**1. Introduction**

Nefiracetam, a member of the racetam family, is a nootropic compound typically administered as a cognitive enhancer. This API (( *N*-(2,6-dimethylphenyl)-2-(2-oxopyrrolidin-1-yl)acetamide)) known under the label DM-9384 is a pyrrolidone derivative produced and developed during the 90s by Daiichi Seiyaku and marketed in 2002 in Japan [1,2]. Recently, a polymorph screen by our group [3] revealed the existence of three anhydrous polymorphs as well as a monohydrate form with the asymmetric units illustrated in Figure 1. Di fferent solid-state forms exhibit distinct physicochemical properties such as the melting point, hygroscopicity, solubility, dissolution rate, and bioavailability. Polymorphs FI and FII are enantiotropically related anhydrous forms with FI found to be the most stable form below 140 ◦C, whereas FII is stable above this temperature. Polymorph FIII is metastable at all temperatures. Evaluation of the solubility/dissolution rate di fferences between polymorphs was challenging due to the fast solvent-mediated transformation of the meta-stable forms into the most stable one in suspension.

Therefore, as polymorphism does not seem a reasonable approach to modulate the dissolution/solubility properties of this drug, due to the high-energy state of its polymorphs, we here investigate an alternative approach focusing on cocrystal and ionic cocrystal formation [4–8]. Such an approach seems promising for Nefiracetam as it is a non-ionizable, low-water soluble drug (Biopharmaceutical Classification System (BCS) II) displaying synthons favorable for hydrogen bonding and metal coordination, but rendering salt-formation impossible. The FDA guidance defines cocrystals as "solids that are crystalline materials composed of two or more di fferent molecules generally held together by hydrogen bonds in the same crystal lattice" [9,10]. Considering that the molecular components have to be neutral and solid under ambient conditions, salts and solvates can be excluded from this terminology [9,11]. Ionic cocrystals (ICC) can also be included in this category with the specificity that they result from cocrystallization between a neutral organic molecule and an inorganic salt through complexation [12,13]. In the last two decades, cocrystallization has been widely used

on pharmaceutical compounds to tune the solubility and/or dissolution rate [14–17], offering novel patentability opportunities in parallel [18]. Metaxalone cocrystals [19] with succinic acid, adipic acid, fumaric acid, salycilic acid, and maleic acid were patented in 2014 showing enhanced physicochemical properties. In 2006, Mc Amara et al. [20] showed that the use of glutaric acid as a cocrystallization agen<sup>t</sup> increased the water solubility of a non-disclosed API about eighteen times and the dissolution rate about three times. Brittain et al. [21–23] recently reported the increasing importance of pharmaceutical cocrystals in the last decade.

**Figure 1.** View of the crystal packing along the a-axis of each (pseudo)-polymorphic form of Nefiracetam (*N*-(2,6-dimethylphenyl)-2-(2-oxopyrrolidin-1-yl)acetamide). The spacefill representation is used to highlight water molecules in the monohydrate crystal structure.
