Evaluation of crystallization behavior on the surface of nifedipine solid dispersion powder using inverse gas chromatography.

PURPOSE: To investigate crystallization behavior on the surface of amorphous solid dispersion powder using inverse gas chromatography (IGC) and to predict the physical stability at temperatures below the glass transition temperature (T (g)). METHODS: Amorphous solid dispersion powder was prepared by melt-quenching of a mixture of crystalline nifedipine and polyvinylpyrrolidon (PVP) K-30. IGC was conducted by injecting undecane (probe gas) and methane (reference gas) repeatedly to the solid dispersion at temperatures below T (g). Surface crystallization was evaluated by the retention volume change of undecane based on the observation that the surface of the solid dispersion with crystallized nifedipine gives an increased retention volume. RESULTS: On applying the retention volume change to the Hancock-Sharp equation, surface crystallization was found to follow a two-dimensional growth of nuclei mechanism. Estimation of the crystallization rates at temperatures far below T (g) using the Avrami-Erofeev equation and Arrhenius equation showed that, to maintain its quality for at least three years, the solid dispersion should be stored at -20°C (T (g) - 65°C). CONCLUSIONS: IGC can be used to evaluate crystallization behavior on the surface of a solid dispersion powder, and, unlike traditional techniques, can also predict the stability of the solid dispersion based on the surface crystallization behavior.

Detection of lot-to-lot variations in the amorphous microstructure of lyophilized protein formulations.

Reconstitution of lyophilized protein formulations sometimes results in a cloudy solution, depending on the compositions and manufacturing conditions, which causes quality concerns. In this study, the lyophilized protein formulation of recombinant human Interleukin-11 (rhIL-11) was investigated using different lots with varying dissolution behaviors upon reconstitution due to differing processing conditions. In an attempt to distinguish the solid structures in the different lots, relatively new techniques such as inverse gas chromatography (IGC) and thermally stimulated depolarized current (TSDC) as well as powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) were adopted for analysis. PXRD, DSC, and IGC all failed to distinguish between the solid structures, but TSDC was able to discern the differences. Interestingly, TSDC suggested that the variations in dissolution behavior were attributable to the differences in molecular mobility and the micro heterogeneity of amorphous components in the solid structures. Since even the cloudiest reconstituted solutions became transparent in several minutes, it was likely that the differences in the solid structures of the different lots of lyophilized cakes were slight. This study demonstrates the usefulness of TSDC in the analysis of lot-to-lot variations in amorphous pharmaceuticals.

Inhibition of a solid phase reaction among excipients that accelerates drug release from a solid dispersion with aging.

Hydrophobic drug substances can be formulated as a solid dispersion or solution using macromolecular matrices with high glass transition temperatures to attain satisfactory dissolution. However, very few marketed products have previously relied on solid dispersion technology due to physical and chemical instability problems, and processing difficulties. In the present study, a modified release product of a therapeutic drug for hypertension, Barnidipine hydrochloride, was developed. The drug product consisted of solid dispersion based on a matrix of carboxymethylethylcellulose (CMEC), which was produced using the spray-coating method. An enteric coat layer was sprayed on the surface of the solid dispersion to control drug release. Interestingly, the release rate accelerated as the drug product aged, while there were no indications of deceleration of the release rate which was due to crystallization of the drug substance. To prevent changes in the dissolution kinetics during storage periods, a variety of processing conditions were tried. It was found that not only use of non-aqueous solvents but also a reduction in coating temperatures consistently resulted in stable solid dispersions. The molecular bases of dissolution of the drug substance from those matrices were investigated. The molecular weight of CMEC was found to be a dominant factor that determined dissolution kinetics, which followed zero-order release, suggesting an involvement of an osmotic pumping mechanism. While dissolution was faster using a higher molecular weight CMEC, the molecular weight of CMEC in the drug product slowly increased with aging (solid phase reaction) depending on the processing conditions, causing the time-induced elevation of dissolution. While no crystalline components were found in the solid dispersion, the amorphous structure maintained a degree of non-equilibrium by nature. Plasticization by water in the coating solution relaxed the amorphous system and facilitated phase separation of the drug substance and CMEC upon production. The solid phase reaction advanced differentially in the solid dispersion depending on the degree of phase separation set initially. The use of non-aqueous solvents and/or a decrease in the coating temperatures inhibited the occurrence of phase separation upon production, thereby preventing the formation of CMEC-rich phases where the solid phase reaction occurred during storage.

De novo design of peptides with L-alpha-nucleobase amino acids and their binding properties to the P22 boxB RNA and its mutants.

A method to design novel molecules that specifically recognize a structured RNA would be a promising tool for the development of drugs or probes targeting RNA. In this study, the de novo design of the alpha-helical peptides having L-alpha-amino acids with nucleobases (nucleobase amino acids, NBAs) was carried out. Binding affinities of the peptides for a hairpin RNA derived from P22 phage were dependent on the types and positions of the NBA units they have. Some NBA peptides bound to the wild-type RNA or its mutant with high affinity and high specificity compared with the native P22 N peptide. These results indicate that the NBA units on the peptides interact with the RNA bases in a specific manner. It is demonstrated that the de novo design of peptides with the NBA units is an effective way to construct novel RNA-binding molecules.