(W0930-02-11) Influence of Coating Parameters on Uniformity and Yield of Immediate Release Coating Formulation of a Low Dose Drug (Linagliptin) onto Metformin HCl ER Tablets - Fixed Dose Combination

Purpose: Immediate release coating formulations of an active pharmaceutical ingredient (API), normally in a low dose, onto the tablets of another API of a high dose is commonly used to prepare fixed dose combinations. The main challenges of this kind of dosage forms are how to achieve content uniformity of low dose drug and high yield at the same time. Optimizing coating parameters is the key to improve the performance of these tablets. The purpose of this study is to investigate the effect of the critical coating parameters on the uniformity and yield of a film coating formulation containing linagliptin (5 mg) onto the extended release tablets of metformin HCl (1000 mg). Further, suitable processing conditions are identified to provide adequate content uniformity and yield of linagliptin.

Methods: Design of Experiment (DoE) was used to carry out the random customized experimental design and 19 experiments were obtained, including one central point. Process air flow, atomizing air pressure, weight gain and coating solids were fixed in the study. Variables included inlet air temperature (55-65°C), pan load (600-1000 g), pan speed (15-25 rpm), spray gun-to-tablet bed distance (5-10cm), pattern air pressure (1.0-2.0 bar), and spray rate (6-8 g/min). All coating trials were performed in a 12’’ fully perforated O`Hara Labcoat M coating pan (O’Hara Technologies, Canada). In each trial, the metformin tablets, seal coated with an HPMC-based film coating system, were then coated to 8-9% weight gain of linagliptin suspended in an Opadry formulation (at 7% solids content). Coated tablets from each trial were assayed using HPLC to evaluate the uniformity and yield of linagliptin coated tablets.

Results: Drug dosage forms with an API coating need to meet the requirements for dose uniformity, as described in major pharmacopoeias ^[1-3]. The results of the statistical analysis of the data indicated that within the design space, there were significant relationships (p＜0.05) between uniformity and pan load, pan speed, and spray rate. Among them, pan load and spray rate had positive impacts; while the pan speed and the interaction between the pan load and gun-to-bed distance had negative impacts. Yield of linagliptin coated on the ER tablets was in the range of 54%-84% in all 19 coating trials. All parameters had significant impacts on yield except the pan speed. The pan load, its interactions with pattern air pressure, spray rate and inlet temperature had positive impacts on yield. The operating range of parameters were identified according to the analytical result. In this case study, a relative standard deviation (RSD) of drug content less than 6% is considered acceptable. Figure 1 shows a plot of acceptable ranges of inlet temperature and gun-to-bed distance to achieve the drug content RSD below 6% and a yield higher than 70% at a constant pan load, pan speed, pattern air pressure and spray rate. The unshaded area of the graph shows the acceptable range of parameters.

Conclusion: DOE experiment was successfully used to identify and characterize the impact of variable critical parameters of a low dose drug coating on metformin HCl tablets. Content uniformity and yield are particularly important for coating of a low dose drug onto tablets, while during the process, it is difficult to achieve the excellent uniformity and high yield at the same time. Through DOE, the acceptable operation range of parameters were obtained for a defined product performance with RSD < 6% and yield > 70%.

References: 1. Uniformity of Dosage Units, Pharmacopoeia Europaea, seventh ed., vol. 7.6, 2013, pp. 4102–4103 (Chapter 2.9.40).
2. Uniformity of Dosage Units, United States Pharmacopoeia, thirty-first ed., vol. 31, Port City Press, Baltimore, 2008, pp. 363–369 (Chapter 905).
3. Uniformity of Dosage Units, Japanese Pharmacopoeia, vol. 16, 2011, pp. 127–129 (Chapter 6.02)

Fig. 1. Acceptable performance area (with constant pan load, pan speed, pattern air pressure and spray rate)