CHAPTER 13 - Solutions PDF

# Solutions ## Objectives After reading this chapter, the student will be able to: 1. Define the various types of oral and topical liquid dosage forms 2. List the advantages and disadvantages of using liquid dosage forms in extemporaneous compounded prescriptions and in patient therapy 3. Compare...

# Solutions ## Objectives After reading this chapter, the student will be able to: 1. Define the various types of oral and topical liquid dosage forms 2. List the advantages and disadvantages of using liquid dosage forms in extemporaneous compounded prescriptions and in patient therapy 3. Compare and contrast liquid dosage forms to solid oral dosage forms 4. Define solubility and describe how different factors increase or decrease solute solubility in a given solvent 5. Evaluate and select a proper solvent and delivery system for a given solute, purpose, and/or patient population ## Physicochemical Terms In physicochemical terms, solutions may be prepared from any combination of a solid, liquid, and gas, the three states of matter. For example, a solid solute may be dissolved in another solid, a liquid, or a gas, and the same being true for a liquid solute and for a gas; nine types of homogeneous mixtures are possible. In pharmacy, however, interest in solutions is for the most part limited to preparations of a solid, a liquid, and less frequently a gas solute in a liquid solvent. ## Pharmaceutical Solutions In pharmaceutical terms, solutions are *liquid preparations that contain one or more chemical substances dissolved in a suitable solvent or mixture of mutually miscible solvents* (1). Because of a particular pharmaceutical solution's use, it may be classified as oral, otic, ophthalmic, or topical. Still other solutions, because of their composition or use, may be classified as other dosage forms. For example, aqueous solutions containing a sugar are classified as syrups (even though some syrups may contain some alcohol), sweetened hydroalcoholic (combinations of water and ethanol) solutions are termed elixirs, and solutions of aromatic materials are termed spirits if the solvent is alcoholic or aromatic waters if the solvent is aqueous. Solutions prepared by extracting active constituents from crude drugs are termed tinctures or fluidextracts, depending on their method of preparation and concentration. Tinctures may also be solutions of chemical substances dissolved in alcohol or in a hydroalcoholic solvent. Certain solutions prepared to be sterile and pyrogen-free and intended for parenteral administration are classified as injections. Although other examples could be cited, it is apparent that a solution, as a distinct type of pharmaceutical preparation, is much further defined than the physicochemical definition of the term solution. Oral solutions, syrups, elixirs, spirits, and tinctures are prepared and used for the specific effects of the medicinal agents they carry. In these preparations, the medicinal agents are intended to provide systemic effects. The fact that they are administered in solution form usually means that they are soluble in aqueous systems and their absorption from the gastrointestinal tract into the systemic circulation may be expected to occur more rapidly than from suspension or solid dosage forms of the same medicinal agent. Solutes other than the medicinal agent are usually present in orally administered solutions. These additional agents are frequently included to provide color, flavor, sweetness, or stability. In formulating or compounding a pharmaceutical solution, the pharmacist must use information on the solubility and stability of each solute with regard to the solvent or solvent system. Combinations of medicinal or pharmaceutical agents that will result in chemical and/or physical interactions affecting the therapeutic quality or pharmaceutical stability of the product must be avoided. For single-solute solutions and especially for multiple-solute solutions, the pharmacist must be aware of the solubility characteristics of the solutes and the features of the common pharmaceutical solvents. Each chemical agent has its own solubility in a given solvent. For many medicinal agents, their solubilities in the usual solvents are stated in the United States Pharmacopeia-National Formulary (USP-NF) as well as in other reference books. ## Solubility Attractive forces between atoms lead to the formation of molecules and ions. The intermolecular forces, which are developed between like molecules, are responsible for the physical state (solid, liquid, or gas) of the substance under given conditions, such as temperature and pressure. Under ordinary conditions, most organic compounds, and thus most drug substances, form molecular solids. When molecules interact, attractive and repulsive forces are in effect. The attractive forces cause