The short version of secondary drying fits in a sentence. The long version — which is the one that helps — is below.
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The physical chemistry of freezing influences whether a formulation forms an amorphous glass or a crystalline solid. Amorphous systems can collapse if product temperature rises above the glass transition temperature of the freeze concentrate. Crystalline systems may show eutectic melting, where ice and solute melt together at a fixed temperature. Formulators add bulking agents, lyoprotectants, and buffers to preserve structure and biological activity. The optimum cycle keeps product temperature below critical thresholds during primary drying while allowing efficient sublimation.
Lyophilization is a dehydration process that removes water from a frozen material by sublimation under low pressure. The material is first frozen so that water becomes ice; then the surrounding pressure is lowered below the vapor pressure of ice. Heat is applied gently so ice changes directly to vapor without passing through a bulk liquid phase. The vapor is collected on a cold condenser, leaving a dry porous matrix. This process differs from simple evaporation because the material remains frozen during the main drying stage.
The process usually has three stages: freezing, primary drying, and secondary drying. Freezing sets the ice crystal structure and can determine pore size in the final cake. Primary drying removes free ice by sublimation at low pressure and low shelf temperature. Secondary drying removes bound water by raising the shelf temperature, although some water may remain as part of the solid. Cycle parameters depend on formulation, fill volume, vial type, and equipment performance.
The physics of lyophilization depends on phase boundaries and heat and mass transfer. During primary drying, heat supplied to the product must equal the latent heat of sublimation, while water vapor moves through the drying cake to the condenser. If shelf temperature or pressure is set too high, the ice front can exceed the collapse temperature, causing meltback or pore collapse. If conditions are too cold, drying slows and costs rise. Formulation excipients, vial geometry, and freezing rate alter these limits.
Equipment for lyophilization includes a vacuum chamber, temperature-controlled shelves, a condenser, and a vacuum pump. A refrigeration system cools the shelves and condenser below the product's freezing point. Process monitoring often uses Pirani and capacitance manometers, thermocouples, and resistance sensors. Cycle development balances product quality with time and energy use. Some products are annealed during freezing to improve crystallization of bulking agents. Open questions remain about scaling cycles between laboratory, pilot, and production freeze-dryers.
Lyophilization, also called freeze-drying, removes water from a frozen material by sublimation under reduced pressure. The process begins with freezing, which converts free water into ice and may also produce a glassy phase. Primary drying then lowers chamber pressure so ice sublimes directly to vapor without passing through a liquid stage. Secondary drying raises the temperature modestly to remove bound water. The result is a porous, dry solid that usually reconstitutes quickly. Each stage influences pore structure, residual moisture, and stability.
| Property | Value | Notes |
|---|---|---|
| Common synonyms | Freeze-drying, lyophilisation | Lyophilisation is the British spelling; the process is not simple evaporation. |
| Primary drying pressure | 0.05–0.3 mbar | Pressure must remain below the vapor pressure of ice at the product temperature. |
| Sublimation temperature | Below 0 °C | Ice changes directly to vapor while the product remains frozen. |
| Typical shelf temperature | −40 to −10 °C | Exact setting depends on formulation critical temperature and equipment. |
| Cycle duration | 12–72 hours | Time varies with fill volume, formulation, and dryer performance. |
Freeze-drying is used for materials whose activity or structure depends on low temperature and low water content. Examples include certain biologics, diagnostic reagents, starter cultures, coffee, and porous inorganic precursors. The dried product forms a cake whose porosity aids rapid wetting and dissolution. Main drawbacks are high energy use, long cycle times, and sensitivity to formulation and equipment variation. Questions remain about how freezing rates and ice morphology affect batch uniformity, especially when moving from laboratory to production scale.
Lyophilization, also called freeze-drying, is a dehydration process in which a solvent, usually water, is frozen and then removed by sublimation under reduced pressure. The method preserves heat-sensitive materials that would degrade in conventional drying. Large-scale use grew during the mid-twentieth century for blood plasma and antibiotics, and it later expanded to vaccines, enzymes, foods, and advanced materials. The process produces a dry, porous solid that usually reconstitutes rapidly. It is distinct from simple evaporation because the solvent bypasses the liquid phase during primary removal.
