Commentary A proposed definition of the ‘activity’ of surface sites on lactose carriers for dry powder inhalation Floris Grasmeijer ⇑ , Henderik W. Frijlink, Anne H. de Boer Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Ant. Deusinglaan 1, 9713 AV Groningen, The Netherlands article info Article history: Received 16 December 2013 Received in revised form 28 January 2014 Accepted 22 February 2014 Available online 5 March 2014 Keywords: Active site Adhesive mixture Carrier surface site activity Dry powder inhalation abstract A new definition of the activity of surface sites on lactose carriers for dry powder inhalation is proposed which relates to drug detachment during dispersion. The new definition is expected to improve the understanding of ‘carrier surface site activity’, which stimulates the unambiguous communication about this subject and may aid in the rational design and interpretation of future formulation studies. In con- trast to the currently prevailing view on carrier surface site activity, it follows from the newly proposed definition that carrier surface site activity depends on more variables than just the physicochemical prop- erties of the carrier surface. Because the term ‘active sites’ is ambiguous, it is recommended to use the term ‘highly active sites’ instead to denote carrier surface sites with a relatively high activity. Ó 2014 Elsevier B.V. All rights reserved. 1. Introduction The notion that some sites on the surfaces of carrier particles in adhesive mixtures are more ‘active’ than others was already intro- duced by Hersey (1975). Although the term ‘active sites’ has been widely used in literature concerning adhesive mixtures for inhala- tion ever since, a specific definition of ‘active sites’, or ‘carrier sur- face site activity’ in general, has never been formulated. This may lead to ambiguous communication about the subject and miscon- ceptions regarding the significance of active sites to powder dis- persion performance. It also hinders the rational design of formulation studies aiming to investigate mechanisms such as the ‘saturation of active sites’ and it could lead to the incorrect use of this mechanism as an explanation for certain effects of for- mulation variables on dispersion performance. A definition of car- rier surface site activity is therefore proposed in this paper. 2. The currently prevailing view on carrier surface site activity and its disadvantages Carrier surface site activity is mostly related to the energy or force with which carrier surface sites bind drug particles, and sites that bind drug particles with a high energy relative to other sites are generally considered to be ‘active sites’ (Hersey, 1975; Kulvanich and Stewart, 1987; Young et al., 2005). Such sites may for example be macroscopic surface irregularities where drug par- ticles can form multiple contact points with the carrier surface, or amorphous regions and contaminations that lead to increased cap- illary interactions or larger contact areas due to plastic deforma- tion upon compression. In addition, the term ‘pseudo-active sites’ was introduced for carrier surface sites of which a high binding en- ergy is mostly the result of a high susceptibility of the drug parti- cles to press-on forces during mixing (Dickhoff, 2006). Active sites are generally considered to be occupied preferentially over sites with lower activity by drug particles during the mixing process (Hersey, 1975). Although it is not clearly defined what constitutes a discrete ‘carrier surface site’, the view of carrier surface site activ- ity in terms of binding energy implicitly defines a carrier surface site as any location on the carrier surface that can host or bind a drug particle. There are several disadvantages associated to the currently prevailing view on carrier surface site activity, two of which are highlighted in the following paragraphs. Firstly, the term ‘active sites’ to denote carrier surface sites with a relatively high activity is deceptive, because it implies that ‘inac- tive sites’ also exist. However, when a drug particle is in contact with the carrier surface, at least London–Van der Waals interaction will occur regardless of the carrier surface site. Therefore, if the activity of carrier surface sites is related to their interaction force or binding energy towards a contacting drug particle, then all sites are active to some extent, whereas none are truly inactive. Only if the occurrence of drug particle detachment from carrier surface sites during dispersion is considered, a discrete classification of carrier surface sites as either ‘active’ or ‘inactive’ could be consis- tent (e.g. ‘inactive’ sites would denote sites from which drug http://dx.doi.org/10.1016/j.ejps.2014.02.012 0928-0987/Ó 2014 Elsevier B.V. All rights reserved. ⇑ Corresponding author. Tel.: +31 (0)50 3633286; fax: +31 (0)50 3632500. E-mail addresses: f.grasmeijer@rug.nl (F. Grasmeijer), h.w.frijlink@rug.nl (H.W. Frijlink), a.h.de.boer@rug.nl (A.H. de Boer). European Journal of Pharmaceutical Sciences 56 (2014) 102–104 Contents lists available at ScienceDirect European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps