What type of compounds are soluble in ethanol

Much of what we now know about the tendency of particles to become more dispersed can be used to understand this kind of change as well. Picture a layer of ethanol being carefully added to the top of some water Figure below. Because the particles of a liquid are moving constantly, some of the ethanol particles at the boundary between the two liquids will immediately move into the water, and some of the water molecules will move into the ethanol.

In this process, water-water and ethanol-ethanol attractions are broken and ethanol-water attractions are formed. The attractions that form between the ethanol and water molecules are also hydrogen bonds Figure below.

Because the attractions between the particles are so similar, the freedom of movement of the ethanol molecules in the water solution is about the same as their freedom of movement in the pure ethanol. The same can be said for the water.

Because of this freedom of movement, both liquids will spread out to fill the total volume of the combined liquids. In this way, they will shift to the most probable, most dispersed state available, the state of being completely mixed. There are many more possible arrangements for this system when the ethanol and water molecules are dispersed throughout a solution than when they are restricted to separate layers.

Figure below. We can now explain why automobile radiator coolants dissolve in water. These substances mix easily with water for the same reason that ethanol mixes easily with water. The attractions broken on mixing are hydrogen bonds, and the attractions formed are also hydrogen bonds. There is no reason why the particles of each liquid cannot move somewhat freely from one liquid to another, and so they shift toward the most probable most dispersed , mixed state.

We have a different situation when we try to mix hexane, C 6 H 14 , and water. If we add hexane to water, the hexane will float on the top of the water with no apparent mixing. The reasons why hexane and water do not mix are complex, but the following gives you a glimpse at why hexane is insoluble in water.

There actually is a very slight mixing of hexane and water molecules. The natural tendency toward dispersal does lead some hexane molecules to move into the water and some water molecules to move into the hexane. When a hexane molecule moves into the water, London forces between hexane molecules and hydrogen bonds between water molecules are broken. New attractions between hexane and water molecules do form, but because the new attractions are very different from the attractions that are broken, they introduce significant changes in the structure of the water.

It is believed that the water molecules adjust to compensate for the loss of some hydrogen bonds and the formation of the weaker hexane-water attractions by forming new hydrogen bonds and acquiring a new arrangement. Overall, the attractions in the system after hexane and other hydrocarbon molecules move into the water are approximately equivalent in strength to the attractions in the separate substances. For this reason, little energy is absorbed or evolved when a small amount of a hydrocarbon is dissolved in water.

To explain why only very small amounts of hydrocarbons such as hexane dissolve in water, therefore, we must look at the change in the entropy of the system. It is not obvious, but when hexane molecules move into the water layer, the particles in the new arrangement created are actually less dispersed lower entropy than the separate liquids. The natural tendency toward greater dispersal favors the separate hexane and water and keeps them from mixing.

This helps explain why gasoline and water do not mix. Gasoline is a mixture of hydrocarbons, including hexane. Gasoline and water do not mix because the nonpolar hydrocarbon molecules would disrupt the water in such a way as to produce a structure that was actually lower entropy ; therefore, the mixture is less likely to exist than the separate liquids.

We can apply what we know about the mixing of ethanol and water to the mixing of two hydrocarbons, such as hexane, C 6 H 14 , and pentane, C 5 H Potassium carbonate K2CO3 is a white salt, soluble in water insoluble in ethanol which forms a strongly alkaline solution. It is a white salt, which is soluble in water. It is deliquescent, often appearing as a damp or wet solid. Potassium carbonate is mainly used in the production of soap and glass….

Potassium carbonate. Barium sulfate is a metal sulfate with formula BaO4S. Virtually insoluble in water at room temperature, it is mostly used as a component in oil well drilling fluid it occurs naturally as the mineral barite.

It has a role as a radioopaque medium. It is a barium salt and a metal sulfate. AgNO3 is very soluble in water. This means water molecules, because of their polar nature, can separate the silver ions from the nitrate ions. Silver bromide AgBr , a soft, pale-yellow, water-insoluble salt well known along with other silver halides for its unusual sensitivity to light. The chemical is both odorless and white as well as hygroscopic, meaning it readily absorbs water and moisture from the air.

Due to this, it is easily soluble in water at a rate of All are white solids. The anhydrous material is hygroscopic, quickly forming the hexahydrate upon standing in air.

