Acid-Base Reactions in Non-dissociating Solvents n-Butylamine and Acetic Acid in Carbon Tetrachloride and Chloroform

Yerger, E. Anne; Barrow, Gordon M.

doi:10.1021/ja01628a042

Cited by 53 publications

(44 citation statements)

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“…4) The data and recent literature on the properties of related substances in different physical states (e.g., complex crystals, ionic liquids) strongly suggested contribution of the multiple functional groups of the consisting molecules to form the interaction (e.g., electrostatic, hydrogen-bonding) networks required for the glass-state amorphous solids. [23][24][25] Multiple amino, carboxyl, and hydroxyl groups in the solute molecules raise transition temperatures of the mixture frozen solutions (TЈ g ) and the freeze-dried solids (T g ). 15) The ammonium carbohydrate ion pairs form multiple hydrogen-bondings in some non-polar solvents.…”

Section: Discussionmentioning

confidence: 99%

“…15) The ammonium carbohydrate ion pairs form multiple hydrogen-bondings in some non-polar solvents. 23,24) Differently protonated carboxyl and carboxylate groups also form an intermolecular hydrogen-bonding network. 25) The amino acids and organic acids containing plural amino or carboxyl groups should have large chance to form the interactions with multiple counterpart molecules.…”

Section: Discussionmentioning

confidence: 99%

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Freeze-Drying of Proteins in Glass Solids Formed by Basic Amino Acids and Dicarboxylic Acids

Izutsu¹,

Kadoya

Yomota³

et al. 2009

Chem. Pharm. Bull.

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43Freeze-drying is a popular method of ensuring the stability of proteins that are not stable enough in aqueous solutions during the period required for storage and distribution. 1,2) Various freeze-dried protein formulations contain excipients (e.g., sugars, polymers, and amino acids) that protect proteins from physical and chemical changes. Disaccharides (e.g., sucrose, trehalose) are the most popular among them because they stabilize proteins both thermodynamically and kinetically in aqueous solutions and freeze-dried solids. [3][4][5] The development of freeze-dried protein formulations containing amino acids is often more challenging than the development of formulations with saccharides because of the varied physical and chemical properties (e.g., crystallinity, glass transition temperature) of the freeze-dried amino acids, as well as their tendency to form complexes with other ingredients. 6) Many amino acids are considered to protect proteins basically in similar mechanisms with disaccharides. They thermodynamically stabilize protein conformation in aqueous solutions and probably in frozen solutions by being preferentially excluded from the immediate surface of proteins. 7) Glass-state amorphous solids formed by freeze-drying of the disaccharides or some amino acids protect proteins from structural changes thermodynamically by substituting surrounding water molecules. 8) They also reduce chemical degradation of freeze-dried proteins kinetically by reducing the molecular mobility. 2,8) In addition, some amino acids (e.g., L-arginine) also prevent protein aggregation in aqueous solutions prior to the drying process and after reconstitution. 9) Choosing appropriate counterions that form glass-state solid should be one of the key factors in designing amino acid-based amorphous freeze-dried formulations. 10,11) For example, glass transition temperatures (T g ) of freeze-dried Lhistidine salts depend largely on the counterions. 12) Colyophilization of L-arginine and multivalent inorganic acids (e.g., H 3 PO 4 , H 2 SO 4 ) results in glass-state amorphous solids that protect proteins during the process and storage (e.g., tissue plasminogen activator formulation, PDR 2003). 13) Some organic acid and inorganic cation combinations (e.g., sodium citrates) also form high glass transition temperature amorphous solids. 14) Various functional groups (e.g., amino, carboxyl, hydroxyl) in the constituting molecules contributes significantly to form the glass-state amorphous salt solids. 15) Producing glass-state amorphous solids by freeze-drying of amino acid and organic acid combinations, and their application in pharmaceutical formulations are interesting topics to explore. 15) The purpose of this study was to produce stable amorphous solids that protect proteins by freeze-drying combinations of amino acids and organic acids. The physical properties of frozen solutions and freeze-dried solids containing the popular excipients and model chemicals were studied. The effect of the excipient combinations on the freeze-drying ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Freeze-Drying of Proteins in Glass Solids Formed by Basic Amino Acids and Dicarboxylic Acids

Izutsu¹,

Kadoya

Yomota³

et al. 2009

Chem. Pharm. Bull.

