Formulation and Evaluation of Extended Release Tablets of Alfuzosin Hydrochloride

G. Nalini* and V. Sai Kishore

Department of Pharmaceutics, Bapatla College of Pharmacy, Bapatla-522101.

ABSTRACT:

The purpose of this work was to develop extended-release matrix tablets of highly water-soluble alfuzosin hydrochloride using different viscosity grades of Hydrxy propyl methyl cellulose polymers by wet granulation method. The influence of three granulating fluids viz. water, dichloromethane: ethanol and isopropyl alcohol on release rate of alfuzosin hydrochloride were studied with a view to design and development of once daily formulations of alfuzosin hydrochloride. The tablets were analysed to determine their hardness, friability, drug content and an in vitro release study was carried out. The dissolution profile indicated that the drug release was found to be influenced by the polymer and granulating fluid employed in the formulation. Based on release rate the polymers can be rated as HPMC K100M > HPMC K15M> HPMC K4M. Based on the dissolution rate the granulating fluids can be rated as water>dichloromethane: ethanol> isopropyl alcohol. The dissolution profiles followed first order kinetics and the mechanism of drug release was governed by peppas model. The n values are found to be more than 0.5 (n>0.5) indicted that the drug release was predominantly controlled by non fickian diffusion. Thus this study clearly indicates that Alfuzosin hydrochloride tablets formulated with HPMC K100M polymer by employing water as granulating fluid is more suitable to design the extended release formulation of alfuzosin hydrochloride matrix tablets for 24 hours.

KEYWORDS: Alfuzosin hydrochloride , HPMC K15M, HPMC K100M , HPMC K4M.

INTRODUCTION:

Alfuzosin hydrochloride, a selective alpha adrenergic antagonist is used against benign prostatic hypertrophy (BPH)^1-3 in elderly males. It is freely soluble in water^4-5and thus readily absorbed after administration. The oral absorption is significantly aided by the presence of food. The dose of immediate release alfuzosin hydrochloride tablet is 2.5 mg thrice daily⁶. The extended release formulations of alfuzosin hydrochloride for once daily administration are associated with small variations in peak and trough serum and drug levels, which may contribute to the lower frequency of cardiovascular adverse effects⁷. In the present investigation an attempt has been made to design extended release drug delivery system for alfuzosin hydrochloride to improve patient connivance and compliance due to less frequent drug administration. Different viscosity grades of Hydrxy propyl methyl cellulose polymers viz; HPMC K4M , HPMC K15M and HPMC 100M(4000,15000,100000 cps at 2% aqueous solution respectively) are used to formulate extended release formulations by wet granulation technique. Water, dichloromethane: ethanol, isopropyl alcohol were used as granulating fluids.

MATERIALS AND METHODS:

Alfuzosin HCl BP (Hetero drugs Ltd, Hyderabad), Microcrystalline cellulose PH 101 (SD Fine chemicals Ltd, Mumbai), HPMC K4M (The Dow Chemical Company, USA), HPMC K15M (The Dow Chemical Company, USA), HPMC K100M (The Dow Chemical Company, USA). Other chemicals used were reagent grade.

Formulation of Tablets:

All the formulations were prepared according to Table 1. The tablets are prepared by wet granulation method. Alfuzosin hydrochloride and polymer were triturated well and allowed to pass through sieve no. 80 and mixed thoroughly, the powders were granulated using sufficient quantity of Water (or) dichloromethane: ethanol(or) isopropyl alcohol till a wet mass was formed. The cohesive mass obtained was passed through sieve no. 12, and the granules were dried at 40 ^OC for 2 hours. The dried granules were re-sieved thorough sieve no.16 and are mixed with talc and magnesium stearate. The granules were punched to get tablets of average weight 350 mg using single punch tableting machine.

