Influence of Manufacturing Process on the Microstructure, Stability, and Sensorial Properties of a Topical Ointment Formulation.

The manufacturing process for ointments typically involves a series of heating, cooling, and mixing steps. Precise control of the level of mixing through homogenization and the cooling rate, as well as temperature at different stages, is important in delivering ointments with the desired quality attributes, stability, and performance. In this work, we investigated the influence of typical plant processing conditions on the microstructure, stability, and sensorial properties of a model ointment system through a Design of Experiments (DoE) approach. Homogenization speed at the cooling stage after the addition of the solvent (propylene glycol, PG) was found to be the critical processing parameter that affects stability and the rheological and sensorial properties of the ointment. A lower PG addition temperature was also found to be beneficial. The stabilization of the ointment at a lower PG addition temperature was hypothesized to be due to more effective encapsulation by crystallizing mono- and diglycerides at the lower temperature. The in vitro release profiles were found to be not influenced by the processing parameters, suggesting that for the ointment platform studied, processing affects the microstructure, but the effects do not translate into the release profile, a key performance indicator. Our systematic study represents a Quality-by-Design (QbD) approach to the design of a robust manufacturing process for delivering stable ointments with the desired performance attributes and properties.

Formulation and Skin Permeation of Active-Loaded Lipid Nanoparticles: Evaluation and Screening by Synergizing Molecular Dynamics Simulations and Experiments.

Encapsulation into nanoparticles (NPs) is a potential method to deliver pharmaceutical/cosmetic actives deep into the skin. However, understanding the NP formulations and underlying mechanism of active delivery to skin has scarcely been studied. We report a simulation platform that screens, evaluates, formulates, and provides atomic-resolution interpretation of NP-based formulations, and reveals the active permeation mechanism from NPs to skin. First, three actives, namely, ferulic acid (FA), clotrimazole (CZE), and tretinoin (TTN), and five lipid excipients' (Compritol, Precirol, Geleol, Gelot, Gelucire) combinations were screened by MD simulations for the best pairs. For each suggested pair, the actual active and lipid compositions for the synthesis of stable NP formulations were then obtained by experiments. MD simulations demonstrate that in NP formulations, FA and CZE actives are present at the surface of the NPs, whereas TTN actives are present at both the surface and interior of the NP core. The NP shapes obtained by simulation perfectly match with experiments. For each NP, separate MD simulations illustrate that active-loaded NPs approach the skin surface quickly, and then actives translocate from NP surface to skin surface followed by penetration of NPs through skin. The driving force for the translocation which initiates during the penetration process, is the stronger active-skin interaction compared to active-NP interaction. Permeation free energy indicates spontaneous transfer of actives from solution phase to the surface of the skin bilayer. The free energy barriers are increased in the order of FA < TTN < CZE. Significantly lower diffusions of actives are obtained in the main barrier region compared to bulk, and the average diffusion coefficients of actives are in the same order of magnitude (∼10-6 cm2/s). The estimated permeability coefficients (log P) of actives are mainly governed by free energy barriers. The study would facilitate the development of novel lipid-based NP formulations for personal-care/pharmaceutical applications.

Influence of wall slip, thixotropy and lubrication regime on the instrumental sensory evaluation of topical formulations.

OBJECTIVE: Drawing parallels from rheotribology can be used to develop a robust instrumental protocol for non-subjective characterization, product development and design of topical dosage forms with desired sensory attributes. However, instrumental characterization of cosmetic products can be influenced by the measurement protocol, thixotropy, flow anomalies like shear banding or wall slip and nature of the film formed on the skin surface. In this study, we evaluated the influence of above parameters on the instrumental sensory evaluation of 12 topical formulations of different galenic forms. METHODS: Oscillatory strain sweep measurements (SAOS and LAOS) were performed to investigate the influence of frequency and wall slip on the material parameters. The textural attributes at different consumer touchpoints were evaluated by accounting time-dependent simulation of viscoelastic flow. Further, the influence of film thickness and sample drying on the tactile properties of the topical formulations were studied on a non-biological skin model using a sliding probe tribometer. RESULTS: The study shows that the flow properties of the semi-solid formulations depend on the timescale of the problem. A few formulations exhibited wall slip to varying degrees in the linear viscoelastic regime where the behaviour was found not to be characteristic of a particular topical dosage form. The material functions obtained from the Lissajous plots suggest that the non-linear flow behaviour of different galenic forms is least influenced by the boundary conditions imposed by the measurement geometry. The results were statistically analysed using principal component analysis where the attributes used for discriminating skin creams during pick up and rub out are found to be closely associated with non-linear rheology. The friction coefficient exhibited speed dependence where it formed different parametric group with rheological data depending on the lubrication regime. CONCLUSION: The study highlights that correlations are possible amongst rheological, tribological and instrumental textural analysis data, which can act an impetus for the development of models to predict attributes that drive perception at different consumer touchpoints. However, the choice of instrumental settings, anomalies associated with rheological measurements and friction dependence on a number of parameters can influence the model prediction.

