Use of Natural Gums and Cellulose Derivatives in Production of Sustained Release Metoprolol Tablets

Abstract

Metoprolol tartrate sustained-release tablets (100 mg) were prepared using xanthan/guar gums and also hydroxypropyl methyl cellulose (HPMC) carboxymethyl-Cellulose (CMC) polymers by direct compression method. Physical characteristics of the tablets and water uptake in addition to their dissolution profiles were compared with standard (Lopressor® SR) tablets. Dissolution test was performed in the phosphate buffer solution (pH 6.8) and the samples were analyzed spectrophotometerically in 275.7 nm. Dissolution studies showed that formulations containing 100 and 80% of HPMC, 100% of guar, and 20% of xanthan followed the Higuchi model, while those containing 60 and 40% HPMC and 100 and 80% xanthan followed a zero-order model. The tablets with 40% xanthen followed a Hixon-Crowell model. In cellulose derivatives the highest MDT and dissolution efficiency until 8 hr (DE₈%) belonged to tablets with 40% HPMC, increasing the amount of CMC decreased the drug release rate, and formulations containing 60 and 40% of HPMC had the USP dissolution standards. While, in the gum formulations, the highest mean dissolution time and the lowest DE₈% belonged to tablets with 100% xanthan, increasing the xanthan decreased the release rate of metoprolol, and formulations containing 80 and 100% xanthan had the USP dissolution standards. Results showed that natural gums are suitable for production of sustained-release tablets of metoprolol.

Keywords :

• Carboxymethyl-Cellulose
• Guar
• Hydroxypropylmethyl-Cellulose
• Metoprolol Tartrate
• Sustained Release Tablets
• Xanthan

Hydrophilic polymers are widely used in the formulation of modified–release oral dosage forms. Various synthetic polymers (HPMC, NaCMC, polymethacrylale, etc.) and natural materials (xanthan, guar gum, and chitosan) have been tried by various researchers. It has been shown that in hydrophilic matrices, swelling as well as erosion of the polymer occurs simultomeously, and both of them contribute to the overall drug release rate (Sujja-areevath et al. 1998).

Guar gum, a natural macromolecular galactomannan, and xanthan gum, a macromolecule product of Xanthomana campestris composed of glucose, mannose, and glucorunic acid (Castro, Tirapegui, and Benedicto 2003), are significantly less expensive than hydroxypropyl-methylcellulose (HPMC) and other cellulosic derivatives (Altaf et al. 1998a). Recently the potential of guar gum as an inexpensive and flexible carrier for oral extended release drug delivery has been highlighted. In vitro and in vivo release of a highly soluble drug (diltiazem) from guar gum matrix tablets was found to be similar to that of a commercial reference product (Altaf et al. 1998b). Guar formulations are relatively insensitive to changes in stirring speed of dissolution test, compaction pressure, or storge under accelerated stress conditions. These tablets also showed good in vitro, and in vivo correlation (Yu et al. 1998). Guar-based tablets of low soluble drugs (ketoprofen and nifedipine) have shown also comparable release to commercial products (Oruvail® and Procardia XL®) (Yu et al. 1997; Friend et al. 1997). However, guar gum alone may not sustain drug release satisfactorily requiring the addition of other hydrocolloids like HPMC in relatively large amounts (Bhalla and Sanzgiri 1987).

The aim of our study was to assess drug release from guar gum and xanthan-based matrix tablet formulations of metoprolol and the capability of these natural gums in production of sustained–release tablets in comparison with cellulosic derivatives. The potential advantages of natural gums as sustained–release excipients are their high viscosity, low cost, and commercial availability (Altaf et al. 1998a). The ultimate goal of our work is to provide natural gum based sustained-release systems that are inexpensive, in terms of raw material and manufacturing coasts, and suitably robust to accommodate a variety of drugs.

MATERIALS AND METHODS

Metoprolol tartrate was gift from Alborz Daru, (Iran). Other materials were Lopressor® SR 100 mg tablets (Novartis, Swithzerland), hydroxypropyl methylcellulose (HPMC K4M) (Shinetsu, Japan), sodium carboxymethyl cellulose (NaCMC), xanthan gum (Arthur Branwell, England), guar gum (Hercules, USA), microcrystalline cellulose (Avicel PH101) (FMC, USA), titanium dioxide (Quitrous, Germany), magnisum stearate (Merck Chemical Company, Germany), and colloidal silicon dioxide (Aerosil) (Aldrich, Germany).

