(W1130-01-05) Preformulation Studies to Guide the Processing of Triamcinolone Acetonide by Hot-Melt Extrusion

Purpose: Triamcinolone acetonide (TA) is an FDA-approved synthetic corticosteroid commonly used in several inflammatory conditions [1,2]. Nevertheless, TA is classified as a BCS class IV drug, characterized by its low water solubility and poor membrane permeation, leading to an erratic oral bioavailability. Hot-melt extrusion (HME) appears as a modern pharmaceutical production technique that could improve the solubility and bioavailability of TA. In such a approach, the drug-polymer interaction plays a pivotal role [3]. Thus, this work aimed to carry out a comprehensive preformulation study to guide the processing of TA by HME.

Methods: Materials were initially screened based on Hansen solubility parameters (HSP). Next, selected formulation compounds were combined with TA and processed to simulate HME conditions and then they were examined using thermal and spectroscopic analyses. Particularly, the interaction between materials and the miscibility of excipients with the drug were evaluated based on the drug's degree of crystallinity using differential scanning calorimetry, while drug-excipient compatibility and possible deleterious interactions were assessed using thermogravimetry. Furthermore, Fourier-transform infrared spectroscopy was utilized to explore possible chemical changes or secondary interactions between the specific functional groups of the components.

Results: The solubility parameter allowed the selection of Eudragit^® L100 (EUD), Parteck^® MXP (PVA), Plasdone^® S-630 (PVPVA), Aquasolve™ AS-MG (HPMCAS), and triethyl citrate (TEC) for the experimental thermal and spectroscopic studies. The experimental miscibility based on the percentage of TA in the amorphous state was EUD (81.1%) > PVA (67.5%) > PVPVA (45.6%) > HPMCAS (8.5%) (Table 1). At the same time, incompatibility between the components at high temperatures was detected in samples containing PVA, PVPVA, and HMPCAS, as well as TEC’s partial evaporation (Figure 1). Infrared spectroscopy analysis suggested that using TEC in PVA or PVPVA melted-based pharmaceutical formulation processes should be avoided as it leads to thermal degradation of PVA and partial oxidation of TA within the PVPVA polymer matrix. Moreover, no evident interaction within the HPMCAS containing samples heated up to 220°C was exhibited, which agreed with thermal and theoretical observations. In EUD samples, spectral events at 1758 and 1802cm^-1 suggested the formation of anhydrides derived from polymer chains at high temperatures ( >160°C). Nonetheless, the TA’s chemical stability appears to be preserved along with TEC’s maintenance within the samples.

Conclusion: The utility of preformulation studies extends beyond merely indicating a qualitative assessment among formulation components, providing more comprehensive insights into the conformation of materials under simulated HME conditions. This allows for anticipation and monitoring of likely chemical and physical events, which is crucial in the development of pharmaceutical formulations. In this context, the integration of theoretical predictions with experimental thermal and spectroscopic techniques effectively guides the selection of suitable materials for drug products produced by HME. Indeed, the experimental phase confirmed the predicted miscibility between TA-EUD-TEC and their compatibility. Also, the findings indicate that using TEC as a plasticizer in PVA and PVPVA melting-based pharmaceutical formulation processes should be avoided, as it leads to unstable PVA-TEC mixtures and partial oxidation of the drug in the PVPVA containing samples. Overall, the outcomes of this preformulation study shows the use of EUD and TEC seems promising for the processing of TA by HME, reinforcing the importance of a meticulous selection of components.

References: 1. Thakkar R, Ashour EA, Shukla A, Wang R, Chambliss WG, Bandari S, et al. A comparison between Lab-scale and Hot-melt-extruder-based anti-inflammatory ointment manufacturing. AAPS PharmSciTech. 2020;21:200.
2. Formica ML, Ullio Gamboa GV, Tártara LI, Luna JD, Benoit JP, Palma SD. Triamcinolone acetonide-loaded lipid nanocapsules for ophthalmic applications. Int J Pharm. 2020;573.
3. Pinho, LA, Lima AL, Sa-Barreto, LL, Gratieri, T, Gelfuso, GM, Marreto, RN, Cunha-Filho, M. Preformulation studies to guide the production of medicines by fused deposition modeling 3D printing. AAPS PharmSciTech, 2021;22:1-12.

Acknowledgements: The authors declare that they have no conflict of interest. The authors acknowledge the Federal District Research Support Foundation (FAP-DF, Brazil, grant n. 00193-00000817/2021-64).


Table 1. DSC interactions observed during the 3rd run of TA as supplied and its mixtures using the plasticizer TEC and the polymers EUD; PVA; PVPVA and HPMCAS. The percentage of the drug’s crystallinity and the associated drug’s enthalpy value are indicated for each mixture, while the TA melting peak indicates the change in the melting temperature of the drug. PM: ternary physical mixtures; HM: heat stressed mixtures.


Figure 1: DTG curves of TA as supplied and its mixtures using the plasticizer TEC and the polymers (a) EUD; (b) PVA; (c) PVPVA, and (d) HPMCAS. The dashed blue line indicates the initial degradation event of the drug as supplied, while the dashed red line indicates the anticipation of the initial mass loss of the sample. The dashed red rectangle indicates a mass loss event related to the evaporation of TEC. The mass loss for each thermal event is represented as a percentage. TA: triamcinolone acetonide; TM: theoretical DTG curve; PM: ternary physical mixture; HM: heat stressed mixtures: BM: binary physical mixtures.