Formulations for Nebulization

The development of a nebulizer solution or suspension formulation is contingent on the same core preformulation data as would be required to support the development of any formulation. Physicochemical parameters such as pKa, log P, isoelectric pH (proteins and peptides), and solubility (vs. pH, ionic strength, buffer, and cosolvent level) are all important. Tonicity and solution pH, though typically regarded as formulation issues, must be investigated during preformulation to ensure selection of an appropriate salt form for development. For example, acidic (pH < 2) hypertonic and hypotonic aerosols have been demonstrated to induce bronchoconstriction in asthmatic subjects [6]. A hydrochloride or sulfate salt of a weakly basic drug that forms a strongly acidic solution, therefore, may not represent the optimum choice if the tonicity of the formulation is compromised as a result of pH adjustment using buffers.

It is important to profile the solution stability of the drug candidate as early as possible to identify the pH of optimum stability. The influence of light, oxygen, and trace metals on compound degradation also needs to be considered to assess the requirement for antioxidants (sodium metabisulfite, ascorbic acid, etc.) or chelating agents (EDTA, citric acid, etc.). Inclusion of such agents, though required to improve the chemical stability, must be weighed against the potential for adverse effects on the lung. Drug stability in solution should be monitored using a stability-indicating assay, following stress storage as a function of elevated temperature. In addition, conditions that promote hydrolysis (pH extremes), photolysis (ultraviolet and visible light), oxidation (O2, O2/light), and trace metal ion catalysis (FeT , FeT , CuT , CoT , etc.) all merit consideration [3]. Temperature cycling is also useful as a means of assessing potential problems relating to complexation or hydrate formation as manifested by precipitation or crystal growth.

As a guide to formulation development, studies should be undertaken to evaluate the contribution of candidate excipients, including preservatives, antioxidants, chelating agents, cosolvents, and buffers on compound stability and solubility. This is particularly important in the development of suspensions for nebulization. Compatibility with packaging components also needs to be considered as a matter of priority. Peptides and proteins in particular are notorious in their ability to adsorb onto a variety of surfaces, particularly plastic.

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