All of the salts are very soluble in both water and ethanol…. Magnesium nitrate. K2 SO4 is very soluble in water. Most alkali metal compounds are water soluble and potassium is an alkali metal. It is highly soluble in water, with a lower solubility in polar solvents such as ethanol and methanol. NaOH is insoluble in ether and other non-polar solvents. Begin typing your search term above and press enter to search. Press ESC to cancel.

In this work we investigated the likelihood of ethanol to result in food-related solubilization effects that might have an impact on absorption and bioavailability of lipophilic poorly soluble drugs. We performed these studies in fluids simulating the fasted state of the small intestine before and after intake of ethanol. At the low concentration, i.

The solubilization effects in the intestine is likely temporary since the ethanol rapidly will be diluted and absorbed from the intestinal compartment. Nevertheless, changed absorption kinetics may result if significantly higher dissolution rate and apparent solubility are obtained in the presence of ethanol.

Ethanol may impact the solubilization capacity of BDM at both the water and the micelle level. The ethanol molecules are completely miscible with the water molecules, resulting in a decrease in the dielectric constant. In addition, the ethanol molecules are also likely to affect the morphology and solubilizing effect of the lecithin and taurocholate aggregates present in the fasted and fed state.

Ethanol has been shown to decrease the critical micelle concentration cmc of surfactants in aqueous media at low concentrations and increase the cmc at higher concentrations. The effect that ethanol has on the cmc of surfactants is related to its impact on the monomer solubility, the aggregate size, and the polarity of the aggregate core. To analyze if ethanol or mixed lipid aggregates had the highest solubilization capacity for poorly soluble lipophilic drugs, we performed Spearman rank analyses.

Hence, for compounds which are lipophilic and poorly water-soluble, simple buffers with ethanol may be sufficient to use as a screen for identifying compounds that are sensitive to ethanol in the preprandial state.

From the obtained results, the compounds whose solubility increases largely after addition of ethanol can be selected and further studied for apparent solubility in BDM in the presence of ethanol. Typically a downward shift is obtained in the p K a for bases, whereas the p K a goes in the opposite direction for acids in the presence of ethanol. In particular, this leads to a significant lower degree of ionization for the compounds with a p K a in the vicinity of the pH of the buffer, i.

In addition to decreased polarization and possibly lower aqueous solubility, this decrease in charge results in a higher apparent lipophilicity at pH 6. Hence, such molecules will respond to the addition of ethanol not only as a result of molecular properties, such as molecular size, flexibility, and aromaticity, but also due to their physicochemical profile in terms of charge and lipophilicity.

For our data series, this effect will be greatest for dipyridamole, ketoconazole, and warfarin, which show significant changes in their p K a in the close vicinity to the buffer pH of 6. In this study we found that neutral and acidic compounds were more soluble in media containing ethanol than in media containing aggregate forming lipids at the concentrations found in the preprandial state.

In contrast, cationic compounds were more substance specific and, for the eight compounds studied, some molecules gained more in solubility by mixed lipid aggregates than by ethanol, whereas others showed the opposite tendency. Molecular properties of importance for the obtained solubility in each of the investigated media were not able to be revealed through analysis of single molecular properties. Therefore, we performed multivariate data analysis to reveal which molecular functions are most influential for solubility in each of the media.

The models developed herein have not yet been tested for their general predictability of ethanol effects; rather they were developed to analyze which molecular structures are likely to show significant changes in apparent solubility when ethanol is present. It became evident that lipophilicity as described by the log D 6. This descriptor was not one of the most important for solubility in FaSSIF, a finding in agreement with our previous study.

In the resulting models, the coefficients for log D 6. The multivariate analysis further revealed that polarizability, electronegativity, and size are important descriptors for solubility in the studied media. Electronegativity was related positively to solubility in all media, and it may be a property that reflects the capacity of a compound to form hydrogen bonds with the water.

Further, the WHIM descriptor E2p, which is a descriptor depicting polarizability of the molecule, proved to be negatively related to solubility in PhB 6.

In contrast, it was not found to be important for solubility in PhB 6. The lower relative contribution of this parameter in the FaSSIF containing ethanol, and the fact it is not an important descriptor for solubility in PhB 6. The negative effect of polarizability on solubility in media containing mixed lipid aggregates was further supported by the 3D descriptors MOR13p. In addition to the multivariate data analyses on absolute solubility obtained in each of the media, we also investigated the fold increase in solubility after addition of lecithin and taurocholate, ethanol, or both mixed lipid aggregates and ethanol, as compared to solubility in the pure buffer.

Through this we could reveal that the compounds whose solubility increased the most in the mixed lipid aggregate-containing media were lipophilic, whereas the compounds that gained most in solubility after addition of ethanol to the buffer were the ones with lower PSA values.

We interpret this to reflect that compounds that were well solubilized in pure water, through the use of hydrogen bonds with water molecules, were affected negatively by the decrease in polarity of the medium after the addition of ethanol.

A number of more complex descriptors were also included in these models, many of which reflected two or more properties e. The interpretation of these is not as straightforward as for the properties log D 6.

Interestingly, the combination of both mixed lipid aggregates and ethanol resulted in the fact that neither log D 6.

Hence, for lipophilic compounds, for which an improved solubility would be expected in BDM, the solubilization when ethanol is present will also be dependent on, among other things, charge and polar surface area of the molecule.

For the investigated negatively charged and neutral compounds the presence of lipid aggregates and ethanol resulted in a synergistic positive effect on solubility. This effect was not seen for bases, which showed negative, positive, or no effects on solubility after inclusion of all additives. These compounds, which carry a net positive charge at pH 6. The multivariate data analysis showed that the lipophilicity of a compound was less restrictive for solubility after the addition of ethanol.

Indeed, the largest influence of high compound lipophilicity was seen in PhB 6. However, other molecular properties are also of importance for this to occur. For example, charge, PSA, size, polarizability, and electronegativity will influence the resulting concentration obtained. The compounds that were able to dissolve in FaSSIF containing ethanol were corticosterone, disopyramide, glibenclamide, and naproxen.

These represent neutral, acidic, and basic compounds which are given in doses ranging from 2. The compounds are hydrophilic disopyramide, log D pH6. Hence, even though dose is not always known in early drug development, the analysis shows that high melting compounds which are also highly lipophilic will be poorly soluble regardless of the solvent used.

However, among the compounds for which the dose was not completely soluble in the simulation experiments of ethanol intake, many still showed significantly higher apparent solubility and dissolution rate after the addition of ethanol. This effect can be disastrous for lipophilic compounds with a narrow therapeutic window. Therefore, possible ethanol effects on intestinal solubility should be evaluated for such molecules during early drug development.

In this work we investigated the likelihood of increased intestinal concentration of poorly soluble compounds to appear after ethanol intake. To simulate this condition in vitro we performed dissolution studies using FaSSIF with and without ethanol.

Acidic and neutral compounds were more solubilized by the addition of ethanol than by the mixed lipid aggregates, whereas bases showed a more substance-specific response to the additives in the buffer. No strong relationships were found between solubility changes in media simulating ethanol intake and single physicochemical properties.

Multivariate data analysis revealed that log D 6. The results of this study clearly indicate that dissolution rate and total concentration of poorly soluble, lipophilic compounds in the intestinal fluid may change tremendously after intake of ethanol. Supporting Information. Author Information.

Christel A. Jonas H. The authors declare no competing financial interest. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings Adv.

Drug Delivery Rev. Lipinski, Christopher A. A review with 50 refs. In the discovery setting 'the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the mol.

Computational methodol. Turbidimetric soly. In the development setting, soly. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with exptl. Predicting drug absorption and the effects of food on oral bioavailability Bull. Gattefosse , 99 9 — 16 Google Scholar There is no corresponding record for this reference.

Guidance for Industry. Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. Google Scholar There is no corresponding record for this reference. Biopharmaceutics classification system: The scientific basis for biowaiver extensions Pharm. Yu, Lawrence X.

Dissolution rate and apparent solubility of poorly soluble drugs in biorelevant dissolution media Mol. Fagerberg, Jonas H. American Chemical Society. A series of poorly sol. BCS class II compds. The compds. The exptl. It was revealed that a majority of the compds. The acidic compds. Five of the ten compds. To conclude, the physiol. Moreover, the results herein indicate that the improvement obtained in BDM may be possible to predict from chem.

In vitro-in vivo correlations for lipophilic, poorly water-soluble drugs Eur. Characterization of fasted-state human intestinal fluids collected from duodenum and jejunum J. Pharmaceutical Press. The soly. In particular, bile salt compn. In this study, we have measured the concns. Total bile salt concns. The following rank order of relative bile salt concn. Ursodeoxycholate could not be detected in HIF.

No statistically significant difference between bile salt compn. The buffer capacity of HIF was compared with other media commonly used for soly. This low buffer capacity was reflected in the change in pH between 4 and 9. Interindividual variability in pH, buffer capacity and bile salt contents of HIF will contribute to differences in the rate and extent of absorption of compds. The variability obsd.

The effects of food on the dissolution of poorly soluble drugs in human and in model small intestinal fluids Pharm. In vivo in vitro correlations for a poorly soluble drug, danazol, using the flow-through dissolution method with biorelevant dissolution media Eur. Elsevier B. The purpose of the study was to design dissoln.

In vitro dissoln. The media used contained bile salt and phospholipid levels relevant for either fasted or fed conditions in vivo. Crude and inexpensive bile components, Porcine Bile Ext. The effect of adding different concns. In vivo release profiles under fasted and fed conditions were obtained from a previous study by deconvolution [Sunesen, V.

Effect of liq. In the fasted state, the physiol. A medium contg. By using the flow-through dissoln. Both hydrodynamics and medium compn. In the fed state an IVIVC could only be obtained by including monoglycerides and fatty acids in the medium. The usefulness of selected conventional surfactant media to enhance dissoln.

Although these media differed largely in their solubilization ability, micelle size, diffusivity and surface tension, similar dissoln. The dissoln. An in vivo pharmacokinetic dog study was carried out with N Comparison of obsd. This study demonstrates the potential of substituting FaSSIF with more simple and cost-effective conventional surfactant media. Use of in vivo prognostic amts.

Can biorelevant media be simplified by using SLS and Tween 80 to replace bile compounds? Open Drug Delivery J. Bentham Science Publishers Ltd. In the scientific literature, the use of a surfactant is recommended for both designing quality control tests for water insol.

Since the no. The aim of the present study was to develop predictive and discriminatory test methods based on surfactants that are recommended in the literature.

Particular respect was given to the use of sodium lauryl sulfate and Tween 80, the two most commonly used surfactants for this purpose. Tamoxifen was used as a model drug. Results were then compared with those deriving from the same test formulations in biorelevant and simplified "biorelevant" media. Results from this study indicate that the concn. However, they also indicate that a well designed and validated test medium contg.

SLS or Tween 80 can be useful in terms of establishing a discriminatory test medium that possibly could also be used to assure batch to batch bioequivalence. Therefore, the approach described in the present paper might be very helpful for developing predictive and discriminatory methods in early formulation development for poorly sol. Simplified biorelevant media for screening dissolution performance of poorly soluble drugs Dissolution Technol.

Dissolution Technologies, Inc. This study aims to develop simplified biorelevant media for screening dissoln. Selected media contg. These can be used to replace biorelevant test media for screening formulations if it can be shown that soly. Validation of the correspondence of results in media contg. In cases where results are similar, the simplified media represent a very promising approach to designing both formulation screening and quality control tests that are relevant to in vivo conditions, while retaining the cost and time efficiencies assocd.

In particular, when taking into account several addnl. Dissolution media simulating conditions in the proximal human gastrointestinal tract: An update Pharm. Biorelevant dissolution media: Aggregation of amphiphiles and solubility of estradiol J. Galia, E. Plenum Publishing Corp.

In this paper we seek to verify the differences in dissoln. Class I powders dissolved rapidly in all media tested. Acetaminophen dissoln. The weak base ketoconazole showed complete dissoln. As predicted, dissoln. With the array of compendial and physiol. The objective of this study was to prep.

BIXX , were compared with data for freshly prepd. What is modulating solubility in simulated intestinal fluids? Ottaviani, Giorgio; Gosling, Daniel J. The aim of this study was to understand which parameters are responsible for the selective modulation of compds. Electrostatic interactions between compds. When the aq. These results suggest that ionization, lipophilicity and crystal packing play important but peculiar roles in controlling soly.