of methanol was added. It was further cooled to -10 to -15° C and stirred at the same temperature for 12 h. The material was filtered, washed with 5 ml of methanol at -10 to -15° C, filtered and dried at 40-45°C for 8 h to obtain 11.5 g of the title compound. Example 6 Preparation of nebivolol base (IX)
Benzylated nebivolol base (VIII) (5.85 g) along with 2-methoxy ethanol (117 ml) and 0.351 g palladium on carbon (10 %) was added to the hydrogenator. 160-170 psi pressure applied with hydrogen gas and heated it to 70 - 75° C. The temperature and pressure conditions were maintained for 3 hrs till the completion of reaction. The reaction mass cooled to room temperature and filtered through (18 g) hyflow bed to separate the catalyst.
The filtrate was evaporated to get solids, isolated the solids in methanol (38 ml) at 0 - 5°C. The solid was dried to get 4.0 g of nebivolol base. Example - 7
Preparation of nebivolol HCI (I) using methanol as reaction solvent and purification of nebivolol HCI (I)
70 ml of methanol and 3.5 g of hydrochloric acid were added to 10 g of nebivolol base (IX) and the reaction mixture was stirred for 4 h at 28-32° C. The


material was filtered & washed with chilled methanol. It was subsequently filtered to dryness. The wet material was refluxed in 300 ml of methanol for 30 min and then filtered through a hyflow bed. The methanol was distilled out completely and to the residue, 100 ml of isopropyl alcohol was added and further stirred for 30 min at 60-65°C. Cooled to 25 -30°C. The material was again stirred at 28-32° C for 3 hrs. The material was filtered, washed with 20.0 ml of isopropyl alcohol and dried at 60-65°C for 8 hrs to obtain 10.5 g of nebivolol hydrochloride (I), m.p. range : 223-227 °C Yield (%): 96.33 % HPLC Purity: 99.89 % Example - 8
Preparation of nebivolol HCI (I) using isopropyl alcohol as reaction solvent and purification of nebivolol HCI (I)
70 ml of isopropyl alcohol and 3.5 g of hydrochloric acid were added to 10 g of nebivolol base (IX) and the reaction mixture was stirred for 4 h at 28-32 °C. The material was filtered, washed with 10.0 ml of isopropyl alcohol and filtered to dryness. The wet material was refluxed in 300 ml of methanol for 30 min and then filtered through a hyflow bed. The methanol was distilled out completely and to the residue, 100 ml of isopropyl alcohol was added and stirred for further 30 min at 60-65°C. Cooled to 28-32 °C. Stirred the material at 28-32°C for 3 hrs, filtered & washed with 20.0 ml of isopropyl alcohol and dried at 60-65°C for 8 hrs to obtain 10.6 g of nebivolol hydrochloride (I), m.p. range : 223-227 °C Yield (%): 97.24 % HPLC Purity : 99.16 % Example - 9
Preparation of nebivolol HCI (I) from nebivolol base (IX) using ethanol as reaction solvent and purification of nebivolol HCI (I)
70 ml of ethanol and 3.5 g of hydrochloric acid were added to 10 g of nebivolol base (IX) and the reaction mixture was stirred for 4 h at 28-32 °C. The material was filtered, washed with 10.0 ml of ethanol and filtered to dryness. The

