Review Cite This: Mol. Pharmaceutics XXXX, XXX, XXX−XXX
pubs.acs.org/molecularpharmaceutics
Recent Advances in Understanding the Micro- and Nanoscale Phenomena of Amorphous Solid Dispersions Ralm G. Ricarte,† Nicholas J. Van Zee,‡ Ziang Li,§ Lindsay M. Johnson,‡ Timothy P. Lodge,*,‡,§ and Marc A. Hillmyer*,‡ †
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Molecular, Macromolecular Chemistry, and Materials Laboratory, CNRS, ESPCI-Paris, PSL Research University, 10 Rue Vauquelin, 75005 Paris, France ‡ Department of Chemistry and §Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, Minnesota 55455-0431, United States S Supporting Information *
ABSTRACT: Many pharmaceutical drugs in the marketplace and discovery pipeline suffer from poor aqueous solubility, thereby limiting their effectiveness for oral delivery. The use of an amorphous solid dispersion (ASD), a mixture of an active pharmaceutical ingredient and a polymer excipient, greatly enhances the aqueous dissolution performance of a drug without the need for chemical modification. Although this method is versatile and scalable, deficient understanding of the interactions between drugs and polymers inhibits ASD rational design. This current Review details recent progress in understanding the mechanisms that control ASD performance. In the solid-state, the use of high-resolution theoretical, computational, and experimental tools resolved the influence of drug/polymer phase behavior and dynamics on stability during storage. During dissolution in aqueous media, novel characterization methods revealed that ASDs can form complex nanostructures, which maintain and improve supersaturation of the drug. The studies discussed here illustrate that nanoscale phenomena, which have been directly observed and quantified, strongly affect the stability and bioavailability of ASD systems, and provide a promising direction for optimizing drug/polymer formulations. KEYWORDS: amorphous solid dispersions, drug−polymer interactions, solubility enhancement
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INTRODUCTION Beginning in the 1990s, the use of combinatorial chemistry and high-throughput in vitro screening assays enabled rapid discovery of novel pharmaceutically active molecules with high potency, binding affinity, and selectivity, thereby revealing a vast array of drugs that could potentially fulfill unmet medical needs. Unfortunately, the approach is biased toward favoring molecules that are hydrophobic and crystalline. These properties lead to poor aqueous solubility (100 kV) to resolve nanoscale structures. For example, we demonstrated that electron diffraction and dark-field TEM imaging can detect crystallinity in griseofulvin/HPMCAS ASDs at levels below the sensitivity limits of laboratory-scale WAXS and modulated DSC (Figure 4A and B).55 Moseson et al. showed that fast Fourier transform analysis of bright-field TEM images may reveal nanocrystalline domains and crystal defects within
indomethacin/PVP-VA ASDs produced by hot melt extrusion.56 Recently, S’ari et al. used low-dose TEM moiré fringe imaging to observe lattice defects in crystallites of various pharmaceutical actives.57 For high-resolution mapping of both crystalline and amorphous drug, analytical electron microscopy techniques, which measure characteristic signals produced by inelastic scattering of the electron beam by the TEM sample, may be used. Energy-dispersive X-ray spectroscopy (EDX), for instance, tracks the emission of X-rays from the sample. The energy and intensity of the X-rays reflect the atomic makeup of the material. By using a conventional TEM converged beam or scanning TEM electron probe, elemental composition may be recorded with nanoscale resolution. Li et al. employed EDX to evaluate the composition of phase separated domains in evacetrapib/PVP-VA ASDs that were stored in high humidity environments,58 while we used the technique to detect the presence of griseofulvin in spray dried ASD particles.59 The utility of EDX for ASD systems, however, is limited. The approach relies on the presence of heteroatoms in drug or polymer, while the low probability of X-ray emission hampers the concentration resolution of the technique.59 Electron energy-loss spectroscopy (EELS), an alternate method which quantifies the kinetic energy distribution of electrons in the transmitted beam, achieves a stronger signal-to-noise ratio than EDX and is not constrained to systems with heteroatoms. We demonstrated that the aromatic π−π* transition EELS signal produced by a variety of drugs may be tracked to enable composition quantification with sub-100 nm spatial resolution. For a phenytoin/HPMCAS ASD annealed at 140 °C, a heterogeneous distribution of drug was detected (Figure 4B and C).60 Because most pharmaceutical actives contain aromatic rings (∼99%)61 and most excipients do not, EELS E
DOI: 10.1021/acs.molpharmaceut.9b00601 Mol. Pharmaceutics XXXX, XXX, XXX−XXX
Review
Molecular Pharmaceutics has the potential to be expanded to a wide variety of ASD systems. While TEM may reveal quantitative information regarding the nanostructure of formulations, the technique is prone to damaging soft material samples. Continuous irradiation alters nanostructures and reduces crystallinity, thereby corrupting image and spectrum analysis. Drug molecules containing a high ratio of conjugated carbons to nonconjugated carbons are relatively resistant to beam damage, but molecules containing hydrogen-bonding moieties can be unstable.62 To enable accurate quantitative analysis, low electron doses must be used. Cooling the sample to cryogenic temperatures also reduces the rate of beam damage.63 Furthermore, great care should be taken when interpreting TEM images or spectra. Because thin samples are required (∼100 nm thick), structures observed by TEM may not be entirely representative of the bulk sample. In contrast to TEM, nondestructive microscopy methods preserve sample integrity during the analysis of crystallinity and nanostructure. One example is second harmonic generation microscopy (SHG), which has recently been developed as a highly sensitive technique for detecting trace crystallinity in SDs (Figure 4E and F). Relying on the nonlinear optical interactions of light waves and noncentrosymmetric crystals, SHG provides image contrast between chiral drug crystals and achiral species in the system. The method achieves a crystallinity limit detection far superior to optical microscopy.64−66 Using SHG, Correa-Soto et al. tracked the growth of dilute amounts of crystals (0.1−0.7 vol %) in ezetimibe/ HPMCAS ASDs stored in a 40 °C and 75% relative humidity environment.67 While SHG by itself does not provide chemical composition information, pairing it with spectroscopic techniques can hasten crystallinity screening of a pharmaceutical active. For formulations of lyophilized abraxane powder (i.e., a commercial form of protein-bound paclitaxel), Schmitt et al. employed SHG to identify crystalline domains. By further analyzing these regions-of-interest using Raman spectroscopy, the domains were confirmed to be crystalline paclitaxel. Compared to simply scanning the entire sample with Raman spectroscopy, the time needed for the SHG-Raman pairing to identify paclitaxel crystallites was over 2 orders of magnitude faster.68 Other microscopy techniques may also be combined with spectroscopy to enable drug and polymer mapping throughout an ASD. Fluorescence optical microscopy and confocal fluorescence microscopy grant the ability to distinguish between drug and polymer via the addition of selective fluorophores to the formulation. Hydrophobic fluorophores (such as prodan) partition into drug-rich domains,21 and hydrophilic fluorophores (such as rhodamine-6G) migrate into polymer-rich regions.69,70 Some drugs, such as indomethacin and itraconazole, even have excitation bands that fall within the wavelength range of typical confocal microscope lasers (Figure 5A).71,72 Because the emission spectrum of the fluorophore is affected by its immediate environment, analysis of the fluorescence spectrum can also reveal miscibility or phase separation between a drug and polymer. For itraconazole/ HPMC ASDs stained with both prodan and rhodamine-6G, Purohit et al. observed that spin coated ASDs had smaller domain sizes than the film casted SD; domains as small as 300 nm in diameter were resolved.73 Confocal microscopy may also be paired with Raman spectroscopy, but the spatial resolution is still diffraction limited.74−76 To achieve finer spatial resolution, ASD surfaces can be characterized using atomic
Figure 5. (A) Confocal fluorescence microscopy reveals phase separation in 80 wt % indomethacin and 20 wt % HPMCAS drop casted ASD film. Green and black domains are indomethacin- and HPMCAS-rich, respectively. Adapted with permission from ref 71. Copyright 2016 American Chemical Society. (B) Nanoscale mid-IR imaging shows that telaprevir/HPMCAS ASD films segregate into drug-rich (blue) and HPMCAS-rich (red) macrophases. Reprinted from ref 78. Copyright 2016 American Chemical Society.
