|Year : 2011 | Volume
| Issue : 1 | Page : 8-13
Effect of grinding on in vitro floating behaviour of effervescent matrix tablets of ciprofloxacin hydrochloride: Negative impact on initial buoyancy
Jeetendra Singh Negi1, Abhinav Trivedi1, Vandana Negi1, Aadesh Upadhyay2, Nikhil Kasliwal3
1 Department of Pharmaceutical Sciences, Sardar Bhagwan Singh PG Institute of Biomedical Sciences and Research, Balawala, Dehradun, India
2 Department of Pharmaceutical Sciences, Guru Ram Das Institute of Management and Technology, Dehradun, India
3 Product Development and Research (Formulation and Development), Jubilant Life Sciences, Noida, India
|Date of Web Publication||15-Jul-2011|
Jeetendra Singh Negi
Department of Pharmaceutical sciences, Sardar Bhagwan Singh PG Institute of Biomedical Sciences and Research, Balawala, Uttarakhand Technical University, Dehradun - 248 161
Source of Support: None, Conflict of Interest: None
| Abstract|| |
The purpose of this study was to form dispersion of sodium bicarbonate in hydroxyl-propyl methyl cellulose (HPMC K4M) matrix and investigate its impact on in vitro floating behaviour and drug release. The dispersion of sodium bicarbonate in HPMC K4M was achieved by grinding method using mortar and pestle. The in vitro floating behaviour and drug release of matrix tablets having grinding dispersion (GD) were compared with matrix tablets having physical mixture. The GD matrix tablets were having higher values of buoyancy lag time (BLT) in comparison to PM matrix tablets. However, the floating duration of GD matrix tablets was higher than that for PM matrix tablets. The swelling extent was also found higher for GD matrix tablets. Higher drug release rate was achieved with GD matrix tablets and drug release kinetics was explained by korsemeyer-peppas model. The values of diffusion coefficient (n) were found between 0.45−0.89, which indicates the anomalous type of drug transport.
Keywords: Buoyancy lag time, floating tablets, grinding, microenvironmental pH, swelling index
|How to cite this article:|
Negi JS, Trivedi A, Negi V, Upadhyay A, Kasliwal N. Effect of grinding on in vitro floating behaviour of effervescent matrix tablets of ciprofloxacin hydrochloride: Negative impact on initial buoyancy. J Pharm Negative Results 2011;2:8-13
|How to cite this URL:|
Negi JS, Trivedi A, Negi V, Upadhyay A, Kasliwal N. Effect of grinding on in vitro floating behaviour of effervescent matrix tablets of ciprofloxacin hydrochloride: Negative impact on initial buoyancy. J Pharm Negative Results [serial online] 2011 [cited 2019 Nov 19];2:8-13. Available from: http://www.pnrjournal.com/text.asp?2011/2/1/8/82984
| Introduction|| |
Several approaches have been applied to prepare dosage form for gastric retention.  Development of floating matrix tablet is one of the successful one for gastric retention.  In addition to gastric retention, drug release can also be sustained for longer duration.  Matrix can be prepared by both effervescent and non-effervescent approaches. , The presence of sodium bicarbonate in effervescent matrix tablets is responsible for carbon dioxide bubbles when tablet comes in contact with acidic medium of gastric region. The bubbles formation and entrapment inside gellified matrix of hydrophilic polymer provide buoyancy to dosage form.  The present work involves the study of effect of grinding on the floating behaviour of effervescent matrix tablets. Generally, physical mixture of sodium bicarbonate and hydrophilic polymer has been utilized for tablet development.  In this work we tried to make molecular dispersion of sodium bicarbonate in hydrophilic polymer matrix in order to improve buoyancy behaviour of tablets. The molecular dispersion can be achieved by several methods like melting method, solvent evaporation and grinding method. ,, The sodium bicarbonate converts into sodium carbonate on heating and solubility of sodium bicarbonate is also not good in organic solvents.  Thus, melt method and solvent evaporation methods could not be utilized for dispersion of sodium bicarbonate in hydrophilic polymer matrix. The grinding method was utilized to form molecular dispersion of sodium bicarbonate in hydrophilic polymer matrix.