the molecules to cohere, whereas the repulsive forces prevent molecular interpenetration and destruction. When the attractive and repulsive forces are equal, the potential energy between two molecules is minimal and the system is most stable. Dipolar molecules frequently tend to align themselves with other dipolar molecules so that the negative pole of one molecule points toward the positive pole of the other. Large groups of molecules may be associated through these weak attractions, known as dipole-dipole or van der Waals forces. Other attractions also occur between polar and nonpolar molecules and ions. These include ion-dipole forces and hydrogen bonding. The latter is of particular interest. Because of small size and large electrostatic field, the hydrogen atom can move in close to an electronegative atom, forming an electrostatic type of association, a hydrogen bond or a hydrogen bridge. Hydrogen bonding involves strongly electronegative atoms such as oxygen, nitrogen, and fluorine. Such a bond exists in water, represented by the dotted lines. H H H H Ο H H H H Water H H H Hydrogen bonds also exist between some alcohol molecules, esters, carboxylic acids, aldehydes, and polypeptides. When a solute dissolves, the substance's intermolecular forces of attraction must be overcome by forces of attraction between the solute and the solvent molecules. This entails breaking the solute-solute forces and the solvent-solvent forces to achieve the solute-solvent attraction. The solubility of an agent in a particular solvent indicates the maximum concentration to which a solution may be prepared with that agent and that solvent. When a solvent at a given temperature has dissolved all of the solute possible, it is said to be saturated. To emphasize the possible variation in solubility between two chemical agents and, therefore, in the amounts of each required to prepare a saturated solution, two official aqueous saturated solutions are cited as examples, Calcium Hydroxide Topical Solution, USP, and Potassium Iodide Oral Solution, USP. The first solution, prepared by agitating an excess amount of calcium hydroxide with purified water, contains only about 140 mg of dissolved solute per 100 mL of the solution at 25°C, whereas potassium iodide solution contains about 100 g of solute per 100 mL of the solution, more than 700 times as much solute as in the calcium hydroxide topical solution. Thus, the maximum possible concentration to which a pharmacist may prepare a solution varies greatly and depends in part on the chemical constitution of the solute. ## Solubilizing Agents Through selection of a different solubilizing agent or a different chemical salt form of the medicinal agent, alteration of the pH of a solution, or substitution in part or in whole of the solvent, a pharmacist can, in certain instances, dissolve greater quantities of a solute than would otherwise be possible. For example, iodine granules are soluble in water only to the extent of 1 g in about 3,000 mL. Using only these two agents, the maximum concentration possible would be approximately 0.03% of iodine. However, through the use of an aqueous solution of potassium iodide or sodium iodide as the solvent, much larger amounts of iodine may be dissolved as the result of the formation of a water-soluble complex with the iodide salt. This reaction is taken advantage of, for example, in Iodine Topical Solution, USP, prepared to contain about 2% iodine and 2.4% sodium iodide. ## Temperature Temperature is an important factor in determining the solubility of a drug and in preparing its solution. Most chemicals absorb heat when they are dissolved and are said to have a positive heat of solution, resulting in increased solubility with an increase in temperature. A few chemicals have a negative heat of solution and exhibit a decrease in solubility with a rise in temperature. Other factors in addition to temperature affect solubility. These include the various chemical and other physical properties of the solute and the solvent, pressure, the pH of the solution, the state of subdivision of the solute, and the physical agitation applied to the solution as it dissolves. The solubility of a pure chemical substance at a given temperature and pressure is constant; however, its rate of solution, that is, the speed at which it dissolves, depends on the particle size of the substance and the extent of agitation. The finer the powder, the greater the surface area, which comes in contact with the solvent, and the more rapid the dissolving process. Also, the greater the agitation, the more unsaturated solvent passes over the drug and the faster the formation of the solution. The solubility of a substance in a given solvent may be determined by preparing a saturated solution of it at a specific temperature and by determining by chemical analysis