Top Ten Additives Commonly Used In Parenteral Products
Simple is better when it comes to parenteral drug formulations. Safety considerations limit the number and choices of additives available for use in parenteral products. In an ideal world, an injectable would only include the active ingredient and water. However, therapeutic molecules and biologics require additives to support their stability, solubility, and biological compatibility when in solution or freeze-dried form. Most parenteral formulations contain at least one additive other than the active ingredient. The majority of formulations contain two or more additives. Below we describe the top ten additives, by type and category, for use in parenteral drug formulations.
#1: Water
Most liquid therapeutic preparations are dilute. Thus, most of the parenteral preparation is the carrier liquid “vehicle” component of the preparation. Of the vehicles available, water is the safest, cheapest, and easiest to use. As a result, water is used in parenteral products whenever possible.
#2: Water-Miscible Co-Solvents
Several solvents can mix evenly with water and have been used as a portion of the vehicle in parenteral formulations. These solvents are used to solubilize certain drugs in water and reduce the drug’s chemical breakdown in water. The most critical solvents that are miscible in water are ethyl alcohol, liquid polyethylene glycol, and propylene glycol. Ethyl alcohol is used particularly in intramuscular preparations. There are limitations with the amount of co-solvent that can be administered due to the risk of cellular toxicity, red blood cell destruction, and drug precipitation (drug falling out of solution) at the injection site.
#3: Nonaqueous Vehicles (Oils)
Oily vehicles, if used, cannot be administered intravenously. The most popular nonaqueous vehicles are fixed oils. Fixed oils must come from a vegetable origin to be metabolized in the body, be a liquid at room temperature, and not become rancid easily. The popular oils for parenteral use are corn oil, cottonseed oil, peanut oil, and sesame oil. Fixed oils are used particularly as vehicles for certain hormone and vitamin preparations. If fixed oils are used, labels must state the vehicle’s name so that any users with allergies avoid product use.
#4: Solubilizing Agents
Solubilizing agents are either co-solvents, complexing agents, or surface-active agents. Ethanol and propylene glycol are the most used co-solvents. Both ethanol and propylene glycol are non-toxic in most parenteral product ranges and can solubilize organic molecules because of a dielectric constant in the 24 to 32 range (water is 78, cottonseed oil is 3). Since poorly soluble drugs will have greater solubility in solvents whose dielectric constant is not as high as water, mixtures of water and one or more water-miscible co-solvent will solubilize slightly polar drugs. The primary problem in using co-solvents is toxicity since all co-solvents destroy red blood cells. If the drug dosage is large (i.e., greater than 5 mL), alternatives to co-solvents are often needed.
Complexing agents or surface-active agents can be used instead of co-solvents. Complexing and surface-active agents are often amphiphilic molecules that can interact with hydrophobic (water-insoluble) and hydrophilic (water-soluble) compounds. Nonionic polyoxyethylene fatty acids (Polysorbates or Tweens) are the most popular surface-active agents used in parenteral formulations. Specifically, polysorbates 20 (polyoxyethylene sorbitan monolaurate) and 80 (polyoxyethylene sorbitan monooleate) are widely used in parenteral formulations. In addition to solubility, surface-active agents are used for biopharmaceutical product development to keep large molecules from aggregating. The most used complexing agent is Captisol R.
#5: Antimicrobial Agents
Antimicrobial agents do not apply to all parenteral product formulations. Single-dose containers don’t require an antimicrobial agent, and large-volume single-dose preparations must not have antimicrobial preservatives. However, antimicrobial agents must be included in parenteral formulations packaged in multiple-dose containers to prevent the growth of microorganisms inadvertently introduced into the preparation while withdrawing partial doses. Antimicrobials are inherently toxic to the patient and must remain within the USP prescribed maximum volume and concentration limits. Benzyl alcohol, phenol, and parabens are the most widely used antimicrobial preservative agents used in injectable products. Phenol and benzyl alcohol are the most common antimicrobial preservatives used in peptide and protein products. Phenoxyethanol is the most frequently used preservative in vaccine products.
#6: Buffers
Buffering agents stabilize a solution against chemical degradation or (in the case of proteins) physical degradation. Buffers are particularly used for pH adjustments. The acid salts most frequently used as buffering agents are citrates, acetates, and phosphates.
#7: Antioxidants
Antioxidants (also known as reducing agents) are preservatives that prevent drug oxidation. Sodium bisulfite and other sulfurous acid salts are the most popular antioxidants for parenteral formulations. Ascorbic acid and its salts and the sodium salt of ethylenediaminetetraacetic acid (EDTA) are also used. If avoiding an additive, displacing the air (oxygen) in and above the solution by purging with inert gas, such as nitrogen, can also control a sensitive drug’s oxidation.
#8: Tonicity Agents
Ideally, every injectable product is isotonic. However, isotonicity is not a requirement for small volume injectables that are administered intravenously. Products administered by all other routes, especially into the eye or spinal fluid, must be isotonic to avoid local cellular tissue damage and pain or tissue irritation upon injection. The most common isotonicity additives are electrolytes (sodium chloride), glycerin, and mono- or disaccharides.
#9: Cryoprotectants and Lyoprotectants
Cryoprotectants and lyoprotectants are specific to biopharmaceutical products and shield biopharmaceuticals from adverse effects during freeze-dry processing. Nonreducing sugars (such as sucrose or trehalose), amino acids (such as glycine or lysine), polymers (such as liquid polyethylene glycol or dextran), and polyols (such as mannitol or sorbitol) are used as cryoprotectants and lyoprotectants.
#10: Competitive Binders
Competitive binders are used if the active ingredient binds excessively to packaging containers or manufacturing equipment surfaces. Competitive binders keep drug formulation potency by competing with the active ingredient for the surface-binding sites. The most popular competitive binder is recombinant human serum albumin (HSA) at concentrations ranging from 0.1% to 1.0%.
Summary
Overall, many solvents and solutes are used to keep parenteral drug formulations safe, stable, and solubilized. While it is best to keep drug formulations as simple as possible, as small molecules and biomolecules increase in complexity, additional additives will be required to ensure these therapeutics are safely administered to patients. Parenteral drug formulation is an extensive process involving repetitive trial and error. If you are looking to outsource the R&D process development work for your parenteral drug formulation, ensure you choose a contract manufacturing organization that can support your unique product needs.
References
Michael J. Akers. Sterile Drug Products Formulation, Packaging, Manufacture, and Quality. Drugs and the Pharmaceutical Sciences. Informa Healthcare. 2010.
