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Pharmaceuticals Resins

Learning objectives

To learn about the resins used in pharmaceuticals, their chemistry, properties, uses as active ingredients and excipients as well as other relevant applications.

Resins are solid or semisolid amorphous hydrocarbon secretion of many plants, particularly coniferous trees, valued for its chemical constituents and uses, such as varnishes, adhesives, as an important source of raw materials for organic synthesis, or for incense and perfume. Chemically they are complex mixtures of resin acids, resin alcohols, resin phenols (resinotannols), resin esters and inert compounds. Resins could be natural or synthetic, typically in a viscous liquid form, which solidify into a hard, durable substance when cured by heat, light, or a chemical hardener. Physically they are usually hard, translucent or transparent and on heating, they soften and finally melt.

Resins are complex mixtures of resin acids, resin alcohols, resin phenols (resinotannols), resin esters and chemically inert compounds.

Properties of resins:

Physical state: Purified resins are amorphous, brittle, translucent or transparent hard solids.

Source: The resins commonly used in pharmacy practice are derived from living natural sources, and most are plant products. Shellac is an important exception which is an insect secretion.

Composition: Resins are mainly composed of carbon, hydrogen, and oxygen, and are supposed to be formed by the oxidation of the essential oils.

Color: Resins are usually colorless or may yellowish brown solid.

Solubility: All resins are practically insoluble in water and usually insoluble in the petroleum sprit. They dissolve more or less completely in organic solvents, e.g. alcohol, oil of turpentine, chloroform, ether and essential oils; those containing resin acids are usually proportionately soluble in alkalis. A solution of a resin in a volatile solvent, when painted on a smooth surface should rapidly and completely dry to form a hard transparent film; to be suitable for varnish the film should not darken with age or become impaired upon exposure to light or moisture.

Electric conductivity: Resins are usually are nonconductors of electricity.

Flammability: They are inflammable substances. They produce smoky flame on burning.

Odor: Many resinous compounds have distinct and characteristic odors.

Purified resins are amorphous, brittle, translucent or transparent hard solids, They are inflammable substances, produce smoky flame on burning. Many have distinct odors.

Chemistry of resins:

Resins are not single chemical compounds, but are usually mixtures of substances of different and complex chemical characters.The resin produced by most plants is a viscous liquid, typically composed mainly of volatile fluid terpenes, with lesser components of dissolved non-volatile solids which make resin thick and sticky. The most common terpenes in resin are the bicyclic terpenes alpha-pinene, beta-pinene, delta-3 carene and sabinene, the monocyclic terpenes limonene and terpinolene, and smaller amounts of the tricyclic sesquiterpenes longifolene, caryophyllene and delta-cadinene. Some resins also contain a high proportion of resin acids. The individual components of resin can be separated by fractional distillation.

The following are the more important groups of compound present in resins:

Oleo-resins: Some resins occur with volatile oils and their mixture is soft and so, known as oleo-resins.

Resin Esters: These resins consist mostly of resin alcohols combined with aromatic acids. When containing large proportion of benzoic acid or cinnamic acid either free or in combination of their esters of these acids they are called balsams (When mixed with essential oils, they form balsams, or oleoresins). Other aromatic acids are less frequently found, e.g. ferulic acid (in asafetida). There are two principal kinds of resin alcohols in combination with these acids.

(a) Resinols - These are colorless, and give a negative reaction when tested with iron salts. The resin in benzoin consists principally of the resinol, benzoresinol, combined with cinnamic and benzoic acids.

(b) Resinotannols - These are phenolic compounds, and give blue, green or violet-coloured compounds with ferric chloride. They are usually named from their source, e.g. the resinotannol in balsam of Tolu is called toluresinotannol, and it occurs combined with benzoic and cinnamic acids; that from Sumatra benzoin is called sumaresinotannol, and it is similarly combined. Like other esters, the resin esters are saponified when boiled with alcoholic solution of potassium hydroxide, and the previously combined acid obtained as a water-soluble potassium salt. From the latter the aromatic acid (practically insoluble in water) may be obtained by distillation of the reaction mixture (to remove the alcohol), extraction of the residue with water, and acidification of the solution with a mineral acid, whereupon the aromatic acid is precipitated.

