Role of stable hydrogen isotope variations in water for drug dissolution managing

Abstract

<jats:title>Abstract</jats:title><jats:p>In the present work, we provide the results of defining by utilizing Laser diffraction spectroscopy, the kinetic isotopic effect of solvent and constant of dissolution rate κ, s<jats:sup>−1</jats:sup> of аn active pharmaceutical ingredient (API) in water with a different content of a stable <jats:inline-formula><jats:alternatives><jats:inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/j_cipms-2020-0017_eq_001.png" /><jats:tex-math>_2^1{\rm{H}}</jats:tex-math></jats:alternatives></jats:inline-formula> isotope on the basis of the laws of first-order kinetics. This approach is based on the analysis of the light scattering profile that occurs when the particles of the dispersion phase in the aquatic environment are covered with a collimated laser beam. For the first time, the dependence of the rate of dissolution is demonstrated not only on the properties of the pharmaceutical substance itself (water solubility mg/ml, octanol–water partition coefficient log P oct/water, topological polar surface area, Abraham solvation parameters, the lattice type), but also on the properties of the solvent, depending on the content of stable hydrogen isotope. We show that the rate constant of dissolution of a sparingly hydrophobic substance moxifloxacin hydrochloride (MF · HCl) in the Mili-Q water is: k=1.20±0.14∙10<jats:sup>−2</jats:sup> s<jats:sup>−1</jats:sup> at 293.15 K, while in deuterium depleted water, it is k=4.24±0.4∙10<jats:sup>−2</jats:sup> s<jats:sup>−1</jats:sup>. Consequently, we have established the development of the normal kinetic isotopic effect (kH/kD &gt;1) of the solvent. This effect can be explained both by the positions of the difference in the vibrational energy of zero levels in the initial and transition states, and from the position of water clusters giving volumetric effects of salvation, depending on the ratio D/H. The study of kinetic isotopic effects is a method that gives an indication of the mechanism of reactions and the nature of the transition state. The effect of increasing the dissolution of the API, as a function of the D/H ratio, we have discovered, can be used in the chemical and pharmaceutical industries in the study of API properties and in the drug production through improvement in soluble and pharmacokinetic characteristics.</jats:p>

Evaluation of Poorly Soluble Drugs’ Dissolution Rate by Laser Scattering in Different Water Isotopologues

“…The kinetics of the dissolution of pharmaceutical substances in water ( Figure 4 ) is the two-step process: the sharp LO decrease from the onset of dissolution (first step) is succeeded by a gradual decrease in the LO values to reach the plateau (second step). As we have shown earlier for moxifloxacin hydrochloride and topiramate [ 47 ], the dissolution process obeys first-order kinetics and the rate constant can be calculated from the slope tangent in the coordinates «ln (LO 0 /LO) − t».…”

Exploring the Effects of Cramped-Impact-Type Mechanical Action on Active Pharmaceutical Ingredient (Levofloxacin)—Prospects for Pharmaceutical Applications

“…The dissolution rate kinetics of Lvf•Hh samples before and after Mact were researched in water solvents: ultrapure water (UPW) (>18 MΩ•cm −1 at 25 • C, TOC ≤ 5 ppb, Merck Millipore). The intensity of laser light scattering over time was determined using a lowangle laser particle dispersion meter Particle Sizer (Malvern Instruments, Malvern, UK) with a scanning wavelength λ = 632 nm and capacitive cell (V = 3 mL) equipped with a mechanical stirrer (Figure 5) [21].…”

Deuterium as a Tool for Changing the Properties of Pharmaceutical Substances (Review)

“…The dissolution kinetics of a large number of pharmaceutical substances controlled by laser obscuration demonstrated an increase in KIE with a decrease in the D/H ratio in water (table 3) [18].…”

“…It was found that in the range of deuterium content from 0.6 to 16 mmol/l in deuterium-depleted water (ddw), the kinetic isotope effect (KIE) of biologically active compounds increases [8,17]. In such water, the rates of dissolution of substances [18] and mutarotation of carbohydrates [19], the optical properties of chiral compounds [12,17] change, the absorption and accumulation of ions of essential trace elements in medicinal and food plants increase [20]. It was proven that obesity in laboratory animals decreases when using ddw water [21].…”

“…Kinetic isotope effects of lactose monohydrate calculated by the rate (k) of dissolution of the substance in aqueous solutionswith different D/H ratios[18] …”