Low aqueous solubility

Its relatively low toxicity is probably the result of very low aqueous solubility (0.002 g/L) and lack of reactivity with acidic (HCl) digestive fluids. 

Recently, there has been much interest in developing water-soluble tributyltin biocides to lessen the costs of application, and to prevent fire hazards when treating material in confined spaces. Bis(tributyltin) oxide itself has a very low aqueous solubility ( 0.001%), but it may be made water-dispersible by the addition of certain (534, 535) quaternary ammonium salts. Formulations of this type, although currently under development as wood preservatives (534), have been used extensively in the United Kingdom for the treatment of stonework to eradicate fungal growths, algae, mosses, and lichens (535). 

Section 3.2 begins with pfCj definitions and a brief description of the state-of-the-art pfCj measurement methods, stressing the needed accuracy, especially with molecules which possess very low aqueous solubility. In a prachcal way, the ioniza-hon constant is treated as a property of the molecule, usually defined at 25 °C in a nonbuffered medium of 0.15 M potassium (or sodium) chloride aqueous... 

IkB kinase-p is a key regulatory enzyme in the NF-kB pathway, and inhibition of this enzyme has the potential for yielding treatments for inflammatory and autoimmune diseases. Morwick et al. [53] report on the optimization of a pM IKKp inhibitor with low aqueous solubility, moderate human liver microsome stability, and inhibition of several CYPs (3A4, 2C9, 1A2) with pM potencies. Modulation of the thiophene core (other thiophene isomer, pyrimidine and oxazole) produces compounds of similar potency to the hit. Fusing the 5-phenyl moiety to the thiophene to form a thieno[2,3-b]pyridine core increases aqueous solubility of the series as well as reduces the CYP liability. While the optimized compound still shows pM IKK(S potency, the aqueous solubility, HLM stability and CYP profiles are much improved. A pharmacophore model was generated that enabled scaffold hopping to yield this new chemotype (Scheme 7). 

Drugs in Class II have low aqueous solubility (but high membrane permeability), and any factor affecting dissolution rate would be expected to have an impact on the absorption of such compounds. Factors that are noted in Fig. 11, such as fluid pH, volume and viscosity, and bile secretion (especially in response to fatty foods), might be expected to play a role in dissolution rate and thereby affect absorption. Compounds that fall into this class include carbamazepine, cyclosporin, digoxin, griseofulvin, and spironolactone. Food would be expected to exert a potentially significant affect on... 

Class IV drugs have low aqueous solubility and poor membrane permeability and as such are often considered as poor drug candidates for oral administration. Other routes of administration may need to be considered. For example, neomycin falls into this category, and its oral use is to achieve sterilization of the gut. There is too little information about these compounds and the effect of food to offer general observations. 

During the past 30 years, there have been significant developments of parenteral disperse formulations. The use of parenteral emulsions can overcome the problems of low aqueous solubility and water hydrolysis of many drugs [184, 185]. Such formulations can avoid the use of conventional co-solvent systems and the undesirable effects caused by precipitation of drugs at the injection site. Recent developments of parenteral disperse formulations have the potential to provide sustained release and targeting of drugs [186-189],... 

These esters of p-hydroxybenzoic acid have been used primarily to prevent growth of molds but in higher concentrations possess some weak antibacterial activity. Their effective use is limited by low aqueous solubility and by reports of stinging and burning sensations related to their use in the eye. They bind to a number of nonionic surfactants and polymers, thereby reducing their bioactivity. They are used in combination, with the methyl ester at 0.03-0.1% and the propyl ester at 0.01-0.02%. Parabens have also been shown to promote corneal absorption [140]. 

In reviewing the pH-partition hypothesis, it is apparent that it is an oversimplification of a very complex process. It does not consider one of the critical physicochemical factors, solubility. Low aqueous solubility is often the cause of the low bioavailability. To address this issue, Dressman et al. [28] developed an absorption potential concept that takes into account not only the partition coefficient but also solubility and dose. Using a dimensional analysis approach, the following simple equation was proposed ... 

If a high turnover (>50%) is observed in the initial screening incubation at 10-50 iM, then a higher substrate concentration should be tested to obtain a good balance between the enzyme productivity and the conversion yield. The substrate concentration should be mainly selected based on the activity of enzymes, and may be increased until the benefit of enzyme productivity increase is offset by cost and availability of the substrate. The solubility of substrate in buffer may limit the use of high concentrations, but a low aqueous solubility compound is readily absorbed by microsomes/S9, which will help to keep the substrate in the incubation mixture even at a much higher concentration than its buffer solubility. Substrate concentration up to sub-millimole level can be used as long as no inhibitory effect is shown and a reasonable turnover is achieved. 

Limited oral drug bioavailability may be explained by poor membrane permeability, low aqueous solubility in gastrointestinal fluids, or extensive first-pass metabolism in the gastrointestinal tract or liver. Successful lipophilic prodrugs... 

It is well appreciated that dietary fat retards proximal gastrointestinal transit. For hydrophobic drugs with low aqueous solubility, dissolution becomes the rate-limiting process the appreciation that fat might increase bioavailability by increasing time available for dissolution and that mixed triglycerides often provide a better solvent than aqueous media has not been lost on formulation scientists. 

Unlike halogenated solvents, it does not produce noxious substances in the inductively coupled plasma, has a very low aqueous solubility, and yields hundredfold concentration in one step. Detection limits ranged from 0.02 jtg/l (cadmium) to 0.6 pg/1 (lead). The results indicate that the proposed procedure should be useful for the precise determination of metals in oceanic water, although a higher sensitivity would be necessary for lead and cadmium. 

The most famous of these compounds is combretastatin A-4 (CA-4,7), isolated by Pettit et al. in 1989 [30]. Pettit s research led to the isolation and structural determination of a series of phenanthrenes, dihydrophenanthrene, stilbene, and bibenzyl compounds [31]. CA-4 (7), alongside CA-1 (8), was found to be an extremely active inhibitor of tubulin polymerization [30,32]. The major problems associated with these compounds were poor bioavailability and low aqueous solubility [33,34], and hence, research in the field was turned to designing better alternatives with the hope of eradicating the negative properties of these potent compounds. 

As already mentioned, certain azo colorants have low aqueous solubility but not sufficiently low for them to be usable as pigments. These azo colorants are prepared from amines and coupling components containing hydroxyl or carboxyl groups in their sodium salt form as a result of alkaline coupling conditions. 

The first-derivative ESR spectra of 2-PCB and 4-PCB yielded interpretable signals, but no significant peaks were found when analyzing sonicated solutions of 2,4,5-PCB. The formation of organic radicals at a detectable level may have been hindered by the low aqueous solubility of 2,4,5-PCB. 

Use carboxymethylcellulose only in small amount in unstructured liquid products, since it has low aqueous solubility. 

It must be noted that the partition coefficient is not the ratio of the pollutant solubilities in the two pure liquids. This change can result in significant differences, particularly with compounds of low aqueous solubility. The measurement of partition coefficients may be complicated by the involvement of other equilibrium processes such as pKa and pH values. For example, the following reaction shows the dissociation of a monoprotic organic acid ... 

All in all, it is important to understand the relevance of how solubility data has been generated and care should be taken when predicting the human Fabs of drugs with a low aqueous solubility. 

Military and ammunition sites contaminated with explosives can cover substantial areas (Gerth et al. 2005). Soil contamination in these sites is often heterogeneous. Explosives are relatively non-volatile, and have low aqueous solubility. Sampling from sites within a few decimetres of one another can result in concentration differences of up to one hundredfold (Jenkins et al. 1996). For example, the coefficients of variation across samples taken from 11 abandoned sites in the USA were 248% for TNT and 137% for Hexogen (Crockett et al. 1998). As a result, sampling error greatly exceeds measurement error. Thus to obtain representative results... 

Soil. In shallow and deep soils, reported half-lives were 10 and 100 yr, respectively (Nauman and Schaum, 1987). Due to its low aqueous solubility, TCDD will not undergo significant leaching by runoff (Helling et al., 1973). 

Solvents used in liquid membranes should have special characteristics such as low aqueous solubility, as a thin film of solvent is in contact with large volumes of aqueous solutions, and low viscosity to provide large diffusion coefficients in the liquid membrane. Furthermore, the analyte should have large partition coefficients between the donor and the membrane phase to give good extraction recovery and, at the same time, interfering substances in the sample should have low partition coefficients for efficient cleanup. 

Unfortunately, the low aqueous solubility of the DCL components precluded templating studies with the intended target microtubulin. As proof of principle, the proteins albumin and subtilisin were substituted as organic solvent tolerant alternatives. Starting from the homodimeric compounds 45 and 48, the amount of heterodimer 51 formed was shown to be influenced by the presence of the proteins. 

---