Gestroretentive tablets of verapamil HCl were developed to increase the gastric retention time of the drug, so that they can be retained in stomach for longer time and help in controlled release of drug up to 24 h. The IGF tablets were made using gel-forming polymers such as CP 934P, CP 940P, HPMC K4M, HPMC K15M, and xanthan gum BP. They are known to be beneficial in improving the buoyancy characteristics and drug release characteristics. When a combination of gas entrapping as well as controlled-release system was there, the use of disintegrating agent was important which does not quickly break the matrix and allows slow disintegration of the swollen matrix. PVP K30 in an optimized concentration (20 mg/tablet) was employed for such unique disintegrating agent (17
). The talc and magnesium stearate were employed for their glidant and lubricant property (18
). The composition of IGF tablets of verapamil HCl is shown in Table . The prepared IGF tablets were evaluated for thickness, weight variation, hardness, friability, drug content, swelling index, in vitro
buoyancy studies, in vitro
drug dissolution studies, and in vivo
gastric retention using X-ray imaging. All the studies were performed in triplicate, and results are expressed as mean ± SD.
Physicochemical Characterization of IGF Tablets
The IGF verapamil HCl tablets were off-white, smooth, and flat shaped in appearance. The results of physicochemical characterizations are shown in Table . The thickness of IGF tablets was measured by digital thickness tester (Mitutoyo, Japan) and was ranged between 2.19
0.073 and 2.61
0.049 mm. The weight variation for different formulations (F1 to F8) was found to be 0.393
0.002% to 0.750
0.005%, showing satisfactory results as per Indian Pharmacopoeia (IP) limit. The hardness of the IGF tablets was measured by Monsanto tester (Indian Equipment Corporation Mumbai, India) and was controlled between 5.0
0.165 and 6.5
Physicochemical Characterization of IGF Tablets of Verapamil HCl (F1 to F8)
In Vitro Buoyancy Studies
All the IGF tablet formulations were prepared by effervescent approach. The in vitro
buoyancy of IGF tablets was induced by sodium bicarbonate and anhydrous citric cid in optimized ratio (5:2) without compromising the matrix integrity with the possible shortest bouncy lag time and buoyancy duration of up to 24 h. It was observed that the gas generated was trapped in the tablet and protected within the gel formed by hydration of polymers, thus decreasing the density of the tablet below 1, and tablet becomes buoyant (19
The IGF tablets F1 and F2 containing CP 934P and CP 940P respectively, exhibited buoyancy lag time of 58.3
4.0 and 78.9
2.5 s, respectively, and floated till 24 h. The IGF tablets F3 and F4 contained HPMC K4M and HPMC K15M, respectively, with short buoyancy lag time of 47.8
3.1 and 55.1
1.9 s, respectively, but the total buoyancy time was less than 24 h (Table ). These might be due to rapid hydration of HPMC polymers which floated in short time as compared to IGF tablets containing CP polymers. The CP produces firm gel that entrapped the gas for longer time as compared to HPMC which has high rate of hydration and disintegrated in presence of PVP K30 (20
). Same results were also observed in swelling studies where initial swelling index was observed higher in HPMC containing IGF tablets F3 and F4. The IGF tablets containing xanthan gum (F5) showed buoyancy lag time 42.8
4.4 s with total buoyancy time more than 24 h which had showed satisfactory results.
Among IGF tablets F6, F7, and F8, the IGF tablet F7 showed shortest buoyancy lag time (36.2
3.6 s) with more than 24 h total buoyancy time (Fig. ). In dissolution studies, CP 940P containing IGF tablets F2 settled to the bottom, which might be due to their high moisture gain, which in turn showed decrease in buoyancy capability upon disturbing.
In Vitro buoyancy studies of IGF tablet (F7)
Swelling is also a vital factor to ensure buoyancy and drug dissolution of the matrix tablet. The IGF tablets composed of polymeric matrices build a gel layer around the tablet core when they come in contact with water. This gel layer governs the drug release from the matrix tablet. Figure shows the swelling index of IGF tablets of F1 to F8. The IGF tablets containing CP 934P and CP 940P (F1 and F2), respectively, showed less swelling index at the beginning but was found higher at the end of 12 h.
Swelling index of IGF tablets of F1 to F8
The IGF tablets containing HPMC K4M and HPMC K15M (F3 and F4) showed higher swelling index at the first 2 h but could not maintain their matrix integrity up to 12 h. The IGF tablets containing xanthan gum (F5) showed constant increase in swelling index up to 12 h. At the end of 12 h, IGF tablet containing HPMC K4M and xanthan gum BP (F7) was slightly less than IGF tablet containing xanthan gum BP alone (F5). But initial swelling index was observed higher in F7 than F5, which might be due to the rapid hydration of HPMC K4M.
In Vitro Dissolution Studies
In vitro dissolution studies of all the formulations of IGF tablets of verapamil HCl were carried out in 0.1 N HCl. The study was performed for 24 h, and cumulative drug release was calculated at 1-h time intervals.
The results of in vitro dissolution studies are shown in Fig. . The higher initial drug dissolution was observed in tablets containing HPMC K4M and HPMC K15M (F3 and F4) as compared to IGF tablets containing CP 934P and CP 940P (F1 and F2).
In Vitro fissolution studies of IGF tablets of verapamil HCl (F1 to F8)
This showed that HPMC hydrated more rapidly than CP in the presence of 0.1 N HCl. But the IGF tablets containing CP showed the drug release up to 24 h in controlled manner without changing their physical integrity in dissolution medium. Moreover, the HPMC containing IGF tablets F3 and F4 could not bear their matrix shape until 24 h and released the drug before 24 h. HPMC K4M containing IGF tablets F3 could not maintain its matrix integrity more than 16 h with release of 99.80% of drug. The IGF tablets containing HPMC K15M (F4) showed release of 98.15% at the end of 22 h; IGF tablets containing xanthan gum (F5) showed constant drug release up to 24 h (93.33%). This controlled release of drug from F5 could be attributed to the formation of a thick gel structure that delayed drug release from the IGF tablet matrix. The IGF tablets containing combination of HPMC K4M and HPMC K15M (F6) disintegrated at 19 h with drug release of 99.46%. The in vitro drug dissolution was slightly more rapid, by combination of xanthan gum with HPMC K4M (F7) and HPMC K15M (F8), than IGF tablets containing xanthan gum alone (F5) due to the rapid hydration of HPMC K4M.
The data obtained from in vitro
dissolution studies were fitted to zero-order, first-order, Higuchi and Korsemeyer–Peppas equations (Table ). To confirm the exact mechanism of drug release, the data were fitted according to Korsemeyer–Peppas equation (21
is fraction of drug released, k
is kinetic constant, t
is release time, and n
is the diffusional exponent for drug release. Peppas stated that the above equation could adequately describe the release of solutes from slabs, spheres, cylinders, and discs regardless of the release mechanism. The “n
” is the slope value of log versus
log time curve. The value of “n
” gives an indication of the release mechanism; when n
1, the release rate is independent of time (zero-order; case II transport), n
0.5 for Fickian diffusion, and when 0.5
1.0, non-Fickian diffusion is implicated. Lastly, when n
1.0, super case II transport is apparent. The slope values which were less than and nearer to 1.0 suggested that the release of verapamil HCl from IGF tablets followed non-Fickian diffusion mechanism with zero-order release kinetic.
Different Kinetic Models for IGF Tablets of Verapamil HCl (F1 to F8)
Evaluation of Gastric Retention Using X-Ray Imaging
The prepared IGF tablets containing xanthan gum and HPMC K4M (F7) were selected for evaluation of gastric retention using X-ray imaging. Figure showed the gastric retention of IGF tablet in mongrel dogs after 5 h. The in vivo
buoyancy of IGF tablets were confirmed by X-ray imaging at 30 min regular time interval after ingestion of IGF tablet containing BaSO4. The behavior of the IGF tablet in the mongrel dog stomach was observed using a radiographic imaging technique. The IGF tablet seen in stomach of mongrel dog till 5 h (n
3) showed the confirmation of buoyancy of the IGF tablets.
Evaluation of gastric retention using X-Ray imaging
The prepared IGF tablets containing xanthan gum and HPMC K4M (F7) were selected for stability study on the basis of in vitro buoyancy and in vitro drug dissolution studies. The IGF tablets were stored at 40°C/75% RH in closed high-density polyethylene bottles for 3 months. The IGF tablets did not show any significant change in physicochemical parameters and other tests (Table ). Thus, it was found that the IGF tablets of verapamil HCl tablets (F7) were stable under these storage conditions for at least 3 months.
Stability Studies of Optimized IGF Tablet (F7) of Verapamil HCl