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We propose an in vitro permeability assay by using a modified lipid membrane to predict the in vivo intestinal passive permeability of drugs. Two conditions were tested, one with a gradient pH (pH 5.5-donor/pH 7.4-receptor) and the other with an iso-pH 7.4. The predictability of the method was established by correlating the obtained apparent intestinal permeability coefficients (Papp) and the oral dose fraction absorbed in humans (fa) of 16 drugs with different absorption properties. The Papp values correlated well with the absorption rates under the two conditions and the method showed high predictability and good reproducibility. On the other hand, with this method, we successfully predicted the transport characteristics of oral sulfadiazine (SDZ). Also, the tradeoff between the increase in the solubility of SDZ by its complex formation with cyclodextrins and/or aminoacids and its oral permeability was assessed. Results suggest that SDZ is transported through the gastrointestinal epithelium by passive diffusion in a pH-dependent manner. These results support the classification of SDZ as a high/low borderline permeability compound and are in agreement with the Biopharmaceutics Classification Systems (BCS). This conclusion is consistent with the in vivo pharmacokinetic properties of SDZ. Fil: Delrivo, Alicia. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina Fil: Aloisio, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina Fil: Longhi, Marcela Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina Fil: Granero, Gladys Ester. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina

Introduction: Cyclodextrins (CD), are known to form inclusion complexes with a variety of guest molecules both in solution and in the solid state. This can lead to the alteration of properties of guest molecules. Unfortunately, the complexation efficiency of CD is rather low, and can be enhanced by formation of ternary complexes using aminoacids (AA). Sulfadiazine (SDZ) is an antibiotic with extremely low water solubility which limits its therapeutic applications and bioavailability. Objetives: The aim of this work was to increase the aqueous solubility of SDZ by preparing ternary complexes of this drug with β-cyclodextrin (βCD) and an AA as a third auxiliary substance. Materials y Methods: Complex formation was studied by phase solubility analysis (PSA), nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), thermogravimetric analysis (TG) and scanning electron microscopy (SEM). Results: The apparent stability constants (K C) of the multicomponent complexes were calculated from the solubility diagrams. By the analysis of the NMR spectra, it could be said that the shifts of some protons evidenced the important role of the AA in the formation of multicomponent complexes. Among the AA, Arginine (ARG) proved to have better solubilizing properties for SDZ, reaching an improvement up to 70 times. The use of DSC, TG and SEM suggested the formation of new solid phases between SDZ:βCD:AA. Conclusions: As a result of this research, it was determined that ternary products were more effective in improving drug solubility than the corresponding SDZ:βCD binary system. Introducción: Las ciclodextrinas (CD), son capaces de formar complejos de inclusión con una variedad de moléculas huésped, tanto en solución y en estado sólido, pudiendo producir la modificación de las propiedades de las moléculas huésped. Desafortunadamente, la eficiencia de la formación de complejos con CD es baja, lo cual se puede mejorar mediante la formación de complejos ternarios utilizando aminoácidos (AA). Sulfadiazina (SDZ) es un antibiótico con muy baja solubilidad en agua que limita su biodisponibilidad y sus aplicaciones terapéuticas. Objetivos: El objetivo de este trabajo fue aumentar la solubilidad acuosa de SDZ mediante la preparación de complejos ternarios con β-ciclodextrina (βCD) y un AA como una tercera sustancia. Materiales y Métodos: La formación de complejos se estudió por análisis de solubilidad de fases (PSA), resonancia magnética nuclear (RMN), calorimetría diferencial de barrido (DSC), análisis termogravimétrico (TG) y microscopía electrónica de barrido (SEM). Resultados: Las constantes de estabilidad aparente (K C) de los complejos multi-componentes se calcularon a partir de los diagramas de solubilidad. Por el análisis de los espectros de RMN se constató, por los corrimientos de algunos protones, el papel importante de los AA en la formación de complejos ternarios. Entre los AA, arginina (ARG) demostró tener mejores propiedades de solubilización para SDZ, alcanzando una mejora de hasta 70 veces. El uso de DSC, TG y SEM sugirió la formación de nuevas fases sólidas entre SDZ:βCD:AA. Conclusiones: Como resultado de esta investigación, se determinó que los productos ternarios fueron más eficaces en la mejora de la solubilidad del fármaco que el sistema binario SDZ: βCD.

The authors thank the Fondo para la Investigación Científica y Tecnológica (FONCYT) Préstamo BID PICT 1376, the Secretaría de Ciencia y Técnica de la Universidad Nacional de Córdoba (SECyT), and the Consejo Nacional de Investigaciones Científicas y Tecnológicas de la Nación (CONICET) for financial support. We also thank Ferromet S.A. (agent of Roquette in Argentina) for its donation of β-cyclodextrin. We are grateful to Dr. Gloria Bonetto for NMR measurements and for her helpful discussion of the 1H NMR spectra., Introduction: Cyclodextrins (CD), are known to form inclusion complexes with a variety of guest molecules both in solution and in the solid state. This can lead to the alteration of properties of guest molecules. Unfortunately, the complexation efficiency of CD is rather low, and can be enhanced by formation of ternary complexes using aminoacids (AA). Sulfadiazine (SDZ) is an antibiotic with extremely low water solubility which limits its therapeutic applications and bioavailability. Objetives: The aim of this work was to increase the aqueous solubility of SDZ by preparing ternary complexes of this drug with β-cyclodextrin (βCD) and an AA as a third auxiliary substance. Materials y Methods: Complex formation was studied by phase solubility analysis (PSA), nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), thermogravimetric analysis (TG) and scanning electron microscopy (SEM). Results: The apparent stability constants (KC) of the multicomponent complexes were calculated from the solubility diagrams. By the analysis of the NMR spectra, it could be said that the shifts of some protons evidenced the important role of the AA in the formation of multicomponent complexes. Among the AA, Arginine (ARG) proved to have better solubilizing properties for SDZ, reaching an improvement up to 70 times. The use of DSC, TG and SEM suggested the formation of new solid phases between SDZ:βCD:AA. Conclusions: As a result of this research, it was determined that ternary products were more effective in improving drug solubility than the corresponding SDZ:βCD binary system., Introducción: Las ciclodextrinas (CD), son capaces de formar complejos de inclusión con una variedad de moléculas huésped, tanto en solución y en estado sólido, pudiendo producir la modificación de las propiedades de las moléculas huésped. Desafortunadamente, la eficiencia de la formación de complejos con CD es baja, lo cual se puede mejorar mediante la formación de complejos ternarios utilizando aminoácidos (AA). Sulfadiazina (SDZ) es un antibiótico con muy baja solubilidad en agua que limita su biodisponibilidad y sus aplicaciones terapéuticas. Objetivos: El objetivo de este trabajo fue aumentar la solubilidad acuosa de SDZ mediante la preparación de complejos ternarios con β-ciclodextrina (βCD) y un AA como una tercera sustancia. Materiales y Métodos: La formación de complejos se estudió por análisis de solubilidad de fases (PSA), resonancia magnética nuclear (RMN), calorimetría diferencial de barrido (DSC), análisis termogravimétrico (TG) y microscopía electrónica de barrido (SEM). Resultados: Las constantes de estabilidad aparente (KC) de los complejos multi-componentes se calcularon a partir de los diagramas de solubilidad. Por el análisis de los espectros de RMN se constató, por los corrimientos de algunos protones, el papel importante de los AA en la formación de complejos ternarios. Entre los AA, arginina (ARG) demostró tener mejores propiedades de solubilización para SDZ, alcanzando una mejora de hasta 70 veces. El uso de DSC, TG y SEM sugirió la formación de nuevas fases sólidas entre SDZ:βCD:AA. Conclusiones: Como resultado de esta investigación, se determinó que los productos ternarios fueron más eficaces en la mejora de la solubilidad del fármaco que el sistema binario SDZ: βCD.

Introduction: Cyclodextrins (CD), are known to form inclusion complexes with a variety of guest molecules both in solution and in the solid state. This can lead to the alteration of properties of guest molecules. Unfortunately, the complexation efficiency of CD is rather low, and can be enhanced by formation of ternary complexes using aminoacids (AA). Sulfadiazine (SDZ) is an antibiotic with extremely low water solubility which limits its therapeutic applications and bioavailability. Objetives: The aim of this work was to increase the aqueous solubility of SDZ by preparing ternary complexes of this drug with β-cyclodextrin (βCD) and an AA as a third auxiliary substance. Materials y Methods: Complex formation was studied by phase solubility analysis (PSA), nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), thermogravimetric analysis (TG) and scanning electron microscopy (SEM). Results: The apparent stability constants (K C) of the multicomponent complexes were calculated from the solubility diagrams. By the analysis of the NMR spectra, it could be said that the shifts of some protons evidenced the important role of the AA in the formation of multicomponent complexes. Among the AA, Arginine (ARG) proved to have better solubilizing properties for SDZ, reaching an improvement up to 70 times. The use of DSC, TG and SEM suggested the formation of new solid phases between SDZ:βCD:AA. Conclusions: As a result of this research, it was determined that ternary products were more effective in improving drug solubility than the corresponding SDZ:βCD binary system.

PURPOSE: To evaluate intereye corneal asymmetry in Pentacam (Oculus Optikgeräte GmbH, Wetzlar, Germany) indices as a diagnostic method between normal patients and patients with keratoconus. METHODS: A retrospective, observational case series of 177 healthy, 44 indeterminate, and 121 patients with keratoconus classified by Pentacam ectasia detection indices, randomized to analysis and validation datasets. Intereye asymmetry in 20 Scheimpflug tomography corneal descriptors was calculated and compared to develop diagnostic models. RESULTS: Intereye asymmetry was not correlated with anisometropia in healthy controls but was correlated with the ectasia grade of the worse eye in patients with keratoconus. Patients with keratoconus had significantly greater intereye asymmetry in all descriptors except for relational thickness indices. Intereye asymmetry in front elevation at the thinnest corneal location afforded the single highest diagnostic performance (71% sensitivity and 85% specificity), whereas the best multivariate model combining intereye asymmetry in anterior and posterior keratometry, corneal thickness, and front and back elevation at the thinnest point provided 65% sensitivity and 97% specificity. Multivariate models upheld their performance in the validation dataset. Most (more than 90%) indeterminate patients, according to conventional Pentacam analysis, showed within-normal-range corneal asymmetry. CONCLUSIONS: Healthy corneas are markedly symmetric irrespective of anisometropia, but corneal asymmetry analysis does not provide sufficient sensitivity to be used alone for detecting keratoconus. However, its remarkable specificity suggests that it could be used combined with conventional single cornea Pentacam analysis to reduce the false-positive rate or in dubious cases. [ J Refract Surg . 2015;31(2):116–123.]

PURPOSE: To evaluate inter-device agreement between Placido topography (iTrace; Tracey Technologies, Houston, TX) and Scheimpflug tomography (Pentacam; Oculus Optikgeräte GmbH, Wetzlar, Germany) for measuring corneal power and cylinder and axis of astigmatism. METHODS: Observational case series of 54 eyes from 54 subjects with no ocular disease. Main outcome measures were corneal power, cylinder power, and axis of astigmatism and their agreement was assessed by Bland–Altman analysis. RESULTS: For corneal power and corneal cylinder, 95% limits of agreement (LoA) were considered good (−0.38 to 0.45 diopters [D] and −0.49 to 0.27 D, respectively). In contrast, the 95% LoA for corneal astigmatism axis exceeded the clinically relevant margins (−14.8 to 13.5): 28 eyes (52%) had a greater than 5° difference, 10 eyes (19%) had a greater than 10° difference, and 4 eyes (7%) had a greater than 20° difference between instruments. This absolute difference was significantly correlated with average corneal cylinder (Spearman’s r = −0.379, P = .005) but not with average corneal power. In eyes with corneal astigmatism 2 D or greater, the 95% LoA for axis were −8.7° to 6.7°, whereas in those with corneal astigmatism less than 1 D, the 95% LoA for axis were −19.1° to 16.6°. CONCLUSIONS: Placido topography and Scheimpflug tomography show good agreement for corneal power and cylinder, but not for corneal astigmatism axis. These instruments could be used interchangeably only in eyes with corneal astigmatism of 2 D or greater. [ J Refract Surg. 2014;30(1):49–53.]

β-cyclodextrin (βCD) and methyl-β-cyclodextrin (MβCD) complexes with sulfamethazine (SMT) were prepared and characterized by different experimental techniques, and the effects of βCD and MβCD on drug solubility were assessed via phase-solubility analysis. The phase-solubility diagram for the drug showed an increase in water solubility, with the following affinity constants calculated: 40.4 ± 0.4 (pH 2.0) and 29.4 ± 0.4 (pH 8.0) M−1 with βCD and 56 ± 1 (water), 39 ± 3 (pH 2.0) and 39 ± 5 (pH 8.0) M−1 with MβCD. According to 1H NMR and 2D NMR spectroscopy, the complexation mode involved the aromatic ring of SMT included in the MβCD cavity. The complexes obtained in solid state by freeze drying were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, and thermal analysis. The amorphous complexes obtained in this study may be useful in the preparation of pharmaceutical dosage forms of SMT. Fil: Zoppi, Ariana. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Delrivo, Alicia. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Aiassa, Virginia. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Longhi, Marcela Raquel. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

PURPOSE: To evaluate corneal biomechanical properties in non-keratoconic myopic eyes and to identify descriptors for improving the specificity of the Ocular Response Analyzer (ORA) (Reichert Ophthalmic Instruments, Depew, NY) testing for subclinical keratoconus detection. METHODS: Observational case series of 52 non-keratoconic non-myopic eyes and 97 non-keratoconic myopic eyes (spherical equivalent ⩽ −5 diopters [D]) in dataset 1 and 87 non-keratoconic eyes and 73 eyes with subclinical keratoconus in dataset 2. Examination included corneal topography, tomography, and biomechanical testing with the ORA. Receiver operating characteristic curves and logistic regression were used to identify optimal combinations of biomechanical indices for keratoconus detection. Main outcome measures were corneal thickness-corrected hysteresis (DifCH) and resistance factor (DifCRF), the difference between these two (CH-CRF), and the diagnostic performance of their combinations. RESULTS: Compared to non-keratoconic non-myopic eyes, non-keratoconic myopic eyes with flat corneas (average corneal power < 44.0 D) had reduced DifCH (mean ± standard deviation, 0.11 ± 1.27 vs −0.79 ± 1.50, P < .01) and DifCRF (0.24 ± 1.16 vs −0.70 ± 1.59, P < .01) values, whereas non-keratoconic myopic eyes with steep corneas showed no difference. Keratoconic eyes exhibited lower DifCH and DifCRF values than non-keratoconic myopic eyes. Combinations of DifCH, DifCRF, and CH-CRF had increased specificity (> 80%) for subclinical keratoconus compared to the DifCRF index alone (71%). CONCLUSIONS: In biomechanical keratoconus screening, some non-keratoconic myopic eyes show altered ocular biomechanical properties and are identified as false-positive cases. The low specificity of DifCRF when dealing with these non-keratoconic eyes could be improved by considering additional biomechanical descriptors such as DifCH and CH-CRF, which seem to be indicative of the aforementioned biomechanical profile. [ J Refract Surg. 2013;29(9):596–602.]

The complex formation between three structurally related sulfonamides (sulfadiazine (SDZ), sulfamerazine (SMR), and sulfamethazine (SMT)) and beta-cyclodextrin (beta-CD) was studied, by exploring its structure affinity relationship. In all the cases, 1:1 stoichiometries were determined with different relative affinities found by phase solubility (SDZ:beta-CD > SMR:beta-CD > SMT:beta-CD) and nuclear magnetic resonance (NMR) (SMT:beta-CD > SMR:beta-CD > SDZ:beta-CD) studies. The spatial configurations determined by NMR were in agreement with those obtained by molecular modeling, showing that SDZ included its aniline ring into beta-CD, while SMR and SMT included the substituted pyrimidine ring. Energetic analyses demonstrated that hydrophobicity is the main driving force to complex formation.