Formulation and evaluation of captopril floating matrix tablets based on gas formation

Captopril has a short elimination half-life and is stable at pH 1.2 and as the pH increases; the drug becomes unstable and undergoes a degradation reaction. The purpose of this study was to develop a gastroretentive controlled release drug delivery system with swelling and floating properties. Seventeen tablet formulations were designed using hydroxyl propyl methyl cellulose (HPMC) K4M, Carbomer 934, Eudragit RS PO as release retarding polymer(s), lactose or Avicel PH 102 as a filler and sodium bicarbonate as a gas former by direct compression. Tablets were evaluated for various physical parameters, floating properties, swelling ability and drug release characteristics in 12 h. Based on the release kinetics, all formulations best fitted the Higuchi, Hixson Crowell model and non-Fickian as the mechanism of drug release. Statistical analyses of data revealed that formulation containing HPMC K4M (42%, w/w), NaHCO3 (8%, w/w) and Avicel PH 102 (32.35%, w/w) was the promising system exhibiting excellent floating properties and sustained drug release (12 h) characteristics.


INTRODUCTION
The drug bioavailability of pharmaceutical dosage forms is influenced by various factors.One of the important factors is the gastric residence time (GRT) of these dosage forms.Variable and short gastric emptying time can result in an incomplete release of drug and diminished efficacy of the administered dose.Floating drug delivery system (FDDS) is one of the gastroretentive dosage forms that could prolong GRT to obtain sufficient drug bioavailability (Sungthongjeen et al., 2008;Strubing et al., 2008a,b;Gambhire et al., 2007).
FDDS is desirable for drugs with an absorption window in the stomach or in the upper small intestine such as furosemide and theophylline.It is also useful for drugs that act locally in the proximal part of GI tract such as antibiotic administration for Helicobacter pylori eradication in the treatment of peptic ulcer, for drugs that exhibit poor solubility in the intestinal tract such as diazepam and verapamil HCl, and for drugs that are unstable in the intestinal fluid such as Captopril (Sungthongjeen et al., 2008;Gambhire et al., 2007;Singh and kim, 2000).
Captopril, (1-[(2S)-3-mercapto-2-methyl propionyl]-1proline), an angiotensin-converting enzyme inhibitor, has been used widely for the treatment of hypertension and congestive heart failure (Brunton et al. 2005).The drug is freely water soluble and has half-life elimination after an oral dose of 2h (Sweetman et al., 2002).It is stable at pH 1.2 and as the pH increase; the drug becomes unstable and undergoes a degradation reaction.Thus, captopril is a candidate for the development of FDDS.Various pharmaceutical approaches for the controlled-release preparation of captopril, including biodegradable microparticles, osmotic pump tablets and hard gelatin capsules, have been reported (Dandagi et al., 2006;Efentakis and Vlachou, 2000;Xu et al., 2006).The effect *Corresponding author.E-mail: jafariazar@iaups.ac.ir.Tel: +98-21-22237147.Fax: +98-21-22233463 of compaction pressure on floating behavior of captopril tablets have been studied (Jimenez et al., 2008).In another study, bilayer floating tablets of captopril have been reported (Ziyaur et al., 2006).In the present study, the details of formulation development and evaluation of gas forming floating tablets of captopril using hydroxyl propyl methyl cellulose (HPMC K4M), Carbomer 934, Eudragit RSPO as release-retarding polymer(s) are described.

Preparation of captopril floating tablets
Tablets containing 50 mg captopril were prepared, according to the design shown in Table 1, by direct compression.The respective powders, namely captopril, release-retarding polymer(s) (HPMC K4M, Carbomer 934 and Eudragit RS PO alone or in combination with each other), a gas-forming agent (NaHCO3) and a filler (Lactose or Avicel PH 102) were passed through sieve no.40, separately.Mixing of powders was carried out using a pestle and mortar for 10 min.Magnesium stearate was passed through sieve no.60 and then added to the mixed powders.Mixing was continued for another 3 min.Finally, 300 mg of each mixture were weighed and fed manually into the die of a single punch tabletting machine (Korsch), equipped with concave punches (10.0 mm), to produce tablets adjusted at a hardness of 5 to 7 kg/cm².The hardness of the tablets was measured using a hardness tester (Erweka TBH 30 GMD, Germany).

