Yttrium and indium complexes of 1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecylacetylbenzylamine (DOTA-BA) and 1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecylacetyl-R-(+)-alpha-methylbenzylamine (DOTA-MBA) were prepared in order to study solution structures of (90)Y- and (111)In-labeled DOTA-biomolecule conjugates. (90)Y and (111)In complexes M(L) (M = (90)Y and (111)In; L = DOTA-BA and DOTA-MBA) were prepared from the reaction of MCl(3) with DOTA-BA and DOTA-MBA, respectively, in ammonium acetate buffer. A reverse phase HPLC method revealed that both (90)Y and (111)In complexes show only one radiometric peak in their radio-HPLC chromatograms. It was also found that (111)In(DOTA-BA) and (111)In(DOTA-MBA) are more hydrophilic than their corresponding (90)Y analogues, suggesting different coordination spheres in (111)In and (90)Y complexes of the same DOTA conjugate. Complexes M(L) (M = Y and In; L = DOTA-BA and DOTA-MBA) were prepared and characterized by HPLC, LC-MS, and NMR ((1)H and (13)C) methods. The HPLC concordance experiments for (90)Y(DOTA-MBA)/Y(DOTA-MBA) and (111)In(DOTA-MBA)/In(DOTA-MBA) show that the same complex is prepared at both tracer and macroscopic levels. The NMR data ((1)H and (13)C) clearly demonstrates that Y(DOTA-BA) and Y(DOTA-MBA) exist in solution as one predominant isomer. VT NMR data ((1)H and (13)C) show that In(DOTA-BA) and In(DOTA-MBA) are fluxional at room temperature while Y(DOTA-BA) and Y(DOTA-MBA) become fluxional only at elevated temperatures. The fluxionality of these complexes is due to rapid rotation of acetate/acetamide chelating arms and inversion of ethylenic groups of the macrocyclic ring.

Methods were developed to systematically screen different polymer-surfactant combinations for the purpose of enhancing amorphous active pharmaceutical ingredient (API) solubility while maintaining its physical stability. Itraconazole (ITZ) was chosen as the model API mostly due to its low aqueous solubility. Special attention was paid to determine the effect of a reduction in the critical micelle concentration (CMC) by specific polymer/surfactant combinations on the ITZ solubility and physical stability. However, only a slight correlation was actually found. Only the polymer/surfactant combinations with the smallest effect on CMC improved solubility and stability of ITZ in simulated intestinal fluids (SIF). Surfactants were found to negate the stabilizing effects of polymers. ITZ crystallization tendency generally depended on the degree of supersaturation and the type of polymer/surfactant combinations used. In general, we found that instead of focusing solely on reducing the CMC, a systematic screening of systems that maintain high ITZ supersaturation proved to be a successful approach.

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