Non-destructive Raman Method Development for Quantifying Active Pharmaceutical Ingredient in an Oral Suspension Through Plastic Dosing Syringes.

For liquid drug products, e.g., solutions or suspensions for oral or parenteral dosing, stability needs to be demonstrated in primary packaging during storage and in dosing devices during in-use periods per quality guidelines from the International Conference on Harmonisation (ICH) and the European Agency for the Evaluation of Medicinal Products (EMEA). One aspect of stability testing for liquid drug products is in-use stability, which typically includes transferring the liquid samples into another container for further sample preparation with extraction diluent and necessary agitation. Samples are then analyzed with traditional chromatography methods, which are laborious, prone to human errors, and time-consuming, especially when this process needs to be repeated multiple times during storage and in-use periods. Being able to analyze the liquid samples non-destructively would significantly improve testing efficiency. We investigated different Raman techniques, including transmission Raman (TRS) and back scatter Raman with a non-contact optic (NCO) probe, as alternative non-destructive tools to the UHPLC method for API quantitation in in-use liquid samples pulled into plastic dosing syringes. The linearity of the chemometric methods for these two techniques was demonstrated by cross-validation sample sets at three levels over an API concentration range of 60 to 80 mg/mL. The accuracy of the chemometric models was demonstrated by the accurate prediction of the API concentrations in independent samples from four different pilot plant batches manufactured at different sites. Both techniques were successful in measuring a signal through a plastic oral dosing syringe, and predicting the suspension API concentration to within 4% of the UHPLC-measured value. For future work, there are opportunities to improve the methodology by exploring additional probes or to expand the range of applications by using different sample presentations (such as prefilled syringes) or formulation matrices for solutions and suspensions.

A Non-destructive Quantitative Transmission Raman Spectroscopy Method for Active Pharmaceutical Ingredient in Drug Product In-Use Samples Prepared in Dosing Vehicles.

Compatibility and in-use stability screening studies are required for dosing vehicle selection based on the FDA's guidance, "Use of Liquids and/or Soft Foods as Vehicles for Drug Administration: General Considerations for Selection and In Vitro Methods for Product Quality Assessments." One of the major analytical challenges in these studies is sample preparation because extracting active pharmaceutical ingredient (API) from the drug product mixed into viscous soft-food matrices (e.g., yogurt or apple sauce) is laborious, prone to human errors, and time-consuming. Additionally, observed in-solution degradation caused by dosing vehicle ingredients causes analytical error. In our study, NIR- and Raman-based non-destructive tests have been explored and developed with drug product powder formulation prepared in dosing vehicles. A transmission Raman chemometrics model was developed and calibrated with samples varying in API content, water content, and milled extrudate particle size distribution. The method was proven to be accurate, linear, selective, and robust. Our work with non-destructive tests eases the laboratory burdens to perform in-use stability studies with dosing vehicles for all phases of development that need to cover all application scenarios of clinical preparation and usage.

Dry Powder Mixing Is Feasible in Continuous Twin Screw Extruder: Towards Lean Extrusion Process for Oral Solid Dosage Manufacturing.

Using discrete element method (DEM) modeling and near-infrared (NIR) spectroscopy, the feasibility of powder mixing in the initial pre-melting zones of a twin screw extruder using two independent feeders was studied. Previous work in the pharmaceutical and food industry has focused on mixing when materials are melted or on material homogeneity at the extruder's output. Depending on the formulation, ensuring a fully blended formulation prior to melting may be desired. Experiments were conducted using a Coperion ZSK-18 extruder to evaluate if blend uniformity can be achieved by exploring screw configuration, screw speed, and powder feed rate. As powder exited the extruder and deposited on a conveyor belt, an in-line NIR spectrophotometer measured spectra of material. Chemometric-based models predicted unknown concentrations to evaluate if blend uniformity was achieved. Using the EDEM software, Hertz-Mindlin contact model, and dimensions of the extruder, DEM simulations complemented the experimental work. The DEM computational models provided understanding of mixing patterns inside the extruder at particle scale and helped select the screw configuration before doing experimentation. The simulations showed good axial mixing for all the screw configurations studied, while good cross (radial) mixing was only observed for the screw configuration with 90-degree kneading elements. Therefore, the screw configuration with two 90-degree kneading elements was chosen for the experimental study. The RTD profiles when using a screw configuration with only conveying screw elements are comparable to a plug flow reactor (PFR), while the profiles when using kneading elements are more comparable to an ideal continuous stirred tank reactor (CSTR). For the screw configuration with 90 degrees kneading elements, the mean residence time (MRT) decreases with an increase in the screw speed. Experimental NIR spectra showed that concentrations can be predicted with an error of 2%. It was demonstrated that the twin screw extruder can provide proper dry powder mixing of two powder feed streams based on a unit dose scale, enabling continuous powder mixing prior to the melting zone in the extruder for the formulation studied with a cohesive API. This setup may also work for other types of formulations. These studies can help in developing lean hot melt as well as wet extrusion/granulation processes using twin screw extruders for the continuous manufacturing of oral solid dosage products.