Ionic Drugs Research Articles

Functionalized thermoresponsive microgels based on N-isopropylacrylamide: Energetics and mechanism of phase transitions

Nano- and micro-sized stimuli-responsive polymer containers capable of an effective controlled binding and release of ionic amphiphilic drugs are highly demanded in drug delivery. Thermoresponsive cross-linked microgels based on N-isopropylacrylamide (NIPAM) were synthesized by precipitation polymerization in aqueous media. The microgels were functionalized by the introduction of an ionic component (acrylic acid, AA, or vinyl sulfonate, VSA) either as a comonomer (NIPAM-co-AA and NIPAM-co-VSA microgels) or interpenetrating polymer network (PNIPAM-PAA microgel). The thermoresponsive behavior of the microgels was investigated by high-sensitivity differential scanning calorimetry. Thermodynamic parameters of the phase transitions (the transition temperature, enthalpy, and width) for the copolymer and interpenetrating microgels were determined. The copolymer microgels involving weak and strong ionogenic groups differ drastically by the transition energetics. This implies different types of their primary structures provided by either comonomer affinity or segregation in the reaction mixture under the polymerization conditions. The microgel functionalization via interpenetrating networks does not affect notably the transition temperature typical of the reference parent PNIPAM microgel but reduces the transition cooperativity. An analysis of the heat capacity profile of the microgel phase transition reveals some features of the mechanism of the thermoresponsivity in the microgels.

Study on Interactions Between Imidazolium Based Surface Active Ionic Liquid and Drug at Different Temperature and Concentrations

The present study aims to investigate the molecular interactions of surface active ionic liquid (IL), 1-pentadecyl-3 methyl imidazolium bromide [C15mim]Br with drug chloramphenicol in aqueous solution. For this the conductivity measurements have been employed to indicate [C15mim]Br –chloramphenicol interactions. The evaluation of Micellar and interfacial parameters such as critical micelle concentration and various thermodynamic parameters such as standard free energy of micellization, standard entropy of micellization and standard enthalpy of micellization has been carried out.

Prediction of aqueous intrinsic solubility of druglike molecules using Random Forest regression trained with Wiki-pS0 database.

The accurate prediction of solubility of drugs is still problematic. It was thought for a long time that shortfalls had been due the lack of high-quality solubility data from the chemical space of drugs. This study considers the quality of solubility data, particularly of ionizable drugs. A database is described, comprising 6355 entries of intrinsic solubility for 3014 different molecules, drawing on 1325 citations. In an earlier publication, many factors affecting the quality of the measurement had been discussed, and suggestions were offered to improve ways of extracting more reliable information from legacy data. Many of the suggestions have been implemented in this study. By correcting solubility for ionization (i.e., deriving intrinsic solubility, S0) and by normalizing temperature (by transforming measurements performed in the range 10-50 °C to 25 °C), it can now be estimated that the average interlaboratory reproducibility is 0.17 log unit. Empirical methods to predict solubility at best have hovered around the root mean square error (RMSE) of 0.6 log unit. Three prediction methods are compared here: (a) Yalkowsky’s general solubility equation (GSE), (b) Abraham solvation equation (ABSOLV), and (c) Random Forest regression (RFR) statistical machine learning. The latter two methods were trained using the new database. The RFR method outperforms the other two models, as anticipated. However, the ability to predict the solubility of drugs to the level of the quality of data is still out of reach. The data quality is not the limiting factor in prediction. The statistical machine learning methodologies are probably up to the task. Possibly what’s missing are solubility data from a few sparsely-covered chemical space of drugs (particularly of research compounds). Also, new descriptors which can better differentiate the factors affecting solubility between molecules could be critical for narrowing the gap between the accuracy of the prediction models and that of the experimental data.

Neutral Diclofenac Causes Remarkable Changes in Phosphatidylcholine Bilayers: Relevance for Gastric Toxicity Mechanisms.

The main objective of this study was to clarify the topical mechanisms underlying diclofenac-induced gastric toxicity by considering for the first time both ionization states of this nonsteroidal anti-inflammatory drug. 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes were the model system chosen to mimic the protective phospholipid layers of the gastric mucosa and to describe the interactions with diclofenac, considering the pH gradient found in the gastric mucosa (3 < pH < 7.4). Complementary experimental techniques were combined to evaluate the drug's affinity for DMPC bilayers, as well as to assess the drug's effects on the structural properties of the phospholipid bilayer. The diclofenac-DMPC interactions were clearly dependent on the drug's ionization state. Neutral diclofenac displayed greater affinity for DMPC bilayers than anionic diclofenac. Moreover, the protonated/neutral form of the drug induced more pronounced and/or distinct alterations in the structure of the DMPC bilayer than the deprotonated/ionized form, considering similar membrane concentrations. Therefore, neutral diclofenac-induced changes in the structural properties of the external phospholipid layers of the gastric mucosa may constitute an additional toxicity mechanism of this worldwide-used drug, which shall be considered for the development of safer therapeutic strategies. SIGNIFICANCE STATEMENT: Neutral or anionic diclofenac exerted distinct alterations in phosphatidylcholine bilayers, which are used in this work as models for the protective phospholipid layers of the gastric mucosa. Remarkable changes were induced by neutral diclofenac in the structural properties of the phospholipid bilayer, suggesting that both ionized and neutral states of nonsteroidal anti-inflammatory drugs must be considered to clarify their mechanisms of toxicity and to ultimately develop safer anti-inflammatory drugs.

Electrochemical Behavior and Detection of Diclofenac at a Microporous Si3N4 Membrane Modified Water–1,6-dichlorohexane Interface System

The electrochemical behavior when the liquid–liquid interface was modified by commercially available, microporous silicon nitride membrane, was achieved using cyclic voltammetry with tetramethyl ammonium. The transfer characteristics of the ionizable drug diclofenac ( DCF − ), as an anti-inflammatory, anti-rheumatic, antipyretic, and analgesic treatment in common use in biomedical applications, were also investigated across microporous silicon nitride-modified liquid interface. Thus, some thermodynamic variables for DCF − , such as the standard Gibbs energy of transfer, the standard transfer potential and lipophilicity were estimated. Furthermore, the influence of possible interfering substances (ascorbic acid, sugar, amino acid, urea, and metal ions) on the detection of DCF − was investigated. An electrochemical DCF sensor is investigated using differential pulse voltammetry (DPV) as the quantification technique, a linear range of 8–56 µM and a limit of detection of 1.5 µM was possible due to the miniaturized interfaces formed within silicon nitride.

HYDROPHOBIC ION-PAIRED DRUG DELIVERY SYSTEM: A REVIEW

Hydrophobic ion-pairing (HIP) complexation technique has been displayed to modify the physicochemical properties, solubility, oral absorption, bioavailability, and the lipophilicity of an ionic drug in the lipid phase. This could affect a higher permeation through biological membranes. HIP complexation was considered through the formation of a neutral molecule by electrostatic interaction of ionizable groups of drugs with oppositely charged functional groups of a complex-forming agent. Subsequently, this ion-pair may encapsulate into many delivery systems. The objective of this manuscript was to study the effectiveness of ion-pair complextion and cover the update application of this strategy through several routes of administration such as ocular, oral, pulmonary, transdermal, and parenteral.

Transdermal patches of lidocaine/aspirin ionic liquid drug-loaded gelatin/polyvinyl alcohol composite film prepared by freeze-thawed procedure.

The objectives of this study are to prepare a 5 wt% lidocaine/aspirin ionic liquid drug-loaded gelatin/polyvinyl alcohol composite film using a freeze-thaw procedure and to evaluate their physicochemical characteristics, in vitro drug release, and stability. Lidocaine/aspirin ionic liquid drugs can be prepared by an ion-pair reaction between the hydrochloride salts of lidocaine and the sodium salts of aspirin, which showed a significant change in their thermal properties when compared to those pure drugs. The results showed that a transdermal patch could feasibly be used in pharmaceutical transdermal patches with good physicochemical properties. A chemical interaction between the drug and polymer base was not found. Decomposition of the lidocaine/aspirin ionic liquid drug was found in the patch; however, the properties of the patch were not changed after drug loading. The patch controlled the drug release and showed good stability during the studied period of three months when kept at 4°C more than at ambient temperature and 45°C.

Multi-spectroscopic monitoring of molecular interactions between an amino acid-functionalized ionic liquid and potential anti-Alzheimer's drugs.

Inhibiting the formation of amyloid fibrils is a crucial step in the prevention of the human neurological disorder, Alzheimer's disease (AD). Ionic liquid (IL) mediated interactions are an expedient approach that exhibits inhibition effects on amyloid fibrils. In view of the beneficial role of ILs, in this work we have explored complexation of anti-Alzheimer's drugs (i.e., tacrine and PC-37) and an amino acid-functionalized IL [AIL (4-PyC8)]. Maintaining standard physiological conditions, the binding mechanism, thermo-dynamical properties and binding parameters were studied by employing UV-vis, fluorescence, FTIR, 1H NMR, COSY and NOESY spectroscopy. The present investigation uncovers the fact that the interaction of anti-Alzheimer's drugs with 4-PyC8 is mediated through H-bonding and van der Waals forces. The Benesi–Hildebrand relation was used to evaluate the binding affinity and PC-37 showed the highest binding when complexed with 4-PyC8. FTIR spectra showed absorption bands at 3527.98 cm−1 and 3527.09 cm−1 for the PC-37 + 4-PyC8 system which is quite promising compared to tacrine. 1H-NMR experiments recorded deshielding for tacrine at relatively higher concentrations than PC-37. COSY investigations suggest that anti-Alzheimer's drugs after complexation with 4-PyC8 show a 1 : 1 ratio. The cross-peaks of the NOESY spectra involve correlations between anti-Alzheimer's drugs and AIL protons, indicating complexation between them. The observed results indicate that these complexes are expected to have a possible therapeutic role in reducing/inhibiting amyloid fibrils when incorporated into drug formulations.

Ionic Diffusion and Drug Release Behavior of Core–Shell-Functionalized Alginate–Chitosan-Based Hydrogel

This paper reports the core–shell structure effects in calcium alginate (CaALG) microbeads due to the threshold water level for phase transition and correlates these properties with respect to pH and electrical conductivity. Further, in this study, we used a novel microfluidic device for drug release testing to study the programmed release of risedronate (RIS-anti-osteoporotic drug) encapsulated in pH-responsive CaALG–chitosan (CHT) microbeads. Our microfluidic device contains a single straight microchannel containing a steplike barrier design used to restrict the mobility of the microbeads at the sample detection zone. For optical and fluorescence microscopy, single fluorescently labeled CaALG–CHT microbead containing RIS was placed in the sample detection zone by flowing through the inlet port with ultrapure water. The RIS release behavior from the microbeads at different pH (2.1, 4, 6.8, and 7.4) conditions was determined by using a spectrophotometer connected to the outlet port of the device. Results of our first study showed that the decrease in the concentration of CaCl2 increases the swelling rate in CaALG microbeads. Maximum swelling was achieved with the lowest molar concentration of CaCl2 used for fabrication of CaALG microbeads. Further, electrical current–voltage characteristic shows the nature of ionic mobility with respect to varying levels of pH indicating electrokinetic forces developed in the CaALG microbeads. By using a microfluidic device for drug release testing, we demonstrated that a sustained release delivery system for RIS can be prepared by coating with pH-sensitive and biodegradable CaALG–CHT. The CaALG–CHT microbeads used for encapsulating RIS are resistant to the acidic environment of the stomach. This may improve the therapeutic effectiveness and reduce the gastric adverse effects associated with RIS by preventing its decomposition in the acidic condition of stomach. The newly developed microfluidic device for drug release testing may find applications in screening novel drugs and delivery systems.

Ionic Liquid Forms of the Antimalarial Lumefantrine in Combination with LFCS Type IIIB Lipid-Based Formulations Preferentially Increase Lipid Solubility, In Vitro Solubilization Behavior and In Vivo Exposure.

Lipid based formulations (LBFs) are commonly employed to enhance the absorption of highly lipophilic, poorly water-soluble drugs. However, the utility of LBFs can be limited by low drug solubility in the formulation. Isolation of ionizable drugs as low melting, lipophilic salts or ionic liquids (ILs) provides one means to enhance drug solubility in LBFs. However, whether different ILs benefit from formulation in different LBFs is largely unknown. In the current studies, lumefantrine was isolated as a number of different lipophilic salt/ionic liquid forms and performance was assessed after formulation in a range of LBFs. The solubility of lumefantrine in LBF was enhanced 2- to 80-fold by isolation as the lumefantrine docusate IL when compared to lumefantrine free base. The increase in drug loading subsequently enhanced concentrations in the aqueous phase of model intestinal fluids during in vitro dispersion and digestion testing of the LBF. To assess in vivo performance, the systemic exposure of lumefantrine docusate after administration in Type II-MCF, IIIB-MCF, IIIB-LCF, and IV formulations was evaluated after oral administration to rats. In vivo exposure was compared to control lipid and aqueous suspension formulations of lumefantrine free base. Lumefantrine docusate in the Type IIIB-LCF showed significantly higher plasma exposure compared to all other formulations (up to 35-fold higher). The data suggest that isolation of a lipid-soluble IL, coupled with an appropriate formulation, is a viable means to increase drug dose in an oral formulation and to enhance exposure of lumefantrine in vivo.

Development of methods of determination of technological houses 3,5-dinitro- and 3,5-diaminobenzoics acids at synthesis of sodium amidotrіzоate

Ionogenic contrast preparations, Triombrast, Urographin and Trasograph containing the active pharmaceutical ingredient (APhI), sodium amidotrizoate, have a positive experience in medical diagnosis.&#x0D; Qualitative control of intermediate products of each stage of AFI to prevent the possibility of technological toxic impurities – a mixture of 3,5-dinitro- and 3,5-diaminobenzoic acids (3,5-dNBK and 3,5-dABK) in the composition of the target product for safety X-ray contrast drugs in their application is a pressing issue today.&#x0D; The aim of the work – to develop a method for determining the technological impurities of 3,5-dNBK and 3,5-dABK acids in the synthesis of amidotrizoate sodium using UV spectrophotometry, which will allow to determine these impurities without their preliminary separation both in the inter-operative process control and in the finished product.&#x0D; The objects of study are aqueous solutions of 3,5-dNBK and 3,5-dABK acids, as well as their binary mixtures. The absorption spectra of the analytes were recorded using a Specord UV VIS spectrophotometer in the ultraviolet region. Calculations of the concentrations of the investigated acids in the composition of their binary compositions were performed according to the Vierordt's method.&#x0D; It is found that the absorption maxima of aqueous solutions of 3,5-dNBK and 3,5-dABK are at wavelengths of 240 nm and 218 nm; in the experimental conditions, the molar absorption coefficient for 3,5-dinitrobenzoic acid was the same (e1240 = e1218) and was equal to 17 940 ± 150. For solutions of 3,5-diaminobenzoic acid, the molar absorption coefficients were different: for a wavelength of 218 nm, the molar e2218 = 28 890 ± 220 and at a wavelength of 240 nm e2240 = 10 770 ± 80.&#x0D; Based on the Firordt method, taking into account the molar absorption coefficients of the investigated acids, we determined mathematical formulas for the quantitative analysis of the composition of mixtures at different ratios of analytes within their total concentration 1–6·10-5 M. Spectrophotometric Vierordt's method of quantitative analysis of 3,5-dinitro- and 3,5-diaminobenzoic acids, as well as their binary mixtures in aqueous solutions can be applied in the industrial production of iodine-containing contrast agents, where in the first stages of synthesis, the corresponding nitrobenzoic acid is reduced. Strict control of the possible amount of impurities in the first stage of synthesis of sodium amidotrizoate – the main active ingredient of ionic iodine-containing X-ray contrast drugs (Triombrast, Urografin, Trasograph) – will improve the quality of the final product and will allow to reduce the final product.

