Abstract:
PURPOSE:To study the impact of different process conditions and formulation compositions on metastable mannitol forms in protein formulations during lyophilization. METHODS:Mannitol was studied with and without other formulation components. A cryostage was used to mimic the different processing steps during lyophilization. The different mannitol forms were monitored and quantified with an in situ Raman spectroscopic method. In addition, a Raman imaging method was developed to characterize the spatial distribution of mannitol forms in final lyophilization samples from the freeze-drying stage. RESULTS:Amorphous mannitol was observed during fast cooling (10 °C/min) and with the addition of other formulation component. Amorphous mannitol crystallized into mainly δ and hemihydrate forms during annealing at -20 °C. Under vacuum without moisture, dried amorphous mannitol could transform to mainly α form at 45 °C and greater. The transformation mechanism of the hemihydrate mannitol was similar to that of amorphous form. CONCLUSION:Mannitol tends to crystallize into stable crystalline forms by itself, but the addition of lyoprotectant (e.g. sucrose) and protein helps stabilize the metastable forms (hemihydrate and amorphous). The metastable forms are capable of transforming into mixtures of different forms, with heat and moisture being the critical processing factors.
journal_name
Pharm Resjournal_title
Pharmaceutical researchauthors
Cao W,Xie Y,Krishnan S,Lin H,Ricci Mdoi
10.1007/s11095-012-0855-9subject
Has Abstractpub_date
2013-01-01 00:00:00pages
131-9issue
1eissn
0724-8741issn
1573-904Xjournal_volume
30pub_type
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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journal_title:Pharmaceutical research
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journal_title:Pharmaceutical research
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journal_title:Pharmaceutical research
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journal_title:Pharmaceutical research
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journal_title:Pharmaceutical research
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1018974131236
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pub_type: 杂志文章
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