Mutual Influence of Mannitol and Trehalose on Crystallization Behavior in Frozen Solutions

Sampreeti Jena; Raj Suryanarayanan; Alptekin Aksan

doi:10.1007/s11095-016-1883-7

Mutual Influence of Mannitol and Trehalose on Crystallization Behavior in Frozen Solutions

Sampreeti Jena, Raj Suryanarayanan, Alptekin Aksan

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

Purpose: Phase separation of trehalose during freeze-drying could render it ineffective as a lyoprotectant. The bulking agent, mannitol, on the other hand, should crystallize readily upon freezing. It is therefore imperative to understand the mutual interaction of these sugars during freezing to ensure preservation of the API during freeze-drying. Methods: We investigated the effect of mannitol to trehalose ratio (R) on the crystallization behavior of both solutes using Differential Scanning Calorimetry, X-Ray Crystallography and FTIR Spectrosopy during controlled freezing and annealing. Results: When R = 1, crystallization of both mannitol (as hemihydrate) and trehalose (as α-anhydrate) were observed. When R ≥ 1, extent of mannitol crystallization was directly proportional to the value of R. When R < 1, trehalose completely suppressed mannitol crystallization. At R > 1, the freeze concentrate was heterogeneous and characterized by two glass transitions – the lower temperature transition (T_g”) attributed to systems containing “extra” unfrozen water. When heated above T_g”, crystallization of mannitol and the associated unfrozen water resulted in T_g’ (glass transition temperature of the freeze-concentrate). Conclusions: R and not the total solute concentration, dictates the composition of the freeze concentrate as well as the physical stability of the excipients

Original language	English (US)
Pages (from-to)	1413-1425
Number of pages	13
Journal	Pharmaceutical research
Volume	33
Issue number	6
DOIs	https://doi.org/10.1007/s11095-016-1883-7
State	Published - Jun 1 2016

Bibliographical note

Funding Information:
This research was funded by an NSF grant (CBET-1335936) to A.A. The authors are grateful to Dr. Seema Thakral for guidance while performing the powder X-ray diffraction. Parts of this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from NSF through the MRSEC program.

Publisher Copyright:
© 2016, Springer Science+Business Media New York.

Keywords

IR spectroscopy
X-ray diffractometry
crystallization
frozen
mannitol
microscopy
trehalose

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title = "Mutual Influence of Mannitol and Trehalose on Crystallization Behavior in Frozen Solutions",

abstract = "Purpose: Phase separation of trehalose during freeze-drying could render it ineffective as a lyoprotectant. The bulking agent, mannitol, on the other hand, should crystallize readily upon freezing. It is therefore imperative to understand the mutual interaction of these sugars during freezing to ensure preservation of the API during freeze-drying. Methods: We investigated the effect of mannitol to trehalose ratio (R) on the crystallization behavior of both solutes using Differential Scanning Calorimetry, X-Ray Crystallography and FTIR Spectrosopy during controlled freezing and annealing. Results: When R = 1, crystallization of both mannitol (as hemihydrate) and trehalose (as α-anhydrate) were observed. When R ≥ 1, extent of mannitol crystallization was directly proportional to the value of R. When R < 1, trehalose completely suppressed mannitol crystallization. At R > 1, the freeze concentrate was heterogeneous and characterized by two glass transitions – the lower temperature transition (Tg”) attributed to systems containing “extra” unfrozen water. When heated above Tg”, crystallization of mannitol and the associated unfrozen water resulted in Tg{\textquoteright} (glass transition temperature of the freeze-concentrate). Conclusions: R and not the total solute concentration, dictates the composition of the freeze concentrate as well as the physical stability of the excipients",

keywords = "IR spectroscopy, X-ray diffractometry, crystallization, frozen, mannitol, microscopy, trehalose",

author = "Sampreeti Jena and Raj Suryanarayanan and Alptekin Aksan",

note = "Funding Information: This research was funded by an NSF grant (CBET-1335936) to A.A. The authors are grateful to Dr. Seema Thakral for guidance while performing the powder X-ray diffraction. Parts of this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from NSF through the MRSEC program. Publisher Copyright: {\textcopyright} 2016, Springer Science+Business Media New York.",

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N2 - Purpose: Phase separation of trehalose during freeze-drying could render it ineffective as a lyoprotectant. The bulking agent, mannitol, on the other hand, should crystallize readily upon freezing. It is therefore imperative to understand the mutual interaction of these sugars during freezing to ensure preservation of the API during freeze-drying. Methods: We investigated the effect of mannitol to trehalose ratio (R) on the crystallization behavior of both solutes using Differential Scanning Calorimetry, X-Ray Crystallography and FTIR Spectrosopy during controlled freezing and annealing. Results: When R = 1, crystallization of both mannitol (as hemihydrate) and trehalose (as α-anhydrate) were observed. When R ≥ 1, extent of mannitol crystallization was directly proportional to the value of R. When R < 1, trehalose completely suppressed mannitol crystallization. At R > 1, the freeze concentrate was heterogeneous and characterized by two glass transitions – the lower temperature transition (Tg”) attributed to systems containing “extra” unfrozen water. When heated above Tg”, crystallization of mannitol and the associated unfrozen water resulted in Tg’ (glass transition temperature of the freeze-concentrate). Conclusions: R and not the total solute concentration, dictates the composition of the freeze concentrate as well as the physical stability of the excipients

AB - Purpose: Phase separation of trehalose during freeze-drying could render it ineffective as a lyoprotectant. The bulking agent, mannitol, on the other hand, should crystallize readily upon freezing. It is therefore imperative to understand the mutual interaction of these sugars during freezing to ensure preservation of the API during freeze-drying. Methods: We investigated the effect of mannitol to trehalose ratio (R) on the crystallization behavior of both solutes using Differential Scanning Calorimetry, X-Ray Crystallography and FTIR Spectrosopy during controlled freezing and annealing. Results: When R = 1, crystallization of both mannitol (as hemihydrate) and trehalose (as α-anhydrate) were observed. When R ≥ 1, extent of mannitol crystallization was directly proportional to the value of R. When R < 1, trehalose completely suppressed mannitol crystallization. At R > 1, the freeze concentrate was heterogeneous and characterized by two glass transitions – the lower temperature transition (Tg”) attributed to systems containing “extra” unfrozen water. When heated above Tg”, crystallization of mannitol and the associated unfrozen water resulted in Tg’ (glass transition temperature of the freeze-concentrate). Conclusions: R and not the total solute concentration, dictates the composition of the freeze concentrate as well as the physical stability of the excipients

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Mutual Influence of Mannitol and Trehalose on Crystallization Behavior in Frozen Solutions

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