Analysis and optimization of drug solubility to improve pharmacokinetics

Thapa, Raj Kumar; Choi, Han‐Gon; Kim, Jong Oh; Yong, Chul Soon

doi:10.1007/s40005-016-0299-z

Cited by 24 publications

(11 citation statements)

References 107 publications

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“…This was slightly soluble in water system, however, it was a reasonable solubility for a new drug candidate. More importantly, new drug candidates may require a balance between hydrophilicity and lipophilicity [24]. Log P value of LMT-28 was 3.65±0.22 by GLpKa analytical system (Pion, USA).…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo pharmacokinetic characterization of LMT-28 as a novel small molecular interleukin-6 inhibitor

Ahn

Heo

Jun

et al. 2020

Asian-Australas J Anim Sci

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Objective: Interleukin-6 (IL-6) is a T cell-derived B cell stimulating factor which plays an important role in inflammatory diseases. In this study, the pharmacokinetic properties of LMT-28 including physicochemical property, in vitro liver microsomal stability and an in vivo pharmacokinetic study using BALB/c mice were characterized.Methods: LMT-28 has been synthesized and is being developed as a novel therapeutic IL-6 inhibitor. The physicochemical properties and in vitro pharmacokinetic profiles such as liver microsomal stability and Madin-Darby canine kidney (MDCK) cell permeability assay were examined. For in vivo pharmacokinetic studies, pharmacokinetic parameters using BALB/c mice were calculated.Results: The logarithm of the partition coefficient value (LogP; 3.65) and the apparent permeability coefficient values (Papp; 9.7×10–6 cm/s) showed that LMT-28 possesses a moderate-high cell permeability property across MDCK cell monolayers. The plasma protein binding rate of LMT-28 was 92.4% and mostly bound to serum albumin. The metabolic half-life (t1/2) values of LMT-28 were 15.3 min for rat and 21.9 min for human at the concentration 1 μM. The area under the plasma drug concentration-time curve and Cmax after oral administration (5 mg/kg) of LMT-28 were 302±209 h∙ng/mL and 137±100 ng/mL, respectively.Conclusion: These data suggest that LMT-28 may have good physicochemical and pharmacokinetic properties and may be a novel oral drug candidate as the first synthetic IL-6 inhibitor to ameliorate mammalian inflammation.

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Section: Discussionmentioning

confidence: 99%

In vitro and in vivo pharmacokinetic characterization of LMT-28 as a novel small molecular interleukin-6 inhibitor

Ahn

Heo

Jun

et al. 2020

Asian-Australas J Anim Sci

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“…It is therefore of some interest to know the solubility of amygdalin in different mixtures of solvents. On the other hand, the knowledge of the solubility behavior in different solvent systems is of high importance in the pharmaceutical industry as it influences the drug efficacy and its pharmacokinetics [20]. Solubility data are also useful for drug purification, refining procedures, and method development [21][22][23].…”

Section: Solubility Of Amygdalin In [Ethanol (1) + Water (2)] Cosolvementioning

confidence: 99%

Solubility, Solution Thermodynamics, and Preferential Solvation of Amygdalin in Ethanol + Water Solvent Mixtures

et al. 2020

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The equilibrium solubility of amygdalin in [ethanol (1) + water (2)] mixtures at 293.15 K to 328.15 K was reported. The thermodynamic properties (standard enthalpy ΔsolnH°, standard entropy ΔsolnS°, and standard Gibbs energy of solution ΔsolnG°) were computed using the generated solubility data via van’t Hoff and Gibbs equations. The dissolution process of amygdalin is endothermic and the driving mechanism in all mixtures is entropy. Maximal solubility was achieved in 0.4 mole fraction of ethanol at 328.15 K and the minimal one in neat ethanol at 293.15 K. Van’t Hoff, Jouyban–Acree–van’t Hoff, and Buchowski–Ksiazczak models were used to simulate the obtained solubility data. The calculated solubilities deviate reasonably from experimental data. Preferential solvation parameters of amygdalin in mixture solvents were analyzed using the inverse Kirkwood–Buff integrals (IKBI) method. Amygdalin is preferentially solvated by water in ethanol-rich mixtures, whereas in water-rich mixtures, there is no clear evidence that determines which of water or ethanol solvents would be most likely to solvate the molecule.

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“…However, the solubility of TEL is dependent on pH of solution. The solubility of an API can significantly affect the drug absorption and, therefore, its bioavailability [17,18]. Various approaches for solubilization and stabilization of TEL have been formulated by modulating microenvironmental pH of compositions [19,20].…”

Section: Introductionmentioning

confidence: 99%

Investigation of Crystallization and Salt Formation of Poorly Water-Soluble Telmisartan for Enhanced Solubility

et al. 2019

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The crystal changes and salt formation of poorly water-soluble telmisartan (TEL) in various solvents were investigated for enhanced solubility, stability and crystallinity. Polymorphic behaviors of TEL were characterized by dispersing in distilled water, acetone, acetonitrile, DMSO, or ethanol using Method I: without heat and then dried under vacuum at room temperature; and Method II: with heat below boiling temperature, cooled at 5 °C, and then dried under vacuum at 40 °C. For salt formation (Method III), the following four powdered mixtures were prepared by dispersing in solution of hydrochloric acid (HCl) (pH 1.2), TEL/HCl; in simulated gastric fluid (pH 1.2 buffer), TEL/simulated gastric fluid (SGF); in intestinal fluid (pH 6.8 buffer), TEL/simulated intestinal fluid (SIF); or in NaOH (pH 6.8), TEL/NaOH, respectively, and then dried under a vacuum at room temperature. The structures of powdered mixtures were then studied using a field emission scanning electron microscope (FESEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), FTIR, 1H nuclear magnetic resonance (1H-NMR), and LC–MS. The solubility of TEL in powdered forms was performed in pH 6.8, pH 1.2, and distilled water. No polymorphic behaviors of TEL were observed in various solvents as characterized by FESEM, DSC, PXRD, and FTIR. However, the structural changes of powdered mixtures obtained from Method III were observed due to the formation of salt form. Moreover, the solubility of salt form (TEL/HCl) was highly increased as compared with pure TEL. There were no significant changes of TEL/HCl compared with TEL in the content assay, PXRD, DSC, and FTIR during stressed storage conditions at 40 °C/75% relative humidity (RH) for 4 weeks under the closed package condition. Therefore, the present study suggests the new approach for the enhanced stability and solubility of a poorly water-soluble drug via salt form.

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Analysis and optimization of drug solubility to improve pharmacokinetics

Cited by 24 publications

References 107 publications

In vitro and in vivo pharmacokinetic characterization of LMT-28 as a novel small molecular interleukin-6 inhibitor

In vitro and in vivo pharmacokinetic characterization of LMT-28 as a novel small molecular interleukin-6 inhibitor

Solubility, Solution Thermodynamics, and Preferential Solvation of Amygdalin in Ethanol + Water Solvent Mixtures

Investigation of Crystallization and Salt Formation of Poorly Water-Soluble Telmisartan for Enhanced Solubility

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