wet material was refluxed in 300 ml of methanol for 30 min and then filtered
through a hyflow bed. The methanol was distilled out completely and to the
residue, 100 ml of isopropyl alcohol was added and stirred for further 30 min at
60-65°C. Cooled to 28 -32 °C, stirred the material at 28 -32 °C for 3 hrs, filtered
& washed with 20.0 ml of isopropyl alcohol and finally dried at 60-65°C to obtain
10.5 g of nebivolol hydrochloride (I). Further, the material is sieved through mesh
# 100.
m.p. range : 223 - 227°C
Yield (%) : 96.33%
HPLC Purity : 99.45 %
Example-10
Preparation of nebivolol hydrochloride (I) from benzylated nebivolol base
(VIII)
Benzylated nebivolol base (40.0 g) along with 2-methoxy ethanol (300 ml) and 10 % Palladium on Carbon (6.0 g) were added to the hydrogenator. 160-170 psi pressure was applied with hydrogen gas and heated to 70-75°C. The temperature & pressure conditions were maintained for 3.0 h and the completion of the reaction checked by TLC/HPLC. The reaction mixture was cooled to room temperature and filtered through hyflow bed to separate the catalyst. The filtrate was heated to 65-70°C with subsequent addition of 14.0 ml of hydrochloric Acid (35 %). The reaction mass was stirred for 2.0 h. The material was filtered followed by addition of methanol (800.0 ml) and heated to 60-65°C to get a clear solution. Filtered over a hyflow bed. The filtrate was distilled under vacuum till the volume remains 20 %. The reaction mass was then cooled to 0-5°C and stirred at the same temperature for 2.0 h. The material was filtered and dried at 55-60°C to obtain 28.0 g of the title compound. HPLC Purity: 99.99 % Example-11 Preparation of Form T1
To 2100 ml of methanol was added 60.0 g of nebivolol hydrochloride at room temperature. The reaction mass was heated to 50-60°C to obtain a clear


solution. The clear solution was spray-dried for a period of 3.5 hours with a feeding rate of 10-12 ml/min, an inlet feeding temperature of 65-110°C and outlet temperature of 65-75 °C. The product was further dried at 60-65°C for a period of 10.0 h to obtain 38.0 g of Form T1. Example-12 Preparation of Form T1
To 2100 ml of methanol was added 60.0 g of nebivolol base at room temperature. The pH of reaction mass was adjusted below 2.0 by addition of concentrated HCI (16.20gm) and stir till clear solution was obtained. Then, the clear solution was spray-dried for a period of 3.5 hours with a feeding rate of 10-12 ml/min, an inlet feeding temperature of 65-110°C and outlet temperature of 65-75 °C. The product was further dried at 60-65°C for a period of 10.0 h to obtain 38.0 g of Form T1.
X-ray Powder Diffraction Data: provided in Table 1 PREPARATION OF SOLID DOSAGE FORM
The ingredients used in the preparation of solid dosage form containing nebivolol hydrochloride in the present invention are given below along with the method of preparation. In all the subsequent examples, the dissolution of the prepared tablets was determined in a paddle apparatus. The rotation speed was set at 50 ± 2 revolutions per minute, the dissolution medium being 0.1 N HCI maintained at a fixed temperature of 37°C (pH 1.2 simulated gastric fluid). The total volume of the dissolution fluid was 500 ml.
Example-13 Preparation of tablet
The resultant material i.e., nebivolol hydrochloride of example 8 is used for the preparation of solid dosage form in the following examples.
Composition of tablet


Procedure:
Nebivolol hydrochloride 5.45 mg (2.72 % w/w) was sieved through mesh # 60, and lactose 125.05 mg (62.53 % w/w) croscarmellose sodium 5.00 mg (2.5 % w/w) and starch 30.00 mg (15.00 % w/w) were all passed through mesh # 60. The sifted materials were blended together. 3 mg (1.50 % w/w) of hydroxylpropyl methyl cellulose (6 cps) was dissolved in 30 ml of purified water (pre-heated to 70°C), and was used as the granulating solution to prepare granules of the above blend till the mass of required consistency was obtained. It required 25 ml of extra purified water. The wet mass was passed through mesh # 08 and the wet granules dried in a tray dryer at 70°C till the loss on drying was 1.28 %. The dried granules were passed through mesh # 20 and blended with a compression mixture comprising of 23.0 mg (11.50 % w/w) of microcrystalline cellulose (Avicel PH 102), 0.5 mg (0.25 % w/w) of colloidal silicon dioxide, 7.0 mg (3.50 % w/w) of croscarmellose sodium and 1.0 mg (0.50 % w/w)of magnesium stearate, previously sieved through mesh # 60. The final

blend thus obtained was compressed into 200 mg tablets on a tablet compression machine using 7.93 mm (10/32 inch) round flat bevel edged punches.
Dissolution Profile of nebivolol hydrochloride of the present invention at pH 1.2 (simulated gastric fluid)
The dissolution of tablets prepared according to the Example - 13 is presented in Table 4.

The reference, i.e., Nebilet is the nebivolol hydrochloride tablet from the innovator, Janssen Pharmaceutics. The dissolution rate of the tablets prepared in the present invention was found to be more than 75% in 45 minutes. Thus, the dissolution of the tablets prepared according to the present invention is acceptable.
Example -14 Preparation of tablet
The resultant material i.e., nebivolol hydrochloride of example 8 is used for the preparation of solid dosage form in the following examples. Composition of tablet



* 8 % (2.4 mg / tablet) extra starch added to compensate moisture loss on drying.
Procedure
Nebivolol hydrochloride 5.45 mg (2.72 % w/w) was sieve through mesh # 60, and lactose 125.05 mg (62.53 % w/w), croscarmellose sodium 5.00 mg (2.5 % w/w) and starch 30.00 mg (15.00 % w/w) were all passed through mesh # 60. The sifted materials were blended together. 3 mg (1.50 % w/w) of polyvinyl pyrrolidone K-30 were dissolved in 30 ml of purified water pre-heated to 70°C, and was used as the granulating solution to prepare granules of the above blend till the mass of required consistency was obtained. It required 25 ml of extra purified water. The wet mass was passed through mesh # 08 and the wet granules dried in a tray dryer at 70°C till the loss on drying was 1.258 %. The dried granules were passed through mesh # 20 and blended with a compression mixture comprising of 23.0 mg (11.50 % w/w) of microcrystalline cellulose (Avicel PH 102), 0.5 mg (0.25 % w/w) of colloidal silicon dioxide, 7.0 mg (3.5 % w/w) of croscarmellose sodium and 1.0 mg (0.50 % w/w) of magnesium stearate, previously sieved through mesh # 60. The final blend thus obtained was compressed into 200 mg tablets on a tablet compression machine using 7.93 mm (10/32 inch) round flat bevel edged punches.

Dissolution Profile of nebivolol hydrochloride of the present invention at pH 1.2 (simulated gastric fluid)
The dissolution of tablets prepared according to the Example - 14 is presented in Table 6.

The reference, i.e., Nebilet is the nebivolol hydrochloride tablet from the innovator, Janssen Pharmaceutica. The dissolution rate of the tablets prepared in the present invention were found to be more than 75 % in 45 minutes. Thus, the dissolution of the tablets prepared according to the present invention is acceptable.
Example -15 Preparation of tablet
The resultant material i.e., nebivolol hydrochloride of example 7 is used for the preparation of solid dosage form in the following examples.

Preparation of tablets by wet granulation method (drug being adsorbed onto the excipients).
The ingredients used in the preparation of tablets containing nebivolol hydrochloride in the present invention by adsorption of drug onto the excipients and subsequent wet granulation method are given below along with the method of preparation of said tablets. Step A: Formula for drug adsorption on to the excipients

Table 7
Procedure
Nebivolol hydrochloride 5.45 mg (2.86 % w/w) (2 % extra to compensate for loss) was added to a solution of methanol 2780 ml with stirring (1% w/v drug solution in methanol) passed lactose 144.62 mg (75.99 % w/w), croscarmellose sodium 28.75 mg (3.02 % w/w) and starch 34.5 mg (18.13 % w/w) through mesh # 60. The sifted materials were blended together. This combined blend was added to the fluidization pan and the drug solution was adsorbed on it by using Fluid bed processor (top spray process). Step B: Preparation of tablets by wet granulation method
The ingredients used in the preparation of tablets containing nebivolol hydrochloride in the present invention by wet granulation method are given below along with the method of preparation of said tablets.


Procedure
3.45 mg (1.50 % w/w) of hydroxypropyl methyl cellulose (6 cps) were dissolved in 35 ml of purified water pre-heated to 70°C and then after cooled, and is used as the granulating solution to prepare granules by mixing with nebivolol hydrochloride adsorbed blend till the mass of required consistency was obtained. It required 25 ml of extra purified water. The wet mass was dried in a tray dryer at 70°C till the loss on drying was 1.48 %. The dried granules were sieved through mesh # 20 and blended with a lubricants comprising of 26.45 mg (11.50 % w/w) of microcrystalline cellulose (Avicel PH 102), 0.575 mg (0.25 % w/w)of colloidal silicon dioxide, 8.05 mg (3.50 % w/w) of croscarmellose sodium and 1.15 mg (0.50 % w/w) of magnesium stearate, previously sieved through mesh # 60. The final blend thus obtained was compressed into 230 mg average weight tablets on a tablet compression machine using 8.73 mm (11/32 inch) round flat-faced beveled edged punches.
Dissolution Profile of nebivolol hydrochloride of the present invention at pH 1.2 (simulated gastric fluid)
The dissolution of tablets prepared according to the Example -15is presented in Table 9.


