(T0930-09-49) Understanding the Effect of Plasticizers in Film Coat Materials on the Physical Stability of Amorphous Solid Dispersions

Purpose: Amorphous solid dispersions (ASDs) have improved the bioavailability of drugs that have poor aqueous solubility. Film coating is applied on tablets for enhancing taste, tablet elegance and protects drugs which are light sensitive. However, there is limited knowledge examining the influence of film coating materials on the physical stability of tablet formulations containing ASDs. A recent report observed “mixed-in” and film coated tablets based on spray-dried intermediates show worse physical stability than uncoated cores of the same formulation.¹ Herein, we hypothesized plasticizers present in film coats can lead to the observed detrimental impact on the physical stability of ASDs. The hypothesis was tested by comparing two commonly used plasticizers in film coats: triacetin and polyethylene glycol 3350 (PEG 3350). The mechanistic insights to understand the detrimental effects of plasticizers on the physical stability of ASDs were unraveled using spectroscopic, thermal, and chemical imaging analyses.

Methods: A blend of 90% w/w hydroxypropyl methylcellulose (HPMC) and 10% w/w plasticizer (Triacetin/PEG 3350) was prepared by dropwise addition of methanol and heating at 70°C. A tri-layered compact was prepared by compacting three layers on each other using a carver press: Plasticizer-HPMC, neat HPMC, and Plasticizer-HPMC, and then stressed under various stability conditions. Laser direct infrared (LDIR) spectroscopy and chemical imaging were performed on the initial and stressed HPMC layer. Solvent-evaporated ASD was prepared by dissolving 50% w/w probucol, 30% w/w Kollidon VA-64 (VA-64), and 20% w/w Triacetin/PEG 3350 in methanol and were analyzed by polarized light microscopy and modulated differential scanning calorimetry (DSC). Triacetin-hydroxypropyl methylcellulose acetate succinate (HPMCAS-L) and triacetin-Plasdone K-29/32 (PVP K29/32) blends were prepared similarly to the method described above except for the solvent in the case of triacetin-PVP K29/32. The glass transition temperatures (Tg) of the polymer-triacetin blends were determined by modulated DSC.

Results: To evaluate the propensity of plasticizer leaching from film coats to ASD core, a tri-layered compact was prepared to mimic a placebo oral tablet, as shown in Figure 1a. After removing the top and bottom layers, the middle layer, which consisted of only HPMC, was used to probe the leaching of triacetin or PEG 3350. Figure 1b shows the IR spectra of the 0.5 mm HPMC layer after stressing in different conditions for the triacetin system. The peak at 1740 cm^-1 was observed due to stretching of the carboxyl group –C=O of the triacetin molecule. The observance of the 1740 cm^-1 peak in the HPMC layers provides evidence of triacetin leaching to the HPMC layer for 60°C/75%RH and 40°C/75%RH conditions for 1 week. Triacetin leaching was not observed in the case of 30°C/65%RH and 5°C/ambient conditions. LDIR chemical imaging shows the presence of triacetin in the stressed tablet, as shown in Figure 1c. A similar analysis was conducted on the PEG 3350 system; a unique peak at 1340 cm^-1 was identified, which belonged to neat PEG 3350. Thus, elucidating PEG 3350 leaching occurs only when stressed under 60°C/75%RH conditions for 1 week, as shown in Figure 1d. Thereby, this study demonstrates that triacetin has a greater propensity of leaching to the ASD core than PEG 3350 in most stress testing conditions. The plasticizer’s impact on ASDs was evaluated using solvent-evaporated probucol-VA-64 dispersion. Figure 2 shows the polarized light microscopy images of solvent-evaporated solid dispersion films of VA-64-probucol containing with and without plasticizers. Triacetin showed conversion of probucol from amorphous to crystalline state as evident from the birefringence of probucol crystals (Figure 2b) and no form conversion in the case of PEG 3350 or without plasticizer. This observation was further corroborated by DSC studies where melting endotherm of probucol was observed only for triacetin and not for PEG 3350 at the same drug loading. Further, to evaluate the impact of triacetin on different ASD polymers, Tg of triacetin-polymer blends out, as shown in Figure 3a. Due to its plasticization impact, incorporating triacetin can lead to a more significant reduction in Tg of all the polymers. Upon equilibrating different amounts of moisture (RH%) to these triacetin-polymer blends at 10% w/w triacetin content, further reduction in Tg was observed, as shown in Figure 3b. This result further illustrates the detrimental influence of triacetin as a plasticizer on ASDs.

Conclusion: Triacetin showed a greater propensity to leach into the ASD core compared to PEG 3350 when stressed under similar conditions. Also, triacetin led to probucol form conversion from amorphous to crystalline state in ASDs at the same drug loading and plasticizer content compared to PEG 3350. Moreover, the impact of triacetin on polymers led to significant Tg depression. Overall, this study shows that triacetin as a plasticizer in film coating can have a greater detrimental effect on the physical stability of ASDs than with PEG 3350

References: 1. Punia, A.; Biyyala, V.; Faassen, F.; Ash, J.; Lamm, M. S., Detrimental Effect of the Film Coat Chemistry and Thickness on the Physical Stability of Amorphous Solid Dispersions in Tablet Formulations. J. Pharm. Sci. 2023, 112 (3), 708-717.

Figure 1: a. Tri-layer compact tablet consisting of top and bottom layers of 10% w/w plasticizer-HPMC blend which mimics the film coat and middle HPMC layer mimics the placebo ASD core; b. IR Spectrum of HPMC layer of triacetin system under different stressing conditions, dotted lines indicate maximum (10% w/w Triacetin-HPMC) and minimum (neat HPMC) controls; c. LDIR chemical imaging of initial and stressed HPMC layer of triacetin system and d. IR spectra of the HPMC layer of the PEG 3350 system under different stressing conditions.

Figure 2: Polarized light microscopy of solvent-evaporated ASDs of 50% w/w Probucol-VA-64: a. No plasticizer; b. 20% w/w Triacetin; and c. 20% w/w PEG 3350.

Figure 3: a. Tg vs. Triacetin content for various ASD polymers and b. Tg vs. RH% for various ASD polymers.