(T1330-11-65) Considerations for Drug layering of Sitagliptin on Placebo Tablets to Manufacture Fixed Dose Combination Drug Products

Purpose: The objective of this study was to evaluate the effect of the coating parameters at pilot and production scales (24” and 48” pan size, respectively), on tablet appearance and content uniformity when sitagliptin phosphate monohydrate (PM) is drug layered at a 1:1 ratio employing an Opadry formulation as a binder.

Methods: Materials and Methods - A fully formulated, HPMC-based, immediate release film coating system (Opadry®, Colorcon Inc. USA) previously optimized for drug layering purposes was selected. The drug layering dispersion was applied on placebo at target weight of 910mg. A sitagliptin PM to Opadry ratio of 1:1 was employed, the target dose of sitagliptin PM was 64.25 mg (equivalent to 50 mg of sitagliptin as free base), the theoretical weight gain was 14.28% w/w. The coating process parameters employed to prepare the drug-layered placebo tablets are shown in Table 1. Table 1. Coating Process Parameters. Three coating runs were carried out in two coating machines, as follows: An O´Hara Lab coat II with a 24” pan, four ploughshare baffles and two spray guns , with a pan charge of 15 Kg of placebos tablets. An O´Hara Fast coat II with a 48” pan, four ploughshare baffles and three spray guns, with a pan charge of 120 Kg of placebos tablets. Baffle design, pan speed and the number of spray guns are key factors that influences uniformity of solid distribution, on the 48” scale these factors were kept constant. Sitagliptin PM was quantified by liquid chromatography. Tablet content uniformity testing was carried out according to the USP General Chapter: < 905 > Uniformity of Dosage Units, where an acceptance value >15.0 does not meet USP criteria. Drug layered tablets were pulled from the coater at the following weight gains to assay actual API content uniformity: 5, 7.5, 10, 12,5 and 14.3%.

Results: The main purpose of the coating trial at the 24” scale was to determine if the optimized Opadry formulation at a 1:1 drug to Opadry ratio was capable to withstand the mechanical stress of the coating process (at an 8 RPMs pan speed) and to produce drug-layered tablets that were free of defects, i.e.: edge chipping and/or cracking. Drug Content Uniformity Testing Content Uniformity for the drug layered tablets is presented in Table 2, acceptance values were calculated using actual content of Sitagliptin PM. Table 2. Content Uniformity. Individual drug layered tablets assayed for actual drug content complied with the USP requirements for content uniformity for both coating trials at 12% solids in the 24” and 48” scale.As for the coating run at 15% solids in the 48” pan, a higher solid content generated higher acceptance values at all weight gains (when compared to the 12% solids), the acceptance value failed the specification at the end of the process. As expected, increasing solid content decreased the degree of uniformity with which atomized solids (including the API) were distributed among individual tablets, this is mainly due to a decrease on the total number of times that the tablets pass through the spray zone during all the process. In other words, at a constant spray rate of 350 g/min, total drug layering dispersion decreased from 142.8Kg to 114.2 Kg, and therefore process time decreased from 6.8 hrs. to 5.4 hrs. Process Efficiency. Process Efficiency for all three coating runs is presented in Table 3. Spray drying was observed in all three coating trials cases in different orders of magnitude which depended on the scale and parameters employed. Table 3. Process Efficiency. Parameters influencing process thermodynamics, droplet size and gun to bed distancing might be optimized to decrease the incidence of spray drying: The 12% solids / 48” pan trial exhibited the highest magnitude of spray drying; in this case an EEF thermodynamic factor of 3.2 in combination with a 7.5-inch distancing from the gun to the bed, and an atomization air pressure of 25 psi yielded a process efficiency of 85.9%. Some adjustments were made for the 15% solids / 48” pan trial, (i) a decrease on the inlet air temperature led to a decrease on the EEF to 2.9, which in combination with a decrease on both, (ii) gun to the bed distancing and (iii) atomization air pressure, allowed to increase process efficiency to 94.2%.

Conclusion: The purpose of this coating study was to generate experimental data that serve as a starting point for the optimization of a drug layering coating process at production scales. A solid concentration of 12% complied with the USP requirements for content uniformity of drug layered Sitagliptin; it is reasonable to expect that these results can be replicated under the same setup, i.e.: perforated side-vented pan with similar pan dimensions, baffle design and number, number and type of spray guns and pan speed.


Table 1. Coating Process Parameters


Table 2. Content Uniformity.


Table 3. Process Efficiency.