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“…27,28) Continuous network of electrostatic interactions and hydrogen-bonding make the salt crystals popular supermolecular building blocks.…”

Section: Discussionmentioning

confidence: 99%

Glass-State Amorphous Salt Solids Formed by Freeze-Drying of Amines and Hydroxy Carboxylic Acids: Effect of Hydrogen-Bonding and Electrostatic Interactions

Kadoya

Izutsu²,

Yonemochi

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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821Glass-state amorphous solids are applied to pharmaceutical formulations as a way to improve dissolution of hydrophobic active ingredients (APIs) or to ensure stability of embedded biomacromolecules (e.g., recombinant proteins) and drug delivery system (DDS) carriers (e.g., liposome). 1-3)Freeze-drying is often a preferable method over other procedures (e.g., quench-cooling of heat-melt solids) for the large-scale production of glass-state solid formulations containing thermally unstable ingredients. Dispersion of drug molecules into nonionic excipient matrices (e.g., trehalose, polyvinylpyrrolidone (PVP)) is a popular way to make the non-crystalline formulations of many APIs that have intrinsic propensity for crystallization or low glass transition temperatures (T g ).1) Insufficient miscibility with certain drug molecules and poor storage stability, however, often hinders the development of solid dispersion formulations using the nonionic matrices.The application of salts or binary complexes is another approach to obtain stable amorphous solids. 4) For example, freeze-drying of sodium indomethacin results in an amorphous solid that has a glass transition temperature (120°C) significantly higher than that of the free acid molecules (45°C). 4,5) Recent studies indicated that the glass-state solids composed of excipient salts or salt-forming excipient combinations are promising as dispersion matrices. 6,7) Some pHadjusting buffer salts (e.g., monosodium citrate) form high T g amorphous solids applicable to protein formulations. 7) Colyophilization of some basic amino acids (e.g., L-arginine, Llysine, L-histidine) with multivalent inorganic acids (e.g., phosphoric acid) also results in the formation of protein-stabilizing glass-state solids.6) High transition temperatures of the mixture freeze-dried solids suggest the contribution of strong intermolecular or inter-ion interactions to reducing the heterogeneous component mobility.In contrast to the extensive studies on the physical properties and local structure of amorphous glass-or rubber-state solids composed of nonionic small molecules (e.g., sucrose, sorbitol) or polymers (e.g., PVP), 3) mechanisms that determine character of organic salts and/or heterogeneous components have not been well elucidated.1,3) Recent intensive studies on ionic liquids (RTMS: room temperature molten salts) provided valuable information regarding the component ion structures, participating interactions, and the physical properties of the microscopically unordered non-crystalline salt systems.8) Some earlier studies indicated feasibility to control the physical property of the amorphous salt solids by optimizing the component structure (e.g., ion radius in indomethacin alkali metal salts) 4) and their compositions that determine the intermolecular and/or inter-ion interactions.The purpose of this study was to elucidate the contribution of functional groups and the size of consisting molecules to the physical properties of multi-component frozen aqueous solutions and their freeze-dri...

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“…Therefore, higher extraction yields are possible with short-chain alcohols. Furthermore, solvents with additional functional groups (alcohols) show much higher yields than expected from their polarity [15,16,[21][22][23]. These solvents are able to release a proton.…”

Section: Screening Of Simple Reactive Extraction Systemsmentioning

confidence: 99%

New reactive extraction systems for separation of bio-succinic acid

Kurzrock

Weuster‐Botz

2011

Bioprocess Biosyst Eng

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Biotechnologically produced succinic acid has the potential to displace maleic acid and its uses and to become an important feedstock for the chemical industry. In addition to optimized production strains and fermentation processes, an efficient separation of succinic acid from the aqueous fermentation broth is indispensable to compete with the current petrochemical production processes. In this context, high molecular weight amines are known to be effective extractants for organic acids. For this reason, as a first step of isolation and purification, the reactive extraction of succinic acid was studied by mixing aqueous succinic acid solutions with 448 different amine-solvent mixtures as extraction agents (mixer-settler studies). The extraction agents consist either of one amine and one solvent (208 reactive extraction systems) or two amines and two solvents (240 reactive extraction systems). Maximum extraction yields of succinic acid from an aqueous solution with 423 mM succinic acid at pH 2.0 were obtained with more than 95% yield with trihexylamine solved in 1-octanol or with dihexylamine and diisooctylamine solved in 1-octanol and 1-hexanol. Applying these optimized reactive extraction systems with Escherichia coli fermentation broth resulted in extraction yields of 78-85% due to the increased ionic strength of the fermentation supernatant and the co-extraction of other organic acids (e.g., lactic acid and acetic acid), which represent typical fermentation byproducts.

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Acid-Base Reactions in Non-dissociating Solvents n-Butylamine and Acetic Acid in Carbon Tetrachloride and Chloroform

Cited by 53 publications

References 1 publication

Freeze-Drying of Proteins in Glass Solids Formed by Basic Amino Acids and Dicarboxylic Acids

Freeze-Drying of Proteins in Glass Solids Formed by Basic Amino Acids and Dicarboxylic Acids

Glass-State Amorphous Salt Solids Formed by Freeze-Drying of Amines and Hydroxy Carboxylic Acids: Effect of Hydrogen-Bonding and Electrostatic Interactions

New reactive extraction systems for separation of bio-succinic acid

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