Thermodynamic solubility measurement without chemical analysis.

In this work, the optical imaging based single particle analysis (SPA) and the gold standard shake-flask (SF) solubility methods are compared. We show that to analyze pharmaceutical compounds spanning 7 log units in solubility and a diverse chemical space with limited resources, several analytical techniques are required (HPLC-UV, LC-MS, refractometry and UV-Vis spectrometry), whereas solely the SPA method is able to analyze all the same compounds. SPA experiments take only minutes, while for SF, it may take days to reach thermodynamic equilibration. This decreases the time span needed for the solubility experiment from initial preparations to obtaining the result from roughly three days to less than three hours. The optimal particle size for SPA ranges from approximately one to hundreds of microns. Challenges include measuring large particles, very fast dissolving compounds and handling small sample sizes. Inherent exclusion of density from the SPA measurement is a potential source of error for compounds with very low or high density values. The average relative difference of 37 % between the two methods is very good in the realm of solubility, where 400 % interlaboratory reproducibility can be expected.

Nonclassical Crystallization and Core-Shell Structure Formation of Ibuprofen from Binary Solvent Solutions.

Liquid-liquidphase separation (LLPS) or dense liquid intermediates during the crystallization of pharmaceutical molecules is common; however, their role in alternative nucleation mechanisms is less understood. Herein, we report the formation of a dense liquid intermediate followed by a core-shell structure of ibuprofen crystals via nonclassical crystallization. The Raman and SAXS results of the dense phase uncover the molecular structural ordering and its role in nucleation. In addition to the dimer formation of ibuprofen, which is commonly observed in the solution phase, methyl group vibrations in the Raman spectra show intermolecular interactions similar to those in the solid phase. The SAXS data validate the cluster size differences in the supersaturated solution and dense phase. The focused-ion beam cut image shows the attachment of nanoparticles, and we proposed a possible mechanism for the transformation from the dense phase into a core-shell structure. The unstable phase or polycrystalline core and its subsequent dissolution from inside to outside or recrystallization by reversed crystal growth produces the core-shell structure. The LLPS intermediate followed by the core-shell structure and its dissolution enhancement unfold a new perspective of ibuprofen crystallization.

Fast imaging-based single particle analysis method for solubility determination.

The solubility and dissolution rates of chemical compounds are crucial properties in several fields of industry and research. However, accurate, rapid and green methods for their measurement, which only consume micrograms of compound, are lacking. Here, the unique approach of non-specific, image-based single particle analysis (SPA) for solubility testing is directly compared to and thus validated on the mid-solubility range with the current gold standard shake-flask method with UV-Vis spectroscopy employed for determining sample concentrations. Five biologically active compounds representing a range of physicochemical properties including pKa and logP were analyzed with both methods. The comparison of SPA and the shake-flask (SF) analysis shows excellent linear correlation (R2 = 0.99). Higher variability of the SPA method is attributed to variability between the properties of individual particles, which cannot be detected with traditional methods. Due to the similar average solubility values compared to those produced with SF, it is concluded that the SPA method has great potential as an analytical tool for small-scale solubility studies. It also has several practical advantages over the current gold standard shake-flask method, such as speed, low consumables consumption, and no requirement for prior knowledge of compound chemistry.

Low- versus Mid-frequency Raman Spectroscopy for in Situ Analysis of Crystallization in Slurries.

Slurry studies are useful for exhaustive polymorph and solid-state stability screening of drug compounds. Raman spectroscopy is convenient for monitoring crystallization in such slurries, as the measurements can be performed in situ even in aqueous environments. While the mid-frequency region (400-4000 cm-1) is dominated by intramolecular vibrations and has traditionally been used for such studies, the low-frequency spectral region (<200 cm-1) probes solid-state related lattice vibrations and is potentially more valuable for understanding subtle and/or complex crystallization behavior. The aim of the study was to investigate low-frequency Raman spectroscopy for in situ monitoring of crystallization of an amorphous pharmaceutical in slurries for the first time and directly compare the results with those simultaneously obtained with mid-frequency Raman spectroscopy. Amorphous indomethacin (IND) slurries were prepared at pH 1.2 and continuously monitored in situ at 5 and 25 °C with both low- and mid-frequency Raman spectroscopy. At 25 °C, both spectral regions profiled amorphous IND in slurries as converting directly from the amorphous form toward the α crystalline form. In contrast, at 5 °C, principal component analysis revealed a divergence in the detected conversion profiles: the mid-frequency Raman suggested a direct conversion to the α crystalline form, but the low-frequency region showed additional transition points. These were attributed to the appearance of minor amounts of the ε-form. The additional solid-state sensitivity of the low-frequency region was attributed to the better signal-to-noise ratio and more consistent spectra in this region. Finally, the low-frequency Raman spectrum of the ε-form of IND is reported for the first time.