Example-16 Preparation of tablet
The resultant material i.e., nebivolol hydrochloride of example 8 is used for the preparation of solid dosage form in the following examples.


Procedure:
Nebivolol hydrochloride 5.45 mg (2.72 % w/w) was sieve through mesh # 60, and lactose 158.05 mg (79.03 % w/w) and croscarmellose sodium 5.00 mg (2.5 % w/w) were all passed through mesh # 60. The sifted materials were blended together. 35 ml of purified water was used as the granulating solution to prepare granules of the above blend till the mass of required consistency was obtained. The wet mass was passed through mesh # 08 and the wet granules dried in a tray dryer at 70°C till the loss on drying was 0.65 %. The dried granules were passed through mesh # 20 and blended with a compression mixture comprising of 23.0 mg (11.50 % w/w) of microcrystalline cellulose, 0.5 mg (0.25 % w/w) of colloidal silicon dioxide, 7.0 mg (3.5 % w/w) of croscarmellose sodium and 1.0 mg (0.50 % w/w) of magnesium stearate, previously sieved through mesh # 60. The final blend thus obtained was compressed into 200 mg tablets on a tablet compression machine using 7.93 mm (10/32 inch) round flat bevel edged punches.
Dissolution Profile of nebivolol hydrochloride of the present invention at pH 1.2 (simulated gastric fluid)
The dissolution of tablets prepared according to the Example - 16 is presented in Table 11.


The reference, i.e., Nebilet® is the nebivolol hydrochloride tablet from the innovator, Janssen Pharmaceutica. The dissolution rate of the tablets prepared in the present invention was found to be more than 75 % in 45 minutes. Thus, the dissolution of the tablets prepared according to the present invention is acceptable. Example-17 Preparation of tablet
The resultant material i.e., nebivolol hydrochloride of example 7 is used for the preparation of solid dosage form in the following examples. Composition of tablet

Procedure
Nebivolol hydrochloride 5.45 mg (2.41 % w/w) was added to methanol with stirring (1 % w/v drug solution in methanol). Passed lactose 179.125 mg (79.07 % w/w) through mesh # 60. This blend was added to the fluidization pan and the drug solution was adsorbed on it by using fluid bed process (top spray process). Preparation of tablets by wet granulation method
The ingredients used in the preparation of tablets containing nebivolol hydrochloride in the present invention by wet granulation method are given below along with the method of preparation of said tablets.

Procedure
Purified water was used as the granulating solution to prepare granules by mixing with nebivolol hydrochloride adsorbed blend till the mass of required consistency was obtained. The wet mass was dried in a tray dryer at 70°C till the loss on drying was 0.71 %. The dried granules were sieved through mesh # 20 and blended with a lubricants comprising of 26.45 mg (11.67 % w/w) of microcrystalline cellulose, 0.575 mg (0.25 % w/w) of colloidal silicon dioxide, 13.8 mg (6.09 % w/w) of croscarmellose sodium and 1.15 mg (0.51 % w/w) of' magnesium stearate, previously sieved through mesh # 60. The final blend thus obtained was compressed into 226.55 mg average weight tablets on a tablet compression machine using 8.73 mm (11/32 inch) round flat faced beveled edged punches.
Dissolution Profile of nebivolol hydrochloride of the present invention at pH 1.2 (simulated gastric fluid)
The dissolution of tablets prepared according to the Example - 17 is presented in Table-13.


Table-13
Example 18 Preparation of tablet
The resultant material i.e., nebivolol hydrochloride of example 8 is used for the preparation of solid dosage form in the following examples. Composition of tablet
Table 14

Procedure:
Nebivolol hydrochloride 5.45 mg (2.73 % w/w) and lactose 170.05 mg (85.03 % w/w) were all passed through mesh # 60. The sifted materials were blended together. 35 ml of purified water was used as the granulating solution to prepare

granules of the above blend till the mass of required consistency was obtained. The wet mass was passed through mesh # 08 and the wet granules dried in a tray dryer at 70°C till the loss on drying was 0.39%. The dried granules were passed through mesh # 20 and blended with a compression mixture comprising of 23.0 mg (11.5 % w/w) of microcrystalline cellulose, 0.5 mg (0.25 % w/w) of colloidal silicon dioxide and 1.0 mg (0.50 % w/w) of magnesium stearate, previously sieved through mesh # 60. The final blend thus obtained was compressed into 200 mg tablets on a tablet compression machine using 7.93 mm (10/32 inch) round flat bevel edged punches. Dissolution Profile of nebivolol hydrochloride of the present invention at pH 1.2 (simulated gastric fluid)
The dissolution of tablets prepared according to the Example - 18 is presented in Table 15.
Table -15

The reference, i.e., Nebilet® is the nebivolol hydrochloride tablet from the innovator, Janssen Pharmaceutics. The dissolution rate of the tablets prepared in the present invention was found to be more than 75 % in 45 minutes. Thus, the dissolution of the tablets prepared according to the present invention is acceptable.


Example-19 Preparation of tablet
The resultant material i.e., nebivolol hydrochloride of example 8 is used for the preparation of solid dosage form in the following examples.
Composition of tablet
Table 16

Procedure
Nebivolol hydrochloride 5.45 mg (2.56 % w/w) was added to methanol with stirring (1 % w/v drug solution in methanol). 179.125 mg of lactose (84.20 % w/w) was passed through mesh # 60. This blend was added to the fluidization pan and the drug solution was adsorbed on it by using fluid bed processor (top spray process). Preparation of tablets by wet granulation method
The ingredients used in the preparation of tablets containing nebivolol hydrochloride in the present invention by wet granulation method are given below along with the method of preparation of said tablets. Procedure
50 ml of purified water is used as the granulating solution to prepare granules by mixing with nebivolol hydrochloride adsorbed blend till the mass of required consistency was obtained. The wet mass was dried in a tray dryer at 70°C till the loss on drying was 1.12 %. The dried granules were sieved through mesh # 20 and blended with a lubricants comprising of 26.45 mg (12.43 % w/w)

of microcrystalline cellulose, 0.575 mg (0.27 % w/w) of colloidal silicon dioxide and 1.15 mg (0.54 % w/w) of magnesium stearate previously sieved through mesh # 60. The final blend thus obtained was compressed into 212.75 mg average weight tablets on a tablet compression machine using 8.73 mm (11/32 inch) round flat faced beveled edged punches.
Dissolution Profile of nebivolol hydrochloride of the present invention at pH 1.2 (simulated gastric fluid)
The dissolution of tablets prepared according to the Example - 1.9 is presented in Table 17.
Table -17

The reference, i.e., Nebilet® is the nebivolol hydrochloride tablet from the innovator, Janssen Pharmaceutica. The dissolution rate of the tablets prepared in the present invention was found to be more than 75 % in 45 minutes. Thus, the dissolution of the tablets prepared according to the present invention is acceptable. Example-20 Preparation of tablet
The resultant material i.e., nebivolol hydrochloride of example 10 is used for the preparation of solid dosage form in the following examples.



Procedure:
A solution of 5.45 mg (2.37 % w/w) of nebivolol hydrochloride and 3.45 mg (1.5 % w/w) of hypromellose was prepared in 440 mg of methanol and 10 mg of water. Lactose 143.475 mg (62.38 % w/w), maize starch 34.50 mg (15 % w/w) (8% extra added to compensate the loss) and croscarmellose sodium 3.45 mg (3 % w/w) were sifted through mesh # 40. The sifted materials were loaded to product container of Fluid Bed Processor (FBP). The solution of nebivolol hydrochloride - hypromellose was adsorbed onto the blend fluidized in the container of the fluid Bed Processor by top spay process. The blend was dried after completion of adsorption of Drug-binder solution. The blend was then granulated with 28 mg water. The wet granules were dried in the Fluid Bed Processor at 60° C. The dried granules were sieved through mesh # 30 and blended with microcrystalline cellulose 26.45 mg (11.5 % w/w), croscarmellose Sodium 3.45 mg (3 % w/w), colloidal silicon dioxide 0.575 mg (0.25 % w/w) pre-sifted through mesh # 40 and pre-sifted magnesium stearate 2.30 mg (1% w/w). The final blend thus obtained was compressed into 230 mg average weight

tablets on a tablet compression machine using 9.0 mm round concave beveled edged punches having scored on one side.
Dissolution Profile of nebivolol hydrochloride of the present invention at pH 1.2 (simulated gastric fluid)
The dissolution of tablets prepared according to the Example - 20 is presented in Table 19.
Table 19

Example-21
Comparative bioavailability data of nebivolol tablet of instant invention
(test formulation) v/s nebilet tablet (reference formulation)
Pharmacokinetics
In a bioequivalence study, 24 healthy human volunteers were enrolled and randomised to receive the test (nebivolol 5mg of Torrent Pharmaceuticals Ltd., India) or reference (Nebilet® 5mg of Berlin-Chemie AG, Germany) formulations. The plasma levels of nebivolol were measured by using a validated LCMS/MS method.
The mean plasma concentrations of nebivolol after an oral dose of 1 tablet (5 mg nebivolol) of the test formulation or 1 tablet (5 mg nebivolol) of the reference formulation are plotted in figure-VI.


The pharmacokinetic parameters were evaluated. For nebivolol test & reference formulations the mean Cmax achieved was 2.605 ± 0.66 ng/ml and 2.574 ± 0.78 ng/ml respectively. There was no major difference in the mean W for both test and reference formulations. The observed mean AUC(0-t) for test and reference formulations was 17.33 ± 29.54 ng.h/ml and 17.71 ± 30.77 ng.h/ml respectively. The observed mean AUC(o-oo) for test and reference formulations was 29.69 + 62.72 ng.h/ml and 21.86 + 41.96 ng.h/ml respectively.
The 90%-confidence interval calculated by means of ANOVA-log for the primary parameter, intra-individual ratio (T/R) of AUC(0-t), AUC(o-») and Cmax of nebivolol was 0.93 - 1.04, 0.95 - 1.17 and 0.95 - 1.10. Safety
The drug was well tolerated. No adverse events were reported in any volunteer in the trial. The laboratory results gave no indications for adverse events or adverse drug reactions. CONCLUSION
The above-mentioned pharmacokinetic parameters for nebivolol of the test (nebivolol 5mg of Torrent Pharmaceuticals Ltd., India) and reference (Nebilet® 5mg of Berlin-Chemie AG, Germany) formulation were bioequivalent with respect to nebivolol as shown in Table 20.


WE CLAIM:
1. An improved process for the preparation of 2H-1-benzopyran-2-methanol, a, a' [iminobis(methylene)]bis[6-fluoro-3,4-dihydro-, [2R*[R*[R*(S*)]]]] i.e. nebivolol base of formula (IX) or its hydrochloride salt,

comprising the steps of:
(a) reacting (A)-6-Fluorodihydro-a-[[(phenylmethyl)amino]-methyl]-2H-1 -
benzopyran-2-methanol i.e., Intermediate-I

with (B)-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran of formula (Vll-B)

in presence of a suitable organic solvent such as defined herein, and isolated at a temperature of -5 to -25°C, and further maintaining the reaction mass at the temperature of isolation for a period of 2 to 40 hours to give benzylated nebivolol of formula (VIII),


(vni)
(b) debenzylating benzylated nebivolol of formula (VIII) obtained in step (a) above to nebivolol base of formula (IX) using 10 % palladium on carbon by a known process,

(c) converting nebivolol base of formula (IX) obtained in step (b) above to obtain nebivolol hydrochloride of formula (I) using a suitable organic solvent, such as defined herein, and hydrochloric acid,

(d) isolating the reaction product of step (c) above.
2. An improved process for the preparation of 2H-1-benzopyran-2-methanol,
a, a' [iminobis(methylene)]bis[6-fluoro-3,4-dihydro-,[2R*[R*[R*(S*)]]]] i.e.
nebivolol base of formula (IX) or its hydrochloride salt,



with (B)-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran of formula (Vll-B)
comprising reacting (A)-6-Fluorodihydro-a-[[(phenylmethyl)amino]-methyl]-2H-1-benzopyran-2-methanol i.e., Intermediate-I

in presence of a suitable organic solvent such as defined herein, and isolated at a temperature of -5 to -25°C, and further maintaining the reaction mass at the temperature of isolation for a period of 2 to 40 hours to give benzylated nebivolol of formula (VIII).
3. The process as claimed in claim 1, wherein the organic solvent as used in step (a) is selected from the group comprising of alcohol, ester and ketone.
4. The process as claimed in claim 3, wherein the alcohol is selected from the group comprising of methanol, ethanol, isopropyl alcohol, n-propyl alcohol, n-butanol, isobutanol.

