کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2484874 | 1114339 | 2012 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Relating particle formation to saltâ and pHâdependent phase separation of nonânative aggregates of alphaâchymotrypsinogen a
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کلمات کلیدی
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
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چکیده انگلیسی
Visible and subvisible particle formation during the storage of protein solutions is of increasing concern for pharmaceutical products. Previous work (Li Y, Ogunnaike BA, Roberts CJ. 2010. J Pharm Sci 99:645-662) showed that the model protein, alphaâchymotrypsinogen A (aCgn), forms nonânative aggregates under accelerated (heated) conditions, but the size and morphology of the resulting aggregates depended sensitively on pH and NaCl. Here, it is shown that aggregates created as highâmolecularâweight soluble aggregates undergo a pHâ and saltâdependent reversible phase transition to a condensed or insoluble phase of suspended microparticles, whereas monomers remain completely soluble in the same regime. The location of the phase boundary is quantitatively consistent with the different regimes of kinetic behavior observed previously for aCgn. This suggests that the while kinetics is important for controlling the rates of monomer loss during nonânative aggregation, it may be possible to tune solution thermodynamics and phase behavior to suppress otherwise soluble aggregates from propagating to form visible or large subvisible particles. Interestingly, the aggregate phase boundary is sensitive to the identity of salt anions in solution, highlighting the importance of electrostatics and preferential salt interactions in mediating aggregate condensation and particle formation.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 101, Issue 10, October 2012, Pages 3651-3660
Journal: Journal of Pharmaceutical Sciences - Volume 101, Issue 10, October 2012, Pages 3651-3660
نویسندگان
Andrew M. Kroetsch, Erinc Sahin, Hsiangâyun Wang, Sintia Krizman, Christopher J. Roberts,