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issn:1530-99.2
1.  Simultaneous Determination of EDTA, Sorbic Acid, and Diclofenac Sodium in Pharmaceutical Preparations Using High-Performance Liquid Chromatography 
AAPS PharmSciTech  2013;14(2):764-769.
A simple high-performance liquid chromatographic method for simultaneous determination of ethylenediaminetetraacetic acid (EDTA), sorbic acid, and diclofenac sodium was developed and validated. Separation was achieved on a C18 column (10 cm × 4.6 mm) using gradient elution. The mobile phase consisted of acetonitrile–ammonium dihydrogen phosphate buffer solution (0.01 M, pH = 2.5, containing 0.8% tetra-n-butyl ammonium hydroxide). The detector wavelength was set at 254 nm. Under these conditions, separation of three compounds was achieved in less than 10 min. The effect of two metal salts and metal concentration on peak area of EDTA was investigated. The pH effect on retention of EDTA and sorbic acid was studied. The method showed linearity for EDTA, sorbic acid, and diclofenac in the ranges of 2.5–100.0, 5.0–200.0, and 20.0–120.0 μg/mL, respectively. The within- and between-day relative standard deviations ranged from 0.52 to 1.94%, 0.50 to 1.34%, and 0.78 to 1.67% for EDTA, sorbic acid, and diclofenac, respectively. The recovery of EDTA, sorbic acid, and diclofenac from pharmaceutical preparation ranged from 96.0–102.0%, 99.7–101.5%, to 97.0–102.5%, respectively. To the best of our knowledge, this is the first report about simultaneous determination of EDTA, sorbic acid, and diclofenac.
doi:10.1208/s12249-013-9962-0
PMCID: PMC3666002  PMID: 23585291
diclofenac sodium; EDTA; high-performance liquid chromatography; pharmaceutical preparations; sorbic acid
2.  Sucrose Stearate-Enriched Lipid Matrix Tablets of Etodolac: Modulation of Drug Release, Diffusional Modeling and Structure Elucidation Studies 
AAPS PharmSciTech  2013;14(2):656-668.
Etodolac is a non-steroidal anti-inflammatory drug having an elimination half-life of 7 h; oral doses are given every 6–8 h. The aim of current work was the development of controlled-release etodolac lipid matrix tablets. The variables influencing design of these tablets (L1–L28) by the hot fusion method were investigated including; (1) lipid type (stearic acid, cetyl alcohol, cetostearyl alcohol, Imwitor® 900K, Precirol® ATO 5 and Compritol® ATO 888), (2) drug/lipid ratio (1:0.25 and 1:0.50, respectively), (3) filler type (lactose, Avicel® PH101 and their physical mixtures; 2:1, 1:1, and 1:2, respectively), (4) surfactant’s HLB (5 and 11), and (5) drug/surfactant ratio (20:1 and 10:1, respectively). Statistical analysis and kinetic modeling of drug release data were evaluated. The inner matrix of the tablet was visualized via scanning electron microscopy (SEM). An inverse correlation was observed between the drug/lipid ratio and the drug release rate. Precirol®- and Compritol®-containing formulae showed more retarded drug release rates. Lactose/Avicel® physical mixture (1:1) was considered as a filler of choice where it minimized the burst effect observed with Avicel®-free formulae. The higher surfactant’s HLB, the higher drug release rate. The similarity factor (f2) between the drug release profiles revealed similarity within the investigated drug/surfactant ratios. Sucrose stearate D1805®-based matrix (L21) succeeded in delivering more than 90% of etodolac over 12 h, following anomalous (non-Fickian) controlled-release kinetics. SEM micrographs confirmed pore formation, within the latter matrix, upon contact with dissolution medium.
doi:10.1208/s12249-013-9951-3
PMCID: PMC3665988  PMID: 23572253
anti-inflammatory; controlled release; etodolac; hot fusion method; lipid matrix tablets; Precirol® ATO 5; sucrose stearate; surfactant; sustained release
3.  A Preformulation Strategy for the Selection of Penetration Enhancers for a Transungual Formulation 
AAPS PharmSciTech  2013;14(2):682-691.
Onychomycosis is associated with the cutaneous fungal infection of the nail and the nail folds (skin surrounding the nail). It is therefore important to target drug delivery into the nail folds along with nail plate and the nail bed. Systematic and strategic selection of the penetration enhancers specific for the skin and the nail is discussed. Twelve penetration enhancers were screened for their ability to improve solubility, in vitro nail penetration, in vitro skin permeation, and in vitro skin penetration of the antifungal drug ciclopirox olamine. In contrast to transdermal drug delivery, the main selection criteria for skin penetration enhancer in topical drug delivery were increased drug accumulation in the epidermis and minimal permeation across the skin. Thiourea improved the solubility and nail penetration of ciclopirox olamine. It also showed enhancement in the transungual diffusion of the drug. Propylene glycol showed a 12-fold increase in solubility and 3-fold increase in epidermal accumulation of ciclopirox olamine, while minimizing the transdermal movement of the drug. Thiourea was the selected nail permeation enhancer and propylene glycol was the selected skin penetration enhancer of ciclopirox olamine. A combination of the selected enhancers was also explored for its effect on drug delivery to the nail and nail folds. The enhancer combination reduced the penetration of ciclopirox in the skin and also the permeation through the nail. The proposed preformulation strategy helps to select appropriate enhancers for optimum topical delivery and paves way towards an efficient topical formulation for passive transungual drug delivery.
