Research Paper Design and Evaluation of Sustained Release Solid Dispersions of Verapamil Hydrochloride

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1 1252 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 4 January-March 2011 Research Paper Design and Evaluation of Sustained Release Solid Dispersions of Verapamil Hydrochloride S.K Swain *, Ch. Niranjan Patra, J.Sruti, M.E. Bhanoji Rao International Journal of Pharmaceutical Sciences and Nanotechnology Department of Pharmaceutics, Roland Institute of Pharmaceutical Sciences, Khodasinghi, Berhampur , (orissa), Ganjam, ORISSA. Volume 3 Issue 4 January March 2011 ABSTRACT: The Purpose of this study was to prepare and characterize solid dispersions of this antiarrhythmic drug Verapamil hydrochloride (VPH) with HPMCK4M, EudragitRSPO and their combination with a view to sustain its dissolution properties. Investigation of the properties of the prepared solid dispersions were performed using release studies and Fourier transform infrared (FT-IR). The results obtained showed that the rate of dissolution of Verapamil hydrochloride was considerably more sustained when formulated in solid dispersions with HPMCK4M and Eudragit RSPO as compared with pure drug and physical mixtures. FT-IR studies confirmed absence of any possible solid state drug and polymer interactions. In order to establish the mechanism and kinetics of drug release, the experimental data was fitted to different kinetic models likes zero order, first order, Higuchi s model, korsmeyer peppa s model. From the above research it may be concluded that HPMCK4M acts as a better release retardant for the model drug. KEYWORDS: Solid dispersions; Sustained release; Drug polymer interaction studies; In-Vitro release kinetic study Introduction Solid dispersions are a dispersion of one (or) more active ingredients in an inert carrier (or) matrix in the solid state prepared by the melting and solvent evaporation method. Reduction in dissolution rate is achieved by incorporating the drug in an insoluble Eudragit RSPO (Ammar et al., 1997), semisynthetic hydrophilic polymer HPMCK4M (Salsa T et al., 1997) and water soluble PEG (Khan GM et al., 1998) etc. Such formulations are considered as a matrix system that helps in prolonging the duration drug release and hence are considered suitable for formulation as sustained release dosage forms. These sustained release solid dispersion system may be useful for enhancing bioavailability and suitable for sustained release formulations (Chiou WL et al., 1971). Problem such as thermal instability and immiscibility have resulted in the development of the fusion solvent method, which is particularly useful for drugs with high melting point or which are thermo labile (Kala H et al., 1995). In recent years much attention has been paid to the oral sustained release drug delivery systems. HPMCK4M and Eudragit * For correspondence: S.K. Swain, Tel: swain - suryakant@yahoo.co.in, swain.suryakanta@rediffmail.com RSPO are widely used in production of inert matrices. The factors affecting drug release from these matrices have been extensively investigated. HPMC, which is commonly used in preparation of solid dispersions for prolonged drug release is mixed alkyl hydroalkyl cellulose ether containing methoxy and hydroxylpropyl groups. The solubility of HPMC is P H independent (Aldrman DA et al., 1984). It has been found to be a very versatile material for soluble matrix formulations (Hamid AM et al., 2006). It has been shown that this technique is a valuable method in retarding drug release rate (Dangprasirt P et al., 1995). Eudragit RSPO is an acrylic acid derivative; large quantities (5-20 %) of dry polymer are used to control the release of an active substance from a tablet matrix. It has less permeability to water hence widely used as release retardant (Rowe RC et al., 2009). Verapamil hydrochloride (VPH) is a Calcium channelblocking agent used in the treatment of angina pectoris, hypertension and cardiac arrthymia. It is completely absorbed from the gastrointestinal tract. Its biological halflife is 4 to 6 hours with a usual dose of 40 to 240 mg three times a day. Because of the high frequency of administration and short biological half-life, Verapamil hydrochloride was considered as an ideal drug for designing SR formulations (Tripathi KD., 2003 and I. P., 1996). 1252

