Controlling the physical form of mannitol in freeze-dried systems

Mehta, Mehak; Bhardwaj, Sunny P.; Suryanarayanan, Raj

doi:10.1016/j.ejpb.2013.04.010

Cited by 63 publications

(49 citation statements)

References 21 publications

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“…Several controlled nucleation methods, including ultrasound, ice fog, quick pressure release of a chamber compressed with inert gas, and quick pressure release of a depressurized chamber are receiving increased attention due to their potential to shorten the ice‐subliming primary drying segment . Application of the controlled ice nucleation alters crystal form profiles of freeze‐dried mannitol . The depressurize/release procedure is applicable for most laboratory‐scale lyophilizers, whereas other methods may allow better process control preferable for the production scale freeze‐drying.…”

Section: Discussionmentioning

confidence: 99%

“…Freeze‐drying of some other APIs (e.g., paracetamol) results in particular structure crystals that are different from those obtained by other production methods (e.g., recrystallization from organic solvents). Controlling the physical properties of d ‐mannitol and glycine are particularly important to ensure stability of many lyophilized formulations containing the bulking agents . Extensive studies indicated the significance of the freezing segment to affect physical forms of d ‐mannitol in the dried solids.…”

Section: Introductionmentioning

confidence: 99%

“…Controlling the physical properties of D-mannitol and glycine are particularly important to ensure stability of many lyophilized formulations containing the bulking agents. 9,[16][17][18][19]22,[27][28][29] Extensive studies indicated the significance of the freezing segment to affect physical forms of D-mannitol in the dried solids. Cosolute composition (e.g., addition of pH buffer) and freezing methods (e.g., cooling speeds, postfreeze heat treatment) affect distribution of mannitol polymorphs in freeze-dried solids.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Effects of Formulation and Process Factors on the Crystal Structure of Freeze-Dried Myo-Inositol

Izutsu

Yomota

Okuda

et al. 2014

Journal of Pharmaceutical Sciences

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of Formulation and Process Factors on the Crystal Structure of Freeze-Dried Myo-Inositol

Izutsu

Yomota

Okuda

et al. 2014

Journal of Pharmaceutical Sciences

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“…One potential drawback with the use of mannitol, however, is its varied crystalline forms, including mannitol hemihydrate, in the freeze-dried solids. 8) Release of the crystallization water from the hemihydrate crystal induces undesirable physical and chemical changes of colyophilized APIs during storage. 7,9,10) Freeze-drying of glycine also leads to the formation of multiple crystal forms.…”

mentioning

confidence: 99%

Physical Characterization of <i>meso</i>-Erythritol as a Crystalline Bulking Agent for Freeze-Dried Formulations

Fujii

Izutsu²,

Kume

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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The purpose of this study was to identify and characterize new crystalline bulking agents applicable to freeze-dried pharmaceuticals. Thermal analysis of heat-melt sugar and sugar alcohol solids as well as their frozen aqueous solutions showed high crystallization propensity of meso-erythritol and D-mannitol. Experimental freeze-drying of the aqueous meso-erythritol solutions after their cooling by two different methods (shelf-ramp cooling and immersion of vials into liquid nitrogen) resulted in cylindrical crystalline solids that varied in appearance and microscopic structure. Powder X-ray diffraction and thermal analysis indicated different crystallization processes of meso-erythritol depending on the extent of cooling. Cooling of the frozen meso-erythritol solutions at temperatures lower than their T g ′ (glass transition temperature of maximally freeze-concentrated phase, 59.7°C) induced a greater number of nuclei in the highly concentrated solute phase. Growth of multiple meso-erythritol anhydride crystals at around 40°C explains the powder-like fine surface texture of the solids dried after their immersion in liquid nitrogen. Contrarily, shelf-ramp cooling of the frozen solution down to 40°C induced an extensive growth of the solute crystal from a small number of nuclei, leading to scale-like patterns in the dried solids. An early transition of the freezing step into primary drying induced collapse of the non-crystalline region in the cakes. Appropriate process control should enable the use of meso-erythritol as an alternative crystalline bulking agent in freeze-dried formulations.Key words meso-erythritol; crystallization; freeze-drying; sugar alcohol; thermal analysis Freeze-drying is a popular method for formulating various therapeutic proteins, liposomes, and antibiotics that are not sufficiently stable during storage in aqueous solutions or during drying at high temperatures.1,2) The process is also used to prepare amorphous solid formulations that foster better dissolution rates and bioavailability of poorly soluble pharmaceuticals. Various active pharmaceutical ingredients (APIs) and excipients composing the freeze-dried solids are either in their amorphous or crystalline states.3) The component crystallinity is determined by various factors including their intrinsic properties, co-solute compositions, and thermal history of the process. 4)Many freeze-dried formulations contain amorphous or crystalline bulking agents to prevent loss of the APIs during handling and/or provide better appearance. Some disaccharides (e.g., sucrose and trehalose) form glass-state amorphous dried solids that protect the conformation of embedded proteins and supramolecular assembly of liposomes from dehydration-induced irreversible conformational changes during the process and from their chemical degradation during storage.5,6) Some excipients (e.g., D-mannitol and glycine) are used to obtain superior appearance of stable crystalline solids, although they do not show protein-stabilizing effects. 7) They crystallize mainly ...

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“…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 them of protein-stabilizing interactions.…”

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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Controlling the physical form of mannitol in freeze-dried systems

Cited by 63 publications

References 21 publications

Effects of Formulation and Process Factors on the Crystal Structure of Freeze-Dried Myo-Inositol

Effects of Formulation and Process Factors on the Crystal Structure of Freeze-Dried Myo-Inositol

Physical Characterization of <i>meso</i>-Erythritol as a Crystalline Bulking Agent for Freeze-Dried Formulations

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

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