The short version of Karl Fischer titration fits in a sentence. The long version — which is the one that helps — is below.
Reviewed 2025-10-04. Anything still debated is marked as such rather than presented as settled.
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.
Stability of a lyophilized solid depends on water content, temperature, and the physical state of the formulation. Amorphous products may slowly absorb moisture and drop below their glass transition temperature, causing collapse or crystallization. Some proteins and peptides can aggregate even in a dry state, especially when exposed to heat or moisture. Accelerated stability studies at elevated temperature and humidity help estimate shelf life, but real-time data remain the basis for expiration dating.
After drying, a lyophilized product is usually sealed under vacuum or an inert gas to limit moisture and oxygen exposure. The container closure system matters because stoppers and seals can allow moisture ingress over time. Storage conditions are selected from stability studies that track potency, cake appearance, and reconstitution behavior. Many freeze-dried materials are kept at controlled room temperature, while some require refrigeration or protection from light.
| 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. |
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.
Residual moisture is a key quality attribute for lyophilized products. Water that remains after secondary drying can affect chemical stability, cake structure, and shelf life. Karl Fischer titration is a common method for measuring water content in the dried solid. The target range varies by product, but many biologics are dried to between 0.5% and 3% water by weight. Acceptable limits are set during development and confirmed by stability studies.
Stability studies examine how temperature, humidity, and time influence a lyophilized product. Accelerated conditions provide early information about degradation pathways, while long-term studies support shelf-life claims. The glass transition temperature of the dried formulation can indicate its physical stability, and storage above this temperature may increase molecular mobility and lead to collapse or aggregation. Container closure integrity also matters because moisture or oxygen ingress can degrade the product, so vial stoppers and seals are part of the quality system.
Amateur mycologists, natural-history societies, and other non-academic collectors have also long played an important part in building fungarium collections and documenting fungal diversity. The collection of Jerzy Wojciech Szulczewski, who gathered specimens in Wielkopolska, Poland, from 1909 to 1966, serves as a representative historical archive. Now housed at Adam Mickiewicz University, it is one of Poland's most extensive records of microfungi and plant pathogens. The archive's transition from decorative 19th-century calligraphy to functional post-war volumes illustrates how biological collections can persist through periods of socio-political disruption. Historical fungaria can also be damaged, dispersed, or lost, and the destruction of collections through war and other disruptions remains a long-term concern for their documentary value. By the early 20th century, curators were already discussing how mycological specimens should be arranged to balance preservation, space efficiency, and ease of access for study, using packets, folders, boxes, and index card systems. Older fungaria could remain effectively inaccessible until specimens were rehoused and rearranged; at the Rijksherbarium, much of the cryptogamic material was once stored in sacks and packets before mounting and boxing made it more accessible for study.
In 1977, Lilly acquired IVAC Corporation, which manufactures vital signs and intravenous fluid infusion monitoring systems. The same year, Lilly acquired Cardiac Pacemakers, Inc., a manufacturer of pacemakers for $127 million. In 1980, Lilly acquired Physio-Control, a pioneering company in defibrillation. Advance Cardiovascular Systems was acquired in 1984 for $85 million in stock. Lilly acquired Hybritech in 1986 for $350 million; it was sold to Beckman Coulter in 1995. In 1988, it acquired Devices for Vascular Intervention for $50 million, with the potential for up to another $150 million in contingent payments. Lilly acquired Pacific Biotech in 1990; it was sold to QuidelOrtho in 1995 for $3.95 million. In 1992, Lilly acquired Origin Medsystems, which was developing several devices for use in laparoscopy. Heart Rhythm Technologies was acquired in 1992. Fluoxetine (Prozac), introduced in 1988, quickly became the company's best-selling product for treatment of depression, but Lilly lost its US patent protection for the product in 2001. Prozac was one of the first therapies in its class to treat clinical depression by blocking the uptake of serotonin within the human brain. In 1989, a joint agrochemical venture between Elanco and Dow Chemical created DowElanco. In 1997, Lilly sold its 40% share in the company to Dow Chemical for $1.2 billion and the name was changed to Dow AgroSciences. In 1991, Vaughn Bryson became president and CEO and Wood became board chairman.
=== Discovery === In the 1950s, a working group at the University of Pittsburgh conducted research on bacteria of the genus Lactobacillus, which require biotin as a growth factor. It has previously been shown that biotin is no longer necessary for the growth of bacteria if certain fatty acids are present in the culture medium instead. When investigating the influence of biotin on fatty acid metabolism, the researchers initially concentrated on the species L. arabinosus, which according to current systematics is classified as L. plantarum is carried out. They cultivated the bacteria in a semi-synthetic culture medium, harvested the cells and extracted the "free" lipids with acetone and diethyl ether. This fraction makes up about 20% of the total lipids. To obtain the "bound" lipids, an acid hydrolysis was then carried out, in which fatty acids bound as esters were released and also extracted with diethyl ether. The fatty acids were methylated with diazomethane to the methyl esters and separated according to their boiling points using fractional distillation. Based on the distillation curve, the presence of esters of C16, C18 and C19 fatty acids was expected. The fatty acid obtained from the C19 fraction showed a melting point at 28-29 °C after purification by recrystallization. The compound was investigated using numerous physical and chemical methods and its molecular formula was determined as C19H36O2. In 1950, this was only the second fatty acid with 19 carbon atoms to be isolated from microorganisms.
A freeze alarm (also called a low-temperature alarm or freeze monitor) is a device that tracks ambient temperature and issues an alert when the temperature falls below a user-defined threshold. Its chief purpose is to warn property owners early enough to prevent freeze-related damage such as burst water pipes, failed heating systems, or losses to temperature-sensitive goods. Repairing a single burst pipe in a residence can cost well over US$10,000 on average, making proactive warnings financially attractive.