2 S.K. Swain et.al. : Design and Evaluation of Sustained Release Solid Dispersions of Verapamil Hydrochloride 1253 Hence the objective of the present research was to prepare sustain release solid dispersions and physical mixtures of Verapamil hydrochloride using polymers like HPMCK4M and Eudragit RSPO. Matrials and Methods Matrials Verapamil hydrochloride was gift sample from Lupin Labs. Ltd., (Pune, India). HPMCK4M and Eudragit RSPO were obtained as gift sample from Lupin Labs. Ltd., (Pune, India). Methanol, 0.1 N HCl, Potassium dihydrogen phosphate and sodium hydroxide were procured from S.D Fine chemicals (Mumbai, India), and all other chemicals /solvents used were of analytical grade. Methods Preparation of sustained release solid dispersions (SDs) The sustained solid dispersions of Verapamil hydrochloride were prepared by the solvent method. The weighed amounts of drug and polymer (HPMCK4M, Eudragit -RSPO and their combinations) were dispersed in a given volume of methanol (Table 1). These were stirred for 15 minutes to ensure homogenous mixing. The dispersions were then evaporated to dryness by storing it in a desicator under vacuum, the mass was then pulverized and fractioned. Size fraction which passed through sieve #40 and retained on #60 i.e. (#40/60) was selected for further studies. Preparation of sustained release physical mixtures (PMs) The weighed amount of drug was mixed with the corresponding amount of polymer (HPMCK4M, Eudragit - RSPO and their combinations) in a glass mortar (table no- 2). This was done by geometric dilution technique to ensure homogeneous distribution. Evaluation methods for sustained release solid dispersions (SDs) and physical mixtures (PMs) Drug content uniformity All the solid dispersions and physical mixtures were tested for drug content uniformity. Accurately weighed amount (10 mg equivalent of verapamil hydrochloride) of solid dispersions and physical mixtures was dissolved in 0.1N HCl in 100 ml volumetric flask and the volume was made up to the mark with 0.1N HCl. The solution was then suitably diluted with 0.1N HCl and assayed for drug content at an absorbance of 278 nm (I. P., 1996) using UV Visible Spectrophotometer (Shimadzu, UV1800ENG, Germany). Drug polymer interaction studies by FT-IR spectroscopy While studying the new formulation it is necessary to check the compatibility with the carrier or excipient used and has not undergone degradation. FT- IR spectra for the pure drug and various physical mixtures were obtained in a FT-IR spectroscopy (Thermo Nicolet Nexus 670 Spectrometer) in the transmission mode with the wave number region 4, cm -1. KBr pellets were prepared by gently mixing 1 mg sample powder with 100mg KBr. The results were shown in Fig. 4. Table 1 Formulae of solid dispersions (SDs) prepared by solvent evaporation method (Total wt = 200 mg) Formulation Drug (VPH) in mg HPMCK4M RSPO RSPO + HPMCK4M 1:0.5 1:1 1:3 1:3 1:5 1:7 1:7:0.25 1:7:0.5 1:7:0.75 F F F F F F F F F

3 1254 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 4 January-March 2011 Formulation Drug (VPH) In mg Table 2 Formulae for physical mixtures (PMs) (Total wt = 200 mg) HPMCK4M Eudragit RSPO Eudragit RSPO + HPMCK4M 1:0.5 1:1 1:3 1:3 1:5 1:7 1:7:0.25 1:7:0.5 1:7:0.75 F F F F F F F F F Evaluation of micromeretic properties of solid dispersions and physical mixtures. Angle of repose Static angle of repose of the solid dispersions and physical mixtures were determined by the funnel method. The accurately weighed solid dispersions were taken in the funnel. The height of the funnel was adjusted in such way that the tip of funnel just touched the apex of the heap of the solid dispersions. The solid dispersions were allowed to flow through the funnel freely on to the surface. The diameter of the powder cone was measured and angle of repose was calculated using the following equation (Cooper and Gunn., 1986). Tan θ = h/r..(1) Where h and r are the height and radius of the powder cone. Bulk density Both loose bulk density (LBD) and tapped bulk density (TBD) were determined. A quantity (10 gm) of solid dispersions and physical mixtures from each formula, previously lightly shaken to break any agglomerates formed was introduced into a 10-mL measuring cylinder. After the initial volume was observed, the cylinder was allowed to fall under its own height onto hard surface from the height of 2.5 cm at 2-second intervals. The tapping was continued until no further change in the volume was noted. (LBD) and (TBD) were calculated using the following formulas (Shah D et al., 1997). LBD = Weight of the powder / volume of the packing..(2) TBD = Weight of the powder / tapped volume of the packing..(3) Compressibility index The Compressibility index of the solid dispersions and physical mixtures was determined by Carr s compressibility index (Aulton ME et al., 1988). Carr s index (%) = [(TBD-LBD) 100] / TBD..(4) Hausner s factor Hausner found that the ratio D F /D O was related to inter particle friction and as such, could be used to predict powder flow properties (Lachman L et al., 1987). Hausner s Factor = Tapped bulk density/loose bulk density..(5) In-vitro dissolution rate studies The dissolution study for the prepared solid dispersions and physical mixtures were carried out using USP XXI Dissolution Test Apparatus-1 (LabIndia, Disso 2000, India) in 900 ml of 0.1N HCl maintained at 37±0.5 C, 100 rpm. The samples of 5 ml were withdrawn at predetermined time interval using pipette. The collected samples were suitably diluted and absorbance was measured spectrophotometrically at 278 nm. (I.P, 1996). Drug release kinetics In order to establish the mechanism of release of drug, the experimental data was fitted to different kinetic models. The drug release data were subjected to various mathematical kinetic models like zero order; first order, Higuchi s model and Korsmeyer plot. The preparation of graphs and calculations were carried out with the help of Microsoft Excel Software.

