Stability

Stability

Physical stability

A solution consists of drug substance solubilized in a vehicle commonly with the aid of pH control, surfactant(s), or cosolvent(s). Physical or chemi-cal changes during storage, such as decrease in the storage temperature, microbial growth resulting in pH change and cosolvent evaporation or loss by selective adsorption, can lead to supersaturation of the drug in the vehi-cle. Supersaturated solutions can form crystal nuclei of the drug when the supersaturated drug concentration reaches above the threshold for nucle-ation (Figure 18.1). The crystal nuclei tend to grow slowly (crystallization) resulting in reduced solution concentration of drug and formation of particu-lates, which, when sufficiently large, can become visible to the naked eye.

Figure 18.1 Time dependence of concentration required for monodispersity. This figure represents supersaturation region of drug solubility between saturation and the concentration that leads to nucleation. (From Narang, A.S. et al., Int. J. Pharm. 345, 9–25, 2007. With Permission.)

In addition, sudden changes in temperature, such as freezing, can result in instantaneous precipitation of the drug in the form of small, amor-phous particles. Formulating a drug solution much below its saturation concentration is preferred to avoid physical instability by precipitation or crystallization.

Chemical stability

Solution dosage form presents an environment with high molecular mobil-ity of reacting species, resulting in higher degradation liability than other dosage forms, such as tablets. Common modes of drug degradation in solution include hydrolysis and oxidation. Drug degradation pathways and stabilization strategies are discussed in Chapter 7.

Degradation of drug in the dosage form leads to decrease in drug potency and formation of impurities. Depending on the therapeutic window and dose of the drug, and the toxicological nature and quantity of impurities formed, the national compendia such as the United States Pharmacopeia (USP) and the international bodies such as the International Council on Harmonization (ICH) recommend maximum limits on the permissible impurities. These limits are identified in terms of reporting, identification, or qualification thresholds—requiring the sponsor of the new drug applica-tion (NDA) to report, identify, or provide toxicological safety data on the given impurity to identify and justify a maximum permissible concentra-tion. In addition, impurities that are suspected to be genotoxic are rigor-ously controlled.

In addition to chemical stability of the drug, adequate potency of other additives critical to the stability and performance of the dosage form, such as antimicrobial agents and antioxidants, must be demonstrated through-out a product’s shelf life.

Microbial stability

Pharmaceutical aqueous solutions generally contain organic com-pounds, including carbohydrates, thus providing a suitable growth environment for bacteria and other microbes. Except in the case of broad-spectrum antibiotics or self-preserving solutions, such as syrups, antimicrobial preservatives are frequently required in solution formu-lations. Methylparaben, propylparaben, and sodium benzoate are the commonly used antimicrobial agents. Methylparaben and propylpara-ben are commonly used in 9:1 w/w ratio at combination at 0.2% w/v total concentration.