Self-Association and Solubility Behaviors of a Novel Anticancer Agent, Brequinar Sodium

doi:10.1002/jps.2600780204

Journal of Pharmaceutical Sciences

Volume 78, Issue 2, February 1989, Pages 95-100

https://doi.org/10.1002/jps.2600780204 Get rights and content

Abstract

To aid in the selection of appropriate excipients to formulate brequinar sodium [6-fluoro-2-(2′-fluoro-1,1′-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid sodium salt; DuP 785], studies were initiated to characterize thoroughly its solubility behavior. The measured solubilities at RT (~23°C) agreed with the theoretical values in the pH range from 0.5 to 7.2, but became significantly greater than theoretical values at pH values above 7.2. This deviation was likely due to the vertical stacking-type self-association between brequinar molecules in water. The NMR and pH methods determined a critical association concentration of 15 mg/mL. Sodium salicylate, which has been proven to interfere with molecular self-association, reduced drug solubility from 116 to 10 mg/mL. But urea, another deaggregative agent, gave about a twofold increase rather than a decrease in solubility. Addition of sodium chloride caused a 226-fold decrease in solubility. The apparent solubility product did not remain constant but decreased as sodium chloride concentration increased, suggesting that the added salt decreased the degree of self-association between brequinar molecules. Among four surfactants examined (a bile salt with a rigid fused ring versus three ordinary surfactants with a flexible chain structure), only sodium cholate significantly increased the aqueous solubility of brequinar sodium.

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Quinoline, a privileged scaffold in medicinal chemistry, has always been associated with a multitude of biological activities. Especially in antimalarial and anticancer research, quinoline played (and still plays) a central role, giving rise to the development of an array of quinoline-containing pharmaceuticals in these therapeutic areas. However, both diseases still affect millions of people every year, pointing to the necessity of new therapies. Quinolines have a long-standing history as antimalarial agents, but established quinoline-containing antimalarial drugs are now facing widespread resistance of the Plasmodium parasite. Nevertheless, as evidenced by a massive number of recent literature contributions, they are still of great value for future developments in this field. On the other hand, the number of currently approved anticancer drugs containing a quinoline scaffold are limited, but a strong increase and interest in quinoline compounds as potential anticancer agents can be seen in the last few years. In this review, a literature overview of recent contributions made by quinoline-containing compounds as potent antimalarial or anticancer agents is provided, covering publications between 2018 and 2020.
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The action and mode of aggregation of drugs from detailed studies can help to comprehend the physicochemical properties of drug/drug–additives systems. Various classes of amphiphilic drugs namely phenothiazine family drugs [53–56] and analgesics [57], benzodiazepine [44,58,59], tranquilizers [60], peptides [39,47,48] and nonpeptides [47,48,61], antibiotics [47,62], tricyclic antidepressants [46,63–65], antihistamines [66,67], anticholinergics [34,66], local anesthetics [68–70], non-steroidal anti-inflammatory [70,71] and anticancer drugs [72,73] have been explored to understand their physicochemical properties in aqueous medium. These investigations have been focused on several prospects which make the area quite vast.
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Synergistic interaction between anti-allergic drug and cationic/anionic surfactants–Experimental and theoretical analysis
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Thermodynamic analysis of binding between drugs and glycosaminoglycans by isothermal titration calorimetry and fluorescence spectroscopy
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The major objective of this study was to investigate and characterize the solution properties of cromolyn sodium (in D₂O or D₂O/H₂O phosphate buffer at pH 7.5) using nuclear magnetic resonance (NMR) spectroscopy. The self-association of cromolyn molecules was examined primarily via one-dimensional ¹H and ¹³C, and two-dimensional homonuclear NOESY NMR. Significant spectral shifts were observed for a majority of cromolyn ¹H and ¹³C resonances, and are attributed to inter-molecular ring-stacking association accompanied by intra-molecular conformational changes. The critical self-association concentration was determined to be 10 mg/mL at pH 7.5 and 25°C by measuring the chemical shift of a specific cromolyn ¹H resonance. The observed magnitude and sign changes of NOESY correlations indicate the formation of cromolyn aggregates with restricted molecular mobility. Mesomorphic liquid crystal formation is suggested by uniformly pronounced line broadening in concentrated cromolyn solutions; the transition concentration was approximately 60 mg/mL at 25°C, which is consistent with literature findings based on other techniques. A stronger tendency toward association was observed at lower temperature but aggregation appeared to be independent of pH. Lastly, it was concluded that self-association of cromolyn is promoted by the presence of monovalent cations as a result of reduced electrostatic repulsive forces. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1351–1358, 2004

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ArticlesSelf-Association and Solubility Behaviors of a Novel Anticancer Agent, Brequinar Sodium

Abstract

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

Int. J. Pharm.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Colloid Interface Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

Cancer Res.

Cancer Res.

Nature

Articles
Self-Association and Solubility Behaviors of a Novel Anticancer Agent, Brequinar Sodium