Development and in vitro evaluation of sustained release multiparticulate tablet of freely water soluble drug

Blends of aqueous dispersion of a hydrophobic and hydrophilic polymer, namely Surelease®: hydroxypropyl methylcellulose (Surelease®: HPMC E15) were used as coating materials to control the drug release from coated pellets of the highly water soluble drug metoprolol succinate. Varying the polymer blends, ranges of drug release patterns were obtained at pH 6.8. The present study dealt with diffusion of drug through plasticized Surelease®/ hydroxypropyl methylcellulose (HPMC E15) films prepared by coating of drug and polymers onto non-pareil seeds using the solution layering technique. The release of metoprolol succinate from coated pellets was decreased with increased coating load of polymer. The optimized formulation was obtained by 32 full factorial design. The release profile revealed that the optimized formulation follows zero order release kinetics. The stability data showed no interaction for storage at 25oC and 60% relative humidity.


INTRODUCTION
Developing oral sustained release systems for freely water soluble drugs having strong first pass metabolism has always posed a challenge to the pharmaceutical technologist.Most of these highly water soluble drugs, if not formulated properly, are released at a high rate and are likely to produce toxic concentrations when administered orally (Lian-Dong, Yang, Xing, Qian, 2006).Polymeric film coatings are often used for achieving sustained release of an active substance from pharmaceutical formulation because a coated dosage form enables prolonged and precise release of drug with good reproducibility (Sousa, Sousa, Moura, Newton, 2002;Vaithiyalingam, Khan, 2002).One of the most widely used hydrophobic polymers in pharmaceutical film coating is ethyl cellulose (Surelease ® ), due to its convenient film formability, good physiochemical properties and minimum toxicity (Mcginity, 1997).Surelease ® is a good polymer for modified release coating.The polymer is usually used in combination with a secondary polymer such as hydroxypropyl methylcellulose (HPMC E15) which confers the film a more hydrophilic nature and alters its structure by virtue of pores and channels through which the drug substance can diffuse more easily to control the release properties of a drug formulation (Aulton, Bdul-Razzak, Hogan, 1981).Surelease ® containing plasticizer is essential to enhance film forming characteristics, workability and serviceability (Frenning, Tuno´N, Alderborn, 2003).Pellets as a drug delivery system offer not only technological advantages but also better flow properties, less friable dosage form, narrow particle size distribution, ease of coating, and uniform packing (Siepmann, Siepmann, Walther, Macrae, Bodmeier, 2005).It also has therapeutic advantages such as less irritation of the gastrointestinal tract, a low risk of side effects associated with dose dumping and reduction of the variation in gastric emptying rates (Evdokia, 2000).Coating of pellets in a coating pan with a polymer is often used as a means of controlling the drug release rate from extended release formulations.The coated pellets can be compacted into multiple unit tablets or used to fill hard gelatin capsules.Both formulations are normally intended to release intact reservoir pellets after administration; thus the overall drug release rate is determined by the release rate from single pellet units.
Metoprolol succinate, a white crystalline powder, is freely soluble in water.Since the solubility of metoprolol succinate is lower at neutral pH, compared to acidic pH, it is released by the mechanism of diffusion through an insoluble polymer film (Ye, Rombout, 2007).It is a cardio selective β-blocker that has been classified as a class I substance according to the Biopharmaceutics Classification System, meaning that it is highly soluble and highly permeable.The drug is readily and completely absorbed throughout the intestinal tract (Rahman, Yuen, 2006) but is subjected to extensive first pass metabolism resulting in incomplete bioavailability (about 50%).After a single oral dose, peak plasma concentration occurs after about 1 to 2 h.The drug is eliminated within 3 to 4 h which, depending on therapeutic activity, makes it necessary to administer the formulation up to 4 times daily.Based on these properties and well defined relationship between the beta blocking effect and plasma drug concentration, metoprolol lends itself to a sustained release formulation.
The goal of this study was to develop a sustained release multiparticulate dosage form as a tablet of metoprolol succinate to reduce the dosing frequency from three times to once a day, and to study the stability of these formulations.Sustained release multiparticulate tablets of metoprolol succinate were prepared by the compression technique in which sustained release pellets were mixed with the cushning agent micro-crystalline cellulose (Avicel ® PH 102), superdisintegrant Indion 414 and lubricant magnesium stearate.

• Preparation of drug pellets
Metoprolol succinate 20% w/v was mixed with a 1% w/v aqueous binder solution of polyvinyl pyrrolidone (PVP) K30 and 2% w/v talc with continuous stirring (Rahman, Yuen, 2006).This drug solution was sprayed onto 200 g of uncoated pellets as non pariel seeds of 14/16 mesh of size 850-1100 µm by the solution layering technique in a coating pan (Instacoat R & D Coater, Ideal Cures Pvt. Ltd., Mumbai, India).The drug layering conditions were as shown in Table I.

