Abstract:
:Health authorities require that suitable stability of the drug substance be shown in relevant materials of construction. ICH Q1A(R2) explicitly states that "stability studies should be conducted on drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution". Stainless steel containers are commonly used for the long-term storage of frozen bulk drug substances (DSs). Hastelloy®-based metal containers are sometimes used due to their higher corrosion resistance and significantly lower iron content to mitigate the potential corrosion-related risks associated with high salt formulations. Despite their benefits, we have found that elevated temperature stability studies in small scale Hastelloy® containers can lead to degradation that is not representative of degradation under typical storage conditions relevant to the manufacturing process. We provide evidence for an oxidation-induced aggregation mechanism that is based on Fenton chemistry with peroxide being supplied by the autoxidation of polysorbate at stress temperatures. Further, variation in the rates of iron leaching between individual small scale containers is shown to be the cause of the variable rates of degradation through strong correlations between leached iron levels and the extents of oxidation and aggregation. The addition of a metal chelator or the removal of polysorbate from the formulation mitigates the oxidation and the non-representative behavior. Extended characterization by LC-MS and 18O labeled peptide mapping shows that a significant portion of the aggregate formed under these conditions is covalently crosslinked and that the predominant covalent species is either a dityrosine or tyrosine-tryptophan crosslink between an Fc peptide and a Fab peptide. This report is the first time either of these two crosslinks have been reported for antibodies with detailed analytical characterization. Because the behavior observed in these studies is not representative of degradation under typical storage conditions relevant to the manufacturing process, this study demonstrates that small scale stress studies in metal containers should be performed with caution and that extended incubation times can lead to non-representative degradation mechanisms.
journal_name
J Pharm Scijournal_title
Journal of pharmaceutical sciencesauthors
Klair N,Kim MT,Lee A,Xiao NJ,Patel ARdoi
10.1016/j.xphs.2020.09.052subject
Has Abstractpub_date
2020-10-07 00:00:00eissn
0022-3549issn
1520-6017pii
S0022-3549(20)30583-9pub_type
杂志文章abstract::The plasma protein binding of zomepirac, a new nonnarcotic analgesic, was studied using equilibrium dialysis. Experiments were performed using human plasma and plasma from mice, rats, and rhesus monkeys, all species of pharmacological or toxicological interest. At concentrations approximating those achieved in vivo, t...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600700733
更新日期:1981-07-01 00:00:00
abstract::Hydrogen triiodide adducts were prepared from N,N-dimethylacetamide, N-alkylpyrrolidone derivatives, and polyvinylpyrrolidone, and their structures were investigated by IR spectra and X-ray structure analyses and compared with the structure of povidone-iodine USP. The results suggest that the iodine in povidone-iodine...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600681211
更新日期:1979-12-01 00:00:00
abstract::Reported estrone pKa and solubility data show wide variation. Improved experimental procedures were designed and used to obtain reproducible results. The pKa values for several estrogens and related compounds also were determined to assess the effects of structural differences on ionization. No evidence was obtained f...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600660504
更新日期:1977-05-01 00:00:00
abstract::The quantitative determinations of phenol in phenolated calamine lotion USP and of phenol and resorcinol in phenol-resorcinol-boric acid solution by high-pressure liquid chromatography are reported. The procedures are simple, rapid (no special preliminary treatment is required), and accurate. There is no interference ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600651139
更新日期:1976-11-01 00:00:00
abstract::(6R,7R)-7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxy- iminoacetamid]-3- [(4-carbamoyl-1-quinuclidinio)methyl]-8-oxo-5-thia-1-azabicyclo [4,2,0]oct-2-ene-2-carboxylate (1; E1040) was isolated as alpha-(decahydrate), beta-(pentahydrate), and gamma-form (anhydrate) crystals and the X-ray amorphous form. The relatio...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600781103
更新日期:1989-11-01 00:00:00
abstract::An isothermal chromatographic (GC) method employing an SE-30 column and flame-ionization detection has been developed for the simultaneous assay of methyl, ethyl, propyl, and butyl 4-hydroxybenzoates and 4-hydroxybenzoic acid in liquid antacid formulations. The method, which uses a silica column chromatographic cleanu...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600730136
更新日期:1984-01-01 00:00:00
