Parenteral Dosage Forms

Solutions

Most injectable products are solutions. Solutions of drugs suitable for parenteral administration are referred to as injections. Although usually aqueous, they may be mixtures of water with glycols, alcohol, or other nonaqueous solvents. Many injectable solutions are manufactured by dissolving the drug and any excipients, adjusting the pH, sterile filtering the resultant solution through a 0.22-p.m membrane filter, and, when possible, autoclaving the final product. Most solutions have a viscosity and surface tension very similar to water, although streptomycin sulfate injection and ascorbic acid injection, for example, are quite viscous.

Sterile filtration, with subsequent aseptic filling, is common because of the heat sensitivity of many drugs. Those drug solutions that can withstand heat should be terminally autoclave sterilized after filling, since this best assures product sterility.

LVPs and small-volume parenterals (SVPs) containing no antimicrobial agent should be terminally sterilized. It is common practice to include an antimicrobial agent in SVPs, which cannot be terminally sterilized or is intended for multiple-dose use. The general exceptions are products that pass the USP Antimicrobial Preservative Effectiveness Test (1) because of the antimicrobial activity of the active ingredient, vehicle, pH, or a combination of these. For example, some barbiturate products have a pH of 9 to 10 and a vehicle that includes propylene glycol and ethanol.

Injections and infusion fluids must be manufactured in a manner that will minimize or eliminate extraneous particulate matter. Parenteral solutions are generally filtered through 0.22-p.m membrane filters to achieve sterility and remove particulate matter. Prefiltration through a coarser filter is often necessary to maintain adequate flow rates, or to prevent clogging of the filters during large-scale manufacturing. A talc or carbon filtration aid (or other filter aids) may also be necessary. If talc is used, it should be pretreated with a dilute acid solution to remove surface alkali and metals.

The formulator must be aware of the potential for binding when filtering protein solutions. Because of the cost of most protein materials, a membrane that minimizes protein adsorption to the membrane surface should be used. Typical filter media that minimize this binding include hydrophilic polyvinylidene difluoride and hydroxyl-modified hydrophilic polyamide membranes (17). Filter suppliers will evaluate the compatibility of the drug product with their membrane media and also validate bacterial retention of the selected membrane.

The total fluid volume that must be filled into a unit parenteral container is typically greater than the volume that would contain the exact labeled dose. The fill volume is dependent on the viscosity of the solution and the retention of the solution by the container and stopper. The USP provides a procedure for calculating the fill dose that is necessary to ensure the delivery of the stated dose. It also provides a table of excess volumes that are usually sufficient to permit withdrawal and administration of the labeled volume.

Suspensions

One of the most difficult parenteral dosage forms to formulate is a suspension. It requires a delicate balance of variables to formulate a product that is easily resuspended and can be ejected through an 18- to 21-gauge needle through its shelf life. To achieve these properties, it is necessary to select and carefully maintain particle size distribution, Z-potential, and rheological properties, as well as the manufacturing steps that control wettability and surface tension. The requirements for, limitations in, and differences between the design of injectable suspensions and other suspensions have been previously summarized (18-20).

A formula for an injectable suspension might consist of the active ingredient suspended in an aqueous vehicle containing an antimicrobial preservative, a surfactant for wetting, a dispersing or suspending agent, and perhaps a buffer or salt.

Two basic methods are used to prepare parenteral suspensions: (i) sterile vehicle and powder are combined aseptically or (ii) sterile solutions are combined and the crystals formed in situ. Examples of these procedures may be illustrated using penicillin G procaine injectable suspension USP and sterile testosterone injectable suspension USP.

In the first example, procaine penicillin, an aqueous vehicle containing the soluble components (such as lecithin, sodium citrate, povidone, and polyoxyethylene sorbitan monooleate) is filtered through a 0.22-p.m membrane filter, heat sterilized, and transferred into a presterilized mixing-filling tank. The sterile antibiotic powder, which has previously been produced by freeze-drying, sterile crystallization, or spray-drying is aseptically added to the sterile solution while mixing. After all tests have been completed on the bulk formulation, it is aseptically filled.