Preparation of Matrix Tablets

Round tablets were prepared by a direct compression method with a single punch tableting machine (Kilian Co, GmbH, Koln-Niehl, Germany). The total weight of the tablets was 320 mg, hardness 70 N, and diameter was 12 mm. Different formulations based on natural gums (xanthan/guar) or cellulose derivatives (HPMC/CMC) are shown in Table 1.

TABLE 1 Different formulations of metoprolol matrix tablets based on natural gums or cellulose derivatives

	Ingredients (mg)
Formulation code	Metoprolol tartrate	HPMC	NaCMC	Guar	Xanthan	Magnesium stearate	Aerosil	Titanium dioxide	Avicel PH101
H1	100	120	—	—	—	2	2	6	90
H2	100	96	24	—	—	2	2	6	90
H3	100	72	48	—	—	2	2	6	90
H4	100	48	72	—	—	2	2	6	90
G1	100	—	—	120	—	2	2	6	90
G2	100	—	—	96	24	2	2	6	90
G3	100	—	—	72	48	2	2	6	90
G4	100	—	—	48	72	2	2	6	90
G5	100	—	—	—	120	2	2	6	90

Drug Release Studies

Dissolution test was carried out according to method II of USP (USP 25, 2002) in 500 ml of phosphate buffer solution (pH 6.8) at 37 ± 0.5°C. Rotating speed of the paddle was 50 rpm. At 0.5, 1, 2, 4, 6, 8, 10, and 11 hr after starting the test, 3-ml samples of the dissolution medium were withdrawn and analyzed spectrophotometrically at 275.7 nm for metoprolol.

Analysis of Release Data

Dissolution efficiency (DE) (Banakar 1992) after 8 hr of release test was used to compare the results of dissolution tests of different formulations:

The other dissolution parameter used for comparing the different formulations was mean dissolution time (MDT), that is calculated from the amount of drug released to the total cumulative drug. MDT is a measure of the rate of the dissolution process: the higher the MDT, the slower the release rate. The following equation was used to calculate the MDT from the mean dissolution data: Where i is the dissolution sample number, n is the number of dissolution sample time, t_mid is the time at the midpoint between i and i − 1, and Δ M is the additional amount of drug dissoloved between i and i − 1 (Gohel and Panchal 2002).

The similarity factor f₂ was calculated from the mean dissolution data according to the following equation: Where n is the number of pull points, w_t is an optional weight factor, R_t is the reference profile at time point t, and T_t is the test profile at the same time point, the value of f₂ should be between 50 and 100 (FDA Guidance 1997). An f₂ value of 100 suggests that the test and reference profiles are identical, and as the value becomes smaller, the dissimilarity between release profiles increases.

Erosion and Water-Uptake of Tablets

The matrix erosion and water-uptake studies were carried out by the method of Dürig and Fassihi (2002) to check the effect of formulation ingredients on matrix erosion and to establish a correlation among matrix erosion, water uptake, and drug released. In brief, tablets were subjected to identical conditions as described for dissolution testing. Fully 3 tablets were used per time point. At times 0.5, 1, 2, 4, 6, 8, 10, and 11 hr, the tablets were carefully removed and patted with tissue paper to remove excess surface water. After determining the wet weight, the tablets were dried at 70°C for 10 days, before reweighing to determine the remaining dry weight. Placebo tablets consisting of pure polymers were treated in the same way.

Water uptake and mass loss were determined gravimetrically according to the following equations:

RESULTS

Metoprolol release profiles from different tablets based on cellulose derivatives with different ratios of HPMC and CMC compared with the standard Lopressor tablets are shown in Figure 1a, whereas Figure 1b compares the drug release from tablets based on mixtures of natural gums (xanthan/guar).

FIG. 1 Metoprolol release profiles from different tablets based on (a) cellulose derivatives and (b) mixtures of natural gums, compared with the standard Lopressor tablets (ST) (n=3).

Comparison of release parameters and diffusion exponent of Peppas equation (M_t/M_∞ = Ktⁿ) for different formulations are shown in Table 2. The results of regression analysis of release data based on best curve-fitting method are shown in Table 3.