force microscopy combined with infrared spectroscopy (AFMIR). Through evaluation of the local infrared spectrum, the composition of a feature observed in the AFM topographical image may be qualitatively measured with sub-100 nm spatial resolution. Using this technique pairing, Van Eerdenbrugh et al. found that felodipine/poly(acrylic acid) spin coated ASDs phase separated upon film casting.77 Later work by Li and Taylor systematically explored the miscibility of the drug telaprevir in HPMC, HPMCAS, and PVP-VA excipients (Figure 5B).78 The ability to simultaneously interrogate both structure and composition makes AFM-IR useful for studying a diverse array of drug-polymer pairs.21,58,79,80 The development and use of high resolution and high sensitivity tools for solid-state characterization enables deep insight into the intermolecular interactions and dynamics of ASD systems (see Table S1 for a comparison of the aforementioned experimental techniques). Theoretical, computational, and experimental findings revealed that these drug and polymer blends may exhibit very rich and complex phase behavior, forming structures at submicron length scales. Moreover, the use of multiple techniques to study a single ASD system provides complementary information and collectively provides a more detailed picture of drug/polymer interactions at the nanoscale. Although full understanding of the relationship between formulation composition and stability has not yet been achieved, the ability to examine nanostructures provides an avenue toward realizing this goal.
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ADVANCES IN UNDERSTANDING ASD DISSOLUTION IN AQUEOUS MEDIA During oral application, an ASD travels to the intestinal tract and dissolves in the intestinal fluid. Upon disintegration or erosion of the formulation, drug is released into an aqueous medium to form a supersaturated solution. The initial supersaturation concentration not only induces free drug in solution to permeate through the intestinal membrane into the bloodstream, but also drives the drug toward crystallization. Moreover, interactions with polymer excipient or other species F
DOI: 10.1021/acs.molpharmaceut.9b00601 Mol. Pharmaceutics XXXX, XXX, XXX−XXX
Review
Molecular Pharmaceutics
maximum in the drug concentration, followed by a decay. In case (c), the drug profile plateaus at a value lower than the targeted concentration, and case (d) depicts slow release of drug from the formulation.4,85 While these in vitro assays can identify an optimal excipient for a particular drug, alone they do not provide insight into the mechanisms that dictate the macroscopic release profile. To obtain a deeper understanding of the interactions between drug and polymer during dissolution, many studies over the past 7 years have paired these assays with high-resolution and sensitivity analytical techniques. As detailed in the following paragraphs, the observations enabled by these techniques revealed that upon addition of an ASD to aqueous media, the system may undergo a fascinating structural evolution. Measurements using spectroscopic and optical tools have elucidated a direct relationship between ASD performance and the formation of colloidal structures >100 nm in size. The idea that colloidal structures are important for bioavailability enhancement had been suggested in multiple papers since 1965,82,88−90 but starting in 2013 the mechanism of structural growth was rigorously explored by Taylor and co-workers. In these works, the dissolution media of various ASD systems were characterized by a combination of UV light transmission, dynamic light scattering, optical microscopy, and fluorescence spectroscopy measurements. Using this quartet of techniques, the authors recognized that once the amount of drug in solution surpassed a critical concentration (i.e., the solubility of the amorphous phase of the drug), amorphous nanodroplets began to appear in the dissolution media (Figure 7). The nanodroplets typically coarsened over time, while the growth rate was contingent on the drug/polymer pairing.70,91−105 Solution NMR experiments suggest that there are multiple possible mechanisms for nanodroplet formation in the dissolution media.106−108 The phase behavior of the supersaturated drug was also determined to be sensitive to the composition of the dissolution medium.109 In their review article on the physical chemistry of supersaturated ASD solutions, Taylor and Zhang proposed that liquid−liquid phase separation in the dissolution medium occurs when the dissolved drug concentration exceeds the amorphous solubility
