Solubility kinetic

At the hit triage stage, it is most common to be able to characterize sets of compounds in a kinetic solubility assay. In the assessment and utilization of these data, the potential disconnects between kinetic and thermodynamic solubility must be considered. Low kinetic solubility for a series of compounds should lead a project team to be concerned about the behavior of compounds in biological assays and buffers, as well as the potential for optimizing drug-like properties in that series. Conversely, while high kinetic solubility is a desirable property, chemists should still remain cognizant of the need to assess thermodynamic solubility as compounds are further optimized. 

During the characterization process, hits are typically tested for kinetic solubility and permeability in a model of passive diffusion such as PAMPA [22]. As new compounds are synthesized, additional parameters also need to be considered, such as pZa, chemical and plasma stability, and protein binding. Calculated properties such as MW, clogP, and PSA should also be tracked. 

Other methods employ a microplate format followed by fast HPLC. Some researchers approach the determination from a different perspective. For example, an alternative method for ionizable substances is the pSol determination based on an acid-base titration.25 26 Kinetic solubility determinations involve determining the concentration of the compound in the buffer of interest when an induced precipitate first appears. 

In this chapter, the first section will focus on the designs of different structures of DDSNs. The basic synthesis methods of pure silica nanoparticles will be briefly summarized at the beginning. The general methods for doping dye molecules into a silica matrix will then be covered followed by the introduction of several DDSN designs. The second section will be a major focus of this chapter. Various advantageous properties of DDSNs will be discussed. These discussions will involve reaction kinetics, solubility, photostability, and fluorescence intensity including quantum yield and lifetime, as well as toxicity. With the rapid development of DDSNs, more features and functionalities of DDSNs are expected in the near future. 

Kinetic solubility This pragmatic approach starts with a concentrated compound solution in pure DM SO further diluted in a buffer medium. The amount of compound in solution is measured after a few minutes incubation either by recording its UV absorbance (with or without a chromatographic step) or precipitate formation using an optical method (turbidimetry, nephelometry or flow cytometry). This approach mimics the typical path of the compound in biochemical, cellular assays or in vivo animal models. Kinetic solubility usually serves as a quality filter prior to cell based assays (see paragraphs on solubility, permeability and cellular assays). 

Careful studies of the physical chemistry of the growth process so as to understand the trade offs between growth rate, pressure, temperature and quality were essential in finding economically successful conditions. In order to understand the kinetics, solubility(10) and p-v-t(77) studies were necessary. The solubility in pure water was found to be too small for crystal growth (0.1 - 0.3 wgt %) but the solubility could be markedly increased by the addition of (OH) which acts as a mineralizer. We have studied mineralizers and their reactions for complexing various refractory oxides and sulfides.(72-76) A variety of complexers are known including (OH) , Cl-, F, Br , r and acid media for the crystallization of Au and other noble metals. Frequently the ratio (solubility/mineralizer concentration) is constant and independent of mineralizer concentration over wide ranges and sometimes it is a small rational number or fraction. 

PURPOSE AND RATIONALE Solubility assays are gaining growing attention in drug discovery, because many pharmaceutically active compounds can be adjusted to in vivo testing merely with co-solvents. Furthermore, in vitro assays may also lead to false results, simply for precipitation of a compound in the assay media. Solubility assays vary in one main point they are either performed from solids or stock solutions. A nomenclature has been established in the literature which tries to distinguish between these methods. Determinations from stock solutions are often called kinetic solubility whereas thermodynamic solubility stands for solubility of solids (Kerns). Thermodynamic solubility takes the crystal lattice forces into account. Batch to batch variations, polymorphism... 

As described in the general introduction for solubility assays, there is a difference between kinetic and thermodynamic solubility. Thermodynamic solubility needs solid material of good quality whereas kinetic solubility relies on organic stock solutions. The sample preparation is therefore different (Kibbey). 

If the standard stock solution is delivered from a centralized stock solution the throughput can be increased significantly. Solubility obtained from organic stock solutions leads to kinetic solubility data (see also chapter 1.2). 

Green C, McKee S, Saunders K A fully automated Kinetic solubility screen in 384-well Plate format usinig nephelometry. BMG, Application Note 117... 

Amorphous materials typically have a higher rate of dissolution and a higher kinetic solubility that their crystalline counterparts (Fig. 1). These characteristics can be exploited to enhance the rate and extent of absorption of poorly water-soluble APIs from the gastrointestinal tract. Such formulation approaches have been described for many APIs including indomethacin, griseofulvin, and several barbiturates. ... 

