Pharmaceutical Solutions II: Nonaqueous Solutions

Although from their physical properties many solvents appear to be desirable for use in pharmaceutical products, the physiological actions of the solvents greatly limit their use. With few exceptions, most organic solvents are irritating or toxic.

Aromatic hydrocarbons cause paralysis of the central nervous system and are irritating to the skin; methyl alcohol is toxic, and butyl and amyl alcohol are irritating; volatile ethers paralyze the central nervous system, and are irritating to mucous membrane increases; ketones are mildly irritating; and the low molecular weight esters are irritating. Thus, toxicity and irritation limit the solvents employed to a few compounds such as glycerin, alcohol, and propylene glycol for internal use. For external use saturated aliphatic hydrocarbons, ether, and glyceryl esters of aliphatic acids may be added to the list of acceptable pharmaceutical solvents.

Propylene glycol has been employed as a solvent for oral and parenteral solutions of drugs such as antihistamines, barbiturates and vitamins. Although orally administered propylene glycol has a low toxicity in animals, it may exhibit a weak central nervous system depressant activity and an antagonistic action against pentylenetetrazol. Thus, the use of propylene glycol as a physiologically inert solvent is not recommended. Infants with rickets have become stuporous for hours after treatment with 600,000 units of vitamin D administered in 60 ml of propylene glycol as single or divided doses in a 24-hour period.

Nonaqueous solutions are those solutions which contain solvents other than water, either alone or in addition to water. Alcohol or a binary mixture containing alcohol is the most commonly used nonaqueous solvent. In addition to the pharmaceutical classes of elixirs, spirits, tinctures, and fluid-extracts, individual products such as Chloroform Liniment and Coal Tar Solution are alcoholic solutions.

Elixirs are defined by the USP as “clear, sweetened, hydroalcoholic liquids intended for oral use.” Their alcohol content ranges from 5-40% (10-80 proof), e.g. Phenobarbital Elixir, USP. Elixirs are flavored hydroalcoholic solutions to which glycerin often is added to enhance the solvent properties and act as a preservative. The alcoholic contents of elixirs varies widely; actually a few commercial elixirs contain no alcohol, while other elixirs may contain as much as 40% alcohol. The concentration of alcohol is determined by the amount required to maintain the drug or volatile oil in solution. The addition of aqueous solutions to elixirs may cause turbidity or separation by lessening the alcohol concentration.

Spirits or essences are alcoholic or hydroalcoholic solutions of volatile substances (usually volatile oils) with alcohol contents ranging from 62-85% (124-170 proof). They are most frequently used as flavoring agents, e.g. Peppermint Spirit USP. Some spirits are used for their medicinal effect, but most spirits are a convenient means of obtaining a proper amount of a flavoring oil. All essences have a high alcohol content, and the addition of water invariably causes turbidity and separation.

Whisky and Brandy are prepared by distillation. Compound Orange Spirit, Camphor Spirit, and Compound Cardamon Spirit are prepared by simple solution.

Tinctures are alcoholic or hydroalcoholic solutions prepared from vegetable or chemical substances. The concentration of solute varies up to 50%, e.g. Vanilla Tincture USP, Iodine Tincture USP. Tinctures are alcoholic solutions of nonvolatile substances which are generally extracted by maceration or percolation. Tinctures of potent drugs represent the activity of 10 g of the drug in each 100 ml of the tincture; they are 10% tinctures. With a few exceptions, nonpotent tinctures represent 20 g of the drug per 100 ml of tincture.

Tinctures are prepared chiefly by percolation and maceration. Percolation is the procedure of choice when the crude drugs are cellular in structure; plant exudates tend to become impacted in the percolator and stop the flow so that maceration is preferred in such preparations. Moderately coarse powders are preferred, because coarse powders are slowly penetrated by the menstruum and fine powders tend to clog the percolator.

Usually alcohol or a hydroalcoholic menstruum is employed. The choice of menstruum depends on the solubility, stability, and ease of removal of the desired constituent. Other inactive constituents are extracted, but if the material is not objectionable, it is allowed to remain.

In the process of percolation, the drug is dampened with the menstruum and allowed to stand for a short period before packing the percolator so that the drug may expand as the menstruum is absorbed. If the drug is packed into the percolator and moistened, the swelling would pack the drug so firmly that the percolate could not flow.

The menstruum is then added to cover the drug and the lower opening is closed when the liquid is about to drip from the percolator. This permits the air between the particles to escape as the menstruum descends. Maceration for a prescribed time permits saturation of the menstruum in contact with the drug, assuring a more nearly complete extraction.

The menstruum is then allowed to flow or percolate at a definite rate. Normally the percolate collected is assayed before final volume is reached, and then it is adjusted to the proper strength.

In the process of maceration the drug is soaked with the menstruum in a closed container. The closed container prevents the loss of volatile constituents and evaporation of the menstruum. The mixture is agitated frequently so the menstruum at the bottom of the container does not become saturated and incapable of extracting further drug. Circulatory maceration is an efficient modification which eliminates the need for agitation. When heat is employed in maceration, the process is known as digestion. The mixture is then transferred to a filter, and the residue is washed with sufficient menstruum to bring the tincture to final volume.

Examination of unofficial liquid pharmaceutical speciality products and similar official products indicates that a minimum of 15% alcohol is required to preserve the product from microbial growth if no other preservative agents are present. Industrial pharmacists usually regard 15% alcohol as adequate for the preservation of products with a pH of 5, while 18% has been considered adequate for neutral or slightly alkaline preparations. It is obvious that products such as tinctures, spirits, and fluid extracts possess alcohol in concentrations that far exceed these values and need no further preservative.

Water Miscible Cosolvent Systems are solutions of water and water miscible solvents such as alcohol, glycerin, propylene glycol, polyethylene glycol 400. These solvent mixtures are used to improve the solubility of poorly soluble organic substances, and may be formulated for oral, topical, or parenteral administration. e.g. Phenytoin Inj.

Glycerins or Glycerites are solutions in composed of no less than 50% glycerin by weight. They are extremely viscous and are rarely used in practice and are generally limited to use in topical products, e.g. Glycerin Otic Solution.

Collodions are liquid preparations containing nitrocellulose pyroxylin in a mixture of ethanol and ethyl ether. They are used as topical protectives or as a topical drug vehicle. They are made “flexible” by the addition of castor oil, e.g. Flexible Collodion USP, Salicylic Acid Collodion USP.

Liniments are solutions of various substances in oil, alcoholic solutions of soap or emulsions which are intended for external application, e.g. Ben Gay.

Oleaginous Solutions are solutions of fat soluble vitamins (Vitamin A, O, and E), or other fat soluble substances in vegetable oils (corn, cottonseed, olive, peanut, and sesame seed oils) or mineral oil. Oleaginous solutions may be formulated for oral, topical or parenteral administration.

The nonpolar solvents used in pharmacy are essentially hydrocarbons or glyceryl esters. Peanut, sesame, corn, cottonseed, and mineral oil are most frequently chosen as solvents or vehicles.

Salicylic Acid in Flexible Collodion: scenario and formulation record.