• Preparation of polymer dispersion
An aqueous dispersion of Surelease ® was diluted to 15% w/v with distilled water.Similarly, a 5% solution of HPMC E15 was prepared in water by dispersing the powder of HPMC E15 in 50 ml of preheated water (80-90 o C) and then diluting it with an additional 50 ml of cold water.The solution was kept overnight.Varying polymer blends of Surelease ® and HPMC E15 were selected for the polymer dispersion of sustained release formulation.To reduce foam, the anti-foaming agent oleic acid was added to the dispersion.

Coating of drug pellets with polymer dispersion
In a mixture of dispersion of varying concentrations of Surelease ® and HPMC E15, a small quantity of talc (2% w/v) was added as an anti-adherent to the coating mixture.The mixture was stirred using a magnetic stirrer prior to and throughout the coating process.The drug pellets (200 g) were coated at different coating loads by the solution layering technique.Coating parameters were set as shown in Table I.The coating fluid was sprayed onto the pellets with an intermittent drying time of 5 min in a coating pan.

Formulation optimization (factorial design)
The optimization of batch was carried out by 3 2 full factorial design as shown in Table II.
Different formulation codes were assigned to the batches of ratios of Surelease ® : HPMC E15 and polymer coating loads.Formulation code F1 indicated the content of Surelease ® and HPMC E15 in the ratio of 70:30 of 15% coating load.Formulation codes F2 to F9, assigned to the varying blends of polymer and coating load, are as shown in Table III.In the factorial design, dependent variables are Y1 as drug release (%), Y2 as t 50% (h), Y3 as t 80% (h) and independent variables are X1 as ratio of Surelease ® : HPMC E15, and X2 as coating load (%).

Curing time
After coating, the pellets were further cured at 40 o C at 75% relative humidity for 24 h (Lecomte, 2004)

Characterization of pellets
Non pareil seeds were evaluated visually to check the spherical nature.The flow property of these was studied using the following tests: • Carr's index Carr's index value for uncoated pellets and coated pellets were determined using formula (Aulton M., 2002): (Tapped density -Fluff density) Carr's Index (%) = -------------x 100 Tapped density • Angle of repose The static angle of repose of uncoated pellets and coated pellets was measured by the fixed funnel and free-standing cone method (Aulton M., 2002) using the formula: Angle of repose (θ) = tan -1 h/r where: h-height of the heap; r-radius of the flat surface occupied by pellets • Drug content Sustained release pellets (400 mg) of MS were triturated and dissolved in 100 ml distilled water.Further dilutions were made using pH 6.8 phosphate buffer solutions.The amount of drug content was estimated UV spectrophotometrically (JASCO V-530, Japan) at 274 nm.

In vitro dissolution
Dissolution testing of formulations F1-F9 was performed using USP XXVIII type I.The test was performed using 500 ml solution of pH 6.8 phosphate buffer maintained at temperature 37 ± 0.5°C stirred at a speed of 50 rpm (United State Pharmacopoeia, 2005).A sample of 5 ml was taken out at an interval of 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 13, 14, 20, 21, 22, 23 and 24 h and immediately replaced with 5 ml fresh pH 6.8 phosphate buffer solution to maintain sink conditions in the dissolution jar.The drug content was analyzed at 274 nm using a UV spectrophotometer (Jasco, Japan).

Sustained release metoprolol succinate tablets
Sustained release pellets having a cushning agent of micro-crystalline cellulose and superdisintegrant of Indion 414 were compressed in a six stations rotary tablet machine (General Machinery Co., Mumbai) equipped with flat-faced punch with a diameter of 9 mm and length of 16mm after lubrication of the punch and die by dusting with magnesium stearate to achieve a 700 mg multiparticulate sustained release tablet (Table IV).
Cushning agents protected the polymer coat while superdisintegrant released the pellets from the multiparticulate tablet.Multiparticulate sustained release tablets were evaluated for hardness, friability, drug content, disintegration test and dissolution test.

Scanning electron microscopy
The morphology of the surfaces and cross sections of the coated pellets were examined before and after compression by scanning electron microscopy (SEM) (Tunon A., 2003).The dried samples were coated by platinum coating using an auto fine coater (JEOL-JFC 1600, Japan) and then observed under different magnifications with an analytical scanning electron microscope (JEOL-JSM 6360A, Japan).

Stability testing protocol
Coated pellets were packaged and sealed in 20 g quantities in high density amber colored bottles.These bottles were then placed inside stability testing instruments (Scientific equipment Pvt. Ltd., Mumbai) previously equilibrated to 25ºC/60% relative humidity (RH).At predetermined time intervals, bottles were pulled out from stations and tested for dissolution (Shao, 2002).

Physical characteristics of pellets
Non pareil seeds and sustained release pellets having Carr's index value in the range 14-16% and angle of repose of 22-24 0 showed good flow property (Aulton, 2002).

