The effect of novel surfactants and Solutol HS 15 on paclitaxel aqueous solubility and permeability across a Caco-2 monolayer.

The effect of novel surfactants on the aqueous solubility and the permeability of paclitaxel across a Caco-2 cell monolayer were examined in this work. The solubility and permeability of paclitaxel was evaluated in the presence of four soft surfactants (SS) KXN441, KXN424, KXN437, and KXN 337 and Solutol HS15. All surfactants increased the aqueous solubility of paclitaxel. Caco-2 cell membrane integrity in the presence of SS and Solutol HS15 was assessed by mannitol permeability and LDH release. All surfactants were tested at 0.5x CMC, 5x CMC and 1.5 mM concentrations. The effect of SSs on paclitaxel permeability was concentration dependent. At all concentrations tested, KXN 441 and Solutol HS 15 showed partially inhibition of drug efflux with no discernable change in mannitol permeability or cytotoxicity as observed with LDH release. At these concentrations, other SSs exhibited some partial efflux inhibition along with compromised membrane integrity and increasing mannitol permeability. In conclusion, all SSs were able to increase the aqueous solubility and permeability of paclitaxel across Caco-2 cells monolayer. However, KXN441 and Solutol HS15 were able to enhance paclitaxel permeability across Caco-2 monolayer without cytotoxicity.

Determination of benzalkonium chloride partition in micelle solutions using ultrafiltration method.

The objectives of this study were to determine the concentrations of free benzalkonium chloride (BAC) and apparent partitions coefficients (Km) in micelle solutions and to explore its application in formulation development. Ultrafiltration (UF) was carried out using 10K Nanosep devices and centrifugation at 5,000 rpm for 5 min. The separation of free BAC from micellar solutions was also conducted using ultracentrifugation (UC) method for the comparison with UF method. Capillary electrophoresis method was used for the identification of micelles. Results showed that a UF method was applicable for quantitatively evaluating BAC-micelle interaction in micellar solutions. Unlike UF, UC could not completely separate free BAC from the micelles. The free BAC concentrations in the micelle solutions decreased with increasing surfactant concentrations. Among polysorbate 80, cremophor EL, and tyloxapol, BAC had the highest Km in polysorbate 80 solutions. The Km was significantly lower in non-buffered aqueous solutions than that in citric buffers. Moreover, increasing surfactant concentrations led to reducing antimicrobial activity. The UF is a rapid and accurate method that minimally alters the micellar equilibrium for the determination of free BAC and Km in micellar solutions. In conclusion, free BAC concentration, which is a function of surfactant type, surfactant concentration, and ion strength of solution, is likely associated with the antimicrobial activity.

Polyoxyethylated nonionic surfactants and their applications in topical ocular drug delivery.

Topical dosing of ophthalmic drugs to the eye is a widely accepted route of administration because of convenience, ease of use, and non-invasiveness. However, it has been well recognized that topical ocular delivery endures a low bioavailability due to the anatomical and physiological constraints of the eye which limit drug absorption from the pre-corneal surface. Nonionic surfactants as versatile functional agents in topical ocular drug delivery systems are uniquely suited to meet the challenges through their potential ability to increase bioavailability by increasing drug solubility, prolonging pre-corneal retention, and enhancing permeability. This review attempts to place in perspective the importance of polyoxyethylated nonionic surfactants in the design and development of topical ocular drug delivery systems by assessing their compatibility with common ophthalmic inactive ingredients, their impact on product stability, and their roles in facilitating ocular drugs to reach the target sites.

Rapid and accurate prediction of degradant formation rates in pharmaceutical formulations using high-performance liquid chromatography-mass spectrometry.

Rapid and accurate stability prediction is essential to pharmaceutical formulation development. Commonly used stability prediction methods include monitoring parent drug loss at intended storage conditions or initial rate determination of degradants under accelerated conditions. Monitoring parent drug loss at the intended storage condition does not provide a rapid and accurate stability assessment because often <0.5% drug loss is all that can be observed in a realistic time frame, while the accelerated initial rate method in conjunction with extrapolation of rate constants using the Arrhenius or Eyring equations often introduces large errors in shelf-life prediction. In this study, the shelf life prediction of a model pharmaceutical preparation utilizing sensitive high-performance liquid chromatography-mass spectrometry (LC/MS) to directly quantitate degradant formation rates at the intended storage condition is proposed. This method was compared to traditional shelf life prediction approaches in terms of time required to predict shelf life and associated error in shelf life estimation. Results demonstrated that the proposed LC/MS method using initial rates analysis provided significantly improved confidence intervals for the predicted shelf life and required less overall time and effort to obtain the stability estimation compared to the other methods evaluated.

