Chapter 9. Analysis of drugs from the terpen group

Terpenes are hydrocarbons of the composition (С₅Н₈) n, where n >2. They are found in nature, especially in the resin of conifers, as well as in many essential oils of plants. Along with terpenes, these resins and essential oils contain their oxygen derivatives (alcohols, aldehydes, ketones, etc.), as well as a large number of related compounds, various functional groups.

Their composition, like that of terpenes, is a multiple of C₅H₈. Therefore, the name “terpenes” used to denote hydrocarbon lost its purpose and was replaced by a more general term “terpenoid”.

The structure of terpenoids is based on the isoprene hydrocarbon:

Depending on the amount of isoprene residues in the molecule, terpenoids are classified into the following groups: monoterpenes C₁₀H₁₆, sesquiterpenes C₁₅H₂₄ (one and a half times), diterpenes C₂₀H₃₂, triterpenes C₃₀H₄₈, tetraterpenes C₄₀H₆₄, polyterpenes (C₅H₈) n, where n >8.

The first works on the chemistry of terpenes date back to the late 18th and early 19th centuries. So, in 1803, the pharmacist Kind using hydrogen chloride on turpentine obtained bornyl chloride, which smells like camphor, for which it was called “artificial camphor”. In 1815-1818, French scientist Bio established the ability of turpentine and camphor to deflect a polarized beam, which was the basis for the characteristics of terpenes and one of the methods for their identification.

One of the first in Russia to begin research on domestic essential oils and plant resins D. I. Mendeleev. Studying the turpentine oil of the domestic resin, Mendeleev proved that our “primordially Russian goods ― turpentine and rosin ― are in no way worse than imported foreign ones”.

Medicinal substances from the group of terpenoids currently used in medical practice are classified according to the number of cycles into monocyclic (levomenthol, validol, terpin hydrate), bicyclic (camphor, bromocamphora, sulfocamphoric acid, procaine + sulfocamphoric acid (sulfoprocaine, sulfocamphoric acid) retinol (retinol acetate, vitamin A).

In medicine, terpenoids are used as antiseptic, local irritants, weak pain relievers (levomenthol). Validol has a sedative effect, has a moderate reflex vasodilating effect due to irritation of sensitive nerve endings. Some of them are capable of irritating the mucous membranes and are used as expectorants (terpin hydrate), some have an exciting effect on the heart and central nervous system (camphor, procaine + sulfocamphoric acid (sulfoprocaine, sulfocamphocaine).

In practical terms, terpenoids are of great importance not only in medicine. So, terpenoids of a number of essential oils, due to their pleasant smell, serve as a source for the synthesis of aromatic substances in the perfumery industry.

Physical and physicochemical properties

As a rule, all terpenes are easily volatile compounds with a characteristic odor (they act on the respiratory center). This property is possessed by levomenthol, validol, camphor, and to a lesser extent retinol. Terpin hydrate is odorless. Levomenthol is volatile, has a melting point of 41-44 °C, camphor has a melting point of 174-180 °C, but it readily sublimes at room temperature. Therefore, levomenthol and camphor are stored in a separate cabinet in tightly closed jars (“odorous” substances).

Retinol acetate has a melting point of 51-57 °C, it is very easily oxidized in air, therefore it is stored in ampoules sealed in a nitrogen flow, in a refrigerator.

Levomenthol and camphor form eutectic mixtures with each other and with various phenols, which is used in dentistry.

All medicinal substances of this group are similar in solubility: they are insoluble in water, but soluble in organic solvents and fatty oils. This determines the choice of appropriate dosage forms: menthol is used in the form of alcoholic and oil solutions, ointments and aerosols; camphor and retinol acetate ― in the form of oil solutions. A water-soluble derivative of camphor ― procaine + sulfocamphoric acid (sulfoprocaine, sulfocamphocaine) is used in the form of a 10% aqueous solution for injection, which excludes complications in the form of oleomas, which are possible with injections of oil solutions of camphor.

Many terpenes have chiral centers in their structure, are optically active compounds, or have cis-, trans-isomerism. This property is used as a characteristic of the authenticity, good quality and assay of compounds (determination of the concentration in solution by the polarimetric method). Not all drug isomers have pharmacological activity. In menthol, only l-menthol is active, but racemate is also used; in terpin hydrate, only the cis isomer in the form of a hydrated form is used in medical practice, the trans isomer does not form a hydrated form and does not possess pharmacological activity. In camphor, both right- and levorotatory isomers are used, and the use of a racemate is allowed for external purposes.

A characteristic property of terpenes is their easy isomerization under the influence of light, moisture, temperature, pH of the medium, catalysts, which causes their diverse interconversions. This property is used when receiving drugs of this group, but it can also take place during storage.

Some terpenoids absorb in the UV region of the spectrum: camphor and its derivatives due to the presence of a keto group in the structure of the molecule, retinol due to the presence of conjugated double bonds.

Derivatives of monocyclic terpenes

Table 9.1. Chemical structures, appearances and solubility of monocyclic terpene derivatives

Chemical structure	Appearance
	Levomentholum. Levomenthol. Menthol. (1R, 2S, 5R)-5-Methyl-2-(propane-2-yl)-cyclohexanol. Colorless crystals or crystalline powder with a strong peppermint odor. Very slightly soluble in water. Freely soluble in alcohol 96%, ether, acetic acid, soluble in liquid paraffin and fatty oils. Volatile at room temperature
	A solution of levomenthol in menthylisovalerate. Validol. Validol. 5-Methyl-2-(propane-2-yl) cyclohexanol (levomenthol) [5-Methyl-2-(propan-2-yl) cyclohexyl] (3-methylbutanoate) (menthylisovalerate). Contains not less than 21.0% and not more than 31.0% levomenthol and not less than 68.5% and not more than 75.0% menthyl isovalerate. Transparent colorless or slightly colored oily liquid with a menthol odor. Soluble with alcohol 96% and chloroform, not miscible with water
	Terpinumhydratum. Terpinhydrate. p-menthanediol-1.8. Colorless transparent crystals or odorless white crystalline powder. Slightly soluble in water, soluble in alcohol