the amount of chemical dissolved in a given weight of solution. The amount of solvent required to dissolve the amount of solute can be determined by a simple calculation. The solubility may then be expressed as grams of solute dissolving in milliliters of solvent; for example, "1 g of sodium chloride dissolves in 2.8 mL of water." When the exact solubility has not been determined, general expressions of relative solubility may be used. These terms are defined in the USP and presented in Table 13.1 (1). ## Weak Acids and Weak Bases Many of the important organic medicinal agents are either weak acids or weak bases, and their solubility depends on a large measure on the pH of the solvent. These drugs react either with strong acids or strong bases to form water-soluble salts. For instance, the weak bases, including many of the alkaloids (atropine, codeine, and morphine), antihistamines (diphenhydramine and promethazine), local anesthetics (cocaine, procaine, and tetracaine), and other important drugs, are not very water soluble, but they are soluble in dilute solutions of acids. Pharmaceutical manufacturers have prepared many acid salts of these organic bases to enable the preparation of aqueous solutions. However, if the pH of the aqueous solution of these salts is changed by the addition of alkali, the free base may separate from solution unless it has adequate solubility in water. Organic medicinals that are weak acids include the barbiturate drugs (e.g., phenobarbital) and the sulfonamides (e.g., sulfadiazine and sulfacetamide). These and other weak acids form water-soluble salts in basic solution and may separate from solution by a lowering of the pH. Table 13.2 presents the comparative solubilities of some typical examples of weak acids and weak bases and their salts. | DESCRIPTIVE TERM | PARTS OF SOLVENT REQUIRED FOR 1 PART OF SOLUTE | |:-----------------------|:-------------------------------------------------------:| | Very soluble | <1 | | Freely soluble | 1-10 | | Soluble | 10-30 | | Sparingly soluble | 30-100 | | Slightly soluble | 100-1,000 | | Very slightly soluble | 1,000-10,000 | | Practically insoluble or | >10,000 | | insoluble | | ## Generalities Although there are no exact rules for unerringly predicting the solubility of a chemical agent in a particular liquid, experienced pharmaceutical chemists can estimate the general solubility of a chemical compound based on its molecular structure and functional groups. The information gathered on a great number of individual chemical compounds has led to the characterization of the solubilities of groups of compounds, and though there may be an occasional inaccuracy with respect to an individual member of a group of compounds, the generalizations nonetheless are useful. As demonstrated by the data in Table 13.2 and other similar data, salts of organic compounds are more soluble in water than are the corresponding organic bases. Conversely, the organic bases are more soluble in organic solvents, including alcohol, than are the corresponding salt forms. Perhaps the most widely written guideline for the prediction of solubility is "like dissolves like," meaning a solvent having a chemical structure most similar to that of the intended solute will be most likely to dissolve it. Thus, organic compounds are more soluble in organic solvents than in water. Organic compounds may, however, be somewhat water soluble if they contain polar groups capable of forming hydrogen bonds with water. In fact, the greater the number of polar groups present, the greater will likely be the organic compound's solubility in water. Polar groups include OH, CHO, COH, CHOH, CH₂OH, COOH,NO2, CO, NH₂, and SOH. The introduction of halogen atoms into a molecule tends to decrease water solubility because of an increase in the molecular weight of the compound without a proportionate increase in polarity. An increase in the molecular weight of an organic compound without a change in polarity reduces solubility in water. Table 13.3 demonstrates some of these generalities with specific chemical examples. | COMPOUND | FORMULA | MILLILITERS OF WATER REQUIRED TO DISSOLVE 1 G OF COMPOUND | |:------------------------|:-------------|:-----------------------------------------------------:| | Benzene | C₆H₆ | 1,430.0 | | Benzoic acid | C₆H₅COOH | 275.0 | | Benzyl alcohol | C₆H₅CH₂OH | 25.0 | | Phenol | C₆H₅OH | 15.0 | | Pyrocatechol | C₆H₄(OH)₂ | 2.3 | | Pyrogallol | C₆H₃(OH)₃ | 1.7 | | Carbon tetrachloride | CCI₄ | 2,000.0 | | Chloroform | CHCI₃ | 200.0 | | Methylene chloride | CH₂CI₂ | 50.0 | ## Inorganic Molecules 1. If both the cation and anion of an ionic compound are monovalent, the solute-solute attractive forces are usually easily overcome, and, therefore, these compounds are generally water soluble (e.g., NaCl, LiBr, KI, NH₄NO₃, and NaNO₂). 