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1.  Physicochemical Characterization of Complex Drug Substances: Evaluation of Structural Similarities and Differences of Protamine Sulfate from Various Sources 
The AAPS Journal  2012;14(3):619-626.
The purpose of this study was to characterize and evaluate differences of protamine sulfate, a highly basic peptide drug, obtained from five different sources, using orthogonal thermal and spectroscopic analytical methods. Thermogravimetric analysis and modulated differential scanning calorimetry showed that all five protamine sulfate samples had different moisture contents and glass transition and melting temperatures when temperature was modulated from 25 to 270°C. Protamine sulfate from source III had the highest residual moisture content (4.7 ± 0.2%) at 105°C, resulting in the lowest glass transition (109.7°C) and melting (184.2°C) temperatures compared with the other four sources. By Fourier-transform infrared (FTIR) spectroscopy, the five sources of protamine sulfate had indistinguishable spectra, and the spectra were consistent with a predominantly random coil conformation in solution and a minor population in a β-sheet conformation (~12%). Circular dichroism spectropolarimetry confirmed the FTIR results with prominent minima at 206 nm observed for all five sources. Finally, proton (1H) nuclear magnetic resonance spectroscopy showed that all five protamine sulfate sources had identical spectra with backbone amide chemical shifts between 8.20 and 8.80 ppm, consistent with proteins with predominantly random coil conformation. In conclusion, thermal analyses showed differences in the thermal behavior of the five sources of protamine sulfate, while spectroscopic analyses showed the samples had a predominantly random coil conformation with a small amount of β-sheet present.
doi:10.1208/s12248-012-9375-0
PMCID: PMC3385841  PMID: 22678712
circular dichroism; differential scanning calorimetry; Fourier-transform infrared spectroscopy; nuclear magnetic resonance; peptide; protamine sulfate; thermogravimetric analysis
2.  Online Monitoring of PLGA Microparticles Formation Using Lasentec Focused Beam Reflectance (FBRM) and Particle Video Microscope (PVM) 
The AAPS Journal  2010;12(3):254-262.
Knowledge of the effects of different product and process variability on microparticle characterization is essential for the successful development, optimization, and scale-up of an encapsulation process. In the current research, the qualitative application of the Lasentec focused beam reflectance (FBRM) system for online monitoring of microparticle size distribution was demonstrated. lasentec particle vision and measurement (PVM) images were also employed to follow up the steps of microparticle formation and ripening. The drug entrapment efficiency and drug release characteristics were found to be dependent on the polymer, drug, and surfactant concentrations. DSC, FTIR, and XRD data revealed that the drug was compatible with the matrix forming polymer in the solid state. As indicated from the chord count data, FBRM was sensitive to the amount of the solid materials and the number of microparticles formed. Linear relationships with good correlations were obtained between polymer, drug, and surfactant levels and the disappearance rate of 5 to 36.8, 18.4 to 135.9, and 63 to 398 µm chord length fractions. Upon organic solvent evaporation, PVM imaging detected various stages of microemulsion droplets, sheath formation, and solidification with subsequent microparticle hardening. This study illustrated the utility of FBRM and PVM in monitoring the progress of particle formation during drug encapsulation.
doi:10.1208/s12248-010-9184-2
PMCID: PMC2895448  PMID: 20352538
biodegradable polymers; FBRM and PVM; Lasentec; microparticles; particle sizing
3.  Near-Infrared Investigations of Novel Anti-HIV Tenofovir Liposomes 
The AAPS Journal  2010;12(2):202-214.
Near-infrared (NIR) approaches is considered one of the most well-studied process analyzers evolving from the process analytical technology initiatives. The objective of this study was to evaluate NIR spectroscopy and imaging to assess individual components within a novel tenofovir liposomal formulation. By varying stearylamine, as a positive charge imparting agent, five batches were prepared by the thin film method. Each formulation was characterized in terms of drug entrapment efficiency, release characteristics, particle sizing, and zeta potential. Drug excipients compatibility was tested using Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. The obtained results showed an increase in drug entrapment and a slower drug release by increasing the incorporated percentage of stearylamine. The compatibility testing revealed a significant interaction between the drug and some of the investigated excipients. The developed NIR calibration model was able to assess drug, phospholipid, and stearylamine levels along the batches. The calibration and prediction plots were linear with correlation coefficients of more than 0.9. The root square standard errors of calibration and prediction did not attain 5% of the measured values confirming the accuracy of the model. In contrast, NIR spectral imaging was capable of clearly distinguishing the different batches, both qualitatively and quantitatively. A linear relationship was obtained correlating the actual drug entrapped and the predicted values obtained from the partial least squares images.
doi:10.1208/s12248-010-9177-1
PMCID: PMC2844515  PMID: 20195931
characterization; chemical imaging; liposomes; near infrared; tenofovir
4.  Formulation and Evaluation of a Protein-loaded Solid Dispersions by Non-destructive Methods 
The AAPS Journal  2010;12(2):158-170.
The purpose of this investigation was to develop solid dispersion (SD) formulation of cyclosporine (CyA) using polyethylene glycol (PEG-6000) to enhance its dissolution rate followed by nondestructive method for the prediction of both drug and carrier. SD formulations were prepared by varying the ratio of CyA and PEG-6000 by solvent evaporation technique and characterized by dissolution, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR), powder X-ray diffraction (PXRD), near infrared (NIR) and near infrared chemical imaging (NIR-CI). Dissolution data revealed enhanced dissolution of CyA when compared with pure CyA. DSC results showed that the crystallinity of PEG-6000 has decreased as indicated by decrease in the enthalpy of fusion and melting peak in the formulations. FTIR data demonstrated no chemical interaction between drug and carrier. The surface morphology of SD formulations was similar to PEG-6000 particle. NIR-CI disclosed homogeneity of SD matrix as indicated by symmetrical histograms with smaller values of skewness. Similar to NIR, a multivariate peak evaluation with principal component analysis and partial least square (PLS) were carried out with PXRD spectral data. PLS models with both techniques showed good correlation coefficient and smaller value of root mean square of errors. The accuracy of model for predicting CyA and PEG-6000 in NIR and PXRD data were 5.22%, 5.35%, 5.27%, and 2.10%, respectively. In summary, chemometric applications of non-destructive method sensors provided a valuable means of characterization and estimation of drug and carrier in the novel formulations.
doi:10.1208/s12248-009-9171-7
PMCID: PMC2844521  PMID: 20127529
cyclosporin; NIR; PEG-6000; PXRD; solid dispersion
5.  Effect of Ethanol on Opioid Drug Permeability Through Caco-2 Cell Monolayers 
The AAPS Journal  2008;10(2):360-362.
doi:10.1208/s12248-008-9046-3
PMCID: PMC2751396  PMID: 18592381
Caco-2; ethanol; hydromorphone; oxycodone; oxymorphone; permeability
6.  Regional permeability of salmon calcitonin in isolated rat gastrointestinal tracts: Transport mechanism using Caco-2 cell monolayer 
The AAPS Journal  2004;6(4):36-40.
The objective of the study was to determine the region of maximum permeation of salmon calcitonin (sCT) through the gastrointestinal tract and to investigate the mechanism of permeation. For regional permeability determination, male Sprague-Dawley rats (250–300 g) were anesthetized and the gastrointestinal tissues were isolated. Stomach, duodenum, jejunum, ileum, or colon tissues were mounted on Navicyte side-by-side diffusion apparatus. Salmon calcitonin solutions (50 μM in phosphate-buffered saline, pH 7.4, 37°C) were added to the donor side, and the samples were removed from the receiver compartment and analyzed by competitive radioimmunoassay (RIA). For mechanistic studies, Caco-2 cells were grown on Transwell inserts (0.4-μm pore size, 0.33 cm2 area) in a humidified 37°C incubator (with 5% CO2). Transport experiments were conducted for sCT solutions (50 μM in Dulbecco's modified eagle's medium [DMEM], pH 7.4) from the apical-to-basolateral (A-to-B) direction and B-to-A direction at 37°C and from the A-to-B direction at 4°C. Cell monolayer integrity was monitored by mannitol permeability and transepithelial electrical resistance (TEER) measurements. The permeability coefficients (× 10−9, cm/sec) for sCT through rat stomach, duodenum, jejunum, ileum, and colon tissues were 0.482±0.086, 0.718±0.025, 0.830±0.053, 1.537±0.32, and 0.934±0.15, respectively. The region of maximum sCT permeability is ileum followed by colon, jejunum, duodenum, and stomach. The permeability coefficients (× 10−6, cm/sec) for sCT through Caco-2 cell monolayer were 8.57±2.34 (A-to-B, 37°C), 8.01±1.22 (A-to-B, 4°C), and 6.15±1.97 (B-to-A, 37°C). The mechanism of its permeation is passive diffusion through the mucosa as determined from the Caco-2 monolayer permeability of sCT.
doi:10.1208/aapsj060431
PMCID: PMC2751227  PMID: 15760096
salmon calcitonin; regional permeability; stomach; duodenum; jejunum; ileum; colon; Caco-2

Results 1-6 (6)