Automated Supersaturation Stability Assay to Differentiate Poorly Soluble Compounds in Drug Discovery

Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases

“… 10 When compared to free base of compound 2 , fumarate cocrystal of compound 1 was found to maintain a 5-fold higher supersaturation in FASSIF achieving a concentration of 73 μM at 16 min. 11 It should be noted that no suitable salt or cocrystal form of compound 2 with the right properties could be identified upon screening with various counterions. Overall, the data presented supported our decision to select compound 1 (LXE408) for further characterization.…”

Preformulation Studies and Enabling Formulation Selection for an Insoluble Compound at Preclinical Stage—From In Vitro, In Silico to In Vivo

“…The measured supersaturated solubility of 28.5 mg/mL equals to 75 mM for ZL006, which indicated the high possibility of supersaturating formulation to enable dose escalation study in preclinical species based on the analysis provided by the literature. 26 The permeability (P app ) of ZL006 on Caco-2 cell from A to B and from B to A were (1.95 ± 0.36) Â 10 À6 cm/s and (17.55 ± 0.26) Â 10 À6 cm/s, respectively, indicating the permeability of the molecule is moderate with significant efflux. Preformulation studies showed that besides the low solubility, the moderate permeability with efflux could also be part of the reasons for the low in vivo exposure and bioavailability of this molecule.…”

“…Supersaturation Solubility Determination. The supersaturation solubility was determined based on the method described by Skolnik 26 with slight changes, which will be discussed later. Specifically, a master stock solution of ZL006 in dimethyl sulfoxide (DMSO) at 10 mg/mL was prepared by dissolving 3 mg of the compound in 300 mL of DMSO.…”

“…The pH shift method is usually used for strong basic compounds that could be dissolved in acidic solution at high concentration and shifted to higher pH solution, whereas the solvent shift method can be used for most compounds and compound is first dissolved in DMSO and then shifted to biorelevant media such as FaSSIF for better mimicking in vivo environment. To determine the supersaturated solubility of this molecule, the method described by Skolnik 26 was referred and slightly modified.…”

“…Thus, it is necessary to understand whether the compound of interest has certain extent of supersaturation stability or the supersaturating propensity before strategy selection. Several literature studies [23][24][25][26] reported in vitro assay of supersaturation to facilitate the compound selection at discovery stage. The supersaturation assay should also be considered as a key component of the preformulation studies.…”