5. The process as claimed in claim 3, wherein the alcohol is methanol.
6. The process as claimed in claim 3, wherein the ester is selected from the group comprising of ethyl acetate, n-butyl acetate.
7. The process as claimed in claim 3, wherein the ketone is selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone (MIBK).
8. The process as claimed in claim 1, wherein the isolation in step (a) is carried out at a temperature of -10° to - 15°C.
9. The process as claimed in claim 1, wherein the reaction mass in step (a) is maintained at the temperature of isolation for a period of 10 -15 hours.
10. The process as claimed in claim 1, wherein the organic solvent used in step (c) is selected from the group comprising of alcohol, ester, ketone, halogenated solvent, acetonitrile and water or mixtures thereof.
11. The process as claimed in claim 10, wherein the alcohol is selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like.
12. The process as claimed in claim 10, wherein the alcohol is methanol.
13. The process as claimed in claim 10, wherein the alcohol is isopropyl alcohol.
14. The process as claimed in claim 10, wherein the alcohol is ethanol.

22. The pharmaceutical composition as claimed in claim 19, wherein the nebivolol hydrochloride is in the range of 0.5% to 10% w/w; diluent is in the range
15. The process as claimed in claim 1, wherein the nebivolol hydrochloride obtained in step (c) is a diastereoisomerically pure mixture of RSSS and SRRR isomers.
16. The process as claimed in claim 15, wherein the purity of the diastereoisomerically pure mixture is more than 99.0 %.
17. The process as claimed in claim 15, wherein the purity of the diastereoisomerically pure mixture is more than 99.5 %.
18. The process as claimed in claim 15, wherein the purity of the diastereoisomerically pure mixture is more than 99.8 %.
19. A pharmaceutical composition comprising nebivolol hydrochloride and a pharmaceutically acceptable carrier, characterized in that said pharmaceutical composition does not contain any wetting agent, and optionally contains a binder and / or a disintegrant.
20. The pharmaceutical composition as claimed in claim 19, wherein said pharmaceutical composition is a tablet or a capsule.
21. The tablet as claimed in claim 20, substantially having the following composition:


of 78 % to 93.05% w/w; lubricant is in the range of 0.25 % to 3% w/w; and glident is in the range of 0.25 % to 3% w/w; optionally binder is in the range of 0.5% to 5 % w/w; and/or disintegrant is in the range of 0.5 % to 10 % w/w.
23. The tablet as claimed in claim 20, characterized in that it has dissolution of more than 75 % in 45 minutes.
24. A process for preparing nebivolol hydrochloride Form T1 comprising the steps of: (a) dissolving nebivolol hydrochloride in an alcohol to form a clear solution;

(b) spray or freeze drying the solution to form nebivolol hydrochloride Form T1; and
(c) isolating nebivolol hydrochloride Form T1.
25. A process for making nebivolol hydrochloride Form T1 comprising the
steps of:
(a) dissolving or suspending nebivolol base in an alcohol;
(b) adding hydrochloric acid or hydrogen chloride to reduce the pH of the solution or suspension below 2.0
(c) spray drying/freeze drying the solution/suspension to form nebivolol
hydrochloride Form T1; and
(d) isolating nebivolol hydrochloride Form T1.
26. An improved process for the preparation of 2H-1-benzopyran-2-methanol,
a, a' [iminobis(methylene)]bis[6-fluoro-3,4-dihydro-,[2R*[R*[R*(S*)]]]] i.e.
nebivolol base of formula (IX) or its hydrochloride salt,


substantially as herein described, particularly with reference to the foregoing examples.
27. A pharmaceutical composition comprising nebivolol hydrochloride and a pharmaceutically acceptable carrier without the use of wetting agent, substantially as herein described, particularly with reference to the foregoing examples.
Dated this 28th day of July 2005.
Abhishek Sen Of S. MAJUMDAR&CO. Applicants Agent

Documents:

811-mum-2004-abstract(29-10-2007).pdf

811-mum-2004-abstract(complete)-(2-8-2005).pdf

811-mum-2004-abstract(granted)-(16-4-2008).pdf

811-mum-2004-annexure to form 3(12-9-2005).pdf

811-mum-2004-annexure to form 3(17-1-2007).pdf

811-mum-2004-cancelled pages (29-10-2007).pdf

811-mum-2004-cancelled pages(29-10-2007).pdf

811-mum-2004-claims(amanded)-(29-10-2007).pdf

811-mum-2004-claims(complete)-(2-8-2005).pdf

811-mum-2004-claims(granted)-(16-4-2008).pdf

811-mum-2004-claims(granted)-(29-10-2007).pdf

811-mum-2004-correspondence (29-10-2007).pdf

811-mum-2004-correspondence(ipo)-(19-12-2006).pdf

811-mum-2004-correspondence(ipo)-(23-5-2008).pdf

811-mum-2004-description(complete)-(2-8-2005).pdf

811-mum-2004-description(granted)-(16-4-2008).pdf

811-mum-2004-description(provisional)-(30-7-2004).pdf

811-mum-2004-drawing(02-08-2005).pdf

811-mum-2004-drawing(complete)-(2-8-2005).pdf

811-mum-2004-drawing(granted)-(16-4-2008).pdf

811-mum-2004-form 1(11-10-2004).pdf

811-mum-2004-form 1(30-7-2004).pdf

811-mum-2004-form 18(02--02-2006).pdf

811-mum-2004-form 2(complete)-(2-8-2005).pdf

811-mum-2004-form 2(granted)-(16-4-2008).pdf

811-mum-2004-form 2(granted)-(29-10-2007).pdf

811-mum-2004-form 2(provisional)-(30-7-2004).pdf

811-mum-2004-form 2(title page)-(complete)-(2-8-2005).pdf

811-mum-2004-form 2(title page)-(granted)-(16-4-2008).pdf

811-mum-2004-form 2(title page)-(provisional)-(30-7-2004).pdf

811-mum-2004-form 3(30--07-2004).pdf

811-mum-2004-form 5(02--08-2005).pdf

811-mum-2004-form 5(2-8-2005).pdf

811-mum-2004-form-pct-isa-210(07-30-2004).pdf

811-mum-2004-power of attorney (17-01-2007).pdf

811-mum-2004-power of attorney(11-10-2004).pdf

abstract1.jpg


Patent Number 219014
Indian Patent Application Number 811/MUM/2004
PG Journal Number 42/2008
Publication Date 17-Oct-2008
Grant Date 16-Apr-2008
Date of Filing 30-Jul-2004
Name of Patentee TORRENT PHARMACEUTICALS LIMITED
Applicant Address TORRENT RESEARCH CENTER, P.O. BHAT 382 428, DIST GANDHINAGAR, STATE OF GUJARAT, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 SHETH RAKESH TORRENT PHARMACEUTICALS LIMITED, TORRENT RESEARCH CENTER, P.O. BHAT, 382 428 DIST GANDHINAGAR, GUJARAT
2 ATTANTI SRINIVASARAO VEERAVENKATA TORRENT PHARMACEUTICALS LIMITED, Torrent Research Center, P.O.Bhat-382 428,Dist.Gandhinagar
3 PATEL HASMUKH MATHURBHAI TORRENT PHARMACEUTICALS LIMITED Torrent Research Center, P.O.Bhat-382 428,Dist.Gandhinagar
4 GUPTA VINODKUMAR TORRENT PHARMACEUTICALS LIMITED, Torrent Research Center, P.O.Bhat-382 428,Dist.Gandhinagar
5 NADKARNI SUNIL SADANAND TORRENT PHARMACEUTICALS LIMITED, Torrent Research Center, P.O.Bhat-382 428,Dist.Gandhinagar
PCT International Classification Number C07D407/12 A61K31/35 A61P9/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA