Optimization of an In Vitro Dissolution Test Method for ...

1 Optimization of an In Vitro Dissolution Test Method for inhalation Formulations Yoen-Ju Son1, Michelle Horng1, Mark Copley2, and Jason T. McConville1,* e-mail: 1. College of Pharmacy, The University of Texas at Austin, Austin, TX, USA. 2. Copley Scientific Limited, Nottingham, UK. ABSTRACT. 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.

2 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.

3 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 procedure for inhalation formulations would involve D. issolution testing allows one to examine the drug particle classification followed by an evaluation of the release behavior of pharmaceutical dosage forms Dissolution behavior of those sorted drug particles that in Vitro to differentiate formulation types and may deposit at various sites in the respiratory tract. perhaps give an estimate of Dissolution behavior in vivo. Experimental difficulties in dose collection exist due to Dissolution testing is routinely used in quality control very fine and electrostatic powder characteristics (1).

4 (QC) studies such as batch-to-batch consistency, stability, Therefore, most existing Dissolution procedures on and detection of manufacturing deviations. While powders have been performed with no aerodynamic there are many standardized Dissolution test methods classification, whereby formulations have been directly for solid dosage forms such as tablets and capsules, there dispersed into an Apparatus 2 Dissolution tester (3) or is no universally accepted Method for estimating the placed directly into a modified basket to prevent drug Dissolution behavior of inhaled active ingredients, particles from escaping directly into the Dissolution although many Dissolution methods for testing aerosols medium (4, 5).

5 Formulations intended for pulmonary have been investigated (1). Designing a standardized delivery are hard to disperse homogeneously into the Method applicable to the lung is not an easy task, because vessel or basket, and dispersed particles stick on the the lung has several unique features that are difficult to vessel wall or paddle/basket during such Dissolution tests . replicate in Vitro , such as the extremely small amount of In addition, floating powders may be inadvertently aqueous fluid and the presence of endogenous lung collected during the sampling procedure. In an attempt surfactants (1, 2). to compensate for some of the shortfalls of this type For inhalation products, the most important step for in of testing using commercial Dissolution systems, several Vitro performance testing is the delivery of a given API custom-built Dissolution apparatus have been investi- from a specified delivery device and its deposition using a gated.

6 Davies and Feddah (6) modified a flow-through cell pharmaceutical impactor/impinger to estimate the actual by direct incorporation of an HPLC pump. In another study dose delivered to the target site of the lung. In pulmonary that used a horizontal diffusion cell, powders were drug delivery, it is well-accepted that particles within the dispersed onto a hydrated membrane, and the Dissolution size range of 1 5 m can be successfully delivered to the rate was estimated by observation of the diffusion rate (7). targeted deep lung. Only a fraction of the API emitted In addition to these methods , the twin-stage impinger from standard delivery devices is usually delivered to this target site, due to the fine particle size distribution for (TSI) (8), Dissolution cell (9, 10), and shaking incubator most inhaler products (2).

7 Thus, an ideal Dissolution test (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 *Corresponding author indicated above for a commercial Dissolution apparatus, 6 Dissolution Technologies | MAY 2010. 6 2010-6-4 13:46:54. problems such as dose collection, adequate particle dispersion, and uniformity of particle size distribution are still evident. Therefore, no single in Vitro test system has previously been described to be universally suitable for performing Dissolution measurements of inhalation formulations. This article describes the features of a newly developed membrane holder that was designed specifically to be incorporated into the Next Generation Impactor (NGI) for better dose collection performance than with a previously reported prototype membrane holder.

8 In the previous Figure 1. Schematic diagram of the Dissolution apparatus. (A) Dissolution station and (B) membrane holder assembly: (a) NGI Dissolution cup, study (13), a prototype membrane holder was used to (b) impaction insert, and (c) securing ring. assess the Dissolution profiles of aerodynamically separated drug particles. Dose collection was achieved by aerodynamic separation into the NGI modified with a Dissolution cup (a), a removable impaction inset (b), a polycarbonate membrane. The Dissolution profiles of a securing ring (c), two sealing o-rings, and a PC membrane model drug were successively estimated by the amount of to function as a highly porous diffusional powder- drug released from the membrane holder.

9 It was clearly retaining layer. shown that there was a significant difference between the bulk formulation and an aerodynamically classified Dose Collection formulation in the Dissolution profile. However, in the To select suitable particle size cutoff ranges for the previous Dissolution setup, modification of the NGI was subsequent Dissolution study, aerodynamic particle required to collect dispersed particles on the membrane, separation was achieved using the NGI. Either the Ventolin and the whole dose collected on the membrane could not HFA device or the Pulmicort Flexhaler device was actuated be used for Dissolution testing due to a substantial five times to obtain a quantifiable amount of drug.

10 The limitation imparted by the prototype holder frame size. NGI was operated at a flow rate of 30 L/min for the The aim of this study was to investigate a standardized Ventolin HFA and 60 L/min for the Pulmicort Flexhaler. Dissolution procedure using the newly manufactured Air-classified particles from each dose-collection plate of membrane holder and to characterize the Dissolution the NGI that were not used in the Dissolution studies were properties of two different types of commercially available reconstituted with mobile phase and analyzed using a inhalation product. validated HPLC Method (14, 15). For the Dissolution studies, the Dissolution cup MATERIALS AND methods .