doi:10.1208/s12249-013-9954-0
PMCID: PMC3666006  PMID: 23572254
ciclopirox olamine; onychomychosis; penetration enhancers; preformulation; topical
4.  A Review of Polymeric Refabrication Techniques to Modify Polymer Properties for Biomedical and Drug Delivery Applications 
AAPS PharmSciTech  2013;14(2):692-711.
Polymers are extensively used in the pharmaceutical and medical field because of their unique and phenomenal properties that they display. They are capable of demonstrating drug delivery properties that are smart and novel, such properties that are not achievable by employing the conventional excipients. Appropriately, polymeric refabrication remains at the forefront of process technology development in an endeavor to produce more useful pharmaceutical and medical products because of the multitudes of smart properties that can be attained through the alteration of polymers. Small alterations to a polymer by either addition, subtraction, self-reaction, or cross reaction with other entities have the capability of generating polymers with properties that are at the level to enable the creation of novel pharmaceutical and medical products. Properties such as stimuli-responsiveness, site targeting, and chronotherapeutics are no longer figures of imaginations but have become a reality through utilizing processes of polymer refabrication. This article has sought to review the different techniques that have been employed in polymeric refabrication to produce superior products in the pharmaceutical and medical disciplines. Techniques such as grafting, blending, interpenetrating polymers networks, and synthesis of polymer complexes will be viewed from a pharmaceutical and medical perspective along with their synthetic process required to attain these products. In addition to this, each process will be evaluated according to its salient features, impeding features, and the role they play in improving current medical devices and procedures.
doi:10.1208/s12249-013-9955-z
PMCID: PMC3665995  PMID: 23543606
alteration; blending; drugs; grafting; interpenetrating polymer networks; medicine; pharmaceutical; polymer complexes; polymer modification
5.  l-Carvyl Esters as Penetration Enhancers for the Transdermal Delivery of 5-Fluorouracil 
AAPS PharmSciTech  2013;14(2):669-674.
To develop effective and safe penetration enhancers, a series of l-carvyl esters, namely, 5-isopropenyl-2-methylcyclohex-2-en-1-yl heptanoate (C-HEP), 5-isopropenyl-2- methylcyclohex-2-en-1-yl octanoate (C-OCT), 5-isopropenyl-2-methylcyclohex-2-en-1-yl decanoate (C-DEC), 5-isopropenyl-2-methylcyclohex-2-en-1-yl dodecanoate (C-DOD), 5-isopropenyl-2-methylcyclohex-2-en-1-yl tetradecanoate (C-TET), and 5-isopropenyl-2-methylcyclohex-2-en-1-yl palmitate (C-PAL), was synthesized from l-carveol and saturated fatty acids (C7–C16). The volatility of l-carveol and l-carvyl esters was evaluated by a live weight loss experiment. The enhancing effects of l-carvyl esters on 5-fluorouracil (FU) were investigated in the in vitro permeation experiment on rat skin. The stratum corneum (SC) uptakes of the enhancers were tested in vitro by gas chromatography. Only the l-carvyl esters with a moderate SC uptake, namely, C-OCT (C8), C-DEC (C10), and C-DOD (C12), showed a potential to enhance FU skin permeation. An evident parabolic relationship was found between the permeation enhancement of FU and the SC uptake of the l-carvyl esters. The l-carvyl esters with a chain length of C8–C12 seemed to be favorable for FU.
doi:10.1208/s12249-013-9952-2
PMCID: PMC3665999  PMID: 23543605
l-carvyl ester; penetration enhancer; skin permeation; stratum corneum uptake; 5-fluorouracil
6.  Influence of Microcrystal Formulation on In Vivo Absorption of Celecoxib in Rats 
AAPS PharmSciTech  2013;14(2):719-726.
