title: Impact of in situ granulation and temperature quenching on crystal habit and micromeritic properties of ibuprofen-cationic dextran conjugate crystanules.
abstract: Ibuprofen was recrystallized in the presence of aqueous solution of cationic dextran derivative, Diethylaminoethyl Dextran (Ddex) using the melt-in situ granulation-crystallization technique in order to produce a stable amorphous ibuprofen-Ddex conjugates with improved morphological, micromeritic and thermo-analytical characteristics without the use of organic solvent. Ddex was used in this study because of its ability to form conjugates with various drug molecules and enhance their physicochemical characteristics and therapeutic activities. Cationic dextrans are also biocompatible and biodegradable. Mechanism of conjugation as well as the impact of conjugation on the ibuprofen crystal habit was investigated. Gaussian type normal particle size distribution was obtained and the size of the crystals in the crystanule conjugates decreased steadily, with increasing concentration of Ddex, to a minimum of 480 nm (440-folds reduction, p<0.05, n=20) at Ddex molar concentration of 0.01 mM. FT-IR spectra showed electrostatic interaction and hydrogen bonding between ibuprofen and Ddex which was confirmed with the (1)H NMR and (13)C NMR spectra. DSC curves exhibited single peaks from the binary ibuprofen-Ddex conjugate crystanules suggesting compatibility and formation of an eutectic product. The conjugate crystanules showed broad and diffuse endothermic peaks with a glass transition temperature (T(g)) of 58.3 and 59.14°C at Ddex molar concentrations of 1.56 × 10(-4) and 3.125 × 10(-4)mM respectively confirming the existence of ibuprofen-Ddex crystanule conjugates in amorphous state. Higher concentrations of Ddex decreased T(g) steadily. TGA curves showed first order degradation at low molar concentrations of Ddex up to 3.125 × 10(-4)mM which coincides with the critical granular concentration of the crystanules while higher concentrations exhibited second order degradation profile. This study provides the basis for the development of stable amorphous drug-polymer conjugates with potential practical application in controlled and extended drug release formulations.
authors.affiliation: Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK. Electronic address: aabioye@dmu.ac.uk.
authors.forename: Amos Olusegun
authors.initials: AO
authors.lastname: Abioye
authors.affiliation: Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK.
authors.forename: Adeola
authors.initials: A
authors.lastname: Kola-Mustapha
authors.affiliation: Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK.
authors.forename: Ketan
authors.initials: K
authors.lastname: Ruparelia
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization; D003637:DEAE-Dextran / Q000737:chemistry*; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding / Q000379:methods; D004355:Drug Stability; D006860:Hydrogen Bonding; D007052:Ibuprofen / Q000737:chemistry*; D010316:Particle Size; D017550:Spectroscopy, Fourier Transform Infrared; D055672:Static Electricity; D013696:Temperature; D044366:Transition Temperature
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D003637:DEAE-Dextran; D007052:Ibuprofen
keywords: Crystal habit; Crystanules; Ibuprofen–Diethylaminoethyl Dextran conjugates; In situ granulation-crystallization; Micromeritics; Temperature quenching