2. If only one of the two ions in an ionic compound is monovalent, the solute-solute interactions are also usually easily overcome and the compounds are water soluble (e.g., BaCl₂, MgI₂, Na₂SO₄, and Na₃PO₄). 3. If both the cation and anion are multivalent, the solute-solute interaction may be too great to be overcome by the solute-solvent interaction, and the compound may have poor water solubility (e.g., CaSO₄, BaSO₄, and BiPO₄; exceptions: ZnSO₄, FeSO₄). 4. Common salts of alkali metals (e.g., Na, K, Li, Cs, and Rb) are usually water soluble (exception: Li₂CO₃). 5. Ammonium and quaternary ammonium salts are water soluble. 6. Nitrates, nitrites, acetates, chlorates, and lactates are generally water soluble (exceptions: silver and mercurous acetate). 7. Sulfates, sulfites, and thiosulfates are generally water soluble (exceptions: calcium and barium salts). 8. Chlorides, bromides, and iodides are water soluble (exceptions: salts of silver and mercurous ions). 9. Acid salts corresponding to an insoluble salt will be more water soluble than the original salt. 10. Hydroxides and oxides of compounds other than alkali metal cations and the ammonium ion are generally water insoluble. 11. Sulfides are water insoluble except for their alkali metal salts. 12. Phosphates, carbonates, silicates, borates, and hypochlorites are water insoluble except for their alkali metal salts and ammonium salts. ## Organic Molecules 1. Molecules having one polar functional group are usually soluble to total chain lengths of five carbons. 2. Molecules having branched chains are more soluble than the corresponding straight-chain compound. 3. Water solubility decreases with an increase in molecular weight. 4. Increased structural similarity between solute and solvent is accompanied by increased solubility. It is the pharmacist's knowledge of the chemical characteristics of drugs that permits the selection of the proper solvent for a particular solute. However, in addition to the factors of solubility, the selection is based on such additional characteristics as clarity, low toxicity, viscosity, compatibility with other formulative ingredients, chemical inertness, palatability, odor, color, and economy. In most instances, especially for solutions to be taken orally, used intranasally, used ophthalmically, or injected, water is the preferred solvent because it comes closer to meeting these criteria than other solvents. When water is used as the primary solvent, commonly an auxiliary solvent is also employed to augment the solvent action of water or to contribute to a product's chemical or physical stability. Alcohol, glycerin, and propylene glycol, perhaps the most widely used auxiliary solvents, have been quite effective in contributing to the desired characteristics of pharmaceutical solutions and in maintaining their stability. Other solvents, such as acetone, ethyl oxide, and isopropyl alcohol, are too toxic to be permitted in pharmaceutical preparations to be taken internally, but they are useful as reagent solvents in organic chemistry and in the preparatory stages of drug development, as in the extraction or removal of active constituents from medicinal plants. For purposes such as this, certain solvents are officially recognized in the compendia. A number of fixed oils, such as corn oil, cottonseed oil, peanut oil, and sesame oil, are useful solvents, particularly in the preparation of oleaginous injections, and are recognized in the official compendia for this purpose. ## Some Solvents for Liquid Preparations - **Alcohol, USP**: Ethyl Alcohol, Ethanol, C₂H₅OH Next to water, alcohol is the most useful solvent in pharmacy. It is used as a primary solvent for many organic compounds. Together with water, it forms a hydroalcoholic mixture that dissolves both alcohol-soluble and water-soluble substances, a feature especially useful in the extraction of active constituents from crude drugs. By varying the proportion of the two agents, the active constituents may be selectively dissolved and extracted or allowed to remain behind, according to their particular solubility characteristics in the menstruum. Alcohol, USP, is 94.9% to 96.0% C₂H₅OH by volume (i.e., v/v) when determined at 15.56°C, the US government's standard temperature for alcohol determinations. Dehydrated Alcohol, USP, also called absolute alcohol, contains not less than 99.5% C₂H₅OH by volume and is used when an essentially water-free alcohol is desired. Alcohol has been well recognized as a solvent and excipient in the formulation of oral pharmaceutical products. Certain drugs are insoluble in water and must be dissolved in an alternative vehicle. Alcohol is often preferred because of its miscibility with water and its ability to dissolve many water-insoluble ingredients, including drug substances, flavorants, and antimicrobial preservatives. Alcohol is frequently used