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  • 1
    Electronic Resource
    Electronic Resource
    Stability of β-Galactosidase, a Model Protein Drug, Is Related to Water Mobility as Measured by 17O Nuclear Magnetic Resonance (NMR) (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 103-108 
    Details
    ISSN: 1573-904X
    Keywords: β-galactosidase ; protein stability ; water mobility ; lyophilization ; 17O nuclear magnetic resonance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The inactivation of freeze-dried β-galactosidase during storage was studied, focusing on the effect of water mobility as measured by the spin-lattice relaxation time, T 1, of water using 17O NMR. Inactivation of β-galactosidase lyophilized from phosphate buffer solution was studied as a function of water content, which in turn affected the T l of water. An increase in the water content of freeze-dried β-galactosidase brought about an increase in the T l of water, as well as a rise in pH. For the freeze-dried enzyme with sufficient water content to be dissolved, the inactivation rate was related to the T l of water rather than to the pH change. It is suggested that as the water content increases, the mobility of water around the enzyme increases, resulting in enhanced enzyme inactivation. The freeze-dried samples with limited moisture showed inactivation rates faster than those expected from the pH and water mobility, suggesting that the inactivation mechanism is different from that for the freeze-dried enzyme with a larger amount of water. Inactivation of β-galactosidase in solutions was also studied as a function of phosphate buffer and sodium chloride concentrations, which in turn affected the T l of water. Because the inactivation rate increased with increasing salt concentrations and the rate extrapolated to zero concentration was negligible, inactivation of the freeze-dried enzyme was apparently induced by the salts used as additives for lyophilization. The enhancing effect of phosphate buffer components, however, was reduced at higher concentrations, an effect related to the decrease in the T l of water. This result may be ascribed to the decrease in water mobility caused by phosphate buffer components and is consistent with the observation that the inactivation rate of the freeze-dried enzyme with a relatively large amount of water decreased with decreasing T 1 of water.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018933315538
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  • 2
    Electronic Resource
    Electronic Resource
    The Effect of Salts on the Stability of β-Galactosidase in Aqueous Solution, as Related to the Water Mobility (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 1484-1487 
    Details
    ISSN: 1573-904X
    Keywords: β-galactosidase ; stability in solution ; water mobility ; spin lattice relaxation time
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The effect of salts (KI, KBr, NaCl, KC1, KF, phosphate, and Na2SO4) on the stability of β-galactosidase in aqueous solution was studied from the aspect of changes in water mobility. At salt concentrations up to 200 mM, the inactivation rate of β-galactosidase in all the salt solutions studied increased with increasing salt concentration. At higher concentrations, those salts which had little effect on the spin-lattice relaxation time, T 1, of water (KI, KBr, and KC1) continued to increase the inactivation rate of β-galactosidase with increasing concentration, while those salts which decreased the T l of water (KF, phosphate, and Na2SO4) decreased the inactivation rate. It appeared that the decrease in water mobility caused by KF, phosphate, and Na2SO4 resulted in stabilization of β-galactosidase. The results indicate that water mobility is an important factor in the denaturation rate of proteins.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018931527176
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  • 3
    Electronic Resource
    Electronic Resource
    Aggregates Formed During Storage of β-Galactosidase in Solution and in the Freeze-Dried State (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 687-691 
    Details
    ISSN: 1573-904X
    Keywords: β-galactosidase ; aggregation ; solution ; freeze-dried
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Aggregates formed during storage of freeze-dried β-galactosidase were compared with those formed in solutions. Freeze-dried β-galactosidase aggregated during storage in the presence of moisture, producing a protein precipitate which was soluble in guanidine hydrochloride solution but not in buffer solution. The protein precipitate dissolved in guanidine solution exhibited a large molecular size by high-performance size exclusion chromatography and converted to proteins of original size in the presence of dithiothreitol. It is suggested that the aggregation involves chemical interaction via covalent disulfide bonding. In contrast, β-galactosidase in aqueous solution aggregated without formation of protein precipitates. Soluble aggregates were converted to proteins of original size in guanidine solution without dithiothreitol, suggesting noncovalent bonding. The difference in aggregation behavior may be ascribed to the difference in the water:protein ratio. We propose that inactivation of β-galactosidase is due to formation of thermally denatured (unfolded) protein, which aggregates dependent on the water:protein ratio, either via noncovalent interactions at a high water:protein ratio in solution or via covalent interaction at a low water:protein ratio in the freeze-dried state.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018951530927
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  • 4
    Electronic Resource
    Electronic Resource
    Is Stability Prediction Possible for Protein Drugs? Denaturation Kinetics of β- Galactosidase in Solution (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 1721-1725 
    Details
    ISSN: 1573-904X
