Investigation and optimization of a solvent/anti-solvent crystallization process for the production of inhalation particles

Dry powder inhalers (DPIs) are commonly used to deliver drugs to the lungs. The drug particles used in these DPIs should possess a number of key properties. These include an aerodynamic particle size < 5mum and particle crystallinity for long term formulation stability. The conventionally used micronization technique to produce inhalation particles offers limited opportunities to control and optimize the particle characteristics. It is also known to induce crystalline disorder in the particles leading to formulation instability. Hence, this research project investigates and optimizes a solvent/anti-solvent crystallization process capable of directly yielding inhalation particles using albuterol sulfate (AS) as a model drug. Further, the feasibility of the process to produce combination particles of AS and ipratropium bromide monohydrate (IB) in predictable proportions and in a size suitable for inhalation is also investigated.;The solvent/anti-solvent systems employed were water/ethyl acetate (EA) and water/isopropanol (IPA). Investigation and optimization of the crystallization variables with the water/EA system revealed that particle crystallinity was significantly influenced by an interaction between the drug solution/anti-solvent ratio (Ra ratio), stirring speed and crystal maturation time. Inducing a temperature difference between the drug solution and anti-solvent (T drug solution > Tanti-solvent) resulted in smaller particles being formed at a positive temperature difference of 65°C. IPA was shown to be the optimum anti-solvent for producing AS particles (IPA-AS) in a size range suitable for inhalation. In vitro aerosol performance of these IPA-AS particles was found to be superior compared to the conventionally used micronized particles when aerosolized from the NovolizerRTM.;The solvent/anti-solvent systems investigated and optimized for combination particles were water/EA, water/IPA, and water/IPA:EA 1:10 (w/w). IPA was found to be the optimum anti-solvent for producing combination particles of AS and IB with the smallest size. These combination particles showed uniform co-deposition during in vitro aerosol performance testing from the NovolizerRTM. Pilot molecular modeling studies in conjunction with the analysis of particle interactions using HINT provided an improved understanding of the possible interactions between AS and IB within a combination particle matrix.