Impact of Heat Treatment on the Physical Properties of Noncrystalline Multisolute Systems Concentrated in Frozen Aqueous Solutions

Izutsu, Ken‐ichi; Yomota, Chikako; Kawanishi, Toru

doi:10.1002/jps.22706

Cited by 6 publications

(8 citation statements)

References 39 publications

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“…Some frozen solutions containing higher mass ratio of inositol showed single broad transitions that suggest incomplete mixing of the solutes. A short heat treatment (−5°C, 3 min) of some inositol‐rich frozen solutions induced two T g ′ transitions that suggested physical changes in the inositol‐dominant (lower T g ′) and solute mixture (higher T g ′) freeze‐concentrated noncrystalline phases, as reportedly observed for some disaccharide and dextran solutions . Longer heat treatment (30 min) of these frozen solutions induced crystallization of myo ‐inositol, which resulted in amorphous dextran in the remaining concentrated phase ( T g ′: approximately −15°C).…”

Section: Resultsmentioning

confidence: 64%

“…The sucrose and dextran mixture frozen solutions showed single transitions at temperatures that shift depending on their concentration ratios both before and after heat treatments. Larger T g ′ deviations in some heat‐treated sucrose‐rich frozen mixture solutions suggested overlapping transitions of coexisting freeze‐concentrated sucrose‐dominant and solute mixture phases . The addition of myo ‐inositol to the dextran and sucrose system apparently lowered the transition temperatures obtained in the first heating scan.…”

Section: Resultsmentioning

confidence: 98%

“…Recent studies indicated amorphous–amorphous phase separation of some freeze‐concentrated polymer (e.g., protein and polysaccharide) and disaccharide mixtures upon exposure of the frozen solutions to higher temperatures (e.g., disaccharides phase and solute mixture phases) . Postfreeze heat treatment (e.g., annealing) is a popular method to obtain large uniform ice crystals that enable fast sublimation as well as to induce solute crystallization in certain freeze‐drying processes .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Miscibility as a Factor for Component Crystallization in Multisolute Frozen Solutions

Izutsu

Shibata

Yoshida

et al. 2014

Journal of Pharmaceutical Sciences

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Section: Resultsmentioning

confidence: 64%

Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Miscibility as a Factor for Component Crystallization in Multisolute Frozen Solutions

Izutsu

Shibata

Yoshida

et al. 2014

Journal of Pharmaceutical Sciences

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“…These solutes may form the multiple amorphous phases basically in the same mechanism with previously reported phase separation in some polymer and disaccharide mixture frozen solutions. 30,31) Freezing of the protein-rich solutions should concentrate all the solutes into practically stable highly viscous amorphous non-ice mixture phase. In contrast, solutions rich in amino acid excipients would form solute-mixture and amino acid-dominant phases during the initial freeze-concentration and/or upon post-freeze heat treatment.…”

Section: Resultsmentioning

confidence: 99%

“…The disaccharide molecules form their dominant concentrated phase above the critical mixing disaccharide/protein mass ratios that vary depending on solute composition (e.g., protein and disaccharide structure, co-solutes) and thermal history. [30][31][32] The proteins and stabilizer molecules should be in the same non-crystalline freeze-concentrated phase to retain protein conformation from the dehydration stresses through the water-substituting molecular interactions (e.g., hydrogen bonding). [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).…”

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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Impact of heat treatment on miscibility of proteins and disaccharides in frozen solutions

Izutsu¹,

Yomota²,

Okuda³

et al. 2013

European Journal of Pharmaceutics and Biopharmaceutics

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Impact of Heat Treatment on the Physical Properties of Noncrystalline Multisolute Systems Concentrated in Frozen Aqueous Solutions

Cited by 6 publications

References 39 publications

Miscibility as a Factor for Component Crystallization in Multisolute Frozen Solutions

Miscibility as a Factor for Component Crystallization in Multisolute Frozen Solutions

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

Impact of heat treatment on miscibility of proteins and disaccharides in frozen solutions

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