with other solvents, such as glycols and glycerin, to reduce the amount of alcohol required. It is also used in liquid products as an antimicrobial preservative alone or with parabens, benzoates, sorbates, and other agents. However, aside from its pharmaceutical advantages as a solvent and a preservative, concern has been expressed over the undesired pharmacologic and potential toxic effects of alcohol when ingested in pharmaceutical products, particularly by children. Thus, the U.S. Food and Drug Administration (FDA) has proposed that insofar as possible manufacturers of over-the-counter (OTC) oral drug products restrict the use of alcohol and include appropriate warnings in the labeling. For OTC oral products intended for children under 6 years of age, the recommended alcohol content limit is 0.5%; for products intended for children 6 to 12 years of age, the recommended limit is 5%; and for products recommended for children over 12 years of age and for adults, the recommended limit is 10%. - **Diluted Alcohol, NF** Diluted Alcohol, NF, is prepared by mixing equal volumes of Alcohol, USP, and Purified Water, USP. The final volume of such mixtures is not the sum of the individual volumes of the two components because the liquids contract upon mixing; the final volume is generally about 3% less than what would otherwise be expected. Thus, when 50 mL of each component is combined, the resulting product measures approximately 97 mL. It is for this reason that the strength of Diluted Alcohol, NF, is not exactly half that of the more concentrated alcohol but slightly greater, approximately 49%. Diluted alcohol is a useful hydroalcoholic solvent in various pharmaceutical processes and preparations. - **Rubbing Alcohol** Rubbing alcohol contains about 70% ethyl alcohol by volume, the remainder consisting of water, denaturants with or without color additives and perfume oils, and stabilizers. Each 100 mL must contain not less than 355 mg of sucrose octaacetate or 1.4 mg of denatonium benzoate, bitter substances that discourage accidental or abusive oral ingestion. According to the Internal Revenue Service, U.S. Treasury Department, the denaturant employed in rubbing alcohol is formula 23-H, which is composed of 8 parts by volume of acetone, 1.5 parts by volume of methyl isobutyl ketone, and 100 parts by volume of ethyl alcohol. The use of this denaturant mixture makes the separation of ethyl alcohol from the denaturants virtually impossible with ordinary distillation apparatus. This discourages the illegal removal for use as a beverage of the alcoholic content of rubbing alcohol. The product is volatile and flammable and should be stored in a tight container remote from fire. It is employed as a rubefacient externally and as a soothing rub for bedridden patients, a germicide for instruments, and a skin cleanser prior to injection. It is also used as a vehicle for topical preparations. Synonym: alcohol rubbing compound. - **Glycerin, USP (Glycerol), CH₂OH-CHOH-CH₂OH** Glycerin is a clear syrupy liquid with a sweet taste. It is miscible with both water and alcohol. As a solvent, it is comparable with alcohol, but because of its viscosity, solutes are slowly soluble in it unless it is rendered less viscous by heating. Glycerin has preservative qualities and is often used as a stabilizer and as an auxiliary solvent in conjunction with water or alcohol. It is used in many internal preparations. - **Isopropyl Rubbing Alcohol** Isopropyl rubbing alcohol is about 70% by volume isopropyl alcohol, the remainder consisting of water with or without color additives, stabilizers, and perfume oils. It is used externally as a rubefacient and soothing rub and as a vehicle for topical products. This preparation and a commercially available 91% isopropyl alcohol solution are commonly employed by diabetic patients in preparing needles and syringes for hypodermic injections of insulin and for disinfecting the skin. - **Propylene Glycol, USP, CH₃CH(OH)CH₂OH** Propylene glycol, a viscous liquid, is miscible with water and alcohol. It is a useful solvent with a wide range of applications and is frequently substituted for glycerin in modern pharmaceutical formulations. - **Purified Water, USP, H₂O** Naturally occurring water exerts its solvent effect on most substances it contacts and, thus, is impure, containing varying amounts of dissolved inorganic salts, usually sodium, potassium, calcium, magnesium, and iron; chlorides; sulfates; and bicarbonates, along with dissolved and undissolved organic matter and microorganisms. Water found in most cities and towns where water is purified for drinking usually contains less than 0.1% of total solids, determined by evaporating a 100-mL sample to dryness and weighing the residue (which weighs <100 mg). Drinking water must meet the U.S. Public Health Service regulations with