FORM-2
THE PATENT ACT, 1970
(39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and Rule 13)
POLYMORPH OF A PHARMACEUTICAL COMPOUND
CIPLA LIMITED
A Indian Company
of 289, Bellasis Road, Mumbai Central, Mumbai-400 008,
Maharashtra India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

Field of invention
The present invention relates to a polymorph of a pharmaceutical compound and a process for making the said compound.
In particular, this invention relates to a polymorph of anhydrous alfuzosin hydrochloride.
Definitions:
As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
"Anhydrous compound " means a compound, which is substantially free of water either adsorbed on its surface or combined as water of crystallization.
"Desiccant" means a porous crystalline substance used to absorb moisture.
"Hygroscopicity" means the relative ability of a substance to absorb, moisture from its surroundings.
"Lower alkanols" means respective alcohols of lower alkanes containing 1 to 4 carbon atoms, such as Methyl alcohol,Ethyl alcohol,Propyl alcohol, Butyl alcohol.

"Molecular sieve" means materials (for example zeolites) having a porous structure that selectively allow some molecules to pass through, but prevent others.
"Normal Storage Conditions" normal storage conditions in the context of this invention and is generally accepted international guideline means at the temperature of 25 ± 2 °C at 60 ± 5% relative humidity.
"Polymorph/Polymorphic compounds" also known as allotropic compounds, are compounds, which exist in two or more forms, which have the same elemental components but exhibit significantly different physical and chemical properties because of differences in their physical structures typically, crystal structures.
"Relative humidity" (R.H.) means the amount of water vapor present in the atmosphere expressed as a percentage of the maximum that could be present at the same temperature.
"Relative intensity" of a peak in an x-ray powder diffractogram means intensity of the peak, expressed as a percentage of the intensity of the highest peak.
"Solvate" means a compound wherein molecules of a suitable solvent are incorporated in the crystal lattice, wherein the suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water etc. When water is the solvent, the molecule is referred to as a "hydrate".

"X-ray powder diffraction (XRD)" is an instrumental technique that is used to identify crystalline materials with different structural variants.
Background Introduction
Alfuzosin hydrochloride (formula I) also chemically termed as N-[3-[(4-amino-6,7-dimethoxy-2-
quinazolinyl)methylamino]propyl]tetrahydrofuran)hydrochloride is known as an antagonist of a 1 adrenergic receptor and it is used as an antihypertensive agent and dysuria curing agent.
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Prior Art:
Anhydrous alfuzosin hydrochloride is described in Japanese examined
patent application publication SHO No. 60-23114.
X-ray diffractogram of anhydrous alfuzosin hydrochloride is disclosed
in figure 1 of US5545738. This form is hereinafter referred as anhydrous
alfuzosin hydrochloride form A.
Anhydrous Alfuzosin hydrochloride is a highly hygroscopic compound.
Different forms of alfuzosin hydrochloride like monohydrate, dihydrate,
trihydrate and tetrahydrate are disclosed in EP 0663398 and US5545738.
These patents provide useful information on the stability of the respective
forms.

Alfuzosin hydrochloride dihydrate is reported to be the most stable form. Under normal storage conditions anhydrous form gets converted to the stable dihydrate form.
"Normal storage conditions" as per ICH guidelines means at the temperature of 25 ± 2 °C with 60 ± 5% relative humidity. In order to carry out investigational studies on long term stability and hygroscopicity all the compounds under study should be subjected to identical conditions in order to arrive at a definite conclusion.
EP0663398 states that anhydrous and dihydrate are extremely stable under the conditions given by the applicant i.e 70 °C. Any anhydrous compound at 70°C will remain anhydrous and trihydrate and tetrahydrate will lose water at this high temperature and get converted to dihydrate or anhydrous after a long time.
The data given in this patent is not relevant with respect to the stability of the anhydrous compound at temperatures found during normal storage conditions. The stability of anhydrous alfusosin hydrochloride Form A as described in EP0663398 was studied under normal storage conditions and the compound was found to be unstable.
There is need for an anhydrous form of alfuzosin hydrochloride, which is stable under normal storage conditions and is suitable for use in formulation. The present invention provides a solution by disclosing a new form of alfuzosin hydrochloride hereinafter referred to as Form C.

