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Active pharmaceutical ingredient (API) nanosuspensions from naproxen (Nap) and itraconazole (Itra) stabilized with Kollidon®VA64 (KVA) and sodium dodecyl sulfate (SDS) were produced in two different size classes each by wet media milling. These API nanosuspensions were spray dried with lactose, trehalose and sucrose as matrix formers in different proportions and at different drying temperatures (Toutlet). Toutlet as well as the API content significantly influenced the redispersibility of the API nanoparticles. It could be shown that these two parameters are related to each other, with an increasing API content leading to a decreasing maximum applicable Toutlet (Tcritical). Drying above Tcritical always led to an alteration of the size characteristics of the API nanoparticles and thus to a non-redispersible product with respect to the defined quality criteria. For each proportion of API to matrix former, a Tcritical could be found. Tcritical showed a linear relation to the API content. The linear regression of this relation was defined as process boundary. The y-intercept of the process boundary correlated well with the glass transition temperature (Tg) of the pure matrix former used for spray drying. The two APIs under investigation led to virtually identical behaviour if other parameters were kept constant. The particle size of the initial nanosuspension had an important influence. Nanosuspensions with comparatively small particle sizes led to a significantly stronger decrease of the process boundaries compared to the use of larger particle sizes. The maximum API content that leads to a redispersible product is thus decisively determined by Toulet of the spray dryer, Tg as well as the proportion of the matrix former and by the particle size of the API nanoparticles used.

In MLL-rearranged cancer cells, disruptor of telomeric silencing 1-like protein (DOT1L) is aberrantly recruited to ectopic loci leading to local hypermethylation of H3K79 and consequently misexpression of leukemogenic genes. A structure-guided optimization of a HTS hit led to the discovery of DOT1L inhibitors with subnanomolar potency, allowing testing of the therapeutic principle of DOT1L inhibition in a preclinical mouse tumor xenograft model. Compounds displaying good exposure in mouse and nanomolar inhibition of target gene expression in cells were obtained and tested in vivo.

[Image: see text] In MLL-rearranged cancer cells, disruptor of telomeric silencing 1-like protein (DOT1L) is aberrantly recruited to ectopic loci leading to local hypermethylation of H3K79 and consequently misexpression of leukemogenic genes. A structure-guided optimization of a HTS hit led to the discovery of DOT1L inhibitors with subnanomolar potency, allowing testing of the therapeutic principle of DOT1L inhibition in a preclinical mouse tumor xenograft model. Compounds displaying good exposure in mouse and nanomolar inhibition of target gene expression in cells were obtained and tested in vivo.

Rearrangements in the mixed lineage leukemia (MLL) gene define a distinct, aggressive form of acute leukemia with poor prognosis. The MLL gene encodes for a SET domain histone methyl transferase that catalyzes the methylation of histone 3 lysine 4 (H3K4) at specific gene loci, thus regulating transcription of developmental genes including HOX genes. In disease-linked translocations, the catalytic SET domain is lost and the remaining part fused to a variety of partners, e.g. AF4, AF9, AF10 and ENL. These MLL fusion proteins directly interact with disruptor of telomeric silencing 1-like protein (DOT1L), the only known H3K79 methyltransferase. The H3K79me2 mark is broadly associated with active transcription. Mislocated enzymatic activity of DOT1L causes local H3K79 hypermethylation, misexpression of leukomogenic genes, e.g. HOXA9 and MEIS1, and the aberrant maintenance of a stem cell-like state. Current treatment options of MLL are limited to chemotherapy and allogeneic hematopoietic stem cell transplantation, and outcomes remain poor. The first and only clinical DOT1L inhibitor Pinometostat (EPZ-5676), an S-Adenosyl Methionine (SAM) competitive inhibitor, showed only modest activity and emerging resistance in adult acute leukemia. Pinometostat is no oral drug, but requires administration as continuous infusion to achieve sufficient exposure and sustained target inhibition. So far, there is no approved DOT1L inhibitor and the need remains to develop effective DOT1L inhibitors. We report the identification of new SAM-competitive, structurally SAM-unrelated DOT1L inhibitors with subnanomolar biochemical potency. Compounds with nanomolar cellular activity and good exposure in mouse were tested in tumor xenograft models. Compounds 8 and 9 showed excellent blood exposure after a single dose. However, repeated dosing led to reduced exposure due to cytochrome P450 (Cyp450) 3A4 induction, insufficient pharmacodynamics (PD) and lack of efficacy. Further modification resulted in compound 10 that could be administered orally and was stable upon repeated dosing. A 300 mg/kg dose covered efficacious blood exposure for 24 h, but was not tolerated by tumor-bearing mice. Unfortunately, a 6-fold reduced dose did not achieve sufficient PD modulation and efficacy. Additional activities led to compound 11, which lost its oral bioavailability and had to be administered subcutaneously. Nevertheless, compound 11 achieved tumor growth inhibition in the MV4-11 and Molm-13 xenograft models in mice. In conclusion, we progressed in making DOT1L inhibitors with improved PK properties, but further optimization is required to generate a viable clinical candidate. The limited efficacy obtained with compound 11 and lack of efficacy observed with subcutaneous administration of EPZ-5676 around the maximally tolerated dose illustrate the difficulty to achieve a sustained level of DOT1L inhibitor in vivo to suppress DOT1L activity sufficiently. Furthermore, H3K79me2 and efficacy in vivo seem disconnected. Citation Format: Andreas Weiss, Frederic Stauffer, Clemens Clemens, Henrik Möbitz, Christian Ragot, Kim S. Beyer, Keith Calkins, Claudio Thoma, Daniel Guthy, Michael Kiffe, Bernard Van Eerdenbrugh, William R. Sellers, Francesco Hofmann, Ralph Tiedt, Christoph Gaul. A new DOT1L inhibitor with in vivo activity in mouse models of MLL-translocated leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1770.

