Characterization of nasal spray pumps and deposition pattern in a replica of the human nasal airway.

Deposition patterns are described of a nasal spray formulation for a novel rhinovirus protease inhibitor. These patterns, which were generated from different nasal spray pumps, were characterized using a multisectional nasal airway model. A human nasal replica was made from an in vivo magnetic resonance imaging (MRI) scan of an adult male human. The nasal replica consisted of 77 acrylic plastic sections, 1.5-mm thick. Our data showed that the aerosols were deposited mainly in the anterior and turbinate regions with little passing beyond the nasopharyngeal region. Detailed deposition information from the turbinate region indicated that deposition was high toward the anterior portion where most deposition was concentrated on the inferior meatus. Spray droplets were also deposited in spots of the middle and posterior portions of the turbinate region, and this nonuniform deposition pattern may be correlated with the flow pattern. The spray angle and droplet size of the nasal spray were found to be important in influencing the deposition pattern in the nasal airway. The droplet size was determined by a laser-diffraction technique and the spray angle by high-speed photography. Larger droplets and a wider spray angle increased deposition in the anterior region of the nasal airway, which prevented more material from depositing in the turbinate region.

Parenteral formulation of Flavopiridol (NSC-649890).

Flavopiridol [5,7-dihydroxy-8-(4-N-methyl-2-hydroxypyridyl)-6' -chloroflavone hydrochloride] is a flavonoid with weak electrolyte properties and an intrinsic aqueous solubility of 0.024 mg/mL. Neither cosolvency complexation, nor pH control alone can produce an acceptable 10 mg/mL formulation that will not precipitate when diluted with blood. However, a combination of buffer and cyclodextrin or buffer and cosolvent can produce an acceptable 10 mg/mL formulation. In this paper, Flavopiridol is shown to be stable for at least one year in 30% hydroxypropyl beta-cyclodextrin/0.1 M citrate buffer (4.52). This formulation does not precipitate for at least one hour upon dilution with Sorensen's phosphate buffer pH 7.4.

Studies in phlebitis VIII: evaluations of pH solubilized intravenous dexverapamil formulations.

Injectable and infusion formulations of dexverapamil are evaluated for their potential to produce phlebitis. The evaluation technique utilizes two independent in vitro methods and two in vivo methods to screen a pH solubilized drug for its potential to induce phlebitis due to precipitation at the injection site. One method is based upon a theoretical calculation that simulates the change of solubility upon dilution. Its predictions are confirmed by the second method which consists of an in vitro precipitation experiment. Thermal and visual evaluations are then obtained from an in vivo rabbit ear injection. Dexverapamil formulations that have low buffering capacity are shown to contribute to the incidence of phlebitis to a greater extent than the properly buffered formulations. The calculation and the in vitro precipitation experiment are found to be useful in formulating pH solubilized parenterals. They enable the formulator to optimize pH, drug concentration, and buffer concentration without the need for animal studies. The results of this study show the importance of selecting a buffer that provides adequate buffer capacity in the formulations.

Studies in phlebitis. VII: In vitro and in vivo evaluation of pH-solubilized levemopamil.

We describe a computational model and an in vitro experiment for assessing whether or not a pH-solubilized drug has the potential to precipitate upon dilution with blood. The computational model enables an efficient means of selecting buffer concentration and pH, and the in vitro test provides a simple experimental validation. Both means of screening are applied to the formulation of the weakly basic drug levemopamil-HCI. A buffered formulation of levemopamil is chosen from the computational model and shown to be free of precipitation upon dilution in vitro and to not produce phlebitis in the rabbit ear model. In comparison, an unbuffered formulation at the same pH and drug concentration precipitates in vitro and causes significant phlebitis in vivo. The results of this study reinforce the importance of buffering parenteral formulations instead of simply adjusting the pH of the formulation.

Self-association of dexverapamil in aqueous solution.

The pKa and intrinsic solubility of monomeric dexverapamil were determined from its pH-solubility profile to be 8.90 and 6.6 x 10(-5) M, respectively. The solubility of dexverapamil below pH 7.0 was higher than expected on the basis of the aforementioned values. This unusually high solubility is believed to be due to the self-association of cationic dexverapamil. The apparent pKa of the self-associated drug is estimated to be approximately 7.99. The self-association of dexverapamil hydrochloride is supported by the fact that it is surface active and that it increases the solubility of both naphthalene and anthracene in aqueous solutions. The dependence of the drug solubility on pH and the solubilization of naphthalene and anthracene as a function of ionized drug concentration suggest that the self-associated dexverapamil is a cationic dimer.