Drug Content
Amount of drug in pellets was found to be 11% estimated spectrophotometrically.

In vitro dissolution data analysis
In 3 2 full factorial design, various factors were studied using all the possible combinations, as it was considered to be most efficient for estimating the influence of individual variables (main effects) and their interactions, using minimum experimentation (Figure 1).

Study of regression coefficient (r 2 ) of different kinetic models
Different kinetic models were studied from dissolution profile of the different formulations of metoprolol succinate sustained release pellets as shown in Table VI.
The general polynomial equation for percent release in terms of coded factors using multiple linear regression analysis is - Where Y represents the measured response and X 1 represents the value of the factors.β 0 , β 1 , β 2 … are the constants representing the intercept, coefficients of first-order  terms, and coefficients of second-order quadratic terms, respectively.Further data was obtained by putting design experts results into the above polynomial equation.
Table VI indicates the best-fit model for each formulation.The model was calculated based on the value of coefficient of regression closest to 0.9999.Out of a total of nine formulations, F1, F3, F4, F9 followed the Higuchi model.Formulations F2, F5, F6, F7, and F8 followed zero-order kinetics.

Comparative study of dissolution profile of optimized formulation and marketed formulation
From data obtained by the feasibility search method, the formulation batch of ratio 80:20 of coating load 22.5% was selected for further study.The dissolution profile of the optimized formulation of sustained release pellets was compared with the marketed matrix tablet formulation as shown in Figure 2 whereas kinetics parameters studied are shown in Table VII.Similarity factor (f2) was calculated using PCP-DISSO software and found to be 79.43.

Characterization of metoprolol succinate multiparticulate sustained release tablet
The evaluation parameters of multiparticulate tablet of tablet size, tablet thickness, weight variation, hardness, friability, drug content and uniformity of content were as depicted in Table VIII.

Dissolution profile
The dissolution profile of multiparticulate sustained release tablet was compared with sustained release marke-ted matrix tablet.The similarity (f2) factor was calculated using PCP-DISSO software and found to be 76.46.
From the value of regression coefficient (r 2 ), the best fit model was found to follow zero order kinetics with r 2 as 0.9939.The t 50% and t 80% of multiparticulate tablet was found to be 7.2 ± 0.4 h and 13.5 ± 0.5 h, respectively (Figure 3).

Scanning electron microscopy of non pareil seeds, coated pellets and compressed sustained release pellets
The coatings of non pareil seeds, coated pellets and sustained release pellets after compression were studied by scanning electron microscopy at both low and high magnifications.The coated pellets at low magnification appeared as spherical discrete units (Figure 4, Figure 6 and Figure 9)   and the surface morphology at high magnification was not homogenous or smooth, acting as entrance or exit points for the dissolution medium to dissolve the drug (Figure 5, Figure 7, Figure 8 and Figure 10).

Stability data
Stability data revealed that pellets were stable at 25ºC/60% relative humidity (RH) for short term stability of three months.The amount of drug in the pellets was found to be the same after three months (Figure11).
The present study investigated the coating effect of a combination of Surelease ® and HPMC E15 on drug release of highly water soluble metoprolol succinate in a coating pan.Coated pellets showed good flow properties    for the development of a tablet as a multiparticulate drug delivery system.This film, formed by the combination of these polymers, strongly retarded the permeation of metoprolol, a highly soluble drug, for extended release.The optimization results revealed that metoprolol succinate sustained release pellet of Surelease ® and HPMC E15 of 80:20 at a 22.5 % coating load showed comparatively better drug release of zero order kinetics than the 90:10 blend.Scanning electron microscopy revealed uniform coating.The surface was uneven at low coating level, but was uniform in an optimized batch of 25% coating load.
Dissolution data from stability testing revealed that metoprolol succinate was stable with surelease ® and hydroxypropyl methylcellulose.

CONCLUSION
In this study, we have shown the effect of varying ratios of polymers of Surelease ® and HPMC E15 to attain the sustained release property of the pellets formulated in the multiparticulate tablet using an economical pan coating process.In conclusion, the blends of polymer represent the potential formulation factor for the sustained release rate of highly water soluble drugs avoiding the risk of dose dumping.

TABLE II -
Factorial design data

TABLE I -
Coating parameters required during coating

TABLE III -
Different combinations of polymers and coating thickness

TABLE IV -
Composition of multiparticulate sustained release tablet

TABLE V -
Percent cumulative release of t 50% and t 80% of metoprolol succinate pellets

TABLE VI -
Kinetic models showing drug release pattern of F1-F9 formulations

TABLE VII -
Kinetic models showing drug release pattern of formulated and marketed formulation

TABLE VIII -
Evaluation parameters of multiparticulate tablet FIGURE 2 -Comparative study of dissolution profile of optimized formulation and marketed Formulation.