Purpose: Low drug loading amorphous solid dispersions (ASDs) are often required to achieve adequate drug release rates so that drug concentrations exceeding amorphous solubility can be obtained. The drug in excess of the amorphous solubility leads to the formation of nano-sized drug-rich aggregates as a result of liquid-liquid phase separation (LLPS). LLPS appears important for enhanced oral bioavailability of poorly soluble drugs but often occurs only at low drug loadings, posing formulation challenge for all but the most potent compounds. The purpose of this research was to identify criteria that impact the rate and extent of drug release and hence the occurrence or not of LLPS upon ASD dissolution. In particular, the effect of drug log P, phase behavior of the hydrated but undissolved ASD matrix and relative dissolution rates of drug and polymer were studied as a function of drug loading. The model drugs studied were nilvadipine (Nil) (clogP=3.04) and cilnidipine (Cil) (clogP=5.54) and the model polymer was polyvinylpyrrolidone/vinyl acetate (PVPVA).
Methods: Nil-PVPVA and Cil-PVPVA ASDs with different drug loadings were prepared. Surface area normalized dissolution rates of both the drug and the polymer from ASD tablets were studied using a rotating disc intrinsic dissolution apparatus. Aliquots from the dissolution medium, removed at various time points were analyzed for drug and polymer amount, using reverse phase high performance liquid chromatography (RP-HPLC) and size exclusion chromatography (SEC) respectively. Dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA) were used to confirm the presence of drug-rich aggregates in the supersaturated solution generated upon dissolution and size information was obtained. Microstructural changes in the ASD tablets before and after partial dissolution were studied using surface analysis techniques, scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS) along with 3D- imaging using micro computed tomography (micro-CT). Powder X-ray diffraction (PXRD) and polarized light microscopy were used to confirm the absence of drug crystallinity initially and at different dissolution time points. Additionally, a 10% drug loading (by weight) Nil-PVPVA ASD tablet was exposed to 97%RH for 12 hours before dissolution in order to induce amorphous-amorphous phase separation (AAPS) and study its impact on dissolution performance.
Results: At low drug loadings, dissolution of Nil-PVPVA and Cil-PVPVA ASDs were found to have congruent (i.e. simultaneous) release of both drug and polymer with comparable release rates and complete drug release. At high drug loadings, incongruent release of drug and polymer was found with negligible drug release even after 2 hours of dissolution. The drug loading at which the switch from congruent to incongruent release of ASD components occurred was similar for both model systems, i.e., between ~6-9% drug molar ratio. ASDs with congruent release resulted in LLPS as confirmed by the presence of amorphous drug-rich aggregates (~200nm) using DLS and NTA. Both SEM and micro-CT analysis on partially dissolved ASD tablets corresponding to incongruently releasing drug loadings showed the presence of characteristic pits or holes, most likely due to faster polymer release in comparison to drug, and the drug enrichment on these tablet surfaces was confirmed by XPS analysis. Incongruent release of drug and polymer at higher drug loadings was speculated to result from the faster kinetics of water-induced AAPS relative to the co-dissolution of ASD components. This supposition was confirmed when an originally congruently releasing ASD tablet (Nil:PVPVA 10:90 by weight) was exposed to high RH conditions in order to induce AAPS and the dissolution subsequently performed demonstrated incongruent release of drug and polymer.
Conclusion: ASD dissolution performance is a result of competitive kinetics between the release rate of ASD components and the rate of phase separation in the hydrated ASD matrix. Rapid, congruent release of drug and polymer appears to be the best scenario for the dissolution of ASDs as it results in LLPS, which is potentially important to achieve enhanced oral bioavailability from ASDs. Interestingly, and contrary to expectations, the drug log P did not impact the drug loading where this switch from congruent to incongruent release of ASD components occurred.
Naila Mugheirbi– Bristol-Myers Squibb Company
Dmitry Zemlyanov– Purdue University
Umesh Kestur– Bristol-Myers Squibb Company
Lynne Taylor– Professor, Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana