Fine Chemicals: Pharmaceuticals

James Richard Fromm


Pharmaceutical materials are all manufactured in very small quantity relative to most other compounds, but their dollar value is exceedingly high. Effective pharmaceuticals from plants have long been known, but pure organic pharmaceutical compounds were first introduced in the nineteenth century. With the exception of antibiotics, virtually all modern pharmaceuticals are complex organic compounds produced by specific chemical synthesis from available starting materials.

Painkillers: Analgesics and Anesthetics

Pain-relieving drugs, or analgesics, were first produced around 1820 when morphine, the active principle of opium, was purified from the original opium poppy material. Modern medical general analgesics such as codeine are usually synthesized. Acetylsalicylic acid, more commonly known by the trivial trade name aspirin, was first prepared in 1899.

Drugs which produce unconsciousness, the general anesthetics, were introduced around 1850; nitrous oxide, N2O, was one of the earliest, followed by diethyl ether (ether) and chloroform. Nitrous oxide was and is prepared by cautious heating of ammonium nitrate and subsequent compression into cylinders. Diethyl ether, CH3CH2-O-CH3CH2, can be prepared by rapid heating of ethanol with sulfuric acid:

2CH3CH2OH + 2H2SO4 rarrow.gif (63 bytes) (CH3CH2)2O + H2SO4 + H2O.

The diethyl ether distills out of the mixture since it has a very high vapor pressure. Chloroform, CHCl3, was first prepared by distillation of bleaching powder, Ca(OCl)2, mixed with water and ethanol. The chloroform produced was impure, and the process has since been supplanted.

Medications which are applied locally, to the skin or by injection, to block pain from a local area of the body without producing loss of consciousness are called local anesthetics. They are widely used in dentistry and minor surgery. Local anesthetics originated in 1884 with cocaine, extracted from the leaves of the coca plant. Synthetic materials began to replace it as early as 1897, since cocaine has both toxic and addictive properties.

Antiseptics

Materials which are intended to kill bacteria by direct application to the skin or to wounds, the antiseptics, were not used until 1867, when the physician Joseph Lister first clearly realized the role of microbes in causing infections. His use of phenol, then known as carbolic acid, created an immediate demand for it. Phenol was one of the first compounds extracted from coal-tar, and was purified for medical use by distillation. Modern antiseptics are varied. Household antiseptics include rubbing alcohol (isopropanol) and tincture of iodine. Tincture of iodine is a solution of iodine in ethanol, with potassium iodide added to increase the solubility of iodine through the formation of the triiodide ion I3-.

Other Pharmaceuticals

Of the approximately 250 microorganisms known to cause disease in man, immunization is possible against only a few of them. More correctly, medical or enhanced immunization is possibly only against a few of them; our natural immune reaction is an excellent defense against many microorganisms, which for that reason are not classified as causing disease. Active immunization, or inoculation with a weakened but real infection, is possible for about 8 diseases including smallpox and tetanus. The effect of this is to create an immunity identical to that which would be naturally created in someone who recovered from the disease. Passive immunization, or inoculation with serum from an animal which itself possesses immunity, is possible for about 5 diseases such as diptheria. Against the almost 250 remaining organisms, we have only our natural defenses and the chemical armory of medicines. Chemical treatments of diseases caused by viruses rather than bacteria is a major, and difficult, area of modern biochemical research.

In 1900, before the chemical technology to synthesize drugs systematically had been developed, many natural drugs were in general if empirical use but only three drugs used against specific diseases were known. Compounds of mercury were used against syphilis; they had been known in Europe since about 1500. Cinchona bark containing quinine was used against malaria; it had been known in Europe since about 1650. Ipecac plant was used against amoebic dysentery since about 1650 - but ipecac is a toxic cumulative poison and useful only in acute cases.

Around 1900, the first synthetic antibacterial drugs, the organic arsenicals, were developed by Paul Ehrlich. These are effective amebicides and are effective also against bacteria, but they are highly toxic. A typical structure is that of arsphenamine. These structures resemble those of organic azo dyes. An alternative amebicide is vioform.

The second class of synthetic antibacterial drugs to become available were the so-called sulfa drugs, or sulfonamides, discovered in 1935 and used throughout World War II to prevent wound infections. They are purposely designed to mimic para-aminobenzoic acid, a necessary metabolic constituent of bacteria.

The R group is variable among the sulfa drugs, being -COCH3 in sulfacetimide. Substitution of other groups on the benzene ring renders the drugs totally ineffective. Sulfa drugs are effective against many different kinds of bacteria and are much less toxic than are organic arsenicals.

The first class of true antibiotics were the penicillins, whose activity against bacteria was noticed by Fleming in 1929. They were in wide use by 1940. Synthesis was by culture of the mold Penicillium notatum, and still is; synthetic penicillin was not achieved until 1959. The general structure of the penicillins is as shown with different substituents in R position. One of the most active and commonly used forms, Penicillin G, has the benzyl group C6H5CH2- in the R position. All natural antibiotics are produced by growing the appropriate organism in a sterile medium and extracting the antibiotic from the resulting broth. Organic synthetic methods are now being used to modify the structures of natural antibiotics and to prepare antibiotic structures for which no natural source is known. While antibiotics show general antibacterial effects, their effectiveness against different forms of bacteria changes significantly with minor changes in their structure.


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Copyright 1997 James R. Fromm