Amorphous drug-polymer solid dispersions have the potential to enhance the dissolution performance and thus bioavailability of BCS class II drug compounds. The principle drawback of this approach is the limited physical stability of amorphous drug within the dispersion. Accurate determination of the solubility and miscibility of drug in the polymer matrix is the key to the successful design and development of such systems. In this paper, we propose a novel method, based on Flory-Huggins theory, to predict and compare the solubility and miscibility of drug in polymeric systems. The systems chosen for this study are (1) hydroxypropyl methylcellulose acetate succinate HF grade (HPMCAS-HF)-felodipine (FD) and (2) Soluplus (a graft copolymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol)-FD. Samples containing different drug compositions were mixed, ball milled, and then analyzed by differential scanning calorimetry (DSC). The value of the drug-polymer interaction parameter χ was calculated from the crystalline drug melting depression data and extrapolated to lower temperatures. The interaction parameter χ was also calculated at 25 °C for both systems using the van Krevelen solubility parameter method. The rank order of interaction parameters of the two systems obtained at this temperature was comparable. Diagrams of drug-polymer temperature-composition and free energy of mixing (ΔG(mix)) were constructed for both systems. The maximum crystalline drug solubility and amorphous drug miscibility may be predicted based on the phase diagrams. Hyper-DSC was used to assess the validity of constructed phase diagrams by annealing solid dispersions at specific drug loadings. Three different samples for each polymer were selected to represent different regions within the phase diagram.

In this study, a comparison of different methods to predict drug-polymer solubility was carried out on binary systems consisting of five model drugs (paracetamol, chloramphenicol, celecoxib, indomethacin, and felodipine) and polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios. The drug-polymer solubility at 25 °C was predicted using the Flory-Huggins model, from data obtained at elevated temperature using thermal analysis methods based on the recrystallization of a supersaturated amorphous solid dispersion and two variations of the melting point depression method. These predictions were compared with the solubility in the low molecular weight liquid analogues of the PVP/VA copolymer (N-vinylpyrrolidone and vinyl acetate). The predicted solubilities at 25 °C varied considerably depending on the method used. However, the three thermal analysis methods ranked the predicted solubilities in the same order, except for the felodipine-PVP system. Furthermore, the magnitude of the predicted solubilities from the recrystallization method and melting point depression method correlated well with the estimates based on the solubility in the liquid analogues, which suggests that this method can be used as an initial screening tool if a liquid analogue is available. The learnings of this important comparative study provided general guidance for the selection of the most suitable method(s) for the screening of drug-polymer solubility.

Abstract:16 Engineered Cocrystals offer an alternative solid drug form with tailored 17 physicochemical properties. Interestingly, although cocrystals provide many 18 new possibilities they also present new challenges, particularly in regard to their 19 design and large-scale manufacture. Current literature has primarily focused on 20 the preparation and characterization of novel cocrystals typically containing only 21 the drug and coformer, leaving the subsequent formulation less explored. In this 22paper we propose, for the first time, the use of hot melt extrusion for the 23 mechanochemical synthesis of pharmaceutical cocrystals in the presence of a 24 meltable binder. In this approach, we examine excipients that are amenable to 25 hot melt extrusion, forming a suspension of cocrystal particulates embedded in a 26 pharmaceutical matrix. Using ibuprofen and isonicotinamide as a model 27 cocrystal reagent pair, formulations extruded with a small molecular matrix 28 carrier (xylitol) were examined to be intimate mixtures wherein the newly 29 formed cocrystal particulates were physically suspended in a matrix. With 30 respect to formulations extruded using polymeric carriers (Soluplus ® and 31 Eudragit ® EPO, respectively), however, there was no evidence within PXRD 32 patterns of either crystalline ibuprofen or the cocrystal. Importantly, it was 33 established in this study that an appropriate carrier for a cocrystal reagent pair 34 during HME processing should satisfy certain criteria including limited 35 interaction with parent reagents and cocrystal product, processing temperature 36 sufficiently lower than the onset of cocrystal Tm, low melt viscosity and rapid 37 solidification upon cooling. 38 3

The potential implications of these findings when applied to a non-ambient processing method such as Hot Melt Extrusion (HME) are also discussed.

Using temperature-composition phase diagrams to probe the relevance of temperature and drug composition in specific polymer candidates facilitates polymer screening for the purpose of formulating solid dispersions.