The goal of the study was to evaluate a miniaturized dissolution-permeation apparatus (μFLUX™ apparatus) for its ability to benchmark several itraconazole (ITZ) formulations for which in vivo PK data was available in the literature. Untreated and micronized powders of ITZ and various enabling formulations of ITZ (commercial Sporanox® solid dispersion, a Soluplus®-based solid dispersion and a nanosuspension) were introduced to the donor compartment of μFLUX™ apparatus. Donor and acceptor chambers were divided from each other by a lipophilic membrane. In addition to the flux evaluations, changes in solid state as a function of time were investigated to gain further insight into the flux changes observed over time for the solid dispersion formulations. Initial flux values from Sporanox®, the nanosuspension and the micronized ITZ showed ratios of 52/4/1 with a decreasing flux from nanosuspension and both solid dispersions after 2.5–3 h. Although the initial flux from the Soluplus® formulation was 2.2 times lower than the one observed for Sporanox®, the decrease in flux observed was milder and became ~ 2 times higher than Sporanox® after approximately 2.5 h. The total amounts of ITZ in the receiver compartment after 240 min showed the same rank order as the rodent AUCs of these formulations reported in literature. It was demonstrated that in vitro flux measurements using lipophilic artificial membranes could correctly reproduce the rank order of PK results for ITZ formulations. The drop in flux over time for solid dispersions could be backed by experimental indications of crystallization.

Amorphous materials are high-energy solids that can potentially enhance the bioavailability of poorly soluble compounds. A major impediment to their widespread use as a formulation platform is the tendency of amorphous materials to crystallize. The aim of this study was to evaluate the relative crystallization tendency of six structural analogues belonging to the dihydropyridine class, in an aqueous environment in the absence and presence of polymers, using wide-angle X-ray scattering synchrotron radiation and polarized light microscopy. The crystallization behavior of precipitates generated from supersaturated solutions of the active pharmaceutical ingredients was found to be highly variable ranging from immediate to several hours in the absence of polymers. Polymers with intermediate hydrophilicity/hydrophobicity were found to substantially delay crystallization, whereas strongly hydrophilic or hydrophobic polymers were largely ineffective. Nuclear magnetic resonance spectroscopy experiments supported the supposition that polymers need to have affinity for both the drug-rich precipitate and the aqueous phase in order to be effective crystallization inhibitors. This study highlights the variability in the crystallization tendency of different compounds and provides insight into the mechanism of inhibition by polymeric additives.

To classify the crystallization behavior of amorphous active pharmaceutical ingredients (API) exposed to aqueous environments. A set of approximately 50 chemically and physically diverse active pharmaceutical ingredients (APIs) was selected for this study. Two experimental setups were employed to characterize the crystallization behavior of the amorphous API in an aqueous environment. For the first approach, precipitation, as evidenced by the development of turbidity, was induced using the solvent shift method, by mixing concentrated API solutions in DMSO with an aqueous buffer in a capillary. Subsequently, crystallization was monitored in situ over time using synchrotron radiation (simultaneous SAXS/WAXS beamline 12-ID-B at the Advanced Photon Source, Argonne National Laboratories, Argonne, IL). In the second approach, amorphous films were prepared by melt quenching; after adding buffer, crystallization was monitored with time using polarized light microscopy. In general, the crystallization behavior of a given compound was similar irrespective of the experimental method employed. However, the crystallization behavior among different compounds varied significantly, ranging from immediate and complete crystallization to no observable crystallization over biorelevant time scales. Comparison of the observed behavior with previous studies of crystallization tendency in non-aqueous environments revealed that the crystallization tendency of individual APIs was somewhat similar regardless of the crystallization environment. API properties, rather than the method by which amorphous materials are generated, tend to dictate crystallization behavior in aqueous media.

