On the Stability and Degradation Pathways of Venetoclax under Stress Conditions

Žigart, Nina; Črnugelj, Martin; Ilaš, Janez; Časar, Zdenko

doi:10.3390/pharmaceutics12070639

Cited by 9 publications

(5 citation statements)

References 56 publications

(107 reference statements)

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“…If the fingerprint region of S=O vibrations between 1000-500 cm -1 is [32] examined, it is noteworthy that Venetoclax and Navitoclax dissolved in DMSO and DMSO have similar peaks (Figure 2). When the FTIR spectrum of powder Venetoclax was examined, it was detected there were similar peaks to Venetoclax dissolved in S3 in the 1600-600 cm -1 range and the orientation of the whole spectrum curve was also similar [33].…”

Section: Resultsmentioning

confidence: 99%

Differential Scanning Calorimetry: A Suitable Methodology to Problem the Binding Properties of BCL-2 Inhibitors

Dinc,

Dogan,

Mavromoustakos

et al. 2023

Preprint

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The Differential Scanning Calorimeter (DSC) technique is commonly used for quantitative analysis of protein stability, and it is one of the methods used to quantify protein-ligand interactions. DSC provides denaturation curves that can be a source of data on binding constants. B-cell leukemia/lymphoma-2 (BCL-2) is an antiapoptotic protein, one of the overexpressed proteins in cancer cells. Here, binding constants for BCL-2 of nine BCL-2 inhibitors were evaluated by utilization of DSC measurements. The binding free energies of suggested inhibitors of BCL-2 were measured by melting temperature, Tm,and heat capacity, Cp. Evaluated BCL-2 binding parameters of candidate molecules agreed with our previously reported biological assays and molecular simulations indicating that the DSC method could be applied for the determination of free energies of enzyme inhibitors with high accuracy. Therefore, our results showed that this fast and relatively cheap technique can be conducted in high throughput drug screening analyses to compare the binding affinity of a set of compounds against a specific target protein. BCL-2 and most of its inhibitors have hydrophobic cavities, and a definite percent of dimethyl sulfoxide (DMSO) was advised to increase the solubility. Our work also suggests that the presence of the recommended high concentration of DMSO as the solvent significantly changes the affinity of the inhibitors to BCL-2, revealing similar DSC curves for all inhibitors.

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Section: Resultsmentioning

confidence: 99%

Differential Scanning Calorimetry: A Suitable Methodology to Problem the Binding Properties of BCL-2 Inhibitors

Dinc,

Dogan,

Mavromoustakos

et al. 2023

Preprint

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show abstract

“…The degradative pathways can be determined based on fragmentation patterns that are observed. After determination of degradant pathways, structure elucidations of degradants are done by synthesizing or isolating methods and further characterized by employing LC-MS, LC-UV, and LC-NMR techniques [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] .…”

Section: Characterisation Of Degradants By Lc-msmentioning

confidence: 99%

Importance of LCMS in Forced Degradation Studies for new Chemical Entities

Kota

Valli

2022

Int J Life Sci Pharm Res

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Forced degradation studies shows the chemical behaviour of the molecule which in turn helps in the development of formulation and package. In addition, the regulatory guidance is very general and does not explain about the performance of forced degradation studies. In pharmaceutical industry, mandatory degradation tests are important to determine the mechanisms and measure the potential degradants during the analysis of drug material and to help to elucidate the composition of degradation materials. The Liquid Chromatography/ Mass Spectrum analysis (L.C.M.S) is a short term widely established liquid chromatography and a methodology utilizing a natural fluid process. L.C.M.S. is commonly employed in the laboratories for qualitative testing of drug substances, drugs and biological samples. Degradation studies, metabolic screening, metabolite identity and in vivo drug screening, impurity identification, amide mapping, glycoprotein mapping were consistently used in pharmaceutical development by LCMS. The FDA and ICH guidelines sets out the requirement for stability testing data to understand how the quality of the drug substance and drug product changes over time under the influence of various environmental factors. Knowledge of molecular stability helps to select the correct formulation and package as well as to provide proper storage conditions and shelf life, which is essential for regulatory documentation. Active pharmaceutical ingredients (APIs) may form impurities when exposed to excipients or environmental variables such as light, high temperatures, acidic or basic conditions, humidity; and the oxidative atmosphere. Considering that these impurities may have an impact on safety and efficacy, it is necessary to know how these impurities are produced from the drug product and to establish the path of their formation. In this context, forced drug degradation studies have been used to characterize the physicochemical stability of APIs. These studies are also essential in the validation of analytical methodologies, in order to demonstrate the selectivity of methodologies. The API and its impurities and to develop strategies to avoid the formation of degradation products. The objective of this review is to demonstrate how forced degradation studies have been conducted and application of LCMS tools in related studies.

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“…In our previous studies on the stability and liquid chromatography analytical method development for venetoclax, we observed that venetoclax formed crystals after a few days from some of the solvents used for the dissolution of venetoclax [59,60]. Therefore, we performed a targeted crystallization experiment from the most promising solvent system identified in our previous study [60].…”

Section: Preparation Of Venetoclax Hydratementioning

confidence: 99%

Crystal Structure and Solid-State Conformational Analysis of Active Pharmaceutical Ingredient Venetoclax

2021

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Venetoclax is an orally bioavailable, B-cell lymphoma-2 selective inhibitor used for the treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma, and acute myeloid leukemia. Venetoclax’s crystal structure was until now determined only when it was bound to a B-cell lymphoma-2 (BCL-2) protein, while the crystal structure of this active pharmaceutical ingredient alone has not been reported yet. Herein, we present the first successful crystallization, which provided crystals of venetoclax suitable for X-ray diffraction analysis. The crystal structure of venetoclax hydrate was successfully determined. The asymmetric unit is composed of two crystallographically independent molecules of venetoclax and two molecules of interstitial water. Intramolecular N–H⋯O hydrogen bonding is present in both molecules, and a molecular overlay shows differences in their molecular conformations, which is also observed in respect to venetoclax molecules from known crystal structures of BCL-2:venetoclax complexes. A supramolecular structure is achieved through various N–H⋯N, O–H⋯O, C–H⋯O, C–H⋯π, C–Cl⋯π, ONO⋯π, and π⋯π interactions. The obtained crystals were additionally characterized with spectroscopic techniques, such as IR and Raman, as well as with thermal analysis.

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On the Stability and Degradation Pathways of Venetoclax under Stress Conditions

Cited by 9 publications

References 56 publications

Differential Scanning Calorimetry: A Suitable Methodology to Problem the Binding Properties of BCL-2 Inhibitors

Differential Scanning Calorimetry: A Suitable Methodology to Problem the Binding Properties of BCL-2 Inhibitors

Importance of LCMS in Forced Degradation Studies for new Chemical Entities

Crystal Structure and Solid-State Conformational Analysis of Active Pharmaceutical Ingredient Venetoclax

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