Nonresonant CARS Imaging of Porous and Solid Silicon Nanoparticles in Human Cells.

Coherent anti-Stokes Raman scattering (CARS), a nonlinear optical method for rapid visualization of biological objects, represents a progressive tool in biology and medicine to explore cells and tissue structures in living systems and biopsies. In this study, we report efficient nonresonant CARS imaging of silicon nanoparticles (SiNPs) in human cells as a proof of concept. As both bulk and porous silicon exhibit a high third-order nonlinear susceptibility, χ(3), which is responsible for the CARS intensity, it is possible to visualize the SiNPs without specific labels. Porous and solid SiNPs were obtained from layers of porous and nonporous silicon nanowires and mesoporous silicon. Electron microscopy and Raman spectroscopy showed that porous SiNPs consisted of ∼3 nm silicon nanocrystals (nc-Si) and pores, whereas solid nanoparticles comprised ∼30 nm nc-Si. All types of SiNPs were nontoxic at concentrations up to 500 µg/mL after 24 h of incubation with cells. We demonstrated that although nc-Si possesses a distinguished narrow Raman band of about 520 cm-1, it is possible to detect a high CARS signal from SiNPs in the epi-direction even in a nonresonant regime. 3D CARS images showed that all types of studied SiNPs were visualized as bright spots inside the cytoplasm of cells after 3-6 h of incubation because of the contrast provided by the high third-order nonlinear susceptibility of SiNPs, which is 1 × 104 to 1 × 105 times higher than that of water and typical biological media. Overall, CARS microscopy can provide localization of SiNPs within biological structures at the cellular level and can be a powerful tool for in vitro monitoring of silicon-based drug delivery systems or use SiNPs as labels to monitor various bioprocesses inside living cells.

Combined Effect of the Preparation Method and Compression on the Physical Stability and Dissolution Behavior of Melt-Quenched Amorphous Celecoxib.

In an earlier investigation, amorphous celecoxib was shown to be sensitive to compression-induced destabilization. This was established by evaluating the physical stability of uncompressed/compressed phases in the supercooled state (Be̅rzins . Mol. Pharmaceutics, 2019, 16(8), 3678-3686). In this study, we investigated the ramifications of compression-induced destabilization in the glassy state as well as the impact of compression on the dissolution behavior. Slow and fast melt-quenched celecoxib disks were compressed with a range of compression pressures (125-500 MPa) and dwell times (0-60 s). These were then monitored for crystallization using low-frequency Raman spectroscopy when kept under dry (∼20 °C; <5% RH) and humid (∼20 °C; 97% RH) storage conditions. Faster crystallization was observed from the samples, which were compressed using more severe compression parameters. Furthermore, crystallization was also affected by the cooling rate used to form the amorphous phases; slow melt-quenched samples exhibited higher sensitivity to compression-induced destabilization. The behavior of the melt-quench disks, subjected to different compression conditions, was continuously monitored during dissolution using low-frequency Raman and UV/vis for the solid-state form and dissolution properties, respectively. Surprisingly the compressed samples exhibited higher apparent dissolution (i.e., higher area under the dissolution curve and initial celecoxib concentration in solution) than the uncompressed samples; however, this is attributed to biaxial fracturing throughout the compressed compacts yielding a greater effective surface area. Differences between the slow and fast melt quenched samples showed some trends similar to those observed for their storage stability.

Effect of trehalose and melibiose on crystallization of amorphous paracetamol.

This paper investigates the solid-state behavior of two-phase solid dispersions involving small molecules. The effect of two sugars, trehalose and melibiose, on the recrystallization of amorphous paracetamol, and vice versa, was investigated. The solid dispersions were prepared via heating and quench-cooling, and then stored at a temperature of 38.5 ± 0.5 °C and relative humidities of 3 ± 1% and 75 ± 1%. X-ray powder diffraction (XRPD) confirmed that the solid dispersions were amorphous, while Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) revealed that the solid dispersions were two-phase systems with drug-rich and excipient-rich regions. XRPD was used to qualitatively and quantitatively study the crystallization of the components, and revealed that, despite the existence of two phases, the sugars hindered the crystallization of paracetamol. In contrast, once the paracetamol crystallization started, it accelerated the crystallization of the sugars. Overall, the study demonstrates that small-molecule solid-dispersions need not be single-phase to observe mutual influences between the components in crystallization behavior, and that these effects are likely mediated through interactions at the phase interfaces, as well as alterations in water sorption and mechanical effects.

Degrees of order: A comparison of nanocrystal and amorphous solids for poorly soluble drugs.

Poor aqueous solubility is currently a prevalent issue in the development of small molecule pharmaceuticals. Several methods are possible for improving the solubility, dissolution rate and bioavailability of Biopharmaceutics Classification System (BCS) class II and class IV drugs. Two solid state approaches, which rely on reductions in order, and can theoretically be applied to all molecules without any specific chemical prerequisites (compared with e.g. ionizable or co-former groups, or sufficient lipophilicity), are the use of the amorphous form and nanocrystals. Research involving these two approaches is relatively extensive and commercial products are now available based on these technologies. Nevertheless, their formulation remains more challenging than with conventional dosage forms. This article describes these two technologies from both theoretical and practical perspectives by briefly discussing the physicochemical backgrounds behind these approaches, as well as the resulting practical implications, both positive and negative. Case studies demonstrating the benefits and challenges of these two techniques are presented.

Machine-Vision-Enabled Salt Dissolution Analysis.

Salt formation is a well-established method to increase the solubility of ionizable drug candidates. However, possible conversion of salt to its original form of free acid or base-disproportionation-can have a drastic effect on the solubility and consequently the bioavailability of a drug. Therefore, during the salt selection process, the salt dissolution behavior should be well understood. Improved understanding could be achieved by a method that enables simultaneous screening of small sample amounts and detailed dissolution process analysis. Here, we use a machine-vision-based single-particle analysis (SPA) method to successfully determine the pH-solubility profile, intrinsic solubility, common-ion effect, pKa, pHmax, and Ksp values of three model compounds in a fast and low sample consumption (<1 mg) manner. Moreover, the SPA method enables, with a particle-scale resolution, in situ observation of the disproportionation process and its immediate effect on the morphology and solubility of dissolving species. In this study, a potentially higher energy thermodynamic solid-state form of diclofenac free acid and an intriguing conversion to liquid verapamil free base were observed upon disproportionation of the respective salts. As such, the SPA method offers a low sample consumption platform for fast yet elaborate characterization of the salt dissolution behavior.

Surface Stabilization and Dissolution Rate Improvement of Amorphous Compacts with Thin Polymer Coatings: Can We Have It All?

The distinction between surface and bulk crystallization of amorphous pharmaceuticals, as well as the importance of surface crystallization for pharmaceutical performance, is becoming increasingly evident. An emerging strategy in stabilizing the amorphous drug form is to utilize thin coatings at the surface. While the physical stability of systems coated with pharmaceutical polymers has recently been studied, the effect on dissolution performance as a function of storage time, as a further necessary step toward the success of these formulations, has not been previously studied. Furthermore, the effect of coating thickness has not been elucidated. This study investigated the effect of these polymer-coating parameters on the interplay between amorphous surface crystallization and drug dissolution for the first time. The study utilized simple tablet-like coated dosage forms, comprising a continuous amorphous drug core and thin polymer coating (hundreds of nanometers to a micrometer thick). Monitoring included analysis of both the solid-state of the model drug (with SEM, XRD, and ATR FTIR spectroscopy) and dissolution performance (and associated morphology and solid-state changes) after different storage times. Stabilization of the amorphous form (dependent on the coating thickness) and maintenance of early-stage intrinsic dissolution rates characteristic for the unaged amorphous drug were achieved. However, dissolution in the latter stages was likely inhibited by the presence of a polymer at the surface. Overall, this study introduced a versatile coated system for studying the dissolution of thin-coated amorphous dosage forms suitable for different drugs and coating agents. It demonstrated the importance of multiple factors that need to be taken into consideration when aiming to achieve both physical stability and improved release during the shelf life of amorphous formulations.

Image-based dissolution analysis for tracking the surface stability of amorphous powders.

