Mechanistic investigations on drug delivery from alginate matrices

MECHANISTIC INVESTIGATIONS ON DRUG DELIVERY FROM ALGINATE MATRICES CHING AI LING (B. Sc. (Pharm.) (Hons.), NUS) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACY NATIONAL UNIVERSITY OF SINGAPORE 2007 ACKNOWLEDGEMENTS I wish to express my heartfelt thanks and sincerest appreciation to my supervisors, A/P Chan Lai Wah, A/P Paul Heng Wan Sia and Dr Celine Valeria Liew, for their guidance and support in my research. I am grateful for their encouragement and the opportunities to learn and explore. It has been enjoyable working and sharing ideas with them. I also appreciate their efforts spent in going through my manuscripts and the countless suggestions made for their improvement. I wish also to thank the Head of the Department of Pharmacy, A/P Chan Sui Yung, for the use of the departmental facilities for my research project. In addition, I am thankful for the research scholarship provided by the National University of Singapore. My sincere appreciation also goes to my laboratory mates and colleagues for their help, humor and encouragement: Huey Ying, Qiyun, Sze Nam, Chin Chiat, Gu Li, Wai See, Constance, Lay Hui, Elaine, Zhi Hui, Siang Meng, Stephanie, Yiran, Teresa and Mei Yin. Last but not least, I wish to thank my husband and my family for their love, confidence and unfailing support. Thank you. Ai Ling January 2007 ii CONTENTS ACKNOWLEDGEMENTS ii CONTENTS iii SUMMARY viii LIST OF TABLES x LIST OF FIGURES xii I. INTRODUCTION A. Alginate for drug delivery A1. Sources of alginate A2. Structure of alginate A3. Functional properties of alginate A3.1 pH-dependent hydration and solubility A3.2 Selective ion binding A4. Advantages of using alginates in pharmaceutical preparations A5. Application of alginates in drug delivery systems A6. Challenges of using alginate matrix tablets as drug delivery systems B. Controlled drug delivery from polymeric matrices 10 B1. Significance of controlled drug delivery technology 10 B2. Matrix systems 11 B3. Mechanisms governing drug release 13 B4. Mathematical models describing kinetics of drug release 15 B4.1 Higuchi Equation 15 B4.2 Power Law 17 iii B4.3 Zero Order Equation 19 C. Factors affecting the performance of polymer matrices 19 C1. Physicochemical properties of the drug 19 C2. Polymer factors 21 C2.1 Polymer concentration 21 C2.2 Physicochemical properties of the polymer 22 C2.2.1 Polymer particle size 22 C2.2.2 Polymer viscosity 23 C2.2.3 Chemical composition of the polymer (alginate) 25 C3. Type of excipients 26 C4. Matrix porosity 28 II. HYPOTHESES AND OBJECTIVES 29 III. EXPERIMENTAL 31 A. Materials 31 A1. Sodium alginate 31 A2. Model drug 31 A3. Tablet excipients 31 A4. Additives 32 A4.1 Calcium salts 32 A4.2 pH-modifiers 32 A5. Dye and pH-indicators 32 A6. Chemicals for dissolution media preparation 32 B. Methods B1. Particle true density determination 33 33 iv B2. Sieving 33 B3. Particle size reduction 33 B3.1 Size reduction of model drug 33 B3.2 Size reduction of sodium alginate 34 B4. Particle size determination 34 B5. Viscosity determination 34 B6. Interaction studies by viscometry 35 B7. Solubility determination 36 B7.1 Solubility of chlorpheniramine maleate 36 B7.2 Solubility of dibasic calcium phosphate 36 B8. Preparation of matrix tablets 36 B9. Preparation of calcium alginate-coated matrices 38 B10. Drug release studies 39 B11. Measurement of liquid transport by gravimetry and image analysis 40 B12. Data analysis 44 B12.1 Analysis of drug release data 44 B12.2 Analysis of data obtained from hydration studies 46 IV. RESULTS AND DISCUSSION 47 Part 1: Influence of alginate physicochemical properties on matrix performance 47 A. Effect of matrix tablet porosity 47 B. Screening the influence of sodium alginate grade on matrix performance 47 B1. Influence of sodium alginate concentration 56 B2. Influence of sodium alginate particle size and viscosity 58 v B3. Influence of mannuronic and guluronic acid ratio in sodium alginate 67 C. Investigation on the effect of alginate viscosity using two viscosity grades of alginate D. Investigation of particle size effect using Manucol LB 70 74 D1. Investigation using sieved fractions of sodium alginate 47 D2. Investigation on the homogeneity of alginate sieved fractions 77 D3. Comminution of sodium alginate 78 Part 2: Mechanistic investigation on the impact of viscosity and MG ratio on the hydration behavior of alginate matrices A. Hydration behavior of alginate matrices 81 81 A1. Gravimetric liquid uptake and matrix erosion 81 A2. Image analysis of matrix swelling and solvent penetration front 88 A2.1 Matrix swelling 88 A2.2 Solvent penetration front 91 A2.3 Crack development in alginate matrices 99 B. Impact of hydration behavior on drug release from alginate matrices 100 Part 3: Formulation strategies to improve the sustained-release performance of alginate matrices A. Impact of cross-linker on matrix performance 103 103 A1. Influence of calcium salts incorporated into matrix tablets on drug release 104 A1.1 Dissolution at pH 1.2 followed by pH 6.8 104 A1.2 Interaction between alginate and calcium ions at pH 6.8 108 A1.3 Dissolution at pH 6.8 110 vi A2. Effect of external calcium source on drug release from alginate matrices 113 A2.1 Influence of calcium ion concentration on drug release 115 A2.2 Liquid penetration study to elucidate mechanism of drug release A2.3 Influence of alginate grade on drug release A3. Dissolution performance of calcium alginate-coated matrices B. Influence of pH-modifiers on alginate matrix performance 118 124 127 132 B1. Influence of pH-modifiers on drug release from alginate matrices 133 B2. Mechanistic study 137 B2.1 Influence on matrix micro-environmental pH 138 B2.2 Influence on alginate matrix morphology during hydration in acidic phase B2.3 Effect on liquid uptake and matrix erosion 141 148 V. CONCLUSION 151 VI. REFERENCES 154 VII. APPENDICES 176 VIII. PUBLICATIONS / PRESENTATIONS ARISING FROM THIS 180 STUDY vii SUMMARY Alginates are natural polymers useful in the design of pharmaceutical dosage forms. Alginates are available in many different grades and these grades vary in their physicochemical properties, namely particle size, viscosity and mannuronic/guluronic acid ratio. The impact of these variables on drug release and hydration behavior of sodium alginate matrix tablets is not well characterized, particularly in simulated gastrointestinal pH conditions. At gastric pH, the integrity of alginate matrix tablets was compromised by crack development, potentially limiting the use of alginate matrices for oral drug delivery. Recent interest in the use of natural polymers in the pharmaceutical industry provided further impetus for this study. The impact of alginate physicochemical properties on drug release and matrix hydration behavior was evaluated using a variety of alginate grades. The median particle size of alginate affected the extent of burst release, indicating its role in alginic acid barrier development. Alginate with higher viscosity showed lower rate of polymer hydration, resulting in enhanced burst and drug release at pH 1.2. However, higher viscosity alginate formed gel barrier with reduced erodibility at pH 6.8, contributing to slower drug release. The MG ratio of alginate appeared to influence the integrity of the alginic acid barrier. High-G alginate matrices showed greater propensity to laminate at acidic pH compared to high-M alginate matrices. These findings suggest that alginate physicochemical properties can be employed to modify drug release profiles. viii Alginate matrices demonstrated pH-dependent hydration, swelling and erosion behavior, resulting in pH-dependent drug release mechanisms. Anisotropy was observed during hydration of alginate matrices and was implicated in crack development. Cross-linking and micro-environmental pH modulation were proposed to reduce the propensity of alginate matrices to crack. Improved mechanical strength and reduced barrier permeability of calcium alginate gel provided the rationale for cross-linking alginate matrices. Matrices pre-coated with calcium alginate could sustain drug release at pH 1.2 followed by pH 6.8 for over 12 h. The presence of cross-linked barrier impeded matrix lamination and preserved matrix structure, contributing to at least three-fold reduction in drug release at pH 1.2. Zero order release as well as delayed burst release was produced by varying the cross-linking conditions used. Lamination was associated with the conversion of sodium alginate to alginic acid. Hence, inclusion of pH-modifiers was employed to raise the microenvironmental pH within matrices undergoing dissolution at gastric pH. The changes in micro-environmental pH of hydrating alginate matrices were visualized with the aid of a pH-indicator and subsequently quantified using image analysis. Transient elevation in micro-environmental pH impeded alginate protonation and minimized or prevented matrix lamination, contributing to preservation of drug diffusion barrier. Significant reduction in the rate of drug release at pH 1.2 was achieved in the presence of such additives. The action of pH-modifiers was synergistically enhanced in the presence of an air barrier formed by effervescing sodium bicarbonate, reducing drug release in the acidic medium from 60 to 20 %. ix LIST OF TABLES Table Effect of centrifugation on flow time of alginate solution. 35 Table Formulations of alginate matrices. 38 Table Beer’s plots for the absorbance of chlorpheniramine maleate in different media. 40 Table Effect of matrix porosity on drug release rate from alginate matrices. 49 Table Physicochemical properties of sodium alginate. 50 Table Curve-fitting of dissolution data obtained at (A) pH 1.2 and (B) pH 6.8. 51-52 Table Drug release rate at pH 1.2 and pH 6.8 for matrices consisting of 10, 30 or 50 % alginate of different grades. 53 Table Correlation between drug release parameters and (A) alginate median particle size or (B) alginate viscosity. 59 Table Influence of MG ratio on drug release from 10, 30 or 50 % alginate matrices at (A) pH 1.2 and (B) pH 6.8. 69 Table 10 Influence of alginate viscosity on drug release at (A) pH 1.2 and (B) pH 6.8 at different particle size fractions and alginate concentrations. 72 Table 11 Influence of particle size fraction on drug release kinetics at pH 1.2. 75 Table 12 Median particle size and kinematic viscosities of sieved and milled Manucol LB. 78 Table 13 Effect of milled alginate on drug release rate at pH 1.2. 80 Table 14 Summary of drug release and hydration kinetics of alginate matrices at pH 1.2 and pH 6.8. 85 Table 15 Influence of axial and radial surface area on directional swelling. 90 Table 16 Equations describing movement of apparent solvent penetration front within hydrating alginate matrices at pH 1.2. Y is the solvent penetration front in mm and X is time of hydration in hour. 98 x King, A. H., Brown seaweed extracts (Alginates), In: Glicksman, M. (Ed), Food hydrocolloids. Vol 2, CRC Press, Boca Raton, Florida (1983) p 143. Klein, L., Stock, J., Vorlop, K. G. Pore size and properties of spherical calcium alginate biocatalyst. Eur. J. Appl. Microbiol. Biotechnol. 18 (1983) 86-91. Korsmeyer, R. W., Gurny, R., Doelker, E., Buri, P., Peppas, N. A. Mechanisms of solute release from porous hydrophilic polymers. Int. J. Pharm. 15 (1983) 25-35. Kuu, W., Wood, R. D., Roseman, T. J. Factors influencing the kinetics of solute release, In: Kydonieus (Ed.), Treatise on controlled drug delivery, Marcel Dekker, New York (1992) p 44-46, 111. Lapidus, H. Lordi, N. G. Drug release from compressed hydrophilic matrices. J. Pharm. Sci. 57 (1968) 1292-1301. Lawson, N. International Specialty Products, Personal communication (2003). Lee, H. Y., Chan, L. W., Heng, P. W. S. Influence of partially cross-linked alginate used in the production of alginate microspheres by emulsification. J. Microencapsul. 22 (3) (2005) 275-280. Lee, K. Y., Bouhadir, K. H., Mooney, D. J. Evaluation of chain stiffness of partially oxidized polyguluronate. Biomacromolecules (6) (2002) 1129-1134. 165 Lide, D. R. (Ed), CRC Handbook of Chemistry and Physics, Internet Version 2006, < http://www.hbcpnetbase.com>, Taylor and Francis, Boca Raton, FL (2006). Lindner, W. D., Lippold, B. C. Drug release from hydrocolloid embeddings with high or low susceptibility to hydrodynamic stress. Pharm. Res. 12 (11) (1995) 1781-1785. Malamataris, S., Hatjichristos. Th., Rees, J. E. Apparent compressive elastic modulus and strength isotropy of compacts formed from binary powder mixes. Int. J. Pharm. 141 (1996) 101-108. Malveau, C.; Baille, W. E.; Zhu, X. X.; Marchessault, R. H. NMR imaging of highamylose starch tablets. 2. Effect of tablet size. Biomacromolecules 3(6) (2002) 12491254. Mancini, M., Moresi, M., Rancini, R. Mechanical properties of alginate gels: empirical characterization. J. Food Eng. 39 (1999) 369-378. Maron, S. H., Lando, J. B. Fundamentals of physical chemistry. New York: Macmillan (1974). McNeely, W. H., Pettitt, D. J., Algin, In: Whistler, R. L., BeMiller, J. N. (Ed), Industrial Gums, 2nd Ed, Academic Press, New York (1973). Miller-Chou, B. A., Koenig, J. L. A review of polymer dissolution. Prog. Polym. Sci. 28 (2003) 1223–1270. 166 Mitchell, K., Ford, J. L., Armstrong, D. J., Elliott, P. N. C., Hogan, J. E., Rostron, C. The influence of the particle size of hydroxypropylmethylcellulose K15M on its hydration and performance in matrix tablets. Int. J. Pharm. 100 (1993) 175-179. Möckel, J. E., Lippold, B. C. Zero-order drug release from hydrocolloid matrices. Pharm. Res. 10 (7) (1993) 1066-1070. Moe, D. V., Rippie, E. G. Nondestructive viscoelastic analysis of anisotropy in compressed tablets. J. Pharm.Sci. 86 (1997) 26-32. Moffat, A.C., Jackson, J.V., Moss, M.S., Bishop, B. (Ed), Clarke's Isolation and identification of drugs in pharmaceuticals, body fluids, and post-mortem material, Pharmaceutical Press, London (1986). Moore, J. W., Flanner, H. H. Mathematical comparison of dissolution profiles. Pharm. Tech. 20 (1996) 64-74. Moreno-Villoslada, I., Oyarzún, F., Miranda, V., Hess, S., Rivas, B. L. Binding of chlorpheniramine maleate to pharmacologically important alginic acid, carboxymethylcellulose, κ-carageenan, and ι-carrageenan as studied by diafiltration. J. Appl. Polym. Sci. 98 (2005) 598–602. Moroni, A., Drefko, W. pH-dependent sustained release, U. S. Patent, US 6,465,014 B1 (2002). 167 Motulsky, H., Christopoulos, A. Fitting models to biological data using linear and nonlinear regression : a practical guide to curve fitting. Oxford, New York : Oxford University Press (2004). Moussa, I. S.; Lenaerts, V.; Cartilier, L. H. Image analysis studies of water transport and dimensional changes occurring in the early stages of hydration in cross-linked amylase matrices. J. Control. Release 52 (1998) 63-70. Mullarney, M. P., Hancock, B. C. Mechanical property anisotropy of pharmaceutical excipient compacts. Int. J. Pharm. 