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1.  AAPS pharmSci: An advanced publication forum has matured 
AAPS PharmSci  2003;5(2):86-87.
PMCID: PMC2751524  PMID: 12866943
2.  Introduction: A welcome to the first special animal health issue of AAPS PharmSci 
AAPS PharmSci  2002;4(4):189-192.
The goal of this special volume is to provide veterinary scientists with state-of-the art reviews in animal health and to inform human health scientists of the various challenges and collaborative opportunities associated with their animal health counterparts. The contributors are highly respected experts, providing invaluable insights into current issues and state-of-the-art advances within veterinary medicine.
PMCID: PMC2751328  PMID: 12647740
Veterinary medicine; harmonization
3.  Mathematical modeling of surface-active and non-surface-active drug transport in emulsion systems 
AAPS PharmSci  2000;2(3):102-113.
Mathematical models were developed for the prediction of surface-active and non- surface-active drug transport in triphasic (oil, water, and micellar) emulsion systems as a function of micellar concentration. These models were evaluated by comparing experimental and simulated data. Fick's first law of diffusion with association of the surface-active or complexation nature of the drug with the surfactant was used to derive a transport model for surface-active drugs. This transport model assumes that the oil/water (O/W) partitioning process was fast compared with membrane transport and therefore drug transport was limited by the membrane. Consecutive rate equations were used to model transport of non- surface-active drugs in emulsion systems assuming that the O/W interface acts as a barrier to drug transport. Phenobarbital (PB) and barbital (B) were selected as surface-active model drugs. Phenylazoaniline (PAA) and enzocaine (BZ) were selected as non- surface-active model drugs. Transport studies at pH 7.0 were conducted using side-by-side diffusion cells and bulk equilibrium reverse dialysis bag techniques. According to the surface-active drug model, an increase in micellar concentration is expected to decrease drug-transport rates. Using the Microft EXCEL program, the non- surface-active drug model was fitted to the experimental data for the cumulative amount of the model drug that disappeared from the donor chamber. The oil/continuous phase partitioning rates (k1) and the membrane transport rates (k2) were estimated. The predicted data were consistent with the experimental data for both the surface-active and non- surface-active models.
PMCID: PMC2761141  PMID: 11741247
4.  Solvation and hydration characteristics of ibuprofen and acetylsalicylic acid 
AAPS PharmSci  2004;6(1):22-30.
Ibuprofen and acetylsalicylic acid were studied by thermoanalytical methods: sublimation calorimetry, solution calorimetry, and with respect to solubility. Upon measuring the temperature dependences of the saturated vapor pressure, enthalpies of sublimation, ΔHsub0, as well as the entropies of sublimation, ΔHsub0, and their respective relative fractions in the total process were calculated. The Gibbs energy of solvation in aliphatic alcohols as well as the enthalpic and entropic fractions thereof were also studied and compared with the respective properties of model substances and other nonsteroidal antiinflammatory drugs (benzoic acid, diflunisal, flurbiprofen, ketoprofen, and naproxen). In all cases, enthalpy was found to be the driving force of the solvation process. Correlations were derived between Gibbs energy of solvation in octanol, ΔGsolvOct, and the transfer Gibbs energy from water to octanol, ΔGtr0. Influence of mutual octanol and water solubilities on the driving force of partitioning is discussed. An enthalpy-entropy-compensation effect in octanol was observed, and consequences of deviation from the general trend are also discussed.
PMCID: PMC2750938  PMID: 18465255
ibuprofen; acetylsalicylic acid; NSAID; sublimation; solvation; hydration; plasma half-life
5.  Prediction of dissolution-absorption relationships from a continuous dissolution/Caco-2 system 
AAPS PharmSci  1999;1(2):27-38.
The objectives were 1) to design a continuous dissolution Caco-2 system to predict the dissolution-absorption relationships for fast and slow dissolving formulations of piroxicam, metoprolol tartrate, and ranitidine HCl, and compare the predicted relationships with observed relationships from clinical studies; 2) to estimate the effect of croscarmellose sodium on ranitidine dissolution-absorption relationships; and 3) to estimate the effect of solubilizing agents on piroxicam dissolution-absorption relationships. A continuous dissolution/Caco-2 system was constructed from a dissolution apparatus and a diffusion cell, such that drug dissolution and permeation across a Caco-2 monolayer would occur sequentially and simultaneously. The continuous system generally matched observed dissolution-absorption relationships from clinical studies. For example, the system successfully predicted the slow metoprolol and slow ranitidiine formulations to be permeation-rate-limited. The system predicted the slow piroxicam formulation to be dissolution-rate-limited, and the fast piroxicam formulation to be permeation-rate-limited, in spite of piroxicam’s high permeability and low solubility. Additionally, the system indicated croscarmellose sodium enhanced ranitidine permeability and predicted solubilizing agents to not modulate permeability. These results suggest a dissolution/Caco-2 system to be an experimentally based tool that may predict dissolution-absorption relationships from oral solid dosage forms, and hence the relative contributions of dissolution and permeation to oral drug absorption kinetics.
PMCID: PMC2761118  PMID: 11741200
6.  Comparative evaluation of tableting compression behaviors by methods of internal and external lubricant addition: Inhibition of enzymatic activity of trypsin preparation by using external lubricant addition during the tableting compression process 
AAPS PharmSci  2001;3(3):32-42.
This study evaluated tableting compression by using internal and external lubricant addition. The effect of lubricant addition on the enzymatic activity of trypsin, which was used as a model drug during the tableting compression process, was also investigated. The powder mixture (2% crystalline trypsin, 58% crystalline lactose, and 40% microcrystalline cellulose) was kneaded with 5% hydroxypropyl cellulose aqueous solution and then granulated using an extruding granulator equipped with a 0.5-mm mesh screen at 20 rpm. After drying, the sample granules were passed through a 10-mesh screen (1680 μm). A 200-mg sample was compressed by using 8-mm punches and dies at 49, 98, 196, or 388 MPa (Mega Pascal) at a speed of 25 mm/min. The external lubricant compression was performed using granules without lubricant in the punches and dies. The granules were already dry coated by the lubricant. In contrast, the internal lubricant compression was performed using sample granules (without dry coating) containing 0.5% lubricant. At 98 MPa, for example, the compression level using the external lubricant addition method was about 13% higher than that for internal addition. The significantly higher compressing energy was also observed at other MPas. By comparison, the friction energy for the external addition method calculated based on upper and lower compression forces was only slightly larger. The hardness of tablets prepared using the internal addition method was 34% to 48% lower than that for the external addition method. The total pore volume of the tablet prepared using the external addition method was significantly higher. The maximum ejection pressure using the no-addition method (ie, the tablet was prepared using neither dry-coated granules nor added lubricant) was significantly higher than that of other addition methods. The order was as follows: no addition, external addition, and then internal addition. The ejection energy (EE) for internal addition was the lowest; for no addition, EE was the highest. In the dissolution test, the tablets obtained using external addition immediately disintegrated and showed faster drug release than those prepared using internal addition. This result occurred because the water penetration rate of the tablet using the external addition was much higher. The trypsin activity in tablets prepared using the external addition method was significantly higher than that produced using the internal addition method at the same pressure. All these results suggest that the external addition method might produce a fast-dissolution tablet. Because the drug will be compressed using low pressure only, an unstable bulk drug may be tableted without losing potency.
PMCID: PMC2751015  PMID: 11741271
Tableting; Trypsin; Preparation; Compression; Dissolution
7.  High glucose concentration in isotonic media alters Caco-2 cell permeability 
AAPS PharmSci  2003;5(3):17-25.
Caco-2 cell permeability was evaluated in isotonic media containing high (25mM) or physiological (5.5mM) glucose concentrations. Transepithelial electrical resistance (TEER) and membrane fluidity were measured to assess glucose-induced alterations in physical barrier properties. In parallel, distribution of the actin filament (F-actin) and zonula occludens-1 (ZO-1) proteins was assessed by confocal microscopy. Transepithelial fluxes of mannitol, hydrocortisone, digoxin, and glycyl sarcosine (Gly-Sar) that permeate the intestinal mucosa by various pathways were measured to quantify the effect of glucose-induced changes on Caco-2 cell permeability. High glucose decreased maximum TEER of cell monolayers by 47%, whereas membrane fluidity at the hydrophobic core and lipid/polar head interphase was significantly increased. F-actin distribution in high glucose cells appeared more diffuse while ZO-1 was unchanged. Mannitol and hydrocortisone fluxes across Caco-2 cells cultured in high glucose increased by 65% and 24%, respectively. In addition, high glucose decreased the maximum transport capacity (Vmax) of PepT-1. P-glycoprotein activity, however, was unchanged. In conclusion, high extracellular glucose concentration in isotonic media significantly alters physical barrier properties of Caco-2 cell monolayers, which predominantly affects transepithelial transport of solutes permeating the cell barrier by paracellular and transcellular passive diffusion and facilitated transport mediated by the proton-dependent oligopeptide transporter (PepT-1).
PMCID: PMC2750934  PMID: 14621959
Caco-2; glucose; tight junctions; TEER; membrane fluidity; solute flux
8.  Influence of solvents on the variety of crystalline forms of erythromycin 
AAPS PharmSci  2003;5(2):39-47.
The influence of the organic solvents widely used in the pharmaceutical industry (acetone, methylethylketone, ethanol, and isopropanol) both in the presence and in the absence of water on the crystallization behavior of erythromycin (Em), a clinically relevant antibiotic of the macrolide group, was investigated. It was observed that despite a high preference for water as a guest molecule, Em rather easily forms solvates with the organic solvents studied. Consequently, 4 distinct solvates of Em have been isolated by recrystallization: acetonate, methylethylketonate, ethanolate, and isopropanolate. It was established that in a pure organic solvent, or 1∶9 or 1∶1 water-organic solvent mixtures, the corresponding solvate is always crystallized. However, the recrystallization of erythromycin from 2∶1 water-organic solvent (excluding methylethylketone) mixture results in the formation of a crystal hydrate form. X-ray powder diffraction revealed the isostructurality of the solvates with acetone and methylethylketone. Thermogravimetric analysis showed that the loss of volatiles by all of the solvated crystals is nonstoichiometric. The desolvation behavior of the solvates with the organic solvents studied by means of variable-temperature x-ray powder diffraction indicates that in contrast to erythromycin dihydrate, they belong to a different class of solvates—those that produce an amorphous material upon desolvation.
PMCID: PMC2751520  PMID: 12866939
erythromycin; crystallization; solvated crystals; isostructurality; clathrate; x-ray diffraction
9.  The composite solubility versus pH profile and its role in intestinal absorption prediction 
AAPS PharmSci  2003;5(1):35-49.
The purpose of this study was to examine absorption of basic drugs as a function of the composite solubility curve and intestinally relevant pH by using a gastrointestinal tract (GIT) absorption simulation based on the advanced compartmental absorption and transit model. Absorption simulations were carried out for virtual monobasic drugs having a range of pKa, log D, and dose values as a function of presumed solubility and permeability. Results were normally expressed as the combination that resulted in 25% absorption. Absorption of basic drugs was found to be a function of the whole solubility/pH relationship rather than a single solubility value at pH 7. In addition, the parameter spaces of greatest sensitivity were identified. We compared 3 theoretical scenarios: the GIT pH range overlapping (1) only the salt solubility curve, (2) the salt and base solubility curves, or (3) only the base curve. Experimental solubilities of 32 compounds were determined at pHs of 2.2 and 7.4, and they nearly all fitted into 2 of the postulated scenarios. Typically, base solubilities can be simulated in silico, but salt solubilities at low pH can only be measured. We concluded that quality absorption simulations of candidate drugs in most cases require experimental solubility determination at 2 pHs, to permit calculation of the whole solubility/pH profile.
PMCID: PMC2751472  PMID: 12713276
GIT; absorption simulation; pH solubility curve; BCS; solid-state properties; solubility screening
10.  Comparison of the formulation requirements of dosator and dosing disc automatic capsule filling machines 
AAPS PharmSci  2002;4(3):45-60.
The overall objective of this study was to provide ‘semi-quantitative’ or ‘rigorous’ definitions of the fluidity, lubricity and compactibility requirements of formulation for representative dosator and dosing disc capsule filling machines. To that end, model formulations were developed for those properties using Carr's compressibility index, ejection force, and plug breaking force at a specified compression force to gauge fluidity, lubricity, and compactibility, respectively. These formulations were each encapsulated on an Hofliger-Karg GKF-400 dosing disc machine and a Zanasi LZ-64 dosator machine. Each machine was instrumented to measure plug compression and ejection forces. The encapsulation process was evaluated for %CV of fill-weight, ejection force, plug breaking force and the dissolution of marker drugs incorporated in the formulations. The f2 metric was used to compare dissolution profiles. The results suggest: (1) formulations should meet different flow criteria for successful encapsulation on the two machines, (2) a relatively lower level of lubricant may be sufficient for the dosing disc machine, (3) a higher degree of formulation compactibility is needed for the dosator machine, and (4) transferring formulations between these machine types (same class, different subclass per FDA's SUPAC-IR/MR Manufacturing Equipment Addendum) could be challenging. In certain cases dissolution profiles for the same formulation filled on the two machines with equivalent compression force were different based on f2<50. Overall, the results of this study suggest a range of formulation characteristics appropriate for transferring formulations between these two types of machines.
PMCID: PMC2751356  PMID: 12423066
Capsules; Formulation; Flow; Compactibility; Lubrication; Filling Machines
11.  Empirical versus mechanistic modelling: Comparison of an artificial neural network to a mechanistically based model for quantitative structure pharmacokinetic relationships of a homologous series of barbiturates 
AAPS PharmSci  1999;1(4):5-13.
The aim of the current study was to compare the predictive performance of a mechanistically based model and an empirical artificial neural network (ANN) model to describe the relationship between the tissue-to-unbound plasma concentration ratios (Kpu's) of 14 rat tissues and the lipophilicity (LogP) of a series of nine 5-n-alkyl-5-ethyl barbituric acids. The mechanistic model comprised the water content, binding capacity, number of the binding sites, and binding association constant of each tissue. A backpropagation ANN with 2 hidden layers (33 neurons in the first layer, 9 neurons in the second) was used for the comparison. The network was trained by an algorithm with adaptive momentum and learning rate, programmed using the ANN Toolbox of MATLAB. The predictive performance of both models was evaluated using a leave-one-out procedure and computation of both the mean prediction error (ME, showing the prediction bias) and the mean squared prediction error (MSE, showing the prediction accuracy). The ME of the mechanistic model was 18% (range, 20 to 57%), indicating a tendency for overprediction; the MSE is 32% (range, 6 to 104%). The ANN had almost no bias: the ME was 2% (range, 36 to 64%) and had greater precision than the mechanistic model, MSE 18% (range, 4 to 70%). Generally, neither model appeared to be a significantly better predictor of the Kpu's in the rat.
PMCID: PMC2751347  PMID: 11741213
12.  Evaluation of a new coprocessed compound based on lactose and maize starch for tablet formulation 
AAPS PharmSci  2004;6(2):27-38.
The development of new direct compression excipients should include a comprehensive and rapid determination of deformation properties. The aim of this study was to characterize StarLac, a new coprocessed compound for direct compression based on lactose and maize starch. For this purpose, the effects of the base materials (maize starch and spraydried lactose) were considered and the influence of the spray-drying process was investigated. This was performed by comparing the physical mixture of starch and spray-dried lactose at the same ratio as for StarLac. For analysis of the deformation behavior, the 3-D model and the Walker equation were applied; for verification, the Heckel equation and the pressure time function (a modified Weibull equation) were used. The advantages of StarLac are its good flowability depending on the spray-drying process, an acceptable crushing force due to its lactose content, its rapid disintegration depending on starch, and a brilliant fast release of an active ingredient, such as theophylline monohydrate. The volume-pressure deformation properties of StarLac were dependent on the lactose properties. Only at high maximum relative density (ϱrel,max) did the influence of starch cause a change in these properties. A network-like structure can be observed using scanning electron microscopy pictures. Overall, StarLac deformed plastically with a low portion of elasticity. The physical mixture exhibited a more elastic behavior than StarLac. However, the part of the powder that was irreversibly compressed was much lower than was observed for the single substances. This behavior is caused by an interaction between the components, which in StarLac is prevented by spray drying.
PMCID: PMC2751008  PMID: 18465268
compression; tableting behavior; lactose starch; drug release
13.  Evaluation of the potential use of poly(ethylene oxide) as tablet- and extrudate-forming material 
AAPS PharmSci  2004;6(2):17-26.
The purpose of this study was to assess the potential use of poly(ethylene oxide) (PEO) as matrix-forming mate-rial for tablets and extrudates. Raw materials were characterized for size, size distribution, and shape. Tablets with 2- and 10-mm diameter were prepared by direct compression at both 13 and 38 MPa from mixtures with poly(ethylene oxide)s, a model drug (propranolol hydrochloride) and lactose. To these mixtures water was added (16%–43%) prior to extrusion in a ram extruder fit with different dies (1-, 3-, 6-, and 9-mm diameter and 4-mm length). Tablets and extrudates were characterized for work of compression or extrusion, respectively, relaxation, tensile strength, friability, and drug release. Both PEOs produced tablets easily and with different properties. Some relaxation was observed, particularly for tablets with higher amounts of PEOs. Release of the drug occurred after swelling of the matrix, and between 10% and 70% drug released, a quasi zero-order release was observed for large tablets. Extrusion was possible for formulations with PEO only with amounts of water between 16% and 50%. Both radial and axial relaxation of both plugs and extrudates were observed. Moreover, different extrusion profiles reflected the different behaviors of the different formulations. The model drug was released in the same fashion as observed for the tablets. It was possible to produce tablets by direct compression and extrudates or pellets from those extrudates from different formulations with PEO. Tablets and pellets have shown distinct properties depending upon the PEO considered. Extrusion was particularly complex with different formulations with PEO.
PMCID: PMC2751007  PMID: 18465267
extrusion; minitablet, pellet; poly(ethylene oxide); tablet
14.  Properties of microcrystalline cellulose and powder cellulose after extrusion/spheronization as studied by fourier transform Raman spectroscopy and environmental scanning electron microscopy 
AAPS PharmSci  2003;5(4):77-89.
In this study, the effect of powder cellulose (PC) and 2 types of microcrystalline cellulose (MCC 101 and MCC 301) on pellet properties produced by an extrusion/spheronization process was investigated. The different investigated types of cellulose displayed different behavior during the extrusion/spheronization process. Pure PC was unsuitable for extrusion, because too much water was required and the added water was partly squeezed during the extrusion process. In contrast, MCC 101 and MCC 301 were extrudable at a wide range of water content, but the quality of the resulting products varied. In the extrusion/spheronization process, MCC 101 was the best substance, with easy handling and acceptable product properties. The properties of the extrudates and pellets were determined by Fourier transform (FT) Raman spectroscopy and environmental scanning electron microscopy (ESEM). FT-Raman spectroscopy was able to distinguish between the original substances and also between the wet and dried extrudates. The particle sizes of the raw material and of the extrudates were determined by ESEM without additional preparation. For MCC, the size of the resulting particles within the extrudate or pellet was smaller. However, in the extrudates of PC, changes in particle size could not be observed.
PMCID: PMC2750993  PMID: 15198519
powder cellulose; microcrystalline cellulose; pellet; Raman spectroscopy; environmental scanning electron microscopy; extrusion/spheronization
15.  Evaluation of sucrose esters as alternative surfactants in microencapsulation of proteins by the solvent evaporation method 
AAPS PharmSci  2003;5(2):123-131.
Sucrose esters (SE) are surfactants with potential pharmaceutical applications because of their low toxicity, biocompatibility, and excellent biodegradability. The objective of the study was to investigate SE as alternative surfactants in stabilizing emulsions for the preparation of protein-loaded microparticles. To achieve this goal, using bovine serum albumin as model protein and 75/25 poly(d,1-lactide-co-glycolide) as polymer carrier, we have investigated the influence of the following formulation variables on particle characteristics: (1) SE concentration from 0.01% to 1% (wt/vol), (2) hydrophile-lipophile balance (HLB) value of SE from 6 to 15, and (3) the nature of emulsion stabilizer. The formulations were characterized using ATR-FTIR spectroscopy, bicinchoninic acid protein assay, optical microscopy and SDS-PAGE. Results showed that at 0.05% (wt/vol) surfactant concentration, SE with HLB of 6 to 15 provided discrete and spherical microparticles with the highest encapsulation efficiency compared with controls polyvinyl alcohol (PVA) and poloxamer 188. These results may be explained by the difference in critical micelle concentration, diffusion, and partition coefficient among the tested surfactants. HLB values were consistent with SE spectral data. The protein molecular weight was preserved after the encapsulation process. The effective SE concentration was far less (20-to 200-fold) than that is usually required for PVA in microencapsulation of proteins. However, the encapsulation efficiency was relatively lower (∼13.5%). These preliminary results suggest that it may be desirable to optimize such formulations in vitro and in vivo for SE to be eventually used as altermative surfactants in the development of microparticulate systems for parenteral delivery of protein and gene medicines.
PMCID: PMC2751529  PMID: 12866947
proteins; microencapsulation; solvent evaporation; sucrose ester; surfactants
16.  Mechanisms of aggregate formation and carbohydrate excipient stabilization of lyophilized humanized monoclonal antibody formulations 
AAPS PharmSci  2003;5(2):21-31.
The purpose of this study was to evaluate the mechanisms of aggregate formation and excipient stabilization in freeze-dried formulations of a recombinant humanized monoclonal antibody. Protein degradation was measured using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE) and native size exclusion chromatography, and protein structure was studied using Fourier transform-infrared spectrometry and circular dichroism. The results showed that protein aggregates present following reconstitution were composed of native antibody structure and a reduced amount of free thiol when compared to protein monomer, which implied that intermolecular disulfides were involved in the aggregation mechanism. An excipient-free formulation resulted in reversible solid-state protein structural alteration and increased aggregation during storage. This correlated with dehydration to an extent that the amount of water was less than the estimated number of surface-accessible hydrogen-bonding sites on the protein. Improved native-like solid-state protein structure and reduced aggregation were obtained by formulation with enough carbohydrate to fulfill the hydrogen-bonding sites on the surface of the protein. Carbohydrate in excess of this concentration has less of an influence on protein aggregation. Reduced aggregation during storage was obtained by the addition of sufficient excipient to both stabilized solid-state protein structure and provide an environment that consisted of an amorphous glassy state matrix.
PMCID: PMC2751518  PMID: 12866937
protein formulation; protein stability; recombinant humanized monoclonal antibody; aggregation; FT-IR spectrometry
17.  Effects of disodium ascorbyl phytostanol phosphates (FM-VP4) on cholesterol accumulation within rat intestinal cells 
AAPS PharmSci  2003;5(1):55-61.
The objective of this study was to determine whether FM-VP4, a novel compound derived from plant sterols, can effectively reduce cholesterol accumulation within rat intestinal epithelial crypt (IEC-6) cells. IEC-6 cells were cultured in Dulbeccos minimal essential medium (DMEM) containing 5% fetal bovine serum, 100 U/mL penicillin, 100 μg/mL streptomycin, and 0.1 units/mL insulin at 37°C under a humidified 5% CO2 atmosphere and seeded at 6.4×104 cells/well in 48-well plates. Experiments were initiated 14 days postconfluence. IEC-6 cells were exposed to [3H]cholesterol micelles (containing oleic and taurcholic acids), co-incubated with FM-VP4 (0, 10, 50, and 100 μM) in Hepes Buffered Sterile Saline (HBSS). Cells were also preincubated with FM-VP4 prior to [3H]cholesterol micelle incubation to determine whether its effects are elicited intracellularly. The cellular localization of cholesterol was determined using digitonin. To determine the effects of cholesterol on the extent of FM-VP4 accumulation within IEC-6 cells, [3H]FM-VP4 was incubated with IEC-6 cells in the presence of unlabeled cholesterol micelles (0, 10, and 50 μM). The extent of [3H]cholesterol or [3H]FM-VP4 associated with cell monolayers was determined after cell lysis using liquid scintillation counting in a Beckman LS6500 Scintillation Counter. Dose-response and time course studies were performed in which control (no FM-VP4 treatment) and FM-VP4 (10–100 μM) were co-incubated with 50-μM [3H]cholesterol micelles from 1 minute to 24 hours. Incubation with only 50-μM FM-VP4 for less than 24 hours resulted in a 50% to 60% reduction (n=6, P<.05) in [3H]cholesterol associated with the monolayer compared with control (n=6). Preincubation of FM-VP4 did not elicit a significant reduction in cholesterol accumulation compared with control (n=6). Approximately 25% of the total [3H]cholesterol associated with the cells was determined to be cytosolic, while 75% was noncytosolic in the presence and/or absence of FM-VP4. [3H]FM-VP4 was also shown to associate with IEC-6 cells at similar concentrations to cholesterol with the most pronounced inhibition of FM-VP4 accumulation occurring at a cholesterol concentration of 50 μM. However, cholesterol-induced inhibition was detectable only after 1 hour of incubation. FM-VP4 inhibits cholesterol accumulation within IEC-6 cells and is most effective at equimolar concentrations with cholesterol. Our findings further suggest that the action of FM-VP4 is likely at the cell surface and not elicited intracellularly.
PMCID: PMC2751474  PMID: 12713278
IEC-6 cells; phytostanols; cholesterol accumulation; cytotoxicity
18.  Polyethylene glycol-induced precipitation of interferon alpha-2a followed by vacuum drying: Development of a novel process for obtaining a dry, stable powder 
AAPS PharmSci  2004;6(1):31-44.
Feasibility studies were performed on the development of a novel process based on polyethylene glycol (PEG)-induced precipitation of proteins followed by vacuum drying in the presence of sugars to obtain dry protein powders. Apparent solubility of interferon alpha-2a (IFNα2a) was determined in the presence of various PEGs and the effect of solution pH, ionic strength, and temperature was investigated. IFNα2a precipitate was dried at a shelf temperature of 25°C at 100 mTorr either as it is or in the presence of mannitol and/or trehalose. The dried IFNα2a formulations were subjected to accelerated stability studies at 40°C (3 months), and the stability was compared with that of a similar lyophilized formulation. The results indicated that more than 90% of the protein could be precipitated using 10% wt/vol PEG the protein could be precipitated using 10% wt/vol PEG 1450 at pH 6.5 at a solution ionic strength of 71 mM. Vacuum drying of the precipitate only resulted in the formation of insoluble aggregates of IFNα2a; however, this was prevented by the addition of either mannitol or trehalose. The addition of excess mannitol resulted in low residual moisture content and better handling of the final dried product. Accelerated storage stability did not show any aggregation and showed less than 5% formation of oxidized IFNα2a in the dried formulation containing IFNα2a: trehalose: mannitol in a 1∶10∶100 wt/wt ratio upon storage at 40°C for 3 months. The stability of this vacuum dried formulation was comparable with that of a similar lyophilized formulation.
PMCID: PMC2750939  PMID: 18465256
protein formulation; polyethylene glycol (PEG); precipitation; vacuum drying; protein powders
19.  Chitosan and sodium alginate—Based bioadhesive vaginal tablets 
AAPS PharmSci  2002;4(4):224-230.
Metronidazole was formulated in mucoadhesive vaginal tablets by directly compressing the natural cationic polymer chitosan, loosely cross-linked with glutaraldehyde, together with sodium alginate with or ine cellulose (MCC). Sodium carboxymethylcellulose (CMC) was added to some of the formulations. The drug content in tablets was 20%. Drug dissolution rate studies from tablets were carried out in buffer pH 4.8 and distilled water. Swelling indices and adhesion forces were also measured for all formulations. The formula (FIII) containing 6% chitosan, 24% sodium alginate, 30% sodium CMC, and 20% MCC showed adequate release properties in both media and gave lower values of swelling index compared with the other examined formulations. FIII also proved to have good adhesion properties with minimum applied weights. Moreover, its release properties (% dissolution efficiency, DE) in buffer pH 4.8, as well as release mechanism (n values), were negligibly affected by aging. Thus, this formula may be considered a good candidate for vaginal mucoadhesive dosage forms.
PMCID: PMC2751333  PMID: 12646014
metronidazole; chitosan; sodium alginate; mucoadhesion; swelling; release study
20.  Evaluation of USP apparatus 3 for dissolution testing of immediate-release products 
AAPS PharmSci  2002;4(1):1-5.
We sought to evaluate whether U.S. Pharmacopeia (USP) apparatus 3 can be used as an alternative to USP apparatus 2 for dissolution testing of immediate-release (IR) dosage forms. Highly soluble drugs, metoprolol and ranitidine, and poorly soluble drugs, acyclovir and furosemide, were chosen as model drugs. The dissolution profiles of both innovator and generic IR products were determined using USP apparatus 2 at 50 rpm and apparatus 3 at 5, 15, and 25 dips per minute (dpm). The dissolution profiles from USP apparatus 3 were compared to those from USP apparatus 2 using the f2 similarity test. The dissolution profile from USP apparatus 3 generally depends on the agitation rate, with a faster agitation rate producing a faster dissolution rate. It was found that USP apparatus 3 at the extreme low end of the possible agitation range, such as 5 dpm, gave hydrodynamic conditions equivalent to USP apparatus 2 at 50 rpm. With appropriate agitation rate, USP apparatus 3 can produce similar dissolution profiles to USP apparatus 2 or distinguish dissolution characteristics for the IR products of metoprolol, ranitidine, and acyclovir. Incomplete dissolution was observed for the furosemide tablets using USP apparatus 3. Although it is primarily designed for the release testing of extended-release products, USP apparatus 3 may be used for the dissolution testing of IR products of highly soluble drugs, such as metoprolol and ranitidine, and some IR products of poorly soluble drugs, such as acyclovir. USP apparatus 3 offers the advantages of avoiding cone formation and mimicking the changes in physiochemical conditions and mechanical forces experienced by products in the gastrointestinal tract.
PMCID: PMC2751286  PMID: 12049485
Dissolution; USP apparatus 2; USP apparatus 3; Immediate-Release; and Product
21.  Allometric scaling of xenobiotic clearance: Uncertainty versus universality 
AAPS PharmSci  2001;3(4):30-43.
Statistical analysis and Monte Carlo simulation were used to characterize uncertainty in the allometric exponent (b) of xenobiotic clearance (CL). CL values for 115 xenobiotics were from published studies in which at least 3 species were used for the purpose of interspecies comparison of pharmacokinetics. The b value for each xenobiotic was calculated along with its confidence interval (CI). For 24 xenobiotics (21%), there was no correlation between log CL and log body weight. For the other 91 cases, the mean±standard deviation of the b values was 0.74±0.16; range: 0.29 to 1.2. Most (81%) of these individual b values did not differ from either 0.67 or 0.75 at P=0.05. When CL values for the subset of 91 substances were normalized to a common body weight coefficient (a), the b value for the 460 adjusted CL values was 0.74; the 99% CI was 0.71 to 0.76, which excluded 0.67. Monte Carlo simulation indicated that the wide range of observed b values could have resulted from random variability in CL values determined in a limited number of species, even though the underlying b value was 0.75. From the normalized CL values, 4 xenobiotic subgroups were examined: those that were (i) protein, and those that were (ii) eliminated mainly by renal excretion, (iii) by metabolism, or (iv) by renal excretion and metabolism combined. All subgroups except (ii) showed a b value not different from 0.75. The b value for the renal excretion subgroup (21 xenobiotics, 105 CL values) was 0.65, which differed from 0.75 but not from 0.67.
PMCID: PMC2751218  PMID: 12049492
allometric scaling; body-weight exponent; clearance; metabolism; metabolic rate; pharmacokinetics; Monte Carlo simulation; power law
22.  pH-Dependent dissolving nano- and microparticles for improved peroral delivery of a highly lipophilic compound in dogs 
AAPS PharmSci  2001;3(1):92-99.
RR01, a new highly lipophilic drug showing extremely low water solubility and poor oral bioavailability, has been incorporated into pH-dependent dissolving particles made of a poly(methacrylic acid-co-ethylacrylate) copolymer. The physicochemical properties of the particles were determined using laser-light-scattering techniques, scanning electron microscopy, high-performance liquid chromatography, and x-ray powder diffraction. Suspension of the free drug in a solution of hydroxypropylcellulose (reference formulation) and aqueous dispersions of pH-sensitive RR01-loaded nanoparticles or microparticles were administered orally to Beagle dogs according to a 2-block Latin square design (n =6). Plasma samples were obtained over the course of 48 hours and analyzed by gas chromatography/mass spectrometry. The administration of the reference formulation resulted in a particularly high interindividual variability of pharmacokinetic parameters, with low exposure to compound RR01 (AUC0–48h of 6.5 μg.h/mL and coefficient of variation (CV) of 116%) and much higher Tmax, as compared to both pH-sensitive formulations. With respect to exposure and interindividual variability, nanoparticles were superior to microparticles (AUC0–48h of 27.1 μg.h/mL versus 17.7 μg.h/mL with CV of 19% and 40%, respectively), indicating that the particle size may play an important role in the absorption of compound RR01. The performance of pH-sensitive particles is attributed to their ability to release the drug selectively in the upper part of the intestine in a molecular or amorphous form. In conclusion, pH-dependent dissolving particles have a great potential as oral delivery systems for drugs with low water solubility and acceptable permeation properties.
PMCID: PMC2751240  PMID: 11741259
Nanoparticles; Microparticles; Oral Administration; Poor Water Solubility; pH-Sensitive Polymer
23.  Estimation of capping incidence by indentation fracture tests 
AAPS PharmSci  2001;3(1):54-65.
The purpose of this study was to predict the capping tendencies of pharmaceutical powders by creating indentation fracture on compacts. Three sets of binary mixtures containing different concentrations of each ingredient were used in the study. The binary mixtures were chosen to represent plastic-plastic, plastic-brittle, and brittle-brittle combination of materials. The mixtures were tableted at different pressures and speeds on Prester®, a tablet press simulator. These mixtures were also compacted on the Instron® Universal Testing Machine 4502. Static indentation tests were done on these compacts at different depths until surface cracking and chipping were observed. The extent of surface cracking and chipping was observed from light microscope and scanning electron microscope images. A rank order correlation was observed between lamination susceptibility and the depth at which indentation failure occurred. It was concluded that indentation fracture tests could provide a useful estimate of lamination properties of pharmaceutical powders.
PMCID: PMC2751237  PMID: 11741256
Indentation Fracture; Capping
24.  Effect of nonionic surfactant on transport of surface-active and non-surface-active model drugs and emulsion stability in triphasic systems 
AAPS PharmSci  2000;2(3):91-101.
The effect of surfactant concentration on transport kinetics in emulsions using surface-active (phenobarbital, barbital) and non- surface-active is determined. Mineral oil was chosen as the oil phase and the nonionic surfactant polyoxyethylene-10-oleyl-ether (Brij 97) was chosen as the emulsifier. Model drug transport in the triphasic systems was investigated using side-by-side diffusion cells mounted with hydrophilic dialysis membranes (molecular weight cutoffs 1 kd and 50 kd) and a novel bulk equilibrium reverse dialysis bag technique. Emulsion stability was determined by droplet size analysis as a function of time, temperature, and the presence of model drugs, using photon correlation spectroscopy. Mineral oil/water (O/W) partition coefficients and aqueous solubilities were determined in the presence of surfactant. The transport rates of model drugs in emulsions increased with an increase in Brij 97 micellar concentrations up to 1.0% wt/vol and then decreased at higher surfactant concentrations. The transport profiles of the model drugs appeared to be governed by model drug O/W partition coefficient values and by micellar shape changes at higher surfactant concentrations.
Total transport rates of phenobarbital and barbital were faster than those of phenylazoaniline and benzocaine. Excess surfactant affected the transport rates of the model drugs in the emulsions depending on drug surface activity and lipophilicity.
PMCID: PMC2761140  PMID: 11741246
25.  Independence of substituent contributions to the transport of small-molecule permeants in lipid bilayer 
AAPS PharmSci  2000;2(2):40-52.
Purpose: To explore the independence of functional group contributions to permeability of nonelectrolytes across egg lecithin bilayers. Methods. The transport rates were measured of a series of α-substituted p-methylhippuric acids (-H,-Cl,-OCH3,-CN,-OH,-COOH, and-CONH2) across egg lecithin lipid bilayers, in the form of large unilamellar vesicles (LUVs) at 25EC. Intrinsic permeability coefficients (PHA) were calculated from apparent permeability coefficients (Papp) measured as a function of pH. Group contributions to the free energy of transfer from water into the barrier domain, Δ(ΔGE)P,X, were calculated for the substituents and compared to the contributions of these groups when attached to p-toluic acid measured earlier. The Δ(ΔGE)P,X values from permeability data were also correlated with Δ(ΔGE)PC,X values of partitioning from water into organic solvents to determine the physicochemical selectivity of the barrier domain. Results. Papp values in LUVs were found to vary approximately linearly with the fraction of neutral permeant over a pH range of 5.5 to 10.5, suggesting that the transport of the ionized species is negligible over this pH range. The Δ(ΔGE)P,X values from the 2 series of compounds appear to be the same, indicating that the functional group contributions are independent. 1,9-Decadiene was found to be the most similar to the chemical environment of the barrier domain. Conclusions. Functional group contributions to transport across egg lecithin bilayers appear to be independent of the compound to which they are attached, even though the thickness of the barrier domain in lipid bilayers is approximately the same as the extended length of the permeant.
PMCID: PMC2751028  PMID: 11741230

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