/'

It is a universally accepted concept that active ingredients or excipients, on exposure to various temperature and moisture conditions, undergo changes through numerous transitional phases of crystal structure.
Polymorphism is the existence of a substance in two or more forms, significantly different in physical or chemical properties.
Different forms of the same drug exhibit marked differences in key properties, such as bio-availability, solubility, density, shock sensitivity, product stability and shelf-life and such properties affect the efficacy of the drugs.
Anhydrous alfuzosin hydrochloride "Form A" is found to be unstable under normal storage conditions. Furthermore anhydrous alfuzosin hydrochloride form A is not suitable for formulation since it causes hardness and cracking of tablets.
Summary
The present invention is directed to new form of anhydrous alfuzosin hydrochloride. This form is designated as Form C.
It is an object of this invention to provide alfuzosin hydrochloride in a new form which is non hygroscopic and stable.

Another object of the present invention is to provide a process for the preparation of alfuzosin hydrochloride Form C.
Further object the present invention is to provide a process for the conversion of any known form of alfuzosin hydrochloride (monohydrate, dihydrate tetrahydrate or solvate) to alfuzosin hydrochloride Form C.
Still further object of the invention is to provide anhydrous alfuzosin hydrochloride, which can be converted into a dosage form such as a tablet in which the tablet is relatively crack resistant.
Anhydrous Form A and Form C of alfuzosin hydrochloride are studied for long term stability under conditions as per international guidelines and the tests are incorporated in examples.
According to this invention there is provided a polymorph of anhydrous N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl] tetrahydrofuran) hydrochloride Form C (Alfuzosin hydrochloride ) characterized by X-ray powder diffraction pattern having significant reflectionsfpeaks] expressed as 2 [theta] values at least about 6.982°(± 0.2°), 10.601°(± 0.2°), 17.079°(±0.2°), 17.921°(± 0.2°), 20.039°(± 0.2°), 20.659°(± 0.2° ), 20.318°(± 0.2° ), 24.360°(± 0.2° ), 25.400°(± 0.2° ), 29.220°(± 0.2°) is disclosed.
In accordance with a preferred embodiment of the invention the alfuzosin hydrochloride polymorh Form C is further characterized by an

infrared spectrum comprising absorption bands at 3117, 2846, 1345, 1279, 1000, 991, 880, 862, 845 cm-1
According to this invention, there is provided A process for preparation
of alfuzosin hydrochloride Form C as claimed in claims, 1 or 2 which
comprises the following steps:
Step (a) suspending alfuzosin in a first solvent to obtain a first
suspension;
Step (b) optionally treating the first Suspension with a composition of
hydrochloride to obtain a second suspension with pH in the range of 4.0
to 5.0;
Step (c) concentrating the first or optionally the second suspension under
vacuum to obtain a first concentrate;
Step (d) admixing the first concentrate and a second solvent and refluxing
the resulting mixture to obtain a clear solution;
Step (e) drying the clear solution by means of a desiccant and separating
the desiccant, typically by filtration
Step (f) concentrating the filtrate under vacuum to obtain a second
concentrate;
Step (g) adding a ketonic solvent to the second concentrate and
filtering the resulting precipitate; and
Step (h) vacuum drying the precipitate to obtain anhydrous alfluzocin Hydrochloride
FormC.
Typically, the alfuzosin is alfuzocin base, alfuzosin hydrochloride Form A, alfuzosin hydrochloride monohydrate, alfuzosin hydrochloride dihydrate and alfuzosin hydrochloride tetrahydrate.