314 (2006) 9-14. Nokhodchi, A., Tailor, A. In situ cross-linking of sodium alginate with calcium and aluminum ions to sustain the release of theophylline from polymeric matrices. Il Farmaco 59 (2004) 999–1004. Odidi, I. O., Newton, J. M. Cylindrical tube and surface tension viscous flow models in the assessment of capillary flow and liquid contact angles in pharmaceutical powders. Int. J. Pharm. 90 (1993) 203-211. Onsøyen, E. Hydration Induced swelling of alginate based matrix tablets at GI-tract pH conditions. Special publication-Royal Society of Chemistry 161 (1995) 108-122. 168 Østberg, T., Lund, E. M., Graffner, C. Calcium alginate matrices for oral multiple unit administration: IV. Release characteristics in different media. Int. J. Pharm. 112 (1994) 241-248. Papadimitriou, E.; Buckton, G.; Efentakis, M. Probing the mechanisms of swelling of hydroxypropylmethylcellulose matrices. Int. J. Pharm. 98 (1993) 57-62. Papageorgiou, M., Kasapis, S., Gothard, M. G. Structural and textural properties of calcium induced, hot-made alginate gels. Carbohydr. Polym. 24 (1994) 199-207. Penman, A., Sanderson, G. R. A method for the determination of uronic acid sequence in alginates. Carbohydr. Res. 25 (1972) 273-282. Peppas, N. A. Analysis of Fickian and non-Fickian drug release from polymers. Pharm. Acta Helv. 60 (4) (1985) 110-111. Pillay, V., Fassihi, R. Electrolyte-induced compositional heterogeneity: A novel approach for rate-controlled oral drug delivery. J. Pharm. Sci. 88 (11) (1999) 11401148. Rajabi-Siahboomi, A. R.; Bowtell, R. W.; Mansfield, P.; Henderson, A.; Davies, M. C.; Melia C. D. Structure and behaviour in hydrophilic matrix sustained release dosage forms: 2. NMR-imaging studies of dimensional changes in the gel layer and core of HPMC tablets undergoing hydration. J. Control. Release 31 (1994) 121-128. 169 Rees, D. A. Polysaccharide conformation in solutions and gels-recent results on pectins. Carbohydr. Polym. (1982) 254-263. Rekhi, G. S., Nellore, R. V., Hussain, A. S., Tillman, L. G., Malinowski, H. J., Augsburger, L. Identification of critical formulation and processing variables for metoprolol tartrate extended-release (ER) matrix tablets. J. Control. Release 59 (1999) 327-342. Rinaki, E., Valsami, G., Macheras, P. The power law can describe the ‘entire’ drug release curve from HPMC-based matrix tablets: a hypothesis. Int. J. Pharm. 255 (2003) 199-2007. Ritger, P. L., Peppas, N. A. 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 (1987a) 23-36. Ritger, P. L., Peppas, N. A. A simple equation for description of solute release. I. Fickian and anomalous release from swellable devices. J. Control. Release (1987b) 37-42. Roy, D. S.; Rohera, B. D. Comparative evaluation of rate of hydration and matrix erosion of HEC and HPC and study of drug release from their matrices. Eur. J. Pharm. Sci. 16 (2002) 193-199. 170 Sathe, P. M., Tsong, Y., Shah, V. P. In vitro dissolution profile comparison: Statistics and analysis, model dependent approach. Pharm. Res. 13 (12) (1996) 1799-1803. Shah, V. P., Tsong, Y., Sathe, P. Liu, J-P. In vitro dissolution profile comparison – Statistics and analysis of the similarity factor, f2. Pharm. Res. 15 (6) (1998) 889-896. Shilpa, A., Agrawal, S. S., Ray, A. R. Controlled delivery of drugs from alginate matrix. J. Macromol. Sci. Polym. Rev. C43 (2) (2003) 187-221. Siepe, S., Herrmann, W., Borchert, H-H., Lueckel, B., Kramer, A., Ries, A., Gurny, R. Microenvironmental pH and microviscosity inside pH-controlled matrix tablets: An EPR imaging study. J. Control. Release 112 (2006) 72-78. Siepmann, J., Peppas, N. A. Modeling of drug release from delivery systems based on hydroxypropylmethylcellulose (HPMC). Adv. Drug Deliv. Rev. 48 (2001) 139-157. Siew, C. K., Williams, P. A. New Insights into the Mechanism of Gelation of Alginate and Pectin: Charge Annihilation and Reversal Mechanism. Biomacromolecules (2005) 963-969. Sirkiä, T., Salonen, H., Veski, P., Jürjenson, H., Marvola, M. Biopharmaceutical evaluation of new prolonged-release press-coated ibuprofen tablets containing sodium alginate to adjust drug release. Int. J. Pharm. 107 (1994) 179-187. 171 Skjåk-Bræk, G. Alginates: biosynthesis and some structure-function relationships relevant to biomedical and biotechnological applications. Biochem. Soc. Trans. 20 (1992) 27-33. Skoug, J. W., Mikelsons, M. V., Vigneron, C. N., Stemm, N. L. Qualitative evaluation of the mechanism of release of matrix sustained release dosage forms by measurement of polymer release. J. Control. Release 27 (1993) 227-245. Smidsrød, O. Molecular basis for some physical properties of alginates in the gel state. J. Chem. Soc. Faraday. Trans. 57 (1974) 263-274. Smidsrød, O., Glover, R. M., Whittington, S. G. The relative extension of alginates having different chemical composition. Carbohydr. Res. 27 (1973) 107-118. Stockwell, A. F., Davis, S. S., In vitro evaluation of alginate gel systems as sustained release drug delivery systems. J. Control. Release (1986) 167-175. Stokke, B. T., Draget, K. I., Yuguchi, Y., Urakawa, H., Kajiwara, K. Small angle xray scattering and rheological characterization of alginate gels. Macromol. Symp. 120 (1997) 91-101. Streubel, A., Siepmann, J., Dashevsky, A., Bodmeier R. pH-independent release of a weakly basic drug from water-insoluble and -soluble matrix tablets. J. Control. Release 67 (2000) 101–110. 172 Tahara, K.; Yamamoto, K.; Nishihata, T. Overall mechanism behind matrix sustained release tablets prepared with hydroxypropyl methylcellulose 2910. J. Control. Release 35 (1995) 59-66. Takeuchi, H, Yasuji, T, Hino, T., Yamamoto, H., Kawashima, Y. Spray-dried composite particles of lactose and sodium alginate for direct tabletting and controlled releasing. Int. J. Pharm. 174 (1998) 91- 100. Takeuchi, H., Yasuji, T., Hino, T., Yamamoto, H., Kawashima, Y. Compaction properties of composite particles consisting of lactose with sodium alginate prepared by spray-drying. Pharm. Res. 16 (8) (1999) 1193-1198. Takka, S., Acartürk, F. Calcium alginate microparticles for oral administration; I: effect of sodium alginate type on drug release and drug entrapment efficiency. J. Microencapsulation 16 (3) (1999) 275-290. Tatavarti, A. S., Hoag, S. W. Microenvironmental pH modulation based release enhancement of a weakly basic drug from hydrophilic matrices. J. Pharm. Sci. 95 (7) (2006) 1459-1468. The United States Pharmacopeia, Chapters < 699 >, < 711 > and < 724 >, United States Pharmacopeial Convention, Inc., Rockville, MD, 2002. 173 Timmins, P., Delargy, A. M., Minchom, C. M., Howard, J. R. Influence of some process variables on product properties for a hydrophilic matrix controlled release tablet. Eur. J. Pharm. Biopharm. 38 (3) (1992) 113-118. Usov, A. I. Alginic acids and alginates: analytical methods used for their estimation and characterization of composition and primary structure. Russ. Chem. Rev. 68 (11) (1999) 957-966. Varma, M. V. S., Kaushal, A. M., Garg, S. Influence of micro-environmental pH on the gel layer behavior and release of a basic drug from various hydrophilic matrices. J. Control. Release 103 (2005) 499-510. Velasco, M. V., Ford, J. L., Rowe, P., Rajabi-Siahboomi, A. R. Influence of drug: hydroxypropylmethylcellulose ratio, drug and polymer particle size and compression force on the release of diclofenac sodium from HPMC tablets. J. Control. Release 57 (1999) 75-85. Veski, P., Marvola, M. Sodium alginates as diluents in hard gelatin capsules containing ibuprofen as a model drug. Pharmazie 48 (1993) 757–760. Wan, L. S. C., Heng, P.W.S., Wong, L.F. Relationship between swelling and drug release in a hydrophilic matrix. Drug Dev. Ind. Pharm. 