In vitro evaluation of the prepared tablets
Tablet weight variation, tablet thickness and tablet friability test were carried out according to USP [31] and BP [21], respectively.

Drug content uniformity
Ten tablets were individually weighed and crushed.A quantity of powder equivalent to the mass of one tablet (300 mg) was dispersed in 100 ml of 0.1 N HCl.The solution was filtered through a cellulose acetate membrane (45 µm).The drug content was determined by UV spectroscopy (UV-1650 PC Double beam spectrometer, Shimadzu, Kyoto, Japan) at a wavelength of 205 nm after a suitable dilution with 0.1 N HCl (Tadros, 2010).

Tablet floating behavior
A tablet was placed in a glass beaker, containing 200 ml of 0.1 N HCl, maintained in a water bath at 37 ± 0.5°C.The floating lag time ''the time between tablet introduction and its buoyancy" and total floating duration ''the time during which tablet remains buoyant" were recorded (Rosa et al., 1994).

Tablet swelling ability
The swelling behavior of the tablets was determined, in triplicate, according to the method described by Dorozynski et al. (2004).Briefly, a tablet was weighed (W1) and placed in a glass beaker, containing 200 ml of 0.1 N HCl, maintained in a water bath at 37 ± 0.5°C.At regular time intervals, the tablet was removed and the excess surface liquid was carefully removed by a filter paper (Patel et al., 2009).The swollen tablet was then reweighed (W2).The swelling index (SI) was calculated using the formula as follows:

Drug release studies
Drug release studies of the prepared floating tablets were performed, in triplicate, using apparatus 2 (Erweka DT 800, Germany) at 37 ± 0.5°C and 50 rpm.The tablets were placed into 900 ml of 0.1 N HCl solution (pH 1.2).Aliquots of 5 ml were withdrawn from the dissolution apparatus at different time intervals and filtered through a cellulose acetate membrane (0.45 µm).The drug content was determined spectrophotometrically at a wavelength of 205 nm, as mentioned earlier.At each time of withdrawal, 5 ml of fresh medium was replaced into the dissolution flask.The resulting data were analyzed by using the software Statistical Package for Social Sciences 19.0 (SPSS Inc., Chicago, USA) applying one way analysis of variance (ANOVA).

Physicochemical characteristics of tablets
To avoid processing variables, all batches were produced under similar conditions.The hardness of the tablets was between 5 and 7 kg/cm² and all formulations had friability less than 1%.Average mass variation was 300.36 ± 0.35 mg, mean thickness was 4.22 ± 0.19 mm and the content uniformity of the tablets was 101.69 ± 0.91%.All formulations, except formulation containing Eudragit RS PO alone with poor compressability, showed acceptable physicochemical properties.

In vitro buoyancy
Floating dosage forms could be floated due to an intrinsic density lower than gastric content, which is reported as 1.004 to 1.010 g/cm³ or due to the formation of a gaseous phase inside the system after contact with gastric fluid (Elkheshen et al., 2004).This attribute allows them to remain afloat on the surface of the gastric content for a longer period of time without affecting the rate of emptying.For evaluation, the effects of the amount of sodium bicarbonate C series were prepared.The formulation C 1 , prepared without sodium bicarbonate, did not show any sign of floating.Therefore, sodium bicarbonate was essential in order to float the tablet.To study the effect of sodium bicarbonate amount on floating lag time, A 2 , C 2 Time (s)  noticeable that the matrices containing Carbomer 934 (more than 25 mg) did not have any floating lag time, while increasing HPMC K4M increased floating lag time.The in vitro behavior of the best formulation is as shown in Figure 1.

Swelling indices
Hydrophilic matrices in contact with water swell and increase their volume due to water diffusion through the matrix.The polymer chains continue the hydration process and the matrix gain more water.The increasing water content dilutes the matrix until a disentanglement concentration is attained.At this point, the polymer molecules are released from the matrix, diffusing to the bulk of the dissolution medium.Then, the matrix volume decreases slowly, because of polymer dissolution.Polymeric matrices experience simultaneously swelling and polymer dissolution and diffusion.The hydration ability of the formulation is important, because it influences tablet buoyancy and drug release kinetics.The test medium uptake by prepared matrices depends on the type and amount of polymer.Higher polymer contents increase the tortuosity and the length of matrices delaying its entire hydration, as shown in Table 2 and Figure 4.
The high affinity of Carbomer to the test medium causes high swelling ability.Hydrophilic groups in Eudragit RS PO are less than other polymers, so the formulation containing it had the lowest swelling.