To investigate the heating-induced dehydration and melting behavior of the trihydrate phase of the calcium salt of atorvastatin.Multivariate curve resolution (MCR) was used to decompose a variable-temperature synchrotron X-ray powder diffraction (VT-XRPD) data matrix into diffraction patterns and concentration profiles of pure drug phases.By means of the MCR-estimated diffraction patterns and concentration profiles, the trihydrate phase of the drug salt was found to dehydrate sequentially into two partially dehydrated hydrate structures upon heating from 25 to 110°C, with no associated breakage of the original crystal lattice. During heating from 110 to 140°C, the remaining water was lost from the solid drug salt, which instantly collapsed into a liquid crystalline phase. An isotropic melt was formed above 155°C. Thermogravimetric analysis, hot-stage polarized light microscopy, and hot-stage Raman spectroscopy combined with principal component analysis (PCA) was shown to provide consistent results.This study demonstrates that MCR combined with VT-XRPD is a powerful tool for rapid interpretation of complex dehydration behavior of drug hydrates, and it is also the first report on a liquid crystalline phase of the calcium salt of atorvastatin.

To examine the precipitation and supersaturation behavior of ten weak bases in terms of the relationship between pH-concentration-time profiles and the solid state properties of the precipitated material.Initially the compound was dissolved at low pH, followed by titration with base to induce precipitation. Upon precipitation, small aliquots of acid or base were added to induce slight subsaturation and supersaturation respectively and the resultant pH gradient was determined. The concentration of the unionized species was calculated as a function of time and pH using mass and charge balance equations.Two patterns of behavior were observed in terms of the extent and duration of supersaturation arising following an increase in pH and this behavior could be rationalized based on the crystallization tendency of the compound. For compounds that did not readily crystallize, an amorphous precipitate was formed and a prolonged duration of supersaturation was observed. For compounds that precipitated to crystalline forms, the observed supersaturation was short-lived.This study showed that supersaturation behavior has significant correlation with the solid-state properties of the precipitate and that pH-metric titration methods can be utilized to evaluate the supersaturation behavior.

Determining the extent of miscibility of amorphous components is of great importance for certain pharmaceutical systems, in particular for polymer-polymer and polymer-small molecule blends. In this study, the application of standard atomic force microscopy (AFM) measurements combined with nanoscale mid-infrared (mid-IR) spectroscopy was explored to evaluate miscibility in binary polymer blends. The miscibility characteristics of a set of 50/50 (w/w) polymer blends comprising of poly(vinylpyrrolidone) (PVP) with dextran or maltodextrin (DEX) of varying molecular weights (MWs) were investigated. Standard AFM characterization results show good agreement with inferences drawn from differential scanning calorimetry (DSC) analysis in terms of forming either single or two phase systems. AFM analysis also provided insight into the microstructure of the two phase systems and how domain sizes varied as a function of polymer MWs. Nanoscale mid-IR evaluation of the blends, performed by collecting local mid-IR spectra or spectral maps, provided an extra dimension of information about the dependence of polymer MWs on chemical composition of the different phases. AFM, combined with nanoscale mid-infrared analysis, thus appears to be a promising technique for the evaluation of miscibility in certain pharmaceutical blends.

To characterize and interpret the miscibility of dextran and maltodextrin with poly(vinylpyrrolidone) (DEX-PVP) as a function of polymer molecular weights. Blend miscibility was studied using 4 different molecular weight (MW) grades of DEX combined with 5 MW grades of PVP, over a broad compositional range. Miscibility was evaluated by inspection of glass transition events measured by differential scanning calorimetry (DSC). Fourier transform mid-infrared spectroscopy (FTIR), combined with curve fitting, was performed to characterize the extent of hydrogen bonding. The observed miscibility behavior was further interpreted in terms of mixing thermodynamics. Miscibility of the blends ranged from fully miscible to completely immiscible with multiple partially miscible systems observed. Increasing polymer molecular weight decreased miscibility. For the lowest DEX grade, hydrogen bonding was independent of PVP MW, as expected since all systems were completely miscible. Higher molecular weights of DEX resulted in reduced intermolecular hydrogen bonding and decreased miscibility, increasingly so for higher MW PVP grades. Evaluation of the mixing thermodynamics supported these findings. With higher combined molecular weights of DEX-PVP blends, phase behavior evolves from completely miscible to virtually immiscible. Concurrently, DEX-PVP hydrogen bonding decreases. From a thermodynamic perspective, the combinatorial mixing entropy was observed to decrease as the molecular weight of the polymers increased, providing a reduced counterbalance to the unfavorable mixing enthalpy thought to accompany this polymer combination.

