Fasoracetam crystalline forms

#Recently, a precision-medicine-based clinical trial was completed reporting successful treatment of attention deficit hyperactive disorder (ADHD) in subjects having at least one genetic alteration in a metabotropic glutamate receptor (mGluR) network gene. In that study, subjects having a genetic alteration in an mGluR network gene were successfully treated with fasoracetam (NFC-1), which has been shown in vitro to be a nonselective activator against all classes of mGluRs (See Hirouchi M, et al. (2000) European Journal of Pharmacology 387:9-17; see also WO2017/044491). Fasoracetam has also been successful in treating subjects having ADHD and 22q11.2 Deletion Syndrome (see, e.g., WO2017/044491), anxiety (see, e.g., WO2017/044503), conduct disorder (see, e.g., WO2017/044502), Tourette's syndrome (see, e.g., WO2017/044497), and suggested for treatment of anorexia (see, e.g., PCT/US2017/050228). Fasoracetam is orally available and to date has typically been made available as a monohydrate. Fasoracetam has one chiral center and the R-enantiomer has been developed clinically in the form of R-fasoracetam monohydrate Form I. We identified a stable hydrate form (hydrate I), and also a second polymorphic form of the hydrate (hydrate II). Using specific conditions, an anhydrate form could also be isolated.

#All references disclosed herein are incorporated by reference in their entirety.

#Disclosed herein are solid forms of fasoracetam. Various spectroscopic and crystallographic techniques may be used to characterize solid forms of compounds such as, for example, a polymorph, a hydrate, a polymorph of a hydrate, or an anhydrate. These include XRPD, single-crystal x-ray, Raman spectroscopy, infrared spectroscopy, and solid-state NMR spectroscopy, among other techniques. Different solid forms of the same compound often also exhibit distinct thermal behavior. Thermal behavior may be analyzed by such techniques as capillary melting point, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) to name a few. These techniques can be used to identify and characterize such solid forms.

#FIG. 1 is an XRPD pattern of R-fasoracetam monohydrate Form I.

#FIG. 2 is a DSC thermogram of R-fasoracetam monohydrate Form I.

#FIG. 3 is a DSC thermogram of R-fasoracetam monohydrate Form I stored under drier conditions compared to ambient conditions.

#In various embodiments of the disclosure, R-fasoracetam monohydrate Form II is provided. This Form II is a polymorph of R-fasoracetam monohydrate Form I in that it has the same chemical composition, but differs in crystal structure. FIG. 4 is an XRPD pattern of R-fasoracetam monohydrate Form II and FIG. 1 is an XRPD pattern of R-fasoracetam monohydrate Form I. FIG. 6 is an overlay XRPD pattern showing the XRPD pattern overlays of Form I, Form II, the anhydrate form of R-fasoracetam, and a mixture thereof. As can be seen from these figures, Form II is clearly distinguishable from Form I and the anhydrate. This is confirmed because each of these three solid forms has a different single crystal structure.

#Form II of R-fasoracetam monohydrate can be characterized by one or more XRPD peaks at about 5.7°2θ, about 11.3°2θ, and about 19.4°2θ. There are no peaks at such angles, to within expected variability, in the XRPD pattern of Form I. In addition, one or more of the peaks above may be characterized together with one or more peaks at about 16.7°2θ, and about 23.3°2θ.

#Form II of R-fasoracetam monohydrate is further characterized by an onset melting point temperature of about 49° C. with or without one or more of the XRPD peaks at about 5.7°2θ, about 11.3°2θ, and about 19.4°2θ. Additional peaks, such as those at about 16.7°2θ, and about 23.3°2θ may be used to characterize Form II. Form II may be characterized by a diffraction pattern substantially the same as that of FIG. 11 and/or a DSC thermogram substantially the same as that of FIG. 5.