Typically, the first solvent is at least one lower alkanol solvent.
Typically, the second solvent is at least one lower alkanol solvent.
Optionally, the first suspension is treated with a composition of hydrochloride.
Typically, the composition of hydrochloride is selected from a group of compositions of hydrochlorides, consisting of 20% HC1 in isopropyl alcohol, dry HC1 gas and HC1 in methanol.
Typically, the desiccant is at least one desiccant selected from a group of desiccants consisting of molecular sieves, activated alumina and Silica Gel.
Typically, the first concentrate and said second solvent are refluxed at the reflux temperature of the second solvent.
Typically, the ketonic solvent is at least one ketonic solvent selected from a group of ketonic solvents consisting of Acetone, methyl isobutyl ketone and methyl ethyl ketone .
Also contemplated as falling within the scope of the present invention are pharmaceutical formulations comprising a therapeutically effective amount of anhydrous alfuzosin hydrochloride Form C of this invention in combination with a suitable pharmaceutically acceptable carrier.

Brief description of the accompanying drawings:
The invention will be described in detail with reference to the
accompanying drawings.
In the accompanying drawings:
Figure 1 illustrates the X-Ray powder diffractogram of anhydrous
Hydrochloride Form C.
Figure 2 illustrates IR Spectra for anhydrous alfuzosin hydrochloride Form C, having characteristic absorption at 3117, 2846, 1345, 1279, 1000,991,880,862,845 cm"1.
Figure 3 illustrates X-Ray powder diffractogram of anhydrous Hydrochloride Form A.
Figure 4 illustrates X-Ray powder diffractogram of hydrochloride dihydrate.
Description:
The present invention discloses a new polymorph of anhydrous alfuzosin hydrochloride and provides a new process to prepare the new polymorph, with the following steps: Alfuzosin is suspended in a suitable solvent to obtain a suspension.
The solvent is typically selected from a group of solvents consisting of lower alkanols such as Methyl alcohol, Ethyl alcohol, Propyl alcohol, Butyl alcohol.
Optionally, the suspension is treated with a composition of hydrochloride to obtain a suspension with pH in the range of 4.0 to 5.0.

When the suspension is optionally treated with the composition of hydrochloride, it is typically selected from a group of hydrochloride compositions consisting of 20% HC1 in isopropyl alcohol, dry HC1 gas and HC1 in Methanol.
The suspension optionally treated with the composition of hydrochloride, is concentrated under vacuum to obtain a first concentrate.
The first concentrate is admixed with a second solvent, typically a lower alkanol such as methanol, ethanol, propanol and butyl alcohol and refluxed at the reflux temperature of the solvent used, to obtain a clear solution.
This clear solution is dried using a desiccating agent. Molecular sieves, act as good desiccating agents for this purpose. The desiccating agent is separated from the reaction vessel by filtration to obtain a clear dried solution.
This dried clear solution is again concentrated under vacuum and treated with a ketonic solvent, typically acetone. The contents are filtered to obtain a precipitate.
Optionally other ketones like methyl isobutyl ketone and methyl ethyl ketone can also be used.
The precipitate is vacuum dried to obtain anhydrous alfluzocin hydrochloride Form C in accordance with this invention.

It has also been observed that alfiizosin hydrochloride can form a solvate with lower alkanols such as methanol, ethanol, propanol and butyl alcohol and can be easily converted to the desired anhydrous alfiizosin FormC.
Characterization
Anhydrous alfiizosin hydrochloride Form C thus obtained is distinguished from other polymorphic form by means of X-ray powder diffraction and IR spectral data.
The polymorph of anhydrous Alfiizosin hydrochloride Form C is characterized by X-ray powder diffraction pattern as shown in Figure 1, having significant reflections(peaks) expressed as 2 [theta]values at about 6.982°(± 0.2°), 10.601°(± 0.2°), 17.079°(± 0.2°), 17.921°(± 0.2°), 20.039°(± 0.2° ), 20.659°(± 0.2° ), 20.318°(± 0.2° ), 24.360°(± 0.2° ), 25.400°(± 0.2°), 29.220°(± 0.2°).
The major peaks and their intensities of X-ray powder diffractogram are shown in Table 1. The intensities of the peaks are expressed as percent of most intense reflection.
In Table 1, "Angle 2-Theta" is related to the interplanar spacing of the crystal, and the intensity is given as a percentage of the highest peak. The individual polymorphic forms may be characterised by reference to the peak intensities of greater than 60%, and more preferably by the peaks having intensities greater than 10%.

