Optimization of an In Vitro Dissolution Test Method for Inhalation Formulations

The aim of this research project was to investigate a potential standardized test method to characterize the dissolution properties of numerous formulation types available for pulmonary delivery. A commercially available dissolution tester was adapted for use as a testing apparatus by the incorporation of a membrane-containing holder. The holder was designed to enclose previously air-classified formulations so that they could be uniformly tested in the dissolution apparatus. Dissolution procedures, the apparatus, dose collection, medium, and test conditions were developed relying on USP General Chapter <1092>. To collect an active pharmaceutical ingredient (API) fraction from the devices for subsequent dissolution studies, aerodynamic particle separation on the membrane holder was achieved using the Next Generation Impactor (NGI) for two commercially available products, Ventolin HFA and Pulmicort Flexhaler. The dissolution profiles of budesonide (BD) and albuterol sulfate (AS) were successfully estimated by analyzing the amount of drug released from the membrane holder. This dissolution method may be applied to quality control studies for various inhalation products. In particular, the in vitro dissolution profiles of the drugs may provide an estimate of their dispersion characteristics, which directly relate to the device or aerosol performances. INTRODUCTION Dissolution testing allows one to examine the drug release behavior of pharmaceutical dosage forms in vitro to differentiate formulation types and perhaps give an estimate of dissolution behavior in vivo. Dissolution testing is routinely used in quality control (QC) studies such as batch-to-batch consistency, stability, and detection of manufacturing deviations. While there are many standardized dissolution test methods for solid dosage forms such as tablets and capsules, there is no universally accepted method for estimating the dissolution behavior of inhaled active ingredients, although many dissolution methods for testing aerosols have been investigated (1). Designing a standardized method applicable to the lung is not an easy task, because the lung has several unique features that are difficult to replicate in vitro, such as the extremely small amount of aqueous fluid and the presence of endogenous lung surfactants (1, 2). For inhalation products, the most important step for in vitro performance testing is the delivery of a given API from a specified delivery device and its deposition using a pharmaceutical impactor/impinger to estimate the actual dose delivered to the target site of the lung. In pulmonary drug delivery, it is well-accepted that particles within the size range of 1–5 μm can be successfully delivered to the targeted deep lung. Only a fraction of the API emitted from standard delivery devices is usually delivered to this target site, due to the fine particle size distribution for most inhaler products (2). Thus, an ideal dissolution test procedure for inhalation formulations would involve particle classification followed by an evaluation of the dissolution behavior of those sorted drug particles that may deposit at various sites in the respiratory tract. Experimental difficulties in dose collection exist due to very fine and electrostatic powder characteristics (1). Therefore, most existing dissolution procedures on powders have been performed with no aerodynamic classification, whereby formulations have been directly dispersed into an Apparatus 2 dissolution tester (3) or placed directly into a modified basket to prevent drug particles from escaping directly into the dissolution medium (4, 5). Formulations intended for pulmonary delivery are hard to disperse homogeneously into the vessel or basket, and dispersed particles stick on the vessel wall or paddle/basket during such dissolution tests. In addition, floating powders may be inadvertently collected during the sampling procedure. In an attempt to compensate for some of the shortfalls of this type of testing using commercial dissolution systems, several custom-built dissolution apparatus have been investigated. Davies and Feddah (6) modified a flow-through cell by direct incorporation of an HPLC pump. In another study that used a horizontal diffusion cell, powders were dispersed onto a hydrated membrane, and the dissolution rate was estimated by observation of the diffusion rate (7). In addition to these methods, the twin-stage impinger (TSI) (8), dissolution cell (9, 10), and shaking incubator (11, 12) apparatus were also modified for conducting in vitro dissolution studies for dry powders. Although these approaches do, in some way, make up for the drawbacks indicated above for a commercial dissolution apparatus, e-mail: [email protected] *Corresponding author diss-17-02-02.indd 6 2010-6-4 13:46:54 dx.doi.org/10.14227/DT170210P6