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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Investigating the Interaction Pattern and Structural Elements of a Drug–Polymer Complex at the Molecular Level...

Strong associations between drug and polymeric carriers are expected to contribute to higher drug loading capacities and better physical stability of amorphous solid dispersions. However, molecular details of the interaction patterns and underlying mechanisms are still unclear. In the present study, a series of amorphous solid dispersions of clofazimine (CLF), an antileprosy drug, were prepared with different polymers by applying the solvent evaporation method. When using hypromellose phthalate (HPMCP) as the carrier, the amorphous solid dispersion system exhibits not only superior drug loading capacity (63% w/w) but also color change due to strong drug–polymer association. In order to further explain these experimental observations, the interaction between CLF and HPMCP was investigated in a nonpolar volatile solvent system (chloroform) prior to forming the solid dispersion. We observed significant UV/vis and 1H NMR spectral changes suggesting the protonation of CLF and formation of ion pairs between CLF and HPMCP in chloroform. Furthermore, nuclear Overhauser effect spectroscopy (NOESY) and diffusion order spectroscopy (DOSY) were employed to evaluate the strength of associations between drug and polymers, as well as the molecular mobility of CLF. Finally, by correlating the experimental values with quantum chemistry calculations, we demonstrate that the protonated CLF is binding to the carboxylate group of HPMCP as an ion pair and propose a possible structural model of the drug–polymer complex. Understanding the drug and carrier interaction patterns from a molecular perspective is critical for the rational design of new amorphous solid dispersions....
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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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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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Tautomeric Polymorphism of 4-Hydroxynicotinic Acid

4-Hydroxynicotinic acid (4-HNA) was discovered to exist in the solid state as either 4-HNA or its tautomer 4-oxo-1,4-dihydropyridine-3-carboxylic acid (4-ODHPCA) in three polymorphs and two hydrates. Packing motifs differ as each of the three oxygen atoms acts as the hydrogen-bond acceptor, respectively, in the anhydrate forms, while in the hydrate forms, water molecules participate in hydrogen bonding with 4-HNA. Phase behaviors of the forms were characterized by differential scanning calorimetry (DSC), hot-stage microscopy (HSM), and thermogravimetric analysis (TGA). It was found that anhydrates I and II converted into III during heating; the two hydrate forms dehydrated at different temperatures and eventually transformed into anhydrate III, and sublimation of all five forms led to form III when the crystals were heated. Quantum mechanical calculations were performed providing further insight into the polymorphism....
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Developing nanocrystals for cancer treatment

Nanocrystals are carrier-free solid drug particles that are sized in the nanometer range and have crystalline characteristics. Due to high drug loading (as high as 100%) – free of organic solvents or solubilizing chemicals – nanocrystals have become attractive in the field of drug delivery for cancer treatment. Top–down and bottom–up approaches have been developed for preparing anticancer nanocrystals. In this review, preparation methods and in vivo performance of anticancer nanocrystals are discussed first, followed by an introduction of hybrid nanocrystals in cancer theranostics....
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Cellular Uptake Mechanism of Paclitaxel Nanocrystals Determined by Confocal Imaging and Kinetic Measurement...

Nanocrystal formulation has become a viable solution for delivering poorly soluble drugs including chemotherapeutic agents. The purpose of this study was to examine cellular uptake of paclitaxel nanocrystals by confocal imaging and concentration measurement. Imaging and quantitative results suggest that nanocrystals could be directly taken up by cells as solid particles, likely via endocytosis. Moreover, it was found that polymer treatment to drug nanocrystals, such as surface coating and lattice entrapment, significantly influenced the cellular uptake. While drug molecules are in the most stable physical state, nanocrystals of a poorly soluble drug are capable of achieving concentrated intracellular presence enabling needed therapeutic effects....
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Reactivity of Triacetone Triperoxide and Diacetone Diperoxide: Insights from Nuclear Fukui Function...

Triacetone triperoxide (TATP) is more sensitive than diacetone diperoxide (DADP) in the solid-state explosion. To explain this reactivity difference, we analyzed the electronic structures and properties of the crystals of both compounds by using Ab initio method to calculate the structures of their individual molecules as well as their lattice structures and particularly calculating Nuclear Fukui function to gain insight into the sensitivity of the initial, rate-determining step of their decomposition. Our results indicate that TATP and DADP crystal structures exhibit significantly different electronic properties. Most notably, the electronic structure of the TATP crystal shows asymmetry among its reactive oxygen atoms as supported by magnitudes of their nuclear Fukui functions. The greater explosion sensitivity of crystalline TATP may be attributed to the properties of its electronic structure. The electronic calculations provided valuable insight into the decomposition sensitivity difference between TATP and DADP crystals....
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Polymorphism and Solid-to-Solid Phase Transitions of a Simple Organic Molecule, 3-Chloroisonicotinic Acid...

Three polymorphs (I, II, and III) have been discovered for 3-chloroisonicotinic acid. The torsion angle between the aromatic ring and the carboxylic acid in form I differs from that of forms II and III, which are similar. All three polymorphs form hydrogen-bonded chains based on the acid–pyridine heterosynthon. Despite the conformational similarity between forms II and III, the hydrogen-bonded chains in form II alternate in direction while those in form III all point in the same direction. Study of the phase behaviors of the three forms by differential scanning calorimetry, hot-stage microscopy, and thermogravimetric analysis revealed two solid-to-solid phase transitions from the metastable forms II and III to the most stable form I. Sublimation of 3-chloroisonicotinic acid also led to form I. A higher-temperature polymorph seemed to be possible but remained elusive. Lattice energy and hydrogen bonding strength calculations provided further insight into the stability of the polymorphs. A search of conformational space for the molecule suggested possibly additional polymorphs of this simple compound. The system may be valuable for further solid-state structure–property relationship studies....
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Solid-State Identity of 2-Hydroxynicotinic Acid and Its Polymorphism...

2-Hydroxynicotinic acid (2-HNA), a derivative of nicotinic acid, was found to exist in four polymorphs. In the solid state, 2-HNA is actually present as its tautomer, 2-oxo-1,2-dihydro-3-pyridinecarboxylic acid (2-ODHPCA). Theoretical studies showed that 2-ODHPCA is more energetically favored than 2-HNA.
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Solution Chemistry and Its Implication on Nucleation of Conformational Polymorphs: A Computational Study of Tolfenamic Acid by Explicit Solvation...

Major solution species of tolfenamic acid were simulated in ethanol by molecular dynamics. Interaction energies among solute and solvent molecules were evaluated by hybrid quantum mechanics and molecular mechanics methods. The results underscore the implication by the mutual dependency between intermolecular interaction and molecular conformation on nucleation mechanism.
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Intermolecular Interactions in Organic Crystals: Gaining Insight from Electronic Structure Analysis by Density Functional Theory...

Conceptual density functional theory is exploited to extend the HSAB (hard and soft acids and bases) principle for investigating the locality and regioselectivity of intermolecular interactions in organic crystals. Local hardness and softness, facilitated by Hirshfeld analysis, appear to quantitatively characterize the strength of intermolecular interactions.
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