Physiologically-Based Pharmacokinetic  models integrate physiological information to simulate drug behavior in various tissues and organs. These models consider organ-specific blood flow, tissue permeability, and drug properties, facilitating predictions of drug concentration at specific sites. PBPK models are instrumental in understanding complex drug behaviors.


Exposure-Response models establish the relationship between drug exposure and clinical response. They play a crucial role in determining the optimal therapeutic range and predicting the likelihood of efficacy or adverse events. These models guide dose individualization based on desired clinical outcomes.


Drug-Drug Interaction models explore the impact of interactions between different drugs on their pharmacokinetics or pharmacodynamics. These models help predict the effects of co-administered drugs on each other, aiding in the identification of potential risks and the adjustment of dosages in the presence of multiple medications.


The natural time course of a disease is often dynamic, with the tendency to become worse without treatment. Disease progression models are mainly used to understand the relationship between treatment, biomarker changes and clinical outcomes. These models describe the disease trajectory, by observing the change in the biomarker level, or the other clinically relevant endpoint that reflects the disease status, over time. [ 4 ]  There are three key classes of disease progression models:  empirical , semi-mechanistic, and systems biology. [ 5 ]  Most of the disease progression models are empirical, describing disease trajectory rather than the physiological background of the disease. [ 6 ]  The simplest model that is used to describe disease progression is a  linear model  when the change of disease status over time is assumed to be constant.


Systems Pharmacology models integrate pharmacokinetics, pharmacodynamics, and systems biology to provide a comprehensive understanding of drug effects. By considering the intricate interplay between drugs, biological systems, and disease pathways, these models contribute to a holistic approach to drug development and personalized medicine.


Mechanistic models provide a detailed understanding of the underlying biological and physiological processes governing drug behavior. These models offer insights into the mechanisms influencing drug absorption, distribution, metabolism, and elimination, aiding in predicting drug responses in diverse scenarios.


Trial models describe variations from the nominal trial protocol due to things such as patient dropout and lack of adherence to the dosing regimen.


Historically, pharmacometrics has been represented in related clinical pharmacology and statistics organizations. A number of smaller local organizations in Europe, United States, and New Zealand/Australia held local meetings. In the early 1990s, The PAGE meeting was organized and has been held yearly since then, although no official organization was present. Ette and Williams have provided a historical context from which the evolution of pharmacometrics can be appreciated. [ 7 ]


In 2011, the  American Society of Pharmacometrics  (ASoP) was founded by a number of local American groups, and over 600 members worldwide joined ASoP within 6 months. In 2012, ASoP evolved to the  International Society of Pharmacometrics  (ISoP) to reflect the increasing number of international members. ISoP's growth continues and the society currently represents over 1000 members from almost 30 countries around the world. [ 8 ]  Regional groups include PAGE in Europe [ 9 ]  and PAGANZ in Australia and New Zealand. [ 10 ]


Pharmacometricians typically come from disciplines such as  Pharmacy ,  Clinical pharmacology ,  Statistics ,  Medicine , or  Engineering .


The first professor of pharmacometrics was Mats Karlsson,  Uppsala University . [ 11 ]


The main journals that publish work in pharmacometrics are:


In Denmark (including  Greenland  and  Faroe Islands ),  pharmaconomists  ( Danish :  farmakonom ) are  experts in pharmaceuticals ( Danish :  lægemiddelkyndig ) who have trained with a 3-year  tertiary degree .  Pharmaconomy  ( Danish :  farmakonomi ) describes either their professional practice or their training courses.


The majority of the Danish pharmaconomists work at  community pharmacies  ( chemists' shops  or drug stores) and at  hospital pharmacies  and  hospitals .


Some pharmaconomists work within the  chemical industry , the  pharmaceutical industry  and in  medical or clinical laboratories .


Other pharmaconomists  teach  pharmacy students and pharmaconomy students at  colleges  or  universities , such as at the University of Copenhagen's  Faculty of Health and Medical Sciences  or at the Pharmakon—Danish College of Pharmacy Practice.


Pharmaconomists are also employed by the Danish  Ministry of Interior and Health ,  Danish Medicines Agency  and  Danish Association of Pharmacies .


Some pharmaconomists do work as  pharmaceutical consultants .


The 3 year higher education corresponds to 180  ECTS points (European Credit Transfer and Accumulation System) .


During his or her  education  programme at  Pharmakon—Danish College of Pharmacy Practice , the pharmaconomist student studies  human  and  animal   anatomy ,  physiology ,  pathology ,  pharmacology ,  pharmaconomy ,  pharmacy practice ,  pharmaceutics ,  toxicology ,  pharmacognosy ,  clinical pharmacy ,  pharmacotherapy ,  pharmaceutical sciences ,  chemistry ,  pharmaceutical chemistry ,  biochemistry ,  biology ,  microbiology ,  molecular biology ,  genetics ,  cytology ,  medicine ,  veterinary medicine ,  zoology ,  diagnosis ,  medical prescription ,  pharmacy law ,  medical sociology ,  patient safety ,  health care ,  psychology ,  psychiatry ,  pedagogy ,  communication ,  information technology (IT) ,  bioethics ,  medical ethics ,  safety ,  leadership ,  organization ,  logistics ,  economy ,  quality assurance (QA) ,  sales  and  marketing .


There are two different professional groups with pharmaceutical education in Denmark:


Due to his or her higher education as a  health professional , the pharmaconomist has by law the same  independent  competence in all Danish pharmacies as a pharmacist —  i.e.  for example to dispense and check medical prescriptions, to counsel and advise  patients / customers  about the use of medicine/pharmaceuticals and to dispense, sell and provide  information  about medical prescriptions and about  prescription medicine  and  over-the-counter medicine (OTC) .


The pharmaconomist also undertakes specialist and  managerial  operation of pharmacies and undertakes managerial  duty  service.


The only difference by law is that only a pharmacist may  own  a Danish pharmacy — i.e. become a pharmacy owner.


Like pharmacists, pharmaconomists can work as pharmacy managers and  HR managers  (or as chief pharmaconomists).


The  Danish Association of Pharmaconomists  is a  trade union  who represents about 5,700 pharmaconomists in Denmark (i.e. 98% of all Danish pharmaconomists).


The Danish title  farmakonom  (pharmaconomist) comes from the  Greek  "pharmakon" (meaning "pharmaceuticals") and "nom" (meaning "expert in").


In Denmark a pharmaconomist is also referred to as  lægemiddelkyndig  (expert in pharmaceuticals).  Lægemiddelkyndig  comes from the Danish "lægemiddel" (meaning "pharmaceuticals") and "kyndig" (meaning "expert in").


Pill prizes  are the idea put forth by  Joseph E. Stiglitz  when he wrote "Prizes, not patents", in order to address shortfalls of using  patents  from a pharmaceutical drug perspective. Patents are awarded to  inventors  and firms in order to promote  innovation  by providing  incentives  beyond traditional market incentives. Stiglitz is critical of patents and how they fail provide similar incentives to innovations which are not marketable to the normal  consumer society  while simply restricting information which is inefficient. Stiglitz provides the idea of  prizes  instead of patents to be awarded in order to further advance pharmaceutical solutions to global problems such as  AIDS .


Patents essentially provide a temporary  monopoly  on a product to the first inventor or firm which comes up with the product. Patents vary in length but are designed to last long enough for the innovator to make a return on  investment . The nature of patents makes them an incentive so long as the product being invented is distributed to consumers through markets. While patented products are in the market, the producer can place any price on the product, regardless of the price of production which typically dictates prices in markets. If a product is not being distributed through markets then a patent cannot provide proper incentive for innovation. Patents do however provide gain through the restriction of information to others. Stiglitz identifies this as a problem of patents for the innovation of  drugs  and other products being distributed not with the purpose of making a  profit , but to solve global problems.


Offering a prize as opposed to a patent, according to Stiglitz, would address the lack of incentive for problems such as disease in  developing countries  and it would provide products immediately affordable instead of pending on a patent expiration. Awarding prizes offers a fixed amount appropriate for reimbursing research into drugs. Today, many drug companies spend much of money earned through patents on  marketing  and  advertising  as opposed to the research for the actual drugs  [ 1 ]


Until  generic  versions of drugs reach the shelves, which occurs after a patent expires, the costs burden  consumers  due to prices not being dictated by the markets. [ 2 ]  These burdens are overwhelming in developing countries and Stiglitz suggests they be lowered by offering prizes instead of patents. Stiglitz discusses the idea of using  foreign aid  assistance funds to finance prizes as it would provide greater foreign aid than what funds are being used for currently. [ 3 ]


Psychiatry Under the Influence: Institutional Corruption, Social Injury, and Prescriptions for Reform  is a 2015 book by  Robert Whitaker  and Lisa Cosgrove. The book discusses the use of  psychiatric medication  in the United States and is critical of the  drug industry  influence on the field of  psychiatry . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]


This article about a  psychology  book is a  stub . You can help Wikipedia by  expanding it .


The Regulatory Affairs Journal Pharma (RAJ Pharma)  is an  English language  international pharmaceutical information and analysis service published by  Informa plc . First published as a monthly print  magazinel  in 1992, it includes articles covering worldwide regulatory affairs within the pharmaceutical industry. The journal has now developed into   an online global  business intelligence  and analysis service. It provides daily news and analysis of developments in  regulation  of the  pharmaceutical industry  worldwide, including regulatory agencies and legislation, application requirements and guidelines,  patents  and  intellectual property , research and development, international  harmonisation , paediatric legislation,  pharmacovigilance  and  pharmacoeconomics .


Articles are written by a four-person in-house editorial team, sourced from locally based correspondents from around the world, and independent contributors from legal firms, pharmaceutical companies and regulatory agencies. [ 1 ]  The RAJ Pharma editorial board comprises a range of regulatory experts from industry and agencies alike. [ 2 ]


A sister publication,  RAJ Devices , covers regulatory affairs within the medical technology industry. It was established in 1995. [ 3 ]


This business magazine or journal-related article is a  stub . You can help Wikipedia by  expanding it .


See tips for writing articles about magazines . Further suggestions might be found on the article's  talk page .


A  remote data entry  ( RDE ) system is a computerized system designed for the  collection of data  in electronic format. The term is most commonly applied to a class of software used in the  life sciences  industry for collecting patient data from participants in  clinical research  studies—research of new drugs and/or medical devices.


Typically, RDE systems provide:


The development of RDE systems started in the mid- to late-1980s as software installed locally on  portable computers  with  modems .  It has largely been replaced by a newer generation of software called  electronic data capture , or EDC, that provides the same type of functionality over the Internet using web pages.


Sanatogen  was a " brain tonic " invented by the Bauer Chemical Company, in  Germany  in  1898  and sold worldwide [ 1 ]


In the US it was advertised as a "nerve revitaliser". The medicine was prohibited in  Australia  in 1915 during   World War I  and a British-made substitute "Sanagen" was introduced to the Australian market the following year, claiming to be "identical to Sanatogen". The product became fashionable in  China  in the early 20th century and won the favour of many renowned people. [ 1 ]


The indications or uses for this product provided by the manufacturer were: "Food tonic. A concentrated nutrient with tonic properties... easily digested and absorbed and is recommended as an effective means of reinforcing the daily diet of anaemic and convalescent patients." [ 2 ]


The ingredients have been described as:


The product was marketed extensively in Europe and the US with such  slogans  as "Endorsed by over 20,000 Physicians". [ 3 ]


In 1913 the product was at the centre of a  United States Supreme Court  case:  Bauer & Cie. v. O'Donnell . The product was also the subject of intellectual property litigation worldwide. [ 4 ]


The Sanatogen brand persists in the UK as a  fortified wine , with an alcohol content of 15%. [ 5 ]


Sanatogen is also the name of a modern  multivitamin  product manufactured by  Fisons  before being sold to  Roche , and later  Bayer . [ 6 ]


Scrip Intelligence (Scrip)  is an  English language  international  pharmaceutical  news, analysis and data service. First published as a weekly print  newsletter  in March 1972, Scrip included articles on side-effects, regulatory changes and  mergers and acquisitions .


Scrip World Pharmaceutical News was initially published by advertising company  J Walter Thomson  but was bought by Dr Philip J Brown in 1976 for £2000, who founded PJB Publishing. Brown sold Scrip, associated titles, and his company to  Informa  for £150 million in 2003. [ 1 ] [ 2 ] [ 3 ]


Scrip has now developed into an online global pharma news and analysis service. It provides daily news and analysis on the  biotechnology  and pharmaceutical industry including areas such as policy & regulation, business news,  research & development ,  generics ,  drug delivery , and  clinical trials .


In 2022, Informa sold its Pharma Intelligence division, including  Scrip , to  Warburg Pincus . [ 4 ]  The business was renamed Citeline. Later in 2022, Citeline was acquired by Norstella.


The Scrip readership has grown to over 100,000 worldwide, [ 5 ]  half of which are in Europe. Scrip is read by managers and executives working across all disciplines in pharmaceutical and biotech companies worldwide. [ 6 ]


Scrip has a large independent editorial team of 21. The journalists are based throughout the world in  Washington, D.C. ,  Tokyo ,  India , and  London  to ensure a global emphasis to the latest news stories.


Sinecatechins  ( USAN , trade names  Veregen  and  Polyphenon E ) is a specific  water extract of green tea leaves  from  Camellia sinensis  that is the  active ingredient  in an ointment approved by the FDA in 2006 as a  botanical drug  to treat  genital warts . [ 1 ] [ 2 ] [ 3 ]   Sinecatechins are mostly  catechins , 55% of which is  epigallocatechin gallate . [ 4 ]   It was the first botanical drug approved by the US FDA. [ 2 ]


A  source document  is a document in which data collected for a clinical trial is first recorded. This data is usually later entered in the  case report form . The  International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use  (ICH-GCP) guidelines define source documents as "original documents, data, and records." [ 1 ]  Source documents contain source data, which is defined as "all information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial." [ 1 ]


The  Food and Drug Administration  (FDA) does not define the term "source document".


A  standard operating procedure  ( SOP ) is a set of step-by-step instructions compiled by an  organization  to help workers carry out routine operations. [ 1 ]  SOPs aim to achieve efficiency, quality output, and uniformity of performance, while reducing  miscommunication  and failure to comply with  industry regulations . [ citation needed ]


Some  military  services (e.g., in the  U.S.  and the  UK ) use the term  standing operating procedure , [ 2 ]  since a military SOP refers to a unit's unique procedures, which are not necessarily standard to another unit. The word "standard" could suggest that only one (standard) procedure is to be used across all units. [ citation needed ]


The term is sometimes used facetiously to refer to practices that are unconstructive, yet the norm. In the  Philippines , for instance, "SOP" is the term for pervasive corruption within the government and its institutions. [ 3 ] [ 4 ]


In clinical research, the  International Council for Harmonisation  (ICH) defines SOPs as "detailed, written instructions to achieve uniformity of the performance of a specific function". SOPs usually get applied in pharmaceutical processing and for related clinical studies. There the focus is always set on repeated application of unchanged processes and procedures and its documentation, hence supporting the segregation of origins, causes and effects. Further application is with  triage , when limited resources get used according to an assessment on ranking, urgence and staffing possibilities. [ 5 ]   Study director is mainly responsible for SOPs. The Quality Assurance Unit are individuals who are responsible for monitoring whether the study report and tests are meeting the SOP. [ citation needed ]


SOPs can also provide employees with a reference to common business practices, activities or tasks. New employees use an SOP to answer questions without having to interrupt supervisors to ask how an operation is performed. The international quality standard  ISO 9001  essentially requires the determination of processes (documented as standard operating procedures) used in any manufacturing process that could affect the quality of the product. [ 6 ]


Procedures are extensively employed to assist with working safely. They are sometimes called "safe work methods statements" (SWMS, pronounced as 'swims'). Their development is usually preceded by various methods of analyzing tasks or jobs to be performed in a workplace, including an approach called  job safety analysis , in which hazards are identified and their control methods described. Procedures must be suited to the literacy levels of the user, so the readability of procedures is important. [ 7 ]


Franco Stevanato (Executive Chairman of the Board of Directors)


Stevanato Group  is an Italian multinational company headquartered in  Piombino Dese ,  Padua  –  Italy .
Founded in 1949, it is also active in the  glass tube  forming technology and inspection systems sector. [ 3 ]


The Group is the first worldwide producer of  insulin  cartridges for diabetes treatment [ 4 ]  and design and production of machinery for glass tubing converting.


Nuova Ompi, the first company of the Group, was founded in  Venice  in 1949 by Giovanni Stevanato, father of the actual president  Sergio Stevanato . In 1959 the company moved to its current location: Piombino Dese, Padua – Italy.
A second company (SPAMI) was established in 1971, specialized in the design and construction of high-speed precision machines and complete lines for the production and control of glass tube containers for pharmaceutical use.
In 1993 Stevanato Group purchased Alfamatic ( Latina, Italy ) and with the acquisition of Medical Glass ( Bratislava ) in 2005, the Group opened to the internationalization.
In 2007 the Group acquired Optrel ( Vicenza ), an Italian company specialized in the design and the construction of inspection machines for the pharmaceutical industry. In addition, Nuova Ompi launched the EZ-fill brand, starting with the production of sterile syringes. [ 5 ]
In 2008 a new production plant called "Ompi North America" was built in  Monterrey, Mexico . [ 6 ]
Two years later the EZ-fill concept was extended to vials and cartridges. [ 7 ]
In 2012 the Group doubled the Monterrey plant started the construction of a new plant in  China  ( Zhangjiagang  -  Shanghai  area).
In 2013 the Group acquired InnoScan, a Danish manufacturer of inspection machines for the pharmaceutical industry.  In 2016 the Group acquired the Danish company SVM Automatik specialized in assembly, packaging and serialization solutions [ buzzword ]  for the pharmaceutical industry and the operative units of Balda Group, specialized in high quality and high precision plastic solutions [ buzzword ]  for diagnostic, pharmaceutical and medical device applications. In 2017 the third greenfield - Ompi do Brasil - plant was opened in  Sete Lagoas .


Stevanato Group comprises two operational divisions: Pharmaceutical Systems with Ompi specialized in glass primary packaging and Balda, focused on specialty plastics and delivery devices; Engineering Systems with Spami, Optrel, InnoScan and SVM, specialized in glass processing, inspection systems, assembly, and packaging solutions. [ buzzword ]


Pharmaceutical Systems Division


With locations throughout the world (Italy, Slovakia, Germany, Mexico, USA, China, Brazil), the Pharmaceutical Systems Division produces both traditional products such as vials and ampoules, and strong growth products such as syringes and cartridges for   autoinjection systems . [ 8 ]
With the acquisition of the operative units of Balda, the division is also specialized now in high quality and high precision plastic solutions [ buzzword ] , developed and manufactured to meet customers’ specific needs. Balda's healthcare segment is active in diagnostic, pharmaceutical and medical device applications. [ 9 ]


Engineering Systems Division


The Engineering Systems Division consists of SPAMI (with its brand Optrel), InnoScan and SVM Automatik.
Spami designs and manufactures machinery for glass tubing converting for the production of vials, cartridges, syringes, ampoules and special devices.
Optrel and InnoScan refer to the  visual inspection  area focused on the inspection machines market for the  pharmaceutical industry . [ 10 ]
SVM Automatik is a company specialized in assembly, packaging and serialization solutions [ buzzword ]  for the pharmaceutical industry.


Nuova Ompi


Nuova Ompi is located in Piombino Dese (Padua) and Latina – Italy and produces pharmaceutical glass primary packaging for injectable use. It manufactures both bulk and sterile vials, cartridges, syringes. The company started supplying sterile syringes (EZ-fill Syringes) in 2007 and then it extended the ready-to-fill concept to vials and cartridges in 2010 (EZ-fill Vials & Cartridges).


Medical Glass


Medical Glass was established in Bratislava in 1991 and acquired by the Group in 2005. Today it produces glass ampoules and vials.


Ompi North America


The plant is located in Monterrey, Mexico. It was built in 2008 and doubled in 2012 in order to serve the American market with the support of the sales office situated in Newtown, Pennsylvania (USA).


Ompi of China


The sales office is situated in Zhangjiagang, about 150 km from Shanghai. The greenfield facility construction started at the end of 2012 and the plant started production in November 2013.


Ompi do Brasil


The plant is situated in Sete Lagoas, Minas Gerais, Brazil.  The greenfield facility construction started at the beginning of 2016 and the plant started production in June 2017.


Balda Medical


Located in Bad Oeynhausen (Germany), it was founded in 1908 as a camera manufacturer and developed a focus on precision injection molding in the fifties. After a diversification in mobile telephony, medical and automotive, the company focused in the medical, healthcare, diagnostic and pharmaceutical segment. In 2016 it was acquired by Stevanato Group. [ 11 ]


Balda C. Brewer and Balda Precision


Based in Oceanside and Ontario (US), they have been acquired by Stevanato Group in 2016 and are specialized in injection molding for medical market and turning machine service supporting the Aerospace, Medical, Electronic and Consumer industries. [ 12 ]


SPAMI


The company refers to the Engineering Systems Division of the Group and was founded in 1971. It is located in Piombino Dese (Padua) – Italy. It produces glass tubing converting machines and inspection machines for pharmaceutical glass containers. [ 13 ]


InnoScan


The company joined the Group in 2013 and it produces high-speed inspection machines for the pharmaceutical industry. [ 14 ]


SVM


The Danish company SVM Automatik has been acquired by Stevanato Group in 2016. It is specialized in assembly, packaging and serialization solutions [ buzzword ]  for the pharmaceutical industry.


Ompi of America


The newest manufacturing site is in  Fishers, Indiana , United States.  The greenfield facility construction started at the beginning of 2021 for a 200,000-square foot facility in the Fishers Life Science and Innovation Park. [ 15 ]  The site opened in early 2024 and will serve the American market with ready-to-use ("EZ-Fill") [ 16 ]  syringes and vials. [ 17 ]


Tigers  (initially titled  White Lies ) [ 2 ]  is a 2014 Indian  drama film  directed by  Danis Tanović , and produced as a joint production between Cinema Time, French production company ASAP Films and  Sikhya Entertainment .


The film is inspired by an episode in Pakistan during the 1990s, a repetition of the  Nestlé baby milk scandal  in 1970s that occurred in developing countries. A Pakistani salesman named Syed Aamir Raza Hussain became a whistle-blower against his former employer  Nestlé ; in 1999, two years after he left Nestlé, Hussain released a report in association with the non-profit organisation  International Baby Food Action Network , in which he alleged that Nestlé was encouraging doctors to push its infant formula products over breastfeeding. [ 3 ]


The film features  Emraan Hashmi  in the leading role as Ayan, based on Hussain, a pharmaceutical representative in Pakistan who discovers his new company's baby formula has killed hundreds of children, after which he begins a lone and dangerous battle against the company. [ 4 ]  The film began filming in 2013 in  Punjab, India , and had its premiere in September 2014 at the  2014 Toronto International Film Festival . [ 5 ] [ 6 ]


The film faced multiple delays during its initial release. After Tanovic decided to fictionalise Raza's battle, he renamed Nestlé as  Lasta  in the film and cast Hashmi after watching  Shanghai  (2012).  Tigers  was publicly released on the streaming platform  ZEE5  on 21 November 2018. [ 7 ] [ 8 ] [ 9 ]


Tilray Brands, Inc.  is an American  pharmaceutical ,  cannabis -lifestyle and consumer packaged goods company, incorporated in the United States, headquartered in New York City. [ 1 ] [ 2 ]  Tilray also has operations in Canada, Australia, New Zealand, [ 3 ] [ 4 ]  and Latin America, [ 5 ]  with growing facilities in Germany and Portugal. [ 6 ] [ 7 ]


In December 2020, the company announced a  merger  with  Aphria , and will operate under the Tilray name and its  ticker symbol  on  NASDAQ [ 8 ]  and the  Toronto Stock Exchange . [ 9 ]


Tilray also owns several breweries and is the 5th largest craft beer company in the US.


Founded in 2014, Tilray was originally incorporated under the umbrella of Seattle-based  Privateer Holdings  and was one of Canada's first licensed producers. [ 10 ] [ 11 ]  At the end of 2014, it secured the first institutional investment in the cannabis industry from Founders Fund, a San Francisco-based venture capital fund. [ 10 ]  In 2016, it became the first cannabis company to conduct a clinical trial approved by Health Canada. [ 10 ]  The trial evaluated the therapeutic potential of medical cannabis. [ 10 ]  In January 2017, Tilray was certified for  good manufacturing practices . [ 12 ]


By October 2018, the company had raised $1.1 billion. [ 10 ]  In July 2018, it became the first cannabis company to trade publicly on a major U.S. stock exchange, [ 13 ]  opening on the  NASDAQ  exchange at a price of $17 per share, which increased in September 2018 to $214 per share, and then descended to $29 per share by August 2019. [ 14 ] [ 15 ]  The  IPO  raised  US$153  million. [ 16 ]


In September 2018, Tilray became the first Canadian cannabis company to legally export medical cannabis to the U.S. for a  clinical trial . [ 17 ]  In December 2018, the company signed a deal with  Novartis  subsidiary  Sandoz  to sell, distribute and co-brand Tilray's non-smokeable/non-combustible  medical cannabis  products in legal markets worldwide. [ 18 ]  On June 19, 2018, Tilray announced the launch of High Park Company which operates in the adult recreational cannabis market to establish unique adult-use brands in Canada. [ 19 ]


Since September 2022, Tilray has been licensed by the Polish and Italian Ministries of Health to import and distribute THC25 medical cannabis throughout Poland and Italy. [ 20 ]


In August 2023, Tilray acquired eight beverage brands in addition to the breweries of the brands from Anheuser-Busch for $85 million. [ 21 ]


In 2018, Tilray announced it had entered into global alliance with Sandoz, a division of Novartis to co-brand and distribute non-combustible medical cannabis products in global markets where it is legally authorized.  The Globe and Mail  dubbed this partnership as ‘big-pharma’s first foray into cannabis’. [ 22 ]


Also in 2018, Tilray announced a $100-million joint venture with the world's largest brewer,  AbInBev  to research non-alcohol  tetrahydrocannabinol  (THC) and  cannabidiol  (CBD)-infused beverages, through their respective subsidiaries,  Labatt Breweries  and High Park Company. [ 23 ]


In 2019, Tilray signed a $250 million revenue-sharing deal with U.S. based brand company,  Authentic Brands Group , to leverage ABG brand names, such as  Juicy Couture ,  Greg Norman , and  Nine West  to create cannabis products. ABG has a portfolio of over 50 brands. [ 24 ]


In February 2019, Tilray acquired Manitoba Harvest, a hemp foods manufacturer, for $317 million from Compass Diversified Holdings. [ 25 ]  The acquisition allowed Tilray to use Manitoba Harvest's retail distribution network to enter the U.S. CBD market. [ 26 ]  Manitoba Harvest's products are available in approximately 13,000 U.S. stores and 3,600 in Canada. [ 25 ]


Also in 2019, Tilray entered into an agreement with Natura Naturals Holdings which owns 155,000 square feet of licensed cultivation  greenhouses  in  Leamington, Ontario . [ 27 ]  The acquisition doubled the cultivation ability of the company in Canada. [ 28 ]  In May 2020, Tilray announced closure of the High Park Gardens site (previously Natura Naturals) for  cost reductions . [ 29 ]


In July 2019, Tilray acquired U.K.-based Smith & Sinclair to develop CBD-infused edibles. [ 30 ]  In August 2019, Tilray acquired Alberta cannabis retailer, Four20. [ 31 ]


On April 10, 2023, Tilray announced an agreement to acquire Hexo Corp. for approximately US$56 million. Hexo shareholders will receive 0.4352 of a share of Tilray common stock in exchange for each share held. [ 32 ]


On 15 December 2020, Aphria conducted a  reverse acquisition  of Tilray, creating the largest global cannabis company by revenue and geographic reach. [ 10 ] [ 8 ]  The  chief executive officer  (CEO) of Aphria, Irwin D. Simon, stated that the merger strategy was to capture Tilray's business assets and public trading exposure in the United States and its  free trade  abilities in Europe, enabling potential for becoming a global operation. [ 8 ]  Irwin was named as CEO and  chairman of the board  for the merged company, and Tilray CEO, Brendan Kennedy, will be a member of the  board of directors . [ 8 ]  The merged companies will keep Tilray's name and trade under the Tilray ticker symbol, TLRY, on the NASDAQ exchange. [ 8 ]


By combining assets, the new Tilray company will develop craft beer and cannabis-infused beverages in partnership with  Anheuser-Busch InBev , and have branded  hemp  and  cannabidiol  products. [ 8 ]  According to one source, the world market potential for cannabis products is $94 billion by 2025. [ 8 ]


Tilray also owns several breweries:  Montauk Brewing Company ,  Good Supply Beer ,  10 Barrel Brewing Company ,  Square Mile Cider Company , and  Truss Beverage Co. [ 33 ]  Tilray's beer division ranked No. 9 on the Brewers Association's annual report of the US nation's top craft companies based on beer sales volume in 2022. [ 34 ] [ 35 ] [ 36 ]


Founded in 1999 in  Alpine, California , the Alpine Beer Company produced award-winning  sour beers . [ 37 ] [ 38 ]  The company would be acquired by the  Green Flash Brewing Company  in 2014 and continued existence as a brand. [ 39 ]


Founded in a former  ice factory  in 1998 to fill the niche of a  Long Island  focused  Microbrewery . [ 40 ]  The company's flagship "Toasted Lager" won a gold medal at the 2006  World Beer Cup  in the American-Style  Amber Lager  category. [ 41 ]  The company distributed their beer to 19 states and  Washington D.C.  before being purchased by Anheuser-Busch InBev on February 5, 2014, for nearly $24 million. Citing financial shortfall in part due to the  2023 Bud Light boycott , Anheuser-Busch sold the brand to Tilray in August 2023. [ 42 ]


Founded in  Breckenridge, Colorado  in 1990 as the state's third craft brewery before moving most of their production to  Denver  in 1992. [ 43 ] [ 44 ]  In 2010 the company merged with the Wynkoop Brewing Company and purchased the Phantom Canyon Brewing company to become the Breckenridge-Wynkoop LLC. [ 45 ]  In 2015 they moved to a new facility in  Littleton, Colorado  and was producing 70,000 barrels of beer per year. [ 46 ]  On December 22, 2015, Anheuser-Busch InBev announced its intent to purchase just Breckenridge Brewery from Breckenridge-Wynkoop LLC, splitting the companies with the purchase finalizing in 2016. [ 47 ]   Anheuser-Busch sold the brand to Tilray in August 2023. [ 42 ]


Founded in 2002 in  Vista, California  before moving to  San Diego  in 2011. [ 48 ]  The company operated a 44,000 barrel per year facility in San Diego in 2011, and a 100,000 barrel per year facility in  Virginia Beach, Virginia  in 2013. [ 49 ] [ 50 ]  By 2014 their beer was being sold in all 50 states, as well as internationally and they purchased the  Alpine Beer Company . [ 51 ] [ 39 ]  The company peaked in 2016 when it was the 37th largest producer of beer in the United States, afterwards the company began a rapid decline due to the rise of rival craft beer producers. [ 52 ]  In 2018 they cut distribution internationally and to 42 states and laid off 15% of their workforce and defaulted on their loans to construct the Virginia Beach facility. [ 53 ] [ 54 ]  The company would be sold to a group of private investors by the end of the year, who would sell the company to Tilray in 2020. [ 55 ]


Founded in  Seattle  in 1981, Redhook specializes in the production of  India pale ales . [ 56 ]  A founding member of the  Craft Brew Alliance , the company's distribution rights were bought by  Cisco Brewers  in 2018. [ 57 ]  In 2019 the Craft Brew Alliance, and its properties, were acquired by Anheuser-Busch InBev with Redhook operating as a brand. [ 58 ]  Anheuser-Busch sold the brand to Tilray in August 2023. [ 42 ]


A Belgian-Style, spiced  Witbeer  brand introduced as a seasonal beer by  Anheuser-Busch  in February 2006, however, the beer's popularity quickly grew and was used as a rival to  Molson Coors '  Blue Moon . The brand entered a decline following a failed rebranding effort in 2017 and, citing financial shortfall in part due to the  2023 Bud Light boycott , Anheuser-Busch sold the brand to Tilray in August 2023. [ 42 ]


A  craft brewery  founded in 1997 by Freddy Bensch and Kevin McNerney in  Atlanta ,  Georgia . [ 59 ]  SweetWater's beers are  unpasteurized  and distribution is limited to select states. SweetWater would be acquired by  Aphria  In November 2020 for $300 million. [ 60 ]  Later, in December 2020, Aphria merged with Tilray bringing SweetWater under Tilray's ownership. [ 8 ]


Founded in 1984 in  Portland, Oregon , the company primarily produced  Hefeweizen . [ 61 ]  In 2007 Widmer  and Redhook announced that they were going to merge to form the Craft Brewers Alliance, which was renamed to the  Craft Brew Alliance  in 2012. [ 62 ]   The goal of which was to offer smaller regional beers a national distribution network. In 2019 Widmer and the whole of the Craft Brew Alliance was bought by Anheuser-Busch InBev, with Widmer operating as a brand. [ 58 ]  Anheuser-Busch sold the brand to Tilray in August 2023. [ 42 ]


HiBall Energy was founded in 2005 by Todd Berardi and was based out of  San Francisco . They produced organic  energy drinks  and were purchased by Anheuser-Busch on July 20, 2017, in an effort to diversify into non-alcoholic beverages. Their products were low in sugar, produced with  fair-trade  ingredients, and were available at 14,000 locations prior to its acquisition by Anheuser-Busch. [ 63 ]  On May 19, 2023, Anheuser-Busch announced that they were discontinuing HiBall alongside their  box wine  brand  Babe Wine , stating that they will be focusing on their "mega brands" instead. This came despite HiBall having a dedicated consumer fan-base that heavily protested the discontinuation. An Anheuser-Busch spokesmen stated that the discontinuation had nothing to do with the  2023 Bud Light boycott . [ 64 ] [ 65 ]   Anheuser-Busch sold the HiBall brand to Tilray alongside seven of their beer brands in August 2023. [ 66 ]


In partnership with  University of Sydney ,  NSW Government , Chris O'Brien Lifehouse, Tilray participated in a  clinical trial  testing the efficacy and tolerability of medical cannabis as a possible treatment for the  side effects  of  chemotherapy . [ 67 ]  Led by  The Hospital for Sick Children , in Toronto, Canada, Tilray provided a  cannabidiol  (CBD) oil product available in Canada to test the efficacy and tolerability of medical cannabis oil as a possible treatment for pediatric epilepsy ( Dravet syndrome ). [ 68 ]  In partnership with the  University of British Columbia , Tilray provided medical cannabis products used to test medical cannabis as a possible treatment for  post-traumatic stress disorder . [ 69 ]  In partnership with the Grupo Español de Investigación en Neurooncología GEINO, in Spain, Tilray supplied medical cannabis products for the trial testing the efficacy and tolerability of medical cannabis as a possible treatment for  glioblastoma . [ citation needed ]


In 2019, Tilray signed an agreement with Cannamedical Pharma GmbH to export $3.3 million worth of medical cannabis from its Portugal facility to Germany, marking Tilray's first export from Tilray Portugal Unipessoal, Lda. [ 70 ]  Tilray also has a research partnership with  Coimbra University  in Portugal. [ 71 ]


In August 2019, Tilray announced a partnership with  New York University  to study the potential ability of CBD to treat  alcohol use disorder  and post-traumatic stress disorder. [ 72 ]  In partnership with New York University, Tilray supplied CBD for a clinical trial studying its possible efficacy for treating disorders caused by  breast cancer  treatments. [ 73 ]


To ensure the best possible microbiological quality of medicinal cannabis flowers, treatment with ionizing radiation has become established worldwide to reduce bacterial counts. This is of great importance to protect patients, some of whom are highly vulnerable. [ 74 ]


Title 21 CFR Part 11  is the part of  Title 21  of the  Code of Federal Regulations  that establishes the United States  Food and Drug Administration  (FDA) regulations on electronic records and  electronic signatures  (ERES).  Part 11 , as it is commonly called, defines the criteria under which electronic records and electronic signatures are considered trustworthy, reliable, and equivalent to paper records (Title 21 CFR Part 11 Section 11.1 (a)). [ 1 ]


21 CFR, Part 11 applies to  drug makers ,  medical device  manufacturers,  biotech  companies,  biologics  developers,  CROs , and other FDA-regulated industries, with some specific exceptions. [ 2 ]  It requires that they implement controls, including audits, system validations,  audit trails , electronic signatures, and documentation for software and  systems  involved in processing the electronic data that FDA predicate rules require them to maintain. A predicate rule is any requirement set forth in the Federal Food, Drug and Cosmetic Act, the Public Health Service Act, or any FDA regulation other than Part 11. [ 3 ]


The rule also applies to submissions made to the FDA in electronic format (e.g., a  New Drug Application ) but not to paper submissions by electronic methods (i.e.,  faxes ).  It specifically does not require the 21 CFR Part 11 requirement for record retention for trackbacks by food manufacturers.  Most food manufacturers are not otherwise explicitly required to keep detailed records, but electronic documentation kept for  HACCP  and similar requirements must meet these requirements.


Broad sections of the regulation have been challenged as "very expensive and for some applications almost impractical", [ 4 ]  and the FDA has stated in guidance that it will exercise enforcement discretion on many parts of the rule.  This has led to confusion on exactly what is required, and the rule is being revised. In practice, the requirements on access controls are the only part routinely enforced  [ citation needed ] .  The "predicate rules", which required organizations to keep records in the first place, are still in effect. If electronic records are illegible, inaccessible, or corrupted, manufacturers are still subject to those requirements.


If a regulated firm keeps "hard copies" of all required records, those paper documents can be considered the authoritative document for regulatory purposes, and the computer system is not in scope for electronic records requirements—though systems that control processes subject to predicate rules still require validation. [ 5 ]   Firms should be careful to make a claim that the "hard copy" of required records is the authoritative document. For the "hard copy" produced from electronic source to be the authoritative document, it must be a complete and accurate copy of the electronic source. The manufacturer must use the hard copy (rather than electronic versions stored in the system) of the records for regulated activities. The current technical architecture of computer systems increasingly makes the Part 11, Electronic Records; Electronic Signatures — Scope and Application for the complete and accurate copy requirement extremely mandatory. [ 6 ]


Various keynote speeches by FDA insiders early in the 21st century (in addition to high-profile audit findings focusing on computer system compliance) resulted in many companies scrambling to mount a defense against rule enforcement that they were procedurally and technologically unprepared for.  Many software and instrumentation vendors released Part 11 "compliant" updates that were either incomplete or insufficient to fully comply with the rule. Complaints about the wasting of critical resources, non-value added aspects, in addition to confusion within the drug, medical device, biotech/biologic and other industries about the true scope and enforcement aspects of Part 11 resulted in the FDA release of:


This document was intended to clarify how Part 11 should be implemented and would be enforced.  But, as with all FDA guidances, it was not intended to convey the full force of law—rather, it expressed the FDA's "current thinking" on Part 11 compliance.  Many within the industry, while pleased with the more limited scope defined in the guidance, complained that, in some areas, the 2003 guidance contradicted requirements in the 1997 Final Rule.


In May 2007, the FDA issued the final version of their guidance on computerized systems in clinical investigations. [ 7 ]


This guidance supersedes the guidance of the same name dated April 1999; and supplements the guidance for industry on Part 11, Electronic Records; Electronic Signatures — Scope and Application and the Agency's international harmonization efforts when applying these guidances to source data generated at clinical study sites.


FDA had previously announced that a new Part 11 would be released late 2006.  The Agency has since pushed that release date back.  The FDA has not announced a revised time of release.  John Murray, member of the Part 11 Working Group (the team at FDA developing the new Part 11), has publicly stated that the timetable for release is "flexible".


21 CFR Part 11 has the following benefits:


The  UCSF Library  is the  library  of the  University of California, San Francisco . It is one of the world's foremost libraries in the  health sciences .


The main branch (Kalmanovitz Library) is located at the Parnassus campus, with secondary locations at the  Mission Bay campus  in the Rutter Center and Mission Hall. Additionally, the library is affiliated with the ZSFG Library at the  Zuckerberg San Francisco General Hospital , the Fishbon Memorial Library at  UCSF Medical Center , the UCSF Fresno Medical Library at UCSF Fresno Medical Education Program, the UCSF Patient Health Library at Mount Zion Medical Center, the Medical Library at  Benioff Children's Hospital Oakland , and the Veterans Affairs Medical Center Library at the  San Francisco VA Medical Center .


The main branch hosts artwork by  Hiroshige ,  Georges Mathieu ,  Helaman Ferguson , Fred Reichman,  R.C. Gorman ,  Bill Woodrow , Robert Cremean, and  Sarah Sze .


The UCSF Archives and Special Collections is part of the UCSF Library located on the Parnassus campus in San Francisco, California. The UCSF archives serve as the official repository for the preservation of selected records, printed and born-digital materials, and realia generated by or about UCSF, including the School of Medicine, School of Nursing, School of Pharmacy, School of Dentistry, the Graduate Division, and the UCSF Medical Center. [ 1 ]  The archives also include rare and unique materials that support research and teaching in the history of the health sciences. [ 2 ]


The institutional archives were officially established in 1963 by UC President  Clark Kerr . He mandated the creation of both a records management system and an archives program at UCSF. The medical history rare book collection began in the 1930s, before the establishment of the institutional archives. [ 1 ]


Significant rare book collections and archival holdings include:


The UCSF  Industry Documents Library  (IDL) is a digital archive of internal tobacco, drug, food, chemical, and fossil fuel corporate documents, acquired largely through litigation, which illustrate industry efforts to influence policies and regulations meant to protect public health. The mission of the UCSF Industry Documents Library is to "identify, collect, curate, preserve, and make freely accessible internal documents created by industries and their partners which have an impact on public health, for the benefit and use of researchers, clinicians, educators, students, policymakers, media, and the general public at UCSF and internationally". [ 8 ]  The collection includes the   Truth Tobacco Industry Documents  and the  Drug Industry Document Archive . [ 9 ]


Wonder Drug: The Secret History of Thalidomide in America and Its Hidden Victims  is a nonfiction book authored by  Jennifer Vanderbes  and published by  Random House  in 2023. It tells the story of how  Frances Oldham Kelsey  of the  Food and Drug Administration  (FDA) found flaws in  thalidomide  research. Contrary to the initial opinion that the FDA declined the drug a license for  morning sickness  in pregnancy and the US was therefore spared the  thalidomide scandal , Vanderbes claims that the drug was still widely distributed there in the late 1950s and 1960s. As a result, many more babies were affected by  phocomelia  than originally believed. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]


This article about a  medical book  is a  stub . You can help Wikipedia by  expanding it .


Chirality  ( / k aɪ ˈ r æ l ɪ t i / ) is a property of  asymmetry  important in several branches of science. The word  chirality  is derived from the  Greek   χείρ  ( kheir ), "hand", a familiar chiral object.


An object or a system is  chiral  if it is distinguishable from its  mirror image ; that is, it cannot be  superposed  (not to be confused with  superimposed ) onto it.  Conversely, a mirror image of an  achiral  object, such as a sphere, cannot be distinguished from the object. A chiral object and its mirror image are called  enantiomorphs  (Greek, "opposite forms") or, when referring to molecules,  enantiomers . A non-chiral object is called  achiral  (sometimes also  amphichiral ) and can be superposed on its mirror image.


The term was first used by  Lord Kelvin  in 1893 in the second  Robert Boyle Lecture  at the  Oxford University Junior Scientific Club  which was published in 1894:


I call any geometrical figure, or group of points, 'chiral', and say that it has chirality if its image in a plane mirror, ideally realized, cannot be brought to coincide with itself. [ 1 ]


Human  hands  are perhaps the most recognized example of chirality. The left hand is a non-superposable mirror image of the right hand; no matter how the two hands are oriented, it is impossible for all the major features of both hands to coincide across all axes. [ 2 ]  This difference in symmetry becomes obvious if someone attempts to shake the right hand of a person using their left hand, or if a left-handed glove is placed on a right hand. In mathematics,  chirality  is the property of a figure that is not identical to its mirror image.


In  mathematics , a figure is chiral (and said to have chirality) if it cannot be mapped to its mirror image by  rotations  and  translations  alone.  For example, a right shoe is different from a left shoe, and clockwise is different from anticlockwise. See [ 3 ]  for a full mathematical definition.


A chiral object and its mirror image are said to be enantiomorphs. The word  enantiomorph  stems from the Greek  ἐναντίος  ( enantios ) 'opposite' +  μορφή  ( morphe ) 'form'.  A non-chiral figure is called achiral or amphichiral.


The  helix  (and by extension a spun string, a screw, a propeller, etc.) and  Möbius strip  are chiral two-dimensional objects in three-dimensional ambient space. The J, L, S and Z-shaped  tetrominoes  of the popular video game  Tetris  also exhibit chirality, but only in a two-dimensional space.


Many other familiar objects exhibit the same chiral symmetry of the human body, such as gloves, glasses (sometimes), and shoes. A similar notion of chirality is considered in  knot theory , as explained below.


Some chiral three-dimensional objects, such as the helix, can be assigned a right or left handedness, according to the  right-hand rule .


In  geometry , a figure is achiral if and only if its  symmetry group  contains at least one  orientation-reversing  isometry.
In two dimensions, every figure that possesses an  axis of symmetry  is achiral, and it can be shown that every  bounded  achiral figure must have an axis of symmetry.
In three dimensions, every figure that possesses a  plane of symmetry  or a center of symmetry is achiral. There are, however, achiral figures lacking both plane and center of symmetry.
In terms of  point groups , all chiral figures lack an improper axis of rotation (S n ). This means that they cannot contain a center of inversion (i) or a mirror plane (σ). Only figures with a point group designation of C 1 , C n , D n , T, O, or I can be chiral.


A  knot  is called  achiral  if it can be continuously deformed into its mirror image, otherwise it is called chiral. For example, the  unknot  and the  figure-eight knot  are achiral, whereas the  trefoil knot  is chiral.


In physics, chirality may be found in the  spin  of a particle, where the handedness of the object is determined by the direction in which the particle spins. [ 4 ]  Not to be confused with  helicity , which is the projection of the spin along the linear momentum of a subatomic particle, chirality is an intrinsic quantum mechanical property, like spin. Although both chirality and helicity can have left-handed or right-handed properties, only in the massless case are they identical. [ 5 ]  In particular for a massless particle the helicity is the same as the chirality while for an antiparticle they have opposite sign.


The  handedness  in both chirality and helicity relate to the rotation of a particle while it proceeds in linear motion with reference to the human hands. The thumb of the hand points towards the direction of linear motion whilst the fingers curl into the palm, representing the direction of rotation of the particle (i.e. clockwise and counterclockwise). Depending on the linear and rotational motion, the particle can either be defined by left-handedness or right-handedness. [ 5 ]  A symmetry transformation between the two is called  parity . Invariance under parity by a  Dirac fermion  is called  chiral symmetry .


Electromagnetic  waves can have handedness associated with their  polarization . Polarization of an  electromagnetic wave  is the property that describes the  orientation , i.e., the  time-varying  direction and  amplitude , of the  electric field   vector . For example, the electric field vectors of left-handed or right-handed  circularly polarized waves  form helices of opposite handedness in space.


Circularly polarized waves of opposite handedness propagate through chiral media at different speeds ( circular birefringence ) and with different losses ( circular dichroism ). Both phenomena are jointly known as optical activity. Circular birefringence causes rotation of the polarization state of electromagnetic waves in chiral media and can cause a  negative index of refraction  for waves of one handedness when the effect is sufficiently large. [ 6 ] [ 7 ]


While optical activity occurs in structures that are chiral in three dimensions (such as helices), the concept of chirality can also be applied in two dimensions.  2D-chiral  patterns, such as flat spirals, cannot be superposed with their mirror image by translation or rotation in two-dimensional space (a plane). 2D chirality is associated with directionally asymmetric transmission (reflection and absorption) of circularly polarized waves. 2D-chiral materials, which are also anisotropic and lossy exhibit different total transmission (reflection and absorption) levels for the same circularly polarized wave incident on their front and back. The asymmetric transmission phenomenon arises from different, e.g. left-to-right, circular polarization conversion efficiencies for opposite propagation directions of the incident wave and therefore the effect is referred to as circular conversion dichroism.
Like the twist of a 2d-chiral pattern appears reversed for opposite directions of observation, 2d-chiral materials have interchanged properties for left-handed and right-handed circularly polarized waves that are incident on their front and back. In particular left-handed and right-handed circularly polarized waves experience opposite directional transmission (reflection and absorption) asymmetries. [ 8 ] [ 9 ]


While optical activity is associated with 3d chirality and circular conversion is associated with 2d chirality, both effects have also been observed in structures that are not chiral by themselves. For the observation of these chiral electromagnetic effects, chirality does not have to be an intrinsic property of the material that interacts with the electromagnetic wave. Instead, both effects can also occur when the propagation direction of the electromagnetic wave together with the structure of an (achiral) material form a chiral experimental arrangement. [ 10 ] [ 11 ]  This case, where the mutual arrangement of achiral components forms a chiral (experimental) arrangement, is known as extrinsic chirality. [ 12 ] [ 13 ]


Chiral mirrors are a class of metamaterials that reflect circularly polarized light of a certain helicity in a handedness-preserving manner, while absorbing circular polarization of the opposite handedness. [ 14 ]  However, most absorbing chiral mirrors operate only in a narrow frequency band, as limited by the causality principle. Employing a different design methodology that allows undesired waves to pass through instead of absorbing the undesired waveform, chiral mirrors are able to show good broadband performance. [ 15 ]


A  chiral molecule  is a type of  molecule  that has a non-superposable  mirror image . The feature that is most often the cause of chirality in molecules is the presence of an  asymmetric carbon atom . [ 16 ] [ 17 ]


The term "chiral" in general is used to describe the object that is non-superposable on its mirror image. [ 18 ]


In chemistry, chirality usually refers to molecules. Two mirror images of a chiral molecule are called  enantiomers  or optical  isomers . Pairs of enantiomers are often designated as " right- ", "left-handed" or, if they have no bias, "achiral". As polarized light passes through a chiral molecule, the plane of polarization, when viewed along the axis toward the source, will be rotated clockwise (to the right) or anticlockwise (to the left). A right handed rotation is dextrorotary (d); that to the left is levorotary (l). The d- and l-isomers are the same compound but are called  enantiomers . An equimolar mixture of the two optical isomers, which is called a  racemic mixture , will produce no net rotation of polarized light as it passes through. [ 19 ]  Left handed molecules have l- prefixed to their names; d- is prefixed to right handed molecules. However, this  d-  and  l-  notation of distinguishing enantiomers does not say anything about the actual spatial arrangement of the ligands/substituents around the  stereogenic  center, which is defined as configuration. Another nomenclature system employed to specify configuration is Fischer convention. [ 20 ]  This is also referred to as the D- and L-system. Here the relative configuration is assigned with reference to D-(+)-Glyceraldehyde and L-(−)-Glyceraldehyde, being taken as standard. Fischer convention is widely used in sugar chemistry and for α-amino acids. Due to the drawbacks of Fischer convention, it is almost entirely replaced by  Cahn-Ingold-Prelog convention , also known as the sequence rule or R and S nomenclature. [ 21 ] [ 22 ]  This was further extended to assign absolute configuration to  cis-trans  isomers with the E-Z notation.


Molecular chirality is of interest because of its application to  stereochemistry  in  inorganic chemistry ,  organic chemistry ,  physical chemistry ,  biochemistry , and  supramolecular chemistry .


More recent developments in chiral chemistry include the development of chiral inorganic  nanoparticles  that may have the similar tetrahedral geometry as chiral centers associated with sp3 carbon atoms traditionally associated with chiral compounds, but at larger scale. [ 23 ] [ 24 ]    Helical and other symmetries of chiral  nanomaterials  were also obtained. [ 25 ]


All of the known life-forms show specific chiral properties in chemical structures as well as macroscopic anatomy, development and behavior. [ 26 ]  In any specific organism or evolutionarily related set thereof, individual compounds, organs, or behavior are found in the same single enantiomorphic form. Deviation (having the opposite form) could be found in a small number of chemical compounds, or certain organ or behavior but that variation strictly depends upon the genetic make up of the organism. From chemical level (molecular scale), biological systems show extreme stereospecificity in synthesis, uptake, sensing, metabolic processing. A living system usually deals with two enantiomers of the same compound in drastically different ways.


In biology, homochirality is a common property of  amino acids  and  carbohydrates . The chiral  protein-making amino acids , which are translated through the ribosome from genetic coding, occur in the  L  form. However,  D -amino acids are also found in nature. The monosaccharides (carbohydrate-units) are commonly found in  D -configuration. DNA double helix is chiral (as any kind of  helix  is chiral), and  B-form of DNA  shows a right-handed turn.


Sometimes, when two enantiomers of a compound are found in organisms, they significantly differ in their taste, smell and other biological actions. For example,(+)- Carvone  is responsible for the smell of  caraway  seed oil, whereas (–)-carvone is responsible for smell of  spearmint  oil. [ 27 ]  However, it is a commonly held misconception that (+)-limonene is found in oranges (causing its smell), and (–)-limonene is found in lemons (causing its smell). In 2021, after rigorous experimentation, it was found that all citrus fruits contain only (+)-limonene and the odor difference is because of other contributing factors. [ 28 ]


Also, for artificial compounds, including medicines, in case of  chiral drugs , the two enantiomers sometimes show remarkable difference in effect of their biological actions. [ 29 ]  Darvon ( dextropropoxyphene ) is a painkiller, whereas its enantiomer, Novrad ( levopropoxyphene ) is an anti-cough agent. In case of  penicillamine , the ( S -isomer is used in the treatment of primary chronic arthritis, whereas the ( R )-isomer has no therapeutic effect, as well as being highly toxic. [ 30 ]  In some cases, the less therapeutically active enantiomer can cause side effects. For example, ( S -naproxen is an analgesic but the ( R -isomer causes renal problems. [ 31 ]  In such situations where one of the enantiomers of a racemic drug is active and the other partner has undesirable or toxic effect one may switch from racemate to a single enantiomer drug for a better therapeutic value. [1]  Such a switching from a racemic drug to an enantiopure drug is called a  chiral switch .


