The administration of pharmacologically active agents by inhalation is a widely used technique especially for the treatment of reversible airway obstruction, inflammation and hyperresponsiveness. The technique is also used for the administration of certain active agents having systemic action, which are absorbed via the lungs into the bloodstream.
Some of the most widely used systems for the administration of drugs to the airways are the dry powder inhalers (DPI's).
DPI's can be divided into two basic types:                i) single dose inhalers, for the administration of pre-subdivided single doses of the active compound;        ii) multidose dry powder inhalers (MDPI't) either with pre-subdivided single doses or pre-loaded with quantities of active ingredient sufficient for multiple doses each dose is created by a metering unit within the inhaler.        
On the basis of the required inspiratory flow rates (1/min) which in turn are strictly depending or their design and mechanical features DPI's are also divided in:                i) low-resistance devices (>90 l/min);        ii) medium-resistance devices (about 60 l/min);        iii) high-resistance devices (about 3 l/min).        
The reported flow rates refer to the pressure drop of 4 KPa (KiloPascal) in accordance with the requirements of the European Pharmacopoeia (Eur Ph) 4th Ed 2004, page 3375.
Drugs intended for inhalation as dry powders should be used in the form of micronised powder so they are characterised by particles of few microns (μm) particle size. In powders for inhalation, the evaluation of particle size both of the active ingredient and of possible excipients or carriers is of primary importance. The particle size is quantified by measuring a characteristic equivalent sphere diameter, known as mass diameter (MD or volume diameter (VD), depending on the used technique. Particle size distribution is described by the mass median diameter (MMD) or the volume median diameter (VMD) which correspond to the diameter of 50 percent by weight or volume respectively, of the particles. The VMD is related to the MMD by the density of the particles (assuming a size independent density or the particles). In the case of active ingredients for inhalation purposes, the particle size is also expressed as mass aerodynamic diameter (MAD) and the particle size distribution as mass median aerodynamic diameter (MMAD). The MAD indicates the capability of the particles of being transported suspended in an air stream. The MMAD corresponds to the mass aerodynamic diameter of 50 percent by weight of the particles. In the prior art the term MMAD has also been improperly used for quantifying the diameter of the carrier particles The particles of active ingredient must have such a particle size as to reach the low respiratory tract. Respirable articles are generally considered to be those with MAD from 0.5 to 10 micron, as they are able of penetrating into the lower airways, i.e. the bronchiolar and alveolar sites, which are the sit of action for the pulmonary drugs and where absorption takes place for the systemic drugs. Larger particles are mostly deposited in the oropharyngeal cavity so they cannot reach said sites, whereas the smaller ones deem to be exhaled.
Hereinafter the terms drug, active ingredient, active and active substance are used as synonymous.
Although micronisation of the drug is essential for deposition into the lower respiratory tract during inhalation, it is also know that the finer are the particles, the stronger are the cohesion forces Strong cohesion forces hinder the handling of the powder during the manufacturing process (pouring, filling). Moreover they reduce the flowability of the particles while favouring in the multidose DPI's the agglomeration and the adhesion thereof to the walls. Said phenomena impair the loading of the powder from the reservoir to the metering chamber. Therefore, strong cohesion forces give rise to handling and metering accuracy problems.
Poor flowability is also detrimental to the respirable fraction of the delivered dose being the active particles unable to leave the inhaler and remaining adhered to the interior of the inhaler or leaving the inhaler as large agglomerates; agglomerated particles, in turn cannot reach the bronchiolar and alveolar sites of the lungs. The uncertainty as to the extent of agglomeration of the particles between each actuation of the inhaler and also among inhalers and different batches of particles leads to poor dose reproducibility as well.