A novel cocrystallization form of
amantadine hydrochloride (AMNH)
with sulfathiazole (SUZ), as the first example of dual-drug cocrystal
simultaneously containing antiviral drug and antibacterial agent,
is designed and successfully synthesized. The structure of resulting
cocrystal SUZ–AMNH is thoroughly characterized. The single
crystal X-ray diffraction reveals that a 1:1 ratio of the two components
exists in the cocrystal structure, in which the interactions between
SUZ and AMNH molecules are mainly dominated by N–H···O
hydrogen bonds and N–H+
(AMNH)···Cl–···H–N(SUZ) charge-assisted
hydrogen bonds, constructing a three-dimensional supramolecular structure.
The dissolubility and permeability of the cocrystal are systematically
studied under physiological pH environments. It has been found that
SUZ in the cocrystal shows a 1.83–5.23 times increase in water
solubility and ca. 2-fold enhancement in penetrability compared with
pure SUZ. Intriguingly, the simultaneously improved physicochemical
properties for SUZ can bring about the strengthening in antibacterial
activities, displaying enhanced inhibition of bacterial strains and
lower values of minimum inhibitory concentration. The present investigation
not only provides a promising method for therapeutic hybridization
of antiviral and antibacterial drugs against coinfection, but also
exploits a new pathway of the drug–drug cocrystallization strategy
toward widening new applications for conventional drugs.
In
order to highlight the advantages of the nutraceutical resveratrol
(RVA) in perfecting the in vitro/in vivo properties of amantadine hydrochloride (ATHC), to realize advantageous
complementarities between the two components and thus fill gaps in
a drug–nutraceutical cocrystal with synergistically antiviral
efficacy, a cocrystallization strategy of bidirectional coupling optimization
has been developed. In this strategy, ATHC’s advantage of high
water solubility is used to enhance RVA’s dissolubility and
bioavailability, thereby activating its auxiliary antiviral effect,
and meanwhile the excessive solubility of ATHC is properly reduced.
The perfected antiviral activity of RVA, in return, contributes cooperativity
with ATHC in antiviral efficacy, achieving a synergistic effect for
the cocrystal. Using this strategy, the first antiviral drug–nutraceutical
cocrystal, ATHC-RVA has been prepared and structurally characterized.
The in vitro/in vivo property evaluations
conducted both by theoretical and experimental methods reveal 152
and 9.64 times improvements, respectively, in the solubility and bioavailability
of RVA, and the risk of toxic effects caused by the excessive solubility
of ATHC is reduced through a slower release. Especially, the antiviral
synergy of ATHC and RVA is significantly increased with CI < 1,
exhibiting a potential to overcome drug resistance. All these benefits
open a new pathway for the development of synergistic antiviral pharmaceutical
cocrystals through cocrystallization techniques.
To give full prominence to the superiority
of phenolic acid nutraceuticals
syringic acid (SYRA) and gallic acid (GALA) in perfection of in vitro
and in vivo performances for cardiotonic drug milrinone (MLN), and
ulteriorly attain novice insights in the development of cardiotonic
drug-nutraceutical cocrystals, two new solid forms of MLN including
one cocrystal with SYRA, and one cocrystal hydrate with GALAnamely,
MLN-SYRA (1) and MLN-GALA- H2O (2)are first assembled and thoroughly characterized. The single-crystal
X-ray diffraction showcases that both cocrystal 1 and
cocrystal hydrate 2 have three-dimensional supramolecular
structures controlled by hydrogen-bonding and aromatic packing interactions,
where the hydrogen-bonding dimers of MLN itself still remain in 1 but are broken in 2, forming hydrophobic cavities
in the former and hydrophilic ones in the latter. Such structural
characteristics and aggregation motifs, because of the introduction
of different phenolic acids in the crystalline lattices, have important
influence on the improvements of dissolvability and permeability for
the two crystalline forms, and in accordance with the theoretical
studies. Intriguingly, the optimized in vitro biopharmaceutical properties
can be effectually transformed to satisfactory in vivo pharmacokinetic
peculiarity, performing the increased bioavailability and extended
half-life. Thus, the current research not only offers promising solid-state
forms for MLN with development foregrounds, but opens up new applications
for nutraceutical phenolic acids in cardiotonic pharmaceutical cocrystals.
In order to give full play to the preponderances of cocrystallization technique in improving the biopharmaceutical limitations in vitro and ameliorating the pharmacokinetic properties in vivo together with heightening the...
The current research aims at taking advantage of low solubility and hepatoprotective activity of phenolic acid nutrient vanillic acid (VAA) for reducing the solubility and dissolution rate of antifungal drug...
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