Miscibility as a Factor for Component Crystallization in Multisolute Frozen Solutions

Izutsu, Ken‐ichi; Shibata, Hiroko; Yoshida, Hiroyuki; Goda, Yukihiro

doi:10.1002/jps.24038

Cited by 3 publications

(3 citation statements)

References 54 publications

(63 reference statements)

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“…In addition to the T g 0 , consideration of miscibility (Izutsu et al, 2014), interaction between solutes (Izutsu et al, 2007), formation of ternary eutectic (Murase and Franks, 1989) and unfrozen water (Patel et al, 2014) have also been reported to govern the inhibitory effect of cosolutes on solute crystallization in multi-component frozen systems. We therefore individually evaluated the contribution of these factors towards inhibitory effect of sugars on GHCl crystallization.…”

Section: Investigation Of the Factors Governing The Counter-intuitivementioning

confidence: 97%

“…Miscibility of solutes in frozen systems is usually determined by assessing the thermal behavior of frozen solutions using DSC wherein, appearance of multiple T g 0 s in the heating curve implies phase separation within the amorphous matrix (Izutsu et al, 2014). All frozen solutions exhibited single T g 0 , thereby suggesting the formation of homogenous amorphous phase in each system.…”

Section: Investigation Of the Factors Governing The Counter-intuitivementioning

confidence: 99%

See 1 more Smart Citation

Counter-intuitive effect of non-crystallizing sugars on the crystallization of gemcitabine HCl in frozen solutions

Munjal

Bansal

2015

International Journal of Pharmaceutics

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Section: Investigation Of the Factors Governing The Counter-intuitivementioning

confidence: 97%

Section: Investigation Of the Factors Governing The Counter-intuitivementioning

confidence: 99%

Counter-intuitive effect of non-crystallizing sugars on the crystallization of gemcitabine HCl in frozen solutions

Munjal

Bansal

2015

International Journal of Pharmaceutics

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“…[33][34][35][36] The amorphous-amorphous phase separation of freeze-concentrated solutes is considered to affect quality of freeze-dried protein formulations in various ways, including altered physical stability of cake structure and crystallization propensity of certain solutes (e.g., myo-inositol). 37,38) Mixing state of freeze-concentrated protein and amino acid molecules is of particular interest.…”

mentioning

confidence: 99%

Amorphous–Amorphous Phase Separation of Freeze-Concentrated Protein and Amino Acid Excipients for Lyophilized Formulations

Izutsu¹,

Yoshida²,

Shibata³

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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The objective of this study was to elucidate the mixing state of proteins and amino acid excipients concentrated in the amorphous non-ice region of frozen solutions. Thermal analysis of frozen aqueous solutions was performed in heating scans before and after a heat treatment. Frozen aqueous solutions containing a protein (e.g., recombinant human albumin, gelatin) or a polysaccharide (dextran) and an amino acid excipient (e.g., L-arginine, L-arginine hydrochloride, L-arginine monophosphate, sodium L-glutamate) at varied mass ratios showed single or double T g ′ (glass transition temperature of maximally freeze-concentrated solutes). Some mixture frozen solutions rich in the polymers maintained the single T g ′ of the freeze-concentrated amorphous solute-mixture phase. In contrast, amino acid-rich mixture frozen solutions revealed two T g ′s that suggested transition of concentrated non-crystalline solute-mixture phase and excipient-dominant phase. Post-freeze heat treatment induced splitting of the T g ′ in some intermediate mass ratio mixture solutions. The mixing state of proteins and amino acids varied depending on their structure, salt types, mass ratio, composition of co-solutes (e.g., NaCl) and thermal history. Information on the varied mixing states should be valuable for the rational use of amino acid excipients in lyophilized protein pharmaceuticals.Key words amorphous; freeze drying; thermal analysis; protein formulation; stabilization; mixing Freeze-drying is a popular method to formulate therapeutic proteins that are insufficiently stable in aqueous solutions during storage.1) Several freeze-dried therapeutic protein formulations contain multiple excipients, including stabilizers, bulking agents, pH buffer agents, and tonicity modifiers besides active pharmaceutical ingredient (API).2-4) Sucrose and trehalose are popular stabilizers that protect proteins from dehydration-induced irreversible structural changes during the process and from chemical degradation during storage. Certain amino acids and their salts are potent stabilizers in the freeze-drying of proteins, frozen storage of liposomes, and spray drying of vaccines.5-11) Application of the amino acid excipients that protect proteins through particular mechanisms not achievable by saccharides (e.g., aggregation-reducing effect of L-arginine (L-Arg) in aqueous solution) would increase formulation strategies in lyophilization of marginally stable proteins. 5,8,[12][13][14][15] Physical states (e.g., crystallinity, crystal polymorph) of the components are important factors that determine chemical and conformational stability of proteins during the freeze-drying process and subsequent storage. [16][17][18] The stabilizing effects of disaccharides are attributed to protection of protein conformation by the substitution of surrounding water molecules and by holding protein molecules in lower molecular mobility glassstate amorphous solids. Crystallization of some sugar alcohols (e.g., mannitol) during the freezing segment of lyophilization deprives the...

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Effect of co-solutes and process variables on crystallinity and the crystal form of freeze-dried myo -inositol

Izutsu

Kusano

Arai

et al. 2016

International Journal of Pharmaceutics

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Miscibility as a Factor for Component Crystallization in Multisolute Frozen Solutions

Cited by 3 publications

References 54 publications

Counter-intuitive effect of non-crystallizing sugars on the crystallization of gemcitabine HCl in frozen solutions

Counter-intuitive effect of non-crystallizing sugars on the crystallization of gemcitabine HCl in frozen solutions

Amorphous–Amorphous Phase Separation of Freeze-Concentrated Protein and Amino Acid Excipients for Lyophilized Formulations

Effect of co-solutes and process variables on crystallinity and the crystal form of freeze-dried myo -inositol

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