Exploring Molecular Speciation and Crystallization Mechanism of Amorphous 2-Phenylamino Nicotinic Acid...

Purpose Molecular understanding of phase stability and transition of the amorphous state helps in formulation and manufacturing of poorly-soluble drugs. Crystallization of a model compound, 2-phenylamino nicotinic acid (2PNA), from the amorphous state was studied using solid-state analytical methods. Our previous report suggests that 2PNA molecules mainly develop intermolecular –COOH∙∙∙pyridine N (acid-pyridine) interactions in the amorphous state. In the current study, the molecular speciation is explored with regard to the phase transition from the amorphous to the crystalline state. Methods Using spectroscopic techniques, the molecular interactions and structural evolvement during the recrystallization from the glassy state were investigated. Results The results unveiled that the structurally heterogeneous amorphous state contains acid-pyridine aggregates – either as hydrogen-bonded neutral molecules or as zwitterions – as well as a population of carboxylic acid dimers. Phase transition from the amorphous state results in crystal structures composed of carboxylic acid dimer (acid-acid) synthon or acid-pyridine chains depending on the crystallization conditions employed. Conclusions The study underlines the structural evolvement, as well as its impact on the metastability, of amorphous samples from local, supramolecular assemblies to long-range intermolecular ordering through crystallization....
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Epithelia transmembrane transport of orally administered ultrafine drug particles evidenced by environment sensitive fluorophores in cellular and animal studies...

Little is known about the in vivo fate of drug particles taken orally, in particular, the drug release kinetics and interaction with the gastrointestinal (GI) membrane. Lacking is analytical means that can reliably identify the integrity of drug particles under the complexity of biological environment. Herein, we explored fluorescent probes whose signals become quenched upon being released from drug carriers. Taking advantage of so-called the aggregation caused quenching (ACQ), particles may be identified by the integrated fluorophores, which are “turned off” when the particles become destructed and dyes are released. In the current study, ultrafine amorphous particles (UAPs) of cyclosporin A (CsA) were prepared with synthesized ACQ dyes physically entrapped. The fluorescence intensity of suspension of these UAPs was found correlated well with the dissolution of the particles. When given to rats orally, it was found that some of the administered UAPs could survive the animal's GI tracts for as long as 18 h. Whole-body fluorescence imaging detected fluorescent signals in the liver and lungs. Particularly noticed in sections of jejunum and ileum, the detection suggested the possibility of direct absorption of UAPs through epithelial membranes. Moreover, 250 nm particles were absorbed faster via transepithelia than larger ones (550 nm), while the latter were preferably taken up by M cells in the follicle-associated epithelium (FAE) region of Peyer's patches. In vitro permeation studies with Caco-2 cells confirmed the transmembrane transport of the dye-integrated UAPs. Our study supports the idea of using ACQ fluorophores for imaging and characterizing the fate of intact particles in a biological environment....
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Effects of Coating Materials and Processing Conditions on Flow Enhancement of Cohesive Acetaminophen Powders by High-Shear Processing With Pharmaceutical Lubricants...

This study has investigated the surface coating efficiency and powder flow improvement of a model cohesive acetaminophen powder by high-shear processing with pharmaceutical lubricants through 2 common equipment, conical comil and high-shear mixer. Effects of coating materials and processing parameters on powder flow and surface coating coverage were evaluated. Both Carr's index and shear cell data indicated that processing with the lubricants using comil or high-shear mixer substantially improved the flow of the cohesive acetaminophen powder. Flow improvement was most pronounced for those processed with 1% wt/wt magnesium stearate, from “cohesive” for the V-blended sample to “easy flowing” for the optimally coated sample. Qualitative and quantitative characterizations demonstrated a greater degree of surface coverage for high-shear mixing compared with comilling; nevertheless, flow properties of the samples at the corresponding optimized conditions were comparable between 2 techniques. Scanning electron microscopy images demonstrated different coating mechanisms with magnesium stearate or l-leucine (magnesium stearate forms a coating layer and leucine coating increases surface roughness). Furthermore, surface coating with hydrophobic magnesium stearate did not retard the dissolution kinetics of acetaminophen. Future studies are warranted to evaluate tableting behavior of such dry-coated pharmaceutical powders....
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Persistent Self-Association of Solute Molecules in Solution...

The structural evolvement of a solute determines the crystallization outcome. The self-association mechanism leading to nucleation, however, remains poorly understood. Our current study explored the solution chemistry of a model compound, tolfenamic acid (TFA), in three different solvents mainly by solution NMR. It was found that hydrogen-bonded pairs of solute–solute or solute–solvent stack with each through forming a much weaker π–π interaction as the concentration increases. Depending on the solvent, configurations of the solution species may be retained in the resultant crystal structure or undergo rearrangement. Yet, the π–π stacking is always retained in the crystal regardless of the solvent used for the crystallization. The finding suggests that nucleation not only involves the primary intermolecular interaction (hydrogen bonding) but also engages the secondary forces in the self-assembly process....
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Integrating In Vitro, Modeling, and In Vivo Approaches to Investigate Warfarin Bioequivalence,...

X Zhang, H Wen, J Fan, B Vince, T Li, W Gao, M Kinjo, J Brown, W Sun, W Jiang, and R Lionberger CPT Pharmacometrics & System Pharmacology, 6,523-531, 2017, doi: 10.1002/psp4.12198 Abstract (from Publisher): We demonstrate the use of modeling and simulation to investigate bioequivalence (BE) concerns raised about generic warfarin products. To test […]
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sp2CH⋯Cl hydrogen bond in the conformational polymorphism of 4-chloro-phenylanthranilic acid, The Royal Society of Chemistry...

Chlorine can participate in numerous interactions such as halogen bonding, hydrogen bonding, and London dispersion in the solid state. In this work, we report the influence of a chlorine substituent on the polymorphism of a potential anticancer drug, 4-chloro-phenylanthranilic acid (CPAA). Three polymorphs have been discovered for this compound, and the three forms were characterized by single-crystal X-ray diffraction, power X-ray diffraction (PXRD), FT-IR, and Raman spectroscopy. Both conformational flexibility of the molecule and the sp2CH⋯Cl hydrogen bond seem to lead to the polymorphism of the system. The phase behavior was investigated by differential scanning calorimetry (DSC), with the conclusion that form II converts to III upon heating. A conformational scan shows the conformational minima corresponds to the conformers existing in the polymorphs. Lattice energy calculations show energies of −106.70, −104.72, and −194.42 kJ mol−1 for forms I to III, providing information on relative stability for each form. Hirshfeld analysis revealed that intermolecular interactions such as H⋯H, C⋯H, H⋯Cl, and H⋯O contribute to the stability of the crystal forms....
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Strong Hydrogen Bond Leads to a Fifth Crystalline Form and Polymorphism of Clonixin...

Over 30 years since the discovery of four crystal forms (I, II, III and IV) of Clonixin [2-(3-chloro-2-methyl-phenylamino)-nicotinic acid], a fifth form, a dimethylformamide (DMF) solvate, has been obtained by crystal growth in DMF. The new form was characterized by single-crystal X-ray diffraction, FT-IR, and Raman spectroscopy. The crystal structure is stabilized by the strong hydrogen bond between the carboxylic acid OH and the DMF carbonyl whose strength is on par with those of the four solvent-free forms, which are based on either the acid-acid homosynthon or the acid-pyridine heterosynthon, depending on the dihedral angle between the two aromatic rings. This solvate loses DMF to convert into form I, as confirmed by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Other aspects of this polymorphic/solvatomorphic system were investigated both experimentally and theoretically. Theoretical studies such as lattice energy calculation, hydrogen-bond strength estimation and Hirshfeld analysis were performed, providing further insight into the polymorphism/solvatomorphism of this system. Based on the analysis of the new form and the whole system, more solvates/cocrystals could be designed and unveiled in due time....
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Effects of Coating Materials and Processing Conditions on Flow Enhancement of Cohesive Acetaminophen Powders by High-Shear Processing With Pharmaceutical Lubricants...

This study has investigated the surface coating efficiency and powder flow improvement of a model cohesive acetaminophen powder by high-shear processing with pharmaceutical lubricants through 2 common equipment, conical comil and high-shear mixer. Effects of coating materials and processing parameters on powder flow and surface coating coverage were evaluated. Both Carr's index and shear cell data indicated that processing with the lubricants using comil or high-shear mixer substantially improved the flow of the cohesive acetaminophen powder. Flow improvement was most pronounced for those processed with 1% wt/wt magnesium stearate, from “cohesive” for the V-blended sample to “easy flowing” for the optimally coated sample. Qualitative and quantitative characterizations demonstrated a greater degree of surface coverage for high-shear mixing compared with comilling; nevertheless, flow properties of the samples at the corresponding optimized conditions were comparable between 2 techniques. Scanning electron microscopy images demonstrated different coating mechanisms with magnesium stearate or l-leucine (magnesium stearate forms a coating layer and leucine coating increases surface roughness). Furthermore, surface coating with hydrophobic magnesium stearate did not retard the dissolution kinetics of acetaminophen. Future studies are warranted to evaluate tableting behavior of such dry-coated pharmaceutical powders....
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Glycine’s pH-Dependent Polymorphism: A Perspective from Self-Association in Solution...

As a simple amino acid, glycine (Gly)’s polymorphism is pH-dependent. The α form is typically obtained from aqueous solution between pH of 4 and 9, while the γ is produced at either lower or higher pH. Formation of cyclic, hydrogen-bonded dimer in water is debated as a possible cause for the formation of the α form. To further understand the pH-dependent polymorphism, our current study examined the self-association of Gly in aqueous solutions under a wide range of pH, utilizing NMR, FTIR, and electronic calculation. The results indicate that glycine molecules form open, not cyclic, hydrogen-bonded dimers in water. It is revealed that the dimerization becomes significant between pH of 4 and 8 but remains trivial at the two pH extremes. The apparent connection between the pH-dependent polymorphism and self-association in solution implies that formation of the α form is driven by the dimerization, and moreover, charged molecular species at the extreme pH facilitate stabilization of γ nuclei....
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Higher-Order Self-Assembly of Benzoic Acid in Solution

Benzoic acid forms hydrogen-bonded dimers in solution that further stack into tetramers by aromatic interactions. Both dimers and higher-order packing motifs are preserved in the resultant crystal structure. The finding hints at the significance in the hierarchy of intermolecular interactions in driving the self-association process in solution.
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Exploring intracellular fate of drug nanocrystals with crystal-integrated and environment-sensitive fluorophores...

Formulating a poorly water-soluble drug substance into nanocrystals offers many advantages. Understanding of the in vivo fate of drug nanocrystals is however very limited. In this study, we utilized the hybrid nanocrystal concept and studied the kinetic process of dissolution in cancer cells. By taking advantage of aggregation-induced emission (AIE), hybrid paclitaxel (PTX) nanocrystals integrated with tetraphenylethene (TPE) enabled a novel way for estimating the intracellular dissolution process of the nanocrystals. When TPE is entrapped in a nanocrystal, fluorescence is emitted when the nanocrystal is optically excited. When an entrapped TPE molecule is released to a liquid medium due to the dissolution of the nanocrystal, its fluorescence is quenched. By monitoring the change in fluorescence, it is possible to quantify the dissolution of nanocrystals in a biological environment. Cellular uptake studies of hybrid nanocrystals were conducted with KB and HT-29 cell lines and characterized by confocal microscopy, flow cytometry, and HPLC. The results suggest that drug nanocrystals were taken up directly by the cells, and subsequently dissolved in the cytoplasm. The extent to which the drug nanocrystal dissolved was estimated according to the fluorescence measurement. The cellular uptake and intracellular dissolution could be influenced by drug concentration, incubation time, and surface coating, as well as the type of cell line....
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Gaining Thermodynamic Insight From Distinct Glass Formation Kinetics of Structurally Similar Organic Compounds...

Arjun Kalra, Paul Luner, Lynne S. Taylor, Stephen R.Byrn and Tonglei Li Journal of Pharmaceutical Sciences, xxx(2017) 1-11, June 2017 Abstract (from Publisher): Thermodynamic and kinetic aspects of crystallization of 12 structurally similar organic compounds were investigated from the supercooled liquid state by calorimetric and rheologic measurements. Based on their crystallization behaviors, these compounds were divided into 3 categories: […]...
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Impact of Supramolecular Aggregation on the Crystallization Kinetics of Organic Compounds from the Supercooled Liquid State...

Despite numerous challenges in their theoretical description and practical implementation, amorphous drugs are of growing importance to the pharmaceutical industry. One such challenge is to gain molecular level understanding of the propensity of a molecule to form and remain as a glassy solid. In this study, a series of structurally similar diarylamine compounds was examined to elucidate the role of supramolecular aggregation on crystallization kinetics from supercooled liquid state. The structural similarity of the compounds makes it easier to isolate the molecular features that affect crystallization kinetics and glass forming ability of these compounds. To examine the role of hydrogen-bonded aggregation and motifs on crystallization kinetics, a combination of thermal and spectroscopic techniques was employed. Using variable temperature FTIR, Raman, and solid-state NMR spectroscopies, the presence of hydrogen bonding in the melt and glassy state was examined and correlated with observed phase transition behaviors. Spectroscopic results revealed that the formation of hydrogen-bonded aggregates involving carboxylic acid and pyridine nitrogen (acid−pyridine aggregates) between neighboring molecules in the melt state impedes crystallization, while the presence of carboxylic acid dimers (acid−acid dimers) in the melt favors crystallization. This study suggests that glass formation of small molecules is influenced by the type of intermolecular interactions present in the melt state and the kinetics associated with the molecules to assemble into a crystalline lattice. For the compounds that form acid−pyridine aggregates, the formation of energy degenerate chains, produced due to conformational flexibility of the molecules, presents a kinetic barrier to crystallization. The poor crystallization tendency of these aggregates stems from the highly directional hydrogen-bonding interactions needed to form the acid−pyridine chains. Conversely, for the compounds that form acid−acid dimers, the nondirectional van der Waals forces needed to construct a nucleus promote rapid assembly and crystallization....
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Pulmonary delivery of nanoparticle chemotherapy for the treatment of lung cancers: challenges and opportunities...