Evaluation of the formulation:

The prepared granules were evaluated for bulk density, true density ,car’s index, and porosity using standard reported methods⁸.weight variation test was conducted as per specifications of IP⁹.Hardness and friability of the tablets formulated were evaluated using a Monsanto hardness tester and a Roche friabilator, respectively.

Drug Conten:¹⁰

Twenty tablets of each formulation were weighed and powdered. The quantity of powder equivalent to 10 mg of Alfuzosin hydrochloride was transferred in to a 100 ml volumetric flask and extracted with distilled water by keeping in sonicator (bath) for 2 hours. Then it was filtered, suitable dilutions made and absorbance was measured by using Elico UV-Visible spectrophotometer (SL 159) at 244nm.

In vitro drug release study:

Release of alfuzosin hydrochloride was determined using a six panel, USPXXIII dissolution apparatus-2 at 100 rpm. The dissolution was studied using 900 ml of 0.01N HCl as dissolution medium. The medium was allowed to equilibrate to temperature of 37 + 0.5 ^OC. The apparatus was operated for 24 hours. At definite time intervals 5 ml of the receptor fluid was withdrawn, filtered, suitable dilutions were done with distill water and analyzed spectrophotometrically at 244nm using Elico UV-Visible spectrophotometer. The rate and the mechanism of release of Alfuzosin hydrochloride from the prepared matrix tablets were analyzed by fitting the dissolution data into¹⁰, zero-order equation, Q=Q₀ –k₀t(1),where Q is the amount of drug released at time t, and k₀ is the release rate. First order equation, Ln Q=Ln Q₀ – k₁t (2), where k₁ is the release rate constant and Higuchi’s equation, Q= k₂t^1/2 (3) where Q is the amount of the drug released at time t and k₂ is the dissolution rate constant. The dissolution data was further analyzed to define the mechanism of release by applying the dissolution data following the empirical equation , M₁/M_a=Ktⁿ (4), where Mt/M_a is the fraction of drug released at time t. K is a constant and n characterizes the mechanism of drug release from the formulations during dissolution process.

RESULTS AND DISCUSSION:

The present investigation was undertaken to fabricate and evaluate the extended release formulation of alfuzosin hydrochloride matrix tablets. The influence of three granulating fluids viz. acetone, isopropyl alcohol and dichloromethane and polymers HPMC K4M , HPMC K15M and HPMC 100M on release rate of alfuzosin hydrochloride were studied with a view to design and development of once daily formulations of Alfuzosin hydrochloride.

Water was used as granulating fluid for the three formulations (F-1 to F-3).The granules were evaluated for angle of repose, bulk density and carr’s index. The bulk density for all the formulations was ranged from 0.467 to 0.478. The angle of repose for all the formulations was ranged from 25⁰32¹-27⁰ 8¹. the carr’s index for all the formulations was ranged from 7.6 – 9.58%. The value of bulk density indicates good packing characters. The value of angle of repose (25⁰-30⁰) for all the formulations indicates good flow property. The values of carr’s index (5-10%) indicates free flowing material.

All the formulated preparations were subjected to weight variation, hardness, friability and drug content. All tablets complied I. P. weight variation test requirement. The hardness was found to be in between 4 - 5 kg. The tablets satisfied USP friability requirement, as the % friability values are less than 1%. The percent drug content was found to be with in 98 - 102% of the labeled amount and hence complied drug content requirement.

Fig 1. Dissolution profiles of Alfuzosin hydrochloride tablets prepared with various polymers.