abstract::The effects of permeant charge (z) on iontophoretic-enhanced transport were investigated with synthetic Nucleopore membranes and with human epidermal membranes using a four-electrode potentiostat with side-by-side diffusion cells. The modified Nernst-Planck model (Nernst-Planck theory with an additional transport term...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1021/js960479m
更新日期:1997-06-01 00:00:00
abstract::The impact of intestinal conjugative metabolism on oral bioavailability was assessed by sequential and simultaneous analyses of the reported data in humans. The data were retrieved from reports on drugs that are metabolized by sulfate conjugation, and the organ availabilities affecting oral bioavailability were differ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.20269
更新日期:2005-03-01 00:00:00
abstract::It is shown that a suitable dosage interval, tau, can be estimated by a factor times the sum of the mean residence time (MRT) of the central compartment (MRTC) and the MRT of the absorption site (MRTA). This value of tau will provide a ratio, maximum steady-state plasma concentration: minimum steady-state plasma conce...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600760111
更新日期:1987-01-01 00:00:00
abstract::A rapid approach for estimating the pK(a) value of small organic molecules was developed using vacuum-assisted multiplexed capillary electrophoresis (VAMCE) with ultraviolet detection. The VAMCE method employed a 96-capillary array, arranged in a standard 8 x 12 microtiter plate configuration, with each row of capilla...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.20275
更新日期:2005-03-01 00:00:00
abstract::The absorption of the model drug carbenoxolone was reevaluated using an in situ rat intestinal perfusion technique in which disappearance from the intestinal lumen, binding to the perfused jejunal segment, and appearance in the mesenteric (jejunal) vein were measured. The effect of the degree of ionization on these pr...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600790510
更新日期:1990-05-01 00:00:00
abstract::Recent in vitro and in vivo studies have suggested transscleral iontophoresis as a means for non-invasive drug delivery to the eye. However, there remains a lack of information of the iontophoretic transport behavior of the sclera. The objective of the present study was to investigate the effects of permeant concentra...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.20293
更新日期:2005-04-01 00:00:00
abstract::Controlling residual solvent levels is a major concern in pharmaceutical freeze-drying from co-solvent systems. This review provides an overview of the factors influencing this process and estimates their potential to reduce residual solvents in freeze-dried products. Decreased solvent contents are potentially correla...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章,评审
doi:10.1016/j.xphs.2018.04.001
更新日期:2018-08-01 00:00:00
abstract::Poly(methyl [1-14C]methacrylate) nanoparticles were injected subcutaneously into rats. Almost all of the radioactivity stayed at the injection site. After an initial urinary and fecal excretion of approximately 1% of the administered dose per day, the rate of elimination dropped to a low level (approximately 0.005%/da...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600721009
更新日期:1983-10-01 00:00:00
abstract::Lipids were extracted from human stratum corneum and the remaining corneocytes were reaggregated with different lyotropic liquid crystals. Water transport through the reaggregated stratum corneum was determined using a diffusion chamber according to Smith and Blank. The permeability constant for the reaggregated strat...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600800506
更新日期:1991-05-01 00:00:00
abstract::A high-performance liquid chromatographic method with spectrofluorometric detection has been developed for the analysis of a new substituted benzamide and its metabolite in body fluids. The detection was performed at 270 nm for excitation, and 370 nm for emission. The proposed technique is selective, reliable, and sen...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600790617
更新日期:1990-06-01 00:00:00
abstract::The blood-brain barrier permeation has been investigated by using a topological substructural molecular design approach (TOPS-MODE). A linear regression model was developed to predict the in vivo blood-brain partitioning coefficient on a data set of 119 compounds, treated as the logarithm of the blood-brain concentrat...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.20081
更新日期:2004-07-01 00:00:00
abstract::Quantitative prediction of unbound drug fraction (fu) is essential for scaling pharmacokinetics through physiologically based approaches. However, few attempts have been made to evaluate the projection of fu values under pathological conditions. The primary objective of this study was to predict fu values (n = 105) of...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1016/j.xphs.2018.02.021
更新日期:2018-07-01 00:00:00
