Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to determine the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as: pharmaceutical drugs, food additives, etc, it attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, whereas pharmacodynamics is the study of how the drug affects the organism. Both together influence dosing and adverse effects, as seen in PK/PD models. Pharmacokinetics describes how the body affects a specific xenobiotic/chemical after administration through the mechanisms of absorption and distribution, as well as the metabolic changes of the substance in the body, the effects and routes of excretion of the metabolites of the drug. Pharmacokinetic properties of chemicals are affected by the route of administration and the dose of administered drug.
These may affect the absorption rate. Models have been developed to simplify conceptualization of the many processes that take place in the interaction between an organism and a chemical substance. One of these, the multi-compartmental model, is the most used approximations to reality; the various compartments that the model is divided into are referred to as the ADME scheme: Liberation – the process of release of a drug from the pharmaceutical formulation. See IVIVC. Absorption – the process of a substance entering the blood circulation. Distribution – the dispersion or dissemination of substances throughout the fluids and tissues of the body. Metabolism – the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into daughter metabolites. Excretion – the removal of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue; the two phases of metabolism and excretion can be grouped together under the title elimination.
The study of these distinct phases involves the use and manipulation of basic concepts in order to understand the process dynamics. For this reason in order to comprehend the kinetics of a drug it is necessary to have detailed knowledge of a number of factors such as: the properties of the substances that act as excipients, the characteristics of the appropriate biological membranes and the way that substances can cross them, or the characteristics of the enzyme reactions that inactivate the drug. All these concepts can be represented through mathematical formulas that have a corresponding graphical representation; the use of these models allows an understanding of the characteristics of a molecule, as well as how a particular drug will behave given information regarding some of its basic characteristics such as its acid dissociation constant and solubility, absorption capacity and distribution in the organism. The model outputs for a drug can be used in industry or in the clinical application of pharmacokinetic concepts.
Clinical pharmacokinetics provides many performance guidelines for effective and efficient use of drugs for human-health professionals and in veterinary medicine. The following are the most measured pharmacokinetic metrics: In pharmacokinetics, steady state refers to the situation where the overall intake of a drug is in dynamic equilibrium with its elimination. In practice, it is considered that steady state is reached when a time of 4 to 5 times the half-life for a drug after regular dosing is started; the following graph depicts a typical time course of drug plasma concentration and illustrates main pharmacokinetic metrics: Pharmacokinetic modelling is performed by noncompartmental or compartmental methods. Noncompartmental methods estimate the exposure to a drug by estimating the area under the curve of a concentration-time graph. Compartmental methods estimate the concentration-time graph using kinetic models. Noncompartmental methods are more versatile in that they do not assume any specific compartmental model and produce accurate results acceptable for bioequivalence studies.
The final outcome of the transformations that a drug undergoes in an organism and the rules that determine this fate depend on a number of interrelated factors. A number of functional models have been developed in order to simplify the study of pharmacokinetics; these models are based on a consideration of an organism as a number of related compartments. The simplest idea is to think of an organism as only one homogenous compartment; this monocompartmental model presupposes that blood plasma concentrations of the drug are a true reflection of the drug's concentration in other fluids or tissues and that the elimination of the drug is directly proportional to the drug's concentration in the organism. However, these models do not always reflect the real situation within an organism. For example, not all body tissues have the same blood supply, so the distribution of the drug will be slower in these tissues than in others with a better blood supply. In addition, there are some tissues (s
A generic drug is a pharmaceutical drug that has the same chemical substance as the drug, developed and innovated. Generic drugs are allowed for sale after the expiry of the patent of the original drugs; because the active chemical substance is the same, the medical profile of generics is believed to be equivalent in performance. The generic drug has the same active pharmaceutical ingredient as the original, but it may differ in characteristics such as manufacturing process, excipients, color and packaging. Although they may not be associated with a particular company, generic drugs are subject to government regulations in the countries in which of the drug. A generic drug must contain the same active ingredients as the original brandname formulation; the U. S. Food and Drug Administration requires generics to be identical to or within an acceptable bioequivalent range of their brandname counterparts, with respect to pharmacokinetic and pharmacodynamic properties. Biopharmaceuticals, such as monoclonal antibodies, differ biologically from small molecule drugs.
Biosimilars have active pharmaceutical ingredients that are identical to the original product and are regulated under an extended set of rules, but they are not the same as generic drugs as the active ingredients are not the same as those of their reference products. In most cases, generic products become available after the patent protections, afforded to a drug's original developer, expire. Once generic drugs enter the market, competition leads to lower prices for both the original brandname product and its generic equivalents. In most countries, patents give 20 years of protection. However, many countries and regions, such as the European Union and the United States, may grant up to five years of additional protection if manufacturers meet specific goals, such as conducting clinical trials for pediatric patients. Manufacturers, wholesalers and drugstores can all increase prices at various stages of production and distribution. In 2014, according to an analysis by the Generic Pharmaceutical Association, generic drugs accounted for 88% of the 4.3 billion prescriptions filled in the United States."Branded generics" on the other hand are defined by the FDA and NHS as "products that are either novel dosage forms of off-patent products produced by a manufacturer, not the originator of the molecule, or a molecule copy of an off-patent product with a trade name."
Since the company making branded generics can spend little on research and development, it is able to spend on marketing alone, thus earning higher profits and driving costs down. For example, the largest revenues of Ranbaxy, now owned by Sun Pharma, came from branded generics. Generic drug names are constructed using standardized affixes that distinguish drugs between and within classes and suggest their action; when a pharmaceutical company first markets a drug, it is under a patent that, until it expires, the company can use to exclude competitors by suing them for patent infringement. Pharmaceutical companies that develop new drugs only invest in drug candidates with strong patent protection as a strategy to recoup their costs to develop the drug and to make a profit; the average cost to a brand-name company of discovering and obtaining regulatory approval for a new drug, with a new chemical entity, was estimated to be as much as $800 million in 2003 and $2.6 billion in 2014. Drug companies that bring new products have several product line extension strategies they use to extend their exclusivity, some of which are seen as gaming the system and referred to by critics as "evergreening", but at some point there is no patent protection available.
For as long as a drug patent lasts, a brand-name company enjoys a period of market exclusivity, or monopoly, in which the company is able to set the price of the drug at a level that maximizes profit. This profit greatly exceeds the development and production costs of the drug, allowing the company to offset the cost of research and development of other drugs that are not profitable or do not pass clinical trials. Large pharmaceutical companies spend millions of dollars protecting their patents from generic competition. Apart from litigation, they may reformulate a drug or license a subsidiary to sell generics under the original patent. Generics sold under license from the patent holder are known as authorized generics. Generic drugs are sold for lower prices than their branded equivalents and at lower profit margins. One reason for this is that competition increases among producers when a drug is no longer protected by patents. Generic companies incur fewer costs in creating generic drugs—only the cost of manufacturing, without the costs of drug discovery and drug development—and are therefore able to maintain profitability at a lower price.
The prices are low enough for users in less-prosperous countries to afford them. For example, Thailand has imported millions of doses of a generic version of the blood-thinning drug Plavix from India, the leading manufacturer of generic drugs, at a cost of 3 US cents per dose. Generic drug companies may receive the benefit of the previous marketing efforts of the brand-name company, including advertising, presentations by drug representatives, distribution of free samples. Many drugs introduced by generic manufacturers have been on the market for a decade or more and may be well known to patients and providers, although under their branded name. India
European Chemicals Agency
The European Chemicals Agency is an agency of the European Union which manages the technical and administrative aspects of the implementation of the European Union regulation called Registration, Evaluation and Restriction of Chemicals. ECHA is the driving force among regulatory authorities in implementing the EU's chemicals legislation. ECHA helps companies to comply with the legislation, advances the safe use of chemicals, provides information on chemicals and addresses chemicals of concern, it is located in Finland. The agency headed by Executive Director Bjorn Hansen, started working on 1 June 2007; the REACH Regulation requires companies to provide information on the hazards and safe use of chemical substances that they manufacture or import. Companies register this information with ECHA and it is freely available on their website. So far, thousands of the most hazardous and the most used substances have been registered; the information is technical but gives detail on the impact of each chemical on people and the environment.
This gives European consumers the right to ask retailers whether the goods they buy contain dangerous substances. The Classification and Packaging Regulation introduces a globally harmonised system for classifying and labelling chemicals into the EU; this worldwide system makes it easier for workers and consumers to know the effects of chemicals and how to use products safely because the labels on products are now the same throughout the world. Companies need to notify ECHA of the labelling of their chemicals. So far, ECHA has received over 5 million notifications for more than 100 000 substances; the information is available on their website. Consumers can check chemicals in the products. Biocidal products include, for example, insect disinfectants used in hospitals; the Biocidal Products Regulation ensures that there is enough information about these products so that consumers can use them safely. ECHA is responsible for implementing the regulation; the law on Prior Informed Consent sets guidelines for the import of hazardous chemicals.
Through this mechanism, countries due to receive hazardous chemicals are informed in advance and have the possibility of rejecting their import. Substances that may have serious effects on human health and the environment are identified as Substances of Very High Concern 1; these are substances which cause cancer, mutation or are toxic to reproduction as well as substances which persist in the body or the environment and do not break down. Other substances considered. Companies manufacturing or importing articles containing these substances in a concentration above 0,1% weight of the article, have legal obligations, they are required to inform users about the presence of the substance and therefore how to use it safely. Consumers have the right to ask the retailer whether these substances are present in the products they buy. Once a substance has been identified in the EU as being of high concern, it will be added to a list; this list is available on ECHA's website and shows consumers and industry which chemicals are identified as SVHCs.
Substances placed on the Candidate List can move to another list. This means that, after a given date, companies will not be allowed to place the substance on the market or to use it, unless they have been given prior authorisation to do so by ECHA. One of the main aims of this listing process is to phase out SVHCs where possible. In its 2018 substance evaluation progress report, ECHA said chemical companies failed to provide “important safety information” in nearly three quarters of cases checked that year. "The numbers show a similar picture to previous years" the report said. The agency noted that member states need to develop risk management measures to control unsafe commercial use of chemicals in 71% of the substances checked. Executive Director Bjorn Hansen called non-compliance with REACH a "worry". Industry group CEFIC acknowledged the problem; the European Environmental Bureau called for faster enforcement to minimise chemical exposure. European Chemicals Bureau Official website
Route of administration
A route of administration in pharmacology and toxicology is the path by which a drug, poison, or other substance is taken into the body. Routes of administration are classified by the location at which the substance is applied. Common examples include intravenous administration. Routes can be classified based on where the target of action is. Action may be enteral, or parenteral. Route of administration and dosage form are aspects of drug delivery. Routes of administration are classified by application location; the route or course the active substance takes from application location to the location where it has its target effect is rather a matter of pharmacokinetics. Exceptions include the transdermal or transmucosal routes, which are still referred to as routes of administration; the location of the target effect of active substances are rather a matter of pharmacodynamics. An exception is topical administration, which means that both the application location and the effect thereof is local. Topical administration is sometimes defined as both a local application location and local pharmacodynamic effect, sometimes as a local application location regardless of location of the effects.
Administration through the gastrointestinal tract is sometimes termed enteral or enteric administration. Enteral/enteric administration includes oral and rectal administration, in the sense that these are taken up by the intestines. However, uptake of drugs administered orally may occur in the stomach, as such gastrointestinal may be a more fitting term for this route of administration. Furthermore, some application locations classified as enteral, such as sublingual and sublabial or buccal, are taken up in the proximal part of the gastrointestinal tract without reaching the intestines. Enteral administration can be used for systemic administration, as well as local, such as in a contrast enema, whereby contrast media is infused into the intestines for imaging. However, for the purposes of classification based on location of effects, the term enteral is reserved for substances with systemic effects. Many drugs as tablets, capsules, or drops are taken orally. Administration methods directly into the stomach include those by gastric feeding tube or gastrostomy.
Substances may be placed into the small intestines, as with a duodenal feeding tube and enteral nutrition. Enteric coated tablets are designed to dissolve in the intestine, not the stomach, because the drug present in the tablet causes irritation in the stomach; the rectal route is an effective route of administration for many medications those used at the end of life. The walls of the rectum absorb many medications and effectively. Medications delivered to the distal one-third of the rectum at least avoid the "first pass effect" through the liver, which allows for greater bio-availability of many medications than that of the oral route. Rectal mucosa is vascularized tissue that allows for rapid and effective absorption of medications. A suppository is a solid dosage form. In hospice care, a specialized rectal catheter, designed to provide comfortable and discreet administration of ongoing medications provides a practical way to deliver and retain liquid formulations in the distal rectum, giving health practitioners a way to leverage the established benefits of rectal administration.
