The use of colloid probe microscopy to predict aerosolization performance in dry powder inhalers: AFM and in vitro correlation.

The atomic force microscope (AFM) colloid probe technique was utilized to measure cohesion forces (separation energy) between three drug systems as a function of relative humidity (RH). The subsequent data was correlated with in vitro aerosolization data collected over the same RH range. Three drug-only systems were chosen for study; salbutamol sulphate (SS), triamcinolone acetonide (TAA), and di-sodium cromoglycate (DSCG). Analysis of the AFM and in vitro data suggested good correlations, with the separation energy being related inversely to the aerosolization performance (measured as fine particle fraction, FPF(LD)). In addition, the relationship between, cohesion, RH, and aerosolization performance was drug specific. For example, an increase in RH between 15% and 75% resulted in increased cohesion and decreased FPF(LD) for SS and DSCG. In comparison, for TAA, a decrease in cohesion and increased FPF(LD) was observed when RH was increased (15-75%). Linear regression analysis comparing AFM with in vitro data indicated R(2) values > 0.80, for all data sets, suggesting the AFM could be used to indicate in vitro aerosolization performance.

The influence of relative humidity on the cohesion properties of micronized drugs used in inhalation therapy.

The influence of relative humidity (RH) on the cohesion properties of three drugs: salbutamol sulphate (SS), triamcinolone acetonide (TAA), and disodium cromoglycate (DSCG) was investigated using the atomic force microscope (AFM) colloidal probe technique. Micronized drug particles were mounted in heat-sensitive epoxy resin for immobilization. Multiple AFM force-distance curves were conducted between each drug probe and the immobilized drug particulates at 15, 45, and 75% RH using Force-Volume imaging. Clear variations in the cohesion profile with respect to RH were observed for all three micronized drugs. The calculated force and energy of cohesion to separate either micronized SS or DSCG increased as humidity was raised from 15 to 75% RH, suggesting capillary forces become a dominating factor at elevated RH. In comparison, the separation force and energy for micronized TAA particles decreased with increased RH. This behavior may be attributed to long-range attractive electrostatic interactions, which were observed in the approach cycle of the AFM force-distance curves. These observations correlated well with previous aerosolization studies of the three micronized drugs.

Effect of humidity on aerosolization of micronized drugs.

The variation of aerosolization with humidity for three micronized drugs used in the treatment of asthma was evaluated by using in vitro methods. Micronized samples of disodium cromoglycate (DSCG), salbutamol sulphate, and triamcinolone acetonide (TAA) were stored for 12hr at 15, 30, 45, 60, and 75% relative humidity (RH). A suitable "reservoir" dry powder inhaler was loaded and tested by using a twin-stage impinger at each specific humidity. The aerosolization efficiency of all three micronized drugs was affected by variations in humidity. The percentage of the delivered dose and the fine particle fraction of the loaded dose (FPFLD) for both DSCG and salbutamol sulphate decreased with increasing humidity; with the largest decrease in FPFLD occurring between 45% and 60% RH for DSCG and 60% to 75% RH for salbutamol sulphate. These observations suggest that the adhesion properties for both DSCG and salbutamol sulphate, which govern the aerosolization efficiency, are predominately influenced by capillary interactions. In contrast, the FPFLD for TAA significantly increased as the humidity increased over the range 15% to 75% RH, suggesting that triboelectric forces predominate particle-particle interactions. These variations in drug particulate behavior highlight the importance of an individual formulation approach when developing dry powder inhalation systems.

Investigation into the effect of humidity on drug-drug interactions using the atomic force microscope.

The atomic force microscope (AFM) has been used to characterize the cohesive nature of a micronized pharmaceutical powder used for inhalation therapy. Salbutamol sulfate (also referred to as albuterol sulfate), a therapeutic drug commonly delivered from dry powder inhalers (DPI), was chosen as a model system because the cohesion and subsequent de-agglomeration during inhalation are critical aspects to the efficacy of such a delivery system. Salbutamol sulfate drug particulates were mounted on V-shaped AFM cantilevers using a novel micromanipulation technique. Force-distance curves obtained from the measurements between cantilever drug probes and model compacts of salbutamol sulfate were integrated to determine separation energies. The effect of humidity (15-75% RH) on the energy required to separate a drug particle from model drug surface was determined using a custom-built perfusion apparatus attached to the AFM. Separation energy measurements over 10 x 10-microm areas of the compact surface (n = 4096) exhibited log normal distributions (apparent linear regression, R(2) >or= 0.97). Significant increases in the median separation energies (p < 0.05) between the salbutamol sulfate drug probes and salbutamol sulfate model surfaces were observed as humidity was increased. This result is most likely attributed to capillary interactions becoming more dominant at higher humidities. This investigation has shown the AFM to be a powerful technique for quantification of the separation energies between micronized drug particulates, highlighting the potential of the AFM as a rapid preformulation tool.