Purpose: In the manufacturing process of solid oral dosages, multiple unit operations such as roller compaction and tableting create pharmaceutical compacts. The density of these pharmaceutical compacts is generally considered a critical quality attribute (CQA) due to its effect on tablet disintegration and dissolution time. With FDA’s initiative towards quality by design (QbD), it is important to monitor and control CQAs of the manufacturing process with process analytical technology (PAT) to ensure the final product quality. In this study, transmission terahertz spectroscopy is further investigated as a PAT tool to measure compact density. Terahertz spectroscopy offers an advantage over other spectroscopic techniques by directly providing refractive indices at terahertz frequencies from phase shift information. Refractive indices are highly correlated with density/porosity. This study specifically investigates the effect of tableting factors (i.e compression force, compression speed, and fill weight) and material properties (i.e. particle size, formulation) on refractive index based density model.
Methods: Terahertz based density models were developed. These models specifically predicted bulk density which was determined by weight and dimension measurements of the compacts. The formulation utilized for making compacts included acetaminophen (model drug), microcrystalline cellulose (MCC), lactose monohydrate, starch, and magnesium stearate. Physical and chemical parameters were varied by utilizing series of design of experiments (DOEs). For chemical composition a mixture design was used in which acetaminophen, microcrystalline cellulose, and lactose monohydrate were varied by small amounts. In total there were four chemical design points. Physical parameters were studied by varying different tableting parameters and particle size. Specifically, Instron universal testing system (Model 5869, Instron Corp.) with 13mm die and punch was used to vary compression force, compression speed, and tablet weight and create compacts with the defined five component formulation. Particle size effect was investigated by producing pure lactose monohydrate and MCC tablets with six different levels of particle size each. Analysis of variance was used to determine the significance of each variable on density and cross validation error was to determine the accuracy of the terahertz based density model.
Results: An analysis of variance table was generated to determine the significance of chemical and physical factors on density for the five component compacts. The compression force was shown to have the highest significance. A partial least squares model built between refractive indices at multiple terahertz frequencies and density of the compacts were developed for both the five component compacts and pure component compacts with varying particle size. The cross-validation error for all models were approximately 0.015 g/mL.
Conclusion: This work demonstrates that terahertz spectroscopy can be used to accurately assess pharmaceutical compact density in the presence of physical and chemical variations. The factors that significantly effect density such as compression force also effects refractive index from terahertz. Therefore, terahertz spectroscopy can be implemented as a PAT tool for compact density assessment.