Improved Aerosolization Performance of Salbutamol Sulfate Formulated with Lactose Crystallized from Binary Mixtures of Ethanol—Acetone WASEEM KAIALY, 1,2 MARTYN D. TICEHURST, 3 JOHN MURPHY, 3 ALI NOKHODCHI 1 1 Chemistry and Drug Delivery Group, Medway School of Pharmacy, University of Kent, Chatham, Kent ME4 4TB, United Kingdom 2 Pharmaceutics and Pharmaceutical Technology Department, University of Damascus, Damascus 30621, Syria 3 Pfizer Global R & D, Pharmaceutical Sciences, Sandwich, Kent CT13 9NJ, United Kingdom Received 15 September 2010; revised 25 November 2010; accepted 20 December 2010 Published online 25 January 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.22483 ABSTRACT: It has been shown that dry powder inhaler (DPI) formulations typically achieve low fine particle fractions (poor performance). A commonly held theory is that this is due, at least in part, to low levels of detachment of drug from lactose during aerosolization as a result of strong adhesion of drug particles to the carrier surfaces. Therefore, the purpose of the present study is to overcome poor aerosolization performance of DPI formulation by modification of lactose particles. Lactose particles were crystallized by adding solution in water to different ra- tios of binary mixtures of ethanol—acetone. The results showed that modified lactose particles had exceptional aerosolization performance that makes them superior to commercial lactose particles. Morphology assessment showed that crystallized lactose particles were less elon- gated, more irregular in shape, and composed of smaller primary lactose particles compared with commercial lactose. Solid-state characterization showed that commercial lactose particles were "-lactose monohydrate, whereas crystallized lactose particles were a mixture of "-lactose monohydrate and $-lactose according to the ratio of ethanol—acetone used during crystalliza- tion process. The enhanced performance could be mainly due to rougher surface and/or higher amounts of fines compared with the lactose crystallized from pure ethanol or commercial lactose. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:2665–2684, 2011 Keywords: pulmonary delivery; particle size; crystallization; precipitation; solid state; dry powder inhalers; crystallized lactose; particle shape; aerosolization performance; salbutamol sulfate. INTRODUCTION Generally, dry powder inhaler (DPI) formulations con- sist of blends of micronized drug particles in the range of 1–5 : m with lactose particles. There are many physicochemical properties such as particle size, 1 par- ticle shape, 2 particle surface texture, 3 particle electro- static properties, 4 particle hygroscopicity, 5 and parti- cle contact area 1 that have been shown to have a sig- nificant impact on the drug delivery via DPIs. This has attracted researchers in the field of particle en- gineering where many attempts have been made to design carrier particles with predetermined proper- Correspondence to: Ali Nokhodchi (Telephone: +44-1634- 202947; Fax: +44-1634-883927; E-mail: a.nokhodchi@kent.ac.uk) Journal of Pharmaceutical Sciences, Vol. 100, 2665–2684 (2011) © 2011 Wiley-Liss, Inc. and the American Pharmacists Association ties that will enhance DPI formulation performance. Many studies were reported about the effect of car- rier size, 6–8 carrier surface texture, 9–11 and carrier particle shape 12,13 on DPI performance. Typically, carrier particles in drug—carrier formulations are used in the size range of 63–90 : m. 14 However, sev- eral studies have shown enhanced DPI performance when the carrier size was below 63 : m. 15–17 Contra- dictory results have been reported regarding the in- crease of aerosol particle surface smoothness 9,16,18,19 or roughness 11,18,20,21 on the improvement of DPI performance. Therefore, an optimum particle sur- face roughness or smoothness was suggested, which gives a maximal inhalation efficiency. 10,22–24 DPI performance has also been enhanced when the elongation ratio of either carrier particles 13,15,16 or drug particles 9,25 increased. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 7, JULY 2011 2665