Identification, isolation and characterization of process related impurities in ezetimibe

Guntupalli, Srikanth; Ray, Uttam Kumar; Murali, N.; Gupta, PBadarinadh; Kumar, Vundavilli Jagadeesh; Satheesh, D.; Islam, Aminul

doi:10.1016/j.jpba.2013.09.020

Cited by 19 publications

(11 citation statements)

References 11 publications

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“…The inclusion complexation could have involved formation of hydrogen bonds between the drug and HPBCD which was also suggested by the proton shifts recorded in H-NMR studies. The NMR spectrum of free drug was the same as reported by Guntupalli et al [33]. Eze has 13 different types of protons and some protons experienced upfield shifts and others, downfield.…”

Section: Discussionsupporting

confidence: 59%

Improved Aqueous Solubility and Antihypercholesterolemic Activity of Ezetimibe on Formulating with Hydroxypropyl-β-Cyclodextrin and Hydrophilic Auxiliary Substances

Srivalli

Mishra

2015

AAPS PharmSciTech

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Abstract. The purpose of this study was to improve the aqueous solubility, dissolution, and pharmacodynamic properties of a BCS class II drug, ezetimibe (Eze) by preparing ternary cyclodextrin complex systems. We investigated the potential synergistic effect of two novel hydrophilic auxiliary substances, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and L-ascorbic acid-2-glucoside (AA2G) on hydroxypropyl-β-cyclodextrin (HPBCD) solubilization of poorly water-soluble hypocholesterolemic drug, Eze. In solution state, the binary and ternary systems were analyzed by phase solubility studies and Job's plot. The solid complexes prepared by freeze-drying were characterized by Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), nuclear magnetic resonance (NMR), and scanning electron microscopy (SEM). The log P values, aqueous solubility, dissolution, and antihypercholesterolemic activity of all systems were studied. The analytical techniques confirmed the formation of inclusion complexes in the binary and ternary systems. HPBCD complexation significantly (p<0.05) reduced the log P and improved the solubility, dissolution, and hypocholesterolemic properties of Eze, and the addition of ternary component produced further significant improvement (p<0.05) even compared to binary system. The remarkable reduction in log P and enhancement in solubility, dissolution, and antihypercholesterolemic activity due to the addition of TPGS or AA2G may be attributed to enhanced wetting, dispersibility, and complete amorphization. The use of TPGS or AA2G as ternary hydrophilic auxiliary substances improved the HPBCD solubilization and antihypercholesterolemic activity of Eze.

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Section: Discussionsupporting

confidence: 59%

Improved Aqueous Solubility and Antihypercholesterolemic Activity of Ezetimibe on Formulating with Hydroxypropyl-β-Cyclodextrin and Hydrophilic Auxiliary Substances

Srivalli

Mishra

2015

AAPS PharmSciTech

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“…However, compound samples with even trace impurities can lead project teams astray. These impurities can be remnants from the chemical synthesis, including transition metal catalysts, leftover starting materials, reactive intermediates, oxidative products, rearrangements or enantiomers, to name a few [146][147][148][149][150][151][152][153]. Therefore, medicinal chemists should insist on in-house HPLC purification (or comparable method) of any compound making its way into critical experiments.…”

Section: The Contribution Of Purification and Analytical Sciences To Htmentioning

confidence: 99%

The Essential Roles of Chemistry in High-Throughput Screening Triage

2014

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It is increasingly clear that academic high-throughput screening (HTS) and virtual HTS triage suffers from a lack of scientists trained in the art and science of early drug discovery chemistry. Many recent publications report the discovery of compounds by screening that are most likely artifacts or promiscuous bioactive compounds, and these results are not placed into the context of previous studies. For HTS to be most successful, it is our contention that there must exist an early partnership between biologists and medicinal chemists. Their combined skill sets are necessary to design robust assays and efficient workflows that will weed out assay artifacts, false positives, promiscuous bioactive compounds and intractable screening hits, efforts that ultimately give projects a better chance at identifying truly useful chemical matter. Expertise in medicinal chemistry, cheminformatics and purification sciences (analytical chemistry) can enhance the post-HTS triage process by quickly removing these problematic chemotypes from consideration, while simultaneously prioritizing the more promising chemical matter for follow-up testing. It is only when biologists and chemists collaborate effectively that HTS can manifest its full promise.

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“…In 13 C NMR spectra, C-16 and C-17 were shift from δ52.35 ppm and δ40.96 ppm to δ46.59 ppm and δ42.18 ppm, respectively. 13 C/ DEPT NMR spectral data of impurity-A confirmed the presence of five methylene carbon atoms. This suggested that the BMH has two extra -CH 2 group δ52.35 ppm at position C-16′ and δ40.96 ppm at position C-17′ when compared with that of impurity-A.…”

Section: Detection Of Impurities and The Stress Testing Resultsmentioning

confidence: 83%

“…These two impurities were isolated, identified and characterized using HPLC (analytical and preparative), MS, 1 H NMR, 13 C NMR and 2D NMR (HSQC, HMBC and COSY). It should be kept in mind that storage in dark at room temperature is important for ensuring the quality and safety of BMH drug product.…”

Section: Resultsmentioning

confidence: 99%

“…To simulate the impurities and degradation products which may be formed during shelf-life period, stress testing including thermal stressed testing, humidity stressed testing and photostability testing of pharmaceutical products must be conducted (11). Recently, there has been series of studies (12)(13)(14)(15) published for characterization of potential drug impurities in drug substance or drug product using ICH Q3A (2) by employing modern sophisticated analytical methods.…”

Section: Introductionmentioning

confidence: 99%

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Determination and Characterization of Two Degradant Impurities in Bendamustine Hydrochloride Drug Product

Wen-hua

Zou

Zhang

et al. 2015

Journal of Chromatographic Science

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Bendamustine hydrochloride is an alkylating antitumor agent with a good efficacy in the treatment of chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin's lymphoma (B-NHL). Under the stressed conditions, two degradant impurities in bendamustine hydrochloride drug product were detected by high-performance liquid chromatography. These two degradant impurities were isolated from preparative liquid chromatography, and were further characterized using Q-TOF/MS and nuclear magnetic resonance (NMR). Based on the MS and NMR spectral data, they were characterized as 4-[5-(2-chloro-ethylamino)-1-methyl-1H-benzoimidazol-2-yl] butyric acid hydrochloride (impurity-A) and 4-{5-[[2-(4-{5-[bis-(2-chloroethyl) amino]-1-methyl-1H-benzoimidazol-2-yl}-butyryloxy)-ethyl]-(2-chloroethyl)amino]-1-methyl-3a, 7a-dihydro-1H-benzoimidazol-2-yl} butyric acid hydrochloride (impurity-B). Isolation, structural elucidation of these two impurities by spectral data (Q-TOF/MS, 1 H NMR, 13 C NMR, D 2 O exchange NMR and two-dimensional NMR) and the probable formation mechanism of the impurities were discussed.

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Identification, isolation and characterization of process related impurities in ezetimibe

Cited by 19 publications

References 11 publications

Improved Aqueous Solubility and Antihypercholesterolemic Activity of Ezetimibe on Formulating with Hydroxypropyl-β-Cyclodextrin and Hydrophilic Auxiliary Substances

Improved Aqueous Solubility and Antihypercholesterolemic Activity of Ezetimibe on Formulating with Hydroxypropyl-β-Cyclodextrin and Hydrophilic Auxiliary Substances

The Essential Roles of Chemistry in High-Throughput Screening Triage

Determination and Characterization of Two Degradant Impurities in Bendamustine Hydrochloride Drug Product

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