A Decision Support System Integrating Process Analytical Technology(PAT) And Population Balance Models For Granulation

High shear wet granulation(HSWG)is widely used in the pharmaceutical industry for the enlargement of fine powders with a binder.The granule size distribution(GSD),uniformity of key ingredients,binder distribution,porosity,strength,friability,and morphology are key granule quality measures since they decide the performances of the final product including disintegration time,dissolution rate,compressibility and flowability.There have been great achievements in the modeling and simulation of granulation processes that involve such complex phenomena as powder nucleation,growth,aggregation and breakage.However,despite these achievements,it has not yet come to a stage that for any given material,any granulator design,reliable models can be rapidly constructed and confidently used for process optimization and scale-up.As a result,in industry,granulation process optimization often relies on experiments,preferably with the help of Design of Experiments,to develop the understanding of the causal relationships between process variables and operational spaces.The purpose of this study is to illustrate the decision support system(DSS),which is different from the first-principles and direct experiment approach to optimize and control of granulation process.The principle is that by being able to measure and understand in real-time evolution of the product quality parameters and process conditions as well as their interactions,and subsequently accurate model,exercise control and product quality can be assured.Integration of multiple PAT(process analytical technology)instruments could be used for real-time characterization of the operational spaces and granule growth behavior,providing a tool for rapid process optimisation and scale-up based on experiments on a granulator.A case study applying the DSS to the granulation of microcrystalline cellulose and mannitol powders using aqueous solution of polyvinylpyrrolidone as the binder is described.The DSS has integrated near infrared spectroscopy(NIR),on-line imaging and image analysis,and population balance(PB)models.The integrated PAT based on NIR and imaging allows multiple process variables and granule properties to be characterised in real-time,including mixing uniformity,binder content,granule size and size distribution,as well as granule growth,aggregation and breakage,and facilitates rapid identification of the operational spaces.The spraying period has shown to experiencing four phases: wetting,nucleation,rapid growth and moderate growth,but the boundaries separating the phases were different depending on the spray rate.At a high spraying rate,the binder contents at which the growth stepped into nucleation regime and rapid growth regime were lower.However,it didn't show significant influence on the median size of the granule formed.In addition,the mixing uniformity during the dry mixing period was monitored using NIR,allowing the identification of the end point of this period and beginning of binder spraying.The population balance model including growth,aggregation and breakage were established and solved,and were applied in three case studies,i.e.crystallization of AIBN,HSWG with pouring on binder and HSWG with spraying binder.The growth parameters in growth model were estimated with data from integrated PAT platform of AIBN crystallization and the growth behavior were simulated.The three aggregation kernels(i.e.SSK,EKE,BMK)were adopted and compared in HSWG with pouring on binder.The PAT platform provides data for estimation of the aggregation and breakage constants in PB models and continuous improvement of the models in spraying HSWG.The inhibitory capabilities of eight polymeric excipients(HPMC,HPC,HEC,D-Cellobiose,CMC-Na,PVP,PEG and PVA)on the polymorph conversion of carbamazepine(CBZ)in slurry-systems and wet granulation were characterized and compared.In HSWG,HPMC could inhibit the transformation completely.HPC,HEC,PVP and PVA showed the intermediate effect,D-Cellobiose,PEG and CMC-Na nearly had no inhibition effect.Comparing with slurry system,granulation process was time-consuming and needed large amount of APIs.Consequently,the simple slurry experiments could be used to screen the effective of polymeric excipients in inhibiting hydrate formulation before implement into granulation.The influence of excipients on granule size,GSDs,morphology,circularity and mechanical properties including Young's modulus,yield stress,breakage energy,elastic limit and fracture limit were also investigated.HPMC and PEG could enlarge the granule medium size significantly,while HEC could decrease the size obviously.Besides the fundamental variables influencing the aggregation in HSWG,the hygro-capacity of excipients that the ability to bind water by absorption in molecular matrix or on the surface would influence the granule size compared with addition in liquid state.