Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Preparation of lapatinib ditosylate solid dispersions using solvent rotary evaporation and hot melt extrusion for solubility and dissolution enhancement Xian-Yue Hu a , Hao Lou b,c, ⁎ , Michael J. Hageman c a Department of Biopharmaceutical Technology, Jinhua Polytechnic, 888 W Haitang Street, Jinhua 321007, China b Pivotal Drug Product, Process Development, Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, CA 91320, USA c Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA ARTICLE INFO Keywords: Solid dispersion Solubility Miscibility Dissolution Hot melt extrusion Solvent evaporation Soluplus (R) ABSTRACT The objective of this study was to enhance solubility and dissolution of lapatinib (LB) ditosylate (DT) using solid dispersions (SD) prepared by solvent rotary evaporation (SRE) and hot melt extrusion (HME). A series of models based on solubility parameter, the solid-liquid equilibrium equation, and the Flory-Huggins equation were employed to provide insight to data and evaluate drug/polymer interactions. Experimentally, nine SD formulas were prepared and characterized by various analytical techniques including differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), scanning electron microscope (SEM), solubility, and dissolution. It was found that both material attributes (e.g., drug loading and solid state) and process parameters (e.g., extrusion temperature) significantly affected manufacturability and solubility/dissolution behaviors. Among the formulas investigated, Formula #9 containing LB-DT, Soluplus®, and poloxamer 188 at a weight ratio of 1:3:1 was screened as the first ranked one. While comparing production routes, the SDs prepared by SRE showed more amorphicity as well as higher solubility/dissolution. This study provided the insight of introducing theoretical models to guide SD formulation/process development and illustrating the potential of bioavailability en- hancement for LB-DT. 1. Introduction Lapatinib (LB) ditosylate (DT), a potent inhibitor of both ErbB-1 (EGFR) and HER2 (ErbB-2) tyrosine kinases, inhibited the proliferation of cancer cells that exhibited the overexpression of these two growth promoting factors (Nelson and Dolder, 2007; Burris, 2004). The com- mercial product TYKERB® (API: LB-DT) was developed into a tablet dosage form and approved in the therapy of advanced or metastatic breast cancer. Unfortunately, in spite of its high tumor-specific se- lectivity, the demonstration of clinical benefits of LB-DT with regards to efficiency and safety was challenging due to poor water solubility and permeability (categorized as a BCS Class IV drug Budha et al., 2012), which further lead to issues such as low bioavailability, large daily dose strength, and unacceptable side effects. Herein, there was interest in improving oral delivery of LB-DT, which might be accomplished via enhancing solubility/dissolution. In an attempt to improve solubility/dissolution, a wide variety of formulation and chemical approaches were explored, including surfactant/micelle, co-solvency, self-emulsification, complexation, prodrug, salt/ionization/pH control, nanosuspension/nanocrystal, polymorphism, solid dispersion (SD), etc (Yalkowsky, 1999). Moreover, the combination of these approaches even engendered synergistic ef- fects. One representative example was a third generation SD, which utilized surfactant or self-emulsifier as carriers/additives (Vo et al., 2013). In general, the surfactants chosen in this type of SD would in- fluence on maintaining supersaturation, aiding manufacture process, enhancing product stability, etc. Hypothetically, for surfactant/micelle system, non-polar drug molecules were incorporated into the hydro- phobic region (core). According to the two-phase (phase separation) model, drug solubility had a linear relationship with surfactant con- centration above critical micelle concentration (CMC) (Yalkowsky, 1999). Comparatively, for SD system, dissolution rate enhancement was attributed to several factors such as transforming crystalline state to amorphous, reducing particle size, improving wettability and porosity, preventing particle agglomeration, etc (Vasconcelos et al., 2007). Based on the solid state of drug molecules, SD could be categorized into the https://doi.org/10.1016/j.ijpharm.2018.09.062 Received 2 July 2018; Received in revised form 22 September 2018; Accepted 25 September 2018 ⁎ Corresponding author at: Pivotal Drug Product, Process Development, Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, CA 91320, USA. E-mail address: hlou@amgen.com (H. Lou). International Journal of Pharmaceutics 552 (2018) 154–163 Available online 27 September 2018 0378-5173/ © 2018 Elsevier B.V. All rights reserved. T