Crystal Structures, Thermal Analysis, and Dissolution Behavior of New Solid Forms of the Antiviral Drug Arbidol with Dicarboxylic Acids

Manin, Alex N.; Surov, Artem O.; Churakov, Andrei V.; Perlovich, German L.

doi:10.3390/cryst5040650

Cited by 19 publications

(17 citation statements)

References 37 publications

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“…The trend can also be influenced by the carbon chain length of the coformers in salts and cocrystals since, in general, the solubility decreases with an increase in the number of C atoms in the carbon chain of carboxylic acids. 26 However, the magnitude of either lattice energy or hydration energy decreases as the size of the counterion increases, which has positive impacts on solubility. Strictly, the lattice energy increases, whereas the hydration energy becomes less exothermic as the size of the counterion increases.…”

Section: Resultsmentioning

confidence: 99%

New Multicomponent Crystal Forms of Adiphenine with Low Hygroscopicity

Ribeiro

Silva

Neto

et al. 2022

Crystal Growth & Design

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Adiphenine is an acetylcholine receptor inhibitor used as an antispasmodic drug due to its strong smooth muscle relaxant action. Adiphenine hydrochloride is largely marketed in drug associations to treat muscle spasms and relieve pain in colic and cramps. However, it presents serious problems with hygroscopicity and chemical stability under high humidity conditions, which have limited its use as an active pharmaceutical ingredient (API). Here, we have solved the adiphenine solid-state hygroscopicity problem through the preparation of stable, nonhygroscopic multicomponent crystal forms thereof. Two new salts of adiphenine were designed by recognition of intermolecular interaction patterns in the Cambridge Structural Database (CSD) and ΔpK a rules. Two generically recognized as safe (GRAS) coformers, namely, citric acid and oxalic acid, were chosen and formed monobasic salts with adiphenine. Crystal structure elucidation reveals that adiphenine adopts different conformations in our salts, while in the literature, hydrochloride adopts one, which is related to different intermolecular arrays. In the dynamic vapor sorption (DVS) analysis, it was verified that adiphenine citrate and adiphenine oxalate starts to incorporate water slowly from 50 to 70% of relative humidity (RH), increasing up to 3.2 and 2.6% of their initial masses in 90% of RH, respectively. At the end of the desorption cycle (RH = 0%), the samples retained only 0.12 and 0.08% of water relative to their initial masses. On the other hand, adiphenine hydrochloride exhibits a classical high hygroscopicity behavior, which retains water fast from 50% of relative humidity (RH), increasing up to 22% of its initial mass in 90% of RH and a net mass gain of 5% at the end of the desorption cycle (RH = 0%). Notably, both carboxylic acid salts had similar solubility as a function of medium pH, while the hydrochloride one was more soluble than them by factors ranging from 6.7 (relative to citrate in pH 1.2) to 28.2 (relative to oxalate in pH 4.5). Nevertheless, the pharmacokinetic parameters of adiphenine after oral administration of the capsules containing the salt forms did not reflect these solubility differences, since all adiphenine salt forms can be considered highly soluble drugs according to the Biopharmaceutics Classification System (dose/solubility ratio < 250 mL). It was observed that the rats treated with capsules containing adiphenine hydrochloride had an increase in AUC 0−∞ (1537 vs 914 vs 991 min μg mL −1 ) compared with rats treated with adiphenine citrate and oxalate capsules, respectively, even though the same t max (48 min) was observed. However, dosage tuning can bring the bioavailability of our salts into that of the hydrochloride salt, with the advantage of nonhygroscopicity and higher chemical stability.

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Section: Resultsmentioning

confidence: 99%

New Multicomponent Crystal Forms of Adiphenine with Low Hygroscopicity

Ribeiro

Silva

Neto

et al. 2022

Crystal Growth & Design

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“…Arbidol has poor water solubility and dissolution, which limits its intestinal absorption and bioavailability after oral administration (Li et al, 2017; Manin et al, 2015; Xu et al, 2007). The commercially available arbidol hydrochloride preparations include ordinary tablets, dispersible tablets, capsules and granules.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic comparison of four arbidol hydrochloride preparations in beagle dogs

Chen

et al. 2021

Biomedical Chromatography

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This study aimed to compare the pharmacokinetic properties of four preparations (dispersible tablets, ordinary tablets, capsules and granules) of arbidol hydrochloride, a broad‐spectrum antiviral drug, in beagle dogs. Briefly, a single dose of 100 mg of the four preparations of arbidol hydrochloride was orally administered to dogs; blood was then collected from the veins of the foreleg at different times after administration to prepare plasma samples. The plasma concentration of arbidol hydrochloride was measured using a validated liquid chromatography–tandem mass spectrometry (LC–MS/MS). The results showed that when orally administered with dispersible tablets, ordinary tablets, capsules and granules suspended with water, there were no significant differences in the pharmacokinetic parameters (including peak time, peak concentration, elimination half‐life, area under the curve (AUC0–t), and mean retention time) of arbidol hydrochloride. However, in the case of the dispersible tablets, the pharmacokinetics of arbidol hydrochloride was significantly affected by the mode of administration. Compared with direct feeding, peak time [0.50 (0.13, 0.50) vs. 1.00 (0.50, 2.00)] was significantly shortened (P = 0.033) and the AUC0–48 h (8726.5 ± 2509.3 vs. 3650.8 ± 1536.9 ng h/ml) was significantly increased (P = 0.012) when the dispersible tablets were orally administered as water dispersion. In conclusion, the pharmacokinetics of four preparations of arbidol hydrochloride were not significant different in beagle dogs. However, compared with direct feeding, the absorption of arbidol hydrochloride was faster and the bioavailability was better when the dispersible tablets were orally administered as water dispersion.

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“…Solubility advantage can be accomplished using a variety of approaches, among which cocrystallization is a very common and convenient way especially applicable to active pharmaceutical ingredients (API) with more soluble excipient. Apart from the well documented APIs’ dissolution behavior improvement, − cocrystals (CC) exhibit various new advantageous physicochemical properties including higher stability − and photostability, , compressibility improvement, − reduced hygroscopicity, , with better permeability through membranes ,,, and enhanced bioavailability. ,− Furthermore, recently, several interesting studies documented specific biological activities improvement via cocrystallization. Among others, it is worth mentioning the antiplasmodial activity improvement of 7-chloroquinolines or cytotoxicity, antioxidant properties, and inhibitory activity against serine protease improvement of quercetin cocrystals .…”

Section: Introductionmentioning

confidence: 99%

Application of Multivariate Adaptive Regression Splines (MARSplines) Methodology for Screening of Dicarboxylic Acid Cocrystal Using 1D and 2D Molecular Descriptors

Przybyłek

Jeliński

Słabuszewska

et al. 2019

Crystal Growth & Design

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Dicarboxylic acids (DiAs) are probably among of the most popular cocrystal formers. Due to the high hydrophilicity and nontoxicity, they are promising solubilizers of active pharmaceutical ingredients (APIs). Although DiAs appear to be highly capable of forming multicomponent crystals with various compounds, some systems reported in the literature are physical mixtures of the solid state without forming stable intermolecular complex. In this study, an accurate cocrystal screening model was developed based on the MARSplines (Multivariate Adaptive Regression Splines) methodology and easily computable descriptors driven simply from the SMILES codes. Additionally, the data set was enriched with several new mixtures of sulfamethazine. As demonstrated, this sulfonamide can form new multicomponent crystals with oxalic, malonic, and maleic acids. In the case of the latter system, a significant 10-fold solubility advantage was observed. The whole data set comprised 608 cocrystals and 104 systems hardy miscible in the solid state, denoted as simple eutectics. The final 7-factor equation was subjected to external and internal validation procedures, which indicated its high predicting power. The reliability of the proposed approach can be illustrated by the proper classification probability of cocrystals reaching 91%. The classification quality of simple binary eutectics was found to be only slightly worse (TN% = 81%).

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Crystal Structures, Thermal Analysis, and Dissolution Behavior of New Solid Forms of the Antiviral Drug Arbidol with Dicarboxylic Acids

Cited by 19 publications

References 37 publications

New Multicomponent Crystal Forms of Adiphenine with Low Hygroscopicity

New Multicomponent Crystal Forms of Adiphenine with Low Hygroscopicity

Pharmacokinetic comparison of four arbidol hydrochloride preparations in beagle dogs

Application of Multivariate Adaptive Regression Splines (MARSplines) Methodology for Screening of Dicarboxylic Acid Cocrystal Using 1D and 2D Molecular Descriptors

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