Simulation And Experimental Study On Characteristics Of Particles During Spray Drying

Spray drying is an important method to produce particles in the food,pharmaceutical and chemical manufacturing industries.In the pharmaceutical process,production of particles is a key step in producing powdered medicine,granules,capsules,and tablets.Spray drying has many advantages,such as continuous operation,stable product properties,quality attributes can be effectively controlled,suitable for industrial production etc.The particle size distribution,polymorph,and morphology are very important characteristics of particles and determine the application and properties of a pharmaceutical.Spray drying is a rapid process,the droplet size is small and it is a coupled gas-liquid-solid.For crystal-formed particle,the classical theory about crystal nucleation and growth is not applicable such a fast and micro-scale process,which makes it difficult to predict the changing droplet size distribution,simulating the size distribution of the spray dried particles and control the polymorph and morphology of particles.At present in the pharmaceutical field,the dosage form needs to meet strict requirements in bioavailability,delivery properties,dose control and dissolution rate.Therefore,it is essential and urgent to develop the study to realize accurate simulation and control of the particle size distribution,polymorphism,and morphology of particles.This research is based on the reaction engineering approach?REA?model of single droplet drying and population balance?PB?modeling to build a combined population balance and reaction engineering approach?PBREA?for simulating the particle size distribution.The morphology and polymorphism of mannitol particles were controlled by changing the composition of the precursor and subsequent optimization of process parameters.The effect of bubbles on crystal growth and self-assembly in droplets was also studied.It revealed a relationship between the crystallization properties and the morphology of particles.The engineered mannitol particles were used in improved in vitro aerosolization and deposition properties of dry powder inhalation?DPI?.The main research and findings of this thesis includes following contents.1.Computer simulation and experimental studies were carried out on the evolution of the droplet size distribution during spray drying of mannitol dissolved in water.The shrink rate of the droplet diameter during spray drying was treated as a negative growth rate in the PB model and was obtained using the REA.The integration of PB and REA gives the PBREA model,which was solved using a high-resolution numerical approach.Images were collected and analyzed to obtain droplet and particle size distributions with in the spray dryer.At a fixed concentration,the relationship between the drying time of droplets and droplet sizes can be expressed by a binominal formula.The change of the mean moisture content of droplets and the droplet size distribution during spray drying were simulated under different spray drying conditions.The ratio of the predicted and measured particle mean diameters are between 1.0 to1.2,and the span is from 0.56 to 0.9.Comparison of the simulated and experimental results show that the PBREA model can predict the mean diameter and span of particle sizes during the spray drying process effectively.The PBREA model could be applied to simulate the particle size distribution in a different spray dryer,for a variety of substances,and process conditions.This is the first time that the population balance model has been applied to spray drying,it is a useful tool for the optimization and control of the particle size distribution.2.Experimental methods were used to assess the effect of ammonium bicarbonate and polyethylene glycol additives,temperature and precursor components on the polymorph,morphology and size distribution of engineered mannitol particles.With ammonium bicarbonate as an additive,the proportion of?-mannitol increased from 4.76%to 59.86%with increasing concentration of ammonium bicarbonate,along with the roughness of the particles.Using polyethylene glycol as the additive,spray dried mannitol particles were irregularly shaped with many pores on the surface and the proportion of?-mannitol was above 90%.The ratio of the polyethylene glycol was a key factor in determining particle mean size and pore mean size,meanwhile temperature controlled the cumulative pore volume.3.An experimental approach was used to study the effect of bubbles on the morphology of the particles and the crystallization process.Generation and disappear once of bubbles improve the mannitol crystal growth and influences the arrangement of mannitol crystals on the surface.Bubbles reduce the drying time of droplets and change the morphology of particles through changing the crystal self-assembly on the surface of the particles.4.Two kinds of engineered mannitol particles were mixed with budesonide particles to prepare DPIs and the morphology,in vitro aerosolization and deposition properties were studied.More budesonide particles were adsorbed on two kinds of engineered mannitol carriers than the commercial mannitol,especially for the carrier with a porous surface and high proportion of?-mannitol.Engineered mannitol carriers also produced DPIs with higher fine particle fraction?FPF?than commercial mannitol.Among all carriers,a 2%w/v concentration of ammonium bicarbonate gave the best in vitro aerosolization and deposition properties,FPF_emittedmitted and FPF_loaded were 54.67%and 29.4%respectively.