The parenteral route is any route, not enteral. Parenteral administration can be performed by injection, that is, using a needle and a syringe, or by the insertion of an indwelling catheter. Locations of application of parenteral administration include: central nervous systemepidural, e.g. epidural anesthesia intracerebral direct injection into the brain. Used in experimental research of chemicals and as a treatment for malignancies of the brain; the intracerebral route can interrupt the blood brain barrier from holding up against subsequent routes. Intracerebroventricular administration into the ventricular system of the brain. One use is as a last line of opioid treatment for terminal cancer patients with intractable cancer pain. Epicutaneous, it can be used both for local effect as in allergy testing and typical local anesthesia, as well as systemic effects when the active substance diffuses through skin in a transdermal route. Sublingual and buccal medication administration is a way of giving someone medicine orally.
Sublingual administration is. The word "sublingual" means "under the tongue." Buccal administration involves placement of the drug between the cheek. These medications can come in the form of films, or sprays. Many drugs are designed for sublingual administration, including cardiovascular drugs, barbiturates, opioid analgesics with poor gastrointestinal bioavailability and vitamins and minerals. Extra-amniotic administration, between the endometrium and fetal membranes nasal administration (th
Breastfeeding known as nursing, is the feeding of babies and young children with milk from a woman's breast. Health professionals recommend that breastfeeding begin within the first hour of a baby's life and continue as and as much as the baby wants. During the first few weeks of life babies may nurse every two to three hours, the duration of a feeding is ten to fifteen minutes on each breast. Older children feed less often. Mothers may pump milk so that it can be used when breastfeeding is not possible. Breastfeeding has a number of benefits to both baby, which infant formula lacks. Deaths of an estimated 820,000 children under the age of five could be prevented globally every year with increased breastfeeding. Breastfeeding decreases the risk of respiratory tract infections and diarrhea, both in developing and developed countries. Other benefits include lower risks of asthma, food allergies, type 1 diabetes, leukemia. Breastfeeding may improve cognitive development and decrease the risk of obesity in adulthood.
Mothers may feel pressure to breastfeed, but in the developed world children grow up when bottle fed. Benefits for the mother include less blood loss following delivery, better uterus shrinkage, decreased postpartum depression. Breastfeeding delays the return of menstruation and fertility, a phenomenon known as lactational amenorrhea. Long term benefits for the mother include decreased risk of breast cancer, cardiovascular disease, rheumatoid arthritis. Breastfeeding is less expensive than infant formula. Health organizations, including the World Health Organization, recommend breastfeeding for six months; this means that no other foods or drinks other than vitamin D are given. After the introduction of foods at six months of age, recommendations include continued breastfeeding until one to two years of age or more. Globally about 38% of infants are only breastfed during their first six months of life. In the United States in 2015, 83% of women begin breastfeeding and 58% were still breastfeeding at 6 months, although only 25% exclusively.
Medical conditions that do not allow breastfeeding are rare. Mothers who take certain recreational drugs and medications should not breastfeed. Smoking, limited amounts of alcohol, or coffee are not reasons to avoid breastfeeding. Changes early in pregnancy prepare the breast for lactation. Before pregnancy the breast is composed of adipose tissue but under the influence of the hormones estrogen, progesterone and other hormones, the breasts prepare for production of milk for the baby. There is an increase in blood flow to the breasts. Pigmentation of the nipples and areola increases. Size increases as well, but breast size is not related to the amount of milk that the mother will be able to produce after the baby is born. By the second trimester of pregnancy colostrum, a thick yellowish fluid, begins to be produced in the alveoli and continues to be produced for the first few days after birth until the milk "comes in", around 30 to 40 hours after delivery. There is no evidence to support increased fluid intake for breastfeeding mothers to increase their milk production.
Oxytocin contracts the smooth muscle of the uterus during birth and following delivery, called the postpartum period, while breastfeeding. Oxytocin contracts the smooth muscle layer of band-like cells surrounding the alveoli to squeeze the newly produced milk into the duct system. Oxytocin is necessary for the milk ejection reflex, or let-down, in response to occur. Not all of breast milk's properties are understood, but its nutrient content is consistent. Breast milk is made from nutrients in the mother's bodily stores, it has an optimal balance of fat, sugar and protein, needed for a baby's growth and development. Breastfeeding triggers biochemical reactions which allows for the enzymes, growth factors and immunologic substances to defend against infectious diseases for the infant; the breast milk has long-chain polyunsaturated fatty acids which help with normal retinal and neural development. The composition of breast milk changes depending on how long the baby nurses at each session, as well as on the child's age.
