Chiral chromatographic separation

Chiral chromatography is most commonly used in separating enantiomers of racemate compounds for drugs because of its high productivity at low cost. Chiral chromatography using simulated moving-bed system has been installed in most of the major pharmaceutical companies, some of which has processed up to 200 tons per year. Very pure compounds can be obtained by direct crystallization after chiral chromatography has been completed in ninety percent of the cases. In August 2003, an enantiomer of an antidepressant drug was approved by the Food & Drug Administration, making it the first drug produced by this technology to be approved.

As stated in previous posts, the amount of chiral drugs produced each year is increasing at a significant rate. This system is less expensive because of the less time it takes to develop, and the traditional methods cost about two to five times more than the simulated moving-bed system. If chiral chromatography is installed continuously at this rate, the pharmaceutical industry is expected to produce 1,200 metric tons per year of single isomer drugs.

Enantiomer uses in Sweeteners

It has already been stated in previous post that enantiomers affect drugs and pesticides, but it also affects commonly used sweeteners.

Compounds such as neohesperidin dihydrochalcone, which contains an isovanillyl sweet compound, is used as a commercial sweetener and is also found in an orange peel. Compounds with similar structures to neohesperidin dihydrochalcone that contain isovanillyl glucophore are found to have high relative sweetness values.

According to a study by Angela Bassoli, Lucio Merlini, and Gabriella Morini, “a strong increase in sweetness was obtained by the introduction of sulfur atoms in the ring and by separation of the enantiomers” (IUPAC). When one or two sulfur atoms were replaced with oxygen atoms, the sweetness increased greatly and formed 1,3-benzoxathiane 8 and 1,3-benzodithiane 9. In addition, using high-performance liquid chromatography (HPLC), a sweet compound, phyllodulcin, containing the isovanillyl glucophoric group, was found to have an enantiomer that is very sweet and another that is tasteless.

Ritalin: worth keeping it a racemic mixture?

People diagnosed with attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) often take Ritalin for its sedative effects. Ritalin’s main active ingredient is called methylphenidate, which exists as two enatiomers. The two enatiomers are known as the d-threo enantiomer and the l-threo enantiomer. Ritalin is a racemic mixture of those two enantiomers. As stated in the previous posts, racemic mixtures have a general problem: one of the enantiomer is responsible for most of the side effects and may well interfere with the correctly functioning enantiomer.

Yu-Shin Ding, Joanna S. Fowler and Nora Volkow are chemists at Brookhaven National Laboratory that studied the effects of the two enantiomers on the brain. Unlike previous studies of methylphenidate that studied the patients’ reactions to the drug, the three chemists visually established where and how the drug acts in the human brain.

“The study showed that the d-threo enantiomer bound precisely to the dopamine targets in the brain, while the binding of l-threo was mostly non-specific. What's more, Ding says, the l-threo enantiomer may have some unwanted influence on the active enantiomer or may contribute unwanted side-effects, although long-term human studies would be needed to confirm this.” (PSLgroup)

FDA’s recorded side effects of Ritalin include nervousness, insomnia, hypersensitivity, anorexia, dizziness, etc. (FDA) As Dr. Ding asks in her interview, should we use a racemic drug or a single enantiomeric drug?

Enantiomer uses in pesticides

Researchers at the University of California, Riverside, showed that single isomer pesticides may be more effective and beneficial to the environment. (UCR)

“…enantiomers are known to selectively interact with biological systems that are usually enantioselective and may behave as drastically different compounds.” (Liu, Gan, Schlenk, Jury)

From experimenting with five commonly used pesticides, the researchers found that one of the isomers can be over ten times more toxic than the other. By using single isomer pesticides, farmers will be able to achieve the same result with less use of pesticides. They also found that an isomer of permethrin stayed twice as longer in the environment than the other.

Currently, 25% of all pesticides are chiral compounds that consist of isomers, and the percentage of these pesticides is expected to rise.

Alcohol that doesn't come in 6-packs

Chiral chemistry, one of the major scientific fields in the area of pharmaceutical development, utilizes stereochemistry to create different drugs while reducing side effects. Besides enantiomers, many pharmaceutical companies use amino alcohols. By the Wikipedia definition, amino alcohols are Compounds possessing both a hydroxyl (-OH) and an amino group (-NH2). Examples of amino alcohols include ethanolamines, heptaminol, isoetharine, norepinephrine, propanolamines, and sphingosine. Some of these have pharmaceutical uses. Norepineprhine, for example, is an amino alcohol that acts as an antidepressant. Many medicines are created to release natural norepinephrine into the brain. In addition, it can be used to maintain attention. Along with dopamine, norepinephrine is used as a treatment for ADHD to help improve clarity and focus. In addition, it can be given intravenously to those who are desperately ill and acts as a vasopressor-which can constrict the blood vessels in case of extra bleeding.

