Formulations for pharmaceutical agents

#This application relates to methods for formulating compounds with low water solubility to yield compositions that improved solubility or dispersion of those compounds in aqueous mixtures.

#In the drug development pipeline, nearly 90% of new active chemical entities are considered poorly water soluble drugs based on the biopharmaceutics classification system (BCS) (Kalepu and Nekkanti, 2015; Tuomela et al., 2016). Hydrophobic drugs exhibit mostly crystalline structure. Those crystalline structures form tightly bonded atoms with high cohesive energy. In addition, hydrophobic drugs exhibit low aqueous solubility, poor absorption, limited dissolution and undesirable drug crystal size growth (Badal Tejedor et al., 2017; Cheow et al., 2014; Curtin et al., 2013; Jensen et al., 2015; Lobmann et al., 2011), resulting in low bioavailability and efficacy. These drugs are not suitable for intravenous (IV) administration because those poorly water-soluble solid aggregated drugs can potentially lead to thrombosis or stroke.

#The term solid dispersion in pharmaceutical formulation is defined as systems where the drug is finely dispersed in a carrier or excipient (Baird and Taylor, 2012; Kauppinen et al., 2017; Marano et al., 2016; Martinez et al., 2017). When the poorly water soluble drug is dispersed in a crystalline-carrier, amorphous-polymer-carrier, surfactant polymer carrier, and poorly water soluble-polymer carrier, the solid dispersion technique is called first, second, third and fourth generation solid dispersions, respectively (Vo et al., 2013).

#FIG. 1. A schematic for the process of preparation of crystal solid dispersion of docetaxel in sodium acetate crystal

#FIG. 2. DSC curve of crystal solid dispersion of docetaxel formulation (C-DXT) (a), physical mixture of DXT and blank sodium acetate (SA) (b), blank (SA, Blank SA is obtained by dissolving sodium acetate anhydrous in glacial acetic acid and subsequently freeze-dried) (c), native DXT (d), and indium (e).

#FIG. 3. P-XRD pattern of crystal solid dispersion of docetaxel (C-DXT) (a), physical mixture of DXT and blank SA (b), blank SA (c), and native DXT (d), respectively.

#Several non-limiting, illustrative embodiments of the invention are described by the following clauses:

#1. A process for improving the aqueous availability of a compound with low water solubility by forming a crystalline solid dispersion (CSD) of the compound, the process comprising the steps:

#(a) forming a solution of the compound and one or more acetate salts selected from the group consisting of LiOAc, NaOAc, KOAc, and CsOAc in glacial acetic acid optionally containing a solvent selected from the list of acetonitrile, methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, tetrahydrofuran, methanol, ethanol, n-propanol, iso-propanol, n-butanol, sec-butanol, dimethyl formamide, acetone, and 2-butanone; and