In vitro dissolution methodologies that adequately capture the oral bioperformance of solid dosage forms are critical tools needed to aid formulation development. Such methodologies must encompass important physiological parameters and be designed with drug properties in mind. Two-phase dissolution apparatuses, which contain an aqueous phase in which the drug dissolves (representing the dissolution/solubility component) and an organic phase into which the drug partitions (representing the absorption component), have the potential to provide meaningful predictions of in vivo oral bioperformance for some BCS II, and possibly some BCS IV drug products. Before such an apparatus can be evaluated properly, it is important to understand the kinetics of drug substance partitioning from the aqueous to the organic medium. A mass transport analysis was performed of the kinetics of partitioning of drug substance solutions from the aqueous to the organic phase of a two-phase dissolution apparatus. Major assumptions include pseudo-steady-state conditions, a dilute aqueous solution and diffusion-controlled transport. Input parameters can be measured or estimated a priori. This paper presents the theory and derivation of our analysis, compares it with a recent kinetic approach, and demonstrates its effectiveness in predicting in vitro partitioning profiles of three BCS II weak acids in four different in vitro two-phase dissolution apparatuses. Very importantly, the paper discusses how a two-phase apparatus can be scaled to reflect in vivo absorption kinetics and for which drug substances the two-phase dissolution systems may be appropriate tools for measuring oral bioperformance.

A novel method for desaturation of aliphatic amines into enamines as well as allylic and homoallylic amines has been developed. This general protocol operates via putative aryl hybrid Pd-radical intermediates, which combine the signature features of radical chemistry, a hydrogen atom transfer (HAT) process, and transition metal chemistry, a selective β-hydride elimination step, to achieve efficient and selective desaturation of amines. These hybrid Pd-radical intermediates are efficiently generated under mild photoinduced conditions and are capable of a 1,n-HAT (n = 5-7) event at C(sp)-H sites. The selectivity of HAT is tunable by varying different auxiliaries, which highlight the generality of this method. Remarkably, this desaturation method, which operates under mild conditions and does not require employment of exogenous photosensitizers or oxidants, can be performed in a practical scalable fashion from simple amines.

Abstract. With the increasing number of poorly water-soluble compounds in contemporary drug discovery pipelines, the concept of supersaturation as an effective formulation approach for enhancing bioavailability is gaining momentum. This is intended to design the formulation to yield significantly high intraluminal concentrations of the drug than the thermodynamic equilibrium solubility through achieving supersaturation and thus to enhance the intestinal absorption. The major challenges faced by scientists developing supersaturatable formulations include controlling the rate and degree of supersaturation with the application of polymeric precipitation inhibitor and maintenance of post-administration supersaturation. This review is intended to cover publications on this topic since April 2009. Scientific publications associated with characterization of supersaturatable systems and related preclinical and clinical pharmacokinetics (PK) studies are reviewed. Specifically, this review will address issues related to assessing the performance of supersaturatable systems including: (1) Diversified approaches for developing supersaturatable formulations, (2) meaningful in vitro test methods to evaluate supersaturatable formulations, and (3) in vivo PK study cases which have demonstrated direct relevance between the supersaturation state and the exposure observed in animal models and human subjects.

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A biphasic in vitro test method was used to examine release profiles of a poorly soluble model drug, celecoxib (CEB), from its immediate release formulations. Three formulations of CEB were investigated in this study, including a commercial Celebrex capsule, a solution formulation (containing cosolvent and surfactant) and a supersaturatable self-emulsifying drug delivery system (S-SEDDS). The biphasic test system consisted of an aqueous buffer and a water-immiscible organic solvent (e.g., octanol) with the use of both USP II and IV apparatuses. The aqueous phase provided a nonsink dissolution medium for CEB, while the octanol phase acted as a sink for CEB partitioning. For comparison, CEB concentration-time profiles of these formulations in the aqueous medium under either a sink condition or a nonsink condition were also explored. CEB release profiles of these formulations observed in the aqueous medium from either the sink condition test, the nonsink condition test, or the biphasic test have little relevance to the pharmacokinetic observations (e.g., AUC, C(max)) in human subjects. In contrast, a rank order correlation among the three CEB formulations is obtained between the in vitro AUC values of CEB from the octanol phase up to t = 2 h and the in vivo mean AUC (or C(max)) values. As the biphasic test permits a rapid removal of drug from the aqueous phase by partitioning into the organic phase, the amount of drug in the organic phase represents the amount of drug accumulated in systemic circulation in vivo. This hypothesis provides the scientific rationale for the rank order relationship among these CEB formulations between their CEB concentrations in the organic phase and the relative AUC or C(max). In addition, the biphasic test method permits differentiation and discrimination of key attributes among the three different CEB formulations. This work demonstrates that the biphasic in vitro test method appears to be useful as a tool in evaluating performance of formulations of poorly water-soluble drugs and to provide potential for establishing an in vitro-in vivo relationship.

A general, efficient, and site-selective visible light-induced Pd-catalyzed remote desaturation of aliphatic alcohols into valuable allylic, homoallylic, and bis-homoallylic alcohols has been developed. This transformation operates via a hybrid Pd-radical mechanism, which synergistically combines the favorable features of radical approaches, such as a facile remote C–H HAT step, with that of transition-metal-catalyzed chemistry (selective β-hydrogen elimination step). This allows achieving superior degrees of regioselectivity and yields in the desaturation of alcohols compared to those obtained by the state-of-the-art desaturation methods. The HAT at unactivated C(sp3)–H sites is enabled by the easily installable/removable Si-auxiliaries. Formation of the key hybrid alkyl Pd-radical intermediates is efficiently induced by visible light from alkyl iodides and Pd(0) complexes. Notably, this method requires no exogenous photosensitizers or external oxidants.

A new method for the synthesis of benzofurans or indoles via ligand-free CuBr-catalyzed coupling/cyclization of terminal alkynes with N-tosylhydrazones derived from o-hydroxy- or o-aminobenzaldehydes has been developed. A wide range of functional groups were found that are able to tolerate the reaction conditions.