Solubility is usually expressed as log S, where S is the saturated compound concentration in mol/1 in equilibrium with its most stable crystalline form under certain defined conditions (e.g., physiological pH at room temperature over an extended period oftime, typically 24—48 h). This is also known as the thermodynamic solubility. The typical log S values for discovery compounds vary from —3(1 mM) down to —7 (0.1 pM). In contrast, kinetic solubility refers to the solubility value determined within a defined period of time, which is usually much shorter than 24 h. Since equilibrium conditions are not often achieved in this time frame, the compound is typically not in its most stable crystalline form. Therefore, the kinetic solubility value is normally higher than that obtained from the thermodynamic approach. Despite these caveats, kinetic solubility measurement can be set up in a high-throughput assay format and has been used by some pharmaceutical companies to identify poorly soluble compounds in the very early stage of drug discovery. 

Kinetic solubilities are by definition very time dependent and as such results can be less reproducible than thermodynamic solubility values. The short timescale also means that they are more dependent on the physical form of the initial precipitate. Consequentially, the correlation between kinetic and thermodynamic solubility is generally poor, with the kinetic measurement usually giving higher values [12, 16]. However, an advantage this can bring is that there will be few compounds excluded as false negatives in this phase. 

As with turbidimetric assays, many of the direct UV absorbance assays are set up to determine kinetic solubility. However, the UV absorbance method also lends itself well to thermodynamic solubility determination by extending the period of sample agitation prior to filtration to 24 h or more. This offers a number of advantages. The solubility data generated are less dependent on the physical form of the initial material precipitated from DMSO and are much closer to thermodynamic solubility values determined later in discovery and in early development. As such, it gives more consistent solubility data through the discovery phase and enables a better quality early assessment to be made of the likely difficulties or otherwise of progressing a lead series into development. 

In the lead identification and lead optimization phases of discovery, there is greater focus on thermodynamic solubility measurements. Thermodynamic solubility assays are designed to determine the solubility of the stable crystalline form of the compound, since this is the physical form that will be sought in the development phase for orally administered drugs. As such, thermodynamic solubilities provide discovery projects with a better risk assessment of likely formulation issues in development. Thermodynamic solubilities, unlike kinetic solubilities, are less dependent on the initial physical form of the compound and being less time critical also tend to be more reproducible. This is particularly important from a molecular design perspective where chemists are seeking to modify molecular structure to improve solubility. 

Lilley, M., Shanter, M., Ardiff, M., Ciolkosz, T., Kashdan, M., Aubin, C. and Goodwin, J. A fully automated workstation for testing flow based kinetic solubility of compounds. Poster Presentation, BD... 

This suggests that DCS Class I compounds are those with high solubility and high permeability based on kinetic solubility and PAMPA or Caco-2 analyses. Class II compounds are those associated with high permeability and by medium or low solubility while Class III compounds are associated with high solubility and medium or low permeability. Class IV materials have both low solubility and low permeability (Figure 4). 

Solubility Score (Kinetic Solubility) Permeability Score (CACO-2 or PAM PA)... 

Figure 4. Estimation of DCS classification based on kinetic solubility and permeability (Caco-2 or PAMPA) information as binned by values cited in the text.

It is often the case that different results are quoted for the solubility of a compound in water as different experimental procedures are regularly used in industry. In very early screening studies nephelometry or laser nephelometry is normally used to give an approximate value for the solubility as the procedure is non-specific, yields rapid results and requires very little compound. It is often referred to as the kinetic solubility. Only some time later this is followed, when more compound is available, by the determination of the true or equilibrium solubility. As described above, it is dehned as the concentration where the solution and undissolved solid are at equilibrium at constant temperature (usually 25°C). For some compounds the two results are similar, whilst for others the Kinetic Solubility may be signihcantly higher. The equilibrium solubility as the physicochemically correct result should be the one to be quoted in submissions to regulatory authorities. 

Three common properties that affect intestinal absorption of drugs after oral administration are solubility, permeability, and p/f. Traditional solubility experiments measure solubility of solids placed into aqueous phases (thermodynamic solubility), but these methods are too slow or they consume too much material for drug discovery. Higher throughput methods must be used. The direct ultraviolet (UV) method [17] adds compound dissolved in dimethyl sulfoxide (DMSO) to an aqueous buffer and measures the UV absorption of the aqueous phase using a 96-well plate reader after equilibration and filtration (kinetic solubility). Lipinski has discussed the pitfalls that inadequate solubility information can have for a drug-discovery organization [18]. 

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