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dc.contributor.authorJabrail, Fawzi Habeeb-
dc.guideGupta, K. C.-
dc.description.abstractThe chitosan in a non-toxic, biocompatible cationic polysaccharide produced by deacetylation of naturally occurring chitin, which is obtained from exoskeleton of crustacean, cudes of insects and wall of fungi. The chitosan is similar to cellulose as both are made by linear P- {1-4} linked monosaccharides. The chitosan is relatively more reactive in comparison to chitin and found in different forms. The presence of primary amino groups and their distribution has recorded special characteristics, which made chitosan useful in biomedical and pharmaceutical applications. The degree of deacetylation and molecular weight of chitosan is normally varied by treating with alkali and acid to produce chitosan of desired properties for developing micro and nano particles, which are used as vehicles for the controlled and sustained delivery of active agents. Since chitosan is a positively charged polyelectrolyte, hence its solution properties are further controlled by solution pH and ionic strength of the medium. The presence of amino and hydroxyl groups in chitosan has further provided opportunities to modify the properties of chitosan by substituting different functionalities in chitosan. The mucoadhesivity and biodegradability of chitosan have made chitosan as a choicematerial for developing various dosage forms for controlled delivery systems, which are intended to deliver drugs at a controlled rate within a specified period of drug delivery. The controlled drug delivery systems overcome the shortcomings of conventional drug delivery formulations. The controlled delivery system may be designed in a manner that could administer the drug, which match the physiological needs at proper time and quantity. Therefore, the design of controlled delivery systems using different crossn linkers was the primary objective of the present investigations using chitosan as encapsulating agent. The literature report on various materials and cross-linking agents used in the formation of controlled delivery systems has been summarized in chapter-I and state ofart ofdelivery systems is briefly described. The oral controlled delivery system for centchroman is hardly reported in the literature, hence centchroman has been used as model drug to test the efficiency of the controlled system prepared with glutaraldehyde cross-linking in chapter-2 using chitosan of different molecular weights and degree of deacetylation. The characteristics of chitosan were estimated by viscometric method and potentiometric method of titration. The degree of deacetylation was also estimated by IR and elemental method of analysis and found to be 48, 62 and 75 wt% in the prepared samples after treating chitosan for 0,4 and 8 hrs with 40 wt% alkali within the temperature range of 60-80 °C. The chitosan samples of different molecular weights were obtained by treating original chitosan sample (2227 kg mol"1) for 6 and 12 hrs with 1.0 MHC1 and depending on the observed molecular weights of chitosan, the samples were categorized as low (260 kg mol"), medium (1134 kg mol"1) and high (2227 kg mol"1) molecular weight chitosan. These samples of chitosan were subsequently used for the preparation of cross-linked microspheres by spray-drying technique. Microspheres before cross-linking and loading with centchroman were characterized for their size by SEM studies, which have been found to vary from 112 urn to 152 urn for chitosan samples with different DDAs ranging from 48 wt% to 75 wt% but constant molecular weight of chitosan (1134 kg mol'1). These chitosan microspheres were also characterized for their shape and surface hydrophobicity using Rose Bengal Dye adsorption method. The chitosan microspheres in have shown variations in degree of hydrophobicity on cross-linking with glutaraldehyde and on increasing the degree of deacetylation in cross-linked microspheres. The hydrophobicity of pure chitosan microspheres at 6wt% concentration of glutaraldehyde has been found to be higher (0.184 mol um"2) than observed in pure chitosan microspheres (0.044 mol urn"2). These chitosan microspheres were characterized with IR and thermal analysis. The characteristics absorption bands in IR spectra were used as a proof for cross-linking with glutaraldehyde and other cross-linkers used for cross-linking with chitosan. The pure chitosan and glutaraldehyde cross-linked chitosan microspheres were characterized for degree of swelling in solution of different pH and by varying the contact time of microspheres with swelling media. The degree of swelling in microspheres of optimized cross-linking (6 wt%) and molecular weight of chitosan (1134 kg mol"1) has been found to be 250 wt%, whereas, microspheres with high degree of deacetylation (75 wt%) and high molecular weight of chitosan (2227 kg mol"1) have shown low degree of swelling. The glyoxal cross-linked chitosan microspheres with similar molecular weight (1134 kg mol1) and degree of deacetylation (62 wt %) have comparatively shown low degree of swelling (192.5 wt%). The size and shape of glyoxal cross-linked microspheres was also different than glutaraldehyde cross-linked chitosan microspheres. The surface hydrophobicity of glyoxal cross-linked chitosan microspheres was more (0.233 mol um"2) than observed with glutaraldehyde cross-linked microspheres. The microspheres cross-linked with TSPP, STPP and SHMP anion cross-linkers were less hydrophobic (0.086 mol um"2) in comparison to chemically cross-linked chitosan microspheres. The degree of swelling in TSPP, STPP and SHMP anions cross-linked chitosan microspheres was high (350 wt%) under similar experimental conditions of IV formation ofmicrospheres and characteristics ofchitosan and concentration ofphosphate anion cross-linker (TSPP). Amongst the phosphate anions cross-linked microspheres, the degree of swelling was highest with TSPP anions cross-linked microspheres and was lowest with SHMP anions cross-linked chitosan microspheres. The degree ofswelling in microspheres has shown adecreasing trend with the increase in degree of deacetylation in the chitosan. The solution pH was more significant in controlling the degree ofswelling in physically cross-linked chitosan microspheres in comparison to chemically crosslinked microspheres. The SHMP anions cross-linked microspheres have shown more swelling at low solution pH in comparison to STPP and TSPP anions cross-linked chitosan microspheres. The variation in degree of swelling was due to the variation in the degree of ionization of the chitosan and the phosphate anion cross-linkers (TSPP, STPP and SHMP). The addition of inorganic and organic salts has influenced the degree of swelling in comparison to microspheres without any additives. The addition of salts was more significant in phosphate anions (STPP, TSPP and SHMP) cross-linked microspheres than chemically chitosan microspheres. The swelling behavior of microspheres is an important parameter for controlling the loading and drug release from delivery systems. After discussing the relative degree of swelling in presence of various cross-linkers, the next important characteristic ofdelivery system has been the efficiency of loading (% EL) or maximum percent loading (% Lmax) of drug in the microspheres prepared with different type of cross-linkers and with different properties of chitosan. The drug loading in microspheres with different cross-linkers has shown a significant variation with MW and DDA ofchitosan and with degree ofcross-linking. The glutaraldehyde cross-linked chitosan microspheres have shown a maximum loading of 37.5 wt% in microspheres with optimized MW (1134 kg mol"1), DDA (62 wt%) and degree of cross-linking (6 wt%), whereas, glyoxal cross-linked chitosan microspheres have shown low percent loading (35.0 wt%) at same concentration of glyoxal (6 wt%), however, the loading in glyoxal cross-linked microspheres was higher (50.5 wt%) at optimized concentration of glyoxal (4 wt%). The loading in TSPP, STPP and SHMP anions cross-liked optimized chitosan microspheres has been found to be 31 wt %, 45 wt% and 62 wt% respectively. The loading capacity of phosphate anions crosslinked chitosan microspheres has been found to be dependent on solution pH and the type of additives used in the preparation of microspheres. The presence of ionic additives has decreased drug-loading capacity more in phosphate anions cross-linked chitosan microspheres in comparison to glutaraldehyde and glyoxal cross-linked microspheres. These additives have modified the interactions between phosphate anions and chitosan, hence the loading capacity of these microspheres was affected significantly than chemically cross-linked chitosan microspheres. The loading capacity has also shown variation with type ofdrugs used for loading as observed during loading ofhydroxy urea, isoniazid, centchroman, ibuprofen and rifampicin in controlled delivery systems prepared with glutaraldehyde and phosphate anions (TSPP, STPP and SHMP) cross-linkers. In glutaraldehyde cross-linked chitosan microspheres, the hydroxy urea has shown a maximum loading of42 wt%, whereas, the loading of rifampicin and ibuprofen was 30.4 wt% and 34 wt% respectively in microspheres prepared with medium molecular weight of chitosan (1134 kg mol"1) and 62 wt% DDA and with 6wt% degree of cross-linking. But in case of phosphate anions cross-linked chitosan microspheres, the loading of vi hydroxy urea (66 wt%),rifampicin (43 wt%) and ibuprofen (41.5 wt%) was high but loading order was same as was found with glutaraldehyde cross-linked chitosan microspheres. This variation in drug loading was due to the variation in size and charge on the drugs, which were used for loading on cross-linked chitosan microspheres. The drug loaded microspheres were further characterized by IR and thermal analysis and appearance of characteristic absorption bands of loaded drugs in the microspheres was used as evidence for the loading of drugs in the microspheres. The variation in thermal stability and energy of activation of decomposition (AEa) was also used as evidence for the loading of drugs in microspheres. The drug loaded microspheres prepared with chitosan of different properties and different cross-linkers were further tested for their drug release characteristics in solution of constant pHandtemperature. The amount of drug released from the microspheres has been determined spectrophotometrically using characteristic wave length (Xmax) of the drug. The amount of drug released at each time interval of 10 h was plotted as a function of square root of release time. The presentation of drug release in this manner has provided opportunities to locate the point of equilibrium swelling in loaded microspheres at which, the microspheres have started releasing a constant amount of drug within a specified period of 10 h. The total amount of drug released in this manner was divided as controlled drug release (% Re) and as burst release (% RB). The amount of drug released in step of burst release of lOh was not constant, which was due to the structural variations taking place in the microspheres, which occurred before reaching the equilibrium degree of swelling in the delivery system. The amount of centchroman released in controlled (%Rc) and burst release (%Rb) manner has not only shown variations with MW and vn DDA of chitosan in glutaraldehyde, glyoxal and phosphate anions (TSPP, STPP and SHMP) cross-linked chitosan microspheres but also shown variations with the type of drug used for loading in the microspheres. The controlled amount of centchroman released from glutaraldehyde cross-linked microspheres was 70.4 wt%, whereas, glyoxal cross-linked microspheres have released 77.8 wt% of loaded drug in controlled manner within a period of 70 hrs from optimized cross-linked microspheres. The TSPP, STPP and SHMP anions cross-linked microspheres have shown controlled release of 52.5 wt%, 65.9 wt% and 60.9 wt% respectively, which has clearly indicated that chemically crosslinked microspheres have released centchroman more in controlled manner than phosphate anions cross-linked chitosan microspheres. But hydroxy urea, isoniazid in SHMP anions cross-linked microspheres have shown a maximum controlled release of 67.8 wt%, whereas ibuprofen and rifampicin in STPP anions cross-linked microspheres have shown a controlled release of 69.7 wt% and 60.5 wt%, which has given an indication that polymer drug interactions have also contributed significantly in release behavior of drugs, hence these drugs have shown better controlled release than that of centchroman from phosphate anions cross-linked microspheres. This has been confirmed further when the controlled release manner of these drugs was compared with glutaraldehyde cross-linked microspheres. The hydroxy urea, isoniazid, ibuprofen and rifampicin have shown controlled release of 31 wt%, 32.6 wt% 52.5 wt% and 58.4 wt% from glutaraldehyde cross-linked microspheres, which was low in comparison to phosphate anions (STPP and SHMP) cross-linked microspheres as shown above. These drugs were having different interactions with chemically and physically cross-linked microspheres, hence the release profiles of same drugs was different in microspheres vni cross-linked with glutaraldehyde and phosphate anion cross-linkers. The controlled (%Rc) and burst release (%RB) of drugs from microspheres have also shown variations with solution pH and has been found to be high (70.4 wt%) at pH 7 with glutaraldehyde cross-linked microspheres for the release of centchroman whereas, glyoxal cross-linked microspheres have shown 72.8 wt% release at same pH but in both cases, the controlled release of centchroman (%Rc) was decreased at pH other than pH 7. The controlled release of centchroman has been found to be 52.5 wt% at pH 5 with TSPP cross-linked microspheres and 65.9 wt% with STPP cross-linked microspheres at pH 5 but SHMP cross-linked microspheres have shown 60.9 wt% release at pH 4. This variation in controlled release of drug with solution pH was due to the variation in interactions in phosphate anion cross-linkers (TSPP, STPP and SHMP) with chitosan. Since crosslinkers were having different dissociation constant, hence pH for maximum controlled release was different for different drugs. The pH of maximum controlled release (%Rc) has shown variations for STPP and SHMP anion cross-linkers. The hydroxy urea, isoniazid, have shown controlled release of 67.8 wt% and 69.6 wt% at pH 4 in SHMP anions cross-linked microspheres, whereas, ibuprofen and rifampicin have shown controlled release of 69.6 wt% and 60.5 wt% at pH 7 with STPP anions cross-linked chitosan microspheres, which has clearly indicated that the controlled release in affected by solution pH and also with type of drug used for controlled delivery. In case of glutaraldehyde cross-linked microspheres, the controlled drug release (%Rc) of hydroxy urea, isoniazid, rifampicin, ibuprofen was found to be 65.1 wt%, 69.0 wt% 61.9 wt% and 68.2 wt% respectively at pH 7, which was due to the variations in degree of swelling and interactions of drugs with polymer. In addition to these factors, the drug release has also IX shown variation with additives, like cations and anions, which modified the ionic interactions of phosphate anion cross-linkers with chitosan and loaded drugs. Similarly the addition of organic acids and P-cyclodextrin has also modified the behavior of drug release from the microspheres. The drug release data obtained from microspheres crosslinked with different cross-linkers were used to determine the mechanism ofdrug release byusing power law equation and depending onthe trend of data, the release behavior was characterized. The initial drug release in microspheres with different cross-linkers was Fickian in nature as initial drug release has shown complete agreement with diffusion model of drug release. The initial trends of drug release were indicative of first order kinetics and release trends after equilibrium swelling indicated for zero order kinetics for drug release. Although studied cross-linkers have shown similar mixed kinetics for drug release but there was variations in the amount of drug released in controlled manner (%Rc) from microspheres prepared with different cross-linkers and chitosan of different characteristics.en_US
dc.typeDoctoral Thesisen_US
Appears in Collections:DOCTORAL THESES (chemistry)

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