Lung cancer is the second most prevalent and the deadliest among all cancer types. Chemotherapy is recommended for lung cancers to control tumor growth and to prolong patient survival. Systemic chemotherapy typically has very limited efficacy as well as severe systemic adverse effects, which are often attributed to the distribution of anticancer drugs to non-targeted sites. In contrast, inhalation routes permit the delivery of drugs directly to the lungs providing high local concentrations that may enhance the anti-tumor effect while alleviating systemic adverse effects. Preliminary studies in animals and humans have suggested that most inhaled chemotherapies are tolerable with manageable pulmonary adverse effects, including cough and bronchospasm. Promoting the deposition of anticancer drugs in tumorous cells and minimizing access to healthy lung cells can further augment the efficacy and reduce the risk of local toxicities caused by inhaled chemotherapy. Sustained release and tumor localization characteristics make nanoparticle formulations a promising candidate for the inhaled delivery of chemotherapeutic agents against lung cancers. However, the physiology of respiratory tracts and lung clearance mechanisms present key barriers for the effective deposition and retention of inhaled nanoparticle formulations in the lungs. Recent research has focused on the development of novel formulations to maximize lung deposition and to minimize pulmonary clearance of inhaled nanoparticles. This article systematically reviews the challenges and opportunities for the pulmonary delivery of nanoparticle formulations for the treatment of lung cancers....
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Impact of surfactant treatment of paclitaxel nanocrystals on biodistribution and tumor accumulation in tumor-bearing mice...

We have previously tested paclitaxel nanocrystals (PTX-NCs) in tumor murine models and learned that the nanocrystal formulation could achieve similar and superior anticancer efficacy to the conventional Taxol® formulation, but with significantly reduced side-effects. The nanocrystals were not coated with any surfactants and a majority of the injected dose was taken up by the liver (N40%), while a minimal amount was present in the blood circulation and quickly eliminated. The aim of this work was to treat the surface of PTX-NCs with PEGbased polymers and examine the impact by surface coating on biodistribution, pharmacokinetics, and tumor retention. Testing in tumor-bearing mice showed that PTX-NCs treated with Pluronic® F68 (PEG-PPG-PEG block polymer) significantly enhanced blood circulation of the drug and accumulation in tumor tissue. The absolute amount reaching the tumor, however, was still minimal relative to the dose....
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Solid-State Spectroscopic Investigation of Molecular Interactions between Clofazimine and Hypromellose Phthalate in Amorphous Solid Dispersions...

It has been technically challenging to specify the detailed molecular interactions and binding motif between drugs and polymeric inhibitors in the solid state. To further investigate drug–polymer interactions from a molecular perspective, a solid dispersion of clofazimine (CLF) and hypromellose phthalate (HPMCP), with reported superior amorphous drug loading capacity and physical stability, was selected as a model system. The CLF–HPMCP interactions in solid dispersions were investigated by various solid state spectroscopic methods including ultraviolet–visible (UV–vis), infrared (IR), and solid-state NMR (ssNMR) spectroscopy. Significant spectral changes suggest that protonated CLF is ionically bonded to the carboxylate from the phthalyl substituents of HPMCP. In addition, multivariate analysis of spectra was applied to optimize the concentration of polymeric inhibitor used to formulate the amorphous solid dispersions. Most interestingly, proton transfer between CLF and carboxylic acid was experimentally investigated from 2D 1H–1H homonuclear double quantum NMR spectra by utilizing the ultrafast magic-angle spinning (MAS) technique. The molecular interaction pattern and the critical bonding structure in CLF–HPMCP dispersions were further delineated by successfully correlating ssNMR findings with quantum chemistry calculations. These high-resolution investigations provide critical structural information on active pharmaceutical ingredient–polymer interaction, which can be useful for rational selection of appropriate polymeric carriers, which are effective crystallization inhibitors for amorphous drugs....
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