Metered Dose Inhaler Formulations

The development of MDI formulations requires the same core preformulation data as described previously. However, additional parameters must also be evaluated, including solubility in propellant vs. concentration and nature of dispersing agent, crystal growth potential (related to solubility), and, most importantly, suspension properties (sedimentation, redispersibility). These issues have been studied very carefully since the early 1990s as pharmaceutical scientists have gained further experience with the "new" pressurized gases HFA134a and HFA 227, which have very different physicochemical properties from the more widely used CFCs that they replaced. Issues relating to physical stability must be addressed early during the development of an MDI suspension formulation. In addition to dispersibility, of particular importance is the potential for the drug to undergo crystal growth. Because this process is solution mediated, the solubility of the active in prospective formulations must be assessed. The influence of crystal and salt form, propellant composition, and surfactant should be evaluated with the objective of minimizing solubility. Although no general rules apply, it is prudent to limit drug solubility to the range of low parts per million to avoid significant problems with crystal growth for suspension formulations.

The solubility of a solute is a function of the particle size of the solute. Small particles, possessing high surface free energy, are more soluble than larger particles. The increase in solubility is dramatic for particles of less than one micrometer [15]. This phenomenon is particularly relevant to the development of MDI suspension formulations because the drug is present as a microfine, polydisperse powder. Preferential dissolution of smaller particles results in localized supersaturation and crystal growth after deposition on larger particles (Ostwald ripening). The propensity of the drug to undergo growth is typically assessed by cycling prototype formulations over a range of temperatures that the product is likely to be subjected to (e.g., 2°C $ room temperature $ 40°C). Samples are evaluated microscopically for evidence of crystal growth after a predetermined number of cycles. Other techniques, including differential scanning calorimetry, solution calorimetry, infrared spectroscopy, and x-ray powder diffraction, can be used to characterize changes in crystal form.

Water should always be regarded as a hostile impurity in propellant-based MDI formulations. Although only sparingly soluble in CFC propellants, it is much more soluble in the HFA propellants (typically 600-2200 ppm, depending on the propellant [16]), and water can act as a powerful cosolvent. As such, it can induce aggregation and catalyze processes described previously. In addition, it can promote degradation of hydrolytically unstable drugs. Because water cannot usually be rigorously excluded from MDI formulations, it is important to evaluate its influence on product integrity and performance [17]. Temperature-cycling experiments should be conducted on formulation prototypes as a function of added water.

From the standpoint of the number and diversity of excipients generally used, propellant MDI formulations are relatively simple formulations. The current technology comprises either propellant-drug-based formulations, suspension formulations that contain one or more solvents (typically ethanol) to aid the solubility of the surface active agents, or solution formulations using known excipients, including glycerol [18]. Excipient compatibility studies can, therefore, be extended at an early stage to include actual formulation prototypes. Factors to be considered as part of the excipient selection process include solubility, chemical and physical compatibility with the drug, and potential interactions with container and valve components. This issue is reported to have affected formulation development activities to the extent that internally coated canisters are now being used for some MDI products.

Chemical compatibility is appropriately assessed by evaluating drug and surfactant blends, using a stability-indicating assay, following storage at elevated temperature of prototype formulations. Potential interactions of the drug with prospective containers and valve components can be evaluated by comparing assay results for samples stored at elevated temperature in plastic-coated glass aerosol bottles with corresponding results for samples stored in contact with prospective packaging components, including aluminum as well as intact or dismantled valves. The oxygen and water content of the test samples should be controlled to establish their role in drug degradation and to avoid misleading results.

Criteria considered so far in the selection of a suitable drug form for MDI development include drug solubility and excipient and component compatibility. In addition to these parameters, suspension properties need to be carefully considered in the selection process. These are discussed in more detail later in this chapter in the section on the development of MDIs.

Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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