International Journal of Pharmaceutics 380 (2009) 105–111 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Monitoring crystallisation of drugs from fast-dissolving oral films with isothermal calorimetry Simon Gaisford a,b,∗ , Amit Verma a , Mark Saunders b , Paul G. Royall b,c a Department of Pharmaceutics, School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK b Synectix Pharmaceutical Solutions Ltd., Tredomen Business and Technology Centre, Ystrad Mynach, Hengoed CF82 7FN, UK c Pharmaceutical Sciences Research Division, School of Biomedical and Health Sciences, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK article info Article history: Received 11 May 2009 Received in revised form 30 June 2009 Accepted 2 July 2009 Available online 22 July 2009 Keywords: Indomethacin Polyvinylpyrrolidone Crystallisation Thin polymer films Stability testing abstract The aim of this study was to evaluate the potential of isothermal calorimetry to monitor and characterize crystallisation in drug-loaded fast-dissolving oral films. Films of polyvinylpyrrolidone (PVP) containing indomethacin were cast into glass ampoules; stability was assessed by monitoring the power changes occurring with time. Three grades of PVP (K10, K25 and K40, where the number multiplied by 1000 gives the average molecular weight) were used. Indomethacin was seen to crystallise from all PVP grades over ca. 24–48h at two study temperatures (25 and 37 ◦ C), as denoted by a large exothermic event. At 25 ◦ C the exothermic event was a single peak; at 37 ◦ C two peaks were observed. Subsequent analysis of the crystals with differential scanning calorimetry (DSC) and polar- ized light microscopy determined that the stable -polymorph of indomethacin formed at 25 ◦ C while both the - and metastable -polymorphs formed at 37 ◦ C. The calorimetric data were converted to rela- tive crystallinity as a function of time and analysed with three crystallisation models (Avrami, Tobin and Urbanovici–Segal) to determine crystallisation kinetics. Of the three models applied the Urbanovici–Segal model best described the data, although this may be because this model contains a term that effectively accounts for deviation from the Avrami model. The rate constants determined were broadly consistent irrespective of the model used. Increasing polymer molecular weight did not generally affect the crys- tallisation rate, although an increase in temperature did result in a concomitant increase in crystallisation rate. The data suggest that isothermal calorimetry is able to monitor drug crystallisation in polymer films and therefore the technique could be a useful tool for conducting stability assays for fast-dissolving oral medicines. © 2009 Elsevier B.V. All rights reserved. 1. Introduction Fast-dissolving thin polymer films for rapid oral delivery are becoming an increasingly popular formulation option because of their wide and varied benefits. The films are designed to dissolve upon contact with a wet surface, such as the tongue, within a few seconds, meaning the consumer can take the product with- out the need for additional liquid. This convenience provides both a marketing advantage and increased patient compliance. Rapid dissolution is assured because the polymeric matrix is predomi- nantly amorphous and the drug is dispersed throughout it, either as a molecular dispersion or as discrete particles. Most commercially ∗ Corresponding author at: Department of Pharmaceutics, School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK. Tel.: +44 020 7753 5863; fax: +44 020 7753 5942. E-mail address: simon.gaisford@pharmacy.ac.uk (S. Gaisford). available formulations, such as Ora-film TM, 1 (benzocaine) or Thera- flu ®, 2 (dextromethorphan/phenylephrine HCl, diphenhydramine HCl/phenylephrine HCl or diphenhydramine HCl), are designed to deliver locally acting drugs or for mouth-freshening (such as Lister- ine PocketPaks TM, 3 ). Formulation of these systems is usually straightforward; the polymer and drug are dissolved (or dispersed) in a solvent (often ethanol or water) and a film is cast by solvent evaporation. Because of the high molecular weight of the polymer, films are frequently amorphous and may have complicated physical forms. In the sim- plest cases the films may be monophasic (if the drug is molecularly dispersed) or multiphasic (if the drug is dispersed as discrete parti- cles); depending on solubility and miscibility factors, drug-rich or 1 Ora-film is a registered trademark of Apothecus Pharmaceutical Corp. 2 Theraflu is a registered trademark of Novartis AG. 3 Listerine Pocketpaks is a registered trademark of Pfizer Inc. 0378-5173/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2009.07.006