    Keywords: protein drug ; denaturation ; aggregation ; kinetics ; Eyring equation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Denaturation and aggregation kinetics of Aspergillus oryzae β-galactosidase in solution were studied in order to determine whether the stability of protein drugs can be predicted. Denaturation of β-galactosidase, monitored by measuring enzyme activity, conformed to first-order kinetics, whereas aggregation of the denatured form, monitored by high performance size exclusion chromatography, showed a reaction order higher than 1. Denaturation of β-galactosidase was irreversible and exhibited a biphasic kinetic pattern which could be explained by assuming that two isoenzymes denatured irreversibly at different rates. Linear Arrhenius plots were obtained for the estimated rate constants, and ΔH
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018955031042
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  • 5
    Electronic Resource
    Electronic Resource
    Determination of Molecular Mobility of Lyophilized Bovine Serum Albumin and γ-Globulin by Solid-State 1H NMR and Relation to Aggregation-Susceptibility (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 926-930 
    Details
    ISSN: 1573-904X
    Keywords: molecular mobility ; spin-spin relaxation time ; aggregation ; solid-echo
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Feasibility of solid-state 1H NMR for determining the mobility of protein molecules in lyophilized cakes was considered. The mobility in cakes with various levels of water content was studied in relation to aggregation-susceptibility. Methods. Spin-spin relaxation time (T2) of protons in lyophilized bovine serum albumin (BSA) and γ-globulin (BGG) was measured as a function of hydration level by solid state 1H NMR using a ‘solid-echo’ pulse sequence. Moisture-induced aggregation of the lyophilized proteins was also determined by high performance size exclusion chromatography. Results. Lyophilized BSA and BGG became susceptive to aggregation when water content exceeded about 0.2 g/g of protein. T2 of protein protons in the lyophilized cakes started to increase at lower water contents. The increase in aggregation susceptibility observed with increasing water content appears to follow the increase in T2 of protein protons. For lyophilized BGG, both aggregation and T2 of protein protons decreased at water contents above 0.5 g/g protein. Conclusions. Mobility of protein molecules in lyophilized cakes was successfully detemined by solid-state 1H NMR. The aggregation susceptibility of proteins was strongly related to their molecular mobility as indicated by T2.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016069532204
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  • 6
    Electronic Resource
    Electronic Resource
    Dependence of the Molecular Mobility and Protein Stability of Freeze-Dried γ-Globulin Formulations on the Molecular Weight of Dextran (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 736-741 
    Details
    ISSN: 1573-904X
    Keywords: molecular mobility ; spin-spin relaxation time ; protein stability ; dextran ; freeze-drying
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The effect of the molecular weight of dextran on the molecular mobility and protein stability of freeze-dried serum γ-globulin (BGG) formulations was studied. The stabilizing effect of higher molecular weight dextran is discussed in relation to the molecular mobility of the formulations. Methods. The molecular mobility of freeze-dried BGG formulations containing dextrans of various molecular weights was determined based on the free induction decay of dextran and water protons measured by proton NMR. The protein stability of the formulations was determined at temperatures ranging from 20 to 70°C by size exclusion chromatography. Results. Changes in the molecular mobility of freeze-dried formulations that occurred at temperatures below the glass transition temperature could be detected as the molecular mobility-changing temperature (Tmc), at which dextran protons started to exhibit a Lorentzian relaxation decay due to higher mobility in addition to a Gaussian relaxation decay. Tmc increased as the molecular weight of dextran increased. The proportion of dextran protons which exhibited the higher mobility relaxation process (Phm) at temperatures above Tmc decreased as the molecular weight of dextran increased. Protein stability was closely related to molecular mobility. The temperature dependence of the denaturation rate changed at around Tmc, and denaturation in the microscopically liquidized state decreased as Phm decreased with increasing molecular weight of dextran. Conclusions. The effect of the molecular weight of dextran on the protein stability of freeze-dried BGG formulations could be explained in terms of the parameters obtained by 1H-NMR such as Tmc and Phm. These parameters appear to be useful in preformulation and stability prediction of freeze-dried formulations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1012194220970
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  • 7
    Electronic Resource
    Electronic Resource
    Temperature Dependence of Bimolecular Reactions Associated with Molecular Mobility in Lyophilized Formulations (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 925-929 
    Details
    ISSN: 1573-904X
    Keywords: acetyl transfer ; hydrolysis ; lyophilized formulation ; temperature dependence ; molecular mobility
