Dissolution Mechanisms of Amorphous Solid Dispersions: Application of Ternary Phase Diagrams To Explain Release Behavior.

The use of amorphous solid dispersions (ASDs) in commercial drug products has increased in recent years due to the large number of poorly soluble drugs in the pharmaceutical pipeline. However, the release behavior of ASDs is complex and remains not well understood. Often, the drug release from ASDs is rapid and complete at lower drug loadings (DLs) but becomes slow and incomplete at higher DLs. The DL where release becomes hindered is termed the limit of congruency (LoC). Currently, there are no approaches to predict the LoC. However, recent findings show that one potential cause leading to the LoC is a change in phase morphology after water-induced phase separation at the ASD/solution interface. In this study, the phase behavior of ASDs in contact with aqueous solutions was described thermodynamically by constructing experimental and computational ternary phase diagrams, and these were used to predict morphology changes and ultimately the LoC. Experimental ternary phase diagrams were obtained by equilibrating ASD/water mixtures over time. Computational ternary phase diagrams were obtained by Perturbed Chain Statistical Associating Fluid Theory (PC-SAFT). The morphology of the hydrophobic phase was studied with fluorescence confocal microscopy. It was demonstrated that critical point (plait point) composition approximately corresponded to the ASD DL, where the hydrophobic phase, formed during phase separation, became interconnected and hindered ASD release. This work provides mechanistic insights into the ASD release behavior and highlights the potential of in silico ASD design using phase diagrams.

Impact of Crystal Nuclei on Dissolution of Amorphous Drugs.

Amorphous drugs are used to improve bioavailability of poorly water-soluble drugs. Crystallization must be managed to take full advantage of this formulation strategy. Crystallization of amorphous drugs proceeds in a sequence of crystal nucleation and growth, with different kinetics. At low temperatures, crystal nucleation is fast, but crystal growth is slow. Therefore, amorphous drugs may generate dense but nanoscale crystal nuclei. Such tiny nuclei cannot be detected using routine powder X-ray diffraction (PXRD) and polarized light microscopy (PLM). However, they may negate the dissolution advantage of amorphous drugs. In this work, for the first time, the impact of crystal nuclei on dissolution of amorphous drugs was studied by monitoring the real-time dissolution from amorphous drug films, with and without crystal nuclei, and the evolving crystallinity in the films. Three model drugs (ritonavir/RTV, posaconazole/POS, and nifedipine/NIF) were chosen to represent different crystallization tendencies in the supercooled liquid state, namely, slow-nucleation-and-slow-growth (SN-SG), fast-nucleation-and-slow-growth (FN-SG), and fast-nucleation-and-fast-growth (FN-FG), respectively. We find that although the amorphous films containing nuclei do not show obvious differences from the nuclei-free films under PLM and PXRD before dissolution, they have inferior dissolution performance relative to the nuclei-free amorphous films. For SN-SG drug RTV, crystal nuclei have negligible impact on the crystallization of amorphous films, dissolution rate, and supersaturation achieved. However, they cause earlier de-supersaturation by inducing crystallization in solution as heterogeneous seeds. For FN-SG drug POS and FN-FG drug NIF, crystal nuclei accelerate crystallization in the amorphous films leading to lower supersaturation achieved with POS, and elimination of any supersaturation with NIF. Dissolution profiles of amorphous films can be further analyzed using a derivative function of the apparent dissolution rate, which yields amorphous solubility, initial intrinsic dissolution rate, and onset of crystallization in the amorphous films. This study highlights that although crystal nuclei are undetectable with routine analytical methods, they can significantly negate, or even eliminate, the dissolution advantage of amorphous drugs. Hence, understanding crystal nucleation process and developing approaches to prevent it are necessary to fully realize the benefits of amorphous solids.

Dissolution Mechanisms of Amorphous Solid Dispersions: A Close Look at the Dissolution Interface.

