INTRODUCTION TO THE INVENTION
The present invention relates to novel polymorphs of Nr (4-amino-6, 7-
dimethoxyquinazol-2-yl)-Ni-methyl-N2- (tetrahydrofuroyl)-2-propylenediamine
hydrochloride, or (R, S)-N- [3-[(4-amino-6, 7-dimethoxy-2-quinazolinyl) methylamino] propyl] tetrahydro-2-furancarboxamide hydrochloride, which is known under the generic name alfuzosin hydrochloride and has Formula I, and processes for the preparation thereof.
Alfuzosin hydrochloride is sold in the form of extended release tablets using the trademark UROXATRAL, for treating benign prostatic hyperplasia.
U. S. Patent No. 4,315,007 discloses alfuzosin hydrochloride, a pharmaceutical composition and their use in treating cardio vascular disorders. It also discloses the process for the preparation of anhydrous alfuzosin hydrochloride (hereinafter referred as Form I for understanding)
U. S. Patent No. 5,545,738 discloses alfuzosin hydrochloride anhydrous, the dihydrate, the trihydrate, and the tetrahydrate.
It is known that different polymorphic forms of a same drug may have substantial differences in certain pharmaceutical^ important properties. The amorphous form of a drug may exhibit different dissolution characteristics and in some case different bioavailability profiles, compared to crystalline forms. For some therapeutic indications one bioavailability profile may be favored over the other. For example, the amorphous form of cefuroxin axetil exhibits a higher bioavailability than its crystalline form. Further, amorphous and crystalline forms of a drug may have

different handling properties, dissolution rates, solubility and stability. For the reasons mentioned heretofore, among others, access to a choice between the amorphous or crystalline forms of drug is desirable for different applications.
Therefore, there is a need for new solid forms of alfuzosin hydrochloride and process for preparation thereof,
SUMMARY OF THE INVENTION
It has now surprisingly been found that the substance alfuzosin hydrochloride can exist in different crystalline forms and amorphous form. The novel crystalline polymorphic forms of alfuzosin hydrochloride described herein are designated as Form II, Form III and Form IV. They are characterized by their X-ray diffraction (XRD) pattern.
In accordance with one aspect, the present invention provides new crystalline Forms II, III, and IV of alfuzosin hydrochloride. The crystalline Form II of alfuzosin hydrochloride has an X-ray diffraction pattern that contains peaks at about 8.1± 0.1, 14.4 ± 0.1, and 17.9 ± 0.1 degrees 20. The crystalline Form-Ill of alfuzosin hydrochloride has an X-ray diffraction pattern that contains peaks at about 6.85 ± 0.1 and 10.5 ± 0.1 degrees 26 and the crystalline Form IV of alfuzosin hydrochloride has an X-ray diffraction pattern that contains peaks at about 10.0 ± 0.1,18.3 ± 0.1 and 20.1 ± 0.1 degrees 26. The XRD patterns are obtained using Cu Kai radiation (1.541
A).
In accordance with another aspect the present invention also provides an amorphous form of alfuzosin hydrochloride.
In accordance with one more aspect, the invention provides a process for preparing the new crystalline forms II, III and IV and amorphous form of alfuzosin hydrochloride.
A process for the preparation of novel crystalline forms II, III and IV of alfuzosin hydrochloride comprises the steps of;
a) reacting alfuzosin free base with hydrochloric acid in a suitable solvent,

b) optionally adding another solvent
c) isolation of the solid
d) drying the solid to get the required form.
In accordance with one more aspect, the invention provides a process for preparing the amorphous form. The process for the preparation of amorphous form comprises the steps of;
a) reacting alfuzosin freebase with hydrochloric acid in a suitable solvent,
b) adding another solvent
c) isolation of the solid
d) drying the wet solid till melt, followed by cooling to regenerate the amorphous form.
In accordance with yet another aspect, the invention provides pharmaceutical compositions containing one or more pharmaceutically acceptable excipients and a prophylactically or therapeutically effective amount of individually or as mixtures in any proportions of the crystalline Forms II, III, and IV, and amorphous form of Alfuzosin hydrochloride.
Also the invention provides a method of treating or preventing a patient suffering from cardiovascular disorders by administering the patient a prophylactically or therapeutically effective amount of individually or as mixtures in any proportions of the crystalline forms II, III and IV and amorphous form of Alfuzosin hydrochloride.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows an X-ray diffraction pattern of the crystalline Form II of Alfuzosin hydrochloride.
Figure 2 shows an X-ray diffraction pattern of Alfuzosin hydrochloride comprising the crystalline Form III.
Figure 3 shows an X-ray diffraction pattern of the crystalline Form IV of Alfuzosin hydrochloride.
Figure 4 shows an X-ray diffraction pattern of the anhydrous alfuzosin hydrochloride Form I prepared by the process of Example 7.

Figure 5 shows an X-ray diffraction pattern of the amorphous form of Alfuzosin hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
According to one aspect, the present invention provides three novel crystalline forms of Alfuzosin hydrochloride. The three crystalline forms obtained by the inventors are designated as Form II, III and IV respectively.
According to one more aspect, the present invention provides a process for preparing the new crystalline forms II, III and IV. A process for the preparation of Forms 11,111 and IV comprising the steps of;
a) reacting alfuzosin freebase with hydrochloric acid in a suitable solvent,
b) optionally adding an anti solvent
c) isolation of the solid
d) drying the solid to get the required form.
For the preparation of form II, the suitable solvents of step a) include CrC4 straight chain alcohols such as methanol, ethanol, and the like or mixtures thereof. Optionally the solution can be seeded with 0.5 to 1.0 % w/w of crystals of anhydrous alfuzosin hydrochloride form II.
The anti solvent that is optionally used in step b) includes but is not limited to any solvent or mixture of solvents. Examples include C3-C6 branched alcohols such as 2-propanol, 2-butanol and the like or mixtures thereof.
For the preparation of form III, the suitable solvents of step a) include ketones such as acetone, ethyl methyl ketone, methyl Isobutyl ketone and the like or mixtures thereof; chloro hydrocarbons such as dichloromethane, ethylene dichloride, chloroform and the like or mixtures thereof.
For the preparation of form IV, the suitable solvents used in step a) include C6-Ci0 straight chain, branched or cyclic hydrocarbons such as n-hexane, n-heptane,

cyclohexane and the like or mixtures thereof; ether solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran and the like or mixtures thereof.
The suitable reagents for conversion of alfuzosin freebase into hydrochloride in step a) include methanolic hydrochloride, isopropanolic hydrochloride, ethyl acetate hydrochloride, aqueous Hydrochloric acid and the like.
The isolation of solid of step c) can be carried out by using conventional techniques, such as centrifugation, gravity filtration, or vacuum filtration.
The drying operation of step d) is carried out by using any technique, such as fluid bed drying (FBD), spin flash drying, aerial drying, oven drying or other techniques known in the art at temperatures of about 95-105° C with or without application of vacuum and/or under inert conditions. The drying is carried out under vaccum at about 100° C.
In accordance with yet another aspect, the present invention provides a process for conversion of alfuzosin hydrochloride form II to anhydrous alfuzosin hydrochloride form I comprising heating the alfuzosin hydrochloride form II at a suitable temperature.
The heating of alfuzosin hydrochloride form II is carried out by using any technique, such as fluid bed drying (FBD), spin flash drying, aerial drying, oven drying or other techniques known in the art at temperatures of about 145-150° C with or without application of vacuum and/or under inert conditions.
In accordance with one more aspect, the invention provides a process for preparing the amorphous form. The process for the preparation of amorphous form comprises the steps of;
a) reacting alfuzosin freebase with hydrochloric acid in a suitable solvent,
b) adding another solvent
c) isolation of the solid
d) drying the wet solid till melt, followed by cooling to regenerate the amorphous form.
For the preparation of amorphous form, the suitable solvents used in step a) includes but are not limited to any solvent or mixture of solvents, in which the

required compounds are soluble. Examples include C1-C2 straight chain alcohols such as methanol, ethanol, and the like; or their mixtures thereof.
The suitable reagent for conversion of alfuzosin freebase into hydrochloride in step a) can be substances such as methanolic hydrochloride, isopropanolic hydrochloride, ethylacetate hydrochloride, aqueous Hydrochloric acid and the like.
The anti solvent that is used in step b) includes C3-C6 branched alcohols such as 2-propanol, 2-butanol and the like or their mixtures thereof.
The product isolation of step c) is carried out by using conventional techniques, such as centrifugation, gravity filtration, or vacuum filtration.
Wet solid of step d) comprises but is not limited to crystalline Forms II of alfuzosin hydrochloride having moisture content 4 to 5%.
Drying operation of step d) is carried out at a suitable temperature and optionally by applying vacuum till solid melt using any technique, such as oven drying, tray drying, rotational drying (such as the Buchi Rotavap), spray drying, freeze-drying, fluid bed drying, flash drying, spin flash drying and Ultra film agitated thin film dryer-vertical (ATFD-V) and the like. Drying operation of step d) is carried out at suitable temperatures of about 130-135° C using rotavapour and optionally by applying vacuum till solid melt. The melted solid can allow cooling at below 45° C or 20-25° C to afford amorphous form of alfuzosin hydrochloride
The crystalline Forms II, III and IV as well as the amorphous form of alfuzosin hydrochloride may be characterized by X-ray diffraction. X-ray diffraction patterns are unique for different crystalline forms. Each crystalline form may exhibit a diffraction pattern with a unique set of diffraction peaks that can be expressed in 2 theta angles, d-spacing values and relative peak intensities. 2 theta diffraction angles and corresponding d-spacing values account for positions of various peaks in the X-ray powder diffraction pattern. D-spacing values can be calculated with observed 2 theta angles and copper K