An HPLC chromatographic reactor approach for investigating the hydrolytic stability of a pharmaceutical compound

Skrdla, Peter J.; Abrahim, Ahmed; Wu, Yan

doi:10.1016/j.jpba.2006.02.005

Cited by 19 publications

(6 citation statements)

References 8 publications

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“…analysis literature), the time-independent/potential energy/enthalpic portion of the activation energy is in very good agreement to the solution-phase values obtained in previous studies (where the FD conversion kinetics were observed to be simple first order, not dispersive) [2]. Using the β parameter (which was used to obtain S ‡ (T ,t), according to Eq.…”

Section: Resultssupporting

confidence: 88%

“…While AP is a chemically stable, nonhygroscopic, crystalline compound, FD is a hygroscopic, amorphous compound that readily decomposes to produce AP (via a hydrolysis mechanism) in both solution and the solid state, primarily at elevated temperatures. The solutionphase chemical reactivity of FD was recently investigated using a high-throughput/high-speed "HPLC column reactor" approach, and the kinetic parameters extracted from the data (i.e., the apparent activation energy and the apparent frequency factor) were found to be comparable to the "true" values obtained using a more traditional, batch reactor approach employing the standard Arrhenius equation [2]. While good agreement between the two approaches was achieved, thus lending support for the continued use of the former, more efficient methodology, the kinetic information obtained in these studies remains fundamentally applicable only to the solution phase, not to the solid state.…”

Section: Introductionmentioning

confidence: 94%

“…Figure 1 shows the molecular structure of FD. As mentioned in the Introduction, cleavage of the phosphate moiety on the molecule, to produce AP, occurs via a hydrolysis mechanism (which is first order in dissolved FD, in solution [2]). It should be noted that the water content in typical FD lots can vary from ∼0.1 to 2.0% (w/w); the content of the specific lot of API used in this study was determined to be 1.1% (w/w) by coulometric Karl-Fischer (KF) titration.…”

Section: Ap/fd Monitoring Via Hplcmentioning

confidence: 99%

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Use of real‐time FT‐IR monitoring of a pharmaceutical compound under stress atmospheric conditions to characterize its solid‐state degradation kinetics

Skrdla

Harrington

Lin

2009

Int J of Chemical Kinetics

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The use of online FT-IR is described for investigating the degradation kinetics of the solid amorphous pharmaceutical compound, fosaprepitant dimeglumine (FD), under stress storage conditions (i.e., high temperature, T, and humidity, % RH). It is found that under conditions of elevated T and % RH, the kinetics are denucleation rate limited for the deliquescence of the amorphous FD solid, based on the high quality fits obtained to the authors' dispersive kinetic model for that mechanism. At elevated T and low % RH, it is found that a classical, first-order hydrolysis mechanism for the degradation of FD (which forms crystalline aprepitant, AP) significantly contributes to the overall conversion rate. That mechanism is similar to the one observed previously for the solution-phase hydrolysis of FD. Appropriate kinetic models are proposed for the FD-to-AP conversion under all of the experimental conditions investigated in this work. C 2009 Wiley Periodicals, Inc. Int J Chem Kinet 42: 25

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Section: Resultssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 94%

Section: Ap/fd Monitoring Via Hplcmentioning

confidence: 99%

See 1 more Smart Citation

Use of real‐time FT‐IR monitoring of a pharmaceutical compound under stress atmospheric conditions to characterize its solid‐state degradation kinetics

Skrdla

Harrington

Lin

2009

Int J of Chemical Kinetics

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“…High-performance liquid chromatography (HPLC) and the chromatographic reactor approach, with solution-phase hydrolysis kinetics can be used for an aprepitant (EmendTM) prodrug and fosaprepitant dimeglumine. [18] In loratidine, the impurity found was ofloratidine;[19] other examples include celecoxib[20] and amikacin. [21]…”