Despite the recent success of amorphous solid dispersions (ASDs) at enabling the delivery of poorly soluble small molecule drugs, ASD-based dosage forms are limited by low drug loading. This is partially due to a sharp decline in drug release from the ASD at drug loadings surpassing the 'limit of congruency' (LoC). In some cases, the LoC is as low as 5% drug loading, significantly increasing the risk of pill burden. Despite efforts to understand the mechanism responsible for the LoC, a clear picture of the molecular processes occurring at the ASD/solution interface remains elusive. In this study, the ASD/solution interface was studied for two model compounds formulated as ASDs with copovidone. The evolution of a gel layer and its phase behavior was captured in situ with fluorescence confocal microscopy, where fluorescent probes were added to label the hydrophobic and hydrophilic phases. Phase separation was detected in the gel layer for most of the ASDs. The morphology of the hydrophobic phase was found to correlate with the release behavior, where a discrete phase resulted in good release and a continuous phase formed a barrier leading to poor release. The continuous phase formed at a lower drug loading for the system with stronger drug-polymer interactions. This was due to incorporation of the polymer into the hydrophobic phase. The study highlights the complex molecular and phase behavior at the ASD/solution interface of copovidone-based ASDs and provides a thermodynamic argument for qualitatively predicting the release behavior based on drug-polymer interactions.

Dissolution Mechanisms of Amorphous Solid Dispersions: Role of Drug Load and Molecular Interactions.

High drug load amorphous solid dispersions (ASDs) have been a challenge to formulate partially because drug release is inhibited at high drug loads. The maximum drug load prior to inhibition of release has been termed the limit of congruency (LoC) and has been most widely studied for copovidone (PVPVA)-based ASDs. The terminology was derived from the observation that below LoC, the polymer controlled the kinetics and the drug and the polymer released congruently, while above LoC, the release rates diverged and were impaired. Recent studies show a correlation between the LoC value and drug-polymer interaction strength, where a lower LoC was observed for systems with stronger interactions. The aim of this study was to investigate the causality between drug-PVPVA interaction strength and LoC. Four chemical analogues with diverse abilities to interact with PVPVA were used as model drugs. The distribution of the polymer between the dilute aqueous phase and the insoluble nanoparticles containing drug was studied with solution nuclear magnetic resonance spectroscopy and traditional separation techniques to understand the thermodynamics of the systems in a dilute environment. Polymer diffusion to and from ASD particles suspended in aqueous solution was monitored for drug loads above the LoC to investigate the thermodynamic driving force for polymer release. The surface composition of ASD compacts before and after exposure to buffer was studied with Fourier transform infrared spectroscopy to capture potential kinetic barriers to release. It was found that ASD compacts with drug loads above the LoC formed an insoluble barrier on the surface that was in pseudo-equilibrium with the aqueous phase and prevented further release of drugs and polymers during dissolution. The insoluble barrier contained a substantial amount of the polymer for the strongly interacting drug-polymer systems. In contrast, a negligible amount was found for the weakly interacting systems. This observation provides an explanation for the ability of strongly interacting systems to form an insoluble barrier at lower drug loads. The study highlights the importance of thermodynamic and kinetic factors on the dissolution behavior of ASDs and provides a potential framework for maximizing the drug load in ASDs.

Release Enhancement by Plasticizer Inclusion for Amorphous Solid Dispersions Containing High Tg Drugs.

PURPOSE: Plasticizers are commonly used in the preparation of amorphous solid dispersions (ASDs) with the main goal of aiding processability; however, to the best of our knowledge, the impact of plasticizers on drug release has not been explored. The goal of this study was to evaluate diverse plasticizers, including glycerol and citrate derivatives, as additives to increase the drug loading where good drug release could be achieved from copovidone (PVPVA)-based dispersions, focusing on high glass transition (Tg) drugs, atazanavir (ATZ) and ledipasvir (LED). METHODS: ASDs were prepared using the high Tg compounds, atazanavir (ATZ) and ledipasvir (LED), as model drugs. Release was evaluated using surface normalized dissolution testing. Differential scanning calorimetry was used to measure glass transition temperature and water vapor sorption was performed on select samples. RESULTS: The presence of a plasticizer at 5% w/w for ATZ and 10% w/w for LED ASDs, led to improved drug release. For ATZ ASDs, in the absence of plasticizer, release was very poor at drug loadings of 10% w/w and above. Good release was obtained for plasticized ASDs up to a drug loading of 25%. The corresponding improvement for LED was from 5 to 20% DL. Interestingly, for a low Tg compound, ritonavir, relatively smaller improvements in release as a function of drug loading were achieved through plasticizer incorporation. CONCLUSIONS: The use of plasticizers represents a potential new strategy to increase drug loading in ASDs for high Tg compounds with a low tendency to crystallize and may help improve a major limitation of ASD formulations, namely the high excipient burden.

Drug Release from Surfactant-Containing Amorphous Solid Dispersions: Mechanism and Role of Surfactant in Release Enhancement.

PURPOSE: To understand how surfactants affect drug release from ternary amorphous solid dispersions (ASDs), and to investigate different mechanisms of release enhancement. METHODS: Ternary ASDs containing ritonavir (RTV), polyvinylpyrrolidone/vinyl acetate (PVPVA) and a surfactant (sodium dodecyl sulfate (SDS), Tween 80, Span 20 or Span 85) were prepared with rotary evaporation. Release profiles of ternary ASDs were measured with surface normalized dissolution. Phase separation morphologies of ASD compacts during hydration/dissolution were examined in real-time with a newly developed confocal fluorescence microscopy method. The water ingress rate of different formulations was measured with dynamic vapor sorption. Microscopy was employed to check for matrix crystallization during release studies. RESULTS: All surfactants improved drug release at 30% DL, while only SDS and Tween 80 improved drug release at higher DLs, although SDS promoted matrix crystallization. The dissolution rate of neat polymer increased when SDS and Tween 80 were present. The water ingress rate also increased in the presence of all surfactants. Surfactant-incorporation affected both the kinetic and thermodynamics factors governing phase separation of RTV-PVPVA-water system, modifying the phase morphology during ASD dissolution. Importantly, SDS increased the miscibility of RTV-PVPVA-water system, whereas other surfactants mainly affected the phase separation kinetics/drug-rich barrier persistence. CONCLUSION: Incorporation of surfactants enhanced drug release from RTV-PVPVA ASDs compared to the binary system. Increased drug-polymer-water miscibility and disruption of the drug-rich barrier at the gel-solvent interface via plasticization are highlighted as two key mechanisms underlying surfactant impacts based on direct visualization of the phase separation process upon hydration and release.

Anisotropic Molecular Organization at a Liquid/Vapor Interface Promotes Crystal Nucleation with Polymorph Selection.

The molecules at the surface of a liquid have different organization and dynamics from those in the bulk, potentially altering the rate of crystal nucleation and polymorphic selection, but this effect remains poorly understood. Here we demonstrate that nucleation at the surface of a pure liquid, d-arabitol, is vastly enhanced, by 12 orders of magnitude, and selects a different polymorph. The surface effect intensifies with cooling and can be inhibited by a dilute, surface-active second component. This phenomenon arises from the anisotropic molecular packing at the interface and its similarity to the surface-nucleating polymorph. Our finding is relevant for controlling the crystallization and polymorphism in any system with a significant interface such as nanodroplets and atmospheric water.

Foslevodopa/Foscarbidopa: A New Subcutaneous Treatment for Parkinson's Disease.

OBJECTIVE: The aim was to demonstrate that continuous s.c. infusion of a soluble levodopa (LD)/carbidopa (CD) phosphate prodrug combination effectively delivers stable LD exposure via a minimally invasive and convenient mode and has the potential to treat Parkinson's disease (PD) patients who are not well controlled on oral medication. METHODS: Foslevodopa and foscarbidopa were prepared and the equilibrium solubility and chemical stability examined in aqueous media with different values of pH. Solutions of foslevodopa/foscarbidopa (ratios ranging from 4:1 to 20:1) were prepared by dissolving pH-adjusted lyophilized materials in water and infused s.c. in healthy volunteers for ≤72 hours. Frequent blood samples were collected to measure LD and CD exposure, and safety was monitored throughout the study. RESULTS: Foslevodopa/foscarbidopa (ABBV-951) demonstrates high water solubility and excellent chemical stability near physiological pH, enabling continuous s.c. infusion therapy. After s.c. infusion, a stable LD pharmacokinetic (PK) profile was maintained for ≤72 hours, and the infusion was well tolerated. INTERPRETATION: Preparation of foslevodopa and foscarbidopa enables preclinical and clinical PK, safety, and tolerability studies in support of their advancement for the treatment of PD. In phase 1 clinical trials, foslevodopa/foscarbidopa demonstrates consistent and stable LD plasma exposure, supporting further studies of this treatment as a potentially transformational option for those suffering from PD. ANN NEUROL 2021;90:52-61.