Secondary drying removes bound water that remains after ice sublimation. Shelf temperature is raised gradually while pressure remains low, reducing water content to a target range. Over-drying can cause brittleness or electrostatic issues, while under-drying affects stability. The endpoint is often judged by pressure rise tests, temperature measurements, or water content analysis. Scale-up depends on matching heat and mass transfer across equipment sizes. Small changes in shelf temperature or pressure can alter cycle length substantially.
Lyophilization, or freeze-drying, removes water from a material by freezing it and then lowering pressure so ice changes directly to vapor. The process relies on sublimation, the phase transition from solid to gas without an intervening liquid state. It is used for heat-sensitive materials that would degrade in conventional drying. The three stages are freezing, primary drying, and secondary drying, each with distinct temperature and pressure requirements. In practice, cycle design balances these variables.
After primary drying, secondary drying removes water that remains bound to the material. This stage raises the shelf temperature while maintaining low pressure, which encourages desorption of unfrozen water. Residual moisture can be reduced to a low percentage, improving stability for many products. The process parameters, including freezing rate, shelf temperature, and chamber pressure, influence the final pore structure and reconstitution behavior. Control of these variables helps prevent collapse or meltback during drying.
A formulation often contains excipients that protect the active ingredient during freezing and drying. Bulking agents provide structure, while lyoprotectants stabilize sensitive molecules. The freezing step can produce ice crystals whose size and distribution affect the drying rate, and cycle design includes freezing, annealing, and drying phases. If the product temperature rises above a critical value, the cake may collapse or lose its porous structure. Successful lyophilization therefore depends on the interaction between formulation, equipment, and cycle design.
Lyophilization is a dehydration process that removes water from a frozen material by sublimation under low pressure. The material is first frozen to convert liquid water into ice. Next, the pressure is reduced below the triple point of water so that ice changes directly into vapor without passing through a liquid phase. This step is called primary drying. The result is a porous solid or cake that retains the original shape of the frozen solution.
The physics of lyophilization couples heat transfer, mass transfer, and phase behavior. Sublimation requires a vapor pressure difference between the ice front and the chamber, and the dried layer adds resistance to vapor flow. Amorphous formulations are characterized by a glass transition temperature of the maximally freeze-concentrated solute, often denoted Tg'. Crystalline bulking agents can provide structure, while amorphous excipients stabilize labile components. Open questions remain about spatial heterogeneity, edge effects, and how laboratory cycles scale to production.
Lyophilization is a drying process in which a solvent, usually water, is removed from a frozen material by sublimation under reduced pressure. The material is first solidified, then placed under vacuum so that ice transitions directly to vapor without a bulk liquid phase. This approach suits heat-sensitive substances that would degrade during conventional evaporation. Primary drying removes unbound ice, while secondary drying reduces water that remains adsorbed to the solid matrix. The result is a porous, lightweight solid that can be reconstituted later.
Technetium also has numerous nuclear isomers, which are isotopes with one or more excited nucleons. Technetium-97m (97mTc; "m" stands for metastable) is the most stable, with a half-life of 91.1 days and excitation energy 0.097 MeV, followed by technetium-95m (62.0 days, 0.039 MeV), and technetium-99m (6.01 hours, 0.143 MeV). Technetium-99 (99Tc) is a major product of the fission of uranium-235 (235U), making it the most common and most readily available isotope of technetium, and the only one detected in nature. One gram of technetium-99 produces 6.2 × 108 disintegrations per second (in other words, the specific activity of 99Tc is 0.62 GBq/g).
== Pharmacokinetics == The absolute bioavailability of lobeglitazone is about 95% in rat. In human, the mean steady state clearance (CLss/F) was 1.13 L/h across in 1 to 4 mg dose range. In the dose range, the mean half-life was 10.3 h. Urine excretion was negligible amount in elimination of lobeglitazone in rat and human. The plasma protein binding of the drug is over 99%. The average blood-to-plasma concentration ratio was 0.636. The unbound fraction of lobeglitazone in microsomal incubation medium was 0.479. Lobeglitazone was primarily distributed to the liver with tissue-to-plasma concentration ratio as 5.59, and less to heart, lung, and fat. The tissue to plasma concentration ratios were ranged from about 0.25 to 4.0 for major tissues, in rat. Among six major membrane transporters recommended by the United States Food and Drug Administration, lobeglitazone interacts with OATP1B1, OAT3, and MDR1. In vitro, lobeglitazone was a substrate of rodent OATP1B2. Lobeglitazone interacted with CYP1A2, 2C9 and 2C19. Distribution to liver of lobeglitazone was inhibited by atorvastatin, in rats.
