Itraconazole Amorphous Solid Dispersion Tablets: Formulation and Compaction Process Optimization Using Quality by Design Principles and Tools.

BCS Class II drugs, such as itraconazole (ITZ), exhibit poor solubility (1-4 ng/mL) and so require solubility enhancement. Therefore, ITZ and Kollidon® VA64 (KOL) amorphous solid dispersions (ASDs) were produced using hot-melt extrusion (HME) to improve ITZ's poor solubility. A novel strategy for tablet formulations using five inorganic salts was investigated (KCl, NaCl, KBr, KHCO3 and KH2PO4). These kosmotopric salts are thought to compete for water hydration near the polymer chain, hence, preventing polymer gelation and, therefore, facilitating disintegration and dissolution. Out of all the formulations, the KCl containing one demonstrated acceptable tensile strength (above 1.7 MPa), whilst providing a quick disintegration time (less than 15 min) and so was selected for further formulation development through a design of the experiment approach. Seven ITZ-KOL-ASD formulations with KCl were compacted using round and oblong punches. Round tablets were found to disintegrate under 20 min, whereas oblong tablets disintegrated within 10 min. The round tablets achieved over 80% ITZ release within 15 min, with six out of seven formulations achieving 100% ITZ release by 30 min. It was found that tablets comprising high levels of Avicel® pH 102 (30%) and low levels of KCl (5%) tend to fail the disintegration target due to the strong bonding capacity of Avicel® pH 102. The disintegration time and tensile strength responses were modeled to obtain design spaces (DSs) relevant to both round and oblong tablets. Within the DS, several formulations can be chosen, which meet the Quality Target Product Profile (QTPP) requirements for immediate-release round and oblong tablets and allow for flexibility to compact in different tablet shape to accommodate patients' needs. It was concluded that the use of inorganic salts, such as KCl, is the key to producing tablets of ITZ ASDs with fast disintegration and enhanced dissolution. Overall, ITZ-KOL-ASD tablet formulations, which meet the QTPP, were achieved in this study with the aid of Quality by Design (QbD) principles for formulation and compaction process development and optimization.

Lead optimization of thiazolo[5,4-c]piperidines: 3-cyclobutoxy linker as a key spacer for H(3)R inverse agonists.

The simpler, the better: H(3) histamine receptor (H(3)R) are of interest as therapeutic targets in cognitive and somnolence disorders. Here, lead optimization of H(3)R inverse agonists bearing a thiazolo[5,4-c]piperidine group gave rise to a clinical candidate with a much simpler unprecedented benzamide scaffold, displaying decreased hERG activity while maintaining high brain receptor occupancies.