Dry Powder Inhalation Formulations

Of critical importance in the development of DPI products is the evaluation, optimization, and control of flow and dispersion (deaggregation) characteristics of the formulation. These typically consist of drug blended with a carrier (e.g., lactose). The properties of these blends are a function of the principal adhesive forces that exist between particles, including van der Waals forces, electrostatic forces, and the surface tension of adsorbed liquid layers [7]. These forces are influenced by several fundamental physicochemical properties, including particle density and size distribution, particle morphology (shape, habit, surface texture), and surface composition (including adsorbed moisture) [8]. In addition, the combination of dry powder formulations and plastics poses the additional problem of offering electrostatically charged surfaces for collection of drug particles. Interparticle forces, which influence flow and dispersion properties, are particularly dominant in the micronized or microcrystalline powders required for inhalation therapy (< 5 mm). It is obvious that the particle size distribution of the drug and the diluent (excipient) need to be optimized during early preformulation and formulation development studies to ensure consistent aerosol cloud formation.

It is imperative, during early development, to characterize the moisture sorption and desorption attributes of the drug in relation to available salt forms. Assuming solubility is sufficient to ensure adequate absorption, a nonhygroscopic form should be explored. This would confer a number of advantages, including improved flow properties and dispersion as well as enhanced physical stability in the bulk and final dosage forms due to minimal moisture transfer between the drug, immediate container (e.g., gelatin capsule shell), and the environment. Furthermore, improved chemical stability may result in the case of hydrolytically labile drugs. Hygroscopic growth during administration would also be minimized. Although inherently attractive, the approach of using nonhygroscopic drug forms must be applied with caution, because, in the case of insulating particles, the level of adsorbed moisture may not be sufficient to dissipate attractive electrostatic forces, resulting in particle adhesion. Particle morphology, including attributes such as crystal habit, surface texture, and porosity, also influences particle adhesion [9]. Anisometric particles, that is, those with extreme "elongation" or "flatness" ratios, tend to build up packing of high porosity, but they are also more readily deformed by compression than packing of isometric particles. Anisometric particles tend to align along their long axis during flow and, thus, to exhibit less internal friction than isometric particles [8]. Powder flow tends to be adversely affected by surface roughness and porosity.

A particle engineering approach that has been the subject of much recent attention is one in which sub-unit-density particles are produced. These particles are attractive because it is the aerodynamic diameter, rather than any other measure, that determines the site of deposition for inhaled particles. The aerodynamic diameter is the characteristic dimension of a hypothetical sphere, of unit density, with an identical setting velocity (the velocity at which a particle moves downward when acted upon only by the force of gravity) to that of the particle in question [10]. Many pharmaceutical aerosol particles are spherical with density of 1 g/cm3, most certainly in the case of liquid aerosols. For these particles, the aerodynamic and geometric diameters are equivalent. However, particles with other than unit density can be "respirable" particles even if their geometrical diameter is not 1-3 mm in size [11]. Thus, the aerodynamic diameter, rather than the geometric diameter, must be given careful consideration when predicting deposition efficiency of a given inhaled aerosol. The distribution of sizes around the aerodynamic median size is also an important parameter in the efficiency of deposition [12].

The efficiency of dispersion, in the case of dry powder aerosols, relative to varying geometric diameters of the particles may also be an important factor. Specifically, dispersion requires the powder to overcome interparticulate forces binding particles in bulk powder and to become entrained as single particles in the inhalatory airstream. Interparticulate forces are dominated by the van der Waals force for particles in a respiratory size range. All other factors being equal, the van der Waals force will decrease as the geometric particle size increases (Fig. 1). Thus, in general terms, probability of deposition in the deep lung is at odds with efficiency of dispersion for dry powder inhalers. Sub-unit-density particles provide a means to decrease interparticulate forces due to their larger geometric diameters, while their aerodynamic diameter is still in the respirable size range.

It should be apparent, based on the brief overview just presented, that prediction of powder rheology based on the potential interplay of a number of physicochemical properties is extremely complicated. Instead, flow and dispersion properties are generally characterized using appropriate derived properties, including, but not limited to, angle of repose, bulk density, compressibility, and dustability. It is important to identify and control critical

Particle diameter I

Figure 1 Phase diagram for typical granular material interactions.

Particle diameter I

Figure 1 Phase diagram for typical granular material interactions.

parameters, both fundamental and derived, to ensure optimum and consistent product performance, although this may not always be possible [13].

Environmental factors, including temperature, humidity, and light, are essential considerations during formulation development. Therefore, it is imperative to evaluate the influence of these factors on the physical and chemical stability of the formulation during early preformulation studies. Light exposure can usually be controlled by judicious choice of product packaging; however, temperature and humidity are not so easily controlled, and they often act in concert to promote product degradation. The effects of elevated temperature and humidity on product stability can be assessed after stress storage. Some years ago Yoshioka and Carstensen [14] proposed several useful kinetic models for the accelerated testing of solid pharmaceuticals based on isothermal storage at controlled elevated temperature and controlled elevated humidity. Temperature-or humidity-cycling experiments can also be useful, particularly for assessing potential physical changes.

Chemical degradation after stress storage is assessed using an appropriate stability-indicating assay. In addition, physical changes are evaluated using an array of techniques available to the preformulation scientist, including polarized light microscopy (aggregation, crystal growth), differential scanning calorimetry, infrared spectroscopy, x-ray diffractometry, solution calorimetry, thermogravi-metric analysis, and hot-stage microscopy (moisture uptake, polymorph interconversion, pseudopolymorph formation). Stressed stored samples should also be evaluated for evidence of caking and discoloration.

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