Rheology and stability of water-in-oil-in-water multiple emulsions containing Span 83 and Tween 80.

Multiple emulsions are often stabilized using a combination of hydrophilic and hydrophobic surfactants. The ratio of these surfactants is important in achieving stable multiple emulsions. The objective of this study was to evaluate the long-term stability of water-in-oil-in-water (W/O/W) multiple emulsions with respect to the concentrations of Span 83 and Tween 80. In addition, the effect of surfactant and electrolyte concentration on emulsion bulk rheological properties was investigated. Light microscopy, creaming volume, and rheological properties were used to assess emulsion stability. It was observed that the optimal surfactant concentrations for W/O/W emulsion long-term stability were 20% wt/vol Span 83 in the oil phase and 0.1% wt/vol Tween 80 in the continuous phase. Higher concentrations of Tween 80 had a destructive effect on W/O/W emulsion stability, which correlated with the observation that interfacial film strength at the oil/water interface decreased as the Tween 80 concentration increased. High Span 83 concentrations increased the storage modulus G' (solidlike) values and hence enhanced multiple emulsion stability. However, when 30% wt/vol Span 83 was incorporated, the viscosity of the primary W/O emulsion increased considerably and the emulsion droplets lost their shape. Salt added to the inner aqueous phase exerted an osmotic pressure that caused diffusion of water into the inner aqueous phase and increased W/O/W emulsion viscosity through an increase in the volume fraction of the primary W/O emulsion. This type of viscosity increase imposed a destabilizing effect because of the likelihood of rupture of the inner and multiple droplets.

Ostwald ripening of water-in-hydrocarbon emulsions.

The purposes of this study are to determine Ostwald ripening rates in water-in-oil (W/O) emulsions and evaluate the potential application of the LSW theory to W/O emulsions. Water-in-oil emulsions were prepared by mixing water and hydrocarbon phases containing Span 83 and homogenizing. n-Heptane, n-decane, n-dodecane, and n-tetradecane were used to obtain a range of solubilities. A linear increase in the cube of the droplet size with time was observed (within the initial period of 1-2 h after emulsion preparation), supporting the LSW theory. Based on this linear relationship, Ostwald ripening rates were determined to be 3.0 x 10(-24), 2.3 x 10(-24), 1.8 x 10(-24), and 5.8 x 10(-25) m3 s(-1) for water-in-heptane, water-in-decane, water-in-dodecane, and water-in-tetradecane emulsions, respectively. These values are in agreement with theoretical predictions calculated using the LSW equation. It was observed that the ripening process gradually slowed, resulting in deviations from the LSW theory. This was attributed to the effect of the interfacial surfactant film through which the dispersed material has to diffuse during Ostwald ripening. This effect is not taken into consideration by the LSW theory. The results showed that Ostwald ripening of W/O emulsions was less sensitive to the nature of oil used and slower compared to O/W emulsions consisting of the same hydrocarbons.

Multiple emulsion stability: pressure balance and interfacial film strength.

The objective of this study was to investigate the significance of inner and outer phase pressure, as well as interfacial film strength on W/O/W multiple emulsion stability using microscopy and long-term stability tests. It was observed that immediately upon applying a coverslip to samples the multiple droplets deformed and there was coalescence of the inner aqueous droplets. Under certain conditions (such as lipophilic surfactant concentration and internal phase osmotic pressure) the destabilized multiple emulsions formed unique metastable structures that had a "dimpled" appearance. The formation of these metastable structures correlated with the real-time instability of the W/O/W multiple emulsions investigated. Multiple emulsion stability also correlated with the interfacial film strength (measured by interfacial elasticity) of the hydrophobic surfactant at the mineral oil/external continuous aqueous phase interface. The formation of the metastable dimpled structures and the long-term stability of the multiple emulsions were dependent on the osmotic pressure of the inner droplets and the Laplace curvature pressure as described by the Walstra Equation (P. Walstra, "Encyclopedia of Emulsion Technology" (P. Becher, Ed.), Vol. 4. Dekker, New York, 1996). It appears that the effect of coverslip pressure on multiple emulsions may be useful as an accelerated stability testing method or for initial formulation screening.