Gum resins: Some resinous products in their natural condition are a mix with gum or mucilaginous substances and known as gum resins, like asafetida and gamboge. The gum resins are purified by dissolving the associated gum in water. Oleo- gum resins are associated with gum and volatile oil both. The volatile oil is removed by steam distillation while gum is separated by dissolving in water. Myrrh, Ipomoea are the examples of oleo-gum resin.

Resenes: The chemical nature of these compounds is unknown. They are very stable and so inert, they remain unaffected by most chemical reagents or by exposure to moisture and light-hence resins consisting principally of resenes yield good varnishes provided the film is hard and therefore resistant to mechanical injury. The resenes are usually named from their source, e.g. that of Sandarac is called Sandaracoresene. The resene containing resins are, of course, those chiefly used in the manufacture of varnishes. Sandarac is used in pharmacy for making pill varnish.

Glyco-resins: Glyco-resins are complex group consisting of the glycosidal resins, which undergo hydrolysis when boiled with mineral acids and produces a sugar (glycone, usually dextrose) and a complex resin acid and simpler acids. Jalap resin and Ipomoea resins are examples of glyco-resins.

Glyco-resins---Hydrolysis----> Glycone (sugar)+ Aglycone (complex resin acid and simpler acids)

Many compound resins have distinct and characteristic odors, from their admixture with essential oils. Certain resins are obtained in a fossilized condition, amber being the most notable instance of this class.

Chemical examinations of resins:

The acid value, saponification value, and iodine value may be determined on lines similar to those for fixed oils and fats.

Acid value: The number of milligrams of potassium hydroxide (KOH) required to neutralize the free acid in 1 gm of substance is expressed by acid value. Low “acid values” or complete absence of acid are important for good pharmaceutical excipients.

Iodine value: This value expresses the number of grams of Iodine that reacts with 100 grams of fat or other unsaturated material. The possibility of decomposition by moisture, acids and oxygen (which leads to ransidify in fat) increases with high iodine value.

Saponification value: The number of milligrams of potassium hydroxide (KOH) required to neutralize the free acid and saponify the esters contained in 1 gm of fat is an indication of the type of (mono, di or tri) glycerides as well as the amount of glyceride present.

The saponification and iodine values are rarely criteria because they differ widely in samples of genuine drug. The acid value is, however, of some importance, particularly in examining resins for varnish making, because these often consist of a mixture of resin acids and resenes in fairly constant proportion. In such cases determination of the acid value serves to detect adulteration with cheaper resins containing more free acid (e.g. colophony) or less.

In many instances, the Pharmacopeia prescribes solubility tests to guard against adulteration or to limit the proportion of impurities. For example, not more than 24.0 per cent of benzoin should be insoluble in 90 per cent alcohol, indicating absence of an undue amount of wood debris, etc.

Uses of resins in Pharmaceuticals:

Vegetative Resins: i. The softer odoriferous oleo-resins (frankincense, elemi, turpentine, copaiba) and gum resins containing essential oils (ammoniacum, asafoetida, gamboge, myrrh, and scammony) are more largely used for therapeutic purposes and incense.

ii. Balsam of Tolu is used as expectorant, stimulant and antiseptic. It is an ingredient of cough mixtures and compound-Benzoin tincture. It is also used as a pleasant flavoring agent in medicinal syrups and medicated chewing gums.

Animal Resins: Sandarac is used in pharmacutials for making pill varnish.

Synthetic Resins: i. Synthetic resins are materials with similar properties to natural resins—viscous liquids capable of hardening. They are typically manufactured by esterification or soaping of organic compounds. The classic variety is epoxy resin, manufactured through polymerization-polyaddition or polycondensation reactions, used as a thermoset polymer for adhesives and composites. In pharmaceuticals, epoxy resins are used as protective coatings or paints to cover manufacturing area. Epoxy resin beds are use also in pharmaceutical dosage forms as polymer excipient.

ii. Ion exchange resin is another important class with application in water purification and catalysis of organic reactions.

Ion exchange resins used in drug formulations:

Ion exchange resins as active ingredients: They are used for isolating and purifying pharmaceutical active ingredients. Besides, three ion-exchange resins-

a. sodium polystyrene sulfonate (an insoluble polymer cation-exchange resin used in the management and treatment of hyperkalemia)

b. colestipol ( a large basic anion-exchange resin copolymer used as cholesterol-lowering drug that reduces the risk of coronary artery disease).

c. cholestyramine

-are used as active ingredients.

Sodium polystyrene sulfonate is a strongly acidic ion-exchange resin and is used to treat hyperkalemia (raised level of K). Colestipol is a weakly basic ion-exchange resin and is used to treat hypercholesterolemia. Cholestyramine is a strongly basic ion-exchange resin and is also used to treat hypercholesterolemia. Colestipol and cholestyramine are known as bile acid sequestrants.

Ion exchange resins as active excipients: Ion-exchange resins are also used as excipients in pharmaceutical formulations such as tablets, capsules, and suspensions. In these uses the ion-exchange resin can have several different functions, including taste-masking, extended release, tablet disintegration, and improving the chemical stability of the active ingredients.

Epoxy resins:

Epoxy Resin is a type of synthetic resin manufactured through polymerization-polyaddition or polycondensation reactions. They are made by reacting an epoxide compound (usually epichlorohydrin) with a hydroxyl containing substance such as bis-phenol-A or a polyhydric alcohol (glycerol). Such resins are thermosetting polymer (softens on heating and becomes hard on cooling) and have high strength and low shrinkage. Epoxy coating have high resistance to attack by chemical corrosion and weathering and to electricity.

So, they are used in pharmaceuticals as protective coatings or paints to cover manufacturing area.

Epoxy resin beds are use also in pharmaceutical dosage forms.

Many Pharmaceutical production and packaging floors are covered by resin surfaces epoxy resin systems to minimize the dust accumulation.

Ion exchange resins as water softener:

Ion exchange resin is another important class with application in water purification. Ion exchange is a reversible chemical process whereby a hard water solution is passed through a column of a material that replaces one kind of ion in solution with another kind of ion. Calcium and magnesium are the hardness ions, sodium can be considered the "softness" ion and they are exchanged to create soft water. Ion exchange takes place in a "resin bed" made up of tiny bead-like material often made of styrene and divenyl-benzene. The beads, having a negative charge, attract and hold positively charged ions such as sodium, but will exchange them whenever the beads encounter another positively charged ion, such as calcium or magnesium minerals. This ion exchange happens very easily since the sodium ions have a positive charge of only one, while magnesium and calcium have a more powerful positive charge of two.

Home and industrial water softeners contain cation exchange resins, which are insoluble macromolecule substances to which negatively charged groups are chemically bonded. The negative charges are counterbalanced by ions such as Na+. When hard water containing the Ca2+ ion passes through a column of this type of resin, the Na+ ion in the resin is replaced by Ca2+ ion.

2NaR (S) + Ca2+ (aq) ¾¾® CaR2 (S) + 2 Na+ Here, R-=Anion exchange resin

The water passing through the column now contains Na+ in place of Ca++and has been softened. Once the resin has been completely converted to the calcium salt, it can be regenerated by flushing the column with a concentrated solution of NaCl to reverse the previous reaction.

CaR2 (S) + 2 NaCl (aq) ¾¾® 2NaR (S) + Ca2+ (aq)

Ion exchange resins in sustained release drug preparation:

Ion Exchange resins can be complexed with drugs by passage of a cationic drug solution through a column that contain resin. The drug is complexed to the resin by replacement of hydrogen atoms.

Examples include Ionamin capsules (Celltech, cationic resin complexes of Phentermine: an appetite suppressant which reduces weight in obese patients) and the Pennkinetic system (Celltech) which incorporates a polymer barrier coating and bead technology in addition to the ion exchange mechanism. After the compounds are complexed, the resin drug complex is washed and tablated, encapsulated, or suspended in aqueous vehicles.

Release of drug from the complex depends on the ionic environment within the gastrointestinal tract and on the properties of resin. Usually release is greater in the highly acidic stomach than in the less acidic small intestine.