To critically evaluate the effect of submicron and micron-sized organic particulates on the ultraviolet (UV) absorption spectra of aqueous systems and assess the applicability of UV/Vis fiber-optic probes for in-situ concentration monitoring in the presence of particles of different sizes.UV absorbance spectra were obtained for aqueous felodipine suspensions containing a range of particle sizes (300 nm-400 μm) and suspension concentrations and for methanolic solutions of different concentrations and amorphous films of different thicknesses. Select suspensions were further characterized using nuclear magnetic resonance (NMR) experiments. Mie theory was used to provide insight into the role of particle size on scattering and absorption of UV radiation.Large increases in absorbance as a function of total suspension concentration were observed for nanosuspensions but not for the other particle sizes evaluated. NMR measurements of solution concentration indicated that the observed increases in UV absorbance values for these systems were not caused by increases in the concentration of dissolved molecules, implying that nanoparticles of felodipine might absorb UV light. Mie theory-based calculations enabled reconstruction of the experimental observations and supported this hypothesis.For solutions containing small (submicron) felodipine particles, UV spectra were influenced by absorption of the particles and contributions from absorption of dissolved molecules and scattering of the particles. Caution should be applied when using in situ UV/VIS-probes to monitor the amount of dissolved material during dissolution, in particular when small particles are present (e.g. dissolution of nanoparticulate formulations) or generated (e.g. precipitation of supersaturated solutions) in the dissolution medium.

In this manuscript, the determination of solubility of crystalline drug nanosuspensions by a range of methods is critically investigated. As the determinations of solubility were performed in the presence of the solubilizing nanosuspension stabilizer d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), the potential effects of this excipient on the measurements were studied first. Solubility data of nanosuspensions of itraconazole, loviride, phenytoin and naproxen were generated using different methodologies. Data obtained using separation-based methodologies (centrifugation, filtration and ultracentrifugation) proved to be of limited use, due to poor nanoparticle separation efficiencies and/or significant adsorption of TPGS onto the nanoparticle surfaces. Light scattering and turbidity were found to be more suitable for the determination of nanosuspension solubility. The obtained data show that, unlike earlier reports, the solubility increases due to nanosizing are small, with measured increases of only 15%. These solubility increases are in fair agreement with what would be predicted based on the Ostwald-Freundlich equation.

In this study, the crystallization behavior of a variety of compounds was studied following rapid solvent evaporation using spin coating. Initial screening to determine model compound suitability was performed using a structurally diverse set of 51 compounds in three different solvent systems [dichloromethane (DCM), a 1:1 (w/w) dichloromethane/ethanol mixture (MIX), and ethanol (EtOH)]. Of this starting set of 153 drug-solvent combinations, 93 (40 compounds) were selected for further evaluation based on solubility, chemical solution stability, and processability criteria. These systems were spin coated and their crystallization was monitored using polarized light microscopy (7days, dry conditions). The crystallization behavior of the samples could be classified as rapid (Class I: 39 cases), intermediate (Class II: 23 cases), or slow (Class III: 31 cases). The solvent system employed influenced the classification outcome for only four of the compounds. The various compounds showed very diverse crystallization behavior. Upon comparison of classification results with those of a previous study, where cooling from the melt was used as a preparation technique 1 , a good similarity was found whereby 68% of the cases were identically classified. Multivariate analysis was performed using a set of relevant physicochemical compound characteristics. It was found that a number of these parameters tended to differ between the different classes. These could be further interpreted in terms of the nature of the crystallization process. Additional multivariate analysis on the separate classes of compounds indicated some potential in predicting the crystallization tendency of a given compound. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3826-3838, 2010.

In this study, the ability of 7 chemically diverse polymers [Eudragit E100 (E100), poly(acrylic acid) (PAA), poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone-vinyl acetate) (PVPVA), poly(styrene sulfonic acid) (PSSA), hydroxypropylmethylcellulose (HPMC) and hydroxypropylmethylcellulose acetate succinate (HPMCAS)] to inhibit the crystallization of 8 readily crystallizable model compounds [benzamide (BD), phenacetin (PH), flurbiprofen (FB), flufenamic acid (FFA), chlorpropamide (CP), chlorzoxazone (CZ), bifonazole (BI) and lidocaine (LI)] was investigated. Films of the different drug-polymer combinations were prepared by rapid evaporation from solution, using a spin coating method. A total of 7 different drug/polymer weight ratios [90/10, 75/25, 60/40, 50/50, 40/60, 25/75 and 10/90 (w/w)] were evaluated for each drug-polymer combination. Crystallization behavior of the films was monitored using polarized light microscopy over 7 days of room temperature storage under dry conditions. It was observed that compounds having a higher crystallization tendency for the pure compound tended to be more difficult to stabilize using the polymeric additives; more polymer was required. In addition, the stabilizing ability of the polymers varied considerably for the individual compounds, with the acidic polymers PAA and PSSA showing the most extreme behavior. The acidic polymers were good stabilizers for the drugs with basic and amide functional groups, but extremely poor stabilizers for acidic drugs. A reasonable correlation between crystallization inhibition in spin coated films versus bulk powders (prepared by rotary evaporation) was observed. The small scale screening method is thus a potentially useful technique to evaluate the role of drug-polymer chemistry in the stabilization of amorphous solid dispersions.

Solid dispersions were successfully prepared by co-spray-drying of TPGS-stabilized itraconazole nanosuspensions with Aerosil200, followed by heat treatment of the powders. The itraconazole/Aerosil200 weight ratios amounted to 50/50, 30/70, 40/60 and 20/80. The itraconazole content of the powders was close to the expected value, with relative errors between 0.3% and 7.8%. X-ray powder diffraction (XRPD), solid state NMR (SSNMR) and differential scanning calorimetry (DSC) evaluation on the powders revealed the formation of amorphous itraconazole and the absence of glassy itraconazole. Dissolution of the powders was enhanced compared to crystalline and glassy itraconazole (a 2-dimensional structured form of itraconazole). However, no clear trend could be observed between drug loading and dissolution performance of the solid dispersions. Upon storage, conversion to crystalline itraconazole was observed for the 50/50 powder based on XRPD, SSNMR and DSC measurements. Although the 40/60 powder remained X-ray amorphous upon storage, DSC did reveal that a small fraction (7.5+/-1.6% after 10 months of storage) of itraconazole crystallized upon storage. For the 30/70 and 20/80 dispersions, no crystallization could be seen. After 10 months of storage, important changes in the dissolution behavior of the powders were observed. A decrease in dissolution performance was seen for the 50/50 dispersion, which could be attributed to the crystallization of itraconazole. On the other hand, the 40/60, 30/70 and 20/80 dispersions showed an increase in dissolution rate (more than 60% after 10 min). Although not completely clear at this stage, adsorption of itraconazole onto the Aerosil200 surface during storage might be responsible for this behavior. Finally, in vivo experiments were performed in the rat. Oral bioavailability of the 30/70 dispersion was, although lower compared to the marketed Sporanox formulation, significantly enhanced compared to the crystalline drug.

In order to establish a knowledge base for nanosuspension production, a screening was performed on 13 different stabilizers at 3 concentrations for 9 structurally different drug compounds. Concerning the stabilizers tested, the group of semi-synthetic polymers was the least performant (stable nanosuspensions were obtained in only 1 out of 10 cases). For the linear synthetic polymers, better results were obtained with povidones, however poly(vinyl alcohol) did not result in adequate stabilization. The synthetic copolymers showed even higher success rates, resulting in nanosuspensions in two out of three cases when applied at a 100 wt% concentration (relative to the drug weight). Finally, the surfactants gave the best results, with TPGS being successful at concentrations of 25 or 100 wt% of the drug weight for all compounds tested. From the point of view of drug compound, large differences could be observed upon evaluation of the relative number of formulations of that compound resulting in nanosuspensions. It was found that the hydrophobicity of the surfaces, as estimated by the adsorbed amount of TPGS per unit of surface area of nanosuspensions stabilized with 25 wt% TPGS, was decisive for the agglomeration tendency of the particles and hence the ease of nanosuspensions stabilization.

In this study, scaling down nanosuspension production to 10 mg of drug compound and evaluation of the nanosuspensions to 1 mg of drug compound per test were investigated. Media milling of seven model drug compounds (cinnarizine–indomethacin–itraconazole–loviride–mebendazole–naproxen–phenytoin) was evaluated in a 96-well plate setup (10, 20, and 30 mg) and a glass-vial-based system in a planetary mill (10, 100, and 1,000 mg). Physicochemical properties evaluated on 1 mg of drug compound were drug content (high-performance liquid chromatography), size [dynamic light scattering (DLS)], morphology (scanning electron microscopy), thermal characteristics (differential scanning calorimetry), and X-ray powder diffraction (XRPD). Scaling down nanosuspension production to 10 mg of drug compound was feasible for the seven model compounds using both designs, the planetary mill design being more robust. Similar results were obtained for both designs upon milling 10 mg of drug compound. Drug content determination was precise and accurate. DLS was the method of choice for size measurements. Morphology evaluation and thermal analysis were feasible, although sample preparation had a big influence on the results. XRPD in capillary mode was successfully performed, both in the suspended state and after freeze-drying in the capillary. Results obtained for the latter were superior. Both the production and the physicochemical evaluation of nanosuspensions can be successfully downscaled, enabling nanosuspension screening applications in preclinical development settings.

During the last 10-15 years, the formulation of drugs as nanocrystals has rapidly evolved into a mature drug delivery strategy, with currently five products on the market. The major characteristic of these systems is the rapid dissolution velocity, enabling bioavailability enhancement after oral administration. This mini-review focuses on recent advances with respect to three topics considering drug nanocrystals. The first topic is nanosuspension stabilization. A current literature status is provided and special attention is given to studies attempting to extend our physicochemical understanding of the underlying principles. The second part describes recent advances on miniaturization of nanosuspension production, to enable formulation screening during preclinical development. Finally, literature available on further nanosuspensions solidification is discussed, focussing on the maintenance of the preservation of the rapid dissolution properties of the nanocrystals after further downstream processing.

The applicability of nanoscale mid-infrared (mid-IR) spectroscopy for the study of the micro- and nanostructure of pharmaceutical drug–polymer systems was explored. Felodipine–poly(acrylic acid) (PAA) blends were used as model systems. Standard atomic force microscopy evaluation as a function of drug–polymer composition suggested limited miscibility, in line with previous findings. Localized spectra on a 50:50 (w/w) felodipine–PAA dispersion revealed that the discrete submicrometer domains formed corresponded to an amorphous felodipine-rich phase while the continuous phase tended to be rich in PAA. Further, spectroscopic imaging at selected wavenumbers, enabling discrimination between both constituents, confirmed this finding and made it possible to chemically image differences in composition between each phase with submicrometer resolution. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:2066–2073, 2012

Formulation of an amorphous solid dispersion (ASD) is one of the methods commonly considered to increase the bioavailability of a poorly water-soluble small-molecule active pharmaceutical ingredient (API). However, many factors have to be considered in designing an API–polymer system, including any potential changes to the physical stability of the API. In this study, the tendency of ASD systems containing a poorly water-soluble API and a polymer to undergo amorphous–amorphous phase separation was evaluated following exposure to moisture at increasing relative humidity. Infrared spectroscopy was used as the primary method to investigate the phase behavior of the systems. In general, it was observed that stronger drug–polymer interactions, low-ASD hygroscopicity, and a less hydrophobic API led to the formation of systems resistant to moisture-induced amorphous–amorphous phase separation. Orthogonal partial least squares analysis provided further insight into the systems, confirming the importance of the aforementioned properties. In order to design a more physically stable ASD that is resistant to moisture-induced amorphous–amorphous phase separation, it is important to consider the interplay between these properties.

The molecular conformation of the title compound, C20H29N3O2, is stabilized by an intramolecular C—H...O hydrogen bond. The orientation of the amide group to the ring system is characterized by a C—C—C—O dihedral angle of 137.5 (3)°. In the crystal, intermolecular N—H...O hydrogen bonds between the amide groups form C(4) chains running parallel to the a axis.

In this article, the use of mid-IR in pharmaceutical settings is reviewed. An overview of mid-IR instrumentation and sampling techniques is provided. Subsequently, different pharmaceutical applications of the technique are described, including structure elucidation and identification, characterization of crystalline (polymorphs, hydrates, salts and co-crystals) and amorphous forms, as well as quantitative and remote sensing applications. Finally, an overview of current trends in FTIR-based imaging applications is provided, with special attention paid to currently emerging FTIR-AFM coupled techniques which have high spatial resolution.

In the title compound, C22H18N2, the dihedral angles formed by the imidazole ring with the phenyl ring and the benzene ring of the biphenyl group are 87.02 (5) and 78.20 (4)°, respectively. In the crystal, molecules interact through intermolecular C—H...N hydrogen bonds, forming chains parallel to the b axis. These chains are further linked into a three-dimensional network by C—H...π stacking interactions

Assessing the viability of an amorphous formulation strategy is of great importance in an era of drug discovery where a large percentage of new molecules have solubility limited dissolution rates, and disruption of the crystal lattice is a potential strategy to improve this process. The objective of the current study was to evaluate the glass forming ability (GFA) of a large data set of organic molecules and also to evaluate potential links between GFA and glass stability (GS). The crystallization tendency from the undercooled melt was evaluated for a group of 51 organic molecules and separated into three separate classes [class (I), class (II), class (III)] based upon the presence/absence of observable crystallization during a heating/cooling/heating cycle, as measured using differential scanning calorimetry (DSC). Class (I) molecules were further delineated based upon the observation of a crystalline [class (I-A)] or amorphous [class (I-B)] solid after quench cooling in liquid N(2). Principal component analysis (PCA) of various physiochemical descriptors suggested that molecules with low GFA tended to be low molecular weight (MW), rigid structures while class (III) molecules tended to be higher MW, more complex structures. For select compounds, it was observed that crystallization from the glassy state was much faster for compounds with a lower GFA. It is believed that nuclei are quenched into the glass during cooling for class (I-B) and (II) molecules, leading to more facile crystallization below T(g). In addition, these quenched in nuclei are also thought to be responsible for the recrystallization observed for these classes of molecules upon heating above T(g). In conclusion, the DSC screening method and classification scheme may be a useful tool to quickly assess the GFA and potential GS of new chemical entities during early drug development.