Poor solubility of crystalline drugs can be overcome by amorphization - the production of high-energy disordered solid with improved solubility. However, the improved solubility comes at a cost of reduced stability; amorphous drugs are prone to recrystallization. Because of recrystallization, the initial solubility enhancement is eventually lost. Therefore, it is important to understand the recrystallization process during storage of amorphous materials and its impact on dissolution/solubility. Here, we demonstrate the use of image-based single-particle analysis (SPA) to consistently monitor the solubility of an amorphous indomethacin sample over time. The results are compared to the XRPD signal of the same sample. For the sample stored at 22 °C/23% relative humidity (RH), full crystallinity as indicated by XRPD was reached around day 40, whereas a solubility corresponding to that of the γ crystalline form was measured with SPA at day 25. For the sample stored at 22 °C/75% RH, the XRPD signal indicated a rapid initial phase of crystallization. However, the sample failed to fully crystallize in 80 days. With SPA, solubility slightly above that of the crystalline γ form was measured already on the second day. To conclude, the solubility measured with SPA directly reflects the solid-state changes occurring on the particle surface. Therefore, it can provide vital information - in a straightforward manner while requiring only minuscule sample amounts - for understanding the effect of storage conditions on the dissolution/solubility of amorphous materials, especially important in pharmaceutical science.

Direct Measurement of Amorphous Solubility.

Amorphous materials exhibit distinct physicochemical properties compared to their respective crystalline counterparts. One of these properties, the increased solubility of amorphous materials, is exploited in the pharmaceutical industry as a way of increasing bioavailability of poorly water-soluble drugs. Despite the increasing interest in drug amorphization, the analytical physicochemical toolbox is lacking a reliable method for direct amorphous solubility assessment. Here, we show, for the first time, a direct approach to measure the amorphous solubility of diverse drugs by combining optics with fluidics, the single particle analysis (SPA) method. Moreover, a comparison was made to a theoretical estimation based on thermal analysis and to a standardized supersaturation and precipitation method. We have found a good level of agreement between the three methods. Importantly, the SPA method allowed for the first experimental measurement of the amorphous solubility for griseofulvin, a fast crystallizing drug, without the use of a crystallization inhibitor. In conclusion, the SPA approach enables rapid and straightforward determination of the supersaturation potential for amorphous materials of less than 0.1 mg, which could prove highly beneficial in the fields of materials science, analytical chemistry, physical chemistry, food science, pharmaceutical science, and others.

Image-Based Investigation: Biorelevant Solubility of α and γ Indomethacin.

Solubility is a physicochemical property highly dependent on the solid-state form of a compound. Thus, alteration of a compound's solid-state form can be undertaken to enhance the solubility of poorly soluble drug compounds. In the Biopharmaceutics Classification System (BCS), drugs are classified on the basis of their aqueous solubility and permeability. However, aqueous solubility does not always correlate best with in vivo solubility and consequently bioavailability. Therefore, the use of biorelevant media is a more suitable approach for mimicking in vivo conditions. Here, assessed with a novel image-based single-particle-analysis (SPA) method, we report a constant ratio of solubility increase of 3.3 ± 0.5 between the α and γ solid-state forms of indomethacin in biorelevant media. The ratio was independent of pH, ionic strength, and surfactant concentration, which all change as the drug passes through the gastrointestinal tract. On the basis of the solubility ratio, a free-energy difference between the two polymorphic forms of 2.9 kJ/mol was estimated. Lastly, the use of the SPA approach to assess solubility has proven to be simple, fast, and both solvent- and sample-sparing, making it an attractive tool for drug development.

Tissue-specific study across the stem reveals the chemistry and transcriptome dynamics of birch bark.

Tree bark is a highly specialized array of tissues that plays important roles in plant protection and development. Bark tissues develop from two lateral meristems; the phellogen (cork cambium) produces the outermost stem-environment barrier called the periderm, while the vascular cambium contributes with phloem tissues. Although bark is diverse in terms of tissues, functions and species, it remains understudied at higher resolution. We dissected the stem of silver birch (Betula pendula) into eight major tissue types, and characterized these by a combined transcriptomics and metabolomics approach. We further analyzed the varying bark types within the Betulaceae family. The two meristems had a distinct contribution to the stem transcriptomic landscape. Furthermore, inter- and intraspecies analyses illustrated the unique molecular profile of the phellem. We identified multiple tissue-specific metabolic pathways, such as the mevalonate/betulin biosynthesis pathway, that displayed differential evolution within the Betulaceae. A detailed analysis of suberin and betulin biosynthesis pathways identified a set of underlying regulators and highlighted the important role of local, small-scale gene duplication events in the evolution of metabolic pathways. This work reveals the transcriptome and metabolic diversity among bark tissues and provides insights to its development and evolution, as well as its biotechnological applications.