4 S.K. Swain et.al. : Design and Evaluation of Sustained Release Solid Dispersions of Verapamil Hydrochloride 1255 Data analysis To analyze the order and mechanism of the drug release the dissolution was fitted to various equations visa vis 1. Cumulative % drug release (Vs) Time (Zero order plot). 2. Cumulative % drug release (Vs) Square root of time (Higuchi s plot). 3. Log cumulative % drug remaining (Vs) Time (First order plot). 4. Log % drug release (Vs) Log Time (Korsmeyer Plot). Results & Discussion A simple technique of sustained release solid dispersions and physical mixtures was used in the present investigation. These were prepared using polymers like Eudragit RSPO, HPMCK4M and combination of both polymers. Standard graph of Verapamil Hydrochloride in 0.1 N HCl showed good linearity. Its r 2 value is and hence obeyed Beer Lambert s law. Various sustained release solid dispersions and physical mixtures were prepared as described in the methodology. The ratios of drug: polymer and their combinations are tabulated in Table 1 & 2. The formulations were evaluated for drug content uniformity, IR studies and for in-vitro drug release. The percentage of drug content was found to be %, which was within acceptable limits (I.P. 1996). The results of the drug content uniformity in each of solid dispersions and physical mixtures are presented in Table 3. Higher drug content for both SDs & PMs indicated that uniform distribution of drug and polymer. In order to further study the possibility of an interaction of Verapamil hydrochloride with HPMCK4M and Eudragit RSPO in the solid state, more information was gathered using FT-IR spectroscopy. Pure Verapamil hydrochloride displayed characteristic peaks at γ (cm -1 ): and (C-H streching vibration in methyl), and (aldihydic C-H stretching vibration), and (C N streching vibration), , and (C=C in aromatic ring), and (C-O Streching in aromatic and aliphatic), (C-N aliphatic Streching vibration), and (Meta substituted benzene). If the drug and polymer would interact, then functional groups in the FT-IR spectra would show band shift and broading compared to the pure drug and polymers (Silverstein et al., 1991). The FTIR spectra obtained from the various physical mixtures showed peaks obtained with the pure drug and pure polymers and spectra s can be simply regarded as the superposition of those of pure drug and polymers. This showed that there was no chemical interaction of the drug with polymers even in the amorphous state when prepared by the solid dispersion method. An increase in the polymer content also did not initiate any drug polymer interactions (shown in Fig.4). FT-IR spectra s indicated reduction in sharpness of peaks in physical mixtures compared to pure drug as well as polymers. It implied that due to reduction in sharpness, crystanillity of verapamil hydrochloride was reduced in solid dispersions (Bugay DE, 2001). Micromeritic properties of the solid dispersions (SDs) and physical mixtures (PMs) indicated a significant improvement of flowability. One of the most important factors affecting bulk density of the SDs and PMs is the interparticulate interaction (Foher et al., 1996). Favorable particle properties and the optimal presence of water diminish the cohesiveness of the SDs and PMs, resulting in an increased bulk density and enhanced flowability (Korhonen etal. 2002). Hence in our experiment increase in the bulk density of SDs and PMs indicated better flowability as shown in Table 5. Similarly increase in tapped bulk density for SDs and PMs indicated better degree of compactibility (Carson et al., 1994). Micromeritic properties of the SDs and PMs such as angle of repose ( ), Carr s index ( ) and Hausner s fraction ( ) revealed that they were well within the theoretical limit (Lachman., 1987). Table 3 Drug content uniformity of solid dispersions (SDs) and physical mixture (PMs) of Verapamil hydrochloride prepared by solvent evaporation technique and physical mixture technique (Mean ±S.D, n=6) Serial No Solid Dispersions % Drug Content Physical Mixtures % Drug Content 1 F ±0.23 F ± F ±0.34 F ± F3 95.6±0.16 F ±0.32 Table 3 contd

