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Booy, M. P. W. M. Te; Ruiter, R. A. De; Meere, A.L.J. de

doi:10.1023/a:1018944113914

Cited by 88 publications

(13 citation statements)

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“…The inhibition of sucrose crystallization in a condensed phase by the presence of other additives has also been reported. 4,11,22 Zografi and co-workers 4 showed that the inhibition of sucrose crystallization, at least in part, can be due to a change in mobility by increases in T g caused by selected additives. For example, T g increased from 74 to 82°C in dry conditions by adding 50% (w/w) lactose.…”

Section: Resultsmentioning

confidence: 99%

“…1,3,[8][9][10] There is precedent that additives and high molecular weight polymers, such as dextran or polyvinyl pyrrolidone (PVP), prevent crystallization of carbohydrates, such as sucrose, by increasing T g and crystallization temperature T c of the specific carbohydrate. 4,11 It appears reasonable to expect that a polymeric material such as a protein could also inhibit crystallization. Thus, the level of protein in a formulation, relative to other excipients, may influence the physical stability of the lyophilized cake.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Bovine Somatotropin (rbSt) Concentration at Different Moisture Levels on the Physical Stability of Sucrose in Freeze-Dried rbSt/Sucrose Mixtures

Sarciaux¹,

Hageman²

1997

Journal of Pharmaceutical Sciences

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The inherent instability of many proteins during freeze-drying and storage necessitates the addition of excipients to protect the proteins. It is emphasized in the literature that lyophilized sugar/protein composites should be stored at temperatures below their glass transition temperature (T(g)) to prevent crystallization of excipients. The influence of bovine somatotropin (rbSt) concentration on inhibition of sucrose crystallization at different relative humidities (RH) was of interest. Thermally modulated differential scanning calorimetry (MDSC) was used to measure T(g) and sucrose crystallization temperatures (T(c)) of the composites. Sorption isotherms of the various sucrose/rbSt mixtures were determined gravimetrically with a controlled atmosphere microbalance (CAM) and verified by Karl Fischer analysis of selected samples. The CAM was also used to determine lag times and sucrose crystal growth rates by monitoring weight losses resulting from water liberation upon crystallization of sucrose at 23 degrees C. Results obtained by MDSC indicate that the T(c) increased linearly from approximately 110 degrees C for pure sucrose to approximately 140 degrees C with 20% rbSt at very low water content (<0.1%). Similarly, at 22% RH (4.4% H2O), T(c) increased from approximately 70 degrees C to 120 degrees C. In neither case was T(g) impacted significantly by increasing protein from 0 to 20%. No T(c) could be noted for samples with > or = 30% rbSt in nonisothermal conditions. Plasticization by water decreased both T(g) and T(c) quite similarly but didn't impact the noted effect of protein on T(c). Induction time for sucrose crystallization (i.e. nucleation) at approximately 45% RH (23 degrees C) increased almost 10-fold by addition of 10% rbSt, whereas rates of water loss due to crystallization decreased by no more than 2-3-fold. The overall results strongly indicate that formulations of higher protein concentration will be more resistant to sucrose crystallization and thus more robust when transiently exposed to storage temperatures above their T(g).

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of Bovine Somatotropin (rbSt) Concentration at Different Moisture Levels on the Physical Stability of Sucrose in Freeze-Dried rbSt/Sucrose Mixtures

Sarciaux¹,

Hageman²

1997

Journal of Pharmaceutical Sciences

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“…1,2,12) Sucrose has been added to many freeze-drying formulations because of its potent structure-stabilizing effect and proven safety, whereas the low glass transition temperatures of the sucrose-based amorphous freeze-dried solids result in stability problems in storage at higher temperature or higher humidity. 13) Various saccharides posses different physical properties and protein-stabilizing effects. [1][2][3] Large saccharide molecules often provide freeze-dried solids with high glass transition temperatures (T g s), which are suitable for protein storage stability.…”

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confidence: 99%

Protection of Protein Secondary Structure by Saccharides of Different Molecular Weights during Freeze-Drying

