PH-Dependent solubility and dissolution of bupivacaine and its relevance to the formulation of a controlled release system

Abstract

Bupivacaine, a local anesthetic is currently being formulated into a biodegradable drug delivery system for prolonged analgesic effect in conditions such as post surgical pain due to herniorrhaphy and thoracotomy. Preformulation studies were conducted to investigate the solubility and dissolution properties of the free base and the hydrochloride salt to select an appropriate drug form for formulation development. The pH solubility profiles showed that the solubility of the unionized form was about 0.15–0.25 mg/ml at pH 8–12, while solubility of the ionized form was 40–50 mg/ml between pH 1.8 to 6. Below pH 1.8, the solubility decreased due to the common ion effect. Overall the pH solubility profiles of the base and salt form were similar. pKa of 8.24 estimated from the pH solubility profile agree with the literature value of 8.17 determined potentiometrically. The intrinsic dissolution rates (IDR) of the base and the HCl salt were determined at 37°C using the Wood's methodology. The IDRs of the base and the HCl salt differed significantly at each pH value and there was no similarity in their pH-dependence despite very similar pH solubility profiles. To explain this anomalous behavior, the solubility of both forms was determined in the dissolution medium at 37°C, and the change in pH of the dissolution medium due to ionization and saturation was monitored. The solubility in the dissolution medium is the solubility in the diffusion layer pH ( C sh = 0). The IDRs of both forms correlated very well with the solubility in the dissolution medium and followed similar pH dependence as expected based on the Noyes-Whitney equation. However, the solubility in the dissolution medium was considerably different from the solubility value of the pH solubility profile at each pH value studied from pH 1 to pH 9 for both the base and the HCl salt form of drug. It was observed that when the dissolving species was undergoing a reaction during dissolution, ionization or unionization; i.e. base at pH 1–5 and salt at pH 5–9, the pH of the dissolution medium was altered and appeared to buffer between pH 4–7. This altered pH has been defined as the diffusion layer pH in the literature. It is the solubility of the dissolving species in the diffusion layer at pH h = 0, which determines the IDR, rather than the solubility in medium at bulk pH. Thus, pH-dependent behavior of IDR of the base and the HCl salt was explained on the basis of self-buffering action of the dissolving species in the diffusion layer. The IDR of base at pH 7.4 was very low and 1.2% of that at pH 1, thus base may not be suitable for the biodegradable device, from which predominant release mechanism is erosion. In contrast, the HCl salt had higher IDRs in the pH range of 1–7.4. The results also suggested that an alteration of the microclimate environment such as pH due to bioerosion of the device can have significant influence on the dissolution and hence the release properties of the drug delivery system. Therefore, these types of preformulation studies are necessary to select an appropriate form of drug to obtain the desired release properties from controlled release product.