There he was reunited with Mark Thompson, who was head coach at Geelong during Robinson's time. In February 2013, Essendon announced that they had reported themselves to Australian Sports Anti-Doping Authority (ASADA) to investigate the possible use of banned substances. Robinson, as the club's fitness boss, was stood down from his position pending the results of the enquiry. His link to Stephen Dank, a controversial sports scientist who was introduced to Essendon by Robinson, was investigated by the AFL. Hinting at further revelations, former ASADA head Richard Ings said "this is not a black day in Australian sport, this is the blackest day." Following the uproar, a chorus of accredited individuals leap to the defence of the newly embattled fitness coach. Central among these was three-time Geelong premiership player and Norm Smith medalist Paul Chapman. Chapman, shocked at the claims involving Robinson, was highly supportive of the man to whom he attributed much of his own personal success. Speaking highly of his former mentor, Chapman said Robinson was a true "family man" and suggested he had been shamed "simply by association". Denouncing the press gallery, Chapman maintained that a trial by media had left Robinson guilty until proven innocent. Geelong captain Joel Selwood expressed similar admiration for the man, describing Robinson as a "legend of a bloke", while football chief Neil Balme and current Gold Coast captain Gary Ablett also lent their support.
Sources: en.wikipedia.org
=== Other === Intravenous lidocaine infusions are also used to treat chronic pain and acute surgical pain as an opiate sparing technique. The quality of evidence for this use is poor so it is difficult to compare it to placebo or an epidural. Inhaled lidocaine can be used as a cough suppressor acting peripherally to reduce the cough reflex. This application can be implemented as a safety and comfort measure for people needing intubation, as it reduces the incidence of coughing and any tracheal damage it might cause when emerging from anaesthesia. A 2019 systematic review of the literature found that intraurethral lidocaine reduces pain in men who undergo cystoscopic procedures. Lidocaine, along with ethanol, ammonia, and acetic acid, may also help in treating jellyfish stings, both numbing the affected area and preventing further nematocyst discharge. For gastritis, drinking a viscous lidocaine formulation may help with the pain. A 2021 study found that lidocaine 5% spray on the glans penis 10-20 minutes prior to sexual intercourse significantly improves premature ejaculation. Another study found that lidocaine-prilocaine cream 5% is effective in premature ejaculation and 20 minutes of application time before sexual intercourse.
== Sustainability == In a survey of fish sandwiches sold in London outlets (published January 2011) by The Jellied Eel ethical food magazine, Upper Crust received a "poor" rating for the sustainability of the fish in their sandwiches and the information about provenance and sustainability of fish ingredients provided by staff, in store and on the sandwich labelling.
[A]bout one-third of the Gratiot-area's families eventually moved to public housing, but 35 percent of the families in the area could not be traced. The best-informed city officials believed that a majority of families moved to neighborhoods within a mile of the Gratiot site, crowding into an already decaying part of the city, and finding houses scarcely better and often more overcrowded than that which they had left.
=== Exercise === Early experimental evidence that skeletal muscle contraction induces vascular endothelial growth factor (VEGF) expression came from studies using electrically stimulated muscle. In a rat model, Hang et al. (1995) demonstrated that electrically stimulated skeletal muscle exhibited significant upregulation of VEGF expression, establishing skeletal muscle fibers as an active source of angiogenic signaling. This work preceded later exercise-training studies and contributed to the understanding of VEGF as a contraction-responsive factor involved in skeletal muscle angiogenesis.
Sources: en.wikipedia.org
=== Dry co-micronization === Dry co-micronization is a nanomilling approach in which the drug substance is milled in a dry state together with GRAS excipients in a single unit operation. The excipients form a protective dispersion matrix around the sub-micron drug particles, preventing the surface-energy-driven reaggregation that otherwise dominates dry submicron powders, and yielding a free-flowing powder that can be tableted or encapsulated without further drying or downstream processing. The most widely commercialized dry co-micronization platform is SoluMatrix Fine Particle Technology, developed by iCeutica and acquired in 2011 by Iroko Pharmaceuticals. The platform has been used to formulate three U.S. Food and Drug Administration–approved low-dose non-steroidal anti-inflammatory drugs: Zorvolex (diclofenac, approved October 2013), Tivorbex (indomethacin, approved February 2014), and Vivlodex (meloxicam, approved October 2015). Each product was approved at a total daily dose 20–35% below the equivalent conventionally-formulated NSAID, on the basis that the increased dissolution rate of sub-micron particles permits comparable analgesic efficacy at lower systemic exposure. Unlike wet media milling, dry co-micronization requires no aqueous suspension or downstream drying step, shortening the unit-operation chain at the cost of constraining the formulation to excipients compatible with high-energy dry impact.
== Etymology == The word hypoglycemia is also spelled hypoglycaemia or hypoglycæmia. The term means 'low blood sugar' from Greek ὑπογλυκαιμία, from ὑπο- hypo- 'under' + γλυκύς glykys 'sweet' + αἷμᾰ haima 'blood'.
==== Peelings ==== Generally treated as waste, potato peels can also be cooked, in times of shortage or in the context of cooking leftovers. In addition to the cases where the tubers are cooked and served with their skins, for example new potatoes, one can also make appetizers in the form of potato peel chips, or fritters, by dipping peels taken from boiled potatoes in a fritter batter. Baked potatoes cut in half and scooped out with a spoon can be used to make nests, which can be stuffed with other ingredients, such as a poached egg in the case of Oeufs Toupinel.
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.
Sealed vials or containers should be kept at the temperature specified by stability data, often controlled room temperature or 2–8 °C. Moisture and oxygen barriers are important because both can degrade sensitive materials. Opened containers may need immediate use or protection from ambient humidity.