TABLE 2 Comparison of release parameters and diffusion exponent (n) of Peppas equation for Lopressor (ST) and different formulations of metoprolol matrix tablets based on natural gums or cellulose derivatives

Formulation code	MDT ± SD (hr)	DE8 ± SD(%)	f2	n ± SD
ST	5.246 ± 0.196	63.928 ± 0.192	—	0.673 ± 0.026
H1	3.533 ± 0.125	92.823 ± 0.181	34.95	0.686 ± 0.027
H2	3.780 ± 0.189	90.236 ± 0.191	36.23	0.768 ± 0.020
H3	5.669 ± 0.206	65.663 ± 0.391	64.13	0.735 ± 0.003
H4	6.232 ± 0.032	41.711 ± 0.085	39.25	0.690 ± 0.015
G1	3.147 ± 0.014	97.201 ± 0.126	31.54	0.833 ± 0.025
G2	3.688 ± 0.241	88.132 ± 0.142	38.04	0.891 ± 0.014
G3	5.114 ± 0.313	71.197 ± 0.190	54.76	0.920 ± 0.009
G4	6.204 ± 0.216	59.288 ± 0.401	54.12	1.095 ± 0.019
G5	6.304 ± 0.381	55.438 ± 0.146	54.75	1.140 ± 0.025

(MDT = mean dissolution time; DE₈% = dissolution efficiency until 8 hr; f₂ = similarity factor) (n = 3).

TABLE 3 Regression analysis (r²) of release data based on best curve-fitting method for Lopressor (ST) and different formulations of metoprolol matrix tablets based on natural gums or cellulose derivatives (n = 3)

Formulation code	Zero-order	First-order	Higuchi	Hixon-Crowell
ST	0.976 ± 0.002	0.941 ± 0.015	0.970 ± 0.005	0. 970 ± 0.010
H1	0.929 ± 0.003	0.958 ± 0.007	0.991 ± 0.001	0.987 ± 0.013
H2	0.953 ± 0.006	0.946 ± 0.007	0.985 ± 0.002	0.975 ± 0.009
H3	0.977 ± 0.003	0.812 ± 0.040	0.952 ± 0.006	0.910 ± 0.022
H4	0.961 ± 0.009	0.923 ± 0.017	0.921 ± 0.006	0.941 ± 0.013
G1	0.904 ± 0.001	0.964 ± 0.013	0.981 ± 0.003	0.971 ± 0.029
G2	0.942 ± 0.004	0.960 ± 0.019	0.983 ± 0.001	0.974 ± 0.015
G3	0.970 ± 0.004	0.899 ± 0.015	0.962 ± 0.007	0.974 ± 0.015
G4	0.986 ± 0.004	0.819 ± 0.030	0.911 ± 0.012	0.899 ± 0.035
G5	0.985 ± 0.002	0.860 ± 0.027	0.908 ± 0.006	0.929 ± 0.011

Figure 2 shows water uptake of metoprolol matrix tablets (a) based on cellulose derivatives and (b) based on natural gums. Erosion percentage of metoprolol tablets with cellulosic matrix and natural gums are shown in Figures 3a and 3b, respectively.

FIG. 2 Water uptake of metoprolol matrix tablets based on (a) cellulose derivatives and (b) natural gums (n=3).

FIG. 3 Erosion percentage of metoprolol tablets based on (a) cellulose derivatives and (b) natural gums (n=3).

DISCUSSION

Cellulosic derivatives like HPMC and CMC are among the most popular hydrophilic polymers used in production of sustained-release (SR) matrix tablets. This is because of their facility for compaction, capability in loading with high percentages of drugs and negligible effect of processing variables on the drug release characteristics from their matrices (Rao, Devi, and Buri 1988; Hogan 1989).

These polymers have been used for preparation of SR matrix tablets like indomethacin (Talukdar et al. 1996), 4-aminopyridin (Juarez, Rico, and Villafuerte 2001), mixture of alpernolol and metoprolol (Rao et al. 1988) and prednisolone (Rao, Haslam, and Stella 2001). However, natural gums like xanthan and guar gum are gaining the researchers' interest in tableting because of their swelling capability, simplicity, and cheap production process (Munday and Cox 2000). Xanthan gum specially has better flow properties than HPMC (Talukdar et al. 1996). These gums have been reported to be used in production of matrix tablets of indomethacin (Talukdar et al. 1996: Talukdar, Rombaut, and Kinget 1998), theophylline (Khullar, Khar, and Agarwal 1998), diltiazem (Altaf et al. 1998a), sodium diclofenac (Munday and Cox 2000), and trimethazidin HCl (Krishniah et al. 2002).

