Miscibility is of great interest for pharmaceutical systems, in particular, for amorphous solid dispersions, as phase separation can lead to a higher tendency to crystallize, resulting in a loss in solubility, decreased dissolution rate, and compromised bioavailability. The purpose of this study was to investigate the miscibility behavior of a model poorly water-soluble drug, telaprevir (TPV), with three different polymers using atomic force microscopy-based infrared, thermal, and mechanical analysis. Standard atomic force microscopy (AFM) imaging together with nanoscale infrared spectroscopy (AFM-IR), nanoscale thermal analysis (nanoTA), and Lorentz contact resonance (LCR) measurements were used to evaluate the miscibility behavior of TPV with three polymers, hydroxypropyl methylcellulose (HPMC), HPMC acetate succinate (HPMCAS), and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA), at different drug to polymer ratios. Phase separation was observed with HPMC and PVPVA at drug loadings above 10%. For HPMCAS, a smaller miscibility gap was observed, with phase separation being observed at drug loadings higher than ∼30-40%. The domain size of phase-separated regions varied from below 50 nm to a few hundred nanometers. Localized infrared spectra, nano-TA measurements, images from AFM-based IR, and LCR measurements showed clear contrast between the continuous and discrete domains for these phase-separated systems, whereby the discrete domains were drug-rich. Fluorescence microscopy provided additional evidence for phase separation. These methods appear to be promising to evaluate miscibility in drug-polymer systems with similar Tgs and submicron domain sizes. Furthermore, such findings are of obvious importance in the context of contributing to a mechanistic understanding of amorphous solid dispersion phase behavior.
The maximum achievable concentration of a drug in solution is dictated by the chemical potential of the solid form. Because an amorphous solid has a higher chemical potential than the corresponding crystal form, in the absence of phase transformations, a higher transient solubility is expected. However, the chemical potential of an amorphous drug can be reduced by mixing with another component. Therefore, upon mixing with a polymer to form an amorphous solid dispersion (ASD), the maximum solution concentration achieved can be potentially altered, in particular if the polymer is poorly soluble in the dissolution medium. Such changes in the chemical potential of the drug may be a critical factor in determining the maximum achievable solution concentration, and could alter the crystallization driving force of the drug. Therefore, the aim of this study was to gain insights into the impact of poorly soluble polymers on the "amorphous solubility" of drugs formulated as amorphous solid dispersions. Lopinavir was selected as a model drug with a low crystallization tendency, enabling determination of the amorphous solubility as a function of ASD composition. Model polymers included cellulose acetate (CA), CA phthalate (CAP), ethylcellulose (EC), Eudragit® RL PO (EUD), hydroxypropylmethylcellulose (HPMC), HPMC acetate succinate (HPMCAS), and HPMC phthalate (HPMCP). The "amorphous solubility" of the drug alone was determined and then the changes in maximum achievable concentration were measured as a function of drug loading. Drug-polymer interactions were characterized using infrared spectroscopy (IR), differential scanning calorimetry (DSC) and moisture sorption analysis. The results showed that the maximum achievable concentration ("amorphous solubility") of lopinavir varied with the extent of drug-polymer interactions, as well as the drug weight fraction in the ASD. This information is of great value when evaluating the maximum achievable concentration of amorphous systems formulated with pH responsive polymers, and should contribute to a broader understanding of drug phase behavior in the context of ASDs.
During the dissolution of amorphous solid dispersions (ASDs), various phase transformations can occur, which will ultimately impact the degree of supersaturation. This study employed dissolution and diffusion measurements to compare the performance of various ASD formulations based on the maximum amount of free drug in the solution that was able to permeate through a cellulose-based membrane. Telaprevir (TPV) was used as the model drug compound, and ASDs were prepared with different drug loadings and with four different polymers. Four possible scenarios that can influence TPV mass flow rates upon ASD dissolution were described and supported with experimental data: (1) a system dissolves readily and completely undergoes phase separation via glass-liquid phase separation (GLPS), forming drug-rich aggregates, and reaches the maximum anticipated mass flow rate; (2) where the maximum mass flow rate decreases due to substantial mixing of the polymer into the drug-rich phase, and/or due to the formation of soluble polymer-drug complexes; (3) a system does not undergo GLPS due to slow drug release and/or matrix crystallization; and (4) a system does not undergo GLPS due to rapid crystallization from the supersaturated solution generated during dissolution. The results described herein support the importance of the combined use of the dissolution-diffusion measurements to determine the maximum level of supersaturation achievable for diverse drug formulations.
Miscibility is critical for amorphous solid dispersions (ASDs). Phase-separated ASDs are more prone to crystallization, and thus can lose their solubility advantage leading to product failure. Additionally, dissolution performance can be diminished as a result of phase separation in the ASD matrix. Water is known to induce phase separation during storage for some ASDs. However, the impact of water introduced during preparation has not been as thoroughly investigated to date. The purpose of this study was to develop a mechanistic understanding of the effect of water on the phase behavior and microstructure of ASDs. Evacetrapib and two polymers were selected as the model system. Atomic force microscopy coupled with Lorentz contact resonance, and transmission electron microscopy with energy dispersive X-ray spectroscopy were employed to evaluate the microstructure and composition of phase-separated ASDs. It was found that phase separation could be induced via two routes: solution-state phase separation during ASD formation caused by water absorption during film formation by a hydrophilic solvent, or solid-phase separation following exposure to high RH during storage. Water contents of as low as 2% in the organic solvent system used to dissolve the drug and polymer were found to result in phase separation in the resultant ASD film. These findings have profound implications on lab-scale ASD preparation and potentially also for industrial production. Additionally, these high-resolution imaging techniques combined with orthogonal analyses are powerful tools to visualize structural changes in ASDs, which in turn will enable better links to be made between ASD structure and performance.
Spray drying is widely used in the manufacturing of amorphous solid dispersion (ASD) systems due to its fast drying rate, enabling kinetic trapping of the drug in amorphous form. Spray-drying conditions, such as solvent composition, can have a profound impact on the properties of spray-dried dispersions. In this study, the phase behavior of spray-dried dispersions from methanol and methanol–water mixtures was assessed using ritonavir and copovidone [poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA)] as dispersion components. The resultant ASDs were characterized using differential scanning calorimetry (DSC), fluorescence spectroscopy, X-ray photoelectron spectroscopy (XPS), as well as surface-normalized dissolution rate (SNDR) measurements. Quaternary phase diagrams were calculated using a four-component Flory–Huggins model. It was found that the addition of water to the solvent system can lead to phase separation during the spray-drying process. A 10:90 H 2 O/MeOH solvent system caused a minor extent of phase separation. Phase heterogeneity in the 50 and 75% drug loading ASDs prepared from this spray solvent can be detected using DSC but not with other techniques used. The 25% drug loading system did not show phase heterogeneity in solid-state characterization but exhibited a compromised dissolution rate compared to that of the miscible ASD prepared from H 2 O-free solvent. This is possibly due to the formation of slow-releasing drug-rich phases upon phase separation. ASDs prepared with a 60:40 H 2 O/MeOH solvent mixture showed phase heterogeneity with all analytical methods used. The surface composition of dispersion particles as measured by fluorescence spectroscopy and XPS showed good agreement, suggesting surface drug enrichment of the spray-dried ASD particles prepared from this solvent system. Calculated phase diagrams and drying trajectories were consistent with experimental observations, suggesting that small variations in solvent composition may cause significant changes in ASD phase behavior during drying. These findings should aid in spray-drying process development for ASD manufacturing and can be applied broadly to assess the risk of phase separation for spray-drying systems using mixed organic solvents or other solvent-based processes.
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