No abstract

A significant number of active pharmaceutical ingredients (APIs) being discovered exhibit expected therapeutic behaviors, but unfortunately have undesirable drug-like properties such as low solubility and poor ADME performance, making formulation into an effective drug product challenging. In fact, more than 40% of the pharmaceutical candidates in the development pipelines are reported to be categorized as poorly soluble.1,2) These compounds are classified as biopharmaceutical classification system (BCS) class II for which their maximum bioavailability is limited by their rate of dissolution. 3,4) Improving the dissolution rate of these compounds is achieved through various approaches of formulation technology. These include particle size reduction/ milling, [5][6][7][8] solution-based precipitation, solid dispersion by hot melt extrusion 9) or spray-drying, 10,11) complexation with cyclodextrins 12,13) and so on, as also described extensively in reviews. 14,15) Cryogenic technologies such as freeze drying 16) and spray freezing into liquid (SFL), [17][18][19] in particular, have lately attracted considerable attention for BCS class II compounds. These processes use cryogen, particularly liquid nitrogen, to form a solid dispersion composed of nano-dispersed domains of API within the hydrophilic polymer matrix. In order to increase universality of unique lyophilization technique in SFL, authors have developed spray freeze-drying (SFD) technique before, which is combined the conventional spraydryer with freeze-dryer, both equipments are available in market. 20) In addition, SFD technique was further improved by adopting four-fluid nozzle (4N) to expand its application in pharmaceutical industry. 21) In the conventional process both API and a hydrophilic excipient, called drug and carrier in this report respectively, are necessary to be dissolved in common spray solution because two-fluid nozzle (2N) has only one liquid-supplying line. Using a common solvent would sometimes lead to restricted combination between API and the carrier. 4N having two liquid passages allows API and the carrier to be dissolved in separate solvents, overcoming this problem. In this research, the organic/aqueous co-solvent spray system was newly established in 4N-SFD process in which the poorly water-soluble drug was dissolved in organic solvent and the dissolution-modified carrier was dissolved in water, which is likely frequent combination for solubilization. Acetonitrile was selected as an organic spray solvent due to its good solvent property for many drugs, its relatively high melting point (Ϫ43.8°C) among organic solvents and its easily evaporated behavior with higher vapor pressure. Phenytoin and ciclosporin were used as a poorly water-soluble drug and two types of carrier were used as a dissolution modifier. In case using phenytoin, which is dissolved in aqueous alkaline solution as well as acetonitrile, 1) aqueous spray system (phenytoin dissolved in aqueous alkaline solution and the carrier dissolved in water; called 4N-SFD-aqua)...