Pre-formulation development of highly potent nontuberculous mycobacterial agents

Area of Science:

• Medicinal Chemistry and Drug Development
• Pharmaceutical Sciences
• Microbiology

Background:

• Nontuberculous mycobacteria (NTM) are significant pathogens, especially in individuals with underlying lung conditions like COPD or cystic fibrosis.
• Novel indole-2-carboxamides (ICs) exhibit potent antimicrobial activity against NTM, including *Mycobacterium tuberculosis* and *Mycobacterium abscessus*, in preclinical models.
• Lead IC compounds face challenges due to poor aqueous solubility and permeability, necessitating high dosing for efficacy.

Purpose of the Study:

• To conduct comprehensive preformulation studies on two lead indole-2-carboxamide (IC) compounds, N2 and N21.
• To characterize the solid-state properties and physicochemical parameters of N2 and N21.
• To assess the potential for in vivo absorption and bioavailability challenges based on Biopharmaceutics Classification System (BCS) criteria.

Main Methods:

• Solid-state characterization using Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Hot-Stage Microscopy (HSM), and X-ray Powder Diffraction (XRD).
• Physicochemical property determination including octanol/water partition coefficient (LogP), pKa, solubility, pH stability, intrinsic dissolution, and Caco-2 cell monolayer permeability.
• Polymorphism screening for N2 and N21.

Main Results:

• Both ICs (N2 and N21) are crystalline solids; N21 exhibits monotropic polymorphism, while N2 does not.
• Compounds display poor aqueous solubility (<0.2 μg/mL) and high Caco-2 permeability (>18 × 10^-6 cm/s), consistent with Biopharmaceutics Classification System (BCS) class II.
• N2 and N21 are weakly acidic, with optimal stability at pH 6.8 and pKa values ranging from 6.7 to 7.9.

Conclusions:

• The preformulation data indicate that N2 and N21 are BCS class II drugs, primarily limited by poor aqueous solubility, which may impact in vivo absorption and bioavailability.
• These findings provide crucial information for the future formulation development of N2 and N21 as potential therapeutics for NTM infections.
• Successful formulation strategies are essential for advancing these drug candidates towards clinical trials and eventual regulatory approval for NTM treatment.