Surfactants Accelerate Crystallization of Amorphous Nifedipine by Similar Enhancement of Nucleation and Growth Independent of Hydrophilic-Lipophilic Balance.

Amorphous formulations, increasingly employed to deliver poorly soluble drugs, generally contain surfactants to improve wetting and dissolution. These surfactants are often liquids and can potentially increase the mobility of the drug and reduce its stability, but little is known about this effect. Here we investigate the effect of four common nonionic surfactants (Tween 80, Span 80, Triton X-100, and Poloxamer 407) on the crystallization of amorphous nifedipine (NIF). We find that the surfactants significantly enhance the rates of crystal nucleation and growth even at low concentrations, by up to 2 orders of magnitude at 10 wt %. The surfactants tested show similar enhancement effects independent of their structural details and hydrophilic-lipophilic balance (HLB), suggesting that surfactant adsorption at solid/liquid interfaces does not play a major role in crystal nucleation and growth. Importantly, the surfactants accelerate crystal nucleation and growth by a similar factor. This result mirrors the previous finding that a polymer dopant in a molecular glass-former causes similar slowdown of nucleation and growth. These results indicate that nucleation and growth in a deeply supercooled liquid are both mobility-limited, and a dopant mainly functions as a mobility modifier (enhancer or suppressor depending on the dopant). The common surfactants tested are all mobility enhancers and destabilize the amorphous drug, and this negative effect must be managed using stabilizers such as polymers. The effect of surfactants on nucleation can be predicted from the effect on crystal growth and the crystallization kinetics of the pure system, using the same principle previously established for drug-polymer systems. We show how the independently measured nucleation and growth rates enable predictions of the overall crystallization rates.

Overcoming Bioavailability Challenges of Dasabuvir and Enabling a Triple-Combination Direct-Acting Antiviral HCV Regimen through a Salt of Very Weak Acid for Oral Delivery.

Dasabuvir is a non-nucleoside polymerase inhibitor for the treatment of hepatitis C virus (HCV) infection. It is an extremely weak diacidic drug (pKa = 8.2 and 9.2) and a prolific solvate former. Due to its exceedingly low aqueous solubility (≤0.127 µg/mL at pH 1-6.8, dose number of 1.31 × 104), crystalline dasabuvir free acid exhibited poor oral bioavailability in initial animal pharmacokinetic (PK) assessment. This necessitated the development of enabling formulation for human clinical studies to achieve the required therapeutic in vivo concentration of dasabuvir. While salt formation has been widely used to enhance the solubility and dissolution rate of solids, this approach has rarely been applied to develop oral solid dosage forms for acidic drugs as weak as dasabuvir due to concerns of rapid disproportionation and crystallization of its free acid. In this contribution, we detail our efforts in identifying dasabuvir monosodium monohydrate as a drug substance that is stable, manufacturable, and, most importantly, significantly enhances the dissolution and oral absorption of this poorly soluble drug. The oral delivery of dasabuvir through the salt approach has enabled the commercialization of the triple-combination direct-acting antiviral HCV regimen, Viekira Pak. The methodologies and solutions identified in targeted studies to overcome technical challenges encountered along the way (i.e., incorporation of polymers to inhibit crystallization and disproportionation and species mapping to enable salt manufacturing process, etc.) can be applied to other insoluble compounds.

Role of Surfactants on Release Performance of Amorphous Solid Dispersions of Ritonavir and Copovidone.

PURPOSE: To understand the role of different surfactants, incorporated into amorphous solid dispersions (ASDs) of ritonavir and copovidone, in terms of their impact on release, phase behavior and stabilization of amorphous precipitates formed following drug release. METHODS: Ternary ASDs with ritonavir, copovidone and surfactants (30:70:5 w/w/w) were prepared by rotary evaporation. ASD release performance was tested using Wood's intrinsic dissolution rate apparatus and compared to the binary drug-polymer ASD with 30% drug loading. Size measurement of amorphous droplets was performed using dynamic light scattering. Solid state characterization was performed using attenuated total reflectance-infrared spectroscopy, differential scanning calorimetry and scanning electron microscopy. RESULTS: All surfactant-containing ASDs showed improvement over the binary ASD. Span 85 and D-α-tocopheryl polyethylene glycol succinate (TPGS) showed complete release with no evidence of AAPS or crystallization whereas Span 20 and Tween 80 showed < 50% release with amorphous amorphous phase separation (AAPS). Span 20 also induced solution crystallization. Sodium dodecyl sulfate (SDS) showed very rapid, albeit incomplete (~ 80%) release. AAPS was not observed with SDS. However, crystallization on the dissolving solid surface was noted. Span 20 and TPGS formed the smallest and most size-stable droplets with ~ 1 µm size whereas coalescence was noted with other surfactants. CONCLUSIONS: Surfactants improved the release performance relative to the binary ASD. Different surfactant types impacted overall performance to varying extents and affected different attributes. Overall, Span 85 showed best performance (complete release, no crystallization/AAPS and small droplet size). Correlation between physicochemical properties and surfactant performance was not observed.

Impact of Surfactants on the Performance of Clopidogrel-Copovidone Amorphous Solid Dispersions: Increased Drug Loading and Stabilization of Nanodroplets.

PURPOSE: Surfactants are increasingly being added to amorphous solid dispersion (ASDs) formulations to enhance processability and release performance. The goal of the current work was to investigate the impact of cationic, anionic and non-ionic surfactants on the rate and extent of clopidogrel (CPD) release from copovidone-based ASDs. METHODS: CPD release was evaluated for ASDs with different drug loadings using a surface normalized intrinsic dissolution apparatus. Studies were also carried out using dynamic light scattering, zeta potential measurements, and nuclear magnetic resonance spectroscopy to probe the impact of surfactants on drug-rich nanodroplet physical stability and clopidogrel-surfactant interactions. RESULTS: CPD ASDs showed good release for drug loadings as high as 40%, before the release fell off a cliff at higher drug loadings. Only sodium dodecyl sulfate, added at a 5% level, was able to improve the release at 50% drug loading, with other surfactants proving to be ineffective. However, some of the surfactants evaluated did show some benefits in improving nanodroplet stability against size enlargement. Ionic and non-ionic surfactants were observed to interact differently with CPD-rich nanodroplets, and variations in the kinetics and morphology of water-induced phase separation were noted in the presence and absence of surfactants in ASD films. CONCLUSIONS: In summary, addition of surfactants to ASD formulations may lead to some improvements in formulation performance, but predictive capabilities and mechanisms of surfactant effect still require further studies.

Surface-enhanced crystal nucleation and polymorph selection in amorphous posaconazole.

Molecules at a liquid/vapor interface have different organizations and mobilities from those in the bulk. These differences potentially influence the rate of crystal nucleation, but the effect remains imperfectly understood. We have measured the crystal nucleation rates at the surface and in the bulk of amorphous poscaconazole, a rod-like molecule known to have a preferred interfacial orientation. We find that surface nucleation is vastly enhanced over bulk nucleation, by ∼9 orders of magnitude, and selects a different polymorph (II) from bulk nucleation (I). This phenomenon mirrors the recently reported case of D-arabitol and stems from the similarity of anisotropic surface molecular packing to the structure of the surface-nucleating polymorph. In contrast to these two systems, the surface enhancement of nucleation is weaker (though still significant) in acetaminophen and in water and does not select a different polymorph. Together, the systems investigated to date all feature surface enhancement, not suppression, of crystal nucleation, and those showing a polymorphic change feature (1) structural reconstruction at the surface relative to the bulk and (2) existence of a different polymorph that can take advantage of the surface environment to nucleate. These results help predict the effect of a liquid/vapor interface on crystal nucleation and polymorph selection, especially in systems with a large surface/volume ratio, such as atmospheric water and amorphous particles.

Polymorphic selectivity in crystal nucleation.

Crystal nucleation rates have been measured in the supercooled melts of two richly polymorphic glass-forming liquids: ROY and nifedipine (NIF). ROY or 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile is known for its crystals of red, orange, and yellow colors and many polymorphs of solved structures (12). Of the many polymorphs, ON (orange needles) nucleates the fastest with the runner up (Y04) trailing by a factor of 103 when compared under the same mobility-limited condition, while the other unobserved polymorphs are slower yet by at least 5 orders of magnitude. Similarly, of the six polymorphs of NIF, γ' nucleates the fastest, ß' is slower by a factor of 10, and the rest are slower yet by at least 5 decades. In both systems, the faster-nucleating polymorphs are not built from the lowest-energy conformers, while they tend to have higher energies and lower densities and thus greater similarity to the liquid phase by these measures. The temperature ranges of this study covered the glass transition temperature Tg of each system, and we find no evidence that the nucleation rate is sensitive to the passage of Tg. At the lowest temperatures investigated, the rates of nucleation and growth are proportional to each other, indicating that a similar kinetic barrier controls both processes. The classical nucleation theory provides an accurate description of the observed nucleation rates if the crystal growth rate is used to describe the kinetic barrier for nucleation. The quantitative rates of both nucleation and growth for the competing polymorphs enable prediction of the overall rate of crystallization and its polymorphic outcome.

Impact of Drug-Polymer Intermolecular Interactions on Dissolution Performance of Copovidone-Based Amorphous Solid Dispersions.

For poorly soluble drugs formulated as amorphous solid dispersions (ASDs), fast and complete release with the generation of drug-rich colloidal particles is beneficial for optimizing drug absorption. However, this ideal dissolution profile can only be achieved when the drug releases at the same normalized rate as the polymer, also known as congruent release. This phenomenon only occurs when the drug loading (DL) is below a certain value. The maximal DL at which congruent release occurs is defined as the limit of congruency (LoC). The purpose of this study was to investigate the relationship between drug chemical structure and LoC for PVPVA-based ASDs. The compounds investigated shared a common scaffold substituted with different functional groups, capable of forming hydrogen bonds only, halogen bonds only, both hydrogen and halogen bonds, or nonspecific interactions only with the polymer. Intermolecular interactions were studied and confirmed by X-ray photoelectron spectroscopy and infrared spectroscopy. The release rates of ASDs with different DLs were investigated using surface area normalized dissolution. ASDs with hydrogen bond formation between the drug and polymer had lower LoCs, while compounds that were only able to form halogen bonds or nonspecific interactions with the polymer achieved considerably higher LoCs. This study highlights the impact of different types of drug-polymer interactions on ASD dissolution performance, providing insights into the role of drug and polymer chemical structures on the LoC and ASD performance in general.

Assessing Physical Stability of Colloidal Dispersions Using a Turbiscan Optical Analyzer.

The physical stability of aqueous colloidal dispersions containing highly concentrated droplets of poorly water-soluble drugs has recently been identified as one of the main considerations in developing amorphous solid dispersions (ASDs). The Turbiscan analyzer, an instrument based on multiple light scattering technology, was employed for the first time to assess colloidal dispersions with ritonavir as the model compound. The physical instability of ritonavir-rich droplets was monitored directly with and without the presence of candidate polymer additives at different drug concentrations and temperatures. The mechanism of the observed instability was confirmed to be coalescence of liquid droplets, based on the low glass transition temperature of water-saturated amorphous ritonavir determined using a newly developed experimental procedure. Temperature and solvent composition, within the range studied, have little influence on the kinetics of ritonavir coalescence. On the contrary, a higher concentration of drug, i.e., more droplets per unit volume, greatly accelerates the coalescence process. In addition, polymers with varying degrees of hydrophobicity resulted in different levels of effectiveness in stabilization, which is likely related to the strength of drug-polymer interactions and the corresponding differences in surface adsorption. This work demonstrates that the Turbiscan optical analyzer can be used as a rapid screening tool that provides a first-pass, high-throughput feasibility ranking of different excipients and additives to support the development of ASD formulations.

Phase Behavior of Amorphous Solid Dispersions of Felodipine: Homogeneity and Drug-Polymer Interactions.

In the current investigation, the role of drug-polymer hydrogen bonding (H-bonding) with respect to the phase behavior of amorphous solid dispersions (ASDs) is studied in depth on a nanometer level. Melt-quenched dispersions of felodipine (FEL) with poly(vinylpyrrolidone), or PVP, poly(vinylpyrrolidone-co-vinylacetate), or PVP/VA, and poly(vinylacetate), or PVAc, were prepared at drug loadings of 50-90% w/w. Modulated differential scanning calorimetry (MDSC) was used to detect microscopic homogeneity for each set of ASDs. A single composition dependent glass transition temperature (Tg) was observed over the entire composition range in MDSC data for each set of ASDs; however some samples within each set of ASDs showed a crystallization exotherm and corresponding melting endotherm in the first heating scan. Solid-state nuclear magnetic resonance spectroscopy (SSNMR) was further employed to understand phase homogeneity in these systems. The proton spin-lattice relaxation times in the laboratory and rotating frame (1H T1 and T1ρ) for the drug and individual polymer for each set of ASDs were measured to evaluate phase homogeneity. On the basis of proton relaxation measurements, it was revealed that FEL:PVP and FEL:PVP/VA ASDs exhibited better compositional homogeneity than FEL:PVAc ASDs. The strength and the extent of H-bonding were studied by using 13C SSNMR spectra. In addition, deconvolution of the carbonyl region of amorphous FEL revealed that 40% of amorphous FEL molecules were hydrogen bonded (H-bonded) through dimers and the remaining 60% were free/non H-bonded. The dimer fraction decreased as the polymer content increased for each set of ASDs, while the free fraction increased. This indicated that the polymers containing hydrogen bond acceptor groups disrupted dimers and formed intermolecular H-bonding interactions with FEL. The strength and extent of FEL:polymer H-bonding was rank ordered as PVP > PVP/VA > PVAc. These findings were also confirmed through DFT calculations on these systems. Our results suggest that drug-polymer H-bonding interaction may impact the phase homogeneity in ASDs formulated by a specific method. The data from the current study further demonstrate that SSNMR is a powerful tool for characterizing phase homogeneity in ASDs with sub-50 nm resolution. In addition, SSNMR can provide insights into drug-polymer interactions and speciation in ASDs.

Direct Visualization of Drug-Polymer Phase Separation in Ritonavir-Copovidone Amorphous Solid Dispersions Using in situ Synchrotron X-ray Fluorescence Imaging of Thin Films.

Amorphous solid dispersions (ASDs) are new formulations currently being used in pharmaceutical industry. The ASDs, in which amorphous drug and polymeric excipients are intimately mixed at the molecular level, exhibit dramatically enhanced solubility and dissolution characteristics relative to their crystalline drug counterparts. In the process of achieving an ever-increasing drug loading (DL), it is noticed, however, that the drug release profile deteriorates significantly beyond a certain DL. As an example, a ritonavir-copovidone ASD achieves continuous and full drug release when DL ≤ 25 wt %. The release drops at 30 wt % and when DL ≥ 35 wt % there is virtually no drug release, behaving like a pure amorphous drug. In this Communication, the phase miscibility of ASD thin films has been investigated by in situ synchrotron X-ray fluorescence (XRF) imaging to elucidate the mechanism for the unique change in the extent of drug release as a function of DL. It is found that the drug release profile correlates well with the amorphous-amorphous phase separation (AAPS) onset. At a lower drug loading (up to 20 wt %), it takes more than 12 h for AAPS to happen while in sharp contrast, it only needs less than 10 min for DL ≥ 32.5 wt %. During AAPS, amorphous drug accumulates on the surface of the film, which prevents further dissolution from the interior of the ASD. The current study provides a mechanistic understanding of the confounding drug release profile of ASDs as a function of DL and opens the door for studying drug-excipient (e.g., polymer, surfactant) interactions via XRF imaging in the future.

Insights into the Dissolution Mechanism of Ritonavir-Copovidone Amorphous Solid Dispersions: Importance of Congruent Release for Enhanced Performance.

The aim of this study was to probe the dissolution mechanisms of amorphous solid dispersions (ASDs) of a poorly water-soluble drug formulated with a hydrophilic polymer. Ritonavir (RTV) and polyvinylpyrrolidone/vinyl acetate (PVPVA) were used as the model drug and polymer, respectively. ASDs with drug loadings (DLs) from 10 to 50 wt % were prepared by solvent evaporation. Surface-normalized dissolution experiments were carried out using Wood's intrinsic dissolution apparatus, and both drug and polymer release were quantified. ASDs at or below 25% DL showed rapid, complete, and congruent (i.e., simultaneous) release of the drug and polymer with dissolution rates similar to that of the polymer alone. The highest drug loading at which congruent release was observed is termed the limit of congruency (LoC) and occurred at 25% DL for RTV-PVPVA. The ASD with 30% DL showed an initial lag time, followed by a period of congruent release. At later times, the release of drug and polymer became incongruent with polymer releasing faster than drug. Higher DL ASDs (40 and 50%) showed slow release of both drug and polymer, whereby the drug release rate was similar to that of the neat amorphous drug. In cases where the release of the ASD components was congruent or close to congruent, the drug concentration exceeded the amorphous solubility, and liquid-liquid phase separation (LLPS) occurred with the formation of colloidal, drug-rich species. Solid state analyses of the ASD tablet surface by infrared spectroscopy and scanning electron microscopy revealed that the partially dissolved tablet surface remains smooth, and drug-polymer miscibility is retained at low DLs; whereas, at a very high DL, the surface is porous and enriched with amorphous drug. In concert, these observations suggest that ASD dissolution and drug release at low DLs is governed primarily by hydrophilic polymer; whereas, at high DLs, amorphous drug controls dissolution. Fluorescence microscopy images of thin ASD films suggested that ASDs at or below the LoC remain homogeneous even after exposure to water. In contrast ASDs with DL above LoC undergo, to various extents, water-induced amorphous-amorphous phase separation (AAPS) leading to demixing of the drug and polymer. Correlating the observations of the dissolution study with the solid state data suggest that the ASDs with DLs higher than the LoC undergo AAPS in the hydrating matrix on the surface of the dissolving solid during dissolution, leading to separation of drug and polymer, the formation of a drug-rich interface, and hence, incongruent and/or slow release of the components. In contrast, low DL ASDs dissolve before AAPS occurs. The competition between these two parallel and competing processes on the surface of ASD solids, i.e., dissolution and AAPS, thus dictates the overall release characteristics of the ASD formulations, which is one of the most important considerations in designing formulations with superior dissolution and absorption.

Assessing Physical Stability Risk Using the Amorphous Classification System (ACS) Based on Simple Thermal Analysis.

The purpose of this study is to develop a classification system utilizing milligram amounts of the compound for physical stability ranking of amorphous pharmaceuticals, which can be used as an early risk assessment tool for amorphous solid dispersion formulations. Simple thermal analysis utilizing a differential scanning calorimeter is used to characterize amorphous pharmaceuticals with respect to their molecular mobility and configurational entropy. Molecular mobility and configurational entropy are considered as two critical factors in determining the physical stability of amorphous phases. Theoretical arguments and numerical simulations suggest that the fragility strength parameter is a good indicator of the molecular mobility below Tg, and the heat capacity change at Tg is a good indicator of the configurational entropy. Using these two indicators, 40 structurally diverse pharmaceuticals with known physical stability were analyzed. Four classes of compounds are defined with class I being the most stable and class IV the least stable. The proposed amorphous classification system and methodology for estimating molecular mobility and configurational entropy provides an easily accessible framework to conduct early risk assessments related to physical stability challenges in developing amorphous formulations.