title: Anomalous dissolution behaviour of tablets prepared from sugar glass-based solid dispersions.
abstract: In this study, anomalous dissolution behaviour of tablets consisting of sugar glass dispersions was investigated. The poorly aqueous soluble diazepam was used as a lipophilic model drug. The release of diazepam and sugar carrier was determined to study the mechanisms governing dissolution behaviour. The effect of carrier dissolution rate and drug load was tested with four different sugars, in the order of decreasing dissolution rates: sucrose, trehalose and two oligo-fructoses; inulinDP11 and inulinDP23 having a number average degree of polymerization (DP) of 11 and 23, respectively. Diazepam was incorporated in these sugar glasses in the amorphous state by means of freeze drying using water and tertiary butyl alcohol (TBA) as solvents. None of the tablets disintegrated during dissolution. Dissolution of 80% of the lipophilic drug within 20 min was found when diazepam and sugar dissolution profiles coincided. The sugar carrier and diazepam dissolved at the same rate, which was constant in time and fast. This condition was met for relatively slow dissolving carriers like the inulins or for low drug loads. For relatively fast dissolving carriers like sucrose or trehalose with high drug loads, release profiles of diazepam and sugar did not coincide: diazepam dissolved much more slowly than the sugars. In case of non-coinciding release profiles, diazepam release was split into three phases. During the first phase non-steady-state dissolution was observed: diazepam release accelerated and a drug rich layer consisting of crystalline diazepam was gradually formed. This first phase determined the further release of diazepam. During the second phase a steady-state release rate was reached: zero-order release was observed for both drug and carrier. During this phase, the remaining (non-crystallised) solid dispersion is dissolved without the further occurrence of crystallisation. The third phase, starting when all carrier is dissolved, involved the very slow dissolution of crystallised diazepam, which was present either as the skeleton of a tablet resulting in a zero-order release profile or as separate particles dispersed in the dissolution medium resulting in a first-order release. To understand the anomalous dissolution behaviour, a model is proposed. It describes the phenomena during dissolution of amorphous solid dispersion tablets and explains that fast dissolution is observed for low drug loads or slow dissolving carriers like inulin.
authors.affiliation: Department of Pharmaceutical Technology and Biopharmacy, Groningen University Institute of Drug Exploration (GUIDE), Antonius Deusinglaan 1, 9713AV, Groningen, The Netherlands.
authors.forename: D J
authors.initials: DJ
authors.lastname: van Drooge
authors.forename: W L J
authors.initials: WL
authors.lastname: Hinrichs
authors.forename: H W
authors.initials: HW
authors.lastname: Frijlink
mesh_terms: D003975:Diazepam / Q000737:chemistry / Q000493:pharmacokinetics; D004187:Disaccharides / Q000737:chemistry* / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000737:chemistry* / Q000493:pharmacokinetics; D005898:Glass / Q000737:chemistry*; D009005:Monosaccharides / Q000737:chemistry* / Q000493:pharmacokinetics; D012995:Solubility / Q000187:drug effects; D013608:Tablets, Enteric-Coated
chemical_list: D004187:Disaccharides; D004337:Drug Carriers; D009005:Monosaccharides; D013608:Tablets, Enteric-Coated; D003975:Diazepam