A Fatal Failure in Chiral Science

Chemists were not always successful in creating chiral drugs. In the 1950s, a major failure affected at least 46 countries with a same problem. During that time period, painkillers for pregnant women were produced, which contained an active ingredient called thalidomide. The companies did not know the chiral property of the individual thalidomide molecules; consequently they inadvertently created a 50/50 mixture of the two enantiomers. As a result, many women who took the drug reported fetal abnormalities. Those companies later discovered the chiral property of thalidomide - one of the enantiomers was an effective sedative, whereas the other one was responsible for the fetal abnormalities. If the companies were aware of the fact that thalidomide molecules existed as enantiomers, then the tragic side effects could have been prevented.

In the USA, FDA has set up regulations to prevent further tragedy.
“Because of thalidomide’s potential for causing birth defects, FDA invoked unprecedented regulatory authority to tightly control the marketing of thalidomide in the United States. A System for Thalidomide Education and Prescribing Safety (S.T.E.P.S) oversight program has been initiated that includes limiting authorized prescribers and pharmacies, extensive patient education about the risks associated with thalidomide and a 100% patient registry. This oversight program is designed to help insure a zero tolerance policy for thalidomide exposure during pregnancy.” (FDA)

Generic names of drugs

Naming new single isomer drugs have started to cause problems for the authorities.

Use of prefixes to denote chirality of compounds opens the door to alphabetized lists of drugs with long, confusing sequences beginning with the prefixes dex-, lev-, ar-, and es-. (C&EN)

Chemical names that are given to drugs are only used by researchers, and since those names are often long and difficult to remember, drugs are also given generic names. Generic names must be approved by the U.S. Adopted Name (USAN) Council and then by the World Health Organization (WHO).

The generic names must be useful. The requirement is that “the name should be short, easy to pronounce, and euphonic” (Gundersen). The names also have stems, such as those mentioned above for chiral drugs. As more single isomer drugs are introduced to the market, more drugs will be named with similar prefixes.

Sterilizaton: The other Pasteur Method

By now, we've already discussed the works of Loius Pasteur, and have gone in depth into the world of enantiomers and their applications in areas such as pharmaceuticals. In addition to this, Pasteur also made another advancement in the field of medicine. Modern sterilization of surgical instruments has been relatively recent concept, compared to the long history of medicine. Many diseases and fatal infections were avoidable, but the bandages, surgical tools, and even doctors carried around bacteria that, afer enterng the body of the sick or injured patient, would spread through the blood stream and possibly kill them. While making a famous speech at the Academy of Medicine, Pasteur declared “This water, this sponge, this lint with which you wash or cover a wound, may deposit germs which have the power of multiplying with great rapidity within the tissue . . . .” He found that nothing around a patient with a wound or in surgery was naturally safe, and new modes of germ prevention needed to be employed.
Louis Pasteur found that there were certain ways to drastically reduce the germ population that entered the body of a patient. The first way was simple. He told the the doctors that before going nto srgery, they should wash their hands thoroughly with soap and water and not touc anything until getting into surgery. This eventually led to famous images of surgeon's with their hands out in front of them, telling people not to touch them because they're sterile. The second way was to heat the hands and the surgical tools. This killed many bacteria that were only able to stand certain temperatures. Of course, the human hand couldn't stand as muh heat as a scalpel, which is one reason for the added precauton of washing the hands. By heating and cleaning, Pasteur helped dramatically reduce the number of outbreaks and infections in susceptible patients, adding yet another tally to his score of achievements.

Developing enantiomeric intermediates

“All of this activity in chiral drugs leads fine chemicals producers to develop new enantiomeric intermediates for the industry and new enantioselective technology to produce intermediates and bulk active drugs to special order” (Stinson, C&EN).

An example of these chemical producers is BASF. This global company has been producing chiral products, especially amines made by enzyme-catalyzed resolution. In order to produce (R)-methoxyacetamide and (S)-amine, BASF treats racemic amine with ethyl methoxyacetate and a lipase. When this reaction produces the desired products, the two enantiomers are separated by distillation.

In addition to those two enantiomers, the company produces enantiomeric alcohols, made by the process of lipase-catalyzed acylation (the same process described above). In this case, in order to produces the enantiomeric alcohols, a racemic -phenethyl alcohol with vinyl propionateis mediated by a lipase from Burkholderia plantarii. This process produces (S)-alcohol and (R)-propionate. These enantiomers are then separated by distillation.

Currently, BASF is producing chiral amines, alcohols, epoxides, acids and other chiral products as chiral intermediates (BASF-Chipros).

Combinations

“In addition to extending patent protection on a racemic drug by later patenting its single active enantiomer, drug companies can "enhance its status”…by combining an old drug with a newer, patented one that treats the same disease condition but by a different mechanism.” (Stinson, C&EN)

An example of this combination is Merck’s cholesterol lowering serum. For this particular drug, Merck combined its simvastatin and Schering’s ezetimibe, which are both single enantiomers that lower cholesterol; however, simvastatin lowers cholesterol by “mediating a step in the biosynthesis of cholesterol” (Stinson, C&EN) whereas ezetimibe reduces the absorption of dietary cholesterol. By combining those two single-enatiomers, Merck created a drug that is more effective because the new drug affects two different ways that cholesterol can build up in the body.

Another example is a combination of Merck’s montelukast with Schering loratidine for asthma. Loratidine is a nonesedating antihistamine, whereas montelukast is a selective leukotriene D4 receptor antagonist. Both of these drugs are used control inflammation (swelling of the airways in the lungs).

Racemic switches

"...drug companies continue to develop chiral drugs as single enantiomers, to use chirality as a tool for drug life-cycle management, and to redevelop racemic mixtures as single enantiomers, which is called a racemic switch.” (Stinson, C&EN)

However, this racemic switch is affecting the market of drugs.

In one case, an enantiomer drug, Baycol, used for lowering cholesterol, caused potentially fatal muscle-wasting side effect in some of the patients. Bayer stopped the sale of this drug, but the European Union has decided to reexamine all of the drugs in this class. If all of these drugs, which account for $15 billion, were taken off the market, severe impact will result for the sales of chiral drugs.

Although many firms are creating single-isomer versions of their drugs to extend the patents, some drugs’ patents have expired. Generic versions of those drugs are then sold to the market, some over the counter at very low prices.

Why the chiral drug industry is growing so fast.

“The chiral drug industry soared through a major milestone last year (as of 2002), as annual sales in this rapidly growing segment of the drug market topped $100 billion for the first time. These compounds now represent close to one-third of all drug sales worldwide.” (Stinson, C&EN)

The two factors responsible for this rapid growth of chiral industry are the fundamentals of biochemistry and the Food & Drug Administration’s policies. The biological messengers and cell surface receptors of the human body, the major targets of medicinal chemists, are chiral. Consequently, the drug molecules must match the biological molecules’ asymmetry.

The FDA’s policies concerning the chiral drugs demand companies to make appropriate choices about making their drugs as single-isomeric or racemate (both enantiomers mixed) forms. Since the FDA requires both isomers of a racemate mixture to be studied in detail, the logistics of testing for single-isomeric forms is simpler than those of racemate forms. (FDA)

Furthermore, the companies may develop chiral drugs in order to extend their blockbuster drugs’ patent lives. (“A Blockbuster drugs is a drug with more than $1 billion per year in sales” Stinson, C&EN).

Diastereomers have feelings (and uses) too!

Though the many uses of enantiomers have been mentioned before, it's counterpart, the diastereomer, also has pharmaceutical properties. One of the most widely used forms is pseudoephedrine, an chemical that acts as a deocongestant. Up until 2004, the over the counter drug, Sudafed, was made with pseudophedrine, though now they have made a switch to the chemical phenylephrine as thier active ingredient.

"The new product was prompted by existing and proposed restrictions on the availability of pseudoephedrine-based products. State laws imposing such restrictions were in response to pseudoephedrine's role as an ingredient used to produce the illegal and highly addictive drug methamphetamine (meth)." (Answers.com)

Phenylephrine is not a diastereomer and it does not create methamphetamine in its byproducts. Because of this, Sudafed has created Sudafed PE and is now a strong component against the pseudophedrine used in over the counter decongestants, now that it is apparent that phenylephrine is just as effective as its predecessor. Still, many OTC drugs, such as Nurofen and DayQuil still use psuedophedrine as its main component, making it a still popular diastereomer.

Other accomplishments of Louis Pasteur

In addition to discovering enantiomers, Louis Pasteur also contributed to science through other accomplishments.

“Mosaic tiles on the tomb commemorate various aspects of Pasteur’s research. Visitors are likely to recognize that a flock of sheep represents his work on the anthrax vaccine and that a dog symbolizes his conquest of rabies.” (Schwarcz 227-228).

As quoted above, Pasteur proved that giving mild forms of anthrax can work as a vaccine by experimenting with sheep. He also created the vaccine for rabies by experimenting with rabbits.

Pasteur showed that yeast is the cause of alcohol produced from fermentation and that organisms such as bacteria produced lactic acid or acetic acid that made the wine sour. In addition, he discovered that these bacteria can be removed by heating it at a high temperature. He applied this to milk and concluded that souring milk can be avoided by heating the milk at high temperatures, a process which is now called pasteurization.

He also studied about where the microorganisms came from and about an epidemic illness of silkworms.

Isometrics-in Stereo

Enantiomers, as we all know by now, are formed by mirror image isomers. However, enantiomers are the exception to a classification of isomers called diastereoisomers. These isomers contain the same chemical formula and bond structure, but the individual atoms are in different positions for each isomer. This excludes, of course, two isomers that are reflections of each other.

Enantiomers and diastereoisomers are the two classifications of Stereoisomers, which are simply isomers that have the same structure but the atoms are placed in different positions. Stereoisomers are only possible when there is a double or triple bond available, because the molecule cannot twist on sigma bonds only.

Stereoisomers come in handy in the field of chiral chemistry, which is important in research regarding pesticides and prescription medications. This is because certain molecules are only effective in creating required results, like keeping plants alive while killing bugs, or reducing side effects in medicine. However, the chemical formula of a molecule may be correct, but they may not achieve the desired effects if they are in a certain arrangement. In this way, stereoisomers are the perfect way to experiment with similar molecules to help with patent situations, as was the case with the Prozac patent in "Molecules and Mirrors."