Understanding Adhesive Mixtures for Inhalation : Particle Dynamics Modelling and Segregation Experiments

Abstract: Pulmonary route has been used as a source of drug delivery to lungs for centuries. Drugformulation decides the type of inhaler devices such as pressurized metered-dose inhalers(pMDIs), nebulizers and dry powder inhalers (DPIs). The most commonly used formulationin DPI consists of an ordered unit consisting of smaller drug particles (3 to 5 μm) (activepharmaceutical ingredient, API) attached to larger inert particles (carrier particles, 100 μm)called adhesive mixtures. APIs are highly cohesive in nature due to high surface to volume ratio.The adhesive mixture prevents self-agglomeration of APIs and helps deliver it to the deep lungs.In the manufacturing of adhesive mixtures, the focus has been on mixing and release insideinhaler. The research work in this thesis focuses on unaddressed issues on mixture stability andsegregation using modeling and experimental techniques. The Discrete Element Method (DEM)was used to investigate the mechanics of adhesive units, formed by randomized distributionof APIs on the surface of carrier particle. Binary collisions (head on and oblique) betweenadhesive units were simulated for different number density of fines on the carrier (surfacecoverage ratio, SCR), surface energy (interfacial adhesion/cohesion energy), shape of APIs(spherical, triangular bipyramidal and tetrahedral), size of carrier particles (50, 100, 200 μm),type of carrier particle (lactose and mannitol) and the angle of impact. To account for variationthree different initial randomized distributions of API on the carrier were considered. The dataobtained was analysed in terms of effective mechanical properties (coefficient of restitution),effective friction, physical stability of adhesive unit and redistribution of fines on the carriersurface. The coefficient of restitution follows a Kawakita type equation for higher velocity andfor different surface energy. The effect of the fine particle shape was predominant for low SCRs,and adhesive units formed from tetrahedral fines exhibited the largest physical stability andlargest friction during oblique collisions. In terms of carrier size and properties it was observedthat mannitol particles are more stable than lactose with similar dispersion performance andthe200 μm carrier is the most stable among the sizes investigated. To complement the modeling,segregation of adhesive mixture (consisting of budesonide and salbutamol sulphate as APIand Inhalac 70 as carrier) was studied. Experiments showed significant loss of APIs and selfagglomeration at higher SCR. The micro mechanical models and experiments lay a foundationtowards a better understanding of the adhesive mixture dynamics.