5 1256 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 4 January-March 2011 Serial No Solid Dispersions % Drug Content Physical Mixtures % Drug Content 4 F4 90.9± 0.24 F ± F5 91.7±0.19 F ± F6 95.9±0.14 F ± F7 93.4±0.32 F ± F8 93.8±0.28 F ± F9 95.3±0.21 F ±0.24 Table 4 In-Vitro Dissolution kinetics of Verapamil hydrochloride solid dispersions Formulation F1 F2 F3 F4 F5 F6 F7 F8 F9 Drug release kinetics (R 2 ) Zero-order First-order Higuchi type Korsmeyer Release exponent (n) Table 5 Tabulation for micromeritic properties, (Mean ± S.D), n=6 Micromeritic Properties Verapamil hydrochloride Physical Mixtures Solid Dispersions Angle of repose (in degree) 52 ± ± ± 0.31 Bulk density (gm/ml) 0.26 ± ± ± 0.37 Tapped density (gm/ml) 0.51 ± ± ± 0.26 Compressibility index (%) ± ± ± 0.36 Hausner s fraction 1.96 ± ± ± 0.31 Effect of HPMCK4M on drug release from SDs and PMs The release rate was found to be decreasing as the concentration of polymer HPMCK4M increased in both SDs & PMs. This was due to the reason that the swelling degree is less because of higher concentration of polymer. Different equations & kinetics models were used to describe the release kinetics. Drug release from PMs followed Higuchi model kinetics and the ratio of Drug: HMPCK4M (1:3) sustained release only up to 8 hrs (Higuchi., 1963). Korsmeyer & Peppas release exponent suggests that the release followed Fickian diffusion mechanism (Koresmeyer etal., 1983). Similarly drug release from SDs followed Higuchi model kinetics and the ratio Drug: HMPCK4M (1:3) showed release

6 S.K. Swain et.al. : Design and Evaluation of Sustained Release Solid Dispersions of Verapamil Hydrochloride 1257 retardation up to 16 hrs. Koresmeyer & Peppas release exponent suggests that the release followed Fickian diffusion mechanism. Therefore it shows a diffusional mechanism of drug release, this may be attributed to the increase in diffusional pathlength for the drug because of swelling of the polymer to form a gel around the matrix, and this gel layer acts as a barrier to drug release (Amaral M.H et al., 2001). Effect of Eudragit RSPO on drug release from SDs and PMs The release rate was found to be decreasing as the concentration of polymer Eudragit RSPO increased in both SDs & PMs. This was due to the reason that Eudragit RSPO swells less & at the same time it showed less permeability to water was the major rate controlling factor in retarding the release of Verapamil hydrochloride (Ammar etal., 1993). Different equations & kinetics models were used to describe the release kinetics. Drug release from PMs followed Higuchi model kinetics and the ratio Drug: Eudragit RSPO (1:7) sustained release only up to 6 hrs. Korsmeyer & Peppas release exponent suggests that the release followed Fickian diffusion mechanism. Similarly drug release from SDs followed Higuchi model kinetics and the ratio Drug: Eudragit RSPO (1:7) showed release retardation up to 10 hrs. Korsmeyer & Peppas release exponent suggests that the release followed Fickian diffusion mechanism. Fig. 1 FT-IR Analysis Report of Verapamil hydrochloride