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. We studied the temperature dependence of acetyltransfer between aspirin and sulfadiazine, a bimolecular reaction, inlyophilized formulations at temperatures near the glass transitiontemperature (Tg) and NMR relaxation-based critical mobilitytemperature (Tmc), to further understand the effect of molecularmobility on chemical degradation rates in solid pharmaceutical formulations.The temperature dependence of the hydrolysis rates of aspirin andcephalothin in lyophilized formulations was also studied as a model ofbimolecular reactions in which water is a reactant. Methods. Degradation of lyophilized aspirin-sulfadiazineformulations containing dextran and various amounts of water at temperaturesranging from 1°C to 80°C was analyzed by HPLC. The degradation ofcephalothin in lyophilized formulations containing dextran andmethylcellulose was also analyzed at temperatures ranging from 10°C to70°C. Results. Acetyl transfer in lyophilizedasprin—sulfadiazine formulations containing dextran exhibited atemperature dependence with a distinct break around Tmc, whichmay be ascribed to a change in the translational mobility of aspirin andsulfadiazine molecules. The hydrolysis of aspirin and cephalothin inlyophilized formulations, which is also a bimolecular reaction, did not showa distinct break, suggesting that water diffusion is not rate-limiting. Conclusions. The diffusion barrier of water molecules inlyophilized formulations appears to be smaller than the activational barrierof the hydrolysis of aspirin and cephalothin based on the results of thisstudy that the temperature dependence of the hydrolysis rate is almostlinear regardless of Tmc and Tg. On the other hand,the diffusion barrier of aspirin and sulfadiazine molecules appears to becomparable to the activational barrier of the acetyl transfer reactionbetween these com pounds, resulting in nonlinear temperature dependence.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007566919000
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  • 8
    Electronic Resource
    Electronic Resource
    Molecular Mobility of Protein in Lyophilized Formulations Linked to the Molecular Mobility of Polymer Excipients, as Determined by High Resolution 13C Solid-State NMR (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1621-1625 
    Details
    ISSN: 1573-904X
    Keywords: lyophilized formulation ; NMR relaxation time ; high resolution13C solid-state NMR ; molecular mobility ; storage stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The mobility of protein molecules in lyophilized protein formulations was compared with that of excipient molecules based on the spin-lattice relaxation time (T1) of each molecule determined by high resolution 13C solid-state NMR. The relationship between molecular mobility and protein stability is discussed. Methods. Protein aggregation of lyophilized bovine serum -γ-globulin (BGG) formulation containing dextran was measured by size exclusion chromatography. The T1 of the BGG carbonyl carbon and dextran methin carbon in the formulation was determined by high resolution 13C NMR, and subsequently used to calculate the correlation time (τC) of each carbon. The spin-spin relaxation time (T2) of BGG and dextran protons was measured by pulsed NMR spectrometry, and the critical temperature of appearance of Lorentzian relaxation due to liquid BGG and dextran protons (Tmc) was determined. Results. The τC of dextran methin carbon in BGG-dextran formulations exhibited a linear temperature dependence according to the Adam-Gibbs-Vogel equation at lower temperatures, and a nonlinear temperature dependence described by the Vogel-Tamman-Fulcher equation at higher temperatures. The temperature at which molecular motion of dextran changed was consistent with the Tmc. The τC of BGG carbonyl carbon exhibited a similar temperature dependence to the τC of the dextran methin carbon and substantially decreased at temperatures above Tmc in the presence of dextran. The temperature dependence of BGG aggregation could be described by the Williams-Landel-Ferry equation even at temperatures 20°C lower than Tmc. Conclusions. High resolution 13C solid-state NMR indicated that the molecular motion of BGG was enhanced above Tmc in association with the increased global segmental motion of dextran molecules.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018973125010
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  • 9
    Electronic Resource
    Electronic Resource
    Isothermal and Nonisothermal Kinetics in the Stability Prediction of Vitamin A Preparations (1990)
    Springer
    Pharmaceutical research 7 (1990), S. 388-391 
    Details
    ISSN: 1573-904X
    Keywords: stability prediction ; nonisothermal method ; isothermal method ; vitamin A ; shelf life
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A nonisothermal method was applied to shelf-life estimation of commercial vitamin A preparations. The usefulness and limitations of the nonisothermal method, as predicted by computer simulation, were validated. Degradation of vitamin A palmitate followed zero-order kinetics, and non-Arrhenius behavior was suggested for the rate constant. The nonisothermal method predicted a higher shelf-life value than the isothermal method for a syrup preparation, and vice versa, for an injection preparation. Analysis of the results suggested that the nonisothermal method provides better estimates of shelf lives than the isothermal method when drug degradation does not follow the Arrhenius equation near ambient conditions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015875507458
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  • 10
    Electronic Resource
    Electronic Resource
    Inactivation Kinetics of Enzyme Pharmaceuticals in Aqueous Solution (1991)
    Springer
    Pharmaceutical research 8 (1991), S. 480-484 
    Details
    ISSN: 1573-904X
    Keywords: enzyme ; inactivation ; degradation ; kinetics ; α-chymotrypsin ; bromelain ; kallikrein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The kinetics of enzyme inactivation in aqueous solution of neutral pH were studied for α-chymotrypsin, bromelain, and kallikrein. Inactivation of α-chymotrypsin and bromelain followed simple first-order kinetics, and the rate constant obtained conformed to the Arrhenius relationship. Kallikrein, however, presented more complicated kinetics of inactivation, which could be described by a kinetic expression combining a reversible and an irreversible pathway. Nonlinear regression analysis suggested that the rate constants conform reasonably well to the Arrhenius relationship. The results suggest that inactivation of enzymes in aqueous solution can be modeled even if the profile is complicated and that the inactivation rates can be predicted based on the relationship between the parameter estimates and temperature.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015899011324
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