Research paper Development of PVP/PEG mixtures as appropriate carriers for the preparation of drug solid dispersions by melt mixing technique and optimization of dissolution using artificial neural networks Panagiotis Barmpalexis a , Ioannis Koutsidis a , Evangelos Karavas a , Dimitra Louka b , Sofia A. Papadimitriou b , Dimitrios N. Bikiaris b,⇑ a Pharmathen S.A., Pharmaceutical Industry, Attiki, Greece b Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece article info Article history: Received 6 December 2012 Accepted in revised form 13 March 2013 Available online xxxx Keywords: Melt mixing Solid dispersions Tibolone PVP/PEG Polymer blends Artificial neural networks abstract The effect of plasticizer’s (PEG) molecular weight (MW) on PVP based solid dispersions (SDs), prepared by melt mixing, was evaluated in the present study using Tibolone as a poorly water soluble model drug. PEGs with MW of 400, 600, and 2000 g/mol were tested, and the effect of drug content, time and temper- ature of melt mixing on the physical state of Tibolone, and the dissolution characteristics from SDs was investigated. PVP blends with PEG400 and PEG600 were completely miscible, while blends were heter- ogeneous. Furthermore, a single T g recorded in all samples, indicating that Tibolone was dispersed in a molecular lever (or in the form of nanodispersions), varied with varying PEG’s molecular weight, melt mixing temperature, and drug content, while FTIR analysis indicated significant interactions between Tibolone and PVP/PEG matrices. All prepared solid dispersion showed long-term physical stability (18 months in room temperature). The extent of interaction between mixture components was verified using Fox and Gordon–Taylor equations. Artificial neural networks, used to correlate the studied factors with selected dissolution characteristics, showed good prediction ability. Ó 2013 Elsevier B.V. All rights reserved. 1. Introduction In recent years, the number of active pharmaceutical ingredi- ents (APIs) with low water solubility is estimated up to 40% of whole drugs. This poor solubility lowers their gastrointestinal track absorption, ultimately leading to a restriction in clinical utility. To confront this, several technological methods have been reported for the improvement of API solubility and dissolution rate [1–3]. Such an approach, with significant advantages, is the formulation of hydrophobic drugs in high-energy amorphous forms [3–5], such as solid dispersions (SDs). A lot of progress has been made concern- ing the methods used for the preparation of SDs, and new tech- niques have been applied [3,4,6]. Among them, hot-melt extrusion (HME), a well-known technique in the field of food and plastics industry for more than a century, only recently gained in- creased acceptance for preparing pharmaceutical SDs. HME is a technique with several advantages such as lower environmental impact (absence of solvents) and reduced cost (few processing steps in a continuous flow operation). Nowadays, HME is consid- ered to be an efficient technique in developing SDs and has been proved to provide immediate, sustained, modified, and targeted drug delivery systems, resulting in improved bioavailability of the drug [7–10]. Formulation of an API in a high-energy amorphous forms is also desired in SDs prepared by HME in order to enhance API’s solubil- ity, dissolution rate and, consequently, oral bioavailability [11]. However, several limitations including API recrystallization due to the crystalline nature of the polymeric carrier [12] and polymor- phism may also take place during melt mixing as verified from pre- vious studies [13,14]. Melt mixing, a similar procedure to HME, has been used also as an alternative technique to prepare SDs with low environmental impact [11]. As HME, melt mixing has significant limitations. Dur- ing processing, drug substances are exposed to elevated tempera- tures for prolonged periods of time (2–10 min), leading to decomposition of thermally unstable APIs. Furthermore, there is a possibility that the API, the polymer or both decompose if an ex- tremely high temperature is used during melt mixing. One way to avoid this is first to convert the API into an amorphous form using an alternative technique such as solvent evaporation and then 0939-6411/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejpb.2013.03.013 ⇑ Corresponding author. Laboratory of Polymer Chemistry and Technology, Department of Chemistry, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece. Tel.: +30 2310 997812; fax: +30 2310 997769. E-mail address: dbic@chem.auth.gr (D.N. Bikiaris). European Journal of Pharmaceutics and Biopharmaceutics xxx (2013) xxx–xxx Contents lists available at SciVerse ScienceDirect European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb Please cite this article in press as: P. Barmpalexis et al., Development of PVP/PEG mixtures as appropriate carriers for the preparation of drug solid disper- sions by melt mixing technique and optimization of dissolution using artificial neural networks, Eur. J. Pharm. Biopharm. (2013), http://dx.doi.org/10.1016/ j.ejpb.2013.03.013