Recrystallization of waxy maize starch during manufacturing of starch microspheres for drug delivery: Influence of excipients Lidia Elfstrand a, * , Ann-Charlotte Eliasson a , Monica Jo ¨ nsson b , Malin Larsson a , Anna Simpraga a , Bernt Thelin c , Marie Wahlgren a a Division of Food Technology, Lund University, P.O. Box 124, SE-221 00 Lund, Sweden b StratoSphere Pharma AB, P.O. Box 50226, SE-202 12 Malmo ¨ , Sweden c Zelmic Technologies AB, S:t Lars va ¨ g 45, SE-222 70 Lund, Sweden Received 23 June 2006; received in revised form 12 December 2006; accepted 12 February 2007 Available online 21 February 2007 Abstract The formation of ordered structure, such as crystallites, in starch was studied by means of differential scanning calorimetry (DSC). The influence of time/temperature treatment and additives such as polyethylene glycol (PEG), bovine serum albumin (BSA) and a car- bonate buffer on the formation was investigated. The experiments were planned with a CCC (Central Composite Circumscribed) design. For all three investigated systems it could be concluded that the incubation time at 6 °C was the decisive factor for the amount of ordered structure obtained during the incubation, while the incubation time at 37 °C was the decisive factor for the thermal stability of the crys- tallites as expressed by T on , T m and T c . The additives seemed to mainly affect the nucleation phase of crystallization process. The addi- tives decreased the time required in order to obtain a certain level of ordering in the incubated starch samples. The carbonate buffer decreased the amount of ordered structure in starch as judged by DSC enthalpy values, while increasing the melting temperature of these structures. The additives PEG and BSA lowered the melting temperatures of the starch in the systems but increased the enthalpy values. By optimization procedure a specific amount of ordered structure with desired thermal characteristics could be predicted. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Starch; PEG (polyethylene glycol); BSA (bovine serum albumin); Sodium carbonate; Recrystallization; Time/temperature treatment; Drug formulation 1. Introduction Starch is a common excipient in drug formulations. Tra- ditionally it has been used in tablets but lately there has been a growing interest in starch microspheres for delivery of active substances through several different routs (Harris, Gauden, Fraser, Williams, & Parker, 2002; Huang, Mehta, & DeLuca, 1997; Morise et al., 2006; Teder, Johansson, d’Argy, Lundin, & Gunnarsson, 1995). The use of starch microparticles has been investigated for several different active substances but peptides and proteins have gained the largest interest (Pereswetoff-Morath, 1998). The background to the work presented in this article is that during the investigation of quality and production of Biosphere Ò , a starch microparticle, it was observed that the physical and molecular properties of the starch material in combination with additives, such as PEG, bovine serum albumin (BSA) and buffer, influenced the quality of the microspheres (Elfstrand, Eliasson, Jo ¨ nsson, Reslow, & Wahlgren, 2006). The Biosphere Ò starch microparticles are prepared by emulsifying starch in an aqueous two-phase system, con- taining polyethylene glycol and then stabilizing the micro- spheres by crystallization of the starch matrix. The manufacture of Biosphere Ò has been described in detail by Reslow, Jo ¨ nsson, and Laakso (2002). During the manufacturing of the microspheres the protein, i.e. the active substance, is encapsulated into the starch matrix. 0144-8617/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.carbpol.2007.02.015 * Corresponding author. Tel.: +46 46 222 83 06; fax: +46 46 222 46 22. E-mail address: Lidia.Elfstrand@food.lth.se (L. Elfstrand). www.elsevier.com/locate/carbpol Carbohydrate Polymers 69 (2007) 732–741