(51b) A Quality by Design Approach to Scale-up of the Melt-Spray-Congeal Multiparticulate Process

The melt-spray-congeal (MSC) process is a rotary atomization technique for the production of a multiparticulate pharmaceutical dosage form. The final drug product consists of a wax matrix microsphere with the active pharmaceutical ingredient (API) dispersed throughout. The drug is released from the microsphere core via porous diffusion through either channels formed as the API dissolves or pores created by various soluble excipients that can be added to the formulation. The rate of dissolution of the drug is typically correlated to the particle size of the microsphere. Thus, it is imperative be able to control the microsphere size during manufacturing to attain a reproducible release profile. For the MSC process the key process parameters which influence the microsphere size are the speed of the spinning disk (rpm), the viscosity of the drug-melt suspension, and the operating temperature of the system.

The main objectives of this work were: (1) to investigate how these process parameters influence the key quality attributes (microsphere size and dissolution) of the final drug product, and (2) to develop predictive models for the melt rheology and microsphere size. To achieve these objectives a full 2^3 factorial design of experiment (DOE) was run using a model drug system. The factors that were investigated in the DOE included % drug loading (correlated to melt viscosity), disk speed (rpm), and operating temperature. In general it was found that increasing API loading (correlated to higher melt viscosity), decreasing temperature, and decreasing disk speed resulted in increased microsphere particle size. In terms of performance it was found that above a certain threshold of drug loading the dissolution profile was insensitive to microsphere particle size. The melt viscosity data was used to develop a power law model which describes the shear dependent viscosity behavior of the drug-melt system. In addition, a predictive model was developed to determine the mean microsphere diameter as a function of melt viscosity and disk speed. A comparison of measured and predicted mean microsphere size for 14 different MSC runs show that all model predictions are within 10% of the experimental data. These two models tie the formulation and the MSC operating conditions to the resulting microsphere particle size and can be used to reduce the time and number of experiments required to develop a melt-spray-congeal formulation.