65 research outputs found
Prediction of Sublimation Functions of Molecular Crystals Based on Melting Points: Cocrystal Formation Thermodynamics Application
On the basis of the values contained
in the literature published
in 1900–2016, we have developed an experimental database including
sublimation Gibbs energies, enthalpies, and melting temperatures of
1515 compounds. We have also suggested an algorithm of database fragmentation
which includes groups/clusters with structurally similar compounds.
For this aim we used Tanimoto similarity coefficients. Clusterization
was carried out for each substance of the test set. All the points
within a cluster were smoothed by a linear function in the coordinates
of Gibbs energy vs melting temperature. Using the training and test
sets, it has been shown that the algorithm suggested by us describes
experimental data well (rms = 3.89 kJ·mol<sup>–1</sup>). We have developed quantitative structure–property relationship
models based on HYBOT physicochemical descriptors and melting points
in order to predict sublimation Gibbs energies and enthalpies of molecular
crystals. The developed approach was applied to determine cocrystal
formation thermodynamics. Twenty nine out of 30 seven cocrystals selected
in the literature have been predicted correctly (78% of the correct
matches)
Thermodynamic Approaches to the Challenges of Solubility in Drug Discovery and Development
This
paper considers fundamental aspects determining the processes
of drug compound dissolution and distribution in solvents/systems
modeling biological media. Special attention is paid to the complex
analysis of thermodynamic functions of sublimation and solvation/hydration
processes during structural modification of lead/hit compounds and
their influence on dissolution processes. The paper shows that at
the first stages of drug design it is necessary to develop algorithms
of optimizing the properties determining absorption, distribution,
metabolism, and excretion (ADME) characteristics of molecules: in
particular, diffusion flux density through lipophilic membranes. Using
sulfonamides and nonsteroidal anti-inflammatory drugs (NSAIDs) as
an example, we have demonstrated the efficiency of approaches to manipulating
thermodynamic functions of the basic processes that result from delivering
compounds to the points of their operation. We have formulated several
criteria of compound selection for further tests
Another Move towards Bicalutamide Dissolution and Permeability Improvement with Acetylated β-Cyclodextrin Solid Dispersion
The complex formation of antiandrogen bicalutamide (BCL) with methylated (Me-β-CD) and acetylated (Ac-β-CD) β-cyclodextrins was investigated in buffer solution pH 6.8. A two-fold strongly binding of BCL to Ac-β-CD as compared to Me-β-CD was revealed. The solid dispersion of BCL with Ac-β-CD was prepared by the mechanical grinding procedure to obtain the complex in the solid state. The BCL/Ac-β-CD complex was characterized by DSC, XPRD, FTIR, and SEM techniques. The effect of Ac-β-CD in the BCL solid dispersions on the non-sink dissolution/permeation simultaneous processes was disclosed using the side-by-side diffusion cell with the help of the cellulose membrane. The elevated dissolution of the ground complex, as compared to the raw drug as well as the simple physical mixture, accompanied by the supersaturation was revealed. Two biopolymers—polyvinylpyrrolidone (PVP, Mn = 58,000) and hydroxypropylmethylcellulose (HPMC, Mn ~ 10,000)—were examined as the precipitation inhibitors and were shown to be useful in prolonging the supersaturation state. The BCL/Ac-β-CD complex has the fastest dissolution rate in the presence of HPMC. The maximal concentration of the complex was achieved at a time of 20, 30, and 90 min in the pure buffer, with PVP and with HPMC, respectively. The effectiveness of the BCL dissolution (release) processes (illustrated by the AUCC(t) parameter) was estimated to be 7.8-, 5.8-, 3.0-, and 1.8-fold higher for BCL/Ac-β-CD (HPMC), BCL/Ac-β-CD (PVP), BCL/Ac-β-CD (buffer), and the BCL/Ac-β-CD physical mixture, respectively, as compared to the BCL_raw sample. The excipient gain factor (EGF), calculated for the dissolution of the BCL complex, was shown to be 2.6 in the presence of HPMC, which is 1.3-fold greater as compared to PVP. From the experimental dissolution results, it can be concluded that the formation of BCL ground complex with Ac-β-CD enhances the dissolution rate of the compound. The permeation was also shown to be advantageous in the presence of the polymers, which was demonstrated by the elevated fluxes of BCL through the membrane. The comparison of the dissolution/permeation processes was illustrated and discussed. The conclusion was made that the presence of HPMC as a stabilizer of the supersaturation state is promising and seems to be a useful tool for the optimization of BCL pharmaceutical formulations manufacturing
New Antifungal Compound: Impact of Cosolvency, Micellization and Complexation on Solubility and Permeability Processes
Poor solubility of new antifungal of 1,2,4-triazole class (S-119)—a structural analogue of fluconazole in aqueous media was estimated. The solubility improvement using different excipients: biopolymers (PEGs, PVP), surfactants (Brij S20, pluronic F-127) and cyclodextrins (α-CD, β-CD, 2-HP-β-CD, 6-O-Maltosyl-β-CD) was assessed in buffer solutions pH 2.0 and pH 7.4. Additionally, 2-HP-β-CD and 6-O-Maltosyl-β-CD were proposed as promising solubilizers for S-119. According to the solubilization capacity and micelle/water partition coefficients in buffer pH 7.4 pluronic F-127 was shown to improve S-119 solubility better than Brij S20. Among biopolymers, the greatest increase in solubility was shown in PVP solutions (pH 7.4) at concentrations above 4 w/v%. Complex analysis of the driving forces of solubilization, micellization and complexation processes matched the solubility results and suggested pluronic F-127 and 6-O-Maltosyl-β-CD as the most effective solubilizing agents for S-119. The comparison of S-119 diffusion through the cellulose membrane and lipophilic PermeaPad barrier revealed a considerable effect of the lipid layer on the decrease in the permeability coefficient. According to the PermeaPad, S-119 was classified as a highly permeated substance. The addition of 1.5 w/v% CDs in donor solution moves it to low-medium permeability class
Experimental Examination of Solubility and Lipophilicity as Pharmaceutically Relevant Points of Novel Bioactive Hybrid Compounds
The important physicochemical properties of three novel bioactive hybrid compounds with different groups (-CH3, -F and -Cl) were studied, including kinetic and thermodynamic solubility in pharmaceutically relevant solvents (buffer solutions and 1-octanol) as well as partition coefficient in system 1-octanol/buffer pH 7.4. The aqueous solubility of these chemicals is poor and ranged from 0.67 × 10−4 to 1.98 × 10−3 mol·L−1. The compounds studied are more soluble in the buffer pH 2.0, simulating the gastrointestinal tract environment (by an order of magnitude) than in the buffer pH 7.4 modelling plasma of blood. The solubility in 1-octanol is significantly higher; that is because of the specific interactions of the compounds with the solvent. The prediction solubility behaviour of the hybrid compounds using Hansen’s three-parameter approach showed acceptable results. The experimental solubility of potential drugs was successfully correlated by means of two commonly known equations: modified Apelblat and van’t Hoff. The temperature dependencies of partition coefficients of new hybrids in the model system 1-octanol/buffer pH 7.4 as a surrogate lipophilicity were measured by the shake flask method. It was found that compounds demonstrated a lipophilic nature and have optimal values of partition coefficients for oral absorption. Bioactive assay manifested that prepared compounds showed antifungal activities equal to or greater than fluconazole. In addition, the thermodynamic aspects of dissolution and partition processes have been examined. Bioactive assay manifested that prepared compounds showed antifungal activities equal to or greater than the reference drug
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