Coupling Between Chemical Reactivity and Structural Relaxation in Pharmaceutical Glasses View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2006-10

AUTHORS

Sheri L. Shamblin, Bruno C. Hancock, Michael J. Pikal

ABSTRACT

PURPOSE: To test the hypothesis that the molecular motions associated with chemical degradation in glassy amorphous systems are governed by the molecular motions associated with structural relaxation. The extent to which a chemical process is linked to the motions associated with structural relaxation will depend on the nature of the chemical process and molecular motion requirements (e.g., translation of a complete molecule, rotational diffusion of a chemical functional group). In this study the chemical degradation and molecular mobility were measured in model systems to assess the degree of coupling between chemical reactivity and structural relaxation. The model systems included pure amorphous cephalosporin drugs, and amorphous molecular mixtures containing a chemically labile drug and an additive expected to moderate molecular mobility. METHODS: Amorphous drugs and mixtures with additives were prepared by lyophilization from aqueous solution. The physical properties of the model systems were characterized using optical microscopy and differential scanning calorimetry. The chemical degradation of the drugs alone and in mixtures with additives was measured using high-performance liquid chromatography (HPLC). Molecular mobility was measured using isothermal microcalorimetry to measure enthalpy changes associated with structural relaxation below T (g). RESULTS: A weak correlation between the rates of degradation and structural relaxation times in pure amorphous cephalosporins suggests that reactivity in these systems is coupled to molecular motions in the glassy state. However, when sucrose was added to one of the cephalosporin drugs stability improved even though this addition reduced T (g) and the relaxation time constant, tau(D)(beta), suggesting that there was no correlation between reactivity and structural relaxation in the cephalosporin mixtures. In contrast, the rate of ethacrynate sodium dimer formation in mixtures was more strongly coupled to the relaxation time constant, tau(D)(beta). CONCLUSIONS: These studies suggest that the extent to which chemical degradation is coupled to structural relaxation in glasses motions is determined by how closely the motions of the rate controlling step in chemical degradation are associated with structural relaxation. Moderate coupling between the rate of dimer formation for ethacrynate sodium in mixtures with sucrose, trehalose and PVP and structural relaxation constants suggests that chemical changes that require more significant molecular motion, and includes at least some translational diffusion, are more strongly coupled to the molecular motions associated with structural relaxation. The observation that sucrose stabilizes cefoxitin sodium even though it lowers T (g) and reduces the relaxation time constant, tau(D)(beta) is perhaps a result of the importance of other kinds of molecular motions in determining the chemical reactivity in glasses. More... »

PAGES

2254-2268

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s11095-006-9080-8

DOI

http://dx.doi.org/10.1007/s11095-006-9080-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1019231725

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/16941232


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