Low temperature vacuum drying: evaluation of excipients in injectable dosage forms.

Low temperature vacuum drying is an alternative to sterile dry filling as a formulation approach for certain ethanol soluble substances that are poorly soluble or unstable in aqueous media. To date this ap­ proach has been limited to formulations containing the drug per se. However, several substances appear suitable as excipients in­ cluding urea, polyethylene glycol 4000, ascorbic acid, methylparaben, and propyl­ paraben. Ascorbic acid appears to increase the stability of bruceantin, a novel plant product that exhibits antitumor activity. Introduction Drugs with limited stability in aqueous so­ lution are usually formulated as sterile "dry fill" preparations or as lyophilized dosage forms that are constituted with a sterile aqueous vehicle before administration. Lyophilization has several advantages over the "dry fill" technique including lower incidence of contamination with insoluble particulate matter (1), more rapid dissolution after reconstitution, and more precise fill tolerances (2). In addition, there may be less risk to health of personnel involved in manufacturing since the material is in dilute solution rather than a concentrated solid. This aspect is of particular concern with locally irritating compounds including certain antitumor agents (3). Unfortunately, lyophilization is an ex­ pensive process and is limited to aqueous so­ lutions. Conventional freeze drying of aqueous solutions containing volatile organic solvents (i.e., water-ethanol mixtures) is unacceptable since expulsion of the drug substance fre­ quently occurs during the drying cycle. Flamberg et al. (4) have described a low temperature vacuum drying technique for the preparation of sterile dry pharmaceuticals from ethanol. The process utilizes a conven­ tional freeze dryer equipped with an external condenser (outside the drying chamber). The solvent does not freeze but slowly evaporates under low pressure and collects on chilled (—70 °C) condenser plates leaving the drug as a dry residue in vials. Depending on solubility the vial contents are dissolved directly in sterile water, dilute ethanol, or undiluted ethanol and then water before administration. The low temperature vacuum drying technique has been used to date in formulations containing only the drug substance. However, we have recently had to formulate several potent plant products that require addition of bulking agents, pH adjustment, antioxidants, etc., to optimize the product. This report evaluates several excipients that may be included in dosage forms processed by low temperature vacuum drying.