International Journal of Pharmaceutics 393 (2010) 74–78 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Following mechanical activation of salbutamol sulphate during ball-milling with isothermal calorimetry Simon Gaisford a,b,∗ , Mansa Dennison a , Mahmoud Tawfik a , Matthew D. Jones a a Department of Pharmaceutics, School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK b Kuecept Ltd, Tredomen Business and Technology Centre, Ystrad Mynach, Hengoed CF82 7FN, UK article info Article history: Received 2 February 2010 Received in revised form 26 March 2010 Accepted 3 April 2010 Available online 10 April 2010 Keywords: Salbutamol sulphate Amorphous content Micronising Particle size reduction Isothermal calorimetry abstract Formulation of actives for pulmonary delivery with dry powder inhaler devices frequently requires a particle size reduction step. The high-energy forces imparted to a material during milling, as well as reduc- ing particle size, can cause a significant change in physicochemical properties, in particular mechanical activation of the surface (manifested as generation of amorphous regions) which can affect formulated product performance. It is not clear whether particle size reduction occurs prior to, or concomitantly with, generation of amorphous content. In this study the formation of amorphous content with time in crystalline salbutamol sulphate was quantified with isothermal gas perfusion calorimetry as the sample was ball-milled. The data showed that the most particle size reduction occurred initially (d 0.5 dropping from 12.83 ± 0.4 to 4.2 ± 0.4 within 5 min). During this time period, no detectable amorphous content was observed. Between 5 and 15 min milling time the particle size distribution remained relatively con- stant but the amorphous content increased non-linearly with time. After 20 min milling time the particle size increased slightly. The data suggest that particle size reduction occurs initially upon application of a force to the crystal. Once maximum particle size reduction has occurred the crystal absorbs the force being applied and the crystal lattice becomes disordered. After extended milling the conditions in the ball mill (heat and/or humidity) may cause crystallisation of some of the amorphous material resulting in particle–particle fusion. It would appear that the ball-milling process could be optimised to achieve the desired particle size distribution but without any loss of crystalline structure. © 2010 Elsevier B.V. All rights reserved. 1. Introduction Delivery of active principals via the pulmonary route is an increasingly popular strategy, but presents a number of unique formulation challenges, in particular the fact that only small par- ticles (between 2 and 5 m) can be successfully deposited in the lower respiratory tract. Powders with such a small particle size distribution can be difficult to aerosolise because of their intrin- sic cohesiveness, caused by their large surface area to mass ratio, irregular morphology, disordered surface chemistry, electrostatic charge and the fact that gravitational forces acting on particles of this size are not as dominant as other physical forces. One approach is to formulate actives for delivery with a dry powder inhaler (DPI) device. Here, the small drug particles are located on the surface of a larger, crystalline carrier (typically lac- tose), bound by a force of adhesion. The aggregates, by virtue of ∗ Corresponding author at: Department of Pharmaceutics, School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK. Tel.: +44 0207 753 5863; fax: +44 0207 753 5942. E-mail address: simon.gaisford@pharmacy.ac.uk (S. Gaisford). larger physical dimensions, have better flowability and are easier to aerosolise. When the patient inspires, the turbulent air-flow causes deaggregation of the drug and carrier. The large carrier particles impact the back of the throat while the micronised drug enters the airways (Telko and Hickey, 2005). Such an approach is convenient, because the inhaler device is breath actuated and hence the aerosolisation step is coordinated with inspiration (a common problem with pressurised metered dose inhalers (pMDI)). However, product performance is critically dependent upon the force of adhesion, which is in turn dependent upon the surface properties, mentioned above, of the active and carrier. It follows the method by which the active is prepared can control final product consistency (Chow et al., 2007). Particle engi- neering approaches such as antisolvent precipitation (Murnane et al., 2008), solution atomisation and crystallisation by sonication (SAX, Pitchayajittipong et al., 2009), supercritical fluid process- ing (Schiavone et al., 2004) and spray-freeze-drying (Amorji et al., 2007) have been employed, but these can be complex to design and difficult to scale to commercial batch manufacture. A more generally used approach is milling, wherein a force is applied to large crystalline particles to achieve particle size reduc- tion. Ball mills or air-jet mills are common designs. In the former 0378-5173/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2010.04.004