Liquid Formulations

Liquid formulations for parenteral use require preparation methods and composition that make the formulation stable and sterile. Other requirements for parenteral formulations are given by the European Pharmacopoeia such as tonicity, efficacy of the antimicrobial preservatives, and no content of endotoxins as well as the formulation being essentially free of particles (66). When preparing liquid formulations, the researcher distinguishes between whether the formulation should be a suspension or a homogeneous solution. The choice might depend on the drug properties. However, stability issues and pharmacological effect profiles should be considered as well. Suspensions are a much greater challenge to formulate than simple solutions and often freeze-dried simple solutions are chosen as opposed to suspensions (7). Wang (1999) gives an excellent review on the various excipients used in liquid formulations and their effect on the chemical and physical stability (18).

Solution

In liquid formulation, optimizing the pH, in essence, optimizing the hydrolytic stability is a major issue. It is important to study the stability especially in the range from pH 3 to 10 early on in the formulation process. The solubility depends on the pH value, as does the physical and chemical stability. There is usually a close relationship between optimum solubility and stability. Minimum solubility is observed around the pi values of the proteins. Typically, one would determine the pH range for obtaining the proper solubility and concentration for dosage and then optimize the stability afterwards (18,67).

The way to maintain the pH of the liquid solutions is to add an appropriate buffer system. This may also affect the overall stability of the formulation; for example, the rate of deamidation appears faster in phosphate and bicarbonate buffers than in sulfate, nitrate, acetate, chloride, and pyruvate buffers (30). The ionic strength of the solution changes as the buffer concentration and other excipients, for example, salts to adjust the tonicity, are added, and this has an influence not just on the stability but also on the solubility (18).

One of the major chemical degradation pathways is oxidation, and therefore the oxidative stability in solution has to be optimized. This can be done by choosing proper preparation procedures, storage temperature, and vials, or by addition of antioxidant. Preparing under inert gas, for example, nitrogen, packing in vials, and using stoppers that do not leach can minimize oxidation (18,30). The antioxidants are typically of three different types: true antioxidants, reducing agents, and chelating agents. Typical excipients and their function in formulations are shown in Table 6.

Physical stability can be optimized by selective choices to avoid adsorption to surfaces. For example, by avoiding unneeded agitation, minimizing the surplus air in the vials (exposure to the air-liquid interface), and adding excipients that are more surface-active than the protein itself. Regarding the increase of the competitive adsorption, some of the more frequently used excipients here are surfactants, for example, polysorbates. Cyclodextrin, albumin, or other proteins can also be used to prevent adsorption of the drug. However, the addition can also have adverse effects on the formulation. In the pharmaceutical product Eprex (Janssen-Cilag) containing the protein erythropoietin (EPO), human serum albumin (HSA) was exchanged for polysorbate 80, glycin was added, and the rubber stopper exchanged. One or more of these changes caused an increase in the immunogenicity (68,69).

There are two main mechanisms of solvent-induced stabilization of proteins: (i) strengthening of the protein-stabilizing forces or (if) destabilization of the denatured state (18). The most tenable and widely accepted mechanism of protein stabilization in aqueous solution is the preferential interaction of proteins. Preferential interaction indicates that a protein prefers to interact with either water or the excipient. The two conventionally applied terms are: preferential hydration, which means that a protein prefers to interact with water, or preferential exclusion, which means that for example the excipient is

Table 6 Typical Excipients and Their Function in Formulations (18,29,30,73)

Formulation effect

Excipient type

Example

Antiadsorption

Surfactants

Polysorbate 80, poloxamer 188, dextran

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