On the Role of Solvent in the Formation of Vacancies on Ibuprofen Crystal Facets

Surface defects play a crucial role in the process of crystal growth, as the incorporation of growth units generally takes place on under-coordinated sites on the growing crystal facet. In this work, we use molecular dynamics simulations to obtain information on the role of the solvent in the roughening of three morphologically-relevant crystal faces of form I of racemic ibuprofen. To this aim, we devise a computational strategy based on combining independent Well Tempered Metadynamics with Mean Force Integration. This approach enables us to evaluate the energetic cost associated with the formation of a surface vacancy for a set of ten solvents, covering a range of polarities and hydrogen-bonding ability. We find that both the mechanism of defect formation on these facets and the work associated with the process are indeed markedly solvent-dependent. The methodology developed in this work has been designed with the aim of capturing solvent effects at the atomistic scale while maintaining the computational efficiency necessary for implementation in high-throughput computational screenings of crystallization solvents.

Formulation and Characterization of Chitosan Based Dexibuprofen Nanoparticles Using Ionotropic Gelation Method

Dexibuprofen is a pharmacologically active enantiomer of racemic ibuprofen (NSAID), which is used to treat pain and inflammation. Like common NSAIDs, Dexibuprofen is an active enantiomer of ibuprofen that suppresses the prostanoid synthesis in the inflammatory cells via inhibition of the COX-2 isoform of the arachidonic acid COX. The therapeutic use of Dexibuprofen is limited by the rapidity of the onset of its action and its short biological half-life. Hence, our aim was to develop Dexibuprofen nanoparticles formulation to overcome these disadvantages using optimized concentration of polymers by appropriate methods for nanoparticle preparation. The drug and the nanoparticle formulation of Dexibuprofen F11 were comparatively assessed for FT IR spectrums by using FT-IR method. The DSC study was used as one of the tool to assess the compatibility between drug and the excipients. As per DSC thermograms, the drug as well as drug with mixture of excipients chitosan, sodium tripolyphosphate had shown no interactions with dexibuprofen. The ionotropic gelation method was used to prepare Dexibuprofen nanoparticles. The chitosan and sodium tripolyphosphate (TPP) of different concentrations were used as polymers to prepare Dexibuprofen nanoparticles. Total eleven different formulations were explored with different concentrations of drug : polymer ratios using ionotropic gelation method to identify optimal concentrations of polymer. Among different formulations, F11 formulation with optimized concentration of 5% chitosan and 1% Sodium tripolyphosphate polymers along with Dexibuprofen showed maximum drug release. The objective was to evaluate the developed Dexibuprofen nanoparticles. In-vitro drug release was evaluated in 0.05M phosphate buffer pH7.2 and found that the drug release of F11 formulation of Dexibuprofen nanoparticle had shown release till 24 hours more than that of other trials. Hence, F11 formulation was considered as the optimized nanoparticle formulation to control drug release till 24 hours. The entrapment efficacy of the formulated Nanoparticles was found to be in the range of 75.48%-91.22% respectively.

Structure and Glass Transition Temperature of Amorphous Dispersions of Model Pharmaceuticals with Nucleobases from Molecular Dynamics

Glass transition temperature (Tg) is an important material property, which predetermines the kinetic stability of amorphous solids. In the context of active pharmaceutical ingredients (API), there is motivation to maximize their Tg by forming amorphous mixtures with other chemicals, labeled excipients. Molecular dynamics simulations are a natural computational tool to investigate the relationships between structure, dynamics, and cohesion of amorphous materials with an all-atom resolution. This work presents a computational study, addressing primarily the predictions of the glass transition temperatures of four selected API (carbamazepine, racemic ibuprofen, indomethacin, and naproxen) with two nucleobases (adenine and cytosine). Since the classical non-polarizable simulations fail to reach the quantitative accuracy of the predicted Tg, analyses of internal dynamics, hydrogen bonding, and cohesive forces in bulk phases of pure API and their mixtures with the nucleobases are performed to interpret the predicted trends. This manuscript reveals the method for a systematic search of beneficial pairs of API and excipients (with maximum Tg when mixed). Monitoring of transport and cohesive properties of API–excipients systems via molecular simulation will enable the design of such API formulations more efficiently in the future.

Characterization and Prediction of the Non-Bonded Molecular Interactions between Racemic Ibuprofen and α-Lactose Monohydrate Crystals Produced from Melt Granulation and Slow Evaporation Crystallization

Granulation of racemic ibuprofen (±IBP) and α-lactose monohydrate (ALM) at a slightly lower (±IBP) melting point is an efficient method of binding the active pharmaceutical ingredients (API) and excipient in a binderless condition. However, the co-crystals may be formed from recrystallization of ±IBP on ALM. The objective of this study is to evaluate the tendency of co-crystal formation of granules (3:7 w/w ratio of ±IBP:ALM) by melt granulation process. Second, investigate the recovery of crystals from polyethylene glycol (PEG) 300 solutions containing ±IBP-ALM mixtures. Characterizations of the samples were performed using Fourier Transform Infrared (FTIR) spectroscopy, Differential Scanning Calorimetry (DSC) and Powder X-Ray Diffraction (PXRD) system of the ±IBP-ALM granules produced from melt crystallization and harvested crystals from PEG 300 solution which is produced using slow evaporation crystallization. Crystal analysis of solution containing ±IBP-ALM mixtures revealed that the crystals formed were not co-crystals. Molecular interactions assessment through binding prediction between ±IBP and ALM terminating surfaces was conducted using molecular modelling technique. The result showed that the favorable binding sites of ±IBP molecules were on the surfaces of (0-20), (1-10), (001) and (011) ALM crystals. Successful binding prediction by the attachment energy method has proven that the co-crystal formation between these molecules is theoretically possible.

Research Article. The Influence of Some Parameters on Chiral Separation of Ibuprofen by High-Performance Liquid Chromatography and Capillary Electrophoresis

Objective: The aim of the study was to compare the influence of mobile phase composition and temperature on chiral separation of racemic ibuprofen by capillary electrophoresis and high performance liquid chromatography with UV detection. Materials and methods: Racemic ibuprofen was analysed on a chiral OVM column with an HPLC system 1100 Agilent Technologies, under isocratic elution, by using potassium dihydrogen phosphate 20 mM and ethanol in mobile phase. The flow rate was set at 1 mL/min, UV detector at 220 nm and different column temperatures were tested. For electrophoresis separation an Agilent CE G1600AX Capillary Electrophoresis System system, with UV detection, was used. The electrophoresis analysis was performed at different pH values and temperatures, with phosphate buffer 25 mM and methyl-β-cyclodextrin as chiral selector. Results: The chromatograhic analysis reveals a high influence of mobile phase pH on ibuprofen enantiomers separation. An elution with a mixture of potassium dihydrogen phosphate 20 mM pH=3 and ethanol, at 25°C, allowed enantiomers separation with good resolution in less than 8 min. Conclusions: The proposed HPLC method proved suitable for the separation of ibuprofen enantiomers with a good resolution, but the capillary electrophoresis tested parameters did not allow chiral discrimination.

Thermodynamic Study of Racemic Ibuprofen Separation by Liquid Chromatography Using Cellulose-Based Stationary Phase

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID), also known for its significant antipyretic and analgesic properties. This chiral drug is commercialized in racemic form; however, only S-(+)-ibuprofen has clinical activities. In this paper the effect of temperature change (from 288.15 to 308.15 K) on the ibuprofen resolution was studied. A column (250×4.6 mm) packed with tris(3,5-dimethylphenylcarbamate) was used to obtain the thermodynamic parameters, such as enthalpy change (ΔH), entropy change (ΔS), variation enthalpy change (ΔΔH), variation entropy change (ΔΔS), and isoenantioselective temperature (Tiso). The mobile phase was a combination of hexane (99%), isopropyl alcohol (1%), and TFA (0.1%), as an additive. The conditions led to a selectivity of 1.20 and resolution of 4.55. The first peak, R-(−)-ibuprofen, presented an enthalpy change of 7.21 kJ/mol and entropy change of 42.88 kJ/K·mol; the last peak, S-(+)-ibuprofen, has an enthalpy change of 8.76 kJ/mol and 49.40 kJ/K·mol of entropy change.