Table I

Diffraction angles (29°) Relative Intensity
6.982 100
8.021 1.1
8.455 1.2
9.782 10.7
10.339 30.8
10.601 63.8
13.320 31.5
13.697 7.8
14.080 11.6
14.239 11.8
14.459 9.2
15.120 8.5
17.079 13.8
17.921 11.8
18.997 7.3
19.640 21.3
20.039 31.9
20.318 34.4
20.659 42.1
20.900 28.6
21.438 3.2
23.221 12.5
24.360 55.2
24.919 21.2
25.400 32.9
26.280 19.6

27.622 9.1
29.220 50.6
29.747 4.3
30.018 9.1
31.378 7.5
32.220 10.0
32.680 1.7
33.397 8.6
34.921 3.1
35.479 4.6
38.759 1.9
39.386 1.1
Comparison of the data from Figure 1, Figure 2, Figure 3, and Figure 4 with the corresponding data for the anhyhydrous alfuzosin hydrochloride form C, provided in this invention shows clearly that the material of the present invention is a different form of alfuzosin hydrochloride, from the previously known forms mentioned in the prior art. The relative intensities of the various peaks within Table 1 may vary due to a number of factors such as for example orientation effects of crystals in the X-ray beam or the purity of the material being analysed or the degree of crystallinity of the sample. But, the peak positions will remain substantially as defined in Table 1.
Measurements using a different wavelength will result in different shifts
according to the Bragg equation~n.lambda.=2d sin .lambda.
x-ray powder diffractogram patterns of N-[3-[(4-amino-6,7-dimethoxy-
2-quinazolinyl)methylamino]propyl]tetrahydrofuran)hydrochloride(

anhydrous alfuzosin hydrochloride Form C) generated by use of alternative wavelengths are considered to be alternative representations of the x-ray powder diffractogram of material of the present invention and as such are within the scope of the present invention.
Anhydrous alfuzosin hydrochloride Form C is further characterized by IR Spectra ( Perkin Elmer Spectrum one) as shown in Figure 2, having characteristic absorption at 3117, 2846, 1345, 1279, 1000, 991, 880, 862, 845 cm"1
The present invention also provides a process wherein other forms of alfuzosin hydrochloride such as anhydrous alfuzosin hydrochloride form A, alfuzosin hydrochloride trihydrate, alfuzosin hydrochloride dihydrate and alfuzosin hydrochloride tetrahydrate are converted to a more stable anhydrous alfuzosin hydrochloride Form C as disclosed in examples.
It has also been observed that alfuzosin hydrochloride can form solvate with lower alkanols and the respective solvates can be easily converted to the desired alfuzosin hydrochloride Form C.
Also contemplated as falling within the scope of the present invention are pharmaceutical formulations comprising therapeutically effective amounts of anhydrous alfuzosin hydrochloride Form C of this invention in combination with suitable pharmaceutically acceptable carrier.
A preferred formulation in accordance with the invention comprises a unit dosage tablet form comprising the active anhydrous alfuzosin hydrochloride Form C compressed with tabletting agents and excipients known in the art.

Inert diluent such as lactose or starch, sucrose are used as adjuvants along with the active compound. The oral dosage forms can also comprise, as is normal practice, additional substances such as lubricating agents e.g. talc,magnesium stearate. Again buffering agents, disintegrants may also be added. For controlled release form suitable polymers like HPLC are used. Still further the tablets may be coated to ensure safe passage of drug through the acidic environment of the stomach.
Pharmaceutical compositions of this invention may contain in addition to therapeutically effective amount of alfuzosin hydrochloride Form C as the active ingredient, inert pharmaceutically acceptable carriers that may be solids or liquids. Solid form compositions include powders, tablets, dispersible granules, capsules.
In powders, the carrier is a finely divided solid,which is in admixture with the finely divided active compound. In the tablet the active compound is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The term "compositions" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it. Tablets, powders, and capsules can be used as solid dosage forms suitable for oral administration.