Ion exchange in supercritical fluid chromatography tandem mass spectrometry (SFC-MS/MS): Application for polar and ionic drugs and metabolites in forensic and anti-doping analysis

Supercritical fluid chromatography (SFC) is an orthogonal technique to UHPLC. In recent years, SFC has demonstrated potential for use in the analysis of a broad variety of analytes of different polarities, if modifiers and additives are utilized as additional mobile phase constituents. However, to date, little research has been carried out on ion-exchange separation of highly polar and ionic analytes using SFC.The objective of this work was to investigate the elution characteristics of polar compounds using SFC combined with tandem mass spectrometry. Highly polar and even ionic drugs and metabolites, with a diversity of functional groups such as gamma-hydroxybutyrate (GHB), gamma-butyrolactone, GHB-glucuronide, ethyl sulfate, ethyl glucuronide as well as meldonium and gamma-butyrobetaine, were selected for the study. To investigate the chromatographic behavior of the solutes using SFC, a systematic chromatographic method development workflow including a basic validation in human urine was implemented. To ensure the best selectivity, columns with different stationary phase chemistries (silica, NH2, CN, SCX, Diol, EP and amide) were screened. Furthermore, different modifier compositions were evaluated, including pure methanol and methanol with various additives (ammonium acetate or ammonium formate, water, and/or ammonia or formic acid in varying amounts). Trends in retention time shifts were investigated by the systematic variation of gradients, backpressure and column compartment temperature. The quality and reliability of the method has been tested in the course of a basic validation by evaluation of selectivity, linearity, limit of identification, limit of quantification, carry-over, precision, and matrix effect.The highest chromatographic selectivity (especially with respect to the separation of the critical pair of zwitterionic meldonium and γ-butyrobetaine) and suitable peak shapes for all target analytes were obtained using the strong cation exchange column. We observed that increasing buffer concentrations improved the peak shape. Ion-exchange stationary phase and polar additives (buffers, bases, acids and water) mixed with organic modifiers enabled separation of small ionic molecules using SFC. Hence, SFC further demonstrated its wide applicability in small molecule analysis, and may be considered an alternative separation technique to improve the separation of polar analytes.

Ionic liquids with N-methyl-2-pyrrolidonium cation as an enhancer for topical drug delivery: Synthesis, characterization, and skin-penetration evaluation

The development of non-toxic ionic liquid-based active pharmaceutical ingredients (IL-APIs) for effective topical drug delivery is still challenging. The properties of IL-APIs can be boosted up by selecting potential biocompatible cations. Here, we introduced N-methyl-2-pyrrolidone (NMP) as a potent biocompatible counter ion to prepare ionic liquefied drugs for topical drug delivery. The cytotoxicity of NMP cation was investigated using mammalian cell lines (HepG2, NIH3T3 and L929 cells) and compared with conventional IL-forming cations. The synthesized NMP cation has lower toxicity than that of conventional IL-forming cations. The NMP cation showed at least 3.6, 15.2 and 58.9 times lower toxicity than that of conventional imidazolium, ammonium and phosphonium cations, respectively. The synthesized NMP-based ionic liquid (NMP-IL) was characterized using 1H &13C NMR, FT-IR, DSC and TGA. NMP-IL showed better physico-thermal stability, enhanced skin penetration, and enriched drug accumulation 2.6 times higher than that of IL [Cho][Ibu] in the target tissue. These results suggested that NMP cation based API-IL can be an effective biocompatible formulation for topical drug delivery by accumulating active drugs in the skin.

Controlled Release of Lidocaine-Diclofenac Ionic Liquid Drug from Freeze-Thawed Gelatin/Poly(Vinyl Alcohol) Transdermal Patches.

The objectives of this work were to prepare a 5 wt% lidocaine-diclofenac ionic liquid drug-loaded gelatin/poly(vinyl alcohol) transdermal patch using a freeze/thaw method and to evaluate its physicochemical properties, in vitro release of lidocaine and diclofenac, and stability test. The lidocaine-diclofenac ionic liquid drug was produced by the ion pair reaction between the hydrochloride salts of lidocaine and the sodium salts of diclofenac. The thermal properties of the final drug product were significantly changed from the primary drugs. The ionic liquid drug could be dissolved in water and mixed in a polymer solution. The resulting transdermal patch was then exposed to 10 cycles of freezing and thawing preparation at - 20°C for 8 h and at 25°C for 4 h, respectively. As a result, it was found that the lidocaine-diclofenac ionic liquid drug-loaded transdermal patch showed good physicochemical properties and could feasibly be used in pharmaceutical applications. The lidocaine-diclofenac ionic liquid drug was not affected by the properties of the transdermal patch due to the lack of chemical interaction between polymer base and drug. The high drug release values of both lidocaine and diclofenac were controlled by the gelatin/poly(vinyl alcohol) transdermal patch. The patch showed good stability over the study period of 3 months when kept at 4°C or under ambient temperature.

A Novel Approach for Bisphosphonates: Ionic Liquids and Organic Salts from Zoledronic Acid.

Novel ionic liquids and organic salts based on mono- or dianionic zoledronate and protonated superbases, choline and n-alkylmethylimidazolium cations, were prepared and characterized by spectroscopic and thermal analyses. Most of the prepared salts display amorphous structures and very high solubility in water and saline solutions, especially the dianionic salts. Among the zoledronate-based ionic compounds, those containing choline [Ch] and methoxyethylmethylimidazolium [C3 OMIM] cations appear to have significant cytotoxicity against human osteosarcoma cells (MG63) and low toxicity toward healthy skin fibroblast cells. Because osteosarcoma is a bone pathology characterized by an increase in bone turnover rate, the results presented herein may be a promising starting point for the development of new ionic pharmaceutical drugs against osteosarcoma.

Choline supported poly(ionic liquid) graft copolymers as novel delivery systems of anionic pharmaceuticals for anti-inflammatory and anti-coagulant therapy

New type of carriers based on grafted poly(ionic liquid)s was designed for delivery of ionically attached salicylates (Sal). Choline derived ionic liquid monomeric units were successfully introduced with various content in the side chains by the controlled radical polymerization. Properly high amounts of ionic pharmaceutics in the polymer systems were achieved by the well-fitted length and grafting degree of the side chains. In aqueous solution the graft copolymers were self-assembled into the spherical superstructures with sizes up to 73 nm. Delivery studies showed “burst” release within 4 h, after that it was slower yielding ~70% of released drug within 80 h. Proposed nanocarriers supported low toxicity against human cells (NHDF and BEAS-2B), anti-inflammation activity evaluated with the use of pro-inflammatory interleukins (IL-6 and IL-8) and antibacterial activities towards E. coli. Adjustment of ionic drug content by structural parameters of graft copolymers, including grafting degree and graft length, are advantageous to tailor nanocarriers with self-assembly properties in aqueous media. Effective release process by ionic exchange and biological activity with low toxicity are promising for further development of this type of drug delivery (DDS).

Phosphonium Polyelectrolyte Complexes for the Encapsulation and Slow Release of Ionic Cargo.

Polyelectrolyte complexation, the combination of anionically and cationically charged polymers through ionic interactions, can be used to form hydrogel networks. These networks can be used to encapsulate and release cargo, but the release of cargo is typically rapid, occurring over a period of hours to a few days and they often exhibit weak, fluid-like mechanical properties. Here we report the preparation and study of polyelectrolyte complexes (PECs) from sodium hyaluronate (HA) and poly[tris(hydroxypropyl)(4-vinylbenzyl)phosphonium chloride], poly[triphenyl(4-vinylbenzyl)phosphonium chloride], poly[tri(n-butyl)(4-vinylbenzyl)phosphonium chloride], or poly[triethyl(4-vinylbenzyl)phosphonium chloride]. The networks were compacted by ultracentrifugation, then their composition, swelling, rheological, and self-healing properties were studied. Their properties depended on the structure of the phosphonium polymer and the salt concentration, but in general, they exhibited predominantly gel-like behavior with relaxation times greater than 40 s and self-healing over 2-18 h. Anionic molecules, including fluorescein, diclofenac, and adenosine-5'-triphosphate, were encapsulated into the PECs with high loading capacities of up to 16 wt %. Fluorescein and diclofenac were slowly released over 60 days, which was attributed to a combination of hydrophobic and ionic interactions with the dense PEC network. The cytotoxicities of the polymers and their corresponding networks with HA to C2C12 mouse myoblast cells was investigated and found to depend on the structure of the polymer and the properties of the network. Overall, this work demonstrates the utility of polyphosphonium-HA networks for the loading and slow release of ionic drugs and that their physical and biological properties can be readily tuned according to the structure of the phosphonium polymer.

Fraction Lipophilicity Index (FLI). A drug-like metric for orally administered ionizable drugs

ABSTRACTFraction Lipophilicity Index (FLI) was developed as a metric for assessing drug likeness of ionizable oral drugs. Considering that both log P and log D have distinct roles in drug action, the metric FLI allocates lipophilicity to a pH dependent neutral fraction of the molecule and is a weighted combination of log P and log D. It is expressed by equation: FLI = 2 x log P–│log D│. A dataset of 368 basic and acidic drugs was analyzed. Based on available % absorption data, drugs were classified into class 1 (268 drugs) and class 2 (100 drugs). The freeware MedChem Designer was used for log P and log D calculations at pH 7.4 and pH 5.5 for acids. Based on class 1, a drug-like FLI range 0–8 was defined. FLI distribution for class 2 is shifted towards significantly lower values. Comparison of FLI with rule of 5 (Ro5) shows that it leads to fewer values outside the established range than the corresponding log P violations for class 1. For class 2 it gives more alerts than Ro5 and can be considered complementary to Ro5, while it also sets lower limits to discriminate drugs with poor absorption.

Effect of diphenhydramine-hydrochloride, guaifenesin and naproxen sodium drugs on water activity in aqueous solutions of 1-butyl-1-methylpyrrolidinium trifluoromethanesulfonate ionic liquid at 298.15 K

Water activities for the binary aqueous solution of ionic liquid of 1-butyl-1-methylpyrrolidinium trifluoromethanesulfonate ([BMP][TfO]), and also three ternary aqueous solutions containing ionic liquid of [BMP][TfO] and drugs of diphenhydramine-hydrochloride, guaifenesin and naproxen sodium were measured using an improved isopiestic method to study the medicines effect on water activity of ionic liquid aqueous solution at T = 298.15 K. Vapor pressure values were calculated from the water activity data measured in this work. NRTL, NRF-NRTL, mNRTL, Wilson and TNRF-mNRTL local composition based models were applied for correlating the water activity data for binary and ternary aqueous solutions containing ionic liquid and drugs considered in this work. All of these models satisfactorily predicted the water activity data for the systems investigated. Water activity data and vapor pressure decreasing were utilized to highlight the solute-solvent interactions.

Correlation between the stability constant and pH for β-cyclodextrin complexes.

In drug formulations, cyclodextrins are used to increase aqueous solubility and chemical stability of drugs via formation of inclusion complexes. For ionizable drug molecules, the complexation strength depends on pH. Increased ionization leads to a more soluble drug, but also results in destabilization of cyclodextrin complexes. Therefore, formulation scientists aim to find a balance between increased drug solubility and high complexation strength. In this work, a theoretical expression for the dependency between the stability constant and pH is presented, allowing the accurate prediction of the stability constant at any pH. The theoretical expression requires three out of four input parameters; the pKa of the free guest molecule, the pKa of the complex, and the stability constants for the neutral and fully ionized complex. Stability constants for β-cyclodextrin and ibuprofen complexes were determined by isothermal titration calorimetry at seven pH values (2.5-5.5) and four temperatures (15-55 °C). All these measured stability constants complied with the theoretical expression. Ten additional data sets from the literature comprising eight different drug molecules and three different cyclodextrins confirmed the ability of the theoretical expression to account for the observed pH-dependence of stability constants.