The ciprofloxacin HCL was selected as model drug due to its better absorption at upper part of GI tract.  The short half-life of 4h also make it suitable drug candidate for sustained delivery. Also, the effect of grinding on drug release behaviour from matrix tablets was studied for 12 h sustained drug delivery.
| Materials and Methods|| |
Ciprofloxacin HCL (CIPRO) and hydroxy propyl methyl cellulose K4M (HPMC K4M) were obtained as gift sample from Sanjivani parenteral ltd. Selaquai, Dehradun. Poly vinyl pyrollidone (PVP K30), Talc and Sodium bicarbonate (SB) were purchased from Central drug house (CDH ltd.), India.
Preparation of physical mixture tablets
CIPRO and other excipients [as listed in [Table 1]] were mixed in a double cone mixer for 5 min. Magnesium stearate (0.5%) was added as lubricant and blended for another 2 min. Tablets were prepared by direct compression using 12 mm flat faced punch on a sixteen station single rotary compression machine (Cadmach Machinery Co. Pvt. Ltd., Ahmedabad, India). The hardness of tablets was kept constant at 5 kg/cm 2 and measured by a Monsanto hardness tester (Rimek, Mumbai, India).
Preparation of grinding dispersion tablets
The different ratio of SB and HPMC K4M [Table 1] were mixed in a double cone mixer for 5 min. The resulted mixture was then grinded in a mortar with help of pestle for 10 min. The grinded mass was mixed with CIPRO and other excipients for 5 min. and directly compressed into tablets using 12 mm flat faced punch on a sixteen station single rotary compression machine (Cadmach Machinery Co. Pvt. Ltd., Ahmedabad, India). The hardness of tablets was kept constant at 5 kg/cm 2 and measured by a Monsanto hardness tester (Rimek, Mumbai, India).
Buoyancy lag time
The time taken by tablets to reach at surface of release medium was recorded as Buoyancy Lag Time (BLT). In-vitro BLT of floating matrix tablets was performed in 900 ml of 0.1 N HCl using the USP XVI apparatus II (Lab India Disso 2000) at 100 rpm and 37°C. 
The duration for which tablet constantly remained buoyant was recorded as floating duration. Tablet was placed into a dissolution flask filled with 900 ml of 0.1 N HCl. The USP XVI apparatus II (Lab India Disso 2000) operated at 100 rpm and temperature was kept constant at 37°C. 
The swelling performance of tablets was evaluated in USP XXVI dissolution apparatus II (Lab India Disso 2000) at 37± 0.5° C and 50 rpm. The tablets were removed at regular time interval and excess water was removed with help of filter paper.  Then weight of swollen tablet was recorded and swelling index was calculated using given formula;
W 1 - initial weight; W 2 - weight after given time interval.
Micro-environmental pH measurement
The tablet was placed in a small beaker having 5 ml. of distilled water. The pH change was measured at regular time interval using pH meter (Systronic, India). 
In-vitro drug release
In-vitro drug release studies of the prepared matrix tablets were conducted in a USP XXVI dissolution apparatus II (Lab India Disso 2000) filled with 900 ml. 0.1 N HCl at 37± 0.5° C and 100 rpm. Aliquot of 5 ml. were withdrawn from dissolution medium at different time intervals of 1, 2, 4, 6, 8 and 12 hr. and replaced with fresh medium on every withdrawal. After filtration and appropriate dilution, the samples were analysed by a UV spectrophotometer (Shimadzu UV-250 1PC double beam spectrometer) at 278 nm.
Drug release kinetics
The drug release data were fitted for zero-order, first-order, Higuchi model and Koresmeyer-Peppas model. Also, drug release mechanism was determined by Ritger-Peppas equation ,
Where, M t /M∞ is fraction of drug release, t is time, k is the constant incorporating structural and geometrical characteristics of dosage form and n is release exponent. The value of n was calculated only for the portion of drug release curve where Mt/M∞ ≤ 0.6.
| Results and Discussion|| |
The dispersion of SB in HPMC matrix was achieved by grinding method. During grinding the temperature may arise due to friction among particles. At higher temperature SB get decompose into other derivatives and lost gas generation ability.  To ensure the chemical stability the X-ray diffraction XRD patterns of grinding mass was compared with XRD patterns of pure SB and physical mixture of SB with HPMC. [Figure 1] indicates that the crystalline pattern of SB was not affected by grinding method. Thus crystalline nature and chemical stability of SB remains unaffected by grinding.
|Figure 1: XRD pattern of (a) SB (b) HPMC K4M (c) Physical mixture (d) Grinding dispersion|
Click here to view
When tablets came in contact with acidic release medium, the SB particles at outer surface of tablets react with acidic medium and rapid formation of CO 2 bubbles take place. This bubble formation propels tablets towards surface of release medium in order to achieve initial buoyancy.
The floating behaviour of effervescent matrix tablets was shown in [Table 2]. The BLT of formulation PM 1 was found 15 sec. However, the BLT of Formulation GD 1 was 9 min. The only difference between PM 1 and GD 1 was the type of mixture of SB and HPMC employed for matrix formation. The PM 1 contains physical mixture of ingredients whereas GD 1 contains dispersion of SB in HPMC prepared by grinding method. Thus, grinding of SB in HPMC matrix was resulted in higher values of BLT [Figure 2]. Initially, we thought that the dispersion of SB in HPMC would result in improvement in BLT but the study concludes just opposite results. This behaviour can be explained in terms of availability of SB on outer surface of tablets. The good dispersion of SB might resulted in unavailability of SB in outer surface and also lower exposure to acidic medium initially. In case of PM tablets, the more SB particles were available to react with acidic medium and more effective initial buoyancy was achieved. Also, as the concentration of SB increased in both PM and GD tablets the BLT was reduced.
|Figure 2: Photographs of GM1 formulation at different time intervals (a), (b) and (c) within one minute (d) after 6 h|
Click here to view
|Table 2: Different physicochemical properties of floating matrix tablets|
Click here to view
Further, the effect of grinding on floating duration was studied. The hydrophilic matrix of HPMC becomes hydrated and swollen gel matrix formation takes place. Initially, bubble tried to escape from matrix but as the swollen gel matrix formed, the bubbles escaping rate was reduced and tablets achieved buoyancy for long duration.
The FD of GD tablets was higher in comparison to PM tablets. Due to good dispersion of SB in HPMC, the instant gel formation and small CO 2 bubble formation occurred and resulted in effective entrapment of CO 2 bubbles right from the start without allowing their easy escape. In PM tablets, as the release medium penetrated the matrix, both CO 2 bubble formation and their quick escape was occurred. Thus grinding of SB in HPMC was resulted in efficient entrapment of bubbles inside gel matrix of HPMC for longer duration.
The hydration of polymeric chains of hydrophilic polymer occurs when tablets came in contact with release medium.  Higher uptake of water with HPMC matrix is due to the faster hydration rate of HPMC.  This faster hydration resulted in faster penetration by release medium into hydrophilic matrix. The hydrophilic chains formed viscous gel and swelling of matrix was occurred.
The volume expansion was higher in the presence of SB. This can be attributed to volume expansion due to CO 2 bubble formation on reaction between SB and acidic release medium. Similar observations were reported by Gutiérrez-Sánchez et al.  The hydration behaviour of PM and GD tablets was shown in [Figure 3]. The GD tablets were having higher volume expansion in comparison to PM tablets. The grinding of SB in HPMC matrix resulted in dispersion in which the gel formation and CO 2 entrapment occurs at the same time. The good dispersion of SB in HPMC matrix resulted in better entrapment of CO 2 bubbles and lead to higher volume expansion in GM tablets.
