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PubMed1992

Basic aspects and future trends in the freeze-drying of pharmaceuticals.

Freeze-drying, as a unit operation in chemical engineering, is a complex multistage process which has to be carefully adjusted to each individual case. Its essential feature, drying from the frozen state, makes it particularly attractive for the stabilization of labile hydrated organic compounds of biological origin. However, it offers equal opportunities for the preparation of three-dimensional porous matrices for diversified physical and chemical applications. As such it is both an advanced technology for the long term preservation of unstable material and a refined operation for the development of new structures. Since freeze-drying, also called lyophilization, has been known for almost a century, and has given rise to numerous publications, this paper will not attempt to give a comprehensive review of its evolution but will focus on some of its basic requirements and potential trends.

Biological Products↗

PubMed1985

Microsurgical application of freeze-dried venous allografts.

Freeze-dried venous interposition allografts with an internal diameter of 1.0 mm and a length of 1.0 cm were placed into the femoral arteries of 17 Sprague-Dawley albino male rats in order to investigate patency and host tissue response. The immediate patency rate was 88%. The epigastric island flap was monitored as a sign of patency in the early postoperative period (defined as 1 to 3 days). Twelve of the 17 subjects were observed for 2 months, at which point 66% (8/12) remained patent. There were two aneurysmal dilatations. Histopathological studies and transmission electron microscopy demonstrated that freeze-dried veins undergo complete remodeling in vivo by a normal reparative process and that they do not induce a cellular immune response in the host.

Abdomen↗

PubMed2002

Influence of freeze-drying on the clotting properties of fibrinogen in plasma.

Freeze-dried plasma standards are often used to calibrate fibrinogen assays. Little is known, however, about the effect of freeze-drying on the clotting properties of fibrinogen. If these properties are altered, the use of freeze-dried calibration standards might influence the results obtained when applying clotting assays to determine fibrinogen concentrations. In order to disclose any discrepancies in fibrinogen concentrations before and after freeze-drying, we determined the fibrinogen concentrations in citrated plasma samples using a total clottable protein method and a clotting-rate assay before and after freeze-drying. When using the clotting-rate assay, significantly higher fibrinogen concentrations were found in fresh-frozen plasma samples compared to freeze-dried samples (P<.001). In freeze-dried plasma samples, the fibrinogen concentrations were significantly higher using the total clottable protein assay than the clotting-rate assay (P<.001). When measuring the fibrinogen concentrations in plasma samples with a wide range of fibrinogen concentrations using the routinely employed clotting-rate assay, significantly higher fibrinogen concentrations were found using the freeze-dried calibration plasma, than the fresh-frozen calibration plasma (P=.02). We conclude that the clotting rate of fibrinogen in citrated plasma is reduced following freeze-drying. When using freeze-dried calibration plasma in a clotting-rate assay, higher fibrinogen concentrations are obtained than by using fresh-frozen plasma. Denaturation of fibrinogen during the freeze-drying process, affecting its polymerization properties, may constitute the main contributor to the reduced clotting rate of freeze-dried plasma.

Adult↗

PubMed1977

Scanning electron microscopy of freeze-dried aortic elastin.

As part of a larger project aimed at claryfying some of the uncertainties that exist concerning the structural basis for an explanation of the mechanical behaviour of elastin, an examination was made of purified porcine aortic elastin under the scanning electron microscopy. In order to avoid structural changes caused by impregnation with organic solvents, specimens were prepared directly from their water-saturated state by either air-drying of freeze-drying processes. Comparison of the results obtained by these techniques demonstrates that freeze-drying of elastin has the advantage of enhancing fine detail, minimizing distortion and reducing specimen shrinkage.

Animals↗

PubMed2002

Freeze-drying using vacuum-induced surface freezing.

A method of freezing during freeze-drying, which avoids undercooling of a solution and allows growth of large, dendritic ice crystals, was investigated. Aqueous solutions of mannitol, sucrose, or glycine were placed under a chamber vacuum of approximately 1 mbar at a shelf temperature of +10 degrees C. Under these conditions, the solutions exhibit surface freezing to form an ice layer of approximately 1-3 mm thickness. On releasing the vacuum and lowering the shelf temperature to below the freezing point of the ice in the solution, crystal growth occurs to yield large, chimney-like ice crystals. The duration of primary drying of a frozen cake--as measured by using inverse comparative pressure measurement--was up to 20% shorter than when using a "moderate" freezing procedure (2 K shelf temperature per min). With mannitol, however, the residual moisture content of the final dried product was higher than with moderate freezing, and with sucrose and glycine there was no difference. These findings are related to the structures of the dried cakes formed during freezing, as examined by light microscopy and wide-angle X-ray diffraction. The introduction of an annealing step (4 h at a shelf temperature slightly above the onset melting point of the ice in the frozen cake) combined with the vacuum-induced surface freezing procedure maintains the rapid primary drying and produces a low residual moisture (0.2%) for the freeze-dried mannitol solution.