The first type, produced during the first days after childbirth, is called colostrum. Colostrum is easy to digest, it has a laxative effect that helps the infant to pass early stools, aiding in the excretion of excess bilirubin, which helps to prevent jaundice. It helps to seal the infants gastrointestional tract from foreign substances, which may sensitize the baby to foods that the mother has eaten. Although the baby has received some antibodies through the placenta, colostrum contains a substance, new to the newborn, secretory immunoglobulin A. IgA works to attack germs in the mucous membranes of the throat and intestines, which are most to come under attack from germs. Breasts begin producing mature milk around the fourth day after birth. Early in a nursing session, the breasts produce foremilk, a thinner milk containing many proteins and vitamins. If the baby keeps nursing hindmilk is produced. Hindmilk has texture because it contains more fat. Breastfeeding can begin after birth; the baby is placed on the feeding starts as soon as the baby shows interest.
According to some authorities the majority of infants do not begin to suckle if placed between the mother's breasts but rather enter a period of rest and quiet alertness. During this time they seem to be more interested in the mother's face her eyes, than beginning to suckle, it has been speculated tha
Regulation of therapeutic goods
The regulation of therapeutic goods, drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency. In other jurisdictions they are regulated at the state level, or at both state and national levels by various bodies, as is the case in Australia; the role of therapeutic goods regulation is designed to protect the health and safety of the population. Regulation is aimed at ensuring the safety and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered. There is some degree of restriction of the availability of certain therapeutic goods depending on their risk to consumers. Modern drug regulation has historical roots in the response to the proliferation of universal antidotes which appeared in the wake of Mithridates' death. Mithridates had brought together physicians and shamans to concoct a potion that would make him immune to poisons.
Following his death, the Romans became keen on further developing the Mithridates potion's recipe. Mithridatium re-entered western society through multiple means; the first was through the Leechbook of the Bald, written somewhere between 900 and 950, which contained a formula for various remedies, including for a theriac. Additionally, theriac became a commercial good traded throughout Europe based on the works of Greek and Roman physicians; the resulting proliferation of various recipes needed to be curtailed in order to ensure that people were not passing off fake antidotes, which led to the development of government involvement and regulation. Additionally, the creation of these concoctions took on ritualistic form and were created in public and the process was observed and recorded, it was believed that if the concoction proved unsuccessful, it was due to the apothecaries’ process of making them and they could be held accountable because of the public nature of the creation. In the 9th century, many Muslim countries established an office of the hisba, which in addition to regulating compliance to Islamic principles and values took on the role of regulating other aspects of social and economic life, including the regulation of medicines.
Inspectors were appointed to employ oversight on those who were involved in the process of medicine creation and were given a lot of leigh weigh to ensure compliance and punishments were stringent. The first official'act', the'Apothecary Wares and Stuffs' Act was passed in 1540 by Henry VIII and set the foundation for others. Through this act, he encouraged physicians in his College of Physicians to appoint four people dedicated to inspecting what was being sold in apothecary shops. In conjunction with this first piece of legislation, there was an emergence of standard formulas for the creation of certain ‘drugs’ and ‘antidotes’ through Pharmacopoeias which first appeared in the form of a decree from Frederick II of Sicily in 1240 to use consistent and standard formulas; the first modern pharmacopoeias were the Florence Pharmacopoeia published in 1498, the Spanish Pharmacopoeia published in 1581 and the London Pharmacopoeia published in 1618. In the United States, regulation of drugs was a state right, as opposed to federal right.
But with the increase in fraudulent practices due to private incentives to maximize profits and poor enforcement of state laws, increased the need for stronger federal regulation. President Roosevelt signed the Federal Food and Drug Act in 1906 which established stricter standards. A 1911 Supreme Court decision, United States vs. Johnson, established that misleading statements were not covered under the FFDA; this directly led to Congress passing the Sherley Amendment which established a clearer definition of ‘misbranded’. Another key catalyst for advances in drug regulation were certain catastrophes that served as calls to the government to step in and impose regulations that would prevent repeats of those instances. One such instance occurred in 1937 when more than a hundred people died from using sulfanilamide elixir which had not gone through any safety testing; this directly led to the passing of the Federal, Food and Cosmetic Act in 1938. One other major catastrophe occurred in the late 1950s when Thalidomide, sold in Germany and sold around the world, led to 100,000 babies being born with various deformities.
