Pharmaceutical Solutions I: Simple, Saturated, Syrups
Upon completion of this exercise, you should be able to:
- Define, give an example of, and/or classify examples of each of the following: Pharmaceutical Solution, Solute, Solvent, Saturated Solution, Supersaturated Solution, Macromolecular Solution, Syrups, Aromatic Waters, Mucilages, Aqueous Acids.
- State at least six (6) pharmaceutical uses or applications of solutions.
- Identify commonly used pharmaceutical solvents.
- Identify at least three (3) necessary criteria of pharmaceutical solvents.
- Make necessary calculations for, prepare, label, and dispense pharmaceutical solutions.
- Define simple syrups, flavoring syrups, medicinal syrups, syrup USP, and caramelization.
- List three (3) methods of preparing syrups.
- Describe and demonstrate how to prepare a syrup by the “agitation with heat” method.
- Describe alternative formulations for “syrups” prepared with non-sugar sweeteners and state their advantages and limitations.
- Make necessary calculations and describe how to preserve a syrup using Alcohol USP.
The study of pharmaceutical solutions is essential to the practicing pharmacist and can be, at times, somewhat complex. In addition to considering the therapeutic appropriateness of the drug, the pharmacist must consider many factors regarding the chemical and physical aspects of the product. Is the drug soluble in an acceptable solvent? Is it chemically stable in solution and for how long? Are two or more solutes chemically and physically compatible in solution? How will changes in temperature, pH or light exposure affect the product? Should the product be preserved, buffered, or flavored and how? How should the product be packaged and stored?
You may be wondering if you really need to know all of these things when so many products are commercially available. Absolutely! Many oral solutions are not produced commercially because they are unstable and have a short shelf-life or are used in such a small patient population that they are unprofitable to produce commercially. Hence, you may be called upon to formulate and dispense many such products.
As with any product, safety and accuracy of dosing are our ultimate goals. Thus, you must learn to read and interpret the prescription properly, to make the necessary calculations to prepare a product of desired strength, and to use the proper judgments and formulation techniques to ensure a stable, potent product. Finally, you must learn to clearly and accurately label the products with the appropriate instructions for use. There may be times when written or verbal instructions are necessary to supplement the label directions.
A solution is a thermodynamically stable, one-phase system composed of 2 or more components, one of which is completely dissolved in the other. The solution is homogeneous because the solute, or dispersed phase, is dispersed throughout the solvent in molecular or ionic sized particles. Broadly defined, a solution may be any combination of solids, liquids, and/or gases. We will restrict our definition of pharmaceutical solutions to those composed of a solid, liquid, or gas dissolved in a liquid solvent.
The assignment of the terms solute and solvent is sometimes arbitrary. Generally, the solute is the component present in the smallest amount and the solvent is the larger, liquid component. Water is nearly always considered the solvent. Pharmaceutical solutes may include active drug components, flavoring or coloring agents, preservatives, and stabilizers or buffering salts. Water is the most common solvent for pharmaceutical solutions, but ethanol, glycerin, propylene glycol, isopropyl alcohol or other liquids may be used, depending on the product requirements. To be an appropriate solvent, the liquid must completely dissolve the drug and other solid ingredients at the desired concentration, be nontoxic and safe for ingestion or topical application, and be aesthetically acceptable to the patient in terms of appearance, aroma, texture, and/or taste.
The solubility of a drug is the expression of the quantity of a drug that can be maintained in solution in a given solvent at a given temperature and pressure. It is usually expressed as the number of milliliters of solvent required to dissolve 1 gram of the drug. Understanding drug solubility is critical in formulating solutions. This topic will be covered in more depth in a later exercise.
A saturated solution is one that contains the maximum amount of solute that the solvent will accommodate at room temperature and pressure. A supersaturated solution is one that contains a larger amount of solute than the solvent can normally accommodate at that temperature and pressure. It is usually obtained by preparing a saturated solution at a higher temperature, filtering out excess solute and reducing the temperature. Saturated and supersaturated solutions are physically unstable and tend to precipitate the excess solute under less than perfect conditions (e.g. when refrigerated or upon the addition of other additives).
A differentiation is sometimes made between solutions on the basis of solute molecular size. Micromolecular solutions consist of dispersed molecules or ions in the 1-10 A size (MW < 10,000). In macromolecular solutions (MW > 10,0000), the solutes are in true solutions, but the solute size of macromolecular solutions lends special properties to them. Because the particles are so large, most cannot be sterilized by filtration. The solutions are also quite viscous, and may be used as thickening agent for other dispersed dosage forms. Macromolecular solutions include those containing acacia, methylcellulose and other cellulose derivatives, and proteins such as albumin.
Solutions have a wide variety of uses in the pharmaceutical industry. They are used therapeutically as vehicles for oral, parenteral, topical, otic, ophthalmic, and nasal products. They are also used as flavorings, buffers, preservatives, and suspending agents for a variety of liquid dosage forms. Concentrated stock solutions often serve as components of extemporaneously prepared products. Test solutions also play an important role in the analysis of pharmaceutical products of all types.
Aqueous solutions are the most prevalent of the oral solutions. Drugs are dissolved in water along with any necessary flavorings, preservatives, or buffering salts. Distilled or purified water should always be used when preparing pharmaceutical solutions.
The following are examples of aqueous pharmaceutical solutions.
- Syrups are concentrated, viscous, sweetened, aqueous solutions that contain less than 10% alcohol, e.g. Syrup USP, Wild Cherry Syrup USP.
- Aromatic waters are saturated solutions of volatile oils in water and are used to provide a pleasant flavor or aroma, e.g. Peppermint Water, USP.
- Mucilages are thick, viscous macromolecular solutions produced by dispersing vegetable gums in water. They are commonly used as suspending or thickening agents, e.g. Acacia Mucilage, Tragacanth Mucilage.
- Aqueous acids are dilute aqueous solutions of acids (usually < 10%), e.g. Diluted HCl, USP.
Syrup, USP contains 850 gm sucrose and 450 ml of water in each liter of syrup. Although very concentrated, the solution is not saturated. Since 1 gm sucrose dissolves in 0.5 ml water, only 425 ml of water would be required to dissolve 850 gm sucrose. This slight excess of water enhances the syrup’s stability over a range of temperatures, permitting cold storage without crystallization.
The high solubility of sucrose indicates a high degree of hydration or hydrogen bonding between sucrose and water. This association limits the further association between water and additional solutes. Hence, syrups have a lower solvent power than water and “salting out” (see Remington’s for explanation) may be a problem.
Syrup, USP is protected from bacterial contamination by virtue of its high solute concentration. More dilute syrups are good media for microbial growth and require the addition of preservatives. Industrially formulated syrups often contain ingredients to improve solubility, stability, taste or appearance which also contribute to product preservation. It is necessary, from an economic standpoint, to consider the additive preservative effects of such ingredients as alcohol, glycerin, propylene glycol, and other dissolve solids. Syrup USP, having a specific gravity of 1.313 and a concentration of 85% w/v is a 65% w/w solution. This 65% by weight is the minimum amount of sucrose which will preserve neutral syrup. If one wants to formulate a syrup containing less sucrose, the quantity of alcohol, or other preservatives, may be estimated by considering the USP Syrup equivalent and the free water equivalent. One may assume that free water is preserved by 18% alcohol.
To calculate the free water equivalent, the volume occupied by the sucrose, the volume preserved by the sucrose, and the volume occupied and/or preserved by other additives must be subtracted from the total volume of the preparation. In Syrup, USP 850 g sucrose occupies an apparent volume of 550 ml; so each gram of sucrose will occupy 550/850 or 0.647 ml. If the 850 g sucrose preserves 450 ml of water, then each gram of sucrose will preserve 450/850 = 0.53 ml of water.
e.g. How much Alcohol USP is required to preserve 1L of syrup containing 500 g sucrose?
If other dissolved solids are present, their volume (often estimated) is subtracted from the free water volume. If glycerin is present, its volume preserves an equal volume of free water. If propylene glycol is present, it is considered equivalent to ethanol.
Preparation of Syrups
Syrups should be carefully prepared in clean equipment to prevent contamination. Three methods may be used to prepare syrups (See Remington’s for a full explanation):
- Solution with heat
- Agitation without heat
Although the hot method is quickest, it is not applicable to syrups of thermolabile or volatile ingredients. When using heat, temperature must be carefully controlled to avoid decomposing and darkening the syrup (caramelization).
Syrups may be prepared from sugars other than sucrose (glucose, fructose), non-sugar polyols (sorbitol, glycerin, propylene glycol, mannitol), or other non-nutritive artificial sweeteners (aspartame, saccharin) when a reduction in calories or glucogenic properties is desired, as with the diabetic patient. The non-nutritive sweeteners do not impart the characteristic viscosity of syrups and require the addition of viscosity adjusters, such as methylcellulose. The polyols, though less sweet than sucrose, have the advantage of providing favorable viscosity, reducing cap-locking (which occurs when sucrose crystallizes), and in some cases acting as cosolvents and preservatives. A 70% sorbitol solution is commercially available for use as a vehicle.