It was manipulated in such a way that it looked like it was actually a Georgian provocation that might undermine a heated status quo, and the Russians simply said no to the provocation." Around the 10th anniversary of the war in August 2018, Matthew Bryza defended Georgian president Saakashvili: "But what president in the world would not respond to his own sovereign territory being attacked by separatists or by anyone else?" He futhrter stated that "The defining moment was indeed Bucharest 2008, and that was a red flag for President Putin; the decision meant that he'd better act quickly because eventually Ukraine and Georgia are going to get NATO membership." In April 2019, former Secretary General of NATO Anders Fogh Rasmussen opined that NATO's decision not to offer a Membership Action Plan (MAP) to Georgia and Ukraine at the 2008 Bucharest summit was a "mistake" because soon after Georgia was invaded and occupied. In August 2019, Georgian artist Vakhtang Kikabidze said in an interview that he had once asked Yevgeny Primakov why Russia needed South Ossetia and Primakov's answer was "So, you will forget about Abkhazia." In August 2022, Daniel Fried said: "We knew what was coming. But we were a little bit slow to quite believe it." He further stated: "Putin wanted his war against Ukraine. And even though the U.S. successfully exposed all of Putin's provocations, he went in anyway. [...] So, to blame Saakashvili and say, well, he fell for the provocations, therefore the war is his fault is nonsense.
== History == High-level vancomycin-resistant E. faecalis and E. faecium are clinical isolates first documented in Europe in 1986 and the United States in 1987. In the United States, vancomycin-resistant E. faecium was associated with 4% of healthcare-associated infections reported to the Centers for Disease Control and Prevention National Healthcare Safety Network from January 2006 to October 2007. VRE can be carried by healthy people who have come into contact with the bacteria, usually in a hospital (nosocomial infection), although it is thought that a significant percentage of intensively farmed chickens also carry VRE. Other regions have noted a similar distribution, but with increased incidence of VRE. For example, a 2006 study of nosocomial VRE revealed a rapid spread of resistance among enterococci along with an emerging shift in VRE distribution in the Middle East region, such as Iran. Treatment failures in enterococcal infections result from inadequate information regarding the glycopeptide resistance of endemic enterococci due to factors such as the presence of VanA and VanB. The study from Iran reported the first case of VRE isolates that carried the VanB gene in enterococcal strains from Iran. This study also noted the first documented isolation of nosocomial Enterococcus raffinosus and Enterococcus mundtii in the Middle East region.
Sources: en.wikipedia.org
==== Paradoxical stimulation of late-stage prostate cancer ==== Though a pure, or silent antagonist of the AR under normal circumstances, bicalutamide, as well as other earlier antiandrogens like flutamide and nilutamide, have been found to possess weak partial agonist properties in the setting of AR overexpression and agonist activity in the case of certain mutations in the ligand-binding domain (LBD) of the AR. As both of these circumstances can eventually occur in prostate cancer, resistance to bicalutamide usually develops and the drug has the potential to paradoxically stimulate tumor growth when this happens. This is the mechanism of the phenomenon of antiandrogen withdrawal syndrome, where antiandrogen discontinuation paradoxically slows the rate of tumor growth. The newer drug enzalutamide has been shown not to have agonistic properties in the context of overexpression of the AR, though certain mutations in the AR can still convert it from an antagonist to agonist. A second mechanism of bicalutamide resistance has been shown to be mediated by an interaction between macrophages and cancer cells. In a typical scenario, the bicalutamide-AR complex translocates inside the nucleus and binds to androgen response elements (AREs). It then recruits a N-CoR corepressor complex which leads to the repression of androgen receptor target genes by preventing their transcription. The triggering of proinflammatory pathways through IL-1 signaling by macrophages infiltration causes the recruitment of TAB2 as a component of the N-CoR complex.
==== European guidelines for phenylketonuria ==== The consensus paper was picked up by the Scientific Advisory Committee of the E.S.PKU. The SAC launched an expert group, the creation the first European Guidelines for Phenylketonuria. This led to the first publication of the key statements in the lancet diabetes and endocrinology. By the end of the year, the complete guidelines were published in the Orphanet Journal of Rare Diseases. The publication also received some critical attention from other medical professionals. A second version of the guidelines is already been worked on.
The Amitāyurdhyāna Sūtra mentions that Vaidehi had, on listening to the teaching in this sutra, attained "great awakening with clarity of mind and reached the insight into the non-arising of all dharmas." Similarly, the Vimalakirti sutra mentions various bodhisattvas (including Vimalakirti) that have attained "the forbearance of the nonarising of dharmas." The Lotus Sutra states that when the "thought of the highest path" arises in sentient beings "they will become convinced of the nonarising of all dharmas and reside in the stage of non-retrogression." The Samdhinirmochana Sutra's chapter 7 mentions a teaching which states: "All phenomena are without an essence, unborn, unceasing, primordially in the state of peace, and naturally in the state of nirvāṇa." However, it states that this teaching is that of the "discourses of provisional meaning", and that it should be taught along with the teachings of the third turning of the wheel of Dharma. Similarly, the Lankavatara sutra explains the doctrine of the unborn and unoriginated nature of dharmas through the idealistic philosophy of mind-only. Since all things are illusory manifestations of the mind, they do not really originate or arise.
=== Pharmacokinetics === After being ingested, clonidine is absorbed into the blood stream rapidly with an overall bioavailability around 70–80%. Peak concentrations in human plasma occur within 60–90 minutes for the "immediate release" (IR) version of the drug, which is shorter than the "extended release" (ER/XR) version. Clonidine is fairly lipid soluble with the logarithm of its partition coefficient (log P) equal to 1.6; to compare, the optimal log P to allow a drug that is active in the human central nervous system to penetrate the blood brain barrier is 2.0. Less than half of the absorbed portion of an orally administered dose will be metabolized by the liver into inactive metabolites, with roughly the other half being excreted unchanged by the kidneys. About one-fifth of an oral dose will not be absorbed, and is thus excreted in the feces. Work with liver microsomes shows in the liver clonidine is primarily metabolized by CYP2D6 (66%), CYP1A2 (10–20%), and CYP3A (0–20%) with negligible contributions from the less abundant enzymes CYP3A5, CYP1A1, and CYP3A4. 4-hydroxyclonidine, the main metabolite of clonidine, is also an α2A agonist but is non lipophilic and is not believed to contribute to the effects of clonidine since it does not cross the blood–brain barrier. Measurements of the half-life of clonidine vary widely, between 6 and 23 hours, with the half-life being greatly affected by and prolonged in the setting of poor kidney function. Variations in half-life may be partially attributable to CYP2D6 genetics.
Alexander Fleming discovered the world's first antibiotic, penicillin, which Florey and Chain then developed. Gerhard Domagk developed sulphonamides, the first broad spectrum synthetic antibacterial drugs.
Sources: en.wikipedia.org
The main change is sublimation, in which ice becomes water vapor without melting into liquid water. This occurs when the chamber pressure is held below the vapor pressure of ice while mild heat is supplied. The result is a dry, porous solid that retains much of its original shape.
Freezing determines ice crystal size, solute distribution, and the pore network left after drying. A slow or fast freezing rate can produce different cake structures and affect reconstitution. It also sets whether the formulation follows an amorphous or crystalline drying path.
It removes most free water during primary drying and part of the bound water during secondary drying. A small residual moisture content often remains and is specified for each product. Complete removal is generally neither practical nor desirable for stability.
Simple drying usually removes water by evaporation from a liquid or solid, often with heat. Lyophilization first freezes the material and then removes ice by sublimation under vacuum. This avoids prolonged exposure to liquid water and high temperatures.