There are two types of MDI formulations: suspension formulations, in which microparticulate drug (typically micronized material) is dispersed in a combination of propellants, and solution formulations, in which the drug freely dissolves in either the propellant or a combination of propellant and an acceptable cosolvent, typically ethanol . Both types of formulations have inherent advantages and disadvantages. Traditionally, suspension formulations have been the more common dosage form, but with the advent of the hydrofluroalkane propellants (HFA 134a, HFA227), which have poor solvency characteristics, the use of cosolvents has become more common, and solution formulations are increasing in use.
Suspension formulations typically have few problems with chemical stability because the drug is dispersed rather than being a homogeneous solution. Furthermore, they are also capable of delivering relatively high drug loads [e.g., Tilade™ (Aventis) is an MDI that delivers 2mg of nedocromil sodium per actuation]. However, suspension formulations suffer from one major drawback: They need to be physically stable to ensure formulation homogeneity and, thus, uniform medication delivery. Particularly for HFA formulations in the absence of suspending agents, there may be rapid separation of the heterogeneous mixture, resulting in either creaming or flocculation, which can lead to poor reproducibility of medication dosing, particularly if the interval between dosing and shaking is inconsistent .
In addition, because the respirable fraction of the aerosol cloud that is emitted from a suspension MDI is highly dependent on the geometric size of the bulk drug particles (i.e., the aerodynamic size cannot be smaller than the initial geometric size of the primary particles), there are limitations to the respirable fraction that can be achieved. As such, solution formulations offer opportunities to circumvent some of these problems, particularly with drugs that have a significant solubility in the volatile propellants, where greater respirable fractions can be obtained .
Since the late 1980s it has become increasingly apparent that CFCs have a detrimental effect on the Earth's ozone layer . This has lead to an extensive search for propellants that could be used as alternatives that have much less of an effect on the environment. The hydroflurocarbons (HFA 134a and 227) are both now being widely used in the pharmaceutical industry  as propellants for MDIs. These materials are pharmacologically inert and have similar properties to the CFC propellants they replaced. However, they are sufficiently different from the CFCs that there has been a significant investment in formulation strategies for the range of drugs traditionally delivered by MDIs.
HFC-134a and -227 are novel pharmaceutical excipients (inactive ingredients) developed for widespread and long-term use as replacements for CFCs in MDIs. Because the propellants in MDIs comprise the large majority of the formulation, often in excess of 98%, and the patients using these drugs are particularly vulnerable to airway irritation or toxicities, extensive testing had to be conducted on these propellants. Thus, both of these HFCs have undergone the same toxicological testing as any new chemical drug substance. Both are now widely approved as propellants suitable for MDI use  (Table 1).
All HFC MDIs contain the same physical components as the CFC MDI products (e.g., drug, propellant, canister, metering valve, and actuator); however, the very different physical properties of the HFC propellants has meant that significant changes have had to be made to the technology for these components. Although the active ingredient remains the same in most cases, whereas almost all CFC MDIs were presented as suspensions, there is now a growing number of HFC-propelled MDIs that have the drug in solution. Some formulations contain a cosolvent such as ethanol to help dissolve the surfactant or drug. There are also products on the market that do not contain a surfactant, simply being a suspension of micronized drug in propellant. Changes in hardware for the formulation has also necessitated changes to the equipment and processes used to manufacture HFA MDIs.
There are a number of companies involved globally in developing HFA MDIs, these include: 3M Pharmaceuticals (USA); GlaxoSmithKline (UK); Boehringer Ingelheim (Germany); Aventis (France/Germany); Cipla (India); Asta-Medica (Germany); Ivax-Norton Healthcare (USA/UK); and Chiesi (Italy). Table 2 outlines a list of some of the currently available formulations (by company) for the most widely prescribed inhaled drugs: salbutamol, beclomethasone, and budesonide.
The first introduction of an HFA MDI for the widely prescribed short-acting b-agonist salbutamol, occurred in the United Kingdom in 1994. Today there are over 60 countries where there is at least one salbutamol (short-acting b-agonist) containing MDI approved and marketed. Another b-agonist (fenoterol—Boehringer Ingleheim) is now also available in a number of European countries.
Table 1 Hydrofluroalkane (HFC) Propellants Used in MDIs
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