Ibuprofen Crystals Research Articles

Mutual Effects of Hydrogen Bonding and Polymer Hydrophobicity on Ibuprofen Crystal Inhibition in Solid Dispersions with Poly(N-vinyl pyrrolidone) and Poly(2-oxazolines).

Poly(N-vinyl pyrrolidone) (PVP), poly(2-methyl-2-oxazoline) (PMOZ), poly(2-ethyl-2-oxazoline) (PEOZ), poly(2-n-propyl-2-oxazoline) (PnPOZ), and poly(2-isopropyl-2-oxazoline) (PiPOZ) were used to prepare solid dispersions with ibuprofen (IB), a model poorly-water soluble drug. Dispersions, prepared by solvent evaporation, were investigated using powder X-ray diffractometry, differential scanning calorimetry, and FTIR spectroscopy; hydrogen bonds formed between IB and all polymers in solid dispersions. PMOZ, the most hydrophilic polymer, showed the poorest ability to reduce or inhibit the crystallinity of IB. In contrast, the more hydrophobic polymers PVP, PEOZ, PnPOZ, and PiPOZ provided greater but similar abilities to reduce IB crystallinity, despite the differing polymer hydrophobicity and that PiPOZ is semi-crystalline. These results indicate that crystallinity disruption is predominantly due to hydrogen bonding between the drug molecules and the polymer. However, carrier properties affected drug dissolution, where PnPOZ exhibited lower critical solution temperature that inhibited the release of IB, whereas drug release from other systems was consistent with the degree of ibuprofen crystallinity within the dispersions.

Impact of Structural Binding Energies on Dissolution Rates for Single Faceted-Crystals

This study investigates the effect of solid-state intermolecular binding energies on the dissolution rates of single faceted-crystals. The nonsteroidal anti-inflammatory drug ibuprofen is employed in a 95% v/v ethanol:water solution as a model system for single-crystal dissolution experiments in a dissolution cell at undersaturation ranging from 1.36% to 8.67%. In vitro dissolution of the ibuprofen crystals is quantified by capturing images during the dissolution process at fixed time intervals using a camera mounted on an inverted optical microscope. The regression rate of crystal faces with time is measured by an image analysis. VisualHabit software is used for a prediction of the crystal morphology and to characterize the intermolecular binding energies in the solid-state structure of the ibuprofen crystals to predict relative, face-specific dissolution rates. The relative face-specific dissolution rates of ibuprofen crystal calculated based on binding energies suggest that the face (011) dissolves faster than face (002). The experimental results on face-specific dissolution rates of single ibuprofen crystals reveal that the dissolution rates of faces (011) and (002) change nonlinearly as a function of undersaturation. The binding energy model is critically evaluated for performance as confronted with the experimental measurements. The binding energy model suggests a pathway to understand dissolution at the microscopic level and to design a crystal morphology for regulating bioavailability optimally during dissolution processes.

Improved dissolution of ibuprofen after crystallization from polymeric solution: Correlation with crystal parameter

The objective of the present work was to investigate the effect of various hydrophilic polymers, such as hydroxypropylmethyl cellulose, methyl cellulose, carboxymethyl cellulose and poly vinyl alcohol, on the in vitro dissolution property of ibuprofen (IBU) crystallized from aqueous polymeric solutions. By using the solvent-change technique, IBU crystal products were produced in the presence of the selected polymers. The results showed that in the presence of polymers, the crystallization yield of IBU was higher than that of pure drug crystals (absence of polymer). SEM photographs revealed visible changes in the crystal morphology in the presence of polymers. The FTIR spectra of the crystallized IBU (polymer-treated) showed a shift of the acid- -dimer peak from 1718 to 1721 cm-1 but the absence of specific peaks for polymers. An XRD study further confirmed the absence of polymers in the crystallized IBU as no specific peaks were observed for the polymers. A higher percentage of cumulative drug release was reported for the polymeric-treated IBU crystals than that of plain IBU. Further in vivo studies are warranted to establish the in vitro?in vivo correlation for future technology transfer of the formulation.

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.

Adsorption of a poorly water-soluble drug onto porous calcium silicate by the sealed heating method

To improve the bioavailability of orally-administered drug, solubilization of poorly water-soluble drug is important. The solubility of a drug in its amorphous form is known to be higher than in its crystalline form. In this study, we attempted to adsorb a sublimable drug onto porous calcium silicate (Florite®, FLR) or non-porous calcium silicate (NPCS) by the sealed heating (SH) method and evaporated (EV) method. Ibuprofen (IBU) was used as the poorly water-soluble, sublimable drug. The physicochemical properties of samples were investigated using powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), and dissolution test. From the PXRD and DSC results, IBU crystals were adsorbed and amorphized by the SH and EV methods with FLR. From the results of FTIR, the shift to a higher frequency by the carbonyl stretching vibration band of IBU suggests an intermolecular interaction between IBU and FLR. In SH with FLR, improved solubilization was observed. IBU adsorbed onto FLR showed a greater dissolution rate than the IBU crystals or NPCS. Thus, the petal-like structure of FLR may be an effective method to adsorb IBU onto FLR using the SH method.

Correlation and prediction of small to large sized pharmaceuticals solubility, and crystallization in binary and ternary mixed solvents using the UNIQUAC-SAC model

The recently reported UNIversal QUAsiChemical Segment Activity coefficient (UNIQUAC-SAC) model [developed by Haghtalab and Yousefi Seyf Ind. Eng. Chem. Res. 2015, 54, 8611] provides a practical thermodynamic framework to be used in VLE, LLE, and SLE calculations. The UNIQUAC-SAC model has the advantage of being independent of area (q) and volume (r) structural parameters used in the combinatorial part. While the UNIFAC or UNIFAC-DMD could not apply to the 47% (44 of 94) of the studied molecules because of the undefined groups. Here, the numbers of solvents with identified segment numbers were extended from 82 to 130 with a slight refinement to the previous values. The model parameters obtained via a large consistent set of VLE (isobaric and isothermal), and LLE experimental data. Also, the model was tested with pharmaceutical solubility experimental data in pure (94 solutes with 6210 solubility data), binary, and ternary solvents. The model provides a robust correlation of pharmaceuticals solubility in a mono-solvent and robust prediction of pharmaceuticals solubility in mixed solvents. The UNIQUAC-SAC model was successfully evaluated in solvent screening in cooling crystallization of ibuprofen and valsartan in both pure and binary solvents mixture (combined cooling and anti-solvent crystallization). The model with 130 solvents as a robust database provides a useful and practical thermodynamic tool in the conceptual design of pharmaceutical processes. A MATLAB based graphical user interface (GUI), finally, was developed to be used in the conceptual segment numbers regression procedure.

Surrogate modeling for fast uncertainty quantification: Application to 2D population balance models

Surrogate modeling is a useful tool for enabling uncertainty quantification (UQ) tasks that require many expensive model evaluations, as it replaces expensive high-fidelity models with cheap-to-evaluate surrogates. This paper investigates sparse polynomial chaos and Kriging methods for surrogate modeling of first-principles models with probabilistic uncertainty in parameters and initial conditions. The surrogate modeling methods are demonstrated on a 2-dimensional population balance (2D-PB) model for batch cooling crystallization of ibuprofen with 20 uncertain parameters. Our analysis indicates that not only sparse polynomial chaos expansions are powerful for probabilistic UQ, but also the approximation accuracy of Kriging surrogate models can be significantly improved when polynomial chaos expansions are used to describe their trend. A basis-adaptive least-angle-regression strategy is shown to be particularly useful for inducing sparsity in polynomial chaos expansions, allowing for dealing with problems with a relatively large number of uncertain inputs. The utility of sparse polynomial chaos- and Kriging-based surrogate models is illustrated for various forward and inverse UQ problems, including global sensitivity analysis as well as Bayesian and maximum a posteriori parameter estimation of the 2D-PB model, where massive savings in computational cost (up to 30,000-fold) are observed.

Crystallization and Kinetic Studies of an Active Pharmaceutical Compound Using Ethyl Lactate As a Green Solvent

The thrust to adopt sustainable greener technologies in chemical and pharmaceutical process industries has been growing since last two decades due to the intense usage of volatile organic solvents from synthesis to purification stages. Hence, the objective of the present study is to analyze the feasibility of replacement of the organic solvent used in the purification of an active pharmaceutical ingredient (API) in a pharmaceutical context. From this perspective, the crystallization of an API-ibuprofen using ethyl lactate as an alternate green solvent is explored for the first time in the present study. Ethyl lactate belongs to the family of lactate esters, which is 100% biodegradable in nature. The feasibility of crystallization of ibuprofen is analyzed and a methodology is developed to crystallize the same. In addition, the kinetic parameters for the unseeded batch cooling crystallization of ibuprofen grown in 50% aqueous ethyl lactate have been estimated. A model of the crystallizer is constructed based on first-principles and a nonlinear optimization based methodology is used for extracting the kinetics. The results show that ibuprofen can be crystallized from aqueous ethyl lactate and the kinetic parameters are reported for the region where the system does not pass through two phase separation.

Liquid Metastable Precursors of Ibuprofen as Aqueous Nucleation Intermediates.

The nucleation mechanism of crystals of small organic molecules, postulated based on computer simulations, still lacks experimental evidence. In this study we designed an experimental approach to monitor the early stages of the crystallization of ibuprofen as a model system for small organic molecules. Ibuprofen undergoes liquid–liquid phase separation prior to nucleation. The binodal and spinodal limits of the corresponding liquid–liquid miscibility gap were analyzed and confirmed. An increase in viscosity sustains the kinetic stability of the dense liquid intermediate. Since the distances between ibuprofen molecules within the dense liquid phase are similar to those in the crystal forms, this dense liquid phase is identified as a precursor phase in the nucleation of ibuprofen, in which densification is followed by generation of structural order. This discovery may make it possible to enrich poorly soluble pharmaceuticals beyond classical solubility limitations in aqueous environments.

Model Building on Selectivity of Gas Antisolvent Fractionation Method Using the Solubility Parameter

Solubility parameters are widely used in the polymer industry and are often applied in the high pressure field as well as they give the possibility of combining the effects of all operational parameters on solubility in a single term. We demonstrate a statistical methodology to apply solubility parameters in constructing a model to describe antisolvent fractionation based chiral resolution, which is a complex process including a chemical equilibrium, precipitation and extraction as well. The solubility parameter used in this article, is the Hansen parameter. The evaluation of experimental results of resolution and crystallization of ibuprofen with (R)-phenylethylamine based on diastereomeric salt formation by gas antisolvent fractionation method was carried out. Two sets of experiments were performed, one with methanol as organic solvent in an undesigned experiment and one with ethanol in a designed experiment. The utilization of D-optimal design in order to decrease the necessary number of experiments and to overcome the problem of constrained design space was demonstrated. Linear models including dependence of pressure, temperature and the solubility parameter were appropriate to describe the selectivity of the GASF optical resolution method in both sets of experiments.

Stochastic back-off-based robust process design for continuous crystallization of ibuprofen

Robust model-based process design in continuous pharmaceutical manufacturing aims to implement quality by design principles under uncertainty. Notably, various studies have discussed the back-off concept to solve the underlying robust optimization problem; however, for the concept to have practical value, its efficiency and convergence must be improved. In this work, we introduce a novel, highly efficient stochastic back-off strategy. Instead of using statistical moments of limited validity, we incorporate the full statistical information of the constraints to solve the robust process design problem. To ensure manageable computational costs, we make use of polynomial chaos expansion for uncertainty quantification and propagation. The proposed concept is demonstrated with the design of a tubular crystallizer for ibuprofen crystallization. The results show that the novel stochastic back-off strategy is considerably faster compared with the standard back-off concept and provides more reliable quality by design results in general.

Combining Morphological Population Balances with Face-Specific Growth Kinetics Data to Model and Predict the Crystallization Processes for Ibuprofen

A route map for modeling pharmaceutical manufacturing processes utilizing morphological population balance (MPB) is presented in terms of understanding and controlling particle shape and size for optimizing the efficiency of both the manufacturing process and final properties of the formulated drugs. This is applied to batch cooling crystallization of the pharmaceutical compound ibuprofen from supersaturated ethanolic solutions in which the MPB is combined with the known crystal morphology and associated face-specific growth kinetics (Nguyen et al. CrystEngComm 2014, 16, 4568–4586) to predict the temporal evolution of the shape and size distributions of all crystals. The MPB simulations capture the temporal evolution of the size and shape of ibuprofen crystals and their distributions at each time instance during the crystallization processes. The volume equivalent spherical diameter and crystal size distribution converted from MPB simulation are validated against the experimental studies on the 1 L scale size (Rashid et al. Chem. Eng. Res. Des. 2012, 90, 158–161), confirming the promise of this approach as a powerful simulation, optimization, and control tool for the digital design of precision pharmaceutical processes and products with the desirable properties, with potential applications in crystallization design for personalized medicines.

Molecular-level insight into hot-melt loading and drug release from mesoporous silica carriers

Drug amorphisation by loading to inorganic mesoporous carriers represents an emerging area of improving the dissolution rate and bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). In this work, for the first time, a molecular-level insight into the process of API loading to mesoporous SiO2 (silica) carriers by the hot-melt impregnation method and its subsequent release during dissolution was obtained using ATR-FTIR spectroscopic imaging. A physical mixture of ibuprofen crystals and mesoporous silica particles was heated and the dynamics of melt loading into the silica pore structure was directly observed in situ by ATR-FTIR spectroscopic imaging. The loss of crystallinity, the redistribution of the API in the silica pore network and the subsequent stabilisation of the amorphous form upon cooling were proven. The API was involved in two different kinds of molecular-level interactions: API dimers in the amorphous bulk, and individual API molecules adsorbed on the silica surface. The melt-loaded silica carriers were comprehensively characterised by DSC, SEM and dissolution tests, which proved dissolution rate enhancement due to amorphisation of the API. Drug release form the hot-melt loaded mesoporous silica carriers was observed in real time and the conditions leading to local re-crystallisation of super-saturated solution of the API were identified.

Dynamic Plantwide Modeling, Uncertainty, and Sensitivity Analysis of a Pharmaceutical Upstream Synthesis: Ibuprofen Case Study

A dynamic plantwide model was developed for the synthesis of the active pharmaceutical ingredient (API) ibuprofen, following the Hoescht synthesis process. The kinetic parameters, reagents, products, and byproducts of the different reactions were adapted from literature, and the different process operations were integrated until the end process, crystallization, and isolation of the ibuprofen crystals. The dynamic model simulations were validated against available measurements from literature and then used as an enabling tool to analyze the robustness of design space. To this end, the sensitivity of the design space toward input disturbances and process uncertainties (from physical and model parameters) is studied using Monte Carlo simulations. The results quantify the uncertainty of the quality of product attributes, with particular focus on crystal size distribution and ibuprofen crystallization. The ranking of the most influential parameters on the chosen quality attributes is presented, with crystal growth and water concentration being the most influential ones. The total amount of saturated solvent, which propagates from upstream processes, has been shown to highly influence the total mass of crystal produced and the underspecified API as well. This dynamic plantwide modeling coupled with Monte Carlo simulations is valuable to improve the design and optimization of pharmaceutical processes at early stages, especially to bottleneck the design space against a range of uncertainties and disturbances.

Dissolution Kinetics of a BCS Class II Active Pharmaceutical Ingredient

This paper presents a laboratory study examining the dissolution kinetics of ibuprofen crystals in water containing a phosphate buffer (pH 7.20) at 37 °C, examining the influences of initial undersaturation ratio, agitation rate, crystal habit, and particle size. For each experiment, the concentration during the dissolution process was followed using UV spectroscopy, ATR-FTIR, and FBRM methods. The dissolution profiles were correlated using eight mathematical models, and the dissolution rate parameters were determined. The Weibull model, the Korsmeyer–Peppas model, and the first-order kinetics model gave better correlation results than the other models used in this paper for the dissolution of ibuprofen crystals. The particle size distribution slightly shifted to the right after dissolution, confirming that smaller particles with higher surface areas dissolved more rapidly. During dissolution, two distinct behaviors were obtained at different levels of undersaturation ratio; therefore, it is postulated that the mechanism of dissolution switches from being mass-transfer-limited at higher levels of undersaturation ratio to being limited by the rate of surface detachment at lower undersaturation ratio levels.

Improving Micromeritic Properties of Ibuprofen: An Agglomeration Approach

Ibuprofen is one of the common NSAIDs having poor water solubility, low dissolution, weak flow properties and reduced compressibility. These downsides of ibuprofen crystal upraise crucial challenges during development of a dosage form. The aim of this present work was to modify the physical form of ibuprofen by changing micromeritic properties. Seven different formulations of ibuprofen agglomerates such as F-1, F-2, F-3, F-4, F-5, F-6 and F-7 were prepared to convert the needle shaped ibuprofen crystals into agglomerates so that the desired micromeritic properties can be achieved. In this study, agglomerates of ibuprofen were prepared by Quasi emulsion solvent diffusion (QESD) method in association with two surfactants (sodium lauryl sulphateand Tween 80) at three different concentrations for each. The micromeritic properties of the prepared agglomerates were evaluated for bulk density, tapped density, Carr’s index, Hausner’s ratio, angle of repose along with the release behavior of agglomerates. From dissolution study, it was observed that the release of drug was directly proportional to the surfactant concentration. Here, it was also revealed that there was no interaction among ibuprofen and other excipients as evident from DSC and FTIR studies.Bangladesh Pharmaceutical Journal 20(1): 90-98, 2017

From Raw Data to Process: The Path to a Batch or a Continuous Crystallizer Design for Ibuprofen

To design a crystallizer for producing an active pharmaceutical ingredient (API) of the desired crystal size, it is necessary to know the solubility, the nucleation metastable zone widths (MSZW), the crystal growth rates, and the nucleation rates. These data are available for the popular anti-inflammatory drug ibuprofen crystallized from absolute ethanol and water–ethanol mixtures. Using these data, methods are outlined to design industrial crystallizers to recover ibuprofen crystals. From ethanol, as the solubility increases greatly with temperature, cooling crystallizers can be used industrially. Both seeded batch and continuous designs are considered.

Diastereomeric salt precipitation based resolution of ibuprofen by gas antisolvent method

We investigated the resolution and crystallization of ibuprofen with (R)-phenylethylamine based on diastereomeric salt formation using the supercritical gas antisolvent (GAS) method. Our goal was to study the effects of the operational parameters (pressure, temperature and the carbon dioxide–organic solvent ratio) during an antisolvent resolution. The diastereomeric purity of the crystalline diastereomer salt (70–80% in a single step) was not affected by either parameter in the range investigated. However, yields, and thus selectivity (a product of yield and diastereomeric purity) was strongly affected by pressure and the carbon dioxide–organic solvent ratio. Using methanol and ethanol, yield curves as a function of the molar carbon dioxide–organic solvent ratio are the same for both solvents. By selecting appropriate parameters, the crystal habit (average crystal size and crystal size distribution) can be influenced. Some crystals formed thin fibers with diameters in the micrometer range (1–3μm), but certain parameters yielded shorter and thicker bladed crystals. At the optimal settings (10MPa, 35°C, 12.3mol/mol carbon dioxide–methanol ratio) the resolvability (0.444) slightly exceeded previously reported values using supercritical carbon dioxide, with a significant reduction in operating time.

Transformation of eutectic emulsion to nanosuspension fabricating with solvent evaporation and ultrasonication technique.

Eutectic solvent can solubilize high amount of some therapeutic compounds. Volatile eutectic solvent is interesting to be used as solvent in the preparation of nanosuspension with emulsion solvent evaporation technique. The mechanism of transformation from the eutectic emulsion to nanosuspension was investigated in this study. The 30% w/w ibuprofen eutectic solution was used as the internal phase, and the external phase is composed of Tween 80 as emulsifier. Ibuprofen nanosuspension was prepared by eutectic emulsion solvent evaporating method followed with ultrasonication. During evaporation process, the ibuprofen concentration in emulsion droplets was increased leading to a drug supersaturation but did not immediately recrystallize because of low glass transition temperature (Tg) of ibuprofen. The contact angle of the internal phase on ibuprofen was apparently lower than that of the external phase at all times of evaporation, indicating that the ibuprofen crystals were preferentially wetted by the internal phase than the external phase. From calculated dewetting value ibuprofen crystallization occurred in the droplet. Crystallization of the drug was initiated with external mechanical force, and the particle size of the drug was larger due to Ostwald ripening. Cavitation force from ultrasonication minimized the ibuprofen crystals to the nanoscale. Particle size and zeta potential of formulated ibuprofen nanosuspension were 330.87±51.49 nm and −31.1±1.6 mV, respectively, and exhibited a fast dissolution. Therefore, the combination of eutectic emulsion solvent evaporation method with ultrasonication was favorable for fabricating an ibuprofen nanosuspension, and the transformation mechanism was attained successfully.

Ultrasound-assisted preparation of novel ibuprofen-loaded excipient with improved compression and dissolution properties

Context: Most of the active pharmaceutical ingredients (APIs) suffer from a drawback of poor aqueous solubility. In addition to the same, some APIs show poor tabletting behavior creating problems in formulation development. Crystal engineering can be an efficient tool in rectification of such problems associated with the APIs. Thus present work deals with crystallization of ibuprofen (a model drug) onto the surface of dicalcium phosphate (DCP) particles using different techniques.Objective: The objective of the present work was to prepare ibuprofen-loaded DCP particles and further to analyze them for compressibility and dissolution behavior.Materials and methods: Various crystallization techniques such as solvent evaporation (SE), melt crystallization (MC), melt sonocrystallization (MSC), antisolvent crystallization (AC), and antisolvent sonocrystallization (ASC) were screened for the preparation of ibuprofen-loaded DCP. Products obtained from different techniques were analyzed for physicochemical, micromeritic and compression properties.Results and discussion: ASC technique was found to be suitable for preparing directly compressible ibuprofen-loaded DCP particles. The change in the crystal habit (needle to plate shape) of ibuprofen and its crystallization in miniscular form onto the surface of DCP particles showed significant improvement in the dissolution rate and compression properties of ibuprofen due to an increase in specific surface area when compared with ibuprofen crystallized by other techniques. Additionally, the tablets prepared from ASC powder did not require binder since ibuprofen acted as melt binder during compression.Conclusion: Directly compressible ibuprofen-loaded DCP particles can serve as an alternative for conventional ibuprofen tablets prepared by wet granulation technique.