(¡) F_{1 -} Tablets prepared with HPMC K4M

(�) F_{2 -} Tablets prepared with HPMC K15M

(¿) F_{3 -} Tablets prepared with HPMC K100M

TABLE 1: COMPOSITION OF ALFUZOSIN HYDROCHLORIDE EXTENDED RELEASE TABLETS

S. No.	Ingredients	F1 (mg)	F2 (mg)	F3 (mg)	F4 (mg)	F5 (mg)
1.	Alfuzosin Hcl	10	10	10	10	10
2.	Avicel CE-15	194	194	194	194	194
3.	HPMC K4M	140	---	---	---	---
4.	HPMC K15M	---	140	---	---	140
5.	HPMC K100M	---	---	140	---	---
6.	Aerosil	2	2	2	2	2
7.	Magnesium Stearate	4	4	4	4	4
8.	Water	Q. S.	Q. S.	Q. S.	--	--
9.	Dichloromethane :Ethanol	---	---	--	Q. S.	--
10.	Isopropyl alcohol	--	--	--	--	Q. S
Total		350	350	350	350	350

TABLE 2 CORRELATION COEFFICIENT (R) VALUES OF ALFUZOSIN HYDROCHLORIDE EXTENDED RELEASE TABLETS

FORMULATION	CORRELATION COEFFICIENT (R) VALUES
	ZERO-ORDER MODEL	FIRST ORDER MODEL	MATRIX	PEPPAS
F1	0.9688	0.9991	0.9876	0.9963
F2	0.9579	0.9870	0.9856	0.9976
F3	0.9196	0.9922	0.9917	0.9956
F4	0.9314	0.9808	0.9938	0.9987
F5	0.9435	0.9728	0.9906	0.9988

TABLE 3: DISSOLUTION PARAMETERS OF ALFUZOSIN HYDROCHLORIDE EXTENDED RELEASE TABLETS

FORMULATION	DISSOLUTION PARAMETERS
	DIFFUSION EXPONENT (n)	FIRST ORDER RATE CONSTANT (h^-1)	T50 (h)	T90 (h)
F1	0.5667	0.127	5.45	18.1
F2	0.6499	0.116	5.97	19.8
F3	0.5967	0.106	6.53	21.6
F4	0.5972	0.110	6.3	20.9
F5	0.6158	0.114	6.07	20.2

The dissolution profile (Fig.1) indicated that the drug release was found to be influenced by the polymer employed in the formulation. Based on release rate the polymers can be rated as HPMC K100M < HPMC K15M< HPMC K15M . Formulation -3 (F-3) shown extended release as compared with other formulations. To find the influence of granulating fluid, alfuzosin hydrochloride tablets were formulated with isopropyl alcohol (F-4) and dichlomethane : ethanol (50:50)(F-5) as granulating fluids. The dissolution profiles (Fig.2) reveals that the drug release was found to be influenced by granulating fluid. Based on the dissolution rate the granulating fluids can be rated as water<dichloromethane:ethanol< isopropyl alcohol.

To ascertain the mechanism of drug release, the dissolution data was analyzed by zero order, first order, and higuchi and peppas equations. The correlation coefficient values (r) were reported in Table 2.These values revealed that the dissolution profiles followed first order kinetics and the mechanism of drug release was governed by peppas model. The n values are found to be more than 0.5 (n>0.5) indicted that the drug release was predominantly controlled by non fickian diffusion. The time required to get 50% drug release (T₅₀) and 90% drug release (T₉₀) was calculated and reported in Table 3 .The first order release rate constants are reported in Table 3.

Fig 2. Dissolution profiles of Alfuzosin hydrochloride tablets prepared with various granulating fluids

F₃(�) _- Tablets prepared with Water

F₄ (¡) - Tablets prepared with Dichloromethane :Ethanol

F₅ (¿) - Tablets prepared with Isopropyl alcohol

Thus this study clearly indicates, that Alfuzosin hydrochloride tablets formulated with HPMC K100M polymer by employing water as granulating fluid is more suitable to design the extended release formulation of alfuzosin hydrochloride matrix tablets for 24 hours.This study concludes that the release rate of drug from the matrix tables can be governed by the granulating fluid and polymer employed in the preparation of tablets.

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Received on 16.09.2010

Accepted on 12.10.2010

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Research Journal of Pharmaceutical Dosage Forms and Technology. 2(6): Nov.-Dec. 2010, 370-373