19 (10) (1993) 1201-1210. Wan, L. S. C. Heng, P. W. S. Wong, L. F. Matrix swelling: a simple model describing extent of swelling of HPMC matrices. Int. J. Pharm. 116 (1995) 159-168. 174 Wan, L.S.C., Heng, P.W.S., Wong, L.F. Relationship between polymer viscosity and drug release from a matrix system. Pharm. Res. (11) (1992) 1510- 1514. Williams III, R. O., Reynolds, T. D., Cabelka, T. D., Sykora, M. A., Mahaguna, V. Investigation of excipient type and level on drug release from controlled release tablets containing HPMC. Pharm. Dev. Technol. (2) (2002) 181-193. Whittington, S. G. Conformational energy calculations on alginic acid. I. Helix parameters and flexibility of the homopolymers. Biopolymers 10 (1971) 1481-1489. Wikipedia contributors, Acid dissociation constant. In: Wikipedia, The Free Encyclopedia. http://en.wikipedia.org/w/index.php?title=Acid_dissociation_constant&oldid=786965 08 (accessed October 3, 2006). Woelki, S., Kohler, H.-H. Orientation of chain molecules in ionotropic gels: a Brownian dynamics model. Chem. Phys. 293 (2003) 323–340. Yuksel, N., Kanık, A. E., Baykara, T. Comparison of in vitro dissolution profiles by ANOVA-based, model-dependent and –independent methods. Int. J. Pharm. 209 (2000) 57-67. Zhang, H., Zheng, H., Zhang, Q., Wang, J., Konno, M. The interaction of sodium alginate with univalent cations. Biopolymers 46 (1998) 395–402. 175 VII. APPENDICES 90 80 70 Matrix swelling (%) 60 50 40 30 20 10 0 0.5 1.5 Time (h) Appendix 1. Effect of cryo-treatment on alginate matrix dimension. Percentage radial (○, ●) and axial (□, ■) swelling measured before (open symbols) and after (closed symbols) immersion in liquid nitrogen. 176 (A) Release rate at pH 1.2 (%min-0.5) 10 20 30 N= 10 10 10 10 30 50 Alginate concentration (%) (B) 20 Y-intercept (%) 10 23 -10 -20 N= 10 10 10 10 30 50 Alginate concentration (%) Appendix 2. Boxplots for (A) drug release rate and (B) Y-intercept values for high-M alginates showing outlier (Kelcosol). Outlier indicated by circles (○). 177 Appendix 3. Multiple comparison using Bonferroni test on (A) drug release rate and (B) Y-axis intercept from matrices containing alginate sieved fractions at and 10 % alginate content. Significance is denoted by P < 0.05 a. (A) 5% 180-250 125-180 90-125 180-250 0.005a 0.000a % 125-180 0.021a 90-125 [...]... B Controlled drug delivery from polymeric matrices B1 Significance of controlled drug delivery technology Achieving optimal drug concentration at the site of action in the body is essential for successful pharmacotherapy Concentrations beyond the optimal range can lead to serious side effects, whereas inadequate drug levels might result in attenuated or lack of pharmacodynamic response Controlled drug. .. the corresponding dimensional changes had a major influence on drug release from these matrices The amount of drug released showed a linear dependence on the extent of releasing area produced by matrix swelling (Colombo et al., 1992) Drug release from swellable matrices is controlled by drug diffusion through the gel layer and drug transport due to polymer relaxation The rate of drug diffusion through... distilled water 110 Table 20 Ionic strength of calcium chloride and sodium chloride solutions 116 Table 21 Influence of alginate grade on drug release rate from alginate matrices