title: Slow dissolution behaviour of amorphous capecitabine.
abstract: In this article, we report the anomalous dissolution behaviour of amorphous capecitabine. In contrast to what is expected from thermodynamic theory, amorphous capecitabine dissolves significantly slower compared to its crystalline counterpart. Our experiments show that this is due to the "gelling" properties of amorphous capecitabine in an aqueous environment. The "gel", which is immediately formed upon contact with water, entraps the capecitabine and significantly slows down its dissolution. This "gelling" property is hypothesized to be related to the low glass transition temperature (Tg 19°C) of amorphous capecitabine, resulting in an instant collapse ("gelling") in an aqueous environment. From IR and DSC analysis it is shown that this collapsed capecitabine is remarkably stable and does not recrystallize upon an increased water content or temperature. This highly reproducible dissolution behaviour can be applied in the development of a sustained release dosage form as substantially less sustained release excipient is required in order to attain the desired release profile. As capecitabine is a high-dosed drug, this is highly favourable in view of the size and thus clinical feasibility of the final dosage form. Currently, we are developing and clinically testing a sustained release formulation making use of amorphous capecitabine and its remarkable dissolution behaviour.
authors.affiliation: Department of Pharmacy & Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands. Jelte.Meulenaar@slz.nl
authors.forename: Jelte
authors.initials: J
authors.lastname: Meulenaar
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Nuijen
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D000069287:Capecitabine; D003460:Crystallization; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D004339:Drug Compounding; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D005240:Feasibility Studies; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D005782:Gels; D015203:Reproducibility of Results; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D044366:Transition Temperature
chemical_list: D000964:Antimetabolites, Antineoplastic; D005079:Excipients; D005782:Gels; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil