Hydrotropic Agent Research Articles

Formulation and evaluation of aceclofenac injection made by mixed hydrotropic solubilization technique.

Aceclofenac is a non-steroidal anti-inflammatory drug (NSAID) that exhibits analgesic, antipyretic and anti-inflammatory activities. It is practically insoluble in water. The effect of hydrotropes such as urea and sodium citrate and blends (urea + sodium citrate) on the solubility of aceclofenac was investigated. The enhancement in the solubility of aceclofenac was more than 5 and 25 folds in 30% sodium citrate solution and 30% urea solution, respectively, as compared to its solubility in distilled water. The enhancement in the solubility of aceclofenac in a mixed hydrotropic solution containing ≥ 20% urea and 10% sodium citrate solution was more than 250 folds (compared to its solubility in distilled water). This proved a synergistic enhancement in solubility of a poorly water- soluble drug due to mixed hydrotropy. Synergistic combination of hydrotropic agents can minimize the amount of hydrotropic agents employed, minimizing the chances of their toxicities. Aqueous injection of aceclofenac, using the mixed hydrotropic solubilization technique, was developed and by using the lyophilization method, the problem of inadequate stability of aceclofenac in aqueous solution was overcome. The developed formulation was studied for physical and chemical stability.

A Simplified Model of Local Structure in Aqueous Proline Amino Acid Revealed by First-Principles Molecular Dynamics Simulations

Aqueous proline solutions are deceptively simple as they can take on complex roles such as protein chaperones, cryoprotectants, and hydrotropic agents in biological processes. Here, a molecular level picture of proline/water mixtures is developed. Car-Parrinello ab initio molecular dynamics (CPAIMD) simulations of aqueous proline amino acid at the B-LYP level of theory, performed using IBM's Blue Gene/L supercomputer and massively parallel software, reveal hydrogen-bonding propensities that are at odds with the predictions of the CHARMM22 empirical force field but are in better agreement with results of recent neutron diffraction experiments. In general, the CPAIMD (B-LYP) simulations predict a simplified structural model of proline/water mixtures consisting of fewer distinct local motifs. Comparisons of simulation results to experiment are made by direct evaluation of the neutron static structure factor S( Q) from CPAIMD (B-LYP) trajectories as well as to the results of the empirical potential structure refinement reverse Monte Carlo procedure applied to the neutron data.

Analysis of bulk sample of salicylic acid by application of hydrotropic solubilization method

In the present investigation, the poorly water-soluble drug, salicylic acid has been solubilized using 0.5 M ibuprofen sodium and 2.0 M sodium salicylate solution as hydrotropic agents for the titrimetric analysis precluding the use of organic solvents. Both hydrotropes are economic and pollution-free. The mean percent estimation of salicylic acid estimated in bulk sample by Indian Pharmacopoeial method is 98.78%. The mean percent estimation by ibuprofen sodium method and sodium salicylate method are 99.25% and 98.82%, respectively. The results of analysis by the proposed method are very close to the results of analysis by the standard method. This confirms the accuracy of the proposed method. The proposed method was validated statistically by low values of statistical parameters viz. standard deviation, percent coefficient of variation and standard error. The proposed method is new, accurate, simple and economic.

Aqueous Solubilization of Paclitaxel Using Hydrotropic Polymer Micelle

Hydrotropic block copolymers, consisting of a hydrophilic poly(ethylene glycol) (PEG) block and a hydrotropic polymer, poly(2-(4-(vinyl benzyloxy)-N,N-diethylnicotinamide)) [P(VBODENA)], block, were synthesized by atom transfer radical polymerization (ATRP) for aqueous solubilization of paclitaxel, a representative poorly water-soluble drug. These polymers showed an excellent solubilizing effect for paclitaxel in aqueous media in comparison with the corresponding hydrotropic agent and a control micelle (PEG-PLA) and such effect was significantly dependent on the polymer concentration and composition. Paclitaxel could be solubilized into polymer micelles in aqueous media without use of an organic solvent. Due to their promising properties such as micellar characteristics and hydrotropic solubilization, the hydrotropic polymer micelle system can be useful for formulation of paclitaxel and other poorly soluble drugs.

Novel application of hydrotropic solubilization in the analysis of some NSAIDs and their solid dosage forms

Quantitative analysis of poorly water-soluble drugs involves use of various organic solvents. Major drawbacks of organic solvents include high cost, volatility and toxicity. Safety of analyzer is affected by toxicity of the solvent used. Sodium benzoate is one of the widely used hydrotropic agents and has demonstrated the enhancement in aqueous solubilities of a large number of poorly water-soluble drugs. In the present investigation 2 M sodium benzoate solution has been used as hydrotropic solubilizing agent for three poorly water-soluble, non-steroidal antiinflammatory drugs ibuprofen, flurbiprofen and naproxen. There were more than 80, 110 and 120 fold enhancements in the solubilities of ibuprofen, flurbiprofen and naproxen, respectively in 2 M sodium benzoate solution as compared to solubilities in distilled water. Therefore, 2 M sodium benzoate solution was employed to solubilize these drugs to carryout their titrimetric analyses. These drugs have been analyzed successfully in basic drug samples and in solid dosage forms. Proposed method is new, simple, economic, safe, rapid, accurate and reproducible. The results of analysis obtained by the proposed methods compared well with those obtained by corresponding pharmacopoeial methods. Recovery studies and statistical data proved the accuracy, reproducibility and the precision of the proposed methods. Presence of sodium benzoate did not interfere in analysis.

Effect of a mixture of caffeine and nicotinamide on the solubility of vitamin (B 2) in aqueous solution

The effect of caffeine (CAF) and nicotinamide (NMD) on the solubility of a vitamin B 2 derivative (FMN) has been evaluated for mixtures containing either a single hydrotrope (CAF or NMD) or the two hydrotropes simultaneously. A model for analysis of ternary systems, which takes into account all possible complexes between the molecules, has been developed and tested with experimental NMR data on the three-component mixture FMN–CAF–NMD. The results indicate that special attention should be given to the concentration of a hydrotropic agent used to enhance the solubility of a particular drug. A decrease in the efficacy of solubility of the vitamin on addition of large amounts of hydrotropic agent is expected in the two-component systems due to the increased proportion of self-association of the hydrotrope. It is found that a mixture of two hydrotropic agents leads to an increase in the solubility of the vitamin in three-component compared to the two-component system. Rather than using just one hydrotropic agent, it is proposed that a strategy for optimising the solubility of aromatic drugs is to use a mixture of hydrotropic agents.

Anionic Gemini Surfactants: A Distinct Class of Surfactants

Anionic gemini surfactants are a new class of surfactants that comprise of two anionic head groups and two hydrophobic tails separated by a spacer group. Anionic gemini surfactants have low cmc values and show extraordinary surface activity. These surfactants have good water solubility and their ability to form micelles and lowering surface tension characteristics are fairly good as compared to conventional anionic surfactants. These surfactants have excellent lime soap dispersing ability (LSDA) too. Because of their higher surface activity these surfactants are used as promising surfactants in industrial detergency and emulsification. These surfactants are cost effective in area such as laundry detergent compositions, soil clean up, enhanced oil recovery and hydrotropic agents. This review deals with structure, synthesis, critical micelle concentration, surface active properties, performance properties, uses and biodegradability of anionic geminis.

Hydrotropic Dendrimers of Generations 4 and 5: Synthesis, Characterization, and Hydrotropic Solubilization of Paclitaxel

Polyglycerol dendrimers (PGDs) with 4-5 generations were synthesized and used to investigate the effect of dendritic architecture and its generation on aqueous solubilization of paclitaxel (PTX), a poorly water-soluble drug. Chemical and physical properties of the PGDs were characterized by NMR, MALDI-TOF mass, GPC, viscosity, and dynamic light scattering measurements. The PTX solubility in all the solutions of PGDs, even below 10 wt %, was much higher than that in PEG400 that is commonly used as a cosolvent or a hydrotropic agent. Increase in the PTX solubility by PGDs was dependent on the dendrimer generation. The dendritic structure was the reason for the enhanced solubility of PTX even at low concentrations. (1)H NMR spectra of PTX before and after mixing with PGDs in D(2)O suggested that the aromatic rings and some methyne groups of PTX were surrounded by PGDs. PGDs, which do not require hydrophobic segment as in polymeric micelles, provide an alternative method of hydrotropic solubilization of poorly soluble drugs.

Hydrotropic agents for study of in vitro paclitaxel release from polymeric micelles

A new experimental method for in vitro release studies of poorly soluble drugs from polymeric micelle systems was developed using a hydrotropic agent, sodium salicylate. It is difficult to maintain a good sink condition for poorly water-soluble drugs, such as paclitaxel (PTX), because of their low aqueous solubility. In this study, a good sink condition for PTX was achieved by using aqueous sodium salicylate solution which solubilized more than 10 times the total amount of PTX incorporated in polymeric micelles. Sodium salicylate at 1 M concentration increased the aqueous PTX solubility by 100 times without destroying the micellar structure of poly(ethylene glycol)-block-poly(phenylalanine) (PEG-b-PPhe) copolymer. PTX was continuously released from PEG-b-PPhe micelles in the hydrotropic release medium. The hydrotropic solution presents a simple method for studying in vitro release behavior of poorly soluble drugs from polymeric micelles in aqueous media.

Aqueous N,N-diethylnicotinamide (DENA) solution as a medium for accelerated release study of paclitaxel

N,N-Diethylnicotinamide (DENA) was identified as an excellent hydrotropic agent for paclitaxel (PTX) in our previous studies. The aqueous solubility of PTX was increased by several orders of magnitude in the presence of DENA. Because of such a high hydrotropic property, DENA was used as a release medium providing a sink condition for the release of PTX from poly(lactic-co-glycolic acid) (PLGA) matrices. The release profiles of PTX from PLGA matrices into DENA, serum and phosphate-buffered saline (PBS) were compared. The stability of PTX in DENA and the degradation of PLGA molecules in DENA were examined. The degradation rate constant of PTX in 2 M DENA was similar to those in other aqueous solutions. The use of 2 M DENA as a release medium allowed differentiation of the release profiles of PTX from PLGA matrices made of different PLGA compositions. The PTX release from PLGA matrices was much faster in DENA solution than in serum or PBS, and the concentration of DENA affected the PTX release rate. The presence of DENA in the release medium increased the hydrolysis rate of PLGA polymers. The faster release of PTX from PLGA matrices in DENA solution may be due to the high PTX solubility and faster degradation of PLGA polymers in the presence of DENA. Our study suggests that the aqueous DENA solution can be used for the accelerated release study of PTX from PLGA matrices.

Hydrotropic solubilization of paclitaxel: analysis of chemical structures for hydrotropic property.

To identify hydrotropic agents that can increase aqueous paclitaxel (PTX) solubility and to study the chemical structures necessary for hydrotropic properties so that polymeric hydrotropic agents can be synthesized. More than 60 candidate hydrotropic agents (or hydrotropes) were tested for their ability to increase the aqueous PTX solubility. A number of nicotinamide analogues were synthesized based on the observation that nicotinamide showed a favorable hydrotropic property. The identified hydrotropes for PTX were used to examine the structure-activity relationship. N,N-Diethylnicotinamide (NNDENA) was found to be the most effective hydrotropic agent for PTX. The aqueous PTX solubility was 39 mg/ml and 512 mg/ml at NNDENA concentrations of 3.5 M and 5.95 M, respectively. These values are 5-6 orders of magnitude greater than the intrinsic solubility of 0.30 +/- 0.02 microg/ml. N-Picolylnicotinamide, N-allylnicotinamide, and sodium salicylate were also excellent hydrotropes for PTX. Solubility data showed that an effective hydrotropic agent should be highly water soluble while maintaining a hydrophobic segment. The present study identified several hydrotropic agents effective for increasing aqueous solubility of PTX and analyzed the structural requirements for this hydrotropic property. This information can be used to find other hydrotropic compounds and to synthesize polymeric hydrotropes that are effective for PTX and other poorly water-soluble drugs.

Interação tensoativo/hidrótropo em sistemas aquosos, utilizando ressonância magnética nuclear de ¹H e 13C

In this work, it was studied the behavior of the nonionic surfactant aqueous solutions, containing or not a hydrotropic agent, by resonance magnetic nuclear (NMR). We have studied monofunctional diblock copolymers of poly(propylene oxide-ethylene oxide) (R-PPO-PEO-OH, where R length is linear C4) as nonionic surfactant and sodium p-toluenesulfonate (NaPTS) as hydrotropic agent. The critical micelle concentration (CMC) of the aqueous copolymer solution was obtained from 1H-NMR. The preliminary study of the interaction between the copolymer, under the unimer and micelle forms, and the hydrotrope, in aqueous solutions, was evaluated by 1H-NMR and 13C-NMR.

Study of adsorption of nonionic surfactants at the liquid-solid interface by FTIR/CIR

Fourier transform infrared spectroscopy (FTIR), using the attenuated total reflectance (ATR) method, can be used to characterize the interface of a system. We investigated the adsorption at the liquid–solid interface of nonionic surfactant aqueous solutions with or without a hydrotropic agent. We studied monofunctional diblock copolymers of poly(ethylene oxide-propylene oxide) (PEO–PPO) as nonionic surfactants and sodium p-toluenesulfonate (NaPTS) as hydrotropic agent. The samples were analyzed by FTIR technique using the circular internal reflectance (CIR) accessory, which confirmed that the hydrotrope shifts the surfactant from the liquid–solid interface. © 2001 John Wiley & Sons, Inc. J Appl Polym Sci 82: 1668–1676, 2001

ASSOCIATION OF KETOROLAC TROMETHAMINE IN AQUEOUS SOLUTIONS AND ITS RELATIONSHIP TO SOLUBILIZATION

Some physico-chemical properties of aqueous racemic Ketorolac Tromethamine (KT) solutions were measured as a function of concentration (0-1.0 M). These included surface tension, osmolality, partition coefficients and electrical conductivity at different temperatures (10, IS, 20, 25, 30, 40 and 50° C). These measurements indicate that KT undergoes nonmicelar self-association in water. Comparison of thesolubilitiesof spironolactone and diazepam in aqueous KT with the corresponding solubilities in known aqueous hydrotropic agents (sodium benzoate and salicylate) nonmicellar chlorpheniramine maleate (BP grade of ⩽ 99 % purity) and miceilar chlorpromazine hydrochloride (BP grade of ⩽ 99 % purity) indicates KT to undergo nonmicellar association, with a capacity for solubilization intermediate between hydrotropic agents and miceilar solubilizers. The solubilities of normal alkanols (C4-C10 ) were also measured against aqueous KT concentration. Compared with their solubilities in miceilar surfactants (sodium dodecylsulfate and chlorpromazine hydrochloride) aqueous KT appears to be a less efficient solubilizer. Molecular mechanical modeling of intermolecular interactions between KT species in water indicate that trimeric species have lower energies compared with those of the same number of monomeric (or monomeric plus dimeric) entities.

Estudo de soluções aquosas de copolímeros em bloco de poli(óxido de etileno)-poli(óxido de propileno) utilizando calorimetria exploratória diferencial (DSC)

O comportamento de sistemas aquosos contendo copolímeros dibloco monofuncionais de poli(óxido de etileno)-poli(óxido de propileno), bloqueados em uma das extremidades da cadeia com segmento hidrocarbônico linear, foi avaliado através de calorimetria exploratória diferencial (DSC). Transições endotérmicas foram observadas no aquecimento das soluções dos copolímeros e as temperaturas iniciais destas transições estão de acordo com os pontos de turvação dos copolímeros estudados. Nas curvas de resfriamento, são observadas duas transições, e quanto mais rápido é resfriada a solução de copolímero, melhor é observada a transição que deve estar relacionada à formação das micelas. A influência da presença de um agente hidrotrópico também foi avaliada em todas as soluções de copolímeros por meio do aumento no ponto de turvação com o aumento da concentração do agente hidrotrópico, visto que os picos endotérmicos foram deslocados para temperaturas mais altas.

The influence of a hydrotropic agent in the properties of aqueous solutions containing poly(ethylene oxide)–poly(propylene oxide) surfactants

The aqueous solution behavior of diblock poly(ethylene oxide)–poly(propylene oxide) (PEO–PPO) copolymers coupled with hydrocarbon groups was studied in the presence of the hydrotropic agent sodium p-toluenesulfonate (NaPTS). The change in phase of the aqueous systems was evaluated by building up temperature–concentration phase diagrams. The critical micelle concentrations (CMC) of the copolymers and the aggregation points of NaPTS and NaPTS/copolymer mixtures were obtained by surface tension measurements, viscometry data and dye solubilization. The copolymers and NaPTS adsorb and reduce the surface tension of the solution until the surface becomes saturated: the CMC values are related to the solubility of the copolymers. Solutions containing NaPTS/copolymer mixtures exhibit the opposite behavior: at constant copolymer concentrations and with increasing NaPTS concentration, the surface tension remains constant until the aggregates of NaPTS start to form. Above this concentration, the surface tension increases. The surface tension and the aggregation points of the NaPTS solutions are dependent on the structure of the copolymer. The influence of the length of the hydrocarbon groups and the PPO position segment in the structure of the copolymers were also studied. From viscometric data, a pronounced increase in solution viscosity was observed as aggregates began to form. The results obtained from dye solubilization are in good agreement with the surface tension and viscometric measurements.

Cyclodextrin Inclusion Complexes of Miconazole and Econazole—Isolation, Toxicity on Human Cells, and Confirmation of a New Interpretation of the Drug Supersaturation Phenomenon

Parameters that influence the precipitation of the β-cyclodextrin (β-CD) inclusion complexes of the antimycotics miconazole and econazole were investigated. The mechanistic reason for the superior antimycotic activity of the miconazole inclusion complex was studied. The toxicity of the complex was estimated. The temperature, the buffer strength, and the effect of the addition of hydrotropic agents on the CD solubility diagrams for the antimycotics were estimated. The miconazole and the CD dissolution rate for the complex was measured. The hemolytic activity of the miconazole inclusion complex, the physical mixture, miconazole, and the nitrate salt were compared. The toxicity on TR146 oral cell layers was measured. Lowering the temperature meant that both complexes precipitated at lower CD concentrations. Addition of hydrotropic agents and variation of the buffer strength affected the solubility diagrams. The dissolution medium was supersaturated with miconazole. The supersaturation was not disclosed by the traditional method to analyze for drug supersaturation. The miconazole complex was more toxic to erythrocytes than the physical mixture. On the other hand, the toxic effects of the two products on the TR146 cell layers were similar. Lowering the temperature eased the isolation of genuine CD inclusion complexes of miconazole and econazole. The miconazole supersaturation is likely to be the reason for the superior antimycotic activity of the complex. The complex and the physical mixture had about the same toxicity on TR146 cell layers.

Behavior of aqueous solutions of poly(ethylene oxide-b-propylene oxide) copolymers containing a hydrotropic agent

The effect of the hydrotropic agent, sodium p-toluenesulfonate (NaPTS), was evaluated on the micelle formation process and on phase behavior of aqueous solutions containing poly(ethylene oxide-b-propylene oxide) (PEO–PPO) copolymers. We have studied monofunctional diblock copolymers coupled with hydrocarbons groups (R—PEO—PPO—OH and R—PPO—PEO—OH, where R length is linear C4 and C12–14). The critical micelle concentration (CMC) and critical micelle temperature (CMT) values of the aqueous copolymers solutions were obtained from both surface tension versus concentration plots and the dye solubilization method. The influence of the hydrocarbons groups length and PPO segment position in the structure of the copolymers were also analyzed. The same measures were obtained for the aqueous solutions of hydrotropic agent which, in turn, also presented molecular aggregation. The presence of the hydrotropic agent in the aqueous copolymers solutions altered the surface tension of these solutions and the occupied molecular area per copolymer molecule at air–water interface and CMC and CMT values of the copolymers. On the other hand, the aggregation points and the surface tension of the NaPTS solutions were dependent on the copolymer structure and composition. © 1998 John Wiley & Sons, Inc. J Appl Polym Sci 69: 2459–2468, 1998

Mechanistic studies on hydrotropic solubilization of nifedipine in nicotinamide solution.

Nicotinamide is a hydrotropic agent that has been demonstrated to solubilize a wide variety of drugs through complexation. Past investigations on the potential interaction of nicotinamide with a solubilized drug have inadequately focused on aliphatic hydrotropes. This study examined the mechanism for the hydrotropic solubilization of nifedipine, a poorly water-soluble drug, in the aqueous solution of nicotinamide using not only nicotinamide analogues but also urea analogues as aliphatic hydrotropes. The values of stability constants, K1:2, at different temperatures in nicotinamide solution were determined by the phase solubility technique, and were utilized to estimate the thermodynamic parameters of complex formation between nifedipine and nicotinamide. The enthalpy change values suggested the participation of intermolecular forces other than hydrogen bonding in complexion. The aqueous solubility of nifedipine was measured in the presence of nicotinamide, urea and their analogues: N-methylnicotinamide, N,N-diethylnicotinamide, nipecotamide, methylurea, ethylurea and butylurea. The drug solubility increased in proportion to the amount of alkyl substituent on the amide nitrogen, and the solubilizing effect of butylurea was as high as that of nicotinamide. Furthermore, the relationship between the logarithmic drug solubilities in 1.0 M aqueous solutions of nicotinamide or urea analogues versus the logarithmic octanol-water partition coefficient values of ligands as an indication of hydrophobicity was found to be linear. The significant contributor to the hydrotropic solubilization of nifedipine with nicotinamide was therefore the ligand hydrophobicity rather than the aromaticity of the pyridine ring.

Effects of Some Hydrotropic Agents on the Formation of Indomethacin/β-Cyclodextrin Inclusion Compounds

The influence of the water structure promoters, mannitol and sucrose, on the indomethacin/β-cyclodextrin inclusion process at different pH values was evaluated using the phase solubility method and circular dichroism spectroscopy. The effect of mannitol and sucrose on the total solubilizing activity of β-cyclodextrin as well as on the stabilization of the complex was moderate, and depended strongly on the pH value of the medium. The most pronounced effect on the association constant of the indomethacin inclusion compound was observed in KCl/HCl buffer of pH 1.6, because mannitol and sucrose, in the absence of β-cyclodextrin, approximately double the indomethacin solubility so that the constant value decreases. On the other hand, a very strong complex formation between indomethacin and β-cyclodextrin was observed in acid medium (KCl/HCl buffer, pH = 1.6), a fact not much discussed in the literature. The apparent association constant of the inclusion compound formed in the absence of mannitol or sucrose was found to be of the same order of magnitude as for the complex formed at pH 6.8. Changes in the optical activity of the indomethacin/β-cyclodextrin inclusion complex were registered in the presence of sucrose, which interacts more strongly than mannitol with water molecules, and could probably adhere to the surface of the inclusion complex, thus changing its configuration and environment.