An example of the second method of parenteral suspension preparation is testosterone suspension. Here, the vehicle is prepared and sterile filtered. The testosterone is dissolved separately in acetone and sterile filtered. The testosterone-acetone solution is aseptically added to the sterile vehicle, causing the testosterone to crystallize. The resulting suspension is then diluted with sterile vehicle, mixed, the crystals allowed to settle, and the supernatant solution siphoned off. This procedure is repeated several times until all the acetone has been removed. The suspension is then brought to volume and filled in the normal manner.

The critical nature of the flow properties of parenteral suspensions becomes apparent when one remembers that these products are frequently administered through 1-in. or longer needles having internal diameters in the range of only 300 to 600 mm. In addition, microscopic examination shows a very rough interior needle surface, further hindering flow. The flow properties of parenteral suspensions are usually characterized on the basis of syringeability or injectability. The term "syringeability" refers to the handling characteristics of a suspension while drawing it into and manipulating it in a syringe. Syringeability includes characteristics such as ease of withdrawal from the container into the syringe, clogging and foaming tendencies, and accuracy of dose measurement. The term "injectability" refers to the properties of the suspension during injection; it includes such factors as pressure or force required for injection, evenness of flow, aspiration qualities, and freedom from clogging. The syringeability and injectability characteristics of a suspension are closely related to viscosity and particle characteristics.

Emulsions

An emulsion is a dispersion of one immiscible liquid in another. This inherently unstable system is made possible through the use of an emulsifying agent, which prevents coalescence of the dispersed droplets. Parenteral emulsions have been used for several purposes, including (i) w/o emulsions of allergenic extracts (given subcutaneously) and (ii) o/w sustained-release depot preparations (given intramuscularly). Formulation options are severely restricted through a very limited selection of stabilizers and emulsifiers, primarily owing to the dual constraints of autoclave sterilization and parenteral injection. Additionally, unwanted physiological effects (e.g., pyrogenic reaction and hemolysis) have further limited the use of IV emulsions.

An increasingly popular class of IV emulsions is lipid emulsions. These preparations have been available in Europe and the United States for over 25 years. Fat is transported in the bloodstream as small droplets called chylomicra. Chylomicra are 0.5 to 1.0 mm spheres consisting of a central core of triglycerides and an outer layer of phospholipids. IV fat emulsions usually contain 10% oil, although they may range up to 20% (Table 3). These emulsions yield triglycerides that provide essential fatty acids and calories during total parenteral nutrition of patients who are unable to absorb nutrients through the gastrointestinal tract. The products commercially available in the United States range from 0.1 to 0.5 mm and have a pH of 5.5 to 8 (blood plasma has a pH of 7.4). Glycerol is commonly added to make the product isotonic. IV lipid emulsions are usually administered in combination with dextrose and amino acids. Drugs are generally not added to these admixtures, with common exceptions being heparin, insulin, and ranitidine.

Dry Powders

Many drugs are too unstable—physically or chemically—in an aqueous medium to allow formulation as a solution, suspension, or emulsion. Instead, the drug is formulated as a dry powder that is reconstituted by addition of water before administration. The reconstituted product is usually an aqueous solution; however, occasionally it may be an aqueous suspension (e.g., ampicillin trihydrate and spectinomycin hydrochloride are sterile powders that are reconstituted to form a sterile suspension).

Table 3 IV Fat Emulsions Composition in % (w/v)

Component

(g/100 mL) Intralipida Liposyn IIb Infonutrolc Lipofundind Liphysane

Table 3 IV Fat Emulsions Composition in % (w/v)

Component

(g/100 mL) Intralipida Liposyn IIb Infonutrolc Lipofundind Liphysane

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