abstract::Minitablets are an appealing option for an age-appropriate pediatric dosage form. In particular, for combination therapies where multiple active ingredients are dosed simultaneously, the use of minitablets will enable independent adjustments of each dose. The work presented describes the development of Compound A and ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1016/j.xphs.2020.08.021
更新日期:2020-12-01 00:00:00
abstract::(13)C labeling was used to enhance the sensitivity of (13)C solid-state NMR to study the effect of tabletting on the polymorphism of a steroidal drug. The steroidal drug Org OD 14 was (13)C labeled and formulated into tablets containing only 0.5-2.5% active ingredient. The tablets were subsequently studied by solid-st...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.20236
更新日期:2005-02-01 00:00:00
abstract::In water, the antineoplastic drug cisplatin, cis-[PtCl2(NH3)2] (1) hydrolyses slowly to the aqua complexes cis-[Pt(NH3)2Cl(H2O)]+ (2) and, to a small extent, cis-[Pt(NH3)2(H2O)2]2+ (3), which are thought to play an important role in the metabolism of cisplatin. HPLC is a useful technique for monitoring 2 and 3, but on...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1021/js980287m
更新日期:1999-03-01 00:00:00
abstract::An HPLC methodology is described which enables the quantitation of thiothixene (N,N-dimethyl-9-[3-(4-methyl-1-piperazinyl)-propylidene]thioxanthe ne-2- sulfonamide) in bulk drug, finished product, and dissolution samples using a single analytical column (SiAl: a mixture of silica and alumina). The Z (cis) and the less...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600760310
更新日期:1987-03-01 00:00:00
abstract::Biopharmaceutics Classification System and Biopharmaceutics Drug Distribution Classification System are complimentary, not competing, classification systems that aim to improve, simplify, and speed drug development. Although both systems are based on classifying drugs and new molecular entities into four categories us...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章,评审
doi:10.1002/jps.23359
更新日期:2013-01-01 00:00:00
abstract::The work aims to provide evidence on the viability of Lactobacillus spp. and a spore form of Bacillus subtilis from nonprocessed bacteria to coated dosage forms (i.e., mini-tablets, pellets, and their coated forms). Lactobacillus spp. were cultivated overnight in MRS broth (10(9) cfu/mL) and B. subtilis spores were pr...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.21609
更新日期:2009-09-01 00:00:00
abstract::The oral dose metabolism of dilazep dihydrochloride [tetrahydro-1H-1,4-diazepine-1,4(5H)-dipropanol 3,4,5-trimethoxybenzoate] was examined in six hypertensive patients receiving a single oral dose of 600 mg of dilazep (3-3.8 mg/kg BW). Blood was collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 h after administratio...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600780404
更新日期:1989-04-01 00:00:00
abstract::The in vitro binding of warfarin by human serum albumin was studied at various temperatures and at pH 7.4 by a frontal gel filtration technique. The results can be best described in terms of a two class-of-binding site model, in which the numbers of primary and secondary sites are constrained to the average values for...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600651127
更新日期:1976-11-01 00:00:00
abstract::This article shows how milling can be used to explore the phase diagram of pharmaceuticals. This process has been applied to sulindac. A short milling has been found to trigger a polymorphic transformation between form II and form I upon heating which is not seen in the nonmilled material. This possibility was clearly...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1016/j.xphs.2019.03.017
更新日期:2019-08-01 00:00:00
abstract::Herein, curcumin amorphous solid dispersions (Cur ASDs) were prepared using binary polymers (Eudragit EPO with polyvinylpyrrolidone K30 [EuD-PVP], Eudragit EPO with hydroxypropyl methylcellulose E50 [EuD-HPMC]) as excipient, and surface tracking of Cur ASDs was mainly addressed. Infrared spectroscopy, in situ Raman im...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1016/j.xphs.2019.10.030
更新日期:2020-02-01 00:00:00
abstract::Glasses were prepared from a number of barbiturates. The viscosities and glass transition temperatures of the glasses were dependent on the structure of the groups present on the C-5 and N-1 atoms. Solid dispersions were prepared from three selected barbiturates formulated with citric acid. The glass transition temper...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600671126
更新日期:1978-11-01 00:00:00
abstract::Small particles of two steroids, cholesteryl acetate and beta-sitosterol, were prepared by the following technique. The steroid was dissolved in an organic solvent, which was emulsified in water in the presence of surfactant, thus giving a water-continuous emulsion. As the organic solvent was evaporated, the steroid p...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600820608
更新日期:1993-06-01 00:00:00