Izutsu

Aoyagi

Kojima

2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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Development of recombinant therapeutic proteins requires rational design of both the formulations and manufacturing processes. [1][2][3][4][5] Freeze-drying is a popular method to retain long-term stability of various proteins that are not sufficiently stable in aqueous solutions, although the stresses incurred during the freeze-drying process often induce partial unfolding and resulting protein aggregation in the rehydrated solutions. [6][7][8] Stable formulation design is required to avoid the biological activity loss and possible immunogenic effect of the structurally and/or chemically altered protein molecules.Many polyols (e.g., saccharides and sugar alcohols) protect proteins from inactivation during freeze-drying and subsequent storage. They protect native protein conformation against dehydration stresses by replacing essential water molecules through molecular interaction (e.g., hydrogen bonding) with the protein molecules.1-4,9) Some polyols also improve the physical and chemical stability of proteins during the freeze-drying process and subsequent storage by keeping the protein within a highly viscose glass-state amorphous solid with limited molecular mobility. 10,11) The choice of an appropriate saccharide and/or saccharide combination is crucial to the formulation design.1,2,12) Sucrose has been added to many freeze-drying formulations because of its potent structure-stabilizing effect and proven safety, whereas the low glass transition temperatures of the sucrose-based amorphous freeze-dried solids result in stability problems in storage at higher temperature or higher humidity. 13) Various saccharides posses different physical properties and protein-stabilizing effects.1-3) Large saccharide molecules often provide freeze-dried solids with high glass transition temperatures (T g s), which are suitable for protein storage stability. In contrast, they often show smaller effect to protect lower concentration enzymes (e.g., 1 mg/ml catalase) from inactivation during freeze-drying. 14)Protein molecules face different stresses during the freezedrying process depending on the initial concentrations, whereas the relationship between the saccharide molecular weights and the protein-stabilizing effect in freeze-drying of pharmaceutically relevant, high concentration (e.g., greater than 1 mg/ml) protein solutions has not been well elucidated.In addition to the low temperature and dehydration stresses, which are independent of the initial protein concentrations, lower concentration proteins are more likely to undergo physical stress on ice, air, and container surfaces. 3,4,15) In the present work, we used Fourier transform infrared (FT-IR) spectroscopy to study the effects of saccharides with different molecular weights on the secondary structure of proteins (BSA, ovalbumin) freeze-dried in high concentration. Addition of sodium tetraborate (Na 2 B 4 O 7 , borax) to aqueous saccharide solutions raises the "effective" saccharide molecular size through complex formation between a tetrahydroxy borate ion and one o...

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“…The stability of such dried systems is the subject of a growing number of investigations, especially for lyoprotected proteins. [1][2][3][4][5][6] The glass transition temperature (T g ) of the sugar matrix is considered to be a critical parameter regarding the long-term stability of the dried protein. Generally, slow chemical and physical degradation is observed in the glassy phase at temperatures below T g , because of the low molecular mobility.…”

Section: Introductionmentioning

confidence: 99%

“…In principle, the T g can be observed as a change in heat capacity with differential scanning calorimetry (DSC), 3,[7][8][9] but in stability studies it is often difficult to detect the glass transition when other thermal events occur in the same temperature range. Recently, a novel extension of DSC, modulated temperature DSC (MTDSC), has been developed.…”

Section: Introductionmentioning

confidence: 99%

Thermal Analysis of Freeze-Dried Liposome–Carbohydrate Mixtures with Modulated Temperature Differential Scanning Calorimetry†

Winden

Talsma

Crommelin

1998

Journal of Pharmaceutical Sciences

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In this study we investigated the use of modulated temperature differential scanning calorimetry (MTDSC) for the detection of the glass transition temperature (Tg) in freeze-dried cakes of lyoprotected liposomes and for the analysis of frozen carbohydrate solutions. The glass transition appeared in the reversing heat flow, whereas the bilayer melting endotherm was observed in the nonreversing heat flow. This enabled the detection of Tg even in samples were the glass and bilayer transition overlapped. In addition, relaxation processes occurring in nonannealed freeze-dried carbohydrate-liposome mixtures, which hinder the determination of Tg with conventional DSC, were also separated from the heat capacity related heat flow. Analysis of frozen carbohydrate solutions with MTDSC facilitated the identification of the glass transition, devitrification peak, and "softening" transition, which could help to further optimize freeze-drying conditions by rationale. Sampling and selection of experimental parameters are discussed for the special case of porous, freeze-dried cakes.

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Cited by 88 publications

References 1 publication

Effects of Bovine Somatotropin (rbSt) Concentration at Different Moisture Levels on the Physical Stability of Sucrose in Freeze-Dried rbSt/Sucrose Mixtures

Effects of Bovine Somatotropin (rbSt) Concentration at Different Moisture Levels on the Physical Stability of Sucrose in Freeze-Dried rbSt/Sucrose Mixtures

Protection of Protein Secondary Structure by Saccharides of Different Molecular Weights during Freeze-Drying

Thermal Analysis of Freeze-Dried Liposome–Carbohydrate Mixtures with Modulated Temperature Differential Scanning Calorimetry†

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