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Universality of supersaturation in protein-fiber formation.

ABSTRACT: The thermodynamics and kinetics of the aggregation of sickle-cell hemoglobin into fibers have been studied in great detail under a wide range of solution conditions. The stability of the fiber is measured by the solubility; the kinetics is characterized by a delay before the appearance of fibers. A review of data in the literature shows that there is no correlation of the delay time with fiber stability and only a weak correlation with the initial protein concentration. There is, however, a striking collapse of all the data onto a single universal curve when the delay time is plotted versus the supersaturation, which is the ratio of the initial protein concentration to the solubility, expressed as activities. Collapse onto the same universal curve is also obtained when using delay times calculated from the double-nucleation theoretical model.

SUBMITTER: Cellmer T

PROVIDER: S-EPMC7329141 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Universality of supersaturation in protein-fiber formation.

Cellmer Troy T Ferrone Frank A FA Eaton William A WA

Nature structural & molecular biology 20160328 5

The thermodynamics and kinetics of the aggregation of sickle-cell hemoglobin into fibers have been studied in great detail under a wide range of solution conditions. The stability of the fiber is measured by the solubility; the kinetics is characterized by a delay before the appearance of fibers. A review of data in the literature shows that there is no correlation of the delay time with fiber stability and only a weak correlation with the initial protein concentration. There is, however, a stri ...[more]

PMID: 27018803

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Project description:The maximum achievable concentration of a drug in solution is dictated by the chemical potential of the solid form. Because an amorphous solid has a higher chemical potential than the corresponding crystal form, in the absence of phase transformations, a higher transient solubility is expected. However, the chemical potential of an amorphous drug can be reduced by mixing with another component. Therefore, upon mixing with a polymer to form an amorphous solid dispersion (ASD), the maximum solution concentration achieved can be potentially altered, in particular if the polymer is poorly soluble in the dissolution medium. Such changes in the chemical potential of the drug may be a critical factor in determining the maximum achievable solution concentration, and could alter the crystallization driving force of the drug. Therefore, the aim of this study was to gain insights into the impact of poorly soluble polymers on the "amorphous solubility" of drugs formulated as amorphous solid dispersions. Lopinavir was selected as a model drug with a low crystallization tendency, enabling determination of the amorphous solubility as a function of ASD composition. Model polymers included cellulose acetate (CA), CA phthalate (CAP), ethylcellulose (EC), Eudragit® RL PO (EUD), hydroxypropylmethylcellulose (HPMC), HPMC acetate succinate (HPMCAS), and HPMC phthalate (HPMCP). The "amorphous solubility" of the drug alone was determined and then the changes in maximum achievable concentration were measured as a function of drug loading. Drug-polymer interactions were characterized using infrared spectroscopy (IR), differential scanning calorimetry (DSC) and moisture sorption analysis. The results showed that the maximum achievable concentration ("amorphous solubility") of lopinavir varied with the extent of drug-polymer interactions, as well as the drug weight fraction in the ASD. This information is of great value when evaluating the maximum achievable concentration of amorphous systems formulated with pH responsive polymers, and should contribute to a broader understanding of drug phase behavior in the context of ASDs.

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Universality of supersaturation in protein-fiber formation.

Publications

Universality of supersaturation in protein-fiber formation.

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