The naturally occurring plant form of alpha-tocopherol ( vitamin E ) is RRR-α-tocopherol whereas the synthetic form (all-racemic vitamin E, or dl-tocopherol) is equal parts of the stereoisomers RRR, RRS, RSS, SSS, RSR, SRS, SRR, and SSR with progressively decreasing biological equivalency, so that 1.36 mg of dl-tocopherol is considered equivalent to 1.0 mg of d-tocopherol. [ 32 ]


Macroscopic examples of chirality are found in the plant kingdom, the animal kingdom and all other groups of organisms. A simple example is the coiling direction of any climber plant, which can grow to form either a left- or right-handed helix.


In anatomy, chirality is found in the imperfect mirror image symmetry of many kinds of animal bodies. Organisms such as  gastropods  exhibit chirality in their coiled shells, resulting in an asymmetrical appearance. Over 90% of gastropod species [ 33 ]  have  dextral  (right-handed) shells in their coiling, but a small minority of species and genera are virtually always  sinistral  (left-handed). A very few species (for example  Amphidromus perversus [ 34 ] ) show an equal mixture of dextral and sinistral individuals.


In humans, chirality (also referred to as  handedness  or  laterality ) is an attribute of humans defined by their unequal distribution of  fine motor skill  between the left and right  hands . An individual who is more  dexterous  with the right hand is called  right-handed , and one who is more skilled with the left is said to be  left-handed . Chirality is also seen in the study of  facial asymmetry  and is known as aurofacial asymmetry. [ 35 ]


According to the  Axial Twist theory ,  vertebrate  animals develop into a left-handed chirality. Due to this, the  brain is turned around  and the  heart  and  bowels  are turned by 90°. [ 36 ]


In the case of the health condition  situs inversus totalis , in which all the internal organs are flipped horizontally (i.e. the heart  placed slightly to the right  instead of the left), chirality poses some problems should the patient require a liver or heart transplant, as these organs are chiral, thus meaning that the blood vessels which supply these organs would need to be rearranged should a normal, non  situs inversus  ( situs solitus ) organ be required.


In the monocot  bloodroot family , the species of the  genera   Wachendorfia  and  Barberetta  have only individuals that either have the style points to the right or the style pointed to the left, with both morphs appearing within the same populations. This is thought to increase  outcrossing  and so boost genetic diversity, which in turn may help to survive in a changing environment. Remarkably, the related genus  Dilatris  also has chirally dimorphic flowers, but here both morphs occur on the same plant. [ 37 ]  In  flatfish , the  summer flounder  or fluke are left-eyed, while  halibut  are right-eyed.


Homochirality  is a uniformity of  chirality , or handedness. Objects are chiral when they cannot be superposed on their mirror images. For example, the left and right hands of a human are approximately mirror images of each other but are not their own mirror images, so they are chiral. In  biology , 19 of the 20 natural  amino acids  are homochiral, being  L -chiral (left-handed), while  sugars  are  D -chiral (right-handed). [ 1 ]  Homochirality can also refer to  enantiopure  substances in which all the constituents are the same  enantiomer  (a right-handed or left-handed version of an atom or molecule), but some sources discourage this use of the term.


It is unclear whether homochirality has a purpose; however, it appears to be a form of information storage. [ 2 ]  One suggestion is that it reduces  entropy  barriers in the formation of large organized molecules. [ 3 ]  It has been experimentally verified that amino acids form large aggregates in larger abundance from an  enantiopure  samples of the amino acid than from  racemic  (enantiomerically mixed) ones. [ 3 ]


It is not clear whether homochirality emerged before or after life, and many mechanisms for its origin have been proposed. [ 4 ]  Some of these models propose three distinct steps:  mirror-symmetry breaking  creates a minute enantiomeric imbalance,  chiral amplification  builds on this imbalance, and  chiral transmission  is the transfer of chirality from one set of molecules to another.


Amino acids are the building blocks of  peptides  and  enzymes  while sugar-peptide chains are the backbone of  RNA  and  DNA . [ 5 ] [ 6 ]  In biological organisms, amino acids appear almost exclusively in the left-handed form ( L -amino acids) and sugars in the right-handed form (R-sugars). [ 7 ] [ verification needed ]  Since the enzymes catalyze reactions, they enforce homochirality on a great variety of other chemicals, including  hormones , toxins, fragrances and food flavors. [ 8 ] : 493–494    Glycine  is achiral, as are some other non- proteinogenic  amino acids that are either achiral (such as  dimethylglycine ) or of the  D  enantiomeric form.


Biological organisms easily discriminate between molecules with different chiralities. This can affect physiological reactions such as smell and taste.  Carvone , a  terpenoid  found in  essential oils , smells like mint in its L-form and  caraway  in its R-form. [ 8 ] : 494  [ verification needed ]   Limonene  tastes like citrus when right-handed and pine when left-handed. [ 9 ] : 168


Homochirality also affects the response to drugs.  Thalidomide , in its left-handed form, cures  morning sickness ; in its right-handed form, it causes birth defects. [ 9 ] : 168   Unfortunately, even if a pure left-handed version is administered, some of it can convert to the right-handed form in the patient. [ 10 ]  Many drugs are available as both a  racemic mixture  (equal amounts of both chiralities) and an  enantiopure drug  (only one chirality). Depending on the manufacturing process, enantiopure forms can be more expensive to produce than stereochemical mixtures. [ 9 ] : 168


Chiral preferences can also be found at a macroscopic level. Snail shells can be right-turning or left-turning helices, but one  form or the other is strongly preferred in a given species. In the edible snail  Helix pomatia , only one out of 20,000 is left-helical. [ 11 ] : 61–62   The coiling of plants can have a preferred chirality and even the chewing motion of cows has a 10% excess in one direction. [ 12 ]


Theories for the origin of homochirality in the molecules of life can be classified as deterministic or based on chance depending on their proposed mechanism. If there is a relationship between cause and effect — that is, a specific chiral field or influence causing the mirror symmetry breaking — the theory is classified as deterministic; otherwise it is classified as a theory based on chance (in the sense of randomness) mechanisms. [ 13 ]


Another classification for the different theories of the origin of biological homochirality could be made depending on whether life emerged before the enantiodiscrimination step (biotic theories) or afterwards (abiotic theories). Biotic theories claim that homochirality is simply a result of the natural autoamplification process of life—that either the formation of life as preferring one chirality or the other was a chance rare event which happened to occur with the chiralities we observe, or that all chiralities of life emerged rapidly but due to catastrophic events and strong competition, the other unobserved chiral preferences were wiped out by the preponderance and metabolic, enantiomeric enrichment from the 'winning' chirality choices. [ citation needed ]  If this was the case, remains of the extinct chirality sign should be found. Since this is not the case, nowadays biotic theories are no longer supported.


The emergence of chirality consensus as a natural autoamplification process has also been associated with the  2nd law of thermodynamics . [ 14 ]


Deterministic theories can be divided into two subgroups: if the initial chiral influence took place in a specific space or time location (averaging zero over large enough areas of observation or periods of time), the theory is classified as local deterministic; if the chiral influence is permanent at the time the chiral selection occurred, then it is classified as universal deterministic. The classification groups for local determinist theories and theories based on chance mechanisms can overlap. Even if an external chiral influence produced the initial chiral imbalance in a deterministic way, the outcome sign could be random since the external chiral influence has its enantiomeric counterpart elsewhere.


In deterministic theories, the enantiomeric imbalance is created due to an external chiral field or influence, and the ultimate sign imprinted in biomolecules will be due to it. Deterministic mechanisms for the production of non-racemic mixtures from racemic starting materials include: asymmetric physical laws, such as the  electroweak interaction  (via cosmic rays [ 15 ] ) or asymmetric environments, such as those caused by  circularly polarized  light,  quartz crystals , or the Earth's rotation, β-Radiolysis or the magnetochiral effect. [ 16 ] [ 17 ]  The most accepted universal deterministic theory is the electroweak interaction. Once established, chirality would be selected for. [ 18 ]


One supposition is that the discovery of an enantiomeric imbalance in molecules in the  Murchison meteorite  supports an extraterrestrial origin of homochirality: there is evidence for the existence of  circularly polarized light  originating from  Mie scattering  on aligned interstellar dust particles which may trigger the formation of an  enantiomeric excess  within chiral material in space. [ 11 ] : 123–124   Interstellar and near-stellar magnetic fields can align dust particles in this fashion. [ 19 ]  Another speculation (the Vester-Ulbricht hypothesis) suggests that fundamental chirality of physical processes such as that of the beta decay (see  Parity violation ) leads to slightly different half-lives of biologically relevant molecules.


Chance theories are based on the assumption that " Absolute asymmetric synthesis, i.e., the formation of enantiomerically enriched products from achiral precursors without the intervention of chiral chemical reagents or catalysts, is in practice unavoidable on statistical grounds alone ". [ 20 ]


Consider the racemic state as a macroscopic property described by a binomial distribution; the experiment of tossing a coin, where the two possible outcomes are the two enantiomers is a good analogy. The discrete probability distribution

 P

 p

 (
 n
 ,
 N
 )

 {\displaystyle P_{p}(n,N)}

  of obtaining n successes out of

 N

 {\displaystyle N}

  Bernoulli trials, where the result of each Bernoulli trial occurs with probability

 p

 {\displaystyle p}

  and the opposite occurs with probability

 q
 =
 (
 1
 −
 p
 )

 {\displaystyle q=(1-p)}

  is given by:


P

 p

 (
 n
 ,
 N
 )
 =

 (

 N
 n

 )

 p

 n

 (
 1
 −
 p

 )

 N
 −
 n

 {\displaystyle P_{p}(n,N)={\binom {N}{n}}p^{n}(1-p)^{N-n}}

  .


The discrete probability distribution

 P
 (
 N

 /

 2
 ,
 N
 )

 {\displaystyle P(N/2,N)}

  of having exactly

 N

 /

 2

 {\displaystyle N/2}

  molecules of one chirality and

 N

 /

 2

 {\displaystyle N/2}

  of the other, is given by:


P

 1

 /

 2

 (
 N

 /

 2
 ,
 N
 )
 =

 (

 N

 N

 /

 2

 )

 (

 1
 2

 )

 N

 /

 2

 (

 1
 2

 )

 N

 /

 2

 ≈

 2

 π
 N

 {\displaystyle P_{1/2}(N/2,N)={\binom {N}{N/2}}\left({\frac {1}{2}}\right)^{N/2}\left({\frac {1}{2}}\right)^{N/2}\approx {\sqrt {\frac {2}{\pi N}}}}

  .


As in the experiment of tossing a coin, in this case, we assume both events (

 L

 {\displaystyle L}

  or

 D

 {\displaystyle D}

 ) to be equiprobable,

 p
 =
 q
 =
 1

 /

 2

 {\displaystyle p=q=1/2}

 . The probability of having exactly the same amount of both enantiomers is inversely proportional to the square root of the total number of molecules

 N

 {\displaystyle N}

 . For one mol of a racemic compound,

 N
 =

 N

 A

 ≈
 6.022
 ⋅

 10

 23

 {\displaystyle N=N_{A}\approx 6.022\cdot 10^{23}}

  molecules, this probability becomes

 P

 1

 /

 2

 (

 N

 A

 /

 2
 ,

 N

 A

 )
 ≈

 10

 −
 12

 {\displaystyle P_{1/2}(N_{A}/2,N_{A})\approx 10^{-12}}

 . The probability of finding the racemic state is so small that we can consider it negligible.


In this scenario, there is a need to amplify the initial stochastic  enantiomeric excess  through any efficient mechanism of amplification. [ 4 ]  The most likely path for this amplification step is by  asymmetric autocatalysis . An autocatalytic chemical reaction is that in which the reaction product is itself a reactive, in other words, a chemical reaction is autocatalytic if the reaction product is itself the catalyst of the reaction. In asymmetric autocatalysis, the catalyst is a chiral molecule, which means that a chiral molecule is catalysing its own production. An initial enantiomeric excess, such as can be produced by polarized light, then allows the more abundant enantiomer to outcompete the other.


In 1953,  Charles Frank  proposed a model to demonstrate that homochirality is a consequence of  autocatalysis . [ 21 ] [ 22 ]  In his model the  L  and  D  enantiomers of a chiral molecule are autocatalytically produced from an achiral molecule A


while suppressing each other through a reaction that he called  mutual antagonism


L
 +
 D

 →

 k

 d

 ∅
 .

 {\displaystyle {\begin{aligned}L+D\xrightarrow {k_{d}} \varnothing .\\\end{aligned}}}


In this model the racemic state is unstable in the sense that the slightest enantiomeric excess will be amplified to a completely homochiral state. This can be shown by computing the reaction rates from the  law of mass action :


where

 k

 a

 {\displaystyle k_{a}}

  is the rate constant for the autocatalytic reactions,

 k

 d

 {\displaystyle k_{d}}

  is the rate constant for mutual antagonism reaction, and the concentration of A is kept constant for simplicity.


The analytical solutions for are found to be

 [
 L
 ]

 /

 [
 D
 ]
 =
 [
 L

 ]

 0

 /

 [
 D

 ]

 0

 e

 k
 d
 (
 [
 L

 ]

 0

 −
 [
 D

 ]

 0

 )
 (

 e

 k

 a

 t

 −
 1
 )

 {\displaystyle [L]/[D]=[L]_{0}/[D]_{0}\,e^{kd([L]_{0}-[D]_{0})(e^{k_{a}t}-1)}}

  . The ratio

 [
 L
 ]

 /

 [
 D
 ]

 {\displaystyle [L]/[D]}

  increases at a more than exponential rate if

 (
 [
 L

 ]

 0

 −
 [
 D

 ]

 0

 )

 {\displaystyle ([L]_{0}-[D]_{0})}

  is positive (and vice versa). Every starting conditions different to


[
 L

 ]

 0

 =
 [
 D

 ]

 0

 {\displaystyle [L]_{0}=[D]_{0}}

  lead to one of the asymptotes

 [
 L
 ]
 =
 0

 {\displaystyle [L]=0}

  or

 [
 D
 ]
 =
 0

 {\displaystyle [D]=0}

 . Thus the equality of

 [
 L

 ]

 0

 {\displaystyle [L]_{0}}

  and

 [
 D

 ]

 0

 {\displaystyle [D]_{0}}

  and so of

 [
 L
 ]

 {\displaystyle [L]}

  and

 [
 D
 ]

 {\displaystyle [D]}

  represents a condition of unstable equilibrium, this result depending on the presence of the term representing mutual antagonism.


By defining the enantiomeric excess

 e
 e

 {\displaystyle ee}

  as


the rate of change of enantiomeric excess can be calculated using  chain rule  from the rate of change of the concentrations of enantiomers  L  and  D .


Linear stability analysis of this equation shows that the racemic state

 e
 e
 =
 0

 {\displaystyle ee=0}

  is unstable. Starting from  almost everywhere  in the concentration space, the system evolves to a homochiral state.


It is generally understood that autocatalysis alone does not yield to homochirality, and the presence of the mutually antagonistic relationship between the two enantiomers is necessary for the instability of the racemic mixture. However, recent studies show that homochirality could be achieved from autocatalysis in the absence of the mutually antagonistic relationship, but the underlying mechanism for symmetry-breaking is different. [ 4 ] [ 23 ]


There are several laboratory experiments that demonstrate how a small amount of one enantiomer at the start of a reaction can lead to a large excess of a single enantiomer as the product. For example, the Soai reaction is  autocatalytic . [ 24 ] [ 25 ]  If the reaction is started with some of one of the product enantiomers already present, the product acts as an  enantioselective  catalyst for production of more of that same enantiomer. [ 26 ]  The initial presence of just 0.2  equivalent  one enantiomer can lead to up to 93%  enantiomeric excess  of the product.


Another study [ 27 ]  concerns the  proline  catalyzed  aminoxylation  of  propionaldehyde  by  nitrosobenzene . In this system, a small enantiomeric excess of catalyst leads to a large enantiomeric excess of product.


Serine octamer clusters [ 28 ] [ 29 ]  are also contenders. These clusters of 8 serine molecules appear in mass spectrometry with an unusual homochiral preference, however there is no evidence that such clusters exist under non-ionizing conditions and amino acid phase behavior is far more prebiotically relevant. [ 30 ]  The recent observation that partial  sublimation  of a 10% enantioenriched sample of  leucine  results in up to 82% enrichment in the sublimate shows that enantioenrichment of amino acids could occur in space. [ 31 ]  Partial sublimation processes can take place on the surface of meteors where large variations in temperature exist. This finding may have consequences for the development of the  Mars Organic Detector  scheduled for launch in 2013 which aims to recover trace amounts of amino acids from the Mars surface exactly by a sublimation technique.


A high asymmetric amplification of the  enantiomeric excess  of sugars are also present in the  amino acid  catalyzed asymmetric formation of  carbohydrates [ 32 ]


One classic study involves an experiment that takes place in the laboratory. [ 33 ]  When  sodium chlorate  is allowed to  crystallize  from water and the collected crystals examined in a  polarimeter , each crystal turns out to be chiral and either the  L  form or the  D  form. In an ordinary experiment the amount of  L  crystals collected equals the amount of  D  crystals (corrected for statistical effects). However, when the sodium chlorate solution is stirred during the crystallization process the crystals are either exclusively  L  or exclusively  D . In 32 consecutive crystallization experiments 14 experiments deliver  D -crystals and 18 others  L -crystals. The explanation for this symmetry breaking is unclear but is related to  autocatalysis  taking place in the  nucleation  process.


In a related experiment, a crystal suspension of a racemic  amino acid  derivative continuously stirred, results in a 100% crystal phase of one of the enantiomers because the enantiomeric pair is able to equilibrate in solution  (compare with  dynamic kinetic resolution ). [ 34 ]


Once a significant enantiomeric enrichment has been produced in a system, the transference of chirality through the entire system is customary. This last step is known as the chiral transmission step. Many strategies in  asymmetric synthesis  are built on chiral transmission. Especially important is the so-called  organocatalysis  of organic reactions by proline for example in  Mannich reactions .


Some proposed models for the transmission of chiral asymmetry are polymerization, [ 35 ] [ 36 ] [ 37 ] [ 38 ] [ 39 ] [ 40 ]  epimerization  [ 41 ] [ 42 ]  or copolymerization. [ 43 ] [ 44 ]


There exists no theory elucidating correlations among  L -amino acids. If one takes, for example,  alanine , which has a small  methyl  group, and  phenylalanine , which has a larger  benzyl  group, a simple question is in what aspect,  L -alanine resembles  L -phenylalanine more than  D -phenylalanine, and what kind of mechanism causes the selection of all  L -amino acids, because it might be possible that alanine was  L  and phenylalanine was  D .


It was reported [ 45 ]  in 2004 that excess racemic  D , L -asparagine  (Asn), which spontaneously forms crystals of either isomer during recrystallization, induces asymmetric resolution of a co-existing racemic amino acid such as  arginine  (Arg),  aspartic acid  (Asp),  glutamine  (Gln),  histidine  (His),  leucine  (Leu),  methionine  (Met),  phenylalanine  (Phe),  serine  (Ser),  valine  (Val),  tyrosine  (Tyr), and  tryptophan  (Trp). The  enantiomeric excess   ee = 100 ×( L - D )/( L + D )  of these amino acids was correlated almost linearly with that of the inducer, i.e., Asn. When recrystallizations from a mixture of 12  D , L -amino acids (Ala, Asp, Arg, Glu, Gln, His, Leu, Met, Ser, Val, Phe, and Tyr) and excess  D , L -Asn were made, all amino acids with the same configuration with Asn were preferentially co-crystallized. [ 45 ]  It was incidental whether the enrichment took place in  L - or  D -Asn, however, once the selection was made, the co-existing amino acid with the same configuration at the α-carbon was preferentially involved because of thermodynamic stability in the crystal formation. The maximal ee was reported to be 100%. Based on these results, it is proposed that a mixture of racemic amino acids causes spontaneous and effective optical resolution, even if asymmetric synthesis of a single amino acid does not occur without an aid of an optically active molecule.


This is the first study elucidating reasonably the formation of chirality from racemic amino acids with experimental evidences.


This term was introduced by  Kelvin  in 1904, the year that he published his Baltimore Lecture of 1884. Kelvin used the term homochirality as a relationship between two molecules, i.e. two molecules are homochiral if they have the same chirality. [ 32 ] [ 46 ]  Recently, however, homochiral has been used in the same sense as  enantiomerically  pure. This is permitted in some journals (but not encouraged), [ 47 ] : 342  [ 48 ]  its meaning changing into the preference of a process or system for a single  optical isomer  in a pair of isomers in these journals.


In transportation infrastructure, a  bidirectional traffic  system divides travellers into two streams of traffic that flow in opposite directions. [ 1 ]


In the design and construction of tunnels, bidirectional traffic can markedly affect ventilation considerations. [ 2 ]


Microscopic traffic flow models  have been proposed for bidirectional automobile, pedestrian, and railway traffic. [ 3 ]  Bidirectional traffic can be observed in  ant  trails [ 4 ]  which have been researched for insight into human traffic models. [ 5 ]  In a  macroscopic theory  proposed by  Laval , the interaction between fast and slow vehicles conforms to the Newell kinematic wave model of moving  bottlenecks . [ 6 ]


In  air traffic control  traffic is normally separated by elevation, with east bound flights at odd thousand feet elevations and west bound flights at even thousand feet elevations (1000 ft ≈ 305m). Above 28,000 ft (~8.5 km) only odd flight levels are used, with FL 290, 330, 370, etc., for eastbound flights and FL 310, 350, 390, etc., for westbound flights. [ 7 ]  Entry to and exit from airports is always one-way traffic, as runways are chosen to allow aircraft to take off and land into the wind, to reduce ground speed. [ 8 ]  Even in no wind cases, a preferred calm wind runway and direction is normally chosen and used by all flights, to avoid collisions. [ 9 ]  In uncontrolled airports, airport information can be obtained from anyone at the airport. Traffic follows a specific traffic pattern, with designated entry and exits. Radio announcements are made, whether anyone is listening or not, to allow any other traffic to be aware of other traffic in the area. [ 10 ]


In the earliest days of railways in the  United Kingdom , most lines were built  double tracked  because of the difficulty of coordinating operations in pre- telegraphy  times.


Most modern roads carry bidirectional traffic, although  one-way traffic  is common in dense urban centres. [ citation needed ]  Bidirectional traffic flow is believed to influence the rate of  traffic collisions . In an analysis of  head-on ,  rear-end , and lane-changing collisions based on the Simon-Gutowitz bidirectional traffic model, it was concluded that "the risk of collisions is important when the density of cars in one lane is small and ... the other lane['s] is high enough," and that "heavy vehicles cause an important reduction of traffic flow on the home lane and provoke an increase of the risk of car accident." [ 11 ]


Bidirectional traffic is the most common form of flow observed in  trails , however, some larger pedestrian concourses exhibit multidirectional traffic. [ 12 ]


Bromochlorofluoroiodomethane  is a hypothetical  haloalkane  with all four stable  halogen  substituents present in it. [ 1 ]


This compound can be seen as a  methane  molecule, whose four  hydrogen  atoms are each replaced with a different  halogen  atom. As the mirror images of this molecule are not superimposable, the molecule has two  enantiomers .  As one of the simplest such molecules, it is often cited as the prototypical  chiral  compound. [ 2 ]  However, since there is no synthetic route known to produce bromochlorofluoroiodomethane, the related simple chiral compound  bromochlorofluoromethane  is used instead when such a compound is required for research.


This article about  theoretical chemistry  is a  stub . You can help Wikipedia by  expanding it .


This  stereochemistry  article is a  stub . You can help Wikipedia by  expanding it .


Bromochlorofluoromethane  or  fluorochlorobromomethane , is a chemical compound and  trihalomethane  derivative with the chemical formula  C H Br Cl F . As one of the simplest possible stable  chiral  compounds, it is useful for fundamental research into this area of chemistry. [ 1 ]  However, its relative instability to  hydrolysis , [ 2 ]  and lack of suitable  functional groups , made separation of the  enantiomers  of bromochlorofluoromethane especially challenging, [ 3 ]  and this was not accomplished until almost a century after it was first synthesised, in March 2005, though it has now been done by a variety of methods. [ 4 ] [ 5 ] [ 6 ] [ 7 ]  More recent research using bromochlorofluoromethane has focused on its potential use for experimental measurement of  parity violation , a major unsolved problem in  quantum physics . [ 8 ] [ 9 ] [ 10 ]  For example, the  S  enantiomer is predicted to be lower in energy by about  2.356 × 10 −16  eV  (56.97 mHz), [ 11 ]  and the frequency of the  C − F  vibrational mode should be about 2.4 mHz lower for the  R -enantiomer. [ 10 ]


This article about a  hydrocarbon  is a  stub . You can help Wikipedia by  expanding it .


Chemical compounds that come as mirror-image pairs are referred to by chemists as  chiral  or handed molecules. [ 1 ]  Each twin is called an  enantiomer . Drugs that exhibit handedness are referred to as  chiral drugs . Chiral drugs that are equimolar (1:1) mixture of enantiomers are called  racemic  drugs and these are obviously devoid of optical rotation. The most commonly encountered stereogenic unit, [ 2 ]  that confers  chirality  to drug molecules are stereogenic center. Stereogenic center can be due to the presence of tetrahedral tetra coordinate atoms (C,N,P) and pyramidal tricoordinate atoms (N,S). The word chiral describes the three-dimensional architecture of the molecule and does not reveal the stereochemical composition. Hence "chiral drug" does not say whether the drug is racemic (racemic drug), single enantiomer (chiral specific drug) or some other combination of stereoisomers. To resolve this issue  Joseph Gal  introduced a new term called  unichiral . [ 3 ] [ 4 ]  Unichiral indicates that the stereochemical composition of a chiral drug is homogenous consisting of a single enantiomer.


Many medicinal agents important to life are combinations of mirror-image twins. Despite the close resemblance of such twins, the differences in their biological properties can be profound. In other words, the component enantiomers of a racemic chiral drug may differ wildly in their pharmacokinetic, pharmacodynamic profile. [ 5 ] [ 6 ] [ 7 ] [ 8 ]  The tragedy of  thalidomide  illustrates the potential for extreme consequences resulting from the administration of a racemate drug that exhibits multiple effects attributable to individual enantiomers. [ 9 ]  With the advancements in chiral technology and the increased awareness about three-dimensional consequences of drug action and disposition emerged specialized field "chiral pharmacology". Simultaneously the chirality nomenclature system also evolved. A brief overview of chirality history and terminology/descriptors is given below. A detailed  chirality timeline  is not the focus of this article.


Chirality can be traced back to 1812, when physicist  Jean-Baptiste Biot  found out about a phenomenon called "optical activity." [ 10 ]   Louis Pasteur , a famous student of Biot's, made a series of observations that led him to suggest that the optical activity of some substances is caused by their molecular asymmetry, which makes nonsuperimposable mirror-images. In 1848, Pasteur grew two different kinds of crystals from the racemic sodium ammonium salt of tartaric acid. He was the first person to separate enantiomeric crystals by hand. [ 11 ]  In fact Pasteur laid the foundations of stereochemistry and chirality.


In 1874,  Jacobus Henricus van 't Hoff  came up with the idea of an asymmetric carbon atom. He said that all optically active carbon compounds have an asymmetric carbon atom. [ 12 ]  In the same year,   Joseph Achille Le Bel  only used asymmetry arguments and talked about the asymmetry of the molecules as a whole instead of the asymmetry of each carbon atom. [ 13 ]  So,        Le Bel's idea could be seen as the general theory of stereoisomerism, while van 't Hoff's could be seen as a special case (restricted to tetrahedral carbon).


Soon, scientists started to look into what chiral compounds meant for living things. In 1903, Cushny was the first person to show that enantiomers of a chiral molecule have different biological effects. [ 14 ]   Lord Kelvin  used the word "chiral" for the first time in 1904. [ 15 ]


This is to give an overview of the evolving chirality nomenclature system commonly employed to distinguish enantiomers of a chiral drug. In the beginning, enantiomers were distinguished based on their ability to rotate the plane of plane-polarized light. The enantiomer that rotates the plane-polarized light to the right is named "dextro-rotatory", abbreviated as  "dextro"  or  "d"  and the counterpart as  "levo"  or  "l" . A racemic mixture is denoted as "(±)",  "rac" , or  "dl" . Now the d/l system of naming based on optical rotation is falling into disuse.


Later, the Fischer convention [ 16 ] [ 17 ]  was introduced to specify the configuration of a stereogenic center and uses the symbols D and L. The use of capital letters is to differentiate from the  "d"  /  "l"  notation (optical descriptor) described earlier. In this system, the enantiomers are named with reference to D- and L-glyceraldehyde which is taken as the standard for comparison. The structure of the chiral molecule should be represented in the Fischer projection formula. If the hydroxyl group attached to the highest chiral carbon is on the right-hand side it is referred to as D-series and if on the left-hand side it is called L-series. This nomenclature system has also become obsolete. But D-/L-system of naming is still employed to designate the configuration of amino acids and sugars. In general the D/L system of nomenclature is superseded by the Cahn-Ingold-Prelog (CIP) rule to describe the configuration of a stereogenic/chiral center.


In the CIP or R/S convention, or sequence rule, the configuration, spatial arrangements of ligands/substituents around a chiral center, is labeled as either "R" or "S". [ 18 ] [ 2 ]  This convention is now almost worldwide in use and become a part of the  IUPAC  (International Union of Pure and Applied Chemistry) rules of nomenclature. In this approach: identify the chiral center, label the four atoms directly attached to the stereogenic center in question, assign priorities according to the sequence rule ( from 1 to 4), rotate the molecule until the lowest priority (number 4) substituent is away from the observer/viewer, draw a curve from number 1 to number 2 to number 3 substituent. If the curve is clockwise, the chiral center is of R-absolute configuration, "R" (Latin,  rectus  = right). If the curve is counterclockwise, the chiral center is of S-absolute configuration, "S" (Latin,  sinister  = left). Refer to figure, the Cahn-Ingold-Prelog rule.


An overview of the nomenclature system is presented in the table below.


For many years scientists in  drug development  have been blind to the three-dimensional consequences of stereochemistry, chiefly due to the lack of technology for making enantioselective investigations. Besides the thalidomide tragedy, another event that raised the importance of issues of stereochemistry in drug research and development was the publication of a manuscript in 1984 entitled, "Stereochemistry, a basis of sophisticated nonsense in pharmacokinetics and clinical pharmacology" by Ariëns. [ 19 ]  This article, and the series of articles that followed, criticized the practice of conducting pharmacokinetic and pharmacodynamic studies on racemic drugs and ignoring the separate contributions of the individual enantiomers. [ 20 ] [ 21 ] [ 22 ] [ 23 ] [ 24 ] [ 25 ]  These papers have served to crystallize some of the important issues surrounding racemic drugs and stimulated much discussion in industry, government and academia.


As a result of these criticisms and the renewed awareness of the three-dimensional effects of drug action fueled by the exponential explosion of chiral technology emerged the new area "stereo-pharmacology". A more specific term is "chiral pharmacology", a phrase popularized by John Caldwell. [ 26 ]  This field has grown itself into a specialized discipline concerned with the three-dimensional aspects of drug action and disposition. This approach essentially views each version of the chiral twins as separate chemical species. To express the pharmacological activities of each of the chiral twins two technical terms have been coined,  eutomer  and  distomer . [ 27 ]  The member of the chiral twin that has greater physiological activity is referred to as the eutomer and the other one with lesser activity is referred to as distomer. It is generally understood that this reference is necessarily to a single activity being studied. The eutomer for one effect may well be the distomer when another is studied. The eutomer/distomer ratio is called the  eudysmic ratio . [ 28 ]


The behavior of the chiral twins depends mainly on the nature of the environment (achiral/chiral) in which they are present. An achiral environment does not differentiate the molecular twins whereas a chiral environment does distinguish the left-handed version from the right-handed version. Human body, a classic bio-environment, is inherently handed as it is filled with chiral discriminators like amino acids, enzymes, carbohydrates, lipids, nucleic acids, etc. Hence when a racemic therapeutic gets exposed to biological system the component enantiomers will be acted upon stereoselectively. [ 29 ]   For drugs, chiral discrimination can take place either in the pharmacokinetic or pharmacodynamic phase.


Easson and Stedman [ 30 ]  (1933) advanced a drug-receptor interaction model to account for the differential pharmacodynamic activity between enantiomeric pairs.  In this model the more active enantiomer (the eutomer) take part in a minimum of three simultaneous intermolecular interactions with the receptor surface (good fit), Figure. A., where as the less active enantiomer (distomer) interacts at two sites only (bad fit), Figure B. [Refer image for Figure: Easson-Stedman model]. Thus the "fit" of the individual enantiomers to the receptor site differs, as does the energy of interaction. This is a simplistic model but used to explain the biological discrimination between enantiomeric pairs.


In reality the drug-receptor interaction is not that simple, but this view of such complex phenomenon has provided major insights into the mechanism of action of drugs.