respect to bacteriologic purity. Acceptable drinking water should be clear, colorless, odorless, and neutral or only slightly acidic or alkaline, the deviation from neutral being due to the nature of the dissolved solids and gases (carbon dioxide contributing to the acidity and ammonia to the alkalinity of water). Ordinary drinking water from the tap is not acceptable for the manufacture of most aqueous pharmaceutical preparations or for the extemporaneous compounding of prescriptions because of the possible chemical incompatibilities between dissolved solids and the medicinal agents being added. Signs of such incompatibilities are precipitation, discoloration, and occasionally effervescence. Its use is permitted in washing, in extraction of crude vegetable drugs, in preparation of certain products for external use, and when the difference between tap water and purified water is of no consequence. Naturally, when large volumes of water are required to clean pharmaceutical machinery and equipment, tap water may be economically employed so long as a residue of solids is prevented by using purified water as the final rinse or by wiping the water dry with a meticulously clean cloth. Purified Water, USP, is obtained by distillation, ion exchange treatment, reverse osmosis, or other suitable process. It is prepared from water complying with the federal Environmental Protection Agency with respect to drinking water. Purified Water, USP, has fewer solid impurities than ordinary drinking water. When evaporated to dryness, it must not yield more than 0.001% of residue (1 mg of solids per 100 mL of water). Thus, purified water has only 1% as much dissolved solids as tap water. Purified Water, USP, is intended for use in the preparation of aqueous dosage forms except those intended for parenteral administration (injections). Water for Injection, USP; Bacteriostatic Water for Injection, USP; or Sterile Water for Injection, USP, is used for injections. These are discussed in Chapter 15. The main methods used in the preparation of purified water are distillation, ion exchange, and reverse osmosis; these methods are described briefly next. - **Distillation Method** Many stills in various sizes and styles with capacities ranging from about 0.5 to 100 gallons of distillate per hour are available to prepare purified water. Generally, the first portion of aqueous distillate (about the first 10% to 20%) must be discarded because it contains many foreign volatile substances usually found in urban drinking water, the usual starting material. Also, the last portion of water (about 10% of the original volume of water) remaining in the distillation apparatus must be discarded and not subjected to further distillation because distillation to dryness would undoubtedly result in decomposition of the remaining solid impurities to volatile substances that would distill and contaminate the previously collected portion of distillate. - **Ion Exchange Method** On a large or small scale, ion exchange for the preparation of purified water offers a number of advantages over distillation. For one thing, the requirement of heat is eliminated and with it, the costly and troublesome maintenance frequently encountered in the operation of the more complex distillation apparatus. Because of the simpler equipment and the nature of the method, ion exchange permits ease of operation, minimal maintenance, and a more mobile facility. Many pharmacies and small laboratories that purchase large volumes of distilled water from commercial suppliers for use in their work would no doubt benefit financially and in convenience through the installation of an ion exchange demineralizer in the work area. The ion exchange equipment in use today generally passes water through a column of cation and anion exchangers consisting of water-insoluble synthetic polymerized phenolic, carboxylic, amino, or sulfonated resins of high molecular weight. These resins are mainly of two types: (a) the cations, or acid exchangers, which permit the exchange of the cations in solution (in the tap water) with hydrogen ion from the resin, and (b) the anions, or base exchange resins, which permit the removal of anions. These two processes are successively or simultaneously employed to remove cations and anions from water. The processes are indicated as follows, with M+ indicating the metal or cation (as Na+) and the X- indicating the anion (as Cl-). Cation exchange: H- resin + M⁺ + X + H₂O → M- resin + H+ + X + H₂O (pure) Anion exchange: Resin -NH₂ + H+ +X+H₂O → Resin -NH₂ HX + H₂O (pure) Water purified in this manner, referred to as demineralized or deionized water, may be used in any pharmaceutical preparation or prescription calling for distilled water. - **Reverse Osmosis** Reverse osmosis is one of the processes referred to in the industry as cross-flow (or tangential flow) membrane filtration (2). In this process, a pressurized stream of water is passed parallel to the inner side of a filter membrane core. A portion of the feed water, or influent, permeates the membrane as filtrate, while the balance of the water sweeps tangentially along the membrane to exit the system without being filtered. The filtered portion is called the permeate because it has permeated the membrane. The water that has passed through the system is called the concentrate because it contains the concentrated contaminants rejected by the membrane. Whereas in osmosis the flow through a semipermeable membrane is from a less concentrated solution to a more concentrated solution, the flow in this cross-flow system is from a more concentrated to a less concentrated solution, thus the term reverse osmosis. Depending on their pore size, cross-flow filter membranes can remove particles defined in the range of microfiltration (0.1 to 2 µm, e.g., bacteria), ultrafiltration (0.01 to 0.1 µm, e.g., virus), nanofiltration (0.001 to 0.01 µm, e.g., organic compounds in the molecular weight range of 300 to 1,000), and reverse osmosis (particles <0.001 µm). Reverse osmosis removes virtually all viruses, bacteria, pyrogens, and organic molecules and 90% to 99% of ions (2). ## Preparation of Solutions Most pharmaceutical solutions are unsaturated with solute. Thus, the amounts of solute to be dissolved are usually well below the capacity of the volume of solvent employed. The strengths of pharmaceutical preparations are usually expressed in terms of percent strength, although for very dilute preparations, expressions of ratio strength may be used. These expressions and examples are shown in Table 13.4. | ABBREVIATED EXPRESSION | EXPRESSION | MEANING AND EXAMPLE | |:--------------------------|:------------------------------------------|:---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------| | % w/v | Percent weight in volume | Grams of constituent in 100 mL of preparation (e.g., 1% w/v = 1 g constituent in 100 mL preparation) | | % v/v | Percent volume in volume | Milliliters of constituent in 100 mL of preparation (e.g., 1% v/v = 1 mL constituent in 100 mL preparation) | | % w/w | Percent weight in weight | Grams of constituent in 100 g of preparation (e.g., 1% w/w = 1 g constituent in 100 g preparation) | | -:- w/v | Ratio of strength to weight in volume | Grams of constituent in stated milliliters of preparation (e.g., 1:1,000 w/v = 1 g constituent in 1,000 mL preparation) | | -:- v/v | Ratio of strength to volume in volume | Milliliters of constituent in milliliters of preparation (e.g., 1:1,000 v/v = 1 mL constituent in 1,000 mL preparation) | | -:- w/w | Ratio of strength to weight in weight | Grams of constituent in stated number of grams of preparation (e.g., 1:1,000 w/w = 1 g constituent in 1,000 g preparation) | To facilitate solution, and when they do, they are careful not to exceed the minimally required temperature, for many medicinal agents are destroyed at elevated temperatures and the advantage of rapid solution may be completely offset by drug deterioration. If volatile solutes are to be dissolved or if the solvent is volatile (as is alcohol), the heat would encourage the loss of these agents to the atmosphere and must therefore be avoided. Pharmacists are aware that certain chemical agents, particularly calcium salts, undergo exothermic reactions as they dissolve and give off heat. For such materials, the use of heat would actually discourage the formation of a solution. The best pharmaceutical example of this type of chemical is calcium hydroxide, which is used in the preparation of Calcium Hydroxide Topical Solution, USP. Calcium hydroxide is soluble in water to the extent of 140 mg/100 mL of solution at 25°C (about 77°F) and 170 mg/100 mL of solution at 15°C (about 59°F). Obviously, the temperature at which the solution is prepared or stored can affect the concentration of the resultant solution. In addition to or instead of raising the temperature of the solvent to increase the rate of solution, a pharmacist may choose to decrease the particle size of the solute. This may be accomplished by comminution (grinding a solid to a fine state of subdivision) with a mortar and pestle on a small scale or industrial micronizer on a larger scale. The reduced particle size increases the surface area of the solute. If the powder is placed in a suitable vessel (e.g., a beaker, graduated cylinder, bottle) with a portion of the solvent and is stirred or shaken, as suited to the container, the rate of solution may be increased by the continued circulation of fresh solvent to the drug's surface and the constant removal of newly formed solution from the drug's surface. Most solutions are prepared by simple mixing of the solutes with the solvent. On an industrial scale, solutions are prepared in large mixing vessels with ports for mechanical stirrers (Fig. 13.1). When heat is desired, thermostatically controlled mixing tanks may be used. ## Oral Solutions and Preparations for Oral Solution Most solutions intended for oral administration contain flavorants and colorants to make the medication more attractive and palatable. When needed, they may also contain stabilizers to maintain the chemical and physical stability of the medicinal agents and preservatives to prevent the growth of microorganisms in the solution. The formulation pharmacist must be wary of chemical interactions between the various components of a solution that may alter the preparation's stability and/or potency. For instance, esters of p-hydroxybenzoic acid (methyl-, ethyl-, propyl-, and butylparabens), frequently used preservatives in oral preparations, have a tendency to partition into certain flavoring oils (3). This partitioning effect could reduce the effective concentration of the preservatives in the aqueous medium of a pharmaceutical product below the level needed for preservative action. Liquid pharmaceuticals for oral administration are usually formulated such that the patient receives the usual dose of the medication in a conveniently administered volume, as 5 (one teaspoonful), 10, or 15 mL (one tablespoonful). A few solutions have unusually large doses, for example, Magnesium Citrate Oral Solution, USP, with a usual adult dose of 200 mL. On the other hand, many solutions for children are given by drop with a calibrated dropper usually furnished by the manufacturer in the product package. **Dry Mixtures for Solution** A number of medicinal agents, particularly certain antibiotics, for example, penicillin V, have insufficient stability in aqueous solution to meet extended shelf-life periods. Thus, commercial manufacturers of these products provide them to the pharmacist in dry powder or granule form for reconstitution with a prescribed amount of purified water immediately before dispensing to the patient. The dry powder mixture contains all of the formulative components, including drug, flavorant, colorant, buffers, and others, except for the solvent. Once reconstituted by the pharmacist, the solution remains stable when stored in the refrigerator for the labeled period, usually 7 to 14 days, depending on the preparation. This is a sufficient period for the patient to complete the regimen usually prescribed. However, in case the medication remains after the patient completes the course of therapy, the patient should be instructed to discard the remaining portion, which would be unfit for use at a later time. Examples of dry powder mixtures intended for reconstitution to oral solutions are the following: - Cloxacillin Sodium for Oral Solution, USP (Teva), an anti-infective antibiotic - Penicillin V Potassium for Oral Solution, USP (Veetids, Geneva), an anti-infective antibiotic - Potassium Chloride for Oral Solution, USP (K-LOR, Abbott), a potassium supplement **Oral Solutions** The pharmacist may be called on to dispense a commercially prepared oral solution; dilute the concentration of a solution, as in the preparation of a pediatric form of an adult product; prepare a solution by reconstituting a dry powder mixture; or extemporaneously compound an oral solution from bulk ingredients. In each instance, the pharmacist should be sufficiently knowledgeable about the dispensed product to expertly advise the patient of the proper use, dosage, method of administration, and storage of the product. Knowledge of the solubility and stability characteristics of the medicinal agents and the solvents employed in the commercial products is useful to the pharmacist for informing the patient of the advisability of mixing the solution with juice, milk, or other beverage upon administration. Information regarding the solvents used in each commercial product appears on the product label and in the accompanying package insert. Table 13.5 presents examples of some oral solutions. Some solutions of special pharmaceutical interest are described later in this chapter. | ORAL SOLUTION | REPRESENTATIVE COMMERCIAL PRODUCTS | CONCENTRATION OF COMMERCIAL PRODUCT | COMMENTS | |:--------------------------|:---------------------------------------------|:--------------------------------------------|:-------------------------------------------------------------------------------------------------------------------------------------------------------------------------| | Antidepressants | | | | | Escitalopram oxalate | Lexapro (Forest) | 1 mg/mL | For major depressive disorder | | Fluoxetine HCI | Prozac Liquid (Dista) | 20 mg fluoxetine/5 mL | For depression, obsessive-compulsive disorder | | Nortriptyline HCI | Pamelor Oral Solution (Mallinckrodt) | 10 mg nortriptyline/5 mL | Tricyclic antidepressant | | Ant