As Figure 1a shows Tablet H₁ that contains only HPMC as the cellulose derivative releases ∼ 90% of the drug during 8 hr while, H₄ that contains 60:40 percent ratio of CMC:HPMC releases only 70% after 11 hr. Considering the USP25 standards (USP25, 2002) for SR metoprolol tablets, H₁ nd H₂ are not suitable while H₃ and H₄ provide the USP standards. Table 2 shows that increasing the CMC of tablets increases the MDT while decreasing the DE₈%. This table also shows that MDT of tablet H₄ is significantly (p < 0.05) higher than other formulations containing cellulosic mixtures and also its DE₈% significantly lower (p < 0.05) than others. Rao et al. (1988) and Juarez et al. (2001) also reported that increasing the CMC content of the SR tablets prolonged the dissolution time. Figures 2a and 3a also show that increasing the CMC ratio decreases the water uptake and erosion of the tablets, which describes the slower drug release with increasing the CMC ratio.

In natural gums series, Figure 1b reveals that tablet G₁ that contains only guar gum as the retarding polymer, releases ∼80% of the drug after 6 hr and ∼ 100% after 8 hr. Meanwhile, G₄ and G₅ that release 85 and 80% of the drug, respectively, after 10 hr, have the slowest release rate among natural gums series. MDT of these tablets also is significantly (p<0.05) higher than other tablets of these series (Table 2). Table 2 also indicates that MDT is increased while DE₈% decreases by increasing the xanthan content of tablets.

Sinha et al. (2004) also reported that increasing the xanthan gum content of 5-flurouracil tablets decreased the drug release rate. The higher water uptake (Figure 2b) but lower erosion (Figure 3b) of tablets containing greater xanthan content, may describe the lower release rate of metoprolol in these tablets (Figure 1b).

Considering that f₂ or similarity factor for tablets H₃, G₃, G₄, and G₅ are more than 50, these tablets may be the most similar to standard tablets (Table 2). However, H₃ has greater f₂ (FDA Guidance 1997) that makes it more similar to the Lopressor tablets compared with natural gums.

According to Peppas equation (Chueh, Zia, and Rhodes 1995), Lopressor tablets show a non-Fickian release mechanism (Table 2) and a zero-order kinetic release (Table 3). Tablets H₁ and H₂ release metoprolol with a Fickian mechanism (Table 2) and a Higuchi kinetic (Table 3). However, tablets H₃ and H₄ with higher percentage of CMC show a non-Fickian mechanism (Table 2) and a zero-order release kinetic (Table 3). As tablet H₄ has the lowest erosion compared to other formulation of cellulosic derivatives, Hixon-Crowell mechanism which is basically according to matrix erosion (Ritger et al. 1987a, b), unlikely plays an important role in drug release from this tablet.

In natural gums, for G₁ and G₂ Higuchi kinetic is dominant (Table 2 and Table 3). In G₃ tablets that show greater erosion compared with G₁ and G₂ (Figure 3b), Hixon-Crowell mechenism plays an important role in drug release. However, in tablets G₄ and G₅ containing higher percentage of xanthan, n exponent is greater than 1 and definitely drug release is a function of chain relaxation of macromolocules (Ritger and Peppas 1987a, 1987b).

In general, drug release from compact matrices follows a Fickian mechanism, but some-times because of the presence of other additives, a mixture of diffusion (Case I) and chain relaxation (Case II) is seen. However, when drug diffusion does not follow a Fickian mechanism, it is too similar to a zero-order continuous and heomogeneous release kinetic (Catellani et al. 1988).

CONCLUSION

Tablets H₃ and H₄ with 60:40 and 40:60 ratio HPMC:CMC, respectively, from cellulosic derivatives meet the USP25 requirements for SR metoprolol tablets and release the drug with a zero-order kinetic. However, just H₃ is smiliar to Lopressor from f₂ point of view. From natural gums, formulations G₄ and G₅ with 80:20 and 100:0 ratio of xanthan:guar, respectively, have the greatest similarity factor to Lopressor and release the drug with a zero-order kinetics. Results show that natural gums with high percentage of xanthan are suitable and promising for production of SR matrix tablets of metoprolol.