In vitro drug release studies
Ideally, a sustained release formulation should release the required quantity of drug with predetermined kinetics in order to maintain effective drug plasma concentration.
To achieve this, the delivery system should be formulated so that it releases the drug in a predetermined and reproducible manner.The release of captopril from GRDDS was analyzed by plotting the cumulative percent drug released against time (Figure 5).It is worth to note that, a burst effect was observed with all formulations.This could be due to the fact that the gel layer, which controls the drug release rate, needs some time to become effective.The rapid drug dissolution from the surface of the tablets could be another possible explanation.Kulkarni and Bhatia (2009) suggested that the resulting gel-like networks surrounding these matrices, upon contact with aqueous media, would produce strong surface barriers that would effectively reduce the burst drug release.This effect significantly reduced when the concentration of HPMC K4M increased or when Carbomer 934 is used as a polymer in combination with HPMC K4M.K4M.On the other hand, the presence of carbon dioxide bubbles, produced after reaction of sodium bicarbonate with the acidic dissolution medium, decrease the drug release rate.Siepmann and Peppas (2001) suggested that the drug release from HPMC matrices is sequentially governed as follows: (1) at the beginning, steep water concentration gradients are formed at the polymer/water interface resulting in water imbibition into the matrix; (2) due to the imbibition of water, HPMC swells resulting in dramatic changes of polymer and drug concentrations and increasing dimensions of the system; (3) upon contact with water, the drug dissolves and diffuses out of the device due to concentration gradients; (4) with increasing water content, the diffusion coefficient of the drug increases substantially.When the amount of HPMC K4M increased, drug release rate decreased (p ˂ 0.05) (Figure 5 (a and b).
The drug release rate from matrices that contained Carbomer 934 and HPMC K4M, in combination, in comparison with HPMC K4M alone significantly reduced (p ˂ 0.05) and it was independent of concentration of Carbomer 934.Yao et al. (2011) suggested that the hydrogen bonds between the -COOH group of the Carbomer and -OH group of the HPMC are more stable than those between the -OH groups of water and HPMC, and the hydrophobicity of the HPMC chains in presence of Carbomer increases, so drug release rate decreases (Figure 5d).
The drug release rate from matrices that contained Eudragit RS PO and HPMC K4M, in combination, in comparison with HPMC K4M alone significantly increased (p ˂ 0.05).Hydrophilic groups that exist in polymer structure play an important role in drug release rate and swelling ability.The number of hydrophilic group in Eudragit RS PO is less than HPMC K4M, so by increasing the amount of Eudragit RS PO drug release rate increases and swelling ability decreases (Figure 5e).The drug release rate in matrices with lactose as filler was faster than that contained in Avicel PH 102 (p ˂ 0.05) (Figure 3).Lactose is water soluble filler, so entrance of water to polymeric network is easier than formula that contained water insoluble Avicel PH 102 (Figure 5b).Moreover, the increased amount of sodium bicarbonate caused a large amount of gas evolution, which in turn resulted in pore formation, which led to rapid hydration of the polymer matrix and thereby to rapid drug release (p ˂ 0.05) (Figure 5c).
In the whole, drug release from Eudragit RS PO was faster than HPMC K4M and it was faster than Carbomer 934P (Figure 6).

Drug release kinetics
The release profile of the optimized formula (C 3 ) fitted best to the Hixson-Crowell (R² = 0.992 and n = 0.518), indicating non-Fickian diffusion or anomalous transport, with release by diffusion and swelling (combination of diffusion and erosion-controlled release).

Conclusion
This study was conducted to develop an effervescent floating drug delivery system using HPMC K4M, Carbomer 934 and Eudragit RS PO in different concentrations.Optimized formulation C 3 showed an excellent buoyant ability and a suitable drug release pattern.This could be advantageous in terms of increased bioavailability of captopril.The developed gastroretentive drug delivery system provides advantages of ease of preparation and sustained drug release for 12 h.

Table 1 .
The composition, in milligrams, of the investigated captopril gas forming floating tablets.

Table 2 .
Floating and swelling properties of the prepared captopril effervescent floating tablets*.