Research paper Intraorally fast-dissolving particles of a poorly soluble drug: Preparation and in vitro characterization Riikka Laitinen a, * , Eero Suihko a,1 , Kaisa Toukola a , Mikko Björkqvist b , Joakim Riikonen b , Vesa Pekka Lehto b , Kristiina Järvinen a , Jarkko Ketolainen a a Department of Pharmaceutics, University of Kuopio, Kuopio, Finland b Laboratory of Industrial Physics, Department of Physics, University of Turku, Turku, Finland article info Article history: Received 21 May 2008 Accepted in revised form 2 September 2008 Available online 12 September 2008 Keywords: Solid dispersion Solid solution Dissolution enhancement PVP PEG Amorphous abstract In this study, the dissolution rate of a poorly soluble drug, perphenazine (PPZ) was improved by a solid dispersion technique to permit its usage in intraoral formulations. Dissolution of PPZ (4 mg) in a small liquid volume (3 ml, pH 6.8) within one minute was set as the objective. PVP K30 and PEG 8000 were selected for carriers according to the solubility parameter approach and their 5/1, 1/5 and 1/20 mixtures with PPZ (PPZ/polymer w/w) were prepared by freeze-drying from 0.1 N HCl solutions. The dissolution rate of PPZ was improved with all drug/polymer mixture ratios compared to crystalline or micronized PPZ. A major dissolution rate improvement was seen with 1/5 PPZ/PEG formulation, i.e. PPZ was dissolved completely within one minute. SAXS, DSC and XRPD measurements indicated that solid solutions of amorphous PPZ in amorphous PVP or in partly amorphous PEG were formed. DSC and FTIR studies sug- gested that PPZ dihydrochloride salt was formed and hydrogen bonding was occurred between PPZ and the polymers. It was concluded that molecular mixing together with salt formation promoted the disso- lution of PPZ, especially in the case of the 1/5 PPZ/PEG dispersion, making it a promising candidate for use in intraoral formulations. Ó 2008 Elsevier B.V. All rights reserved. 1. Introduction Drug delivery via the oral mucosa is a promising route, when one wishes to achieve a rapid onset of action or improved bioavail- ability for drugs with high first-pass metabolism [1]. Thus, there is a growing interest in developing alternative dosage forms, i.e. oral- ly fast disintegrating tablets, which allow a rapidly dissolving drug to absorb directly into the systemic circulation through the oral mucosa. These kinds of dosage forms are also convenient for chil- dren, elderly patients with swallowing difficulties, and in the ab- sence of potable liquids [2]. However, in addition to formulation considerations, the properties of the active compound have to be appropriate in order to achieve drug delivery into systemic circula- tion after intraoral administration. The drug has to be soluble, fast dissolving and stable, and this might represent an obstacle for lipo- philic drugs [3]. Due to the small volume of saliva in the oral cavity, the therapeutic dose of an intraoral drug must be relatively small and in most cases dissolution enhancers must be applied [4]. To overcome these problems, a solid dispersion approach can be utilized. Solid dispersions are generally prepared by incorporating the drug into a water soluble carrier using techniques like solvent evaporation or melt extrusion. The improvement of drug dissolu- tion from solid dispersions is attributed to drug particle size reduc- tion and possible amorphization within the dispersion, improved wetting of the drug, as well as a possible solubilization effect of the carrier and specific molecular interactions between the drug and polymer [5,6]. Depending on the solid state solubility of the drug in a polymer, either a suspension or a molecular dispersion of the drug in the polymer matrix can result. In the former, clusters of either amorphous or crystalline drug are present, thus a phase- separated system will result. In the latter case, the drug is homog- enously dispersed in a carrier matrix and its size is at an absolute minimum, which is beneficial for the dissolution rate [5]. Molecu- lar-level mixing can be achieved either by dissolving each compo- nent in a mutually common solvent followed by solvent removal or by directly mixing the two liquids if the drug and the carrier are miscible with each other [7,8]. However, in spite of intensive re- search in the field of solid dispersions, dispersion of the drug and its particle size within a polymer matrix are rarely studied. Micro- scopic methods have been used for this purpose, however they are not able to detect molecular dispersions [9–11]. Instead, alterna- tive techniques such as micro-Raman [12] and potential new methods, such as Small-angle X-ray scattering (SAXS) [13] could be used. 0939-6411/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ejpb.2008.09.001 * Corresponding author. Department of Pharmaceutics, University of Kuopio, P.O. Box 1627, FI-70211 Kuopio, Finland. Tel.: +358 40 355 3881; fax: +358 17 162 252. E-mail address: riikka.laitinen@uku.fi (R. Laitinen). 1 Present address: Orion Corporation, P.O. Box 1780, FI-70701 Kuopio, Finland. European Journal of Pharmaceutics and Biopharmaceutics 71 (2009) 271–281 Contents lists available at ScienceDirect European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb