In vitro assessment of commercial sunscreens available in Latin America.

In Latin America, people have largely abandoned the practice of wearing hats and traditional clothing that provided skin protection. Sunscreen application has therefore become essential to protect against the increased sun exposure. The physician-prescribed medical-grade sunscreens provide sufficient sun protection but the requirement for regular use puts a financial burden on the patient that is often not sustainable. An appropriate sunscreen should provide a high and broad ultraviolet (UV) protection against UVB and UVA. Several over-the-counter (OTC) sunscreens have been developed for sale at affordable prices and are available for purchase in convenient locations, such as local grocery stores. The aim of this study was to assess the in vitro UV protection of 34 popular OTC sunscreens found in the Latin American market. UV absorbance/transmittance was quantified by diffusion transmission spectroscopy using coarse silica plaques. Photostability was tested by irradiating them with simulated solar light and calculating the sun protection factor (SPF), critical length of absorption (C lambda ), UVA/UVB ratio, and the spectral uniformity index (SUI). The results indicated that the in vitro SPFs were significantly lower than the value declared on the labels, particularly for those claiming high SPF values; however, the majority of these sunscreens offered high levels of UV protection. Considering the advantages of low cost and ample accessibility, we concluded that this sample of OTC sunscreens can be beneficial to the general public by providing some level of skin protection from solar radiation, and may be promoted to improve compliance with recommended photoprotection behavior.

In vitro assessment of commercial sunscreens available in Latin America / Valoración in vitro de protectores solares comerciales existentes en Latinoamérica

In Latin America, people have largely abandoned the practice of wearing hats and traditional clothing that provided skin protection. Sunscreen application has therefore become essential to protect against the increased sun exposure. The physician-prescribed medical-grade sunscreens provide sufficient sun protection but the requirement for regular use puts a financial burden on the patient that is often not sustainable. An appropriate sunscreen should provide a high and broad ultraviolet (UV) protection against UVB and UVA. Several over-the-counter (OTC) sunscreens have been developed for sale at affordable prices and are available for purchase in convenient locations, such as local grocery stores. The aim of this study was to assess the in vitro UV protection of 34 popular OTC sunscreens found in the Latin American market. UV absorbance/transmittance was quantified by diffusion transmission spectroscopy using coarse silica plaques. Photostability was tested by irradiating them with simulated solar light and calculating the sun protection factor (SPF), critical length of absorption (C λ ), UVA/UVB ratio, and the spectral uniformity index (SUI). The results indicated that the in vitro SPFs were significantly lower than the value declared on the labels, particularly for those claiming high SPF values; however, the majority of these sunscreens offered high levels of UV protection. Considering the advantages of low cost and ample accessibility, we concluded that this sample of OTC sunscreens can be beneficial to the general public by providing some level of skin protection from solar radiation, and may be promoted to improve compliance with recommended photoprotection behavior.

En Latinoamérica, la población ha abandonado la costumbre de usar sombrero y ropa tradicional para protegerse del sol. En consecuencia, es básico el uso de protectores solares si se realizan actividades bajo sol. Los protectores solares que se usan en la práctica médica son adecuados, pero su uso frecuente condiciona una carga económica que muchos pacientes no pueden solventar debido a sus costos considerables. Un protector apropiado contiene una amplia y elevada protección ultravioleta (UV) A y B. En las tiendas de conveniencia, existen numerosos protectores solares a precios más accesibles. El objetivo del estudio fue determinar la protección UV in vitro de 34 protectores solares con amplia presencia comercial (de venta sin prescripción médica) en el mercado latinoamericano. La absorbancia/transmitancia de la radiación UV se cuantificó mediante espectroscopía de transmisión difusa. Placas de sílice esmerilado fueron recubiertas con el producto y expuestas a radiación solar simulada para conocer su fotoestabilidad. Se calcularon índices como el factor de protección solar (SPF), longitud crítica de absorción (C λ), relación UVA/UVB y el índice de uniformidad espectral (SUI). Se encontró que el SPF in vitro fue inferior al establecido en las etiquetas, especialmente en aquellos con valores altos. No obstante, la mayoría de los protectores incluidos ofrecen niveles de protección UV elevados. Considerando su amplia accesibilidad y menor costo, concluimos que esta muestra comercial de protectores solares podría utilizarse en el entorno clínico para favorecer su apego junto a las otras medidas de fotoprotección sugeridas.

Experimental and theoretical insights into photochemical transformation kinetics and mechanisms of aqueous propylparaben and risk assessment of its degradation products.

The kinetics and mechanisms of ultraviolet photochemical transformation of propylparaben (PPB) were studied. Specific kinetics scavenging experiments coupled with quantum yield determinations were used to distinguish the roles of various reactive species induced by self-sensitized and direct photolysis reactions, and the excited triplet state of PPB ((3) PPB*) was identified as the most important species to initiate the photochemical degradation of PPB in aquatic environments. The computational results of time-resolved absorption spectra proved that (3) PPB* is a highly reactive electron acceptor, and a head-to-tail hydrogen transfer mechanism probably occurs through electron coupled with proton transfer. Physical quenching by, or chemical reaction of (3) PPB* with, O2 was confirmed as a key step affecting the initial PPB transformation pathways and degradation mechanisms. The transformation products were identified and the toxicity evolutions of PPB solutions during photochemical degradation under aerobic and anaerobic conditions were compared. The results indicate that anaerobic conditions are more likely than aerobic conditions to lead to the elimination and detoxification of PPB but less likely to lead to PPB mineralization.

Synthesis of silver nanoparticles using a biosurfactant produced in low-cost medium as stabilizing agent

Background A biosurfactant produced by Pseudomonas aeruginosa cultivated in a low-cost medium formulated with 2.5% vegetable oil refinery residue and 2.5% corn steep liquor and distilled water was employed to stabilize silver nanoparticles in the liquid phase. The particles were initially synthesized using NaBH4 as reducing agent in biosurfactant reverse micelles and were extracted from the micellar solution to disperse in heptane. Results A silver particle size in the range of 1.13 nm was observed. The UV-vis absorption spectra proposed that silver nanoparticles could be formed in the reverse micelles and relatively stabilized for at least 3 months without passivator addition. The Transmission Electron Microscope (TEM) shows that the silver nanoparticles are of spherical form and relatively uniform. Conclusions This process provided a simpler route for nanoparticle synthesis compared to existing systems using whole organisms or partially purified biological extracts, showing that the low-cost biosurfactant can be used for nanoparticle synthesis as a non-toxic and biodegradable stabilizing agent.

Forward solvers for photon migration in the presence of highly and totally absorbing objects embedded inside diffusive media.

In this paper, after a critical review of the literature, we present two forward solvers and a new methodology for description of photon migration in the presence of totally absorbing inclusions embedded in diffusive media in both time and CW domains. The first forward solver is a heuristic approach based on a higher order perturbation theory applied to the diffusion equation (DE) [denoted eighth-order perturbation theory (EOPT)]. The second forward solver [denoted eighth-order perturbation theory with the equivalence relation (EOPTER) ] is obtained by combining the EOPT solver with the adoption of the equivalence relation (ER) [J. Biomed. Opt.18, 066014 (2013)]. These forward solvers can possibly overcome some evident limitations of previous approaches like the theory behind the so-called banana-shape regions or exact analytical solutions of the DE in the presence of highly or totally absorbing inclusions. We also propose the ER to reformulate the problem of a totally absorbing inclusion in terms of another inclusion having a finite absorption contrast and a re-scaled volume. For instance, we have shown how this approach can indeed be used to simulate black inclusions with the Born approximation. By means of comparisons with the results of Monte Carlo simulations, we have shown that the EOPTER solver can model totally absorbing inclusions with an error smaller than about 10%, whereas the EOPT solver shows an error smaller than about 20%, showing a performance largely better than that observed with solvers proposed previously.

A Monte Carlo study of fluorescence generation probability in a two-layered tissue model.

It was recently reported that the time-resolved measurement of diffuse reflectance and/or fluorescence during injection of an optical contrast agent may constitute a basis for a technique to assess cerebral perfusion. In this paper, we present results of Monte Carlo simulations of the propagation of excitation photons and tracking of fluorescence photons in a two-layered tissue model mimicking intra- and extracerebral tissue compartments. Spatial 3D distributions of the probability that the photons were converted from excitation to emission wavelength in a defined voxel of the medium (generation probability) during their travel between source and detector were obtained for different optical properties in intra- and extracerebral tissue compartments. It was noted that the spatial distribution of the generation probability depends on the distribution of the fluorophore in the medium and is influenced by the absorption of the medium and of the fluorophore at excitation and emission wavelengths. Simulations were also carried out for realistic time courses of the dye concentration in both layers. The results of the study show that the knowledge of the absorption properties of the medium at excitation and emission wavelengths is essential for the interpretation of the time-resolved fluorescence signals measured on the surface of the head.

Comparative analysis of discrete and continuous absorption weighting estimators used in Monte Carlo simulations of radiative transport in turbid media.

We examine the relative error of Monte Carlo simulations of radiative transport that employ two commonly used estimators that account for absorption differently, either discretely, at interaction points, or continuously, between interaction points. We provide a rigorous derivation of these discrete and continuous absorption weighting estimators within a stochastic model that we show to be equivalent to an analytic model, based on the radiative transport equation (RTE). We establish that both absorption weighting estimators are unbiased and, therefore, converge to the solution of the RTE. An analysis of spatially resolved reflectance predictions provided by these two estimators reveals no advantage to either in cases of highly scattering and highly anisotropic media. However, for moderate to highly absorbing media or isotropically scattering media, the discrete estimator provides smaller errors at proximal source locations while the continuous estimator provides smaller errors at distal locations. The origin of these differing variance characteristics can be understood through examination of the distribution of exiting photon weights.

Closed-form solution of the steady-state photon diffusion equation in the presence of absorbing inclusions.

We have developed a theoretical model for photon migration through scattering media in the presence of an absorbing inhomogeneity. A closed-form solution for the average diffuse intensity has been obtained through an iterative approximation scheme of the steady-state diffusion equation. The model describes absorbing defects in a wide range of values. Comparisons with the results of Monte Carlo simulations show that the error of the model is lower than 3% for size inclusion lower than 4 mm and absorption contrast up to the threshold value of the "black defect." The proposed model provides a tractable mathematical basis for diffuse optical and photoacoustic tomographic reconstruction techniques.

Comparison of a layered slab and an atlas head model for Monte Carlo fitting of time-domain near-infrared spectroscopy data of the adult head.

Near-infrared spectroscopy (NIRS) estimations of the adult brain baseline optical properties based on a homogeneous model of the head are known to introduce significant contamination from extracerebral layers. More complex models have been proposed and occasionally applied to in vivo data, but their performances have never been characterized on realistic head structures. Here we implement a flexible fitting routine of time-domain NIRS data using graphics processing unit based Monte Carlo simulations. We compare the results for two different geometries: a two-layer slab with variable thickness of the first layer and a template atlas head registered to the subject's head surface. We characterize the performance of the Monte Carlo approaches for fitting the optical properties from simulated time-resolved data of the adult head. We show that both geometries provide better results than the commonly used homogeneous model, and we quantify the improvement in terms of accuracy, linearity, and cross-talk from extracerebral layers.

Radiative transfer equation for predicting light propagation in biological media: comparison of a modified finite volume method, the Monte Carlo technique, and an exact analytical solution.

We examine the accuracy of a modified finite volume method compared to analytical and Monte Carlo solutions for solving the radiative transfer equation. The model is used for predicting light propagation within a two-dimensional absorbing and highly forward-scattering medium such as biological tissue subjected to a collimated light beam. Numerical simulations for the spatially resolved reflectance and transmittance are presented considering refractive index mismatch with Fresnel reflection at the interface, homogeneous and two-layered media. Time-dependent as well as steady-state cases are considered. In the steady state, it is found that the modified finite volume method is in good agreement with the other two methods. The relative differences between the solutions are found to decrease with spatial mesh refinement applied for the modified finite volume method obtaining <2.4%. In the time domain, the fourth-order Runge-Kutta method is used for the time semi-discretization of the radiative transfer equation. An agreement among the modified finite volume method, Runge-Kutta method, and Monte Carlo solutions are shown, but with relative differences higher than in the steady state.

A physiologically based pharmacokinetic model for the prediction of the depletion of methyl-3-quinoxaline-2-carboxylic acid, the marker residue of olaquindox, in the edible tissues of pigs.

To estimate the consumer exposure to olaquindox (OLA) residues in porcine edible tissues, a physiologically based pharmacokinetic (PBPK) model for methyl-3-quinoxaline-2-carboxylic acid (MQCA), the marker residue of OLA, was developed in pigs based on the assumptions of the flow-limited distribution, hepatic metabolism, and renal excretion. The model included separate compartments corresponding to blood, muscle, liver, kidney, adipose, and an extra compartment representing the remaining carcass. Physiological parameters were determined from literatures. Plasma protein binding, partition coefficients, and renal clearance for MQCA were determined in in vitro and in vivo studies. The metabolic conversion of OLA to MQCA was assumed as a simple, one-step process, and an apparent first-order rate constant (k) was employed to describe this metabolic process. The PBPK model was optimized and validated with plasma and tissue data from literatures and our study. Sensitivity analysis and Monte Carlo simulation were also implemented to estimate the influence of model parameters on the goodness of fit. When compared with the observed data, the PBPK model underestimated the MQCA level in all compartments at the early time points, whereas gave excellent predictions of MQCA concentration in porcine edible tissues at later time points. The correlation coefficients between the predicted and observed values were over 0.88. The consistency between the model predictions and the real residues of OLA in pigs proved the good applicability of our model in food safety risk assessment.

In vitro assessment of 3-T MRI issues for a bioabsorbable, coronary artery scaffold with metallic markers.

OBJECTIVE: Coronary artery stents are made from metallic mesh and, therefore, to ensure patient safety, these implants must be evaluated to determine risks associated with MRI. Recently, bioabsorbable scaffolds, which have metallic markers, have been developed for use in the coronary arteries. Because of the metallic materials, these implants may present issues for patients undergoing MRI. Therefore, the objective of this investigation was to assess MRI issues (i.e., magnetic field interactions, MRI-related heating, and artifacts at 3 T) for a new bioabsorbable, coronary artery scaffold with metallic markers. METHODS: A bioabsorbable, coronary artery scaffold (Mirage Microfiber Scaffold) underwent assessments for magnetic field interactions, MRI-related heating, and artifacts at 3-Tesla using standard techniques. MRI-related heating was evaluated with the scaffold placed in a gelled-saline-filled phantom and MRI was performed at an MR system reported, whole body averaged SAR of 2.9W/kg for 15 minutes. Artifacts were characterized using T1-weighted spin echo and gradient echo, pulse sequences. RESULTS: There were no magnetic field interactions. The highest temperature rise was 1.6°C (highest background temperature rise, 1.6°C). Artifacts were relatively small in relation to the size and shape of this coronary artery scaffold. Notably, the lumen of the scaffold could be visualized on the GRE pulse sequence. CONCLUSION: The results demonstrated that the coronary artery scaffold is acceptable (or "MR conditional," using current MRI labeling terminology) for a patient undergoing an MRI procedure at 3 T or less. To our knowledge, this is the first bioabsorbable, coronary artery scaffold that has been evaluated for MRI issues.

Intramolecular and lateral intermolecular hole transfer at the sensitized TiO2 interface.

Characterization of the redox properties of TiO2 interfaces sensitized to visible light by a series of cyclometalated ruthenium polypyridyl compounds containing both a terpyridyl ligand with three carboxylic acid/carboxylate or methyl ester groups for surface binding and a tridentate cyclometalated ligand with a conjugated triarylamine (NAr3) donor group is described. Spectroelectrochemical studies revealed non-Nernstian behavior with nonideality factors of 1.37 ± 0.08 for the Ru(III/II) couple and 1.15 ± 0.09 for the NAr3(•+/0) couple. Pulsed light excitation of the sensitized thin films resulted in rapid excited-state injection (k(inj) > 10(8) s(-1)) and in some cases hole transfer to NAr3 [TiO2(e(-))/Ru(III)-NAr3 → TiO2(e(-))/Ru(II)-NAr3(•+)]. The rate constants for charge recombination [TiO2(e(-))/Ru(III)-NAr3 → TiO2/Ru(II)-NAr3 or TiO2(e(-))/Ru(II)-NAr3(•+) → TiO2/Ru(II)-NAr3] were insensitive to the identity of the cyclometalated compound, while the open-circuit photovoltage was significantly larger for the compound with the highest quantum yield for hole transfer, behavior attributed to a larger dipole moment change (Δµ = 7.7 D). Visible-light excitation under conditions where the Ru(III) centers were oxidized resulted in injection into TiO2 [TiO2/Ru(III)-NAr3 + hν → TiO2(e(-))/Ru(III)-NAr3(•+)] followed by rapid back interfacial electron transfer to another oxidized compound that had not undergone excited-state injection [TiO2(e(-))/Ru(III)-NAr3 → TiO2/Ru(II)-NAr3]. The net effect was the photogeneration of equal numbers of fully reduced and fully oxidized compounds. Lateral intermolecular hole hopping (TiO2/Ru(II)-NAr3 + TiO2/Ru(III)-NAr3(•+) → 2TiO2/Ru(III)-NAr3) was observed spectroscopically and was modeled by Monte Carlo simulations that revealed an effective hole hopping rate of (130 ns)(-1).

Qualitative and quantitative assessment of water sorption in natural fibres using ATR-FTIR spectroscopy.

In the field of composite materials, natural fibres appear to be a viable replacement for glass fibres. However, in humid conditions, strong hydrophilic behaviour of such materials can lead to their structural modification. Then, understanding moisture sorption mechanisms in these materials is an important issue for their efficient use. In this work, the water sorption on three natural fibres (flax, hemp and sisal) was studied using Fourier transformed infrared spectroscopy. The spectral information allowed both qualitative and quantitative analyses of the moisture absorption mechanisms. The main chemical functions involved in the water sorption phenomenon were identified. The absolute water content of the fibres was also determined by using a partial least square regression (PLS-R) approach. Moreover, typical sorption isotherm curves described by Park model were fitted as well as water diffusion kinetics. These last applications confirmed the validity of the FTIR spectra based predictive models.

A BrachyPhantom for verification of dose calculation of HDR brachytherapy planning system.

PURPOSE: To develop a calibration phantom for (192)Ir high dose rate (HDR) brachytherapy units that renders possible the direct measurement of absorbed dose to water and verification of treatment planning system. METHODS: A phantom, herein designated BrachyPhantom, consists of a Solid Water™ 8-cm high cylinder with a diameter of 14 cm cavity in its axis that allows the positioning of an A1SL ionization chamber with its reference measuring point at the midheight of the cylinder's axis. Inside the BrachyPhantom, at a 3-cm radial distance from the chamber's reference measuring point, there is a circular channel connected to a cylindrical-guide cavity that allows the insertion of a 6-French flexible plastic catheter from the BrachyPhantom surface. The PENELOPE Monte Carlo code was used to calculate a factor, P(sw)(lw), to correct the reading of the ionization chamber to a full scatter condition in liquid water. The verification of dose calculation of a HDR brachytherapy treatment planning system was performed by inserting a catheter with a dummy source in the phantom channel and scanning it with a CT. The CT scan was then transferred to the HDR computer program in which a multiple treatment plan was programmed to deliver a total dose of 150 cGy to the ionization chamber. The instrument reading was then converted to absorbed dose to water using the N(gas) formalism and the P(sw)(lw) factor. Likewise, the absorbed dose to water was calculated using the source strength, Sk, values provided by 15 institutions visited in this work. RESULTS: A value of 1.020 (0.09%, k = 2) was found for P(sw)(lw). The expanded uncertainty in the absorbed dose assessed with the BrachyPhantom was found to be 2.12% (k = 1). To an associated Sk of 27.8 cGy m(2) h(-1), the total irradiation time to deliver 150 cGy to the ionization chamber point of reference was 161.0 s. The deviation between the absorbed doses to water assessed with the BrachyPhantom and those calculated by the treatment plans and using the Sk values did not exceed ± 3% and ± 1.6%, respectively. CONCLUSIONS: The BrachyPhantom may be conveniently used for quality assurance and/or verification of HDR planning system with a priori threshold level to spot problems of 2% and ± 3%, respectively, and in the long run save time for the medical physicist.

Experimental and analytical comparative study of optical coefficient of fresh and frozen rat tissues.

Optical properties of fresh and frozen tissues of rat heart, kidney, brain, liver, and muscle were measured in the 450- to 700-nm range. The total reflectance and transmittance were measured using a well-calibrated integral sphere set-up. Absorption coefficient µa and reduced scattering coefficient µ's were derived from the experimental measurements using the inverse adding doubling technique. The influence of cryogenic processing on optical properties was studied. Interindividual and intraindividual variations were assessed. These new data aim at filling the lack of validated optical properties in the visible range especially in the blue-green region of particular interest for fluorescence and optogenetics preclinical studies. Furthermore, we provide a unique comparison of the optical properties of different organs obtained using the same measurement set-up for fresh and frozen tissues as well as an estimate of the intraindividual and interindividual variability.

Fiber-optic probe design and optical property recovery algorithm for optical biopsy of brain tissue.

Optical biopsy techniques offer a minimally invasive, real-time alternative to traditional biopsy and pathology during tumor resection surgery. Diffuse reflectance spectroscopy (DRS) is a commonly used technique in optical biopsy. Optical property recovery from spatially resolved DRS data allows quantification of the scattering and absorption properties of tissue. Monte Carlo simulation methods were used to evaluate a unique fiber-optic probe design for a DRS instrument to be used specifically for optical biopsy of the brain. The probe diameter was kept to a minimum to allow usage in small surgical cavities at least 1 cm in diameter. Simulations showed that the close proximity of fibers to the edge of the probe resulted in boundary effects due to reflection of photons from the surrounding air-tissue interface. A new algorithm for rapid optical property recovery was developed that accounts for this reflection and therefore overcomes these effects. The parameters of the algorithm were adjusted for use over the wide range of optical properties encountered in brain tissue, and its precision was evaluated by subjecting it to random noise. This algorithm can be adapted to work with any probe geometry to allow optical property recovery in small surgical cavities.

Monte Carlo simulation of light transport in tissue for optimizing light delivery in photoacoustic imaging of the sentinel lymph node.

Noninvasive or minimally invasive identification of sentinel lymph node (SLN) is essential to reduce the surgical effects of SLN biopsy. Photoacoustic (PA) imaging of SLN in animal models has shown its promise for clinical use in the future. Here, we present a Monte Carlo simulation for light transport in the SLN for various light delivery configurations with a clinical ultrasound probe. Our simulation assumes a realistic tissue layer model and also can handle the transmission/reflectance at SLN-tissue boundary due to the mismatch of refractive index. Various light incidence angles show that for deeply situated SLNs the maximum absorption of light in the SLN is for normal incidence. We also show that if a part of the diffused reflected photons is reflected back into the skin using a reflector, the absorption of light in the SLN can be increased significantly to enhance the PA signal.

Monte Carlo simulation of near-infrared light propagation through homogeneous mixed media.

ABSTRACT. Noninvasive blood analysis devices that can measure levels of small constituents of blood are of interest in the medical community. An important step in creating these devices is to understand the interaction of photons with human tissue in increasingly greater physiological detail. Models based on layered biological materials give excellent results for many applications but may not be as accurate as needed when those materials are finely intertwined to the point of resembling a homogeneous mixture. To explore the ramifications of treating materials as layers versus a mixture, we have modeled, using a Monte Carlo technique, the interaction of photons through epidermis, blood, and water arranged both in layers and in a homogeneous blend. We confirm the expected linear relation between photon attenuation and material volumetric percentage in two-layer models. However, when the materials are homogeneously mixed together and volumetric percentage is replaced with interaction volume percentage, this relationship becomes nonlinear. These nonlinearities become significant when the values of the interaction coefficient, µt, differ by an order of magnitude or more.

Assessing the risk of pH-dependent absorption for new molecular entities: a novel in vitro dissolution test, physicochemical analysis, and risk assessment strategy.

Weak base therapeutic agents can show reduced absorption or large pharmacokinetic variability when coadministered with pH-modifying agents, or in achlorhydria disease states, due to reduced dissolution rate and/or solubility at high gastric pH. This is often referred to as pH-effect. The goal of this study was to understand why some drugs exhibit a stronger pH-effect than others. To study this, an API-sparing, two-stage, in vitro microdissolution test was developed to generate drug dissolution, supersaturation, and precipitation kinetic data under conditions that mimic the dynamic pH changes in the gastrointestinal tract. In vitro dissolution was assessed for a chemically diverse set of compounds under high pH and low pH, analogous to elevated and normal gastric pH conditions observed in pH-modifier cotreated and untreated subjects, respectively. Represented as a ratio between the conditions, the in vitro pH-effect correlated linearly with clinical pH-effect based on the Cmax ratio and in a non-linear relationship based on AUC ratio. Additionally, several in silico approaches that use the in vitro dissolution data were found to be reasonably predictive of the clinical pH-effect. To explore the hypothesis that physicochemical properties are predictors of clinical pH-effect, statistical correlation analyses were conducted using linear sequential feature selection and partial least-squares regression. Physicochemical parameters did not show statistically significant linear correlations to clinical pH-effect for this data set, which highlights the complexity and poorly understood nature of the interplay between parameters. Finally, a strategy is proposed for implementation early in clinical development, to systematically assess the risk of clinical pH-effect for new molecular entities that integrates physicochemical analysis and in vitro, in vivo and in silico methods.