The increase in concentration of SB in both PM and GD tablets resulted in increase in swelling of tablets. After achieving maximum swelling the volume of matrix started to reduce. This reduction indicates the erosion or detachment of gel matrix. The escape of CO 2 bubbles further resulted in faster erosion rate. The rate of CO 2 bubble escape was low in GD tablets, which might be the reason of low erosion rate from GD 1 .
Distilled water hydrate and penetrates the matrix to form swollen gel matrix and CIPRO get diffuse through viscous gel layer. Initially, the pH of microenvironment was reduced for all formulations [Table 3]. This reduction in pH might be due to the diffusion of drug into distilled water. The degree of reduction in pH was different in GD and PM tablets. The micro-pH reduction was found dependent on the concentration of SB in tablets due to pH increasing tendency of SB. The micro-pH of PM 1 after one hour was 4.13, whereas the micro-pH of PM 2 after one hour was 3.69. As the concentration of SB increased the less reduction in micro-pH was observed. Less reduction in micro-pH after one hour was observed with GD 1 tablets in comparison to PM 1 tablets. This might be due to better dispersion of SB in HPMC matrix which efficiently counteracts the micro-pH reduction of CIPRO. Further, the micro-pH of tablets was increased and became constant at the end. Again this increase in micro-pH was SB concentration dependent.
The drug release from hydrophilic matrix depends on the following events; hydration of polymeric chains; swelling of hydrated chains; diffusion of drug from swollen gel matrix.  As the concentration of SB was increased from 20 mg to 56 mg, the drug release was also increased. Further, the drug release rate from GD tablets was higher in comparison to PM tablets [Figure 4]. The grinding dispersion of SB in HPMC resulted in higher drug release. As already discussed in previous section, the presence of more and efficient CO 2 bubble entrapment occurs in GD tablets. This again might be the reason for more hydration of matrix and faster drug release from GD tablets. The release data was further treated with different models in order to find out the kinetics of drug release. The model having best r 2 value was considered as the suitable kinetics. Most of the formulations followed koresmeyer-peppas model of kinetics, which encompasses the effect of both polymer swelling and drug diffusion.  Further, drug release mechanism from effervescent tablets was determined by measuring value of diffusion constant n using ritger-peppas model. The value of n [Table 4] was found between 0.45−0.89 (anomalous drug transport), and thus drug release was found depends on both diffusion and polymeric chain relaxation.
|Figure 4: Cumulative per cent drug release profiles of different formulations (n = 3)|
Click here to view
|Table 4: R2 for different release kinetics models with n for various matrix tablets|
Click here to view
| Conclusions|| |
The grinding method was successfully employed to form a dispersion of SB in HPMC K4M. The grinding dispersion of SB in HPMC K4M resulted in increase in BLT value. Thus, physical mixture of SB with HPMC K4M is found better for initial buoyancy than grinding dispersion. However, the grinding resulted in higher FD of matrix tablets. Thus, the effect of grinding dispersion of SB in HPMC K4M on in vitro buoyancy was found negative for BLT and positive for FD.
| Acknowledgements|| |
The authors are grateful to Sardar Bhagwan Singh PG Institute of Biomedical Sciences and research, Balawala for promoting and providing adequate research facilities. The authors also like to thank National Centre of Experimenatal Mineralogy & Petrology, Allahabad for providing XRD facility.
