The influence of water on the stability of lyophilized formulations with inositol and mannitol as excipients.

The stability of a moisture-sensitive drug in lyophilized products was investigated under conditions with varying water content and temperature using two model formulations: a formulation containing inositol (IF) as the excipient and a formulation containing mannitol (MF) as the excipient. IF showed better chemical stability (a lower hydrolysis rate) than MF when both formulations contained 2% water. However, in the case of formulations with 8% water, MF showed similar or better stability than IF. From the results of hygroscopicity and phase transition experiments for both formulations, it was assumed that this stability profile was exhibited because 1) more water was taken up into the amorphous inositol in IF than into the crystalline Form-III mannitol in MF at a low water content, so that drug hydrolysis in IF was suppressed compared with MF and 2) when the water content increased, the amorphous inositol crystallized to anhydrate in IF causing expulsion of absorbed water from the excipient, meaning that IF lost its superior chemical stability due to the highly mobile water generated by the crystallization. This assumption was supported by the results of the (2)H-NMR measurement, which estimated water mobility from the signal shape and the spin-lattice relaxation time (T(1)) of deuterium oxide.

Binding of alpha1-acid glycoprotein to membrane results in a unique structural change and ligand release.

Alpha(1)-acid glycoprotein (AGP) consists of 183 amino acid residues and 5 carbohydrate chains and binds to basic and neutral drugs as well as steroid hormones. We investigated the structural properties and ligand-binding capacity of AGP under mild acidic conditions and its interactions with liposomes prepared from neutral or anionic lipids and the neutral drug, progesterone. Interestingly, AGP had a unique structure at pH 4.5, at which the tertiary structure changed, whereas the secondary structure remained intact. Furthermore, the binding capacity of AGP for progesterone did not significantly change under these conditions. It was also observed that AGP was strongly bound to the anionic membrane at pH 4.5, forming an alpha-helix-rich structure from the original beta-sheet-rich structure, which significantly decreased the binding capacity of AGP for progesterone. The structural transitions as well as the membrane binding were suppressed by adding NaCl. These results indicate that AGP has a unique structure on the membrane surface under mild acidic conditions. The conformational change induces binding to the membrane aided by electrostatic interaction, and AGP subsequently takes on a predominantly alpha-helical conformation.

Molecular assembly of C2-symmetric Bis-(2S)-2-methyldodecanoylamides of alpha,omega-alkylidenediamines into coiled coil and twisted ribbon aggregates.

A series of 10 didodecanoylamides of alpha,omega-alkylidenediamines bridged by a straight carbon chain varying in length from 0 to 9 carbons was examined as possible gelator molecules of organic liquids to gain information on the relationships between the spacial arrangement of two amide groups in a molecule and their effects on the microscopic structures of the gel. The structural characteristics of these amides are parallel and antiparallel arrangements of two amide carbonyl groups, which depend on the even and odd numbers of a bridging zigzag carbon chain. The linear alkyl chain moieties and a center carbon chain of diamides intermolecularly interact with each other within the van der Waals contact. Two amide moieties of an even number carbon chain diamide intermolecularly interact with each other by using two pairs of hydrogen bonds with two other molecules in a plane, which formed ribbonlike self-complementarily assembled aggregates. On the other hand, a diamide of an odd number carbon chain forms four independent hydrogen bonds with four other molecules not in a plane, which assembled into woven aggregates. Asymmetric introduction of a methyl group at the alpha-position of the amide groups successfully twists the two side chain van der Waals cores of the chiral diamides in the fixed direction, giving helically twisted ribbon and coiled coil aggregates. The helically twisted ribbon and coiled coil aggregates of these chiral diamides were directly observed by CD, SEM, and TEM, providing a basis for the design of a sophisticated small molecular gelator of a tailor-made shape.