title: Investigation of the release mechanism of a sparingly water-soluble drug from solid dispersions in hydrophilic carriers based on physical state of drug, particle size distribution and drug-polymer interactions.
abstract: In the present study the release mechanism of the sparingly water-soluble drug felodipine (FELO) from particulate solid dispersions in PVP or PEG was investigated. FT-IR data indicated that a N-H...O hydrogen bond is formed between FELO and polymers. The drug-polymer interaction was theoretically studied with the density functional theory with the B3LYP exchange correlation function. The interaction energies have been estimated at -31.8 kJ/mol for PVP and -18.8 kJ/mol for PEG. Also, detailed vibrational analysis of the complexes showed that the red shift of the N-H bond stretching in FELO molecule due to H-bonding was higher in the FELO-PVP complex than in the FELO-PEG complex. Both the experimental and theoretical data indicated that a stronger interaction of FELO with PVP than with PEG was developed. The interactions of FELO with the polymer appeared to control the physical state (amorphous or crystalline) and the particle size of FELO in the solid dispersions. In the FELO/PVP dispersions, the drug is found as amorphous nanoparticles whereas in FELO/PEG dispersions the drug is dispersed as crystalline microparticles. The size of drug particles in the dispersion was also influenced by drug proportion, with an increase in drug content of the dispersion resulting in increased drug particle size. The particle size of drug, the proportion of drug in the dispersion and the properties of the polymer (molecular weight) appeared to determine the mechanism of drug release from the solid dispersions, which was drug diffusion (through the polymer layer)-controlled at low drug contents and drug dissolution-controlled at high drug contents. In situ DLS measurements indicate that the large initial particles of FELO/PVP and FELO/PEG solid dispersions with low drug content (10-20 wt%) are very rapidly decreased to smaller particles (including nanoparticles) during dissolution, leading to the observed impressive enhancement of FELO release rate from these dispersions.
authors.affiliation: Pharmathen S.A., Pharmaceutical Industry, Attiki, Greece.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Karavas
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Georgarakis
authors.forename: Michael P
authors.initials: MP
authors.lastname: Sigalas
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Avgoustakis
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Bikiaris
mesh_terms: D004337:Drug Carriers; D015736:Felodipine / Q000008:administration & dosage* / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D010316:Particle Size; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011145:Polyvinyls / Q000008:administration & dosage; D011759:Pyrrolidines / Q000008:administration & dosage; D012995:Solubility; D014961:X-Ray Diffraction
chemical_list: D004337:Drug Carriers; D011145:Polyvinyls; D011759:Pyrrolidines; C505150:poly(N-vinylpyrrolidine); D011092:Polyethylene Glycols; D015736:Felodipine