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PubMed1992

Formulation and stability of freeze-dried proteins: effects of moisture and oxygen on the stability of freeze-dried formulations of human growth hormone.

This research presents the results of a series of stability studies on freeze-dried formulations of human growth hormone (hGH). Chemical decomposition via methionine oxidation and asparagine deamidation as well as irreversible aggregation are characterized by HPLC. Water sorption isotherms, DSC thermograms, and pulsed proton NMR data are also obtained. No glass transition temperatures are observed in the temperature range of the stability studies. The pulsed NMR data suggest onset of greater mobility in the solid at a water content slightly higher than BET "monolayer" level. Stability of freeze-dried solids at 25 degrees C and 40 degrees C is studied as a function of residual moisture and exposure to oxygen. Formulations with and without a glycine/mannitol excipient system are studied. Significant levels of chemical decomposition and irreversible aggregation occur under most conditions with the effects of residual water content and "headspace oxygen" strongly dependent on the formulation. At low water content with minimal oxygen in the vial headspace, the glycine/mannitol formulation yields optimum stability. However, for either high water content or high oxygen content in the vial, stability of hGH without excipients is superior. The qualitative effect of residual moisture on stability depends on the temperature of the stability study. Generally, the stability of a sample adjusted to a given water content by desorption (during freeze-drying) is identical to the stability of a sample prepared by sorption of water on to a previously highly dried sample.

Calorimetry, Differential Scanning↗
PubMed1998

The physical state of mannitol after freeze-drying: effects of mannitol concentration, freezing rate, and a noncrystallizing cosolute.

The objectives of this study were to (1) measure the effects of freezing rate and mannitol concentration on the physical state of freeze-dried mannitol when mannitol is present as a single component, (2) determine the relative concentration threshold above which crystalline mannitol can be observed by X-ray powder diffraction in the freeze-dried solid when a variety of noncrystallizing solutes are included in the formulation, and (3) measure the glass transition temperature of amorphous mannitol and to determine the degree to which the glass transition temperature of freeze-dried solids consisting of mannitol and a disaccharide is predicted by the Gordon-Taylor equation. Both freezing rate and mannitol concentration influence the crystal form of mannitol in the freeze-dried solid when mannitol is present as a single component. Slow freezing of 10% (w/v) mannitol produces a mixture of the alpha and beta polymorphs, whereas fast freezing of the same solution produces the delta form. Fast freezing of 5% (w/v) mannitol results primarily in the beta form. The threshold concentration above which crystalline mannitol is detected in the freeze-dried solid by X-ray diffraction is consistently about 30% (w/w) when a second, noncrystallizing solute is present, regardless of the nature of the second component. The glass transition temperature of amorphous mannitol measured from the quench-cooled melt is approximately 13 degreesC. Accordingly, mannitol is an effective plasticizer of freeze-dried solids when the mannitol remains amorphous. Glass transition temperatures of mixtures of mannitol and the disaccharides sucrose, maltose, trehalose, and lactose are well predicted by the Gordon-Taylor equation with values of k in the range of 3 to 4.

Chemical Phenomena↗
PubMed2006

Freeze-drying of nanocapsules: impact of annealing on the drying process.

Freeze-drying process was recently applied to improve the long-term storage stability of nanocapsules. Thermal treatment by annealing is an interesting process to optimize a freeze-drying cycle of these colloidal vectors. The objective of this paper is to investigate the impact of annealing on primary and secondary drying characteristics and on nanocapsules (NC) properties. Nanocapsules were prepared from poly-epsilon-caprolactone (PCL) biodegradable polymer and stabilized by polyvinyl alcohol (PVA), and then freeze-dried with two cryoprotectants: sucrose and poly vinyl pyrrolidone (PVP). Freeze-dried nanocapsules were characterized by size measurement and transmission electron microscopy after reconstitution. The effect of annealing on the kinetics of sublimation, on the mass transfer resistance and on the porosity of the freeze-dried product has been studied in the case of PVP. Finally, the effect of annealing on the kinetic of secondary drying was studied and the results were coupled with the isotherm of sorption. Results showed that PCL nanocapsules could be freeze-dried without any modification of their properties in presence of the two cryoprotectants used. Annealing of nanocapsules suspensions could accelerate the sublimation rate without any modification of nanocapsules size in the case of the two studied cryoprotectants. Such improvement could be explained by the increase of ice crystals size after annealing and by the diminution of mass transfer resistance by the dried layer. The acceleration of sublimation rate seems to depend on the temperature of annealing. The annealing of sucrose solution slows down the secondary drying kinetic whereas no effect is observed in the case of PVP.

Capsules↗
PubMed1982

The structure of the cytoplasmic matrix preserved by freeze-drying and freeze-substitution.

This paper reports a study of the cytoplasmic matrix in whole cultured cells examined by high voltage electron microscopy. In order to acquaint ourselves with the influence of preparation procedures on the morphology depicted, PtK2 cells were prepared for examination by first freezing in propane at -185 degrees C and then drying while maintained at -95 degrees C. Other cells of the same type were first fixed with glutaraldehyde and OsO4 and then frozen dried. Others were prepared by freeze-substitution and eventually dried by the critical-point method from CO2. And finally, some were preserved by conventional techniques of glutaraldehyde and OsO4 followed by dehydration in alcohol and critical-point drying. The observations are presented in stereo images. The morphologies after these various procedures are quite similar. All show the characteristic three-dimensional lattice or meshwork of slender filaments called microtrabeculae. In cells rapidly frozen and then dried from the frozen state, there is less evidence of shrinkage and probable change in the trabecular structure than in cells first fixed with glutaraldehyde and then frozen dried. The differences we relate to the demonstrable failure of glutaraldehyde to penetrate the cell quickly and fix instantly any component that is in active motion. Other differences that can be observed between all four types of preparation are not recognizably striking and are thought to reflect as much as anything morphological diversity in the original cells. In some instances, the amorphous ice of the initial freezing at -185 degrees C was allowed to crystallize at -80 degrees C. The small crystals that form push aside the microtrabeculae and leave obvious imprints on the structure. The essential message from these experiments is that the cytomatrix is structured.