Section: Photolytic Cleavagementioning

confidence: 99%

Recent trends in the impurity profile of pharmaceuticals

Pilaniya¹,

Chandrawanshi²,

Pilaniya³

et al. 2010

J Adv Pharm Technol Res

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Various regulatory authorities such as the International Conference on Harmonization (ICH), the United States Food and Drug administration (FDA), and the Canadian Drug and Health Agency (CDHA) are emphasizing on the purity requirements and the identification of impurities in Active Pharmaceutical Ingredients (APIs). The various sources of impurity in pharmaceutical products are — reagents, heavy metals, ligands, catalysts, other materials like filter aids, charcoal, and the like, degraded end products obtained during \ after manufacturing of bulk drugs from hydrolysis, photolytic cleavage, oxidative degradation, decarboxylation, enantiomeric impurity, and so on. The different pharmacopoeias such as the British Pharmacopoeia, United State Pharmacopoeia, and Indian Pharmacopoeia are slowly incorporating limits to allowable levels of impurities present in APIs or formulations. Various methods are used to isolate and characterize impurities in pharmaceuticals, such as, capillary electrophoresis, electron paramagnetic resonance, gas–liquid chromatography, gravimetric analysis, high performance liquid chromatography, solid-phase extraction methods, liquid–liquid extraction method, Ultraviolet Spectrometry, infrared spectroscopy, supercritical fluid extraction column chromatography, mass spectrometry, Nuclear magnetic resonance (NMR) spectroscopy, and RAMAN spectroscopy. Among all hyphenated techniques, the most exploited techniques for impurity profiling of drugs are Liquid Chromatography (LC)-Mass Spectroscopy (MS), LC-NMR, LC-NMR-MS, GC-MS, and LC-MS. This reveals the need and scope of impurity profiling of drugs in pharmaceutical research.

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“…Estimation of impurities and Diastereomers in APT bulk drug substance [6], Characterization and Quantization of APT drug substance polymorphs by Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy [7], stability of an extemporaneous oral liquid APT formulation [8], estimation of APT capsules by RP-HPLC [9], Stability-indicating HPLC method for quantitative analysis of APT [3,10] were reported. Metabolic disposition of Aprepitant in rats and dogs was also reported [11].…”

mentioning

confidence: 99%

Determination of Aprepitant in Human Plasma by Using LC-MS/MS with Electrospray Ionization

PVDLS¹

2013

JBB

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A precise, sensitive and high throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of Aprepitant (APT) in human plasma was developed and validated using Quetiapine (QTP) as internal standard. The analyte and internal standard were extracted from human plasma using liquid-liquid extraction. Chromatographic separation was performed on Discovery C18 10 cm×4.6 mm, 5 μm column with an isocratic mobile phase composed of 5 mM Ammonium Acetate (pH 4.00):Acetonitrile (10:90), at a flow-rate of 0.9 ml/ min. The MS-MS detection was performed on a AB Sciex API 3200 tandem mass spectrometer operated in Multiple reaction monitoring (MRM) at positive mode at m/z 535.10/277.10 and 384.00/253.10 for APT and QTP respectively. A linear dynamic range of 10.004-5001.952 ng/ml for APT was evaluated with mean correlation coefficient (r) of 0.9991. The precision of the assay (expressed as coefficient of variation, CV) was less than 15% at concentrations of LQC, MQC, HQC and was less than 20% for LLOQQC. Percent recoveries for APT at high, middle and low quality control samples was found to be 71.9%, 68.0%, and 63.8% respectively and for internal standard 77.7%. The analyte was found to be stable throughout five freeze-thawing cycles, bench top, wet extract, dry extract, auto sampler and interim stability studies. Therefore, the proposed method was found to be suitable for the routine quality control analysis of Aprepitant in human plasma in bioequivalence studies.

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An HPLC chromatographic reactor approach for investigating the hydrolytic stability of a pharmaceutical compound

Cited by 19 publications

References 8 publications

Use of real‐time FT‐IR monitoring of a pharmaceutical compound under stress atmospheric conditions to characterize its solid‐state degradation kinetics

Use of real‐time FT‐IR monitoring of a pharmaceutical compound under stress atmospheric conditions to characterize its solid‐state degradation kinetics

Recent trends in the impurity profile of pharmaceuticals

Determination of Aprepitant in Human Plasma by Using LC-MS/MS with Electrospray Ionization

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