found in the intestinal tract (e.g., micelle-forming surfactants and food substances) affect solution stability and permeation of the drug. Ultimately, the dissolution performance and bioavailability of an ASD reflect the interplay between several mass transport processes within a very heterogeneous and dynamic environment.4,81 To gain insight into how formulation composition affects drug release and supersaturation, in vitro dissolution assays are performed. Although many variations of these dissolution assays exist, they typically involve submerging the ASD in aqueous solution and measuring the amount of drug that remains in solution over time.82−84 Figure 6 features
Figure 6. Schematics of commonly observed dissolution profiles of amorphous solid dispersions in nonsink conditions. (a) Desired scenario with rapid dissolution and drug supersaturation maintenance at target concentration; (b) dissolution profile that follows the “spring and parachute” model; (c) dissolution profile with intermediate drug supersaturation and sustained maintenance; (d) dissolution profile with a slowly increasing drug concentration over time. Adapted from ref 86.
characteristic release profiles that are commonly observed in various nonsink assay methods (i.e., where the instantaneous drug concentration in the dissolution medium is nonzero).85−87 Case (a) represents the desired dissolution profile, commonly referred to as the “spring and plateau” scenario, where the drug is quickly and completely released into solution and remains there over the entire time period. In contrast, the “spring and parachute” scenario of case (b) features a
Figure 7. Dissolution profiles of ASDs featuring 10 wt % danazol and 90 wt % of either (A) PVP or (B) HPMCAS. During dissolution, UV spectroscopy and fluorescence spectroscopy were simultaneously performed. Pyrene was used as the fluorescence probe. The red dashed line represents the amorphous solubility of danazol. For both ASDs, UV absorbance showed the concentration of drug in solution surpassed the amorphous solubility limit. The decrease in the pyrene emission ratio suggested that the probe moved from aqueous buffer into a hydrophobic drug-rich phase. At later times, the increase in the pyrene emission ratio corresponded to crystallization of the danazol. Figures adapted from ref 98. Copyright 2016 American Chemical Society. G
DOI: 10.1021/acs.molpharmaceut.9b00601 Mol. Pharmaceutics XXXX, XXX, XXX−XXX
Review
Molecular Pharmaceutics
Figure 8. (A) Cryo-TEM image of 10 wt % phenytoin (PHY) and 90 wt % HPMCAS ASD dissolution media at 10 min. (B) Low-dose cryo-TEM image and (C) electron diffraction pattern of the dissolution media at 40 min. The red circle in (B) depicts the position of selected area diffraction aperture during the diffraction pattern acquisition. Lack of sharp Bragg diffraction spots implied that the nanoparticles were amorphous. (D) SAXS patterns of the dissolution media at various time points. The characteristic shoulder revealed the presence and disappearance of a metastable nanostructure. (E) Radius of gyration, Rg, calculated by fitting the SAXS patterns to an empirical scattering model. (F) Comparison of the ASD dissolution profile and the estimated nanoparticle scattering intensity, εelp. Error bars for (E) and (F) were the standard deviation of the nonlinear fitting. The measured drug concentration directly correlated with the presence of nanoparticles in the dissolution media. Figure adapted from ref 120. Copyright 2017 American Chemical Society.
of the compound, leading to a drug-rich phase (nanodroplets) and a drug-lean phase.4 Further permeation cell experiments seemed to demonstrate that the nanodroplets may act as drug reservoirs. When free drug was removed from the aqueous medium, the nanodroplets replenished and maintained the concentration of dissolved drug in solution.110−116 Also, loss of drug from solution may possibly occur due to crystallization within the nanodroplets.4 While supersaturation drives the drug to undergo macrophase separation, interactions between the drug and polymer excipient may also induce the formation of nanostructures (