Solid dispersions were successfully prepared by co-spray-drying of TPGS-stabilized itraconazole nanosuspensions with Aerosil200, followed by heat treatment of the powders. The itraconazole/Aerosil200 weight ratios amounted to 50/50, 30/70, 40/60 and 20/80. The itraconazole content of the powders was close to the expected value, with relative errors between 0.3% and 7.8%. X-ray powder diffraction (XRPD), solid state NMR (SSNMR) and differential scanning calorimetry (DSC) evaluation on the powders revealed the formation of amorphous itraconazole and the absence of glassy itraconazole. Dissolution of the powders was enhanced compared to crystalline and glassy itraconazole (a 2-dimensional structured form of itraconazole). However, no clear trend could be observed between drug loading and dissolution performance of the solid dispersions. Upon storage, conversion to crystalline itraconazole was observed for the 50/50 powder based on XRPD, SSNMR and DSC measurements. Although the 40/60 powder remained X-ray amorphous upon storage, DSC did reveal that a small fraction (7.5+/-1.6% after 10 months of storage) of itraconazole crystallized upon storage. For the 30/70 and 20/80 dispersions, no crystallization could be seen. After 10 months of storage, important changes in the dissolution behavior of the powders were observed. A decrease in dissolution performance was seen for the 50/50 dispersion, which could be attributed to the crystallization of itraconazole. On the other hand, the 40/60, 30/70 and 20/80 dispersions showed an increase in dissolution rate (more than 60% after 10 min). Although not completely clear at this stage, adsorption of itraconazole onto the Aerosil200 surface during storage might be responsible for this behavior. Finally, in vivo experiments were performed in the rat. Oral bioavailability of the 30/70 dispersion was, although lower compared to the marketed Sporanox formulation, significantly enhanced compared to the crystalline drug.

Magnetohydrodynamic nanoparticle dispersion is an energy efficient method to deaggregate nanoparticles, combining hydrodynamic forces of turbulent flow with Lorentz forces generated by a magnetic field.

Four alternative matrix formers [Avicel®PH101, Fujicalin® (CaHPO4), Aerosil®200 (SiO2) and Inutec®SP1] were evaluated for their capability in preserving rapid dissolution after spray-drying of nanosuspensions. Model drug compounds selected were cinnarizine (CIN), itraconazole (ITR) and phenylbutazone (PHB) as they showed a decrease in dissolution rate upon spray-drying in the absence of additional matrix formers, yielding release values after 5 min of dissolution (release5 min) of 57.7 ± 1.0% (CIN), 56.3 ± 3.8% (ITR) and 67.4 ± 1.3% (PHB). Compared to the situation without matrix former inclusion, the performance of Avicel®PH101 was good for CIN (release5 min = 90.9 ± 7.7%), intermediate for PHB (release5 min = 81.0 ± 6.4%) and poor for ITR (release5 min = 42.1 ± 4.2%). For Fujicalin®, intermediate (PHB: release5 min = 87.7 ± 3.0%) or poor (CIN: release5 min = 66.1 ± 3.4%; ITR: release5 min = 55.9 ± 5.2%) performance was seen. Results for Aerosil®200 were good for all compounds (CIN: release5 min = 91.5 ± 2.5%; ITR: release5 min = 83.8 ± 3.4%; PHB: release5 min = 95.5 ± 2.4%), indicating that the large specific surface area was in this case translated into good matrix forming capabilities. Finally, the best results were obtained for Inutec®SP1 (CIN: release5 min = 88.7 ± 1.2%; ITR: release5 min = 93.4 ± 2.4%; PHB: release5 min = 101.3 ± 4.9%). Except for Avicel®PH101, Cl-maps from X-ray microanalysis of the itraconazole powders supported the hypothesis that better dispersion of drug in the powders results in faster dissolution.

d-alpha-Tocopherol polyethylene glycol 1000 succinate (TPGS)-stabilized nanosuspensions (25wt%, relative to the drug weight) were produced by media milling for 9 model drug compounds [cinnarizine, griseofulvin, indomethacin, itraconazole, loviride, mebendazole, naproxen, phenylbutazone and phenytoin]. After 3 months of storage at room temperature, Ostwald ripening occurred in all of the samples, except for indomethacin. Whereas lowering the temperature could slow down the ripening, it markedly increased upon storage at 40 degrees C. As for ripening, settling generally became more pronounced at 40 degrees C compared to 4 degrees C. As the nanosuspensions were afflicted by Ostwald ripening and settling, we explored nanosuspension drying as a strategy to circumvent these stability issues. Spray-drying and freeze-drying were evaluated for nanosuspensions and coarse reference suspensions of the compounds. Nanoparticle agglomeration could be visually observed in all of the powders. To evaluate the effect of agglomeration on the key characteristic of drug nanocrystals (i.e. rapid dissolution), dissolution experiments were performed under poor sink conditions. It was found that the compounds could be categorized into 3 groups: (i) compounds for which it was impossible to differentiate between coarse and nanosized products (griseofulvin, mebendazole, naproxen), (ii) compounds that gave clear differences in dissolution profiles between the nanosized and the coarse products, but for which drying of the nanosuspensions did not decrease the dissolution performance of the product (indomethacin, loviride, phenytoin) and (iii) compounds that showed differences between coarse and nanosized products, but for which drying of the nanosuspensions resulted in a significant decrease of the dissolution rate (cinnarizine, itraconazole, phenylbutazone). To gain insight on the influence of the drug compound characteristics on the dissolution of the dried products, the dissolution behavior of the compounds of the second and the third group was linked to the compound's characteristics. It was found that compounds with a more hydrophobic surface resulted in agglomerates which were harder to disintegrate, for which dissolution was compromised upon drying. The same was found for compounds having higher logP values.

Itraconazole nanosuspensions, stabilized with 10% TPGS (relative to the weight of itraconazole), were transformed into nanoparticulate powders by freeze-drying. The crystalline itraconazole nanoparticles showed peak broadening in the X-ray powder diffraction spectra and a lower melting point as inferred from differential scanning calorimetry. As it was found that freeze-drying compromised dissolution behavior, sucrose was added as a matrix, former (50,100 and 200%, relative to the weight of itraconazole). Higher amounts of sucrose unexpectedly resulted in a decrease in the dissolution rate. After thorough evaluation of the powders, it was found that whereas higher sucrose content showed a cryoprotective effect, agglomeration during the final phase of the subsequent drying step tended to increase with higher amounts of sucrose. Therefore, microcrystalline cellulose (MCC) was evaluated as an alternative matrix former. The inclusion of MCC resulted in fast dissolution that increased with increasing amounts of MCC [for powders containing 50%,100% and 200% MCC, (relative to the weight of itraconazole), the times required for 63.2% release were 10.5+/-0.7, 6.4+/-1.2 and 3.1+/-0.5min, respectively]. The dissolution profiles showed an initial phase of burst dissolution, followed by a phase of slower release. As the fraction showing burst dissolution increased with higher MCC content, the system holds promise to maintain the dissolution enhancing properties of nanoparticles in the dry form.

The purpose of this study was to understand how different polymers affect the crystal growth rates of two chemically diverse organic drug molecules (bifonazole and nimesulide) from the undercooled melt regime close to the glass transition temperature. Bifonazole is an antifungal drug that contains no traditional hydrogen bond donors, only acceptors. In contrast, nimesulide contains both hydrogen bond donor and acceptor groups. Therefore, the potential hydrogen bonding interactions with polymers vary between the two compounds. For bifonazole, poly(vinylpyrrolidone) (PVP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), poly(vinylpyrrolidone-vinyl acetate) (PVP/VA) and poly(acrylic acid) (PAA) were investigated, while for nimesulide, PVP, PVP/VA and poly(vinyl acetate) (PVAc) were probed. Polymers were incorporated at a level of 5%w/w by cryomilling followed by melt quenching. Linear crystal growth rates in the presence and absence of polymers were measured as a function of temperature (18–100 °C for bifonazole and 18–80 °C for nimesulide) using optical microscopy. Differential scanning calorimetry (DSC) and infrared spectroscopy were performed for further characterization. All of the polymers decreased the growth rates of both drugs, however large differences could be observed between polymers in terms of the extent of crystal growth inhibition. For bifonazole, PAA was a notably better crystal growth inhibitor compared to the other polymers. This may be related to formation of specific interactions between the drug and the polymer. For nimesulide, the order of effectiveness was PVP∼PVP/VA>PVAc and, compared to bifonazole, differences seen between polymers were more modest. Infrared (IR) spectroscopy and density functional calculations strongly suggested that amorphous nimesulide formed an intramolecular hydrogen bond. IR spectroscopy showed that drug-polymer intermolecular hydrogen bonding did occur, but was hampered by the partial loss of the hydrogen bond donor to the intramolecular hydrogen bond. Hence the effectiveness of a polymer appears to depend not only on the chemistry of the drug, but also on the availability of hydrogen bonding groups.

In this study, a design approach to produce organic systems in which crystallization is prevented was achieved by extending the molecular recognition framework described in the field of crystal engineering to binary amorphous systems. Easily crystallizing, chemically diverse drug-like organic molecules and polymers were employed for proof of concept studies. To assess the potential of the polymers to disrupt drug–drug intermolecular interactions, prospective intra-species hydrogen bonding was evaluated using a variety of approaches. Based on the resultant evaluations, it was possible to arrive at an ab initio rank order of the crystallization inhibiting performance of the polymers for a given compound. The predicted rank order agreed well with the observed crystallization behavior of an extensive experimental dataset. This approach will enable the rational design of multicomponent glassy systems with optimal resistance to crystallization.

The structure of the title compound, C14H12O2, displays the expected intermolecular hydrogen bonding of the carboxylic acid groups, forming dimers. The dihedral angle between the two aromatic rings is 27.01 (7)°.