In another embodiment of the present invention, therefore, there is provided pharmaceutical compositions comprising a therapeutically effective amount of anhydrous alfuzosin hydrochloride form C in combination with other active pharmaceutical ingredients such as beta blockers, diuretics, angiotensin converting enzyme inhibitors.
The invention will now be described with reference to the following non-limiting example.
Examples Example 1
Preparation of anhydrous alfuzosin hydrochloride Form C from a free alfuzosin base.
Free alfuzosin base (100 gms) was suspended in Methanol (500 ml). The reaction mass pH was adjusted to 4.3 using 20 % HC1 gas in Isopropanol. The reaction mass was then stirred for minutes at 20-25 °C after pH adjustment. The reaction mass was concentrated under vacuum below 50 °C to obtain a residue.
Methanol (1.0 litre) was added and the reaction mass was heated to 70-80 °C to get a clear solution. Molecular sieve (50 gms) was added and the reaction mass stirred for 1 hour and filtered through Celite. The filtrate was concentrated under vacuum below 50 °C to get a residue. Acetone (1.0 litre) was added and stirred for 1 hour at 25-30 °C. The resulting solid was filtered and washed with Acetone, the solid was further dried under vacuum at 50°C for 10-12hours to get 90gms of anhydrous Alfuzosin hydrochloride Form C having moisture content less than 1.0%.
Example 2

Preparation of anhydrous alfuzosin hydrochloride Form C from alflizosin hydrochloride Methanol solvate
Free alfuzosin base (50 gms) was suspended in 250 ml of Methanol. pH was adjusted to 4.5 with isopropyl alcohol and HCl at 25-30°C. The reaction mass was stirred for 1 hour at 25-30 °C and further chilled to 0 °C. The resulting suspension was stirred at 0 °C for 1 hour filtered and washed with chilled Methanol. The solid was dried under vacuum at 50°C to get anhydrous alfuzosin hydrochloride solvate(35 gms).alfuzosin hydrochloride-methanol solvate (35 gms) was suspended in Methanol (300 ml) and the reaction mass was heated to 80 °C to get a clear solution. Molecular sieve (20 gms) was added and the reaction mass stirred for 1 hour and was filtered through Celite. The clear filtrate was concentrated under vacuum below 50 °C to residue. To the residue Acetone (300ml) was added and cooled to 25-30 °C and further stirred for 1 hour at 25-30 °C.
The resulting mixture was filtered to obtain a solid mass. The solid mass was washed with Acetone and dried under vacuum at 50 °C for 10-12..hours to get anhydrous alfuzosin hydrochloride Form C (32gms) having moisture content less than 1.0 %.
Example 3.
Preparation of anhydrous alfuzosin hydrochloride form C
Free alfuzosin base (100 gms) was dissolved in Methanol (500 ml). The
reaction mass was cooled to 10-15 °C. The reaction mass pH was adjusted
to 4.7 using Isopropyl alcohol and HCl. The reaction mass was stirred
for 30 minutes at 25 to 30 °C, Acetone (200 ml) was added and stirred.
The solvent was removed completely by distillation. Acetone (500 ml)
was added and the suspension was cooled to 20-25 °C. The solid was

filtered and washed with Acetone(200 ml). The solid was dried under vacuum at 60-70 °C for 8-10...hours to get anhydrous alfuzosin hydrochloride Form A.
Anhydrous alfuzosin hydrochloride Form A thus obtained, was suspended in Methanol (1000 ml) and the reaction mass was heated to 70-80 °C to get a clear solution. Molecular sieve (50 gms) was added and the reaction mass stirred for 1 hour and was filtered through Celite. The clear filtrate was concentrated under vacuum below 50 °C to residue. To the residue Acetone (1.0 litre) was added and cooled to 25-30 °C and further stirred for 1 hour at 25-30 °C.
The resulting mixture was filtered to obtain a solid mass. The solid mass was washed with Acetone and dried under vacuum at 50 °C for 10-12 hours to get anhydrous alfuzosin hydrochloride Form C (90gms) having moisture content less than 1.0 %.
Example 4
Preparation of anhydrous alfuzosin hydrochloride Form C from Alfuzosin
hydrochloride trihydrate.
Alfuzosin Hydrochloride trihydrate (50 gms) was suspended in Ethanol
(500 ml), and the reaction mass was heated to 70-90 °C to get a clear
solution. Molecular sieve (30 gms) was added and the reaction mass
stirred for 1 hour and filtered through Celite.
The filtrate was concentrated under vacuum below 50 °C to get a residue.
Acetone (500ml) was added and stirred for 1 hour at 25-30 °C. The
resulting solid was filtered and washed with Acetone, the solid was
further dried under vacuum at 50°C for 10 tol2hours to get 35gms of