The UK's Chief Medical Officer had established a group to look into safety of drugs on the market in 1959 prior to the crisis and was moving in the direction of address the problem of unregulated drugs entering the market. The crisis created a greater sense of emergency to establish safety and efficacy standards around the world; the UK started a temporary Committee on Safety of Drugs while they attempted to pass more comprehensive legislation. Though compliance and submission of drugs to the Committee on Safety of Drugs was not mandatory after, the pharmaceutical industry larger complied due to the thalidomide situation; the European Economic Commission passed a directive in 1965 in order to impose greater efficacy standards before marketing a drug. The United States congress passed the Drug Amendments Act of 1962 The Drug Amendments Act required the FDA to ensure that new drugs being introduced to the market had passed certain tests and standards. Both the EU and US acts introduced the requirements to ensure efficacy.
Of note, increased regulations and standards for testing led to greater innovation in pharm
Simplified molecular-input line-entry system
The simplified molecular-input line-entry system is a specification in the form of a line notation for describing the structure of chemical species using short ASCII strings. SMILES strings can be imported by most molecule editors for conversion back into two-dimensional drawings or three-dimensional models of the molecules; the original SMILES specification was initiated in the 1980s. It has since been extended. In 2007, an open standard called. Other linear notations include the Wiswesser line notation, ROSDAL, SYBYL Line Notation; the original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. Acknowledged for their parts in the early development were "Gilman Veith and Rose Russo and Albert Leo and Corwin Hansch for supporting the work, Arthur Weininger and Jeremy Scofield for assistance in programming the system." The Environmental Protection Agency funded the initial project to develop SMILES. It has since been modified and extended by others, most notably by Daylight Chemical Information Systems.
In 2007, an open standard called "OpenSMILES" was developed by the Blue Obelisk open-source chemistry community. Other'linear' notations include the Wiswesser Line Notation, ROSDAL and SLN. In July 2006, the IUPAC introduced the InChI as a standard for formula representation. SMILES is considered to have the advantage of being more human-readable than InChI; the term SMILES refers to a line notation for encoding molecular structures and specific instances should be called SMILES strings. However, the term SMILES is commonly used to refer to both a single SMILES string and a number of SMILES strings; the terms "canonical" and "isomeric" can lead to some confusion when applied to SMILES. The terms are not mutually exclusive. A number of valid SMILES strings can be written for a molecule. For example, CCO, OCC and CC all specify the structure of ethanol. Algorithms have been developed to generate the same SMILES string for a given molecule; this SMILES is unique for each structure, although dependent on the canonicalization algorithm used to generate it, is termed the canonical SMILES.
These algorithms first convert the SMILES to an internal representation of the molecular structure. Various algorithms for generating canonical SMILES have been developed and include those by Daylight Chemical Information Systems, OpenEye Scientific Software, MEDIT, Chemical Computing Group, MolSoft LLC, the Chemistry Development Kit. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database; the original paper that described the CANGEN algorithm claimed to generate unique SMILES strings for graphs representing molecules, but the algorithm fails for a number of simple cases and cannot be considered a correct method for representing a graph canonically. There is no systematic comparison across commercial software to test if such flaws exist in those packages. SMILES notation allows the specification of configuration at tetrahedral centers, double bond geometry; these are structural features that cannot be specified by connectivity alone and SMILES which encode this information are termed isomeric SMILES.
A notable feature of these rules is. The term isomeric SMILES is applied to SMILES in which isotopes are specified. In terms of a graph-based computational procedure, SMILES is a string obtained by printing the symbol nodes encountered in a depth-first tree traversal of a chemical graph; the chemical graph is first trimmed to remove hydrogen atoms and cycles are broken to turn it into a spanning tree. Where cycles have been broken, numeric suffix labels are included to indicate the connected nodes. Parentheses are used to indicate points of branching on the tree; the resultant SMILES form depends on the choices: of the bonds chosen to break cycles, of the starting atom used for the depth-first traversal, of the order in which branches are listed when encountered. Atoms are represented by the standard abbreviation of the chemical elements, in square brackets, such as for gold. Brackets may be omitted in the common case of atoms which: are in the "organic subset" of B, C, N, O, P, S, F, Cl, Br, or I, have no formal charge, have the number of hydrogens attached implied by the SMILES valence model, are the normal isotopes, are not chiral centers.
All other elements must be enclosed in brackets, have charges and hydrogens shown explicitly. For instance, the SMILES for water may be written as either O or. Hydrogen may be written as a separate atom; when brackets are used, the symbol H is added if the atom in brackets is bonded to one or more hydrogen, followed by the number of hydrogen atoms if greater than 1 by the sign + for a positive charge or by - for a negative charge. For example, for ammonium. If there is more than one charge, it is written as digit.