undergoing dissolution in calcium chloride solution 125 Table 22 Drug loss during immersion in cross-linking solution 129 Table 23 Influence of various salt additives on drug release from Manugel DMB matrices at pH 1.2 (2 h) followed... barrier formation at low polymer content Matrix surface consisting of (A) large or (B) small particles at the same alginate concentration 63 Fig 10 Contour plots showing the influence of alginate median particle size on the extent of change in (A) T25% and (B) Y-intercept values with an increase in alginate concentration 65 Fig 11 Drug release profiles from matrices containing sieved fractions of 180-250... ‘disentanglement concentration’ is only applicable to disordered polymers, which form topological entanglements In the case of alginates, the disentanglement concentration occurs only for matrices consisting of sodium alginate, which was in the form of disordered coils This phenomenon is not applicable for calcium alginate matrices, where alginate was converted to an ordered form via crosslinking with calcium ions... solvent ingress and drug release Further solvent imbibition into the matrix leads to matrix bulk hydration and drug dissolution, followed by matrix swelling and erosion Ultimately, the drug release profiles from such matrices are controlled by the rate of matrix hydration, swelling, drug diffusion through the gel layer and matrix erosion (Roy and Rohera, 2002) Essentially, drug release from a swellable... all possible associations of ordered polyguluronate chains with calcium ions to form dimers concluded that the “egg-box model” adequately described the dimerization of polyguluronate (Braccini et al., 2001) 5 The cations act as bridges between the anionic alginate polymer chains, constituting junction zones which are responsible for the formation of a hydrogel network The junction zone is an alignment... depends on drug dissolution and matrix erosion, both affecting the drug concentration gradient in gel layer (Colombo et al., 2000b) Drug concentration gradient within the gel layer is also affected by the swelling process (Colombo et al., 1999) The polymer relaxation process was found to contribute to the translocation of solid drug particles within the gel layer towards the matrix erosion front (Bettini... In swellable-erodible polymer matrices, constant drug delivery rate can be achieved when a constant gel layer thickness is attained by synchronization of the swelling and eroding fronts (Conte et al., 1988; Baveja et al., 1987) Constant drug release rate was also observed with matrices consisting of low viscosity polymer where polymer dissolution controlled the rate of drug release (Möckel and Lippold,... calcium salt inclusion on drug release rates from Manugel DMB or Manucol SS/LL matrix at pH 1.2 (2h) followed by pH 6.8 105 Table 18 Influence of calcium salt on flow time of dilute sodium alginate solution 109 Table 19 Effect of calcium salt inclusion on drug release rates from Manugel DMB or Manucol SS/LL matrix at pH 6.8 Dissolution of Manugel DMB matrices containing 20 % calcium gluconate was also carried . preparations A5. Application of alginates in drug delivery systems A6. Challenges of using alginate matrix tablets as drug delivery systems B. Controlled drug delivery from polymeric matrices B1. Significance. external calcium source on drug release from alginate matrices A2.1 Influence of calcium ion concentration on drug release A2.2 Liquid penetration study to elucidate mechanism of drug release A2.3. A2.2 Solvent penetration front A2.3 Crack development in alginate matrices B. Impact of hydration behavior on drug release from alginate matrices Part 3: Formulation strategies to improve