Cell-Nanoparticle Interactions at (Sub)-Nanometer Resolution Analyzed by Electron Microscopy and Correlative Coherent Anti-Stokes Raman Scattering.

A wide variety of nanoparticles are playing an increasingly important role in drug delivery. Label-free imaging techniques are especially desirable to follow the cellular uptake and intracellular fate of nanoparticles. The combined correlative use of different techniques, each with unique advantages, facilitates more detailed investigation about such interactions. The synergistic use of correlative coherent anti-Stokes Raman scattering and electron microscopy (C-CARS-EM) imaging offers label-free, chemically-specific, and (sub)-nanometer spatial resolution for studying nanoparticle uptake into cells as demonstrated in the current study. Coherent anti-Stokes Raman scattering (CARS) microscopy offers chemically-specific (sub)micron spatial resolution imaging without fluorescent labels while transmission electron microscopy (TEM) offers (sub)-nanometer scale spatial resolution and thus visualization of precise nanoparticle localization at the sub-cellular level. This proof-of-concept imaging platform with unlabeled drug nanocrystals and macrophage cells revealed good colocalization between the CARS signal and electron dense nanocrystals in TEM images. The correlative TEM images revealed subcellular localization of nanocrystals inside membrane bound vesicles, showing multivesicular body (MVB)-like morphology typical for late endosomes (LEs), endolysosomes, and phagolysosomes. C-CARS-EM imaging has much potential to study the interactions between a wide range of nanoparticles and cells with high precision and confidence.

Understanding Dissolution and Crystallization with Imaging: A Surface Point of View.

The tendency for crystallization during storage and administration is the most considerable hurdle for poorly water-soluble drugs formulated in the amorphous form. There is a need to better detect often subtle and complex surface crystallization phenomena and understand their influence on the critical quality attribute of dissolution. In this study, the interplay between surface crystallization of the amorphous form during storage and dissolution testing, and its influence on dissolution behavior, is analyzed for the first time with multimodal nonlinear optical imaging (coherent anti-Stokes Raman scattering (CARS) and sum frequency generation (SFG)). Complementary analyses are provided with scanning electron microscopy, X-ray diffraction and infrared and Raman spectroscopies. Amorphous indomethacin tablets were prepared and subjected to two different storage conditions (30 °C/23% RH and 30 °C/75% RH) for various durations and then dissolution testing using a channel flow-through device. Trace levels of surface crystallinity previously imaged with nonlinear optics after 1 or 2 days of storage did not significantly decrease dissolution and supersaturation compared to the freshly prepared amorphous tablets while more extensive crystallization after longer storage times did. Multimodal nonlinear optical imaging of the tablet surfaces after 15 min of dissolution revealed complex crystallization behavior that was affected by both storage condition and time, with up to four crystalline polymorphs simultaneously observed. In addition to the well-known α- and γ-forms, the less reported metastable ε- and η-forms were also observed, with the ε-form being widely observed in samples that had retained significant surface amorphousness during storage. This form was also prepared in the pure form and further characterized. Overall, this study demonstrates the potential value of nonlinear optical imaging, together with more established solid-state analysis methods, to understand complex surface crystallization behavior and its influence on drug dissolution during the development of amorphous drugs and dosage forms.

Preparation and characterization of multi-component tablets containing co-amorphous salts: Combining multimodal non-linear optical imaging with established analytical methods.

Co-amorphous mixtures have rarely been formulated as oral dosage forms, even though they have been shown to stabilize amorphous drugs in the solid state and enhance the dissolution properties of poorly soluble drugs. In the present study we formulated tablets consisting of either spray dried co-amorphous ibuprofen-arginine or indomethacin-arginine, mannitol or xylitol and polyvinylpyrrolidone K30 (PVP). Experimental design was used for the selection of tablet compositions, and the effect of tablet composition on tablet characteristics was modelled. Multimodal non-linear imaging, including coherent anti-Stokes Raman scattering (CARS) and sum frequency/second harmonic generation (SFG/SHG) microscopies, as well as scanning electron microscopy, X-ray diffractometry and Fourier-transform infrared spectroscopy were utilized to characterize the tablets. The tablets possessed sufficient strength, but modelling produced no clear evidence about the compaction characteristics of co-amorphous salts. However, co-amorphous drug-arginine mixtures resulted in enhanced dissolution behaviour, and the PVP in the tableting mixture stabilized the supersaturation. The co-amorphous mixtures were physically stable during compaction, but the excipient selection affected the long term stability of the ibuprofen-arginine mixture. CARS and SFG/SHG proved feasible techniques in imaging the component distribution on the tablet surfaces, but possibly due to the limited imaging area, recrystallization detected with x-ray diffraction was not detected.

Crystallization Kinetics of an Amorphous Pharmaceutical Compound Using Fluorescence-Lifetime-Imaging Microscopy.

Pharmaceutical scientists are increasingly interested in amorphous drug formulations especially because of their higher dissolution rates. Consequently, the thorough characterization and analysis of these formulations are becoming more and more important for the pharmaceutical industry. Here, fluorescence-lifetime-imaging microscopy (FLIM) was used to monitor the crystallization of an amorphous pharmaceutical compound, indomethacin. Initially, we identified different solid indomethacin forms, amorphous and γ- and α-crystalline, on the basis of their time-resolved fluorescence. All of the studied indomethacin forms showed biexponential decays with characteristic fluorescence lifetimes and amplitudes. Using this information, the crystallization of amorphous indomethacin upon storage in 60 °C was monitored for 10 days with FLIM. The progress of crystallization was detected as lifetime changes both in the FLIM images and in the fluorescence-decay curves extracted from the images. The fluorescence-lifetime amplitudes were used for quantitative analysis of the crystallization process. We also demonstrated that the fluorescence-lifetime distribution of the sample changed during crystallization, and when the sample was not moved between measuring times, the lifetime distribution could also be used for the analysis of the reaction kinetics. Our results clearly show that FLIM is a sensitive and nondestructive method for monitoring solid-state transformations on the surfaces of fluorescent samples.

Time-Gated Raman Spectroscopy for Quantitative Determination of Solid-State Forms of Fluorescent Pharmaceuticals.

Raman spectroscopy is widely used for quantitative pharmaceutical analysis, but a common obstacle to its use is sample fluorescence masking the Raman signal. Time-gating provides an instrument-based method for rejecting fluorescence through temporal resolution of the spectral signal and allows Raman spectra of fluorescent materials to be obtained. An additional practical advantage is that analysis is possible in ambient lighting. This study assesses the efficacy of time-gated Raman spectroscopy for the quantitative measurement of fluorescent pharmaceuticals. Time-gated Raman spectroscopy with a 128 × (2) × 4 CMOS SPAD detector was applied for quantitative analysis of ternary mixtures of solid-state forms of the model drug, piroxicam (PRX). Partial least-squares (PLS) regression allowed quantification, with Raman-active time domain selection (based on visual inspection) improving performance. Model performance was further improved by using kernel-based regularized least-squares (RLS) regression with greedy feature selection in which the data use in both the Raman shift and time dimensions was statistically optimized. Overall, time-gated Raman spectroscopy, especially with optimized data analysis in both the spectral and time dimensions, shows potential for sensitive and relatively routine quantitative analysis of photoluminescent pharmaceuticals during drug development and manufacturing.

Interdependence of particle properties and bulk powder behavior of indomethacin in quench-cooled molten two-phase solid dispersions.

Solid dispersions (SDs) hold a proven potential in formulating poorly water-soluble drugs. The present paper investigates the interfacial phenomena associated with the bulk powder flow, water sorption, wetting and dissolution of the SDs prepared by a modified melt and quench-cooling (QC) method. Poorly water-soluble indomethacin (IND) was QC molten with solubilizing graft copolymer (Soluplus®) or polyol sugar alcohol (xylitol, XYL). The interfacial interactions of SDs with air/water were found to be reliant on the type (amorphous/crystalline) and amount of the carrier material used. The final SDs were composed of fused agglomerates (SOL) or large jagged particles (XYL) with good wetting and powder flow properties. The initial dissolution of IND was accelerated by both carrier materials studied. The QC molten SDs with amorphous Soluplus® significantly improved the dissolution rate of IND at pH 6.8 (79.9 ±â€¯0.2% at 30 min) compared to that of pure crystalline drug. The substantial improvement in the dissolution rate of IND was in connection with the amorphous state of the drug being stabilized by Soluplus® in the QC molten SDs. However, it is evident that a strong H-bond formation between the components in some regions of the QC molten SDs can limit the dissolution of IND. The QC molten two-phase SDs with a polyol carrier (XYL) showed rapid and continuous drug release without reaching a plateau.