The objective of this study was to prepare celecoxib microcrystals using different stabilizers in order to evaluate the influence of microcrystal formulation on the in vitro dissolution rate and in vivo absorption after oral administration of celecoxib in rats. Three celecoxib microcrystals (MC1, MC2, and MC3) were prepared using solvent change method. Microcrystals were evaluated for morphology, particle size, crystallinity, solubility, in vitro dissolution, and in vivo absorption in rats. Scanning electron microscopy images showed distinct differences in the morphologies and dimensions of various celecoxib microcrystals. The particle size of all microcrystals was significantly (P < 0.05) reduced relative to plain celecoxib. The DSC and XRD results revealed that MC1 retain drug crystallinity relative to control crystals, MC2, and MC3. All microcrystals showed marked increase in the drug dissolution parameters particularly MC1 that exhibited a prompt drug release and significantly (P < 0.05) higher values of % dissolution efficiency as compared to control celecoxib and the other microcrystals. The influence of microcrystals on the in vivo absorption of celecoxib was studied in rats in comparison to plain drug. The results of in vivo absorption study in rats indicated that MC1 significantly improved the rate and extent of celecoxib absorption than plain celecoxib. The mean relative bioavailability of MC1 formulation to plain celecoxib was 157.55 ± 20.18%. In conclusion, microcrystal formulation of celecoxib results not only in an enhancement of dissolution parameters but also improves the bioavailability of celecoxib in rats.
doi:10.1208/s12249-013-9957-x
PMCID: PMC3666008  PMID: 23543607
celecoxib; dissolution; in vivo absorption; microcrystals; particle size
7.  Formulation and Development of Extended-Release Micro Particulate Drug Delivery System of Solubilized Rifaximin 
AAPS PharmSciTech  2013;14(2):639-648.
Rifaximin (RFX), a semi-synthetic antibiotic belonging to BCS class IV category, has been used in the treatment of traveler’s diarrhea. An attempt has been made to improve aqueous solubility of RFX in the presence of β-cyclodextrin (β-CD) and hydroxy propyl β-cyclodextrin (HP-β-CD) and control its release in the gut by enteric coating. The stoichiometric proportion of RFX and complexing agent’s β-CD and HP-β-CD were determined by phase solubility studies. RFX–β-CD and RFX–HP-β-CD were prepared in 1:2 ratio by solvent evaporation technique using rota-evaporator with yield of 78% and 84% respectively followed by their evaluation using different techniques such as saturation solubility, Fourier transform infrared, differential scanning calorimeter, powder X-ray diffractometer, in vitro antimicrobial activity. The saturation solubility of RFX had improved from 0.0736 mg/ml to 0.2354 mg/ml and 0.5681 mg/ml in presence of β-CD and HP-β-CD respectively resulting in an increased zone of inhibition in the later complex during antimicrobial studies. The RFX–HP-β-CD complex particles were coated with eudragit L 100 (EL 100) by spray drying technique. The 32 factorial design was applied to formulate the micro particles. All formulations exhibited pH dependant drug release. The % EE was 69% and the release of RFX was retarded by enteric coating in the optimized batch FB2. Therefore, it can be concluded that solubility of some BCS class IV drugs can be improved by β-CD complexation and release of such inclusion complexes can be retarded to increase the residence time of RFX in the gastrointestinal tract.
doi:10.1208/s12249-013-9949-x
PMCID: PMC3666012  PMID: 23516110
cyclodextrin complexes; eudragit L100; micro particles; rifaximin; spray dryer
8.  Formulation and In Vitro Evaluation of Salbutamol Sulphate In Situ Gelling Nasal Inserts 
AAPS PharmSciTech  2013;14(2):712-718.
The aim of this study was to formulate salbutamol sulfate (SS), a model drug, as mucoadhesive in situ gelling inserts having a high potential as nasal drug delivery system bypassing the first-pass metabolism. In situ gelling inserts, each containing 1.4% SS and 2% gel-forming polymer, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose sodium (CMC Na), sodium alginate (AL), and chitosan (CH) were prepared. The inserts were investigated for their different physicochemical properties. The weight of inserts was 16–27 mg, drug content was 3.9–4.2 mg, thickness ranged between 15 and 28 μm and surface pH was 5–7. Cumulative drug released from the inserts exhibited extended release for more than 10 h following the decreasing order: CH > AL > CMC Na > HPMC. The drug release from CMC Na and AL inserts followed zero-order kinetics while HPMC and CH inserts exhibited non-Fickian diffusion mechanism. The inserts exhibited different water uptake (7–23%) with the smallest values for CH. Differential scanning calorimetry study pointed out possible interaction of SS and oppositely charged anionic polymers (CMC Na and AL). The mucoadhesive in situ gelling inserts exhibited satisfactory mucoadhesive and extended drug release characteristics. The inserts could be used for nasal delivery of SS over about 12 h; bypassing the hepatic first-pass metabolism without potential irritation.
doi:10.1208/s12249-013-9956-y
PMCID: PMC3666017  PMID: 23516112
in situ gelling inserts; mucoadhesion; nasal delivery; salbutamol sulfate
9.  Drug-Loaded Zein Nanofibers Prepared Using a Modified Coaxial Electrospinning Process 
AAPS PharmSciTech  2013;14(2):675-681.
This study investigated the preparation of drug-loaded fibers using a modified coaxial electrospinning process, in which only unspinnable solvent was used as sheath fluid. With zein/ibuprofen (IBU) co-dissolving solution and N, N-dimethylformamide as core and sheath fluids, respectively, the drug-loaded zein fibers could be generated continuously and smoothly without any clogging of the spinneret. Field emission scanning electron microscopy and transmission electron microscopy observations demonstrated that the fibers had ribbon morphology with a smooth surface. Their average diameters were 0.94 ± 0.34 and 0.67 ± 0.21 μm when the sheath-to-core flow rate ratios were taken as 0.11 and 0.25, respectively. X-ray diffraction and differential scanning calorimetry verified that IBU was in an amorphous state in all fiber composites. Fourier transform infrared spectra showed that zein had good compatibility with IBU owing to hydrogen bonding. In vitro dissolution tests showed that all the fibers could provide sustained drug release files via a typical Fickian diffusion mechanism. The modified coaxial electrospinning process reported here can expand the capability of electrospinning in generating fibers and provides a new manner for developing novel drug delivery systems.
doi:10.1208/s12249-013-9953-1
PMCID: PMC3666020  PMID: 23516111
coaxial electrospinning; drug-loaded fibers; sheath solvent; sustained release; zein
10.  The Effect of Nonideal Cascade Impactor Stage Collection Efficiency Curves on the Interpretation of the Size of Inhaler-Generated Aerosols 
AAPS PharmSciTech  2013;14(2):497-510.
Cascade impactors, operating on the principle of inertial size separation in (ideally) laminar flow, are used to determine aerodynamic particle size distributions (APSDs) of orally inhaled product (OIP) aerosols because aerodynamic diameter can be related to respiratory tract deposition. Each stage is assumed typically to be an ideal size fractionator. Thus, all particles larger than a certain size are considered collected and all finer particles are treated as penetrating to the next stage (a step function stage efficiency curve). In reality, the collection efficiency of a stage smoothly increases with particle size as an “S-shaped” curve, from approximately 0% to 100%. Consequently, in some cases substantial overlap occurs between neighboring stages. The potential for bias associated with the step-function assumption has been explored, taking full resolution and two-stage abbreviated forms of the Andersen eight-stage nonviable impactor (ACI) and the next-generation pharmaceutical impactor (NGI) as example apparatuses. The behavior of unimodal, log-normal APSDs typical of OIP-generated aerosols has been investigated, comparing known input values to calculated values of central tendency (mass median aerodynamic diameter) and spread (geometric standard deviation, GSD). These calculations show that the error introduced by the step change assumption is larger for the ACI than for the NGI. However, the error is sufficiently small to be inconsequential unless the APSD in nearly monodisperse (GSD ≤1.2), a condition that is unlikely to occur with realistic OIPs. Account may need to be taken of this source of bias only for the most accurate work with abbreviated ACI systems.
Electronic supplementary material
The online version of this article (doi:10.1208/s12249-013-9936-2) contains supplementary material, which is available to authorized users.
doi:10.1208/s12249-013-9936-2
PMCID: PMC3666003  PMID: 23508617
cascade impactor; inhaler aerosol; inhaler testing; size distribution
11.  Evaluation of Colloidal Solid Dispersions: Physiochemical Considerations and In Vitro Release Profile 
AAPS PharmSciTech  2013;14(2):620-628.
Colloidal solid dispersion is an innovative breakthrough in the pharmaceutical industry that overcomes the solubility-related issue of poorly soluble drugs by using an amorphous approach and also the stability-related issue by means of a complex formation phenomenon using different carrier materials. In the present study, a newly developed adsorption method is introduced to incorporate a high-energy sulfathiazole–polyvinylpyrrolidone (Plasdone® K-29/32) solid dispersion on porous silicon dioxide (Syloid® 244FP). Different ternary systems of sulfathiazole–Plasdone® K-29/32–Syloid® 244FP were prepared (1:1:2, 1:1:3, and 1:2:2) and categorized depending on the mechanism by which Syloid® 244FP was incorporated. Modulated differential scanning calorimetry (MDSC), X-ray diffraction, Fourier transform infrared spectroscopy, and in vitro dissolution studies were conducted to characterize the ternary systems. The X-ray diffraction and MDSC data showed a lack of crystallinity in all internal and external ternary systems, suggesting a loss of the crystallinity of sulfathiazole compared to the physical mixtures. USP apparatus II was used to measure the in vitro dissolution rate of the prepared systems at 75 rpm in different media. The dissolution rate of the optimum ratio (1:2:2) containing an internal ternary solid dispersion system was found to be three times higher than that of the external and physical systems. Thus, the porous silicon dioxide incorporated into the conventional binary solid dispersion acted as a carrier to disperse the complex and increase the dissolution rate.
Electronic supplementary material
The online version of this article (doi:10.1208/s12249-013-9947-z) contains supplementary material, which is available to authorized users.
doi:10.1208/s12249-013-9947-z
PMCID: PMC3666021  PMID: 23494469
amorphous; colloidal solid dispersion; FTIR; porous silicon dioxide; ternary solid dispersion
12.  Design of an Interpolyelectrolyte Gastroretentive Matrix for the Site-Specific Zero-Order Delivery of Levodopa in Parkinson’s Disease 
AAPS PharmSciTech  2013;14(2):605-619.
This study focused on developing a gastroretentive drug delivery system employing a triple-mechanism interpolyelectrolyte complex (IPEC) matrix comprising high density, swelling, and bioadhesiveness for the enhanced site-specific zero-order delivery of levodopa in Parkinson’s disease. An IPEC was synthesized and directly compressed into a levodopa-loaded matrix employing pharmaceutical technology and evaluated with respect to its physicochemical and physicomechanical properties and in vitro drug release. The IPEC-based matrix displayed superior mechanical properties in terms of matrix hardness (34–39 N/mm) and matrix resilience (44–47%) when different normality’s of solvent and blending ratios were employed. Fourier transform infrared spectroscopy confirmed the formation of the IPEC. The formulations exhibited pH and density dependence with desirable gastro-adhesion with Peak Force of Adhesion ranging between 0.15 and 0.21 N/mm, densities from 1.43 to 1.54 g/cm3 and swellability values of 177–234%. The IPEC-based gastroretentive matrix was capable of providing site-specific levodopa release with zero-order kinetics corroborated by detailed mathematical and molecular modeling studies. Overall, results from this study have shown that the IPEC-based matrix has the potential to improve the absorption and subsequent bioavailability of narrow absorption window drugs, such as levodopa with constant and sustained drug delivery.
doi:10.1208/s12249-013-9945-1
PMCID: PMC3666024  PMID: 23494468
gastroretention; interpolyelectrolyte complex; levodopa; narrow absorption window drugs; Parkinson’s disease
13.  Solid-State Characterization and Dissolution Properties of Meloxicam–Moringa Coagulant–PVP Ternary Solid Dispersions 
AAPS PharmSciTech  2013;14(2):569-577.
The effect of ternary solid dispersions of poor water-soluble NSAID meloxicam with moringa coagulant (obtained by salt extraction of moringa seeds) and polyvinylpyrrolidone on the in vitro dissolution properties has been investigated. Binary (meloxicam–moringa and meloxicam–polyvinylpyrrolidone (PVP)) and ternary (meloxicam–moringa–PVP) systems were prepared by physical kneading and ball milling and characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffractometry. The in vitro dissolution behavior of meloxicam from the different products was evaluated by means of United States Pharmacopeia type II dissolution apparatus. The results of solid-state studies indicated the presence of strong interactions between meloxicam, moringa, and PVP which were of totally amorphous nature. All ternary combinations were significantly more effective than the corresponding binary systems in improving the dissolution rate of meloxicam. The best performance in this respect was given by the ternary combination employing meloxicam–moringa–PVP ratio of [1:(3:1)] prepared by ball milling, with about six times increase in percent dissolution rate, whereas meloxicam–moringa (1:3) and meloxicam–PVP (1:4) prepared by ball milling improved dissolution of meloxicam by almost 3- and 2.5-folds, respectively. The achieved excellent dissolution enhancement of meloxicam in the ternary systems was attributed to the combined effects of impartation of hydrophilic characteristic by PVP, as well as to the synergistic interaction between moringa and PVP.
doi:10.1208/s12249-013-9941-5
PMCID: PMC3665984  PMID: 23483432
amorphization; moringa coagulant; solubility enhancement; synergism; ternary solid dispersions
14.  Process Optimization of a Novel Immediate Release Film Coating System using QbD Principles 
AAPS PharmSciTech  2013;14(2):531-540.
This work describes a quality-by-design (QbD) approach to determine the optimal coating process conditions and robust process operating space for an immediate release aqueous film coating system (Opadry® 200). Critical quality attributes (CQAs) or associated performance indicators of the coated tablets were measured while coating process parameters such as percent solids of the coating dispersion, coating spray rate, inlet air temperature, airflow rate and pan speed were varied, using a design of experiment protocol. The optimized process parameters were then confirmed by independent coating trials. Disintegration time of coated tablets was not affected by the coating process conditions used in this study, while tablet appearance, as determined by measurement of tablet color, coating defects and gloss was determined to be a CQA. Tablet gloss increased when low spray rate and low percent solids were used, as well as with increased coating pan speed. The study used QbD principles and experimental design models to provide a basis to identify ranges of coating process conditions which afford acceptable product quality. High productivity, color uniformity, and very low defect levels were obtained with Opadry 200 even when using a broad range of coating process conditions.
doi:10.1208/s12249-013-9935-3
PMCID: PMC3666010  PMID: 23483430
film coating; immediate release; Opadry 200; quality by design
15.  Concomitant Pseudopolymorphs of 10-Deacetyl Baccatin III 
AAPS PharmSciTech  2013;14(2):558-568.
Three new solvates [mono-dimethyl sulfoxide (mono-DMSO), mono-dimethyl acetamide (mono-DMA) and mono-dimethyl formamide (mono-DMF)] of 10-Deacetyl baccatin III, were generated by slow evaporation in DMSO, DMF, and DMSO/DMA (1:1) solvent systems respectively. Two concomitant forms mono-DMSO(a new form) and di-DMSO (a known form) were obtained in the DMSO solvent system. Yet two other concomitant forms mono-DMA (a new form) and di-DMSO (a known form) were obtained in DMSO/DMA (1:1) solvent system. A fourth solvate mono-DMF (a new form) was crystallized in unimolar ratio using DMF as a solvent. These solvates were characterized using powder X-ray diffraction, differential scanning calorimeter, thermogravimetric analysis (TGA), and spectroscopic [13C solid-state nuclear magnetic spectroscopy, solution 1H NMR, and Fourier transform infrared] techniques. The interactions between host and guest molecules were elucitated by single-crystal X-ray diffraction data. In all the cases, guest molecules are connected to the host molecules by O–H···O hydrogen bonds. A remarkable difference in the desolvation onset temperatures of di- and mono-DMSO solvates was observed which was also featured by a corresponding weight loss during TGA analysis.
doi:10.1208/s12249-013-9940-6
PMCID: PMC3666025  PMID: 23483431
10-deacetyl baccatin III; concomitant; pseudopolymorphs; solid-state characterization
16.  PEGylated Single-Walled Carbon Nanotubes as Nanocarriers for Cyclosporin A Delivery 
AAPS PharmSciTech  2013;14(2):593-600.
Single-walled carbon nanotubes (SWCNTs) have attracted the attention of many researchers due to their remarkable physicochemical features and have been found to be a new family of nanovectors for the delivery of therapeutic molecules. The ability of these nanostructures to load large amounts of drug molecules on their outer surface has been considered as the main advantage by many investigators. Here, we report the development of a PEGylated SWCNT-mediated delivery system for cyclosporin A (CsA) as a potent immunosuppressive agent. The available OH group in the CsA structure was first linked to a bi-functional linker (i.e., succinic anhydride) in order to provide a COOH terminal group. CsA succinylation process was optimized by using the modified simplex method. The resulting compound, CsA–CO–(CH2)2–COOH, was then grafted onto the exterior surface of SWCNTs, previously PEGylated with phospholipid–PEG5000–NH2 conjugates, through the formation of an amide bond with the free amine group of PEGylated SWCNTs. Drug loading, stability of the PEGylated SWCNT–CsA complex, and in vitro release of the drug were evaluated. Loading efficiencies of almost 72% and 68% were achieved by UV spectrophotometry and elemental analysis methods, respectively. It was observed that 57.3% of cyclosporine was released from CsA–Pl–PEG5000–SWCNTs after 3 days. In this investigation, we conjugated CsA to an amine-terminated phospholipid–polyethylene glycol chain attached on SWCNTs via a cleavable ester bond and demonstrated the possible potential of PEGylated SWCNT-based systems for CsA delivery.
doi:10.1208/s12249-013-9944-2
PMCID: PMC3666015  PMID: 23479049
carbon nanotubes; cyclosporin A; drug loading; elemental analysis; functionalization
17.  Improving Oral Bioavailability and Pharmacokinetics of Liposomal Metformin by Glycerolphosphate–Chitosan Microcomplexation 
AAPS PharmSciTech  2013;14(2):485-496.
The purpose of this study was to develop a new delivery system capable of improving bioavailability and controlling release of hydrophilic drugs. Metformin-loaded liposomes were prepared and to improve their stability surface was coated with chitosan cross-linked with the biocompatible β-glycerolphosphate. X-ray diffraction, differential scanning calorimetry, as well as rheological analysis were performed to investigate interactions between chitosan and β-glycerolphosphate molecules. The entrapment of liposomes into the chitosan-β-glycerolphosphate network was assessed by scanning electron microscopy and transmission electron microscopy. Swelling and mucoadhesive properties as well as drug release were evaluated in vitro while the drug oral bioavailability was evaluated in vivo on Wistar rats. Results clearly showed that, compared to control, the proposed microcomplexes led to a 2.5-fold increase of metformin Tmax with a 40% augmentation of the AUC/D value.
doi:10.1208/s12249-013-9926-4
PMCID: PMC3666019  PMID: 23471836
chitosan; controlled release; in vivo bioavailability; liposomes; oral delivery
18.  Validation of a New 96-Well Plate Spectrophotometric Method for the Quantification of Compound 48/80 Associated with Particles 
AAPS PharmSciTech  2013;14(2):649-655.
A new, simple, inexpensive, and rapid 96-well plate UV spectrophotometric method was developed and validated for the quantification of compound 48/80 (C48/80) associated with particles. C48/80 was quantified at 570 nm after reaction with acetaldehyde and sodium nitroprusside in an alkaline solution (pH 9.6). The method was validated according to the recommendations of the ICH Guidelines for specificity, linearity, range, accuracy, precision, and detection and quantification limits (DL and QL). All the validation parameters were assessed in three different solvents, i.e., deionized water, blank matrix of chitosan nanoparticles, and blank matrix of chitosan/alginate nanoparticles. The method was found to be linear in the concentration range of 5 to 160 μg/ml (R2 > 0.9994). Intraday and interday precision was adequate, with relative standard deviation lower than those given by the Horwitz equation. The mean recoveries of C48/80 from spiked samples ranged between 98.1% and 105.9% for calibration curves done with the blank matrices and between 89.3% and 103.3% for calibration curves done with water, respectively. The DL were lower than 1.01 μg/ml and the QL were lower than 3.30 μg/ml. The results showed that the developed method is sensitive, linear, precise, and accurate for its intended use, with the additional advantages of being cost-effective and time-effective, allowing the use of small-volume samples, and the simultaneous analysis of a large number of samples. The proposed method was already successfully applied to evaluate the loading efficacy of C48/80 chitosan-based nanoparticles and can be easily applied during the development of other C48/80-based formulations.
doi:10.1208/s12249-013-9950-4
PMCID: PMC3665997  PMID: 23468340
C48/80; chitosan nanoparticles; mast cell activator; method validation; p-Methoxy-N-methylphenethylamine
19.  An Automated System for Monitoring and Regulating the pH of Bicarbonate Buffers 
AAPS PharmSciTech  2013;14(2):517-522.
The bicarbonate buffer is considered as the most biorelevant buffer system for the simulation of intestinal conditions. However, its use in dissolution testing of solid oral dosage forms is very limited. The reason for this is the thermodynamic instability of the solution containing hydrogen carbonate ions and carbonic acid. The spontaneous loss of carbon dioxide (CO2) from the solution results in an uncontrolled increase of the pH. In order to maintain the pH on the desired level, either a CO2 loss must be completely avoided or the escaped CO2 has to be replaced by quantitative substitution, i.e. feeding the solution with the respective amount of gas, which re-acidifies the buffer after dissociation. The present work aimed at the development of a device enabling an automatic pH monitoring and regulation of hydrogen carbonate buffers during dissolution tests.
doi:10.1208/s12249-013-9933-5
PMCID: PMC3666009  PMID: 23468339
bicarbonate media; hydrogen carbonate buffer; modified release; physiological buffers; biorelevant dissolution
20.  Nano-extrusion: a One-Step Process for Manufacturing of Solid Nanoparticle Formulations Directly from the Liquid Phase 
AAPS PharmSciTech  2013;14(2):601-604.
This paper presents a novel one-step process for converting a liquid stabilized nano-suspension into a solid formulation via hot-melt extrusion combined with an internal devolatilization process (nano-extrusion, NANEX). A polymer (Soluplus®) was fed into the extruder and molten, after which a stable nano-suspension was added via side-feeding devices. The solvent (water) was removed by devolatilization and the polymer solidified at the outlet. The solid material can be tableted or filled in a capsule directly. The results showed that the obtained extrudates comprised nanocrystals in the de-aggregated form, confirming that a solid nano-formulation was prepared. This method is capable of overcoming many of the problems associated with other processes involving solid nano-dosage forms and poses a straightforward approach towards manufacturing such products.
doi:10.1208/s12249-013-9946-0
PMCID: PMC3665983  PMID: 23463263
hot-melt extrusion; nano-suspension; one-step process; solid nano-formulation
21.  Chitosan-Modified PLGA Nanoparticles with Versatile Surface for Improved Drug Delivery 
AAPS PharmSciTech  2013;14(2):585-592.
Shortage of functional groups on surface of poly(lactide-co-glycolide) (PLGA)-based drug delivery carriers always hampers its wide applications such as passive targeting and conjugation with targeting molecules. In this research, PLGA nanoparticles were modified with chitosan through physical adsorption and chemical binding methods. The surface charges were regulated by altering pH value in chitosan solutions. After the introduction of chitosan, zeta potential of the PLGA nanoparticle surface changed from negative charge to positive one, making the drug carriers more affinity to cancer cells. Functional groups were compared between PLGA nanoparticles and chitosan-modified PLGA nanoparticles. Amine groups were exhibited on PLGA nanoparticle surface after the chitosan modification as confirmed by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. The modified nanoparticles showed an initial burst release followed by a moderate and sustained release profile. Higher percentage of drugs from cumulative release can be achieved in the same prolonged time range. Therefore, PLGA nanoparticles modified by chitosan showed versatility of surface and a possible improvement in the efficacy of current PLGA-based drug delivery system.
doi:10.1208/s12249-013-9943-3
PMCID: PMC3665987  PMID: 23463262
chitosan; drug delivery system; nanoparticles; PLGA; versatility
22.  The Effect of N-Alkyl Substituents on the Usability of Imidazolium Cation-Based Ionic Liquids in Microemulsion Systems: A Technical Note 
AAPS PharmSciTech  2013;14(2):551-557.
doi:10.1208/s12249-013-9939-z
PMCID: PMC3666005  PMID: 23463260
drug delivery; hemolysis; imidazolium; ionic liquids; microemulsion
23.  Photodegradation of Fleroxacin Injection: II. Kinetics and Toxicological Evaluation 
AAPS PharmSciTech  2013;14(2):578-584.
Photodegradation kinetics of fleroxacin were investigated in different injections. Five commercial formulations were analyzed before and after irradiation by determining residual volumes of fleroxacin with high-pressure liquid chromatography (HPLC), and different decomposition functions and models were obtained. Concentration levels of fleroxacin in injections caused the differences in photodegradation kinetics instead of ingredients. Influences of different pH values and presence of NaCl on photodegradation of fleroxacin were observed. Low pH value decreased the efficacy of photolysis and enhanced photostability of fleroxacin injections. Tentative structure of a new degradation product afforded was proposed. An acute toxicity assay using the bioluminescent bacterium Q67 was performed for fleroxacin injections after exposure to light. The research proved that fleroxacin was more photolabile in dilute injection, and acute toxicity of dilute injection increased more rapidly than that of concentrated injection during irradiation.
doi:10.1208/s12249-013-9942-4
PMCID: PMC3666016  PMID: 23463261
fleroxacin injection; kinetics; photodegradation; toxicity
24.  The Influence of Recrystallized Caffeine on Water-Swellable Polymethacrylate Mucoadhesive Buccal Films 
AAPS PharmSciTech  2013;14(2):475-484.
The aim of this work was to investigate the influence of particles on the properties of polymethacrylate films intended for buccal delivery. A solvent casting method was used with Eudragit RS and RL (ERS and ERL, respectively) as film-forming rate-controlling polymers, with caffeine as a water-soluble model drug. The physicochemical properties of the model films for a series of formulations with increasing concentrations of caffeine were determined in terms of morphology, mechanical and mucoadhesive properties, drug content uniformity, and drug release and associated kinetics. Typically regarded as non-mucoadhesive polymers, ERS and mainly ERL, were found to be good mucoadhesives, with ERL01 exhibiting a work of mucoadhesion (WoA) of 118.9 μJ, which was about five to six times higher than that observed for commonly used mucoadhesives such as Carbopol® 974P (C974P, 23.9 μJ) and polycarbophil (PCP, 17.4 μJ). The mucoadhesive force for ERL01 was found to be significantly lower yet comparable to C974P and PCP films (211.1 vs. 329.7 and 301.1 mN, respectively). Inspection of cross-sections of the films indicated that increasing the concentration of caffeine was correlated with the appearance of recrystallized agglomerates. In conclusion, caffeine agglomerates had detrimental effects in terms of mucoadhesion, mechanical properties, uniformity, and drug release at large particle sizes. ERL series of films exhibited very rapid release of caffeine while ERS series showed controlled release. Analysis of release profiles revealed that kinetics changed from a diffusion controlled to a first-order release mechanism.
doi:10.1208/s12249-012-9891-3
PMCID: PMC3666026  PMID: 23456475
buccal films; caffeine; Eudragit®; mucoadhesive polymer; solvent casting
25.  Real-Time Particle Size Analysis Using Focused Beam Reflectance Measurement as a Process Analytical Technology Tool for a Continuous Granulation–Drying–Milling Process 
AAPS PharmSciTech  2013;14(2):523-530.
Focused beam reflectance measurement (FBRM) was used as a process analytical technology tool to perform inline real-time particle size analysis of a proprietary granulation manufactured using a continuous twin-screw granulation–drying–milling process. A significant relationship between D20, D50, and D80 length-weighted chord length and sieve particle size was observed with a p value of <0.0001 and R2 of 0.886. A central composite response surface statistical design was used to evaluate the effect of granulator screw speed and Comil® impeller speed on the length-weighted chord length distribution (CLD) and particle size distribution (PSD) determined by FBRM and nested sieve analysis, respectively. The effect of granulator speed and mill speed on bulk density, tapped density, Compressibility Index, and Flowability Index were also investigated. An inline FBRM probe placed below the Comil-generated chord lengths and CLD data at designated times. The collection of the milled samples for sieve analysis and PSD evaluation were coordinated with the timing of the FBRM determinations. Both FBRM and sieve analysis resulted in similar bimodal distributions for all ten manufactured batches studied. Within the experimental space studied, the granulator screw speed (650–850 rpm) and Comil® impeller speed (1,000–2,000 rpm) did not have a significant effect on CLD, PSD, bulk density, tapped density, Compressibility Index, and Flowability Index (p value > 0.05).
doi:10.1208/s12249-013-9934-4
PMCID: PMC3666011  PMID: 23435807
continuous granulation-drying-milling; focused beam reflectance measurement (FBRM); process analytical technology (PAT); real-time particle size measurement

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