anhydrous alfuzosin hydrochloride Form C having moisture content less than 1.0%.
Example 5
Preparation of anhydrous alfuzosin hydrochloride Form C from alfuzosin hydrochloride Ethanol solvate
Free Alfuzosin base (100 gms) was suspended in 450 ml of Ethanol. pH was adjusted to 4.8 with isopropyl alcohol and HC1 at 25-30 °C. The reaction mass was stirred for 1 hour at 25-30 °C and further chilled to 0 °C. The resulting suspension was stirred at 0 C for 1 hour filtered and washed with chilled Ethanol. The solid was dried under vacuum at 50 °C to get anhydrous alfuzosin hydrochloride ethanol solvate (60 gms). Alfuzosin hydrochloride solvate ( 60 gms) was suspended in ethanol (1000 ml) and the reaction mass was heated to 70-90 °C to get a clear solution. Molecular sieve (50 gms) was added and the reaction mass stirred for 1 hour and was filtered through Celite. The clear filtrate was concentrated under vacuum below 50 °C to residue. To the residue Acetone (1.0 litre) was added and cooled to 25-30 °C and further stirred for 1 hour at 25-30 °C.
The resulting mixture was filtered to obtain a solid mass. The solid mass was washed with Acetone and dried under vacuum at 50 °C for 10-12hours to get anhydrous alfuzosin hydrochloride Form C (90gms) having moisture content less than 1.0 %.
Characterization
Anhydrous alfuzosin hydrochloride Form C obtained above was characterized by X-ray powder diffraction.

The X-Ray powder diffractogram of AlfuzosinHydrochloride Form C was measured on a Rigaku Miniflex advance x-ray powder diffractometer having a copper-k-a radiation.
The polymorph of anhydrous Alfuzosin hydrochloride Form C is characterized by X-ray powder diffraction pattern as shown in Figure 1, having significant reflections(peaks) expressed as 2 [theta]values at about 6.982°(± 0.2°), 10.601°(± 0.2°), 17.079°(± 0.2°), 17.921°(± 0.2°), 20.039°(± 0.2° ), 20.659°(± 0.2° ), 20.318°(± 0.2° ), 24.360°(± 0.2° ), 25.400°(± 0.2°), 29.220°(± 0.2°).
The peak intensities are summarised in Table 1.
Anhydrous alfuzosin hydrochloride Form C was further characterized by IR Spectra( Perkin Elmer Spectrum one) as shown in Fig 2, having characteristic absorption at 3117, 2846, 1345, 1279, 1000, 991, 880, 862, 845 cm"1
Hygroscopic test
Anhydrous alfuzosin hydrochloride Form A and anhydrous alfuzosin hydrochloride Form C obtained above, were kept under normal storage conditions i.e. at 25 ± 2 °C at 60 ± 5% relative humidity for a period of 1 year.
Equal quantities (5gms) of alfuzosin hydrochloride Form A and anhydrous alfuzosin hydrochloride Form C and alfuzosin hydrochloride dihydrate were stored under equivalent storage conditions at 25 ± 2 °C at 60 ± 5% relative humidity.
The moisture content was periodically (at the intervals of 3, 6, 9 and 12 months) checked using a K.F.Aquameter. The results are shown in table 2.

Table 2.

Polymoprh Initial Kf 3month 6 months 9 month 12 month
Form A 1.5% 4.2 % 8.5 % 9.2% 9.8%
Form C 0.85% 0.85% 0.89% 0.92% 1%
Dihydrate Form 8.0 8.5 9.0 10.5 11
At the end of the total observation period, moisture content of anhydrous alfuzosin hydrochloride Form A was significantly high (9.8%) with respect to the moisture content of anhydrous alfuzosin hydrochloride Form C(l%),while the moisture content of alfuzosin hydrochloride dihydrate was( 11%).
Thus anhydrous alfuzosin hydrochloride Form C offers a distinctly better unhygroscopic profile and hence is more suitable for use in formulations.
Tablet preparation
Preparation of tablets
Microcrystalline cellulose, Alfuzosin hydrochloride Form C, Lactose, starch and sodium starch glycollate were dry mixed in a fluid bed equipment for 5 minutes at room temperature. A granulation liquid consisting of water, starch and PVP was prepared and used to granulate the dry mix under specified conditions.
The granules are dried till specified LOD is achieved. The dried granules are sized using 30 mesh. The sized granules are lubricated with sodium

starch glycollate and magnesium stearate and subsequently compressed to 1000 tablets using a single punch tablet compression machine. A typical prepared tablet contained (2.5 mg) of anhydrous Alfuzosin hydrochloride Form C and was white and circular with a thickness of 2.8 mm and a target weight of 100 mg.
1000 tablets containing anhydrous alfuzosin hydrochloride Form C and 1000 tablets containing anhydrous alfuzosin hydrochloride Form A were prepared with the same procedure and under similar conditions.
These tablets were subjected to following different tests in order to compare the various formulation parameters for the respective alfuzosin hydrochloride anhydrous polymorphic forms.
Hardness
Hardness tester (PharmaTest PTB, INCORP) was used to determine the
hardness of tablet samples.
Tablets containing anhydrous alfuzosin hydrochloride Form A (n=50) and
Tablets containing anhydrous alfuzosin hydrochloride Form C(n= 50 )
were tested for Hardness and average Hardness for respective Tablets was
calculated.
Disintegration test
Tablets containing anhydrous alfuzosin hydrochloride Form A (n=50) and Tablets containing anhydrous alfuzosin hydrochloride Form C(n=50 ) were tested for disintegration time. Average disintegration time for respective Tablets was calculated.

Dissolution tests for Tablets
Anhydrous alfuzosin hydrochloride Form A and anhydrous alfuzosin hydrochloride Form C dissolution performance was evaluated for the respective tablets.
Dissolution was determined on the resulting tablets using in 0.0IM HCl as a dissolution medium
Table 3
Comparative data

Sample Parameters J. Alfuzosin hydrochloride Form A Tablets Alfuzosin hydrochloride FormC Tablets
Hardness kg/cm 4.0-4.0 4.0- 5.5
Disintegration time (seconds) 3.0 4.0
Dissolution Studies 95.00-98.00 98.00-103.00
The results set forth in Table 3 demonstrate that the tablets containing anhydrous alfuzosin hydrochloride Form C made Alfuzosin hydrochloride available more rapidly than the tablets having anhydrous alfuzosin hydrochloride Form A .
As can be seen from Table 3, concerning the tablet having anhydrous alfuzosin hydrochloride Form C, at least 90% of the labeled amount of alfuzosin hydrochloride dissolves in 45 minutes in 900 ml of 0.01 M HCl

at 37.degree. C, representing a significant enhancement in bioavailability over tablets containing anhydrous alfuzosin hydrochloride Form A.
Furthermore tablets containing anhydrous alfuzosin Form C showed better hardness and disintegration time.
While considerable emphasis has been placed herein on the specific steps of the preferred process, it will be appreciated that many steps can be made and that many changes can be made in the preferred steps without departing from the principles of the invention. These and other changes in the preferred steps of the invention will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.

