Table 2 Typical HFA MDI Formulations

Drug compound Formulation

Company producing



3M Pharmaceuticals Ivax-Norton Healthcare GlaxoSmithKline Cipla

3M Pharmaceuticals

Ivax-Norton Healthcare




134a alone

Beclomethasone Ethanol/134a


Ethanol/134a/glycerol Ethanol/134a/glycerol 134a alone

In addition to the introduction of beta-agonist HFC MDIs, there is a growing number of controller medications available as HFC MDIs. These include beclomethasone, fluticasone, disodium cromoglycate, and nedocromil sodium. Further product introductions are anticipated in the coming years; however, it should be noted that some products cannot or will not be reformulated with HFCs as MDIs and so alternatives (such as DPIs) are being developed. It was estimated that in 2002 there were over 100 million HFA MDIs produced globally, representing approximately 25% of worldwide MDI production.

The degree to which a high-respirable dose can be achieved with an MDI is dependent on obtaining a low, uniform primary particle size of the active agent. Often, material is milled (ball milled) or micronized (jet milled) using any one of the suitable systems that are commercially available. Clearly, this becomes difficult if small amounts of bulk material are available, as is often the case in early formulation development studies. Several smaller jet mills are available and can be used for this purpose [39]. However, it needs to be recognized that the use of high-energy forces on the bulk material may impart undesirable physical change, so this should be monitored carefully. Other methods of producing small particles can be explored, including controlled crystallization, because this can sometimes be the only way to produce sufficiently small material, particularly if the active material is thermally unstable or has a low melting point.

MDIs, be they solution or suspension formulations, typically contain a surfactant or dispersing agent. These materials generally need to have some solubility in the propellant blend. Commonly used surfactants include sorbitan trioleate (SPAN 85), oleic acid, and lecithins, at levels between 0.1% and 2.0% wt/wt [40]. These agents are required both to maintain the disperse nature of the drug (in suspension formulations) and to provide lubrication for operation of the metering valves. However, these surfactants have poor solubility in the HFA

propellants, so alternate formulation strategies, using cosolvents, have been developed, with some success [18,36].

The fundamental requirement of an MDI formulation is that the drug dose be delivered accurately and reproducibly as an aerosol containing a significant fraction of drug particles in the respirable range (aerodynamic diameter < 5 mm) [41]. This requirement can be met only by a suspension formulation, if the drug can be homogeneously distributed, in a deaggregated state, with minimal segregation during the period before administration. The extent and rate of drug separation (sedimentation or creaming) can in theory be reduced to some extent by manipulating the physicochemical properties of the formulation. According to Stokes' law, the rate of settling of a spherical particle, in a fluid medium, is directly proportional to the difference in density of the particle and the medium and the square of the particle's radius. Balancing the density of the drug and continuous phase of an MDI formulation as a means of eliminating settling would appear to be one option for achieving effective formulations, although the ranges are limited given the nature of the new HFA propellants.

As anticipated by Stokes' law, the rate of drug separation in an MDI suspension is also related to the particle size and particle size distribution. Within this context, it is important to define particle in its broadest sense to include primary drug particles and multiparticulate aggregates that may coexist or even predominate in suspension. The extent of aggregation is moderated by the use of appropriate nonionic surfactants, which adsorb on particle surfaces, reducing solid-liquid interfacial tension. Repulsion, due to steric interaction of hydrophobic surfactant chains projecting from particle surfaces, is viewed as the dominant mechanism in inhibiting particle aggregation in low-dielectric propellants [42]. Aggregation to form stable, loosely adherent masses (flocs) occurs when van der Waals forces of attraction slightly override electronic and steric forces of repulsion. Stability is conferred because the interacting particles reside in a secondary potential energy minimum. The forces of cohesion are generally small enough that the particles can be readily redispersed on mixing. The technique of controlled flocculation is often used as a means of optimizing oral suspensions. The principal involves increasing the size of the flocs by manipulation of zeta potential and surfactant concentration, to a point where the sedimentation ratio (sediment volume/total volume) is maximized (ideally F = 1). This approach has been widely used in developing HFA formulations. What is clear is that in developing an MDI suspension, the suspension properties must be viewed in terms of their relevance to aerosol output (maximized respirable fraction) as well as content homogeneity and redispersibility (optimized dose-to-dose reproducibility). These parameters can be reliably assessed only by the appropriate testing of trial formulations.

Typical Containers

There are essentially two types of containers that are currently used for MDI products. These are either glass, which are typically laminated or plastic coated so that they can withstand high pressures, or aluminum products. The latter are generally preferred and much more widely used because they are lighter, robust, and impervious to light. However, in some cases the inert nature of glass containers makes them a more suitable choice for use in solution formulations. These containers are sufficiently robust to withstand internal pressures of up to 150psig without deformation.

Aluminum containers for use in MDI products are typically in the range of 15 to 30 mL in capacity, with a neck diameter of 20 mm. They are prepared in one of two ways: either from a monobloc of aluminum, by rapid impact slugging, or from a more precise deep-drawing process [39]. This gives the canisters more wall uniformity and, thus, greater weight uniformity, which is important in the multistage filling process. Both of these processes result in seamless canisters, which makes them more robust. The cans should be thoroughly cleaned before use because they may often contain residual particulates or a small oily residue as a result of the manufacturing process. A variety of can finishes (internal and external) are available. These are typically either epoxy or epoxy-type resins [40] or, more recently, fluoropolymer coated and, as such, either assist in conferring a more aesthetic appeal to the product or minimize drug adhesion to the canister walls.

Metering Valves

The metering valve in an MDI is the critical component in the design of an effective delivery system. The main function of the metering valve is to reproducibly deliver a portion of the liquid phase of the formulation in which the medication is either dissolved or dispersed. The valve also forms the seal atop the canister to prevent loss of the pressurized contents. The valves generally comprise at least seven components that are constructed from a variety of inert materials. Typical materials of construction are acetal or polyester for the valve body, stainless steel or acetal for the valve stem, generally anodized aluminum for the ferrule, and butyl, nitrile, or neoprene for the elastomers used in the seals and gaskets [43].

These valves are essentially designed to work in the inverted (stem down) position. Depression of the valve stem allows the contents of the metering chamber to be dispensed through the orifice in the valve stem. After actuation, the metering chamber refills from the bulk liquid formulation, once the metering chamber is sealed from the atmosphere and is ready to dispense the next dose. This is essential; otherwise, continuous spray would be achieved. Typical volumes that are dispensed range from 25 to 100 mL. The accuracy of the dosing is dependent on the selection of suitable components within the valve that show compatibility with the formulation and the design of a stable (physically) formulation. Incorrect assembly of the valve would result in poor metering performance. Thus, exhaustive tests are carried out on stratified samples of each batch of valves manufactured by the suppliers.

It should be pointed out, however, that because these valves are designed to dispense volumetrically, changes in the formulation density (by varying the propellant ratios) can affect the amount (by weight) that is dispensed. Hence, during the formulation design process, say, for a nominal target dose of 100 mg, these need to be taken into account. Key components of the metering valve are the elastomer seals and gaskets. As discussed previously, these form the barrier to the external environment, preventing ingress of materials (e.g., water) into the formulation, but they also minimize product leakage. They are selected for their durability during repeated use and for their compatibility with the formulation (propellants). A typical valve could be actuated up to 200 times during the lifetime of the product, and the seals and gaskets need to perform equally well throughout this cycle, with minimal deformation.

Where the pressurized propellant is charged through the valve (pressure-filled products), there needs to be a high degree of deformation of the filling gasket to occur for the filling to be easily accomplished. Thus, these valves are complex in their requirements and in design. Furthermore, the elastomer components also need to have suitable swelling characteristics when in contact with the propellants. This issue has been highlighted during the development of the HFA propellants, where new elastomeric materials were required to maintain value functionality [42]. Elastomers also need to have low levels of extractable materials. When there is a tendency for materials to be leached out of the valve by components within the formulation, this tendency can be minimized by prewashing or extracting of the valves (or their components).

Actuators and Inhalation Aids

The actuator (or mouthpiece) of an MDI is generally constructed from a range of polyethylene or polypropylene materials by injection-molding techniques. The actuator is the means by which the valve stem in the metering chamber is depressed and patients, by cupping their lips around the squat end (Fig. 4), inhale the dose. The aerosol cloud generated after the depression of the valve stem is dependent on the vapor pressure (propellant ratio) of the formulation, the geometric size of the active drug if the product is a suspension formulation, the volume of the metering chamber, and, critically, the diameter of the jet orifice in the mouthpiece. The diameter of this orifice also controls the rate of spray formation [44]. The free flow of the expanding aerosol cloud through this orifice is essential. To ensure that this critical orifice does not become partially blocked during repeated use of the actuator, regular washing of the actuator is recommended [45]. Studies conducted during formulation development can mimic patient use and, thus, establish the frequency with which buildup of drug on the orifice is likely to occur.

The common design of actuators is the classic "L" shape [39]. However, despite very clear instructions, many patients (in particular, children) find it difficult to coordinate the actuation and inspiration essential for the effective use of MDIs. This has led to the development of a variety of spacer and extension types of mouthpieces. The original concept of the plume- (or cone-) shaped device came from the work of Moren [46]. These devices aid patient coordination by allowing them to actuate into the reservoir and then, subsequently, to inhale from the resulting cloud. The inclusion of a small vent in the spacer prevents exhaling into the reservoir. Today the most widely used spacer is the AeroChamber™ (Monohagan Medical), which has been widely studied for its effectiveness in aiding drug delivery (see Fig. 5). In addition it comes with a wide range of face masks for use with infants.

Extended mouthpiece devices are also available (e.g., Azmacort™, Aventis). With this device, the point of inspiration is removed further from the point of actuation, allowing greater evaporation time for the less volatile propellants, plus large particle sedimentation in the airstream, with a concomitant

Figure 5 Photo of an AeroChamber™.

decrease in aerodynamic particle size of the cloud and a reduction in oropharyngeal impaction.

Another very elegant and highly portable device that aids patient coordination is the breath-actuated inhaler, originally developed by Riker Laboratories (3M) [47] and further enhanced by Ivax-Norton (EasiBreathe). In this type of device, a mechanical release mechanism is used, firing the MDI when a certain threshold inspiratory flowrate is reached. Once the dose has been dispensed, the device is then reprimed, ready for use. This type of device has gained wide acceptance in Europe and has been introduced for several MDI products.

Manufacture and Evaluation of Metered-Dose Inhalers

There are essentially two processes for the filling of MDIs, pressure-filling and cold-filling. In the pressure-filling process, typically a concentrate of drug (after comminution), excipients, and propellant is prepared in a suitable batching vessel. These are almost always in suspension, so the contents of the vessel need to be thoroughly mixed using a high-shear mixer. Often, this will then be recirculated from the batching vessel through the filler and back to the vessel to maintain the homogeneity of the suspension. This concentrate is then filled into purged canisters using a volumetric filler, and the valve is crimped into place. Additional propellant is then added through the metering valve, under pressure, using high-speed fillers. This process is known as gassing. A modification to this approach is to prepare the whole formulation in a pressure vessel and then to volumetrically fill this into a prepurged canister through the metering valve, which has already been crimped in place. Filling at subambient temperatures may aid precision of the process.

The alternative approach is to use cold-filling. As the term suggests, cold temperatures are applied in order to liquefy all the propellants. These are then filled volumetrically into canisters, and the valve is crimped into place. Cold-filling has some advantages in small batch manufacture. However, as in any process of scale-up, it is important to recognize that there may be subtle differences in performance between one product manufactured by a process on a laboratory scale and another on a full production scale.

One feature critical to both filling processes is that manufacturing conditions must be at low humidity so that the level of condensed water within the product is kept to a minimum. The significance of water, and the destructive role that it can play in MDI formulations, has been described in some detail by Miller [17] and is critically important, particularly for HFA formulations, where the solubility of water is far greater than with CFCs.

After filling, the canisters are leak tested. This can be accomplished by passing the filled canisters through a heated waterbath (typically at 50°C) to raise the vapor pressure. The canisters will be cleaned during this process, and any "gross leakers" are identified. Furthermore, container integrity can be assessed, and canisters showing structural weakness can be rejected. The canisters are then dried and stored under ambient conditions to allow equilibration of the components within the metering valve. After, equilibration, canisters are check weighed, and latent leakers (those that fall below the specified minimum fill weight based on the storage condition) are detected and discarded. This is an important check on processing conditions, in particular, valve damage during the filling process or the use of inappropriate valve crimp dimensions. The canisters are then spray tested and inserted into their actuators and final package.

As in any pharmaceutical manufacturing process, careful control and inspection of the various product components are essential. Dimensional checks on the can, valve, and actuator need to be carried out. In addition, standard identity and purity tests for active and excipients, including propellants, must be performed. In-process checks also need to be made regarding the active concentration in the concentrate and also the level of dispersion. A careful check on valve crimp dimensions will minimize latent leakers. In a two-stage filling process, precision of fill at each stage is critical to the concentration of active in the finished product. Thus, gravimetric determination of the fill weights of both stages is also required.

There is a range of tests that need to be carried out on MDIs during formulation development and stability evaluation. The scope and nature of these tests have been widely debated for several years, and they are still being discussed. A detailed discussion on the merits of these tests is beyond the scope of this text; the FDA has issued a guidance document on these tests [41] and how they should be applied; this should be carefully reviewed before embarking on any inhaled-product development activity. It is, however, important to highlight some of the more crucial tests for MDIs. Clearly, many of the standard tests for other pharmaceutical dosage forms also apply to MDIs. These include stability, purity, and dose uniformity; however, MDIs require special consideration because of their uniqueness. The two most important tests, in addition to those described previously, are the metering performance of the valve and the aerodynamic particle size of the dispersed aerosol cloud.

There is much debate about these particular tests and their appropriateness. However, the concept of the use of aerodynamic particle size testing as a compendial test is now well established. Both impactor testing and impingers testing have a role in the development of MDIs, because they are useful tools in studying aerosol clouds and can provide information that leads to formulation optimization (at least in terms of respirable dose). It should be emphasized that these data should not be taken in isolation, and other appropriate particle-sizing techniques should also be used. A more complete discussion of this topic can be found in Chapter 11.

In summary, the MDI is a safe and well-established inhalation delivery system. The transition from CFC propellants has begun but has been plagued with technical challenges and has taken far longer than many expected. This has encouraged scientists to look for alternate means of delivering drugs to the lungs. MDIs containing HFA propellants where the drugs are dissolved in a mixture of propellant and cosolvent are being proposed as a means to achieve efficient delivery of drugs, including macromolecules, to the lung [38].


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