Toward Developing Discriminating Dissolution Methods for Formulations Containing Nanoparticulates in Solution: The Impact of Particle Drift and Drug Activity in Solution.

Enabling formulations are an attractive approach to increase the dissolution rate, solubility, and oral bioavailability of poorly soluble compounds. With the growing prevalence of poorly soluble drug compounds in the pharmaceutical pipeline, supersaturating drug delivery systems (SDDS), a subset of enabling formulations, have grown in popularity due to their properties allowing for drug concentrations greater than the corresponding crystalline solubility. However, the extent of supersaturation generated as the enabling formulation traverses the gastrointestinal (GI) tract is dynamic and poorly understood. The dynamic nature of supersaturation is a result of several competing kinetic processes such as dissolution, solubilization by formulation and endogenous surfactants, crystallization, and absorption. Ultimately, the free drug concentration, which is equivalent to the drug's inherent thermodynamic activity amid these kinetic processes, defines the true driving force for drug absorption. However, in cases where solubilizing agents are present (i.e., surfactants and bile salts), drug molecules may associate with colloidal nanoscale species, complicating drug activity determination. These nanoscale species can drift into the aqueous boundary layer (ABL), increasing the local API activity at the membrane surface, resulting in increased bioavailability. Herein, a novel approach was developed to accurately measure thermodynamic drug activity in complex media containing drug distributed in nanoparticulate species. This approach captures the influence of the ABL on the observed flux and, ultimately, the predicted unbound drug concentration. The results demonstrate that this approach can help to (1) measure the true extent of local supersaturation in complex systems containing solubilizing excipients and (2) elucidate the mechanisms by which colloidal aggregates can modulate the drug activity in solution and potentially enhance the flux observed across a membrane. The utilization of these techniques may provide development scientists with a strategy to evaluate formulation sensitivity to nanospeciation and allow formulators to maximize the driving force for absorption in a complex environment, perhaps enabling the development of dissolution methods with greater discrimination and correlation to pre-clinical and clinical data sets.

Development of a Robust Method for Simultaneous Quantification of Polymer (HPMC) and Surfactant (Dodecyl ß-D-Maltoside) in Nanosuspensions.

This report describes the development of a chromatographic method for the simultaneous quantification of a polymer, hydroxypropyl methylcellulose (HPMC), and a surfactant, dodecyl ß-D-maltoside (DM), that are commonly used in the physical stabilization of pharmaceutical formulations such as nanosuspensions and solid dispersions. These excipients are often challenging to quantify due to the lack of chromophores. A reverse phase size exclusion chromatography (SEC) with evaporative light scattering detector (ELSD) technique was utilized to develop an accurate and robust assay for the simultaneous quantification of HPMC and DM in a nanosuspension formulation. The statistical design of experiments was used to determine the influence of critical ELSD variables including temperature, pressure, and gain on accuracy, precision, and sensitivity of the assay. A robust design space was identified where it was determined that an increase in the temperature of the drift tube and gain of the instrument increased the accuracy and precision of the assay and a decrease in the nebulizer pressure value increased the sensitivity of the assay. In the optimized design space, response data showed that the assay could quantify HPMC and DM simultaneously with good accuracy, precision, and reproducibility. Overall, SEC-ELSD proved to be a powerful technique for the simultaneous quantification of HPMC and DM. This technique can be used to quantify the amount of HPMC and DM in nanosuspensions, which is critical to understanding their effects on the physical stability of nanosuspensions.

Thermodynamics of aggregate formation between a non-ionic polymer and ionic surfactants: An isothermal titration calorimetric study.

This report examines the energetics of aggregate formation between hydroxypropyl methylcellulose (HPMC) and model ionic surfactants including sodium dodecyl sulfate (SDS) at pharmaceutically relevant concentrations using the isothermal titration calorimetry (ITC) technique and a novel treatment of calorimetric data that accounts for the various species formed. The influence of molecular weight of HPMC, temperature and ionic strength of solution on the aggregate formation process was explored. The interaction between SDS and HPMC was determined to be an endothermic process and initiated at a critical aggregation concentration (CAC). The SDS-HPMC interactions were observed to be cooperative in nature and dependent on temperature and ionic strength of the solution. Molecular weight of HPMC significantly shifted the interaction parameters between HPMC and SDS such that at the highest molecular weight (HPMC K-100M;>240kDa), although the general shape of the titration curve (enthalpogram) was observed to remain similar, the critical concentration parameters (CAC, polymer saturation concentration (Csat) and critical micelle concentration (CMC)) were significantly altered and shifted to lower concentrations of SDS. Ionic strength was also observed to influence the critical concentration parameters for the SDS-HPMC aggregation and decreased to lower SDS concentrations with increasing ionic strength for both anionic and cationic surfactant-HPMC systems. From these data, other thermodynamic parameters of aggregation such as ΔHagg°, ΔGagg°, Hagg°, ΔSagg°, and ΔCp were calculated and utilized to postulate the hydrophobic nature of SDS-HPMC aggregate formation. The type of ionic surfactant head group (anionic vs. cationic i.e., dodecyltrimethylammonium bromide (DTAB)) was found to influence the strength of HPMC-surfactant interactions wherein a distinct CAC signifying the strength of HPMC-DTAB interactions was not observed. The interpretation of the microcalorimetric data at different temperatures and ionic strengths while varying properties of polymer and surfactant was a very effective tool in investigating the nature and energetics of HPMC and ionic surfactant interactions.

Determination of key parameters for a mechanism-based model to predict Doxorubicin release from actively loaded liposomes.

Despite extensive study of liposomal drug formulations, reliable predictive models of release kinetics in vitro and in vivo are still lacking. Progress in the development of robust, predictive release models has been hindered by a lack of systematic, quantitative characterization of these complex drug delivery systems with respect to the myriad of factors that may influence drug release kinetics and the wide range of dissolution media/methods employed to monitor release. In this paper, the key processes and parameters needed to develop a complete mechanism-based model for doxorubicin release from actively loaded liposomal formulations resembling Doxil(®) are determined. Quantitative models must account for the driving force(s) [i.e., activity gradient(s) of the permeable species between the intraliposomal and external media] and the permeability-area product(s) for lipid bilayer transport. These factors are intertwined as membrane permeability-area products require knowledge of the drug species and concentrations that account for the release. The necessary information includes values for the drug pKa, identity of the permeable species and species permeability coefficients, a model to describe drug self-association and the relevant equilibrium constant(s), the bilayer/water partition coefficient of the predominant drug species under relevant pH conditions, and the solubility product (Ksp ) for intraliposomal precipitates that exist in such formulations.

Mechanistic model and analysis of doxorubicin release from liposomal formulations.

Reliable and predictive models of drug release kinetics in vitro and in vivo are still lacking for liposomal formulations. Developing robust, predictive release models requires systematic, quantitative characterization of these complex drug delivery systems with respect to the physicochemical properties governing the driving force for release. These models must also incorporate changes in release due to the dissolution media and methods employed to monitor release. This paper demonstrates the successful development and application of a mathematical mechanistic model capable of predicting doxorubicin (DXR) release kinetics from liposomal formulations resembling the FDA-approved nanoformulation DOXIL® using dynamic dialysis. The model accounts for DXR equilibria (e.g. self-association, precipitation, ionization), the change in intravesicular pH due to ammonia release, and dialysis membrane transport of DXR. The model was tested using a Box-Behnken experimental design in which release conditions including extravesicular pH, ammonia concentration in the release medium, and the dilution of the formulation (i.e. suspension concentration) were varied. Mechanistic model predictions agreed with observed DXR release up to 19h. The predictions were similar to a computer fit of the release data using an empirical model often employed for analyzing data generated from this type of experimental design. Unlike the empirical model, the mechanistic model was also able to provide reasonable predictions of release outside the tested design space. These results illustrate the usefulness of mechanistic modeling to predict drug release from liposomal formulations in vitro and its potential for future development of in vitro - in vivo correlations for complex nanoformulations.

Coprecipitation of nonoxynol-9 with polyvinylpyrrolidone to decrease vaginal irritation potential while maintaining spermicidal potency.

The aim of this study was to test the hypothesis that polyvinylpyrrolidone (PVP) would increase the critical micelle concentration (CMC) of nonoxynol-9 (N-9), providing a reduction in its irritation potential, while maintaining essential spermicidal activity. Solid coprecipitates of N-9 with PVP were manufactured with the use of a modified lyophilization process. The irritation potential of N-9 was estimated by an in vitro assay, monitoring the extent of hemolysis of red blood cells. CMCs of N-9 were measured in the presence of various concentrations of PVP. A modified Sander-Cramer assay was implemented to measure the spermicidal activity of N-9 and the N-9/PVP coprecipitates. With the use of the lyophilization process and more suitable solvents, solid coprecipitates of N-9/PVP were manufactured with no residual organic solvents. The irritation potential of N-9 was reduced when in the presence of PVP-50% hemolysis values increased from 0.054 mM to more than 0.2mM. N-9 CMC values increased in the presence of PVP from 0.085 mM (0% PVP) to 0.110 mM (3.5% PVP) and 0.16 6mM (10% PVP). However, spermicidal activities ranged from 0.213 mM to 0.238 mM, N-9 remaining steady regardless of the amount of PVP. By use of N-9/PVP coprecipitates, the self-association properties and irritation potentials of N-9 were altered. This result suggests a process to produce a spermicidal product that reduces the detrimental implications to the vaginal epithelium while maintaining the essential spermicidal activity.