Fabrication Of Multi-component Bioactive Microparticles Via Spray Drying And Exploration Of Particle Formation Process

Dispersion and encapsulation of active drug ingredients or other bioactive substances in an inert carrier matrix can effectively protect the activity of the ingredients during processing and storage,enhance the bioavailability of the drug,and regulate the in vivo release behaviour of the components.Spray drying technique is an effective and rapid approach to convert the feed liquid containing bioactive substances and protectants into a powder form.The composition of the protective carrier and the properties of spray dried powder influence the functionality of the bioactive particles.The design of bioactive particles with desired functionality requires the understandings on the interaction mechanisms between the protective carrier and the bioactive ingredients,as well as on the particle formation behavior of atomized droplets during during spray drying.However,in such a process,there are billions of atomized droplets being simultaneously dried in a spray dryer,so it is difficult to continuously monitor the changing process of individual droplets.In this study,the Single Droplet Drying(SDD)and Analysis technique was employed,to study the drying process of a single droplet containing either a bioactive substance or only protectant(s)under conditions analogous to spray drying.By monitoring the drying kinetics of the droples,changes in droplet morphology,and changes in the activity of the encapsulated ingredients,the particle formation process and the.underlying mechanism of various bioactive particles were investigated.The results were used to develop optimized spray drying process.First,the production of powders containing active dry probiotics were studied.A lactic acid bacteria(LAB),Lactobacillus rhamnosus GG(LGG),was used as a model strain.Changes in LGG viability during drying was monitored using the SDD experiments,and LGG-containing powders were produced using a microfluidic jet spray dryer(MFJSD).Powder properties and the viability and growth capability of LGG cells were characterized to investigate the effects of protectant compositon and pre-adaptation procedure on LGG survival after spray drying.Antioxidant or calcium were added into two matrix carriers,lactose and trehalose,respectively.The viability of LGG in spray dried powders only increased in EGCG-supplementing powders,showing an increase in survival ratio from 4%to around 12%.The results indicated that lowering the oxidation-induced damage on LGG cells can protect cell viability during spray drying,but the effect is specific to the type of antioxidant used.When 1 mM CaCl2 was added to either of the main carriers,the survival ratio of LGG in the powders was increased from 5%to around 30%,while the powder properties remained similar.The results indicated that the protective effect of Ca2+may be attributed to its interactions between LGG cells.Both findings confirmed that the protectant can regulate the stress tolerance of LAB cells to improve cell survival after spray drying.To further the investigation on the influence of cell stress tolerance,the growth conditions of LGG cells were altered and the mixing procedure of LGG cells and protectants were adjusted to obtain LGG cells with enhanced stress tolerance,as well as to reduce potential stresses during processing.Increasing the growth temperature from 37 to 42℃ resulted in a 1-fold increase in LGG survival ratio after spray drying.Preadapting LGG cells during the mixing stage increased the survival ratio to around 80%,with skim milk as spray drying protectant.The results indicating that when LAB is encapsulated as a unique type of bioactive substance,its intrinsic property is one of the key factors governing the functionality of final powders.Many active drug ingredients are hydrophobic,and their powder production process involves the use of organic solvent.To investigate the influence of different solvents on droplet drying kinetics,particle formation process,and the final particle microstructure for the same solute material,an innovative SDD technique was developed in this study.Using the new technique,the drying process of single solvent droplet and composite solvent droplet was quantitatively studied,and a complex drying process,namely antisolvent-vapor-infused drying,was systematically investigated to examine the adsorption of antisolvent vapor,the evaporation of original solvent,and solid particle formation.When air was used as drying medium,composite solvent droplets exhibited two-stage drying behavior,with volatile solvent being firstly evaporated followed involatile solvent.During drying of drug carrier droplets,the particle formation behavior and surface morphology of final particles exhibited notable difference when the compositon of composite solvent droplet was varied.Increasing the proportion of poor solvent resulted in a substantial increase of final wrinkles on the surface of dried carrier particles.In the antisolvent-vapor drying,the vapor of an antisolvent was introduced to the drying medium to dry a solute droplet dissolved in a benign solvent.While the benign solvent was evaporated,the droplet absorbed the vapor of the poor solvent,and the rate of evaporation and absorption were dependent on the property of the benign solvent,the property of the poor solvent vapor,and the mutual solubility of the two solvents.Under the control of the ethanol fraction,the mixture droplet underwent an equilibrium stage at the later stage of drying,where the droplet temperature was kept around the wet-bulb temperature of a pure ethanol droplet.The morphology of final particles was controlled by the molar fraction of ethanol in the droplet,showing urchin-like,crosslinked network,and uniform amorphous microspheres with particle sizes ranging from 2 μm to 100μm.In summary,this study focused on two systems,namely the production of powders containing active dry LAB and the drying of organic droplets.The influence of protectant material,intrinsic properties of the active substance,solvent composition,and drying medium composition on the fabrication process of multi-component bioactive particles were investigated.The results revealed the improvement of the stress tolerance of LAB cells caused by different protectant material and by pre-adaptation procedure,providing useful approaches for producing LAB powders with high activity retention.A new SDD technique was developed,allowing the quantitative study of the drying kinetics of organic droplets.The mechanisms reported for the antisolvent-vapor-infused drying will be useful for fabricating submicron drug particles of 1-2 μm size.