Does Solubility Increase With Temperature

Solubility

Li Di , Edward H. Kerns , in Drug-Like Properties (Second Edition), 2016

7.2.3 Structural Properties Bear on Solubility

Solubility is heavily affected past the compound's structural properties and form. The backdrop and their effects on solubility are

•

Ionizability (pGrand _a)—increasing ionizability increases solubility, depending on the solution pH

•

Lipophilicity (log P)—increasing lipophilicity decreases solubility

•

Polarity, hydrogen bond donation (HBD), hydrogen bail credence (HBA), topological polar surface area (TPSA)—increasing these increases solubility

•

Size (molecular weight (MW))—increasing molecular size decreases solubility

•

Crystal lattice energy (Melting Point)—increasing intermolecular crystal forces in the concrete form reduces solubility

Medicinal chemists alter the structure, which modifies these backdrop, to brand subsequent chemical series analogs more soluble. Structural modification of polarity, hydrogen bonding, molecular size, ionizability, and intermolecular crystal forces are discussed in Section vii.4. Structural modifications that enhance drug-solvent molecule interactions or decrease drug-drug molecule interactions are productive in enhancing solubility. The crystalline forms tin be modified past crystallization weather.

7.2.3.1 Lipophilicity and Crystal Intermolecular Forces Affect Solubility

The effect of lipophilicity and crystal intermolecular forces on solubility is represented by the empirically derived "general solubility equation" [ 2]. It estimates the aqueous solubility of a compound based on measurable or calculable properties:

$\log S=0.8–log{P}_{\mathrm{O}\mathrm{W}}-0.01\left(\mathrm{M}\mathrm{P}–25\right)\text{,}$

where S is solubility, log P _OW is the octanol-h2o partition coefficient (a measure of lipophilicity), and MP is the melting point (a mensurate of crystal intermolecular forces). Increasing log P _OW tends to enhance drug-drug nonpolar interactions in the solid. MP increases when hydrogen bonding, lipophilicity, or polar interactions heighten intermolecular crystal packing forces of the solid. log P _OW is reduced, for case, past increased hydrogen bonding, increased polarity, and reduced MW (meet Chapter 5). The equation shows that solubility decreases ten fold as

•

log P _OW increases by 1 unit

•

melting bespeak increases by 100   °C

7.2.3.2 Ionizability Greatly Affects Solubility

pYard _a and solution pH are very of import, considering the charged course of a drug has higher aqueous solubility than the neutral form. At a particular pH, there is a distribution of molecules in solution between the neutral and ionized land. Therefore, the solubility of a compound at a particular pH is the sum of the solubility of the neutral molecules times the fraction of neutrals, plus the solubility of the ionized molecules times the fraction of ions. This has implications for the solubility of compounds in various physiological fluids and solutions that have dissimilar pH values.

The important effects of ionization can exist described. Drugs ionize according to the reactions:

$\mathrm{H}\mathrm{A}+{\mathrm{H}}_{\mathrm{ii}}\mathrm{O}={\mathrm{H}}_{\mathrm{three}}{\mathrm{O}}^{+}+{\mathrm{A}}^{-}\left(\mathrm{acrid}\right)$

$\mathrm{B}+{\mathrm{H}}_2\mathrm{O}={\mathrm{O}\mathrm{H}}^{-}+{\mathrm{H}\mathrm{B}}^{+}\left(\mathrm{base\; of\; operations}\right)$

At equilibrium the solubility (S) of a monoacid or monobase is described as

$\mathrm{South}=\left[\mathrm{H}\mathrm{A}\right]+\left[{\mathrm{A}}^{-}\right]\left(\mathrm{acid}\right)$

$\mathrm{Southward}=\left[\mathrm{B}\right]+\left[{\mathrm{H}\mathrm{B}}^{+}\right]\left(\mathrm{base\; of\; operations}\right)$

A mathematical derivation of the Henderson-Hasselbach equation (run across Chapter 6) provides insights for solubility:

$S=S_0\left(\mathrm{one}+10^{\left(\mathrm{p}\mathrm{H}-\mathrm{p}{K}_{\mathrm{a}}\right)}\right)\left(\mathrm{acrid}\right)$

$S=S_0\left(1+10^{\left(\mathrm{p}{K}_{\mathrm{a}}-\mathrm{p}\mathrm{H}\right)}\right)\left(\mathrm{base}\right)\text{,}$

where S ₀ is the intrinsic solubility (solubility of the neutral compound). Therefore, solubility changes linearly with S ₀, simply it changes exponentially with the difference betwixt pH and pK _a. This is why adding an ionizable group is oftentimes the start choice in structure modification to increment solubility. Examples of the effects of intrinsic solubility and pOne thousand _a of acids are shown in Tabular array vii.one [3]. Barbital and amobarbital accept the same pYard _a (7.nine, weak acid), but barbital has college intrinsic solubility than amobarbital (seven.0   mg/mL vs. 1.two   mg/mL). Therefore, barbital has higher full solubility than amobarbital at pH 9 (95   mg/mL vs. 15   mg/mL). Naproxen and phenytoin have like intrinsic solubility, only unlike pK _a values. This results in dramatically unlike solubility at pH 9. Naproxen is much more acidic (pK _a 4.6) than phenytoin (pChiliad _a 8.iii), and is, therefore, much more than soluble, because solubility increases exponentially with the difference between pH and pK _a. This example demonstrates why introducing an ionization heart is an effective structure modification strategy for increasing solubility.

Table 7.1. Solubility at a Given pH is a Function of the Intrinsic Solubility of the Neutral Portion of the Molecule and Solubility of the Ionized Portion of the Molecule [3]

	pM a	Intrinsic Solubility (mg/mL)	Solubility @ pH 9 (mg/mL)
Barbital	7.9	7.0	95
Amobarbital	seven.9	i.2	15
Naproxen	4.6	0.016	430
Phenytoin	8.iii	0.02	0.12

Discovery scientists should avert disruptive the pOne thousand _a titration curve for the pH-solubility curve. The pThousand _a titration curve (Effigy seven.1) plots the change in ionization with pH. The sharp rise of the bend is in the region of the pThou _a and the inflection betoken is where the pH equals the pK _a. Scientists may remember that a sharp rise in solubility should correspond to where the pH equals the pK _a. In fact, the pH region of the sharp rise in solubility is dependent on the intrinsic solubility (Southward ₀), as shown in Figure 7.2. This figure plots the pH-solubility profiles of 4 acidic compounds with the same pK _a of 4.v, simply with different intrinsic solubilities (0.1, 1, 10, and 100   mg/mL). The inflection bespeak does not correspond to the pK _a of the compound. The pOne thousand _a of the compound is at the pH when total solubility is two times the intrinsic solubility, because solubility and pK _a follow a log-linear correlation. A plot of solubility on a log calibration versus pH on a linear scale (see Effigy 7.2 insert) shows that the turning point pH is the pThousand _a of the compound.

Figure 7.1. pK _a titration curve for a compound with a pK _a of 8.2.

Figure 7.ii. pH-solubility profiles for compounds all having pK _a  =   four.5, but with dissimilar South ₀ values. When pH   =   pChiliad _a, then the total solubility equals twoSouthward ₀.

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Chemical compound Properties AND DRUG QUALITY

Christopher A. Lipinski , in The Practice of Medicinal Chemistry (Second Edition), 2003

Improving aqueous solubility

Aqueous solubility tin be improved past medicinal chemistry despite the edgeless SAR feature and our internal record has been quite successful in this respect. Withal, to improve solubility requires commitment to a combination of computational and experimental interventions and a existent effort on the part of chemists to incorporate solubility information into synthesis design. The importance of rapid experimental feedback is particularly important given the current inability to predict computationally poor solubility arising from crystal packing interactions. It is critical not to miss a serendipitous comeback in solubility attendant on a molecular change. Owing to the edgeless SAR feature, the easiest way to improve solubility with respect to library blueprint is to try to blueprint the best solubility profile right at the outset.

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Solubility Methods

Li Di , Edward H. Kerns , in Drug-Similar Backdrop (2d Edition), 2016

25.i Introduction

Solubility measurement is a valuable activity throughout drug discovery. This is because solubility information assists diverse research activities, such as biological activity cess, structure optimization, pharmacokinