(M1130-02-10) Effect of Binary vs Ternary Systems on Stability and Drug Release Performance of Amorphous Solid Dispersions

Purpose: Amorphous Solid dispersions (ASDs) is one of the most widely investigated technique to increase the solubility and bioavailability of poorly soluble drugs. Traditionally, binary solid dispersions containing an amorphous drug dispersed in single polymeric matrix has been explored for amorphous stabilization of poorly soluble drugs. However, this approach has limitations with respect to API loading in ASD and may lack necessary physical stability and can revert to the crystalline form on storage [1]. Surfactants are commonly added to improve the drug loading, enhance wetting, improve dispersibility, inhibit crystallization, stabilize the amorphous state of APIs, and enhance dissolution and supersaturation. on the contrary, the presence of surfactants in ASDs can also promote undesired crystallization as well as leaching of API from the drug-rich particles into the surrounding medium and can influence particulate species formation which could impact the stability of the ASD system. To address this challenge, ternary systems of ASD were explored using Ritonavir as the model drug in combination with polymer blends of Copovidone /HPMC AS-LF and Copovidone /Eudragit EPO.

Methods: Ritonavir (RTV) was used as model drug and Copovidone (Kollidon VA-64), HPMC AS-LF and Eudragit EPO were used as polymeric excipients in the study. The binary ASD of Ritonavir with Copovidone (Kollidon VA-64) polymer were prepared at 20%w/w and 50%w/w drug loading, whereas the drug-polymer-polymer ternary solid dispersions with different ratios of polymer combination at 20%w/w, and 50%w/w drug loading were prepared by Nano 16 HME as shown in table 1. The powder X-ray diffraction (PXRD) and modulated differential scanning calorimetry (mDSC) were performed to characterize the amorphous nature and homogeneous single-phase system of the ASDs. The crystalline and amorphous solubility was determined by shake flask method and antisolvent precipitation by supersaturated solution method, respectively. The in-vitro drug release was performed under non-sink dissolution conditions using USP II Paddle apparatus at 75 RPM in 900 mL of simulated intestinal fluid (pH=6.8) maintained at 37±0.5°C.DVS was performed to determine the hygroscopicity of the formulations.

Results: All ASD prototypes were evaluated by mDSC and XRPD. XRPD diffractograms were absent of any Bragg peaks and mDSC thermograms exhibited a single glass transition in the second heating cycle, indicating all prototypes were amorphous in nature. As illustrated in Fig 1, ternary ASD of Ritonavir at 20% w/w drug load prepared with Copovidone /HPMC AS-LF at polymer ratio of 1:0.25 and 1:0.67, demonstrated better dissolution enhancement of Ritonavir in comparison to binary ASD at similar drug loading. The insoluble nature of Eudragit EPO at pH 6.8, led to slower drug release from ternary ASDs prepared with Copovidone /Eudragit EPO polymer combination. For higher drug loading (50%w/w) ASD formulations, only the ternary ASD with Copovidone /HPMC AS-LF (polymer ratio of 1:0.67) showed a higher solubility compared to crystalline RTV and a higher dissolution compared to ASD using Copovidone as a single carrier, Fig 2.

Conclusion: The selected polymer combination of Copovidone with HPMC AS-LF in ternary solid dispersions enhanced drug loading, drug release rate and prolonged supersaturation for a period of ~9 hours compared to binary ASDs comprising of binary systems. Moreover, the use of hydrophobic polymer such as HPMC AS-LF or Eudragit EPO with hydrophilic polymers such as Copovidone can provide better physical stability for the ASD formulation containing moisture-sensitive molecules. Thus, a well-designed combination of polymers with hydrophilicity property /rapid release capability and drug crystallization inhibition capability could provide higher drug loading and superior drug release performance from the Ternary ASD. Hence, a thorough screening and selection of the right binary polymer systems could potentially address the challenges associated with ASDs and pave the path for bringing more ASD products to market.

References: 1. Rahman, M., Coelho, A., Tarabokija, J., Ahmad, S., Radgman, K., & Bilgili, E. (2020). Synergistic and antagonistic effects of various amphiphilic polymer combinations in enhancing griseofulvin release from ternary amorphous solid dispersions. Eur J Pharm Sci, 150, 105354. doi:10.1016/j.ejps.2020.105354


Figure 1. Dissolution profile of Binary RTV ASD and Ternary RTV ASD at lower drug loading 20% w/w in simulated intestinal fluid (pH 6.8) [n=3]. The maximum theoretical dissolution was 35 μg/mL.

Figure 2. Dissolution profile of Binary RTV ASD and Ternary RTV ASD at higher drug loading 50% w/w in simulated intestinal fluid (pH 6.8) [n=3]. The maximum theoretical dissolution was 35 μg/mL.