| References|| |
|1.||Deshpande AA, Shah NH, Rhodes CT, Malick W. Development of a novel controlled-release system for gastric retention. Pharm Res 1997;14:815-9. |
|2.||Talukder R, Fassihi R. Gastroretentive Delivery Systems: A Mini Review. Drug Dev Ind Pharm 2004; 30:1019-28. |
|3.||Arora S, Javed A, Ahuja A, Khar RK, Baboota S. Floating drug delivery system: A review. AAPS PharmSciTech 2006;6:E372-90. |
|4.||Rahman Z, Ali M, Khar RK. Design and evaluation of bilayer floating tablets of captopril. Acta Pharm 2006;56:49-57. |
|5.||Streubel A, Siepmann J, Bodmeier R. Floating matrix tablets based on low density foam powder: Effects of formulation and processing parameters on drug release. Eur J Pharm Sci 2003;12:37-45. |
|6.||Chavanpatil M, Jain P, Chaudhari S, Shear R, Vavia P. Development of sustained release gastroretentive drug delivery system for ofloxacin: In-vitro and in-vivo evaluation. Int J Pharm 2005;304:178-84. |
|7.||Swain K, Pattnaik S, Mallick S, Chowdary KA. Influence of hydroxypropyl methylcellulose on drug release pattern of gastroetentive floating drug delivery system using a 3 2 full factorial design. Pharm Dev Technol 2009;14:193-8. |
|8.||Rane Y, Mashru R, Sankalia M, Sankalia J. Effect of Hydrophilic Swellable Polymers on Dissolution Enhancement of Carbamazepine Solid Dispersions Studied Using Response Surface Methodology. AAPS PharmSciTech 2007;8:2. |
|9.||Shah TJ, Amin AF, Parikh JR, Parikh RH. Process Optimization and Characterization of Poloxamer Solid Dispersions of a Poorly Water-soluble Drug. AAPSPharmSciTech 2007;8:Article 29. |
|10.||Yamada T, Saito N, Imai T, Otagiri M. Effect of grinding with hydroxypropyl cellulose on the dissolution and particle size of a poorly water-soluble drug. Chem Pharm Bull 1999;47:1311-3. |
|11.||Sheskey PJ, Rowe RC, Weller PJ. Handbook of Pharmaceutical Excipients. 6 th ed. London: PhP Pharmaceutical Press; 2009. p. 629-32. |
|12.||Tadros MI. Controlled-release effervescent floating matrix tablets of ciprofloxacin hydrochloride: Development, optimization and in vitro-in vivo evaluation in healthy human volunteers. Eur J Pharm Biopharm 2010;74:332-9. |
|13.||Arza RA, Gonugunta CS, Veerareddy PR. Formulation and Evaluation of Swellable and Floating Gastroretentive Ciprofloxacin Hydrochloride Tablets. AAPS PharmSciTech 2009;10:1220-6. |
|14.||Adhikary A, Vavia PR. Bioadhesive Ranitidine Hydrochloride for Gastroretention with Controlled Microenvironmental Ph. Drug Dev Ind Pharm 2008;34:860-9. |
|15.||Ritger PL, Peppas NA. A simple equation for description of solute release. I. Fickian and non-Fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs. J Control Release 1987;5:23-36. |
|16.||Ritger PL, Peppas NA. A simple equation for description of solute release. II. Fickian and anomalous release from swellable devices. J Control Release 1987;5:37-42 |
|17.||Colombo P, Bettini R, Santi P, De Ascentiis A, Peppas NA. Analysis of the swelling and release mechanisms from drug delivery systems with emphasison drug solubility and water transport. J Control Release 1996;39:231-7. |
|18.||Agarwal V, Mishra B. Design, development, and biopharmaceutical properties of buccoadhesive compacts of pentazocine. Drug Dev Ind Pharm 1999;25:701-9. |
|19.||Gutiérrez-Sánchez PE, Hernández-León A, Villafuerte-Robles L. Effect of Sodium Bicarbonate on the Properties of Metronidazole Floating Matrix Tablets. Drug Dev Ind Pharm 2008;34:171-80. |
|20.||Colombo P, Bettini R, M´aximo G, Catellani PL, Santi P, Peppas NA. Drug diffusion front movement is important in drug release control from swellable matrix tablets. J Pharm Sci 1995;84:991-7. |
|21.||Zeng A, Yuan B, Fu Q, Wang C, Zhao G. Influence of sodium dodecyl sulfate on swelling, erosion and release behavior of HPMC matrix tablets containing a poorly water-soluble drug. PharmDev Technol 2009;14:499-505. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]