7 1258 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 4 January-March 2011 Fig. 2 FT-IR Analysis Report of Verapamil hydrochloride & Eudragit RSPO Fig. 3 FT-IR Analysis Report of Verapamil hydrochloride & HPMCK4M

8 S.K. Swain et.al. : Design and Evaluation of Sustained Release Solid Dispersions of Verapamil Hydrochloride 1259 Fig. 4 FT-IR spectra of, Verapamil Hydrochloride, Physical Mixture of Verapamil Hydrochloride with Eudragit RSPO and Verapamil Hydrochloride with HPMCK4M

9 1260 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 4 January-March Zero Order Plot For VPH:HPMCK4M Cum.% Drug Release F1 F2 F3 F10 F11 F12 Time (hrs) Fig. 5 Release profile of solid dispersions and physical mixtures containing (HPMCK4M) Zero Order Plot For VPHRSPO 120 Cum. % Drug Releas F4 F5 F6 F13 F14 F15 Time (hrs) Fig. 6 Release profile of solid dispersions and physical mixtures containing (Eudragit RSPO)

10 S.K. Swain et.al. : Design and Evaluation of Sustained Release Solid Dispersions of Verapamil Hydrochloride 1261 Zero Order Plot For VPHRSPOHPMCK4M 120 Cum. % Drug release F7 F8 F9 F16 F17 F18 time (hrs) Fig. 7 Release profile of solid dispersions and physical mixtures containing (Eudragit RSPO and HPMCK4M) Effect of combination of HPMCK4M and Eudragit RSPO on drug release from SDs and PMs Combination of the two selected polymers showed a synergistic effect in retarding the release of the drug; hence selection of suitable proportion of the two polymers can be used to optimize the release of drug. Different equations & kinetics models were used to describe the release kinetics. Drug release from PMs followed Higuchi model kinetics and the ratio Drug: Eudragit RSPO: HPMCK4M (1:7:0.5) sustained release only up to 8 hrs. Koresmeyer & Peppas release exponent suggests that the release followed Fickian diffusion mechanism. Similarly drug release from SDs followed Higuchi model kinetics and the ratio Drug: Eudragit RSPO: HPMCK4M (1:7:0.5) showed release retardation up to 12 h. Koresmeyer & Peppas release exponent suggests that the release followed Fickian diffusion mechanism. Conclusions A systematic study involving preparation and evaluation of sustained release solid dispersions of Verapamil hydrochloride using release retarding polymers was made. PMs could sustain the release of drug only upto 8 hrs whereas In-Vitro release profile suggested that the drug release has been extended with solid dispersions (Drug: HPMCK4M) up to 16 hrs in case F3 (1:3) whereas solid dispersions (Drug: Eudragit RSPO) up to 10 hrs in case F6 (1:7) and solid dispersions (Drug: Eudragit RSPO: HPMCK4M)) up to 12 hrs in case F8 (1:7:0.5) respectively. Approximately, all the sustained release solid dispersions exhibit polymer concentration dependent release retardation effect. From the above research it may be concluded that HPMCK4M acts as a better release retardant for the model drug. References Alderman DA. A review of cellulose ethers in hydrophilic matrices for oral controlled release dosage forms. Int. J. Pharm. Tech prods. Mfr. 5: 1-9 (1984). Amaral M H, Lobo JMS and Ferreira DC. Effect of HPMC and hydrogenated castor oil on Naproxen release from sustained release tablets. AAPS Pharm. Sci.Tech. 2/2: article 6 (2001). Ammar HO, Khali RM. Preparation and evaluation of sustained release solid dispersions of drugs with eudragit polymers. Drug Dev. Ind. Pharm.23(11): (1997). Aulton ME and Wells TI. Pharmaeutics: The Science of Dosage Form Design. Churchill Livingstone, London, England, 1988, pp Bugay DE. Charaterization of the solid-state: spectroscopic techniques. Adv. Drug Deliv. Rev. 48(1): (2001). Carson JW and Marinelli J. Characterize bulk solids to ensure smooth flow, Chemical Engineering. 4:78-98 (1994).

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