Crystallization↗

PubMed2026

Comprehensive study on pesticide residues and mycotoxins in freeze-dried strawberries and raspberries.

Freeze-dried fruit has gained popularity because it preserves the flavour and nutritional value of fresh fruit while providing extended shelf life. Despite this, there are concerns regarding its chemical safety. This study evaluated 58 freeze-dried fruit products from the Czech retail market, focusing on potential contamination. Pesticide residues and mycotoxins were determined using LC-MS/MS and GC-MS/MS. Overall, 111 pesticide residues (or their metabolites) and 3 mycotoxins were quantified. After applying processing factors, 12 pesticide residues exceeded EU maximum residue limits. Prohibited substances, including carbofuran, omethoate, and haloxyfop, were detected. Tenuazonic acid was found in 71% of samples, while alternariol and tentoxin were detected less frequently. More than half (54%) of strawberry samples contained 10 or more pesticide residues, indicating potential cumulative exposure concerns, particularly for children with lower body weight. These findings highlight the need for continued monitoring of freeze-dried fruits and further assessment of dietary exposure.

Pesticide Residues↗

PubMedDate not supplied

The effects of freeze-drying and ethylene oxide sterilization on the mechanical properties of human patellar tendon.

Human patellar tendon allografts are used to replace injured anterior cruciate ligaments. They are often stored by freeze-drying or freezing before use and have been sterilized by gamma irradiation or ethylene oxide gas. Studies comparing the mechanical properties of tendons preserved by freeze-drying and sterilized by ethylene oxide have yielded conflicting results. This study examined the effects of freeze-drying and ethylene oxide sterilization on the mechanical properties of human patellar tendons obtained from 11 human cadavers; all were free of musculoskeletal disease. The 22 patellar tendons were halved longitudinally; 7 were frozen at -70 degrees C for 8 weeks and served as controls; 8 were freeze-dried; and 7 were freeze-dried and sterilized with ethylene oxide gas. Ultimate tensile stress and longitudinal strain were greater for frozen than for freeze-dried, but not greater than freeze-dried, ethylene oxide-sterilized tendons (P < 0.05). The modulus of elasticity was similar in all tendon groups. The study suggests that some in vitro mechanical properties of frozen tendons may be marginally superior to the properties of freeze-dried tendons, even after correction for size difference. Ethylene oxide gas sterilization had no adverse effect on tendon mechanical properties.

Aged↗

PubMed1997

The effects of glucose oligomers (maltodextrins) on freeze-drying liposomes.

Liposomes were freeze-dried with glucose oligomers (maltodextrins) consisting of 2 (maltose) to 7 (maltoheptaose) glucoside units, and the effects of the glucoside unit number of the maltodextrin on the lyophilization of the liposomes were investigated. When the molar ratio of the glucoside units of maltodextrins to lipids was reduced below 6, two distinct endotherms were observed after annealing the freeze-dried L-alpha-dipalmitoylphosphatidylcholine (DPPC) liposome by differential scanning calorimetry (DSC). When the molar ratio was raised above 6, only the lower of the two endotherms was observed in all maltodextrins tested. At a molar ratio of 6, the gel to liquid crystalline transition temperature (Tm) of the first scan of these samples was measured. The Tm with maltose was observed to be ca. 65 degrees C, whereas the Tm with the other maltodextrins was observed to increase as the number of glucoside units was increased. Using Fourier transform IR, the phosphate asymmetric stretching band of DPPC liposomes lyophilized with these maltodextrins was observed to shift to lower frequencies. In all cases, the phosphate asymmetric stretching was observed to be roughly 1240 and 1224 cm-1 in the presence of these saccharides. The ratio of the absorbance at 1224 to that at 1240 cm-1 of DPPC liposomes freeze-dried with maltose was greater than the ratio of those stabilized with any of the other maltodextrins tested. These results suggest that the rate of hydrogen bonding between the phosphate of the lipid and maltodextrins was highest when maltose was used as the cryoprotectant. Because of this interaction, the space between the lipid molecules may become wider, causing an increase in the flexibility of the liposomal membrane.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2004

Freeze-drying of proteins: some emerging concerns.

Freeze-drying (lyophilization) removes water from a frozen sample by sublimation and desorption. It can be viewed as a three-step process consisting of freezing, primary drying and secondary drying. While cryoprotectants can protect the protein from denaturation during early stages, lyoprotectants are needed to prevent protein inactivation during drying. The structural changes as a result of freeze-drying have been investigated, especially by FTIR (Fourier-transform IR) spectroscopy. In general, drying results in a decrease of alpha-helix and random structure and an increase in beta-sheet structure. In the case of basic fibroblast growth factor and gamma-interferon, enhanced FTIR showed large conformational changes and aggregation during freeze-drying, which could be prevented by using sucrose as a lyoprotectant. It is now well established that structural changes during freeze-drying are responsible for low activity of freeze-dried powders in nearly anhydrous media. Strategies such as salt activation can give 'activated' enzyme powders, e.g. salt-activated thermolysin-catalysed regioselective acylation of taxol to give a more soluble derivative for therapeutic use. In the presence of moisture, freeze-dried proteins can undergo disulphide interchange and other reactions which lead to inactivation. Such molecular changes during storage have been described for human insulin, tetanus toxoid and interleukin-2. Some successful preventive strategies in these cases have also been mentioned as illustrations. Finally, it is emphasized that freeze-drying is not an innocuous process and needs to be understood and used carefully.

Crystallization↗

PubMedDate not supplied

Effects of various sugars added to growth and drying media upon thermotolerance and survival throughout storage of freeze-dried Lactobacillus delbrueckii ssp. bulgaricus.

The aim of this research effort was to investigate the role of various sugar substrates in the growth medium upon thermotolerance and upon survival during storage after freeze-drying of Lactobacillus bulgaricus. Addition of the sugars tested to the growth medium, and of these and sorbitol to the drying medium (skim milk) was investigated so as to determine whether a relationship exists between growth and drying media, in terms of protection of freeze-dried cells throughout storage. The lowest decrease in viability of L. bulgaricus cells after freeze-drying was obtained when that organism was grown in the presence of mannose. However, L. bulgaricus clearly survived better during storage when cells had been grown in the presence of fructose, lactose or mannose rather than glucose (the standard sugar in the growth medium). A similar effect could not be observed in terms of thermotolerance; in this case, the growth medium supplemented with lactose was found to yield cells bearing the highest heat resistance. Supplementation of the drying medium with glucose, fructose, lactose, mannose or sorbitol led in most cases to enhancement of protection during storage, to a degree that was growth medium-dependent.

Adaptation, Physiological↗

PubMed2005

Effect of freeze-drying and gamma irradiation on biomechanical properties of bovine pericardium.

Freeze-drying and gamma irradiation are the techniques widely use in tissue banking for preservation and sterilization of tissue grafts respectively. However, the effect of these techniques on biomechanical properties of bovine pericardium is poorly known. A total of 300 strips of bovine pericardium each measured 4 cm x 1 cm were used in this study to evaluate the effect of freeze-drying on biomechanical properties of fresh bovine pericardium and the effect of gamma irradiation on biomechanical properties of freeze-dried bovine pericardium. The strips were divided into three equal groups, which consist of 100 strips each group. The three groups were fresh bovine pericardium, freeze-dried bovine pericardium and irradiated freeze-dried bovine pericardium. The biomechanical properties of the pericardial strips were measured by a computer controlled instron tensiometer while the strips thickness was measured by Mitutoyo thickness gauge. The results of the study revealed that freeze-drying has no significant (p > 0.05) effect on the tensile strength, Young's modulus (stiffness) and elongation rate of fresh bovine pericardium. Irradiation with 25 kGy gamma rays caused significant decreased in the tensile strength, Young's modulus and elongation rate of the freeze-dried pericardium. However, gamma irradiation has no significant effect on the thickness of freeze-dried bovine pericardium, while freeze-drying caused significant decreased in the thickness of the fresh bovine pericardium. The outcome of this study demonstrated that freeze-drying has no significant effect on the biomechanical properties of fresh bovine pericardium, and gamma irradiation caused significant effect on the biomechanical properties of freeze-dried bovine pericardium.

Animals↗

PubMed1991

Compression of foods during freeze-drying: water plasticization at the ice-dry layer interface.

The compressive mechanical properties of freeze-dried green beans show a pronounced decrease in rigidity when moisture content and/or temperature are increased. There exist several temperature and moisture combinations which give common values for mechanical properties. These combinations also give a common compressive behavior. Using this information on mechanical properties, it is possible to predict a stress-strain relationship, if given either a temperature, a moisture content, or the value of a pertinent mechanical property. It is shown that the moisture contents and temperatures that exist in the dry layer during freeze-drying result in mechanical properties that are suitable for compression of the dry layer. From studies on compression behavior during freeze-drying, it is shown that applied compressive pressure is the main determinant of final degree of compression. Increasing the compressive pressure gave a higher compression effect and gave a more rapid drying, presumably due to improved heat transfer in the compressed dry layer. From the above information, a simple method to predict compression behavior during freeze-drying was developed.

Fabaceae↗

PubMed1994

Stability study of drug-loaded proteinoid microsphere formulations during freeze-drying.

Drug-loaded proteinoid microspheres were freeze-dried to facilitate shipping and handling and to enable long term storage. Heparin was chosen as the model drug in developing the optimum lyophilization process. The factors influencing the integrity of either heparin-loaded or unloaded ('empty') proteinoid microspheres during freeze-drying were determined, with emphasis on: selecting an optimum freezing and resuspending temperature; choosing an appropriate cryoprotectant and its optimum concentration in the formulation; and, designing a suitable method for formulating the microspheres. Freezing at/below -70 degrees C was found to minimize damage to the microspheres. Addition of sugars, such as trehalose and lactose, as cryoprotectants, further increased the stability of the heparin-loaded microspheres during freeze-drying. The optimum trehalose or lactose concentrations were determined to be 5% (w/v). Using the optimumized lyophilization process described in this manuscript, microspheres remained intact during freeze-drying. The freeze-dried microspheres were stable for at least three months post-lyophilization.

Cryoprotective Agents↗

PubMed1986

Freeze-dried embedded specimens for biological microanalysis.

The main problems associated with freeze-drying of biological material for electron microscopy concern the freeze-drying temperatures and times necessary to minimize artifacts. Due to the many parameters involved these problems have to be resolved experimentally. It can be shown that good morphological preservation of chemically unfixed material is possible when freeze-drying is done exclusively in a temperature range between -80 degrees C and -50 degrees C. OsO4 vapour fixation of the freeze-dried tissue is not necessary and should be avoided because it may cause ion redistribution artifacts. Embedding at low temperature of properly freeze-dried material does not seem to disturb structure and ion distribution of the freeze-dried material. Hence, sections of such freeze-dried material and embedded biological material seem to be suitable for microanalysis. Preliminary micro-analytical results obtained from sections of freeze-dried and Lowicryl K11M embedded muscle reveal an uneven distribution of potassium in the sarcomeres similar to the visualized uneven distribution of the electron dense thallium (potassium surrogate) in frozen hydrated cryosections. A comparison of different cryomethods shows that freeze-drying and embedding is the simplest way to obtain stable thin sections of chemically unfixed biological material which, for instance, may be used for future microanalytical investigation of the interaction of proteins with physiological and non-physiological ions.

Animals↗

PubMed2002

Excipient crystallinity and its protein-structure-stabilizing effect during freeze-drying.

The relationship between mannitol crystallization during freeze-drying and its effects on stabilizing protein structures was studied using lysozyme, bovine serum albumin, ovalbumin, beta-lactoglobulin and lactate dehydrogenase as model proteins. FT-IR analysis of the protein secondary structure indicated perturbation of both alpha-helix and beta-sheet regions in freeze-drying without cosolutes, whereas the proteins retained most of their native structure in co-lyophilization with sucrose. Mannitol protected the protein structure to different degrees depending on the crystallinity. The combination of mannitol with potassium phosphate buffer reduced the mannitol crystallinity and the structural changes occurring during freeze-drying, whereas mannitol by itself showed little stabilizing effect. Heat-treatment of the frozen solutions at -10 degrees C resulted in a higher mannitol crystallinity and a smaller stabilizing effect in freeze-drying. The secondary structure perturbation was mostly reversible in rehydrated solutions. The varied structure-stabilizing effects of mannitol paralleled its effects on maintaining lower concentrations of enzyme activity during freeze-drying. These results confirm the contribution of molecular interactions between amorphous excipients and proteins (e.g. hydrogen bonding) to structure stabilization during freeze-drying.

Crystallization↗

PubMed2006

Potential use of freeze-drying technique for estimation of tissue water content.

Desiccation and freeze-drying methods were used for the estimation of water content of various rat tissues. In the desiccation method, the tissue samples were cut into small pieces and subsequently dried at 40 degrees C to constant weight. In the freeze-drying method, the prefrozen tissue samples were freeze-dried (-50 degrees C) for 24 h. Tissue water contents obtained by the desiccation and freeze-drying methods were very similar, with no significant difference between them. Regardless of the method, the highest tissue water content was found in testes (0.841 +/- 0.010 ml/g for freeze-drying and 0.865 +/- 0.002 ml/g for desiccation); the lowest values were obtained in bone (0.254 +/- 0.007 ml/g for freeze-drying and 0.267 +/- 0.003 ml/g for desiccation). Upon correction for the water content of residual tissue blood, regardless of the drying method, significant differences were found between corrected and uncorrected tissue water values of all tissues. However, for a given method, the difference between the tissue water contents was not significant after correcting for residual blood. The water content values for all tissues (except bone) agree well with those published previously and obtained by desiccation. All these clearly suggest that the freeze-drying method can be used as an alternative to desiccation for estimation of tissue water content.

Animals↗

PubMed1997

Effect of freeze-drying or gamma-irradiation on remodeling of tendon allograft in a rat model.

Freezing or freeze-drying and gamma-irradiation are techniques currently used for processing tendon allografts. However, it is still unknown how these processing methods affect graft remodeling. In this study, we used a rat patellar tendon transplantation model to investigate the effect of various processing methods on remodeling by quantifying loss of collagen labeled with a radioactive isotope. The grafts were divided into the following four groups according to the processing method: fresh-frozen, freeze-dried, fresh-frozen and gamma-irradiated, or freeze-dried and gamma-irradiated. The percentage of donor collagen, calculated from hydroxyproline content and radioactivity level, was used as an indicator of graft remodeling. At 2 weeks, the level of donor collagen in the fresh-frozen group was 62%; in the freeze-dried group, 59%; in the fresh-frozen and irradiated group, 57%; and in the freeze-dried and irradiated group, 44%. At 4 weeks, the percentage of donor collagen remaining in grafts decreased to 38% in the fresh-frozen group, 19% in the freeze-dried group, 27% in the fresh-frozen and irradiated group, and 12% in the freeze-dried and irradiated group. Finally, at 12 weeks, the levels were 19% in the fresh-frozen group, 20% in the freeze-dried group, 15% in the fresh-frozen and irradiated group, and 6% in the freeze-dried and irradiated group. The percentages of donor collagen in the freeze-dried and the fresh-frozen and irradiated groups were significantly lower than that in the fresh-frozen group at 4 weeks. The values for the freeze-dried and irradiated group were significantly lower than those for the fresh-frozen and irradiated group at 4 and 12 weeks. These data suggest that freeze-drying, freeze-drying followed by gamma-irradiation, and fresh-freezing followed by gamma-irradiation temporarily accelerate graft remodeling.

Animals↗

PubMed2005

Cake shrinkage during freeze drying: a combined experimental and theoretical study.

The aim of this study is to investigate, by experimental studies and theoretical analysis, the phenomenon of cake shrinkage during the lyophilization process and to investigate the effect of shelf temperature during primary drying and secondary drying on the degree of cake shrinkage. Freeze-drying experiments were performed using 5% w/v sucrose where the drying protocols were altered in order to produce differing product temperature profiles. Resistance data during freeze drying were evaluated by the Manometric Temperature Measurement (MTM) method. Theoretical simulation of the freeze-drying process was performed using the Passage Freeze-Drying software. The difference between the glass transition temperature and the product temperature (Tg-T) obtained from the theoretical analysis was calculated and used for correlation with experimental shrinkage data. The Brunauer, Emmeth, Teller (BET) Specific Surface Area (SSA) Analysis was used as a method to quantify the degree of shrinkage. Samples were also analyzed for pore volume by mercury porosimetry. The SSA analysis on the freeze-dried samples showed an increase in SSA when samples were freeze dried at a lower shelf temperature during primary drying and at a slower ramp rate during secondary drying. The trend in surface area values was consistent with that obtained for pore size values. However, differences obtained among the various samples are small and cake diameter measurements showed that there was approximately 17% shrinkage even in the sample freeze dried at temperatures well below the Tg' and Tg. Variations in process and product temperature only accounted for an additional 2%-3% shrinkage. Resistance data obtained at various primary drying shelf temperatures showed a good correlation with surface area. The Tg-T behavior of the freeze-dried samples showed that a slow ramp rate of 0.1 degrees C/min during secondary drying maintains a product well below the Tg at all times and a higher ramp rate gives negative values of Tg-T. The obtained data suggest that conditions of secondary drying do impact shrinkage, and it is important to maintain a sample well below the collapse temperature during primary drying and below the Tg at all times during secondary drying; however, drying conditions are a second order effect. It seems that, in the case of a sample like sucrose, nearly 17% shrinkage will occur no matter what the product temperature history.

Chemistry, Pharmaceutical↗