OBJECTIF: il est possible d'établir des parallèles à partir de la rhéotribologie pour développer un protocole instrumental robuste pour la caractérisation non subjective, le développement de produits et la conception de formes posologiques topiques avec les attributs sensoriels souhaités. Cependant, la caractérisation instrumentale des produits cosmétiques peut être influencée par le protocole de mesure, la thixotropie, les anomalies de flux comme la bande de cisaillement ou le glissement de fluides et la nature du film formé à la surface de la peau. Dans cette étude, nous avons évalué l'influence des paramètres ci-dessus sur l'évaluation sensorielle instrumentale de 12 formulations topiques de différentes formes galéniques. MÉTHODES: des mesures de balayage de la tension oscillatoire (SAOS et LAOS) ont été effectuées pour étudier l'influence de la fréquence et du glissement de fluides sur les paramètres des matériaux. Les attributs texturaux à différents points de contact avec les consommateurs ont été évalués en tenant compte de la simulation dépendante du temps du flux viscoélastique. En outre, l'influence de l'épaisseur du film et du séchage de l'échantillon sur les propriétés tactiles des formulations topiques a été étudiée sur un modèle cutané non biologique à l'aide d'un tribomètre à sonde coulissante. RÉSULTATS: l'étude montre que les propriétés de flux des formulations semi-solides dépendent de l'échelle de temps du problème. Quelques formulations ont montré un glissement de fluides à des degrés variables dans le régime viscoélastique linéaire où le comportement ne s'est pas avéré être caractéristique d'une forme posologique topique particulière. Les fonctions matérielles obtenues à partir des tracés de Lissajous suggèrent que le comportement de flux non linéaire des différentes formes galéniques est le moins influencé par les conditions limites imposées par la géométrie de la mesure. Les résultats ont été analysés statistiquement à l'aide d'une analyse en composante principale dans laquelle les attributs utilisés pour distinguer les crèmes cutanées lors du prélèvement et de la friction se sont avérés être étroitement associés à la rhéologie non linéaire. Le coefficient de frottement présentait une dépendance à la vitesse, où il formait un groupe paramétrique différent avec des données rhéologiques selon le régime de lubrification. CONCLUSION: l'étude souligne que des corrélations sont possibles entre les données d'analyses rhéologiques, tribologiques et instrumentales de la texture, pouvant donner une impulsion au développement de modèles permettant de prédire les attributs qui stimulent la perception à différents points de contact avec les consommateurs. Cependant, le choix des paramètres instrumentaux, les anomalies associées aux mesures rhéologiques et la dépendance à la friction sur un certain nombre de paramètres peuvent influencer la prédiction du modèle.

Molecular dynamics simulations to elucidate translocation and permeation of active from lipid nanoparticle to skin: complemented by experiments.

One of the most realistic approaches for delivering actives (pharmaceuticals/cosmetics) deep into skin layers is encapsulation into nanoparticles (NPs). Nonetheless, molecular-level mechanisms related to active delivery from NPs to the skin have scarcely been studied despite the large number of synthesis and characterization studies. We herein report the underlying mechanism of active translocation and permeation through the outermost layer of skin, the stratum corneum (SC), via molecular dynamics (MD) simulations complemented by experimental studies. A SC molecular model is constructed using current state-of-the-art methodology via incorporating the three most abundant skin lipids: ceramides, free fatty acids, and cholesterol. As a potent antioxidant, ferulic acid (FA) is used as the model active, and it is loaded into Gelucire 50/13 NP. MD simulations elucidate that, first, FA-loaded NP approaches the skin surface quickly, followed by slight penetration and adsorption onto the upper skin surface; FA then translocates from the NP surface to the skin surface due to stronger NP-skin interactions compared to the FA-NP interactions; then, once FA is released onto the skin surface, it slowly permeates deep into the skin bilayer. Both the free energy and resistance to permeation not only indicate the spontaneous transfer of FA from the bulk to the skin surface, but they also reveal that the main barrier against permeation exists in the middle of the lipid hydrophobic tails. Significantly lower diffusion of FA is obtained in the main barrier region compared to the bulk. The estimated permeability coefficient (log P) values are found to be higher than the experimental values. Importantly, the permeation process evaluated via MD simulations perfectly matches with experiments. The study suggests a molecular simulation platform that provides various crucial insights relating to active delivery from loaded NP to skin, and it could facilitate the design and development of novel NP-based formulations for transdermal delivery and the topical application of drugs/cosmetics.

Understanding the Salt-Dependent Outcome of Glycine Polymorphic Nucleation.

The salt-dependent polymorphs of glycine crystals formed from bulk solutions have been a longstanding riddle. In this study, in order to shed fresh light, we studied the effects of seven common salts on primary nucleation of the metastable α-glycine and the stable γ-glycine. Our nucleation experiments and in-depth data analyses enabled us to reveal that (NH4)2SO4, NaCl and KNO3, in general, promote γ-glycine primary nucleation very significantly while simultaneously inhibiting α-glycine primary nucleation, thereby explaining why these three salts induce γ-glycine readily. In comparison, Ca(NO3)2 and MgSO4 also promote γ-glycine and inhibit α-glycine primary nucleation but not sufficiently to induce γ-glycine. More interestingly, Na2SO4 and K2SO4 promote not only γ-glycine but also α-glycine primary nucleation, which is unexpected and presents a rare case where a single additive promotes the nucleation of both polymorphs. As a result, the promoting effects of Na2SO4 and K2SO4 on γ-glycine do not enable γ-glycine nucleation to be more competitive than α-glycine nucleation, with γ-glycine failing to appear. These observations help us to better understand salt-governed glycine polymorphic selectivity.

Microemulsion composed of combination of skin beneficial oils as vehicle: Development of resveratrol-loaded microemulsion based formulations for skin care applications.

Microemulsion can be a potential delivery vehicle to deliver skin care actives to deep skin layer for chronic skin care benefits. On top of skin care active, microemulsion vehicle composed of multiple skin beneficial oils can deliver additional skin care efficacies. In this study, microemulsions were developed using combinations of two skin beneficial oils, tea tree oil and medium chain triglyceride instead of single oil. For that, pseudo ternary phase diagrams were constructed on these oil combinations at different ratios of surfactant/co-surfactants. Ratio of oils and surfactant/co-surfactant combinations exhibited significant impact on the microemulsion region. A few compositions were selected from the single phase microemulsion regions of these phase diagrams for the preparation of resveratrol-loaded microemulsion and microemulsion gel formulations. The particle size of the resveratrol-loaded microemulsions were <50 nm. Cryogenic scanning electron microscope image clearly showed nano-droplets dispersed in continuous phase. Both physical and chemical stability of the formulations varied depending on their compositions, such as surfactant/co-surfactant combination and % total oil. The presence of chelating agent and anti-oxidant was also crucial to stabilize the formulations. The selected formulations demonstrated good physicochemical stability at 5 °C, 25 °C, and 40 °C/75 % RH (relative humidity) stability conditions. The results further showed that the % total oil and surfactant phase composition had huge influence on resveratrol release and skin permeation patterns from the microemulsion gels. In vitro skin permeation result indicated that the microemulsion gels can help resveratrol penetration into deep skin layer. Therefore, the developed resveratrol-loaded microemulsion gels can be utilized as skin care product with multiple skin care benefits.

Development of microemulsion based topical ivermectin formulations: Pre-formulation and formulation studies.

The aim of this work was to develop microemulsions and microemulsion gels which can be used as vehicles for the topical delivery of ivermectin. Tea tree oil and ethyl butanoate were found to be suitable for ivermectin-loaded microemulsion formulations due to the higher solubility of ivermectin in these two oils than other tested oils. The pseudo-ternary phase diagrams were constructed based on these selected oils and combination of different surfactant/co-surfactant at different ratios. Ivermectin-loaded stable microemulsions and microemulsion gels were successfully formulated based on the selected compositions from the phase diagrams. Ivermectin-loaded microemulsions showed spherical nano-droplets dispersed in the continuous phase (via cryogenic field emission scanning electron microscope image) and the particle size was less than 100 nm (via dynamic light scattering measurement). Ethyl butanoate based microemulsion appeared to be the best microemulsion formulation considering the stability and permeation profiles while tea tree oil based microemulsion showed the best stability profile. Overall, microemulsion gel formulations exhibited better stability profiles than their microemulsion counterparts. All microemulsion gel formulations demonstrated significantly faster in vitro membrane permeation (release) rate of ivermectin than Soolantra cream (reference marketed product by Galderma, USA).The developed microemulsion and microemulsion gel formulations appear to be promising vehicles for topical delivery of ivermectin.

Preparation of quercetin nanorod/microcrystalline cellulose formulation via fluid bed coating crystallization for dissolution enhancement.

This study reports a novel quercetin nanorod/microcrystalline cellulose (MCC) formulation prepared by fluid bed coating crystallization technique. The process comprises fluidized bed spray coating of quercetin acetone solution onto MCC particles, solvent evaporation and crystallization of quercetin nanorods on MCC surface. Depending on the quercetin solution concentration, quercetin nanorods with 100-300 nm in diameter and 1-3 µm in length were obtained. Owing to the small particle size and large surface area, a higher dissolution rate was achieved for quercetin nanorods in contrast to the raw quercetin, which therefore led to higher antioxidant activities. In addition, the obtained quercetin nanorod/MCC formulation exhibited a good storage stability within 12 months. The developed quercetin nanorod/MCC formulation could be used for further pharmaceutical dosage or food supplements processing.

Agomelatine-hydroquinone (1:1) cocrystal: novel polymorphs and their thermodynamic relationship.

Polymorphism of active pharmaceutical ingredients (APIs) is of significance in the pharmaceutical industry because it can affect the quality, efficacy and safety of the final drug product. In this regard, polymorphic behavior of cocrystals is no exception because it can influence the development of cocrystals as potential drug formulations. The current contribution aims to introduce two novel polymorphs [forms (III) and (IV)] of agomelatine-hydroquinone (AGO-HYQ) cocrystal and to describe the thermodynamic relationship between the cocrystal polymorphs. All polymorphs were characterized using powder X-ray diffraction, differential scanning calorimetry, hot-stage microscopy and solubility measurements. In addition, the crystal structure of form (II), which has been previously solved from powder diffraction data [Prohens et al. (2016), Cryst. Growth Des. 16, 1063-1070] and form (III) were determined from the single-crystal X-ray diffraction data. Thermal analysis revealed that AGO-HYQ cocrystal form (III) exhibits a higher melting point and a lower heat of fusion than those of form (II). According to the heat of fusion rule, the polymorphs are enantiotropically related, with form (III) being stable at higher temperatures. Our results also show that the novel form (IV) is the most stable form at ambient conditions and it transforms into form (II) on heating, and therefore, the two polymorphs are enantiotropically related. Furthermore, solubility and van't Hoff plot results suggest that the transition points are approximately 339 K for the pair form (IV)-(II) and 352 K for the pair form (II)-(III).

Antibiotic elution and mechanical property of TiO2 nanotubes functionalized PMMA-based bone cements.

To overcome the disadvantage of current antibiotic bone cements with low drug elution efficiency, the hollow nanostructured titanium-dioxide (TiO2) nanotubes (TNTs) were formulated with antibiotic loaded bone cement to create nano diffusion networks, enabling enhanced release of antibiotic. By incorporation of TNTs into Poly(methyl methacrylate) (PMMA) based bone cement, more than 50% of loaded antibiotic (such as gentamicin or vancomycin) could be released in two months. As comparison, only about 5% of total drug release was achieved in the absence of TNTs. The mechanical properties of PMMA-based bone cements were well preserved after incorporation of TNTs. Furthermore, the compression strength and bending modules of TNTs formulated antibiotic bone cements could be maintained after the drug release for 70 days or aging in PBS buffer for 3 months. The insoluble TNTs in bone cement is believed to support the mechanical properties after wet aging.

Solvates of the antifungal drug griseofulvin: structural, thermochemical and conformational analysis.

Four solvates of an antifungal drug, griseofulvin (GF), were discovered. All the solvates were characterized by differential scanning calorimetry, thermogravimetric analysis, and their crystal structures were determined by single-crystal X-ray diffraction. The solvents that form the solvates are acetonitrile, nitromethane and nitroethane (2:1 and 1:1). It was found that all the solvates lose the solvent molecules from the crystal lattice between 343 and 383 K, and that the melting point of the desolvated materials matched the melting point of the solvent-free GF (493 K). The conformation of the GF molecule in solvent-free form was found to be significantly different from the conformations found in the solvates. Solution stability studies revealed that the GF-acetonitrile solvate transforms to GF and that GF-nitroethane (1:1) solvate transforms to GF-nitroethane (2:1) solvate. On the other hand, GF-nitromethane and GF-nitroethane (2:1) solvates were found to be stable in solution. Our results highlight the importance of the co-crystallization technique in the pharmaceutical drug development; it not only expands the solid form diversity but also creates new avenues for unraveling novel solvates.

Molecular simulation study of the effect of various additives on salbutamol sulfate crystal habit.

The effects of polyvinylpyrrolidone (PVP), hydroxypropyl methyl cellulose (HPMC), and lecithin additives on salbutamol sulfate (SS) crystal growth are studied using molecular dynamics (MD) simulation, to provide an insight into the interaction between the additives and SS crystal faces at the atomistic level. The interaction energy between additives and crystal faces is presented. The intermolecular contacts between the additives and the crystal faces are analyzed by calculating the average number of contacts between O atoms of the additives and the H atoms of the first layer of the SS crystal. The mobility of each additive on SS crystal faces is also reported by determining the mean square displacement. Our results suggest that PVP is the most effective among the three additives for the inhibition of SS crystal growth. The methodology used in this study could be a powerful tool for selection of habit-modifying additives in other crystallization systems.

N,N-Dimethylpyridin-4-aminium 1-phenyl-cyclo-pentane-1-carboxyl-ate monohydrate.

The cation of the title salt, C(7)H(11)N(2) (+)·C(12)H(13)O(2) (-)·H(2)O, is planar (r.m.s. deviation = 0.0184 Å). In the crystal, the cation, anion and water mol-ecule are linked by O-H⋯O and N-H⋯O hydrogen bonds, forming a chain running along the a axis.

Quantification of polymorphic impurity in an enantiotropic polymorph system using differential scanning calorimetry, X-ray powder diffraction and Raman spectroscopy.

The ability to detect and quantify polymorphism of pharmaceuticals is critically important in ensuring that the formulated product delivers the desired therapeutic properties because different polymorphic forms of a drug exhibit different solubilities, stabilities and bioavailabilities. The purpose of this study is to develop an effective method for quantitative analysis of a small amount of one polymorph within a binary polymorphic mixture. Sulfamerazine (SMZ), an antibacterial drug, was chosen as the model compound. The effectiveness and accuracy of powder X-ray diffraction (PXRD), Raman microscopy and differential scanning calorimetry (DSC) for the quantification of SMZ polymorphs were studied and compared. Low heating rate in DSC allowed complete transformation from Form I to Form II to take place, resulting in a highly linear calibration curve. Our results showed that DSC and PXRD are capable in providing accurate measurement of polymorphic content in the SMZ binary mixtures while Raman is the least accurate technique for the system studied. DSC provides a rapid and accurate method for offline quantification of SMZ polymorphs, and PXRD provides a non-destructive, non-contact analysis.

Nitro-furan-toin methanol monosolvate.

The anti-biotic nitro-furan-toin {systematic name: (E)-1-[(5-nitro-2-fur-yl)methyl-idene-amino]-imidazolidine-2,4-dione} crys-tallizes as a methanol monosolvate, C(8)H(6)N(4)O(5)·CH(4)O. The nitro-furan-toin mol-ecule adopts a nearly planar conformation (r.m.s. deviation = 0.0344 Å). Hydrogen bonds involve the co-operative N-H⋯O-H⋯O heterosynthons between the cyclic imide of nitro-furan-toin and methanol O-H groups. There are also C-H⋯O hydrogen bonds involving the nitro-furan-toin mol-ecules which support the key hydrogen-bonding synthon. The overall crystal packing is further assisted by weak C-H⋯O inter-actions, giving a herringbone pattern.

Pyrimidin-2-amine-1-phenyl-cyclo-pentane-1-carb-oxy-lic acid (1/1).

In the crystal structure of the title co-crystal, C(4)H(5)N(3)·C(12)H(14)O(2), the components are linked by N-H⋯O and O-H⋯N hydrogen bonds. Self-assembly of these dimeric units results in a four-component supra-molecular unit featuring a homosynthon between two mol-ecules of the pyrimidin-2-amine involving two N-H⋯O hydrogen bonds, and two heterosynthons between each one mol-ecule of pyrimidin-2-amine and 1-phenyl-cyclo-pentane-1-carb-oxy-lic acid involving N-H⋯O and O-H⋯N hydrogen bonds.

Acceleration of crystal growth rates: an unexpected effect of tailor-made additives.

The importance of relative growth rates in the preponderance of alpha- over gamma-glycine during solution crystallisation has been confirmed. Most surprisingly tailor-made additives drastically accelerated the growth of gamma-glycine--an unexpected and key factor in the polymorphic outcome of glycine crystallisation.

Conformational polymorphism of tolbutamide: A structural, spectroscopic, and thermodynamic characterization of Burger's forms I-IV.

Crystal polymorphism of the anti-diabetic drug Tolbutamide (TB) has been studied using various analytical techniques. TB crystallizes in four polymorphic forms (Forms I-IV), which differ in their mode of packing and in molecular conformation but with similar hydrogen bonding synthon (urea tape motif). All the structures were solved from single crystal X-ray data, except for Form IV, which was solved using conventional powder X-ray diffraction (PXRD) data. The conformational differences in the TB molecule arise primarily from torsional variations in the alkyl tail which result in two types of conformers (U and chair). The packing differences are mainly due to the orientation of adjacent molecules in the hydrogen bonding networks. Based on the DSC data, thermodynamic stability relationships of polymorphic pairs were evaluated and graphically visualized in a schematic energy-temperature diagram. Form II is found to be the thermodynamically stable polymorph from absolute zero to approximately 353 K and beyond which Form I(H) is the stable polymorph. The anisotropic lattice contraction of TB polymorphs which resulted in severe variations in PXRD patterns at ambient and low temperature was highlighted. The present work also highlights and resolves several discrepancies in the published data on the structural and thermodynamic features of TB polymorphs.

2-Amino-pyridinium 1-phenyl-cyclo-propane-1-carboxyl-ate.

In the title salt, C(5)H(7)N(2) (+)·C(10)H(9)O(2) (-), 2-amino-pyridine and 1-phenyl-cyclo-propane-1-carb-oxy-lic acid crystallize together, forming a 2-amino-pyridinium-carboxyl-ate supra-molecular heterosynthon involving two N-H⋯O hydrogen bonds, which in turn dimerizes to form a four-component supra-molecular unit also sustained by N-H⋯O hydrogen bonding. A C-H⋯π inter-action between a pyridine C-H group and the centroid of the phenyl ring of the anion further stabilizes the four-component supra-molecular unit. The overall crystal packing also features C-H⋯O inter-actions.

Ethenzamide-gentisic acid-acetic acid (2/1/1).

In the title co-crystal solvate, 2-ethoxy-benzamide-2,5-dihydroxy-benzoic acid-ethanoic acid (2/1/1), 2C(9)H(11)NO(2)·C(7)H(6)O(4)·C(2)H(4)O(2), two nonsteroidal anti-inflammatory drugs, ethenzamide (systematic name: 2-ethoxy-benzamide) and gentisic acid (systematic name: 2,5-dihydroxy-benzoic acid), together with acetic acid (systematic name: ethanoic acid) form a four-component mol-ecular assembly held together by N-H⋯O and O-H⋯O hydrogen bonds. This assembly features two symmetry-independent mol-ecules of ethenzamide, forming supra-molecular acid-amide heterosynthons with gentisic acid and acetic acid. These heterosynthons involve quite strong O-H⋯O [O⋯O = 2.5446 (15) and 2.5327 (15) Å] and less strong N-H⋯O [N⋯O = 2.9550 (17) and 2.9542 (17) Å] hydrogen bonds. The overall crystal packing features several C-H⋯O and π-π stacking inter-actions [centroid-centroid distance = 3.7792 (11) Å].