We Claim:
1. A process for preparation of alfuzosin hydrochloride Form C as
claimed in claims, 1 or 2 which comprises the following steps:
Step (a) suspending alfuzosin in a first solvent to obtain a first
suspension;
Step (b) optionally treating the first Suspension with a composition of
hydrochloride to obtain a second suspension with pH in the range of 4.0
to 5.0;
Step (c) concentrating the first or optionally the second suspension under
vacuum to obtain a first concentrate;
Step (d) admixing the first concentrate and a second solvent and refluxing
the resulting mixture to obtain a clear solution;
Step (e) drying the clear solution by means of a desiccant and separating
the desiccant, typically by filtration
Step (f) concentrating the filtrate under vacuum to obtain a second
concentrate;
Step (g) adding a ketonic solvent to the second concentrate and
filtering the resulting precipitate; and
Step (h) vacuum drying the precipitate to obtain anhydrous alfluzocin Hydrochloride
FormC.
characterized by X-ray powder diffraction pattern having significant
reflections(peaks) expressed as 2[theta]values at least about 6.982°(± 0.2°
), 10.601°(± 0.2° ) 17.079°(± 0.2° ), 17.921°(± 0.2° ), 20.039°(± 0.2° ),
20.659°(± 0.2° ), 20.318°(± 0.2° ), 24.360°(± 0.2° ), 25.400°(± 0.2° ),
29.220°(±0.2°).
2. The polymorph as claimed in claim 1 further characterized by an
infrared spectrum comprising absorption bands at 3117, 2846, 1345,
1279, 1000, 991, 880, 862, 845 cm-1

3. A process for preparation of alfuzosin hydrochloride Form C as
claimed in claims, 1 or 2 which comprises the following steps:
Step (a) suspending alfuzosin in a first solvent to obtain a first
suspension;
Step (b) optionally treating the first Suspension with a composition of
hydrochloride to obtain a second suspension with pH in the range of 4.0
to 5.0;
Step (c) concentrating the first or optionally the second suspension under
vacuum to obtain a first concentrate;
Step (d) admixing the first concentrate and a second solvent and refluxing
the resulting mixture to obtain a clear solution;
Step (e) drying the clear solution by means of a desiccant and separating
the desiccant, typically by filtration
Step (f) concentrating the filtrate under vacuum to obtain a second
concentrate;
Step (g) adding a ketonic solvent to the second concentrate and
filtering the resulting precipitate; and
Step (h) vacuum drying the precipitate to obtain anhydrous alfuzosin Hydrochloride
FormC.
4. A process as claimed in claim 3, wherein the said alfuzosin is at least one compound selected from a group of compounds consisting of alfuzosin base, alfuzosin hydrochloride Form A, alfuzosin hydrochloride monohydrate, alfuzosin hydrochloride dihydrate and alfuzosin hydrochloride tetrahydrate.
5. A process as claimed in claim 3, wherein the first solvent is at least one lower alkanol solvent.

6. . A process as claimed in claim 3, wherein said second solvent is at least one lower alkanol solvent.
7. . A process as claimed in claim 3, wherein said composition of hydrochloride is selected from a group of compositions of hydrochlorides, consisting of 20% HC1 in isopropyl alcohol, dry HC1 gas and HC1 in methanol.
8.. A process as claimed in claim 3, wherein said desiccant is at least one desiccant selected from a group of desiccants consisting of molecular sieves, activated alumina and Silica Gel.
9. A process as claimed in claim 3, wherein said first concentrate and
said second solvent are refluxed at the reflux temperature of the second
solvent.
10. A process as claimed in claim 3, wherein said ketonic solvent is at
least one ketonic solvent selected from a group of ketonic solvents
consisting of Acetone, methyl isobutyl ketone and methyl ethyl ketone.
11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and therapeutically effective amount of anhydrous alfuzosin hydrochloride Form C of claim 1.
12. A process for preparation of alfuzosin hydrochloride Form C as described herein with reference to the accompanying examples.
Dated this 19th day of April 2006.
Mohan Dewan
of R. K. Dewan & Co
Applicant's Patent Attorneys

ABSTRACT
A polymorh of alfuzosin hydrochloride and a process for its preparation is described. The polymorph has significant enhancement in bioavailability and tablets made therefrom have better hardness and improved disintegration time.