Animals↗
PubMed1998

Effects of additives on the stability of recombinant human factor XIII during freeze-drying and storage in the dried solid.

Freeze-drying is often used to improve storage stability of therapeutic proteins. In order to obtain a product with optimal storage stability it is important to understand the mechanisms by which solutes protect the protein against freeze-drying-induced stresses and also against damage induced during subsequent storage. The objective of the current study was to examine the importance of various mechanisms proposed to account for acute and long-term storage stability using recombinant human Factor XIII (rFXIII)4 as a model protein. Initially, for acute stability during freeze-drying, it was found that solutes which formed an amorphous phase stabilized rFXIII to a greater degree than solutes which crystallized during freeze-drying. However, only amorphous solutes which were able to hydrogen bond to the protein, and thus preserve the native protein structure in the dried solid, provided optimal acute stability. Thus, in addition to forming an amorphous phase, it was also important to possess the ability to hydrogen bond to the protein. Long-term storage stability was found to be optimal in the presence of solutes which formed and maintained amorphous phases with Tg values above the storage temperature and which also preserved the native protein structure during freeze-drying. Solute crystallization during storage compromised storage stability.

Dextrans↗
PubMed1990

Biohazards in pharmaceutical freeze drying.

Among freeze-dried drugs there are many which may imperil manufacturing personnel, e.g. cytostatic drugs possessing carcinogenic effects. Production zones must be specially adapted for handling such drugs. There are many risks endangering a freeze-drying operation--power or water supply failure, but also improperly established freeze-drying cycle. A production batch of a rare, expensive and sensitive product represents a big value; modern equipment therefore features sophisticated automation, overriding possible human error. Problem of particulate contamination is less severe with vials stoppered inside the vacuum chamber, but rubber closures still may become a source of haze. Back-migration of oil from vacuum pumps may be another source. Economy of industrial freeze-drying may be much improved if freezing sequence, drying rate, adjustment of vacuum by "bleeding" nitrogen are tailored specially for each particular product.

Drug Contamination↗
PubMed2005

Practical formulation and process development of freeze-dried products.

Freeze-drying science and technology continues to evolve and increase in importance because of the emergence of biotechnology drugs that are too unstable to be commercially available as ready-to-use solutions. As more new drug compounds need to be developed as freeze-dried products, this mini-review article provides practical guidance and commentary on the latest literature articles on formulation and process development of freeze-dried products. This article contains a table that provides the quantitative formulations of all commercial freeze-dried protein pharmaceutical products through 2004.

Chemical Phenomena↗
PubMed1998

Modeling of the primary and secondary drying stages of the freeze drying of pharmaceutical products in vials: numerical results obtained from the solution of a dynamic and spatially multi-dimensional lyophilization model for different operational policies.

A rigorous unsteady state and spatially multidimensional model is presented and solved to describe the dynamic behavior of the primary and secondary drying stages of the lyophilization of a pharmaceutical product in vials for different operational policies. The results in this work strongly motivate the aggressive control of freeze drying and it is found that heat input control that runs the process close to the melting and scorch temperature constraints yields (i) faster drying times, and (ii) more uniform distributions of temperature and concentration of bound water at the end of the secondary drying stage.

Freeze Drying↗
PubMed2002

Freeze-drying of tert-butanol/water cosolvent systems: a case report on formation of a friable freeze-dried powder of tobramycin sulfate.

A case study is presented in which a tert-butanol (TBA)/water cosolvent system was found to be a useful means of producing freeze-dried tobramycin sulfate that readily forms a loose powder upon agitation in a specialized application in which a critical quality attribute is the ability to pour the sterile powder from the vial. Both formulation and processing variables are important in achieving acceptable physical properties of the cake as well as minimizing residual TBA levels. Liquid/liquid phase separation was observed above critical concentrations of both drug and TBA, resulting in a two-layered lyophilized cake with unacceptable appearance, physical properties, and residual TBA levels. However, the choice of tobramycin sulfate and TBA concentrations in the single-phase region of the phase diagram resulted in a lyophilized solid that can readily be poured from vials. Crystallization of TBA before drying is critical to achieving adequately low residual TBA levels, and this is reflected in the effect of thermal history of freezing on residual TBA levels, where rapid freezing results in incomplete crystallization of TBA and relatively high levels of residual solvent. Annealing at a temperature above T'(g) of the system after an initial freezing step significantly reduces the level of residual TBA. Secondary drying, even at increased temperature and for extended times, is not an effective method of reducing residual TBA levels.

Anti-Bacterial Agents↗
PubMed1998

Development of normal mice from oocytes injected with freeze-dried spermatozoa.

Freeze-dried mouse spermatozoa are all motionless and dead in the conventional sense. When injected into oocytes, however, their nuclei can support normal embryonic development even after three month preservation in a dried state. Although the freeze-drying protocol reported here will need further improvement, the results suggest that it may be possible to store the male genomes at room temperature.

Animal Husbandry↗