International journal of pharmaceutics

Quantification of in situ granulation-induced changes in pre-compression, solubility, dose distribution and intrinsic in vitro release characteristics of ibuprofen-cationic dextran conjugate crystanules.

PMID 24886691


The direct effect of intermolecular association between ibuprofen and diethylaminoethyl dextran (Ddex) and the novel 'melt-in situ granulation-crystallization' technique on the solubility, dose distribution, in vitro dissolution kinetics and pre-compression characteristics of the ibuprofen-Ddex conjugate crystanules have been investigated using various mathematical equations and statistical moments. The research intention was to elucidate the mechanisms of ibuprofen solubilization, densification and release from the conjugate crystanules as well as its dose distribution in order to provide fundamental knowledge on important physicochemical, thermodynamic and system-specific parameters which are key indices for the optimization of drug-polymer conjugate design for the delivery of poorly soluble drugs. The process of melt-in situ-granulation-crystallization reduced the solubility slightly compared with pure ibuprofen, however, the ibuprofen-Ddex conjugate crystanules exhibited increased ibuprofen solubility to a maximum of 2.47×10(-1) mM (at 1.25×10(-4) mM Ddex) and 8.72×10(-1) mM (at 6.25×10(-4) mM Ddex) at 25 and 37 °C, respectively. Beyond these concentrations of Ddex ibuprofen solubility decreased steadily due to stronger bond strength of the conjugate crystanules. The enthalpy-entropy compensation plot suggests a dominant entropy-driven mechanism of solubilization. In the same vein, the addition of Ddex increased the rate and extent of in vitro ibuprofen release from the conjugate crystanule to 100% within 168 h at Ddex concentration of 1.56×10(-4) mM, followed by a decrease with Ddex concentration. The conjugate crystanules exhibited controlled and extended-complete release profile which appeared to be dictated by the concentration of the Ddex and its strong affinity for ibuprofen. A comparison of the real experimental with the predicted data using artificial neural network shows excellent correlation between solubility and dissolution profiles (average error=0.2348%). Heckel, Kawakita, Cooper-Eaton and Kuno equations were employed to determine the mechanism of densification during tapping process. Ddex in the crystanules consistently improved particle rearrangement in the order of 2.5-7 folds compared with pure ibuprofen and stabilized ibuprofen against fragmentation during tapping process. Primary and secondary particle rearrangements were the prominent mechanisms of densification while deformation and fragmentation did not occur. Lower concentrations of Ddex below its critical granular concentration (<6.25×10(-4) mM) hindered plastic deformation and fragmentation, however, the summation of primary and secondary rearrangement parameters was greater than unity suggesting that the overall rearrangement of the conjugate crystanules cannot be explained exclusively by these two steps. This study has demonstrated the formulation of a novel ibuprofen-polymer conjugate which exhibited improved dose distribution and pre-compression characteristics as well as controlled and extended-complete release profiles - a potential drug delivery strategy for poorly soluble drugs.