OUTLINE

Introduction

Vehicles for Oral Liquid Preparations

Vehicles for Topical Liquid Preparations

I. IINTRODUCTION

A. A vehicle for a liquid dosage form may be a pharmaceutical solvent, a solution, an emulsion, or a suspension.

B. The desired or required properties of the vehicle depend on the route of administration for the preparation and the type of solvent system needed or desired. The definitions and descriptions of pharmaceutical solvents are given in Chapter 15. The various types of liquid systems, such as syrup, elixir, spirit, suspension, and emulsion, are given in Chapters 27 through 29, which discuss each individual liquid dosage form type. The ingredients used in liquid vehicles are described in Chapters 15 through 21.

C. This chapter discusses the general properties of liquid vehicles for oral and topical products and gives examples and descriptions of potential vehicles. For ease of use, the information in this chapter is divided into two sections: vehicles for oral use and vehicles for topical use.

D. As noted in previous chapters of Part 4, this text uses the convention of upper-case first letters for official USP-NF articles and lower-case first letters for words designating chemical substances or generic preparation.

II. VEHICLES FOR ORAL LIQUID PREPARATIONS

A. Restrictions

1. Neonates (birth to 1 month): Add only the essentials.

a. Alcohol and preservatives should not be added. The organ and enzyme systems of these tiny infants are not fully mature and do not metabolize alcohol and preservatives efficiently (1–5).

b. Because colors, flavors, and sweeteners are not needed, they also should be avoided.

c. Hypertonic solutions should not be used—that is, no concentrated sugar syrups, 70% sorbitol, and so on. The gastrointestinal (GI) tracts of neonates are delicate; there are reports of injury to the GI tracts of neonates caused by administration of hypertonic solutions (6–8).

d. A 1% methylcellulose gel that is preservative-free is a suitable liquid vehicle for this age group.

2. Children: Use judgment based on the child’s age; young infants are obviously more sensitive than are 6-year-olds.

a. Use little to no alcohol (1,2). In practical terms, this means use the minimum amount of alcohol that is absolutely necessary for solubility purposes if a solution is needed. Do not use alcohol as a preservative when there are alternatives.

(1) Food and Drug Administration recommendations for alcohol use in children are discussed in the alcohol section of Chapter 15, Pharmaceutical Solvents and Solubilizing Agents.

(2) The American Academy of Pediatrics Committee on Drugs has recommended that the quantity of ethanol contained in a single dose of a drug product or preparation should not be able to cause a blood concentration greater than 25 mg/100 mL. The Academy’s published article, “Ethanol in Liquid Preparations Intended for Children,” gives equations and tables of values that allow prescribers and pharmacists to calculate the volumes and concentrations of preparations containing alcohol that will result in safe blood concentrations in children (1). An example of the use of this equation is given with Sample Prescription 31.2 in Chapter 31.

(3) Alcohol content can be minimized even for solubility purposes by the addition of a less toxic solvent such as glycerin. For example, a recommended formula for phenobarbital elixir cuts down on the alcohol content by the addition of glycerin. This is illustrated with Example 37.5 and Table 37.7 in Chapter 37, Compatibility and Stability of Drug Products and Preparations.

b. Preservatives are not contraindicated but, especially for infants, should be used only when necessary. In some cases, you may substitute refrigeration and a short beyond-use date for the preservative. If this is done, be certain that the caregiver understands the importance of proper storage conditions and the hazards associated with administering a preparation that has passed its beyond-use date.

3. Patients with restrictions based on allergies or medical or physiologic conditions

a. Diabetics: no sugar; alcohol only if necessary and never with oral antidiabetic agents, such as chlorpropamide, which may give a disulfiram reaction

b. Patients on a ketogenic diet: no carbohydrates, including maltodextrin (9), which is a filler in many nonsugar sweeteners

c. Patients with nasogastric tubes: no restrictions, but there is no need to add auxiliary agents such as flavors, sweeteners, or colors

d. Patients who are alcoholics or patients on a drug that gives a disulfiram reaction: no alcohol

B. Liquid vehicles prepared in the pharmacy

1. At one time, many pharmacies, particularly those in hospitals, made their own vehicles for compounding oral liquid dosage forms. Over the last few decades, many excellent liquid vehicles have become available commercially. These manufactured vehicles should be used when possible because they have well-tested formulations with generally longer expiration dates, and they are made with quality control processes that are difficult to duplicate in most pharmacies. Many of these commercial vehicles are described later in section II. C.

2. In some situations, a pharmacy-prepared liquid vehicle is needed. Examples include the following:

a. Special formulation requirements exist. These might include vehicles that are preservative-free or carbohydrate-free, vehicles requiring a very low osmolarity or a particularly low or high pH, and vehicles that meet patient preferences for flavor, components, or vehicle consistency.

b. A vehicle is needed immediately and the pharmacy does not have in stock the needed commercial product.

c. A needed vehicle is temporarily not supplied by the manufacturer.

3. The following are some vehicles that can be made in the pharmacy when this is necessary. Some may be customized and made with or without preservatives, alcohol, flavors, and sweeteners. The first group of vehicles contain sucrose, the second group includes sugar-free vehicles and components, and the final section gives an anhydrous oral liquid vehicle. When the vehicle has a USP or NF monograph, a compounding procedure may be found in the official compendia, including the USP Pharmacists’ Pharmacopeia.

4. Sucrose-containing oral vehicles

a. Syrup NF (Simple Syrup) (10)

(1) This saturated solution of sucrose in water is highly hypertonic. It is an 85% w/v or 65% w/w solution of sucrose in water. Its specific gravity is 1.3.

(2) It has the following formula (10):

This solution is most easily made by adding sucrose to boiling water, but the NF monograph describes a percolation method that does not use heat. If heat is used, care must be exercised to prevent caramelization of the sucrose.

(3) When made correctly, Syrup NF is fully saturated and self-preserving. However, if it is diluted in any way, it will support mold or other microbial growth. When Syrup is diluted in compounding, use precautions such as storage under refrigeration or addition of a preservative. The NF monograph states that it should contain a preservative unless it is used immediately after preparation (10). Syrup has a pH in the range of 5 to 7.

(4) It is available from pharmaceutical vendors, in which case it is preserved, usually with sodium benzoate or potassium sorbate. The paraben-propylene glycol preservative described in Chapter 16 is also an acceptable preservative.

(5) Syrup can be diluted to give liquid vehicles of various concentrations, and other ingredients, such as flavors may be added. It is more useful for compounding oral solutions than suspensions because it does not contain ingredients that provide the structure helpful for suspending particles in a suspension.

b. Citric Acid Syrup

(1) This syrup, also known as Syrup of Lemon, was formerly official in the USP. It contains 1 g of citric acid dissolved in 1 mL of Purified Water, 1 mL of Lemon Tincture, and Syrup sufficient to make 100 mL of preparation (11). Other artificial fruit flavors may be used in place of the Lemon Tincture.

(2) This syrup is useful when a vehicle with an acidic pH is needed, such as for drugs that need an acid vehicle for stability or solubility purposes. It has a pH of approximately 2.5.

(3) Like Syrup NF, Citric Acid Syrup is a saturated sucrose solution which is hypertonic and self-preserving unless diluted. Sodium benzoate and potassium sorbate are useful preservatives for this preparation.

c. Vehicle for Oral Solution NF (10)

(1) This is a sugar-based vehicle that is intended for making oral solutions. Like Syrup, it is not as well suited for making suspensions because it does not contain ingredients to provide the structure helpful for suspending particles in a suspension. It does contain both an antimicrobial preservative system and a buffer to maintain the pH at 4 to 5, a range favorable to the stability of many drugs. It has a content that is similar to that of the commercial vehicle Ora-Sweet.

(2) The official formula contains (10):

The vehicle can be prepared as follows: Place about 30 mL of Purified Water in a beaker that has been precalibrated at 100 mL. Heat the water to 70° to 75°C. Add the glycerin and methylparaben and stir well until the methylparaben is dissolved. Add the dibasic sodium phosphate, citric acid, potassium sorbate, and sorbitol to the beaker and mix thoroughly. Gradually add the sucrose with mixing until it is completely dissolved. Remove the beaker from the heat and allow the solution to cool. Add Purified Water to the calibration mark and mix well. Check the pH of the solution and adjust if necessary to within the range of 4 to 5 (10).

(3) The NF monograph instructs packaging this preparation in a tight, light-resistant container and storing at controlled room temperature; under these conditions, a beyond-use date of 6 months is recommended (10).

(4) Vehicle for Oral Solution, sometimes in combination with Vehicle for Oral Suspension NF (see section B. 5. C. (4) of this chapter) is a formulation component in many USP compounded oral liquid preparations.

d. Suspension Structured Vehicle NF (10)

(1) This vehicle has the advantage of including a preservative–buffer system and xanthan gum, an ingredient that confers some structure and makes this useful as a suspending vehicle for making suspensions. Its disadvantage is that it is more difficult to make than the simpler sucrose-based vehicles.

(2) The formula below is official in NF 25 (10).

To prepare this vehicle, a temperature-controlled hot plate with a magnetic stirring device is very useful, although not essential. Place the potassium sorbate in a beaker precalibrated at 100 mL and add 50 mL of Purified Water to dissolve the potassium sorbate. Use the magnetic stirring device or manual stirring to create a vortex in the solution; then slowly sift the xanthan gum into the solution vortex. Using minimal heat (about 45°C), add the citric acid and the sucrose and stir to dissolve these and obtain a homogeneous mixture. Add Purified Water to the calibration mark and mix well.

(3) The NF monograph instructs packaging this preparation in a tight, light-resistant container, storing at controlled room temperature, and avoiding freezing; under these conditions, a beyond-use date of 30 days is recommended. Because this is a suspension, it should be labeled for the user to shake well before using (10).

e. Natural product flavored syrups

(1) Several other sucrose-containing syrup-type vehicles are official in the NF. These include Acacia Syrup, Cherry Syrup, Chocolate Syrup, Orange Syrup, and Tolu Balsam Syrup. Because these syrups contain natural juices and flavors as ingredients, they are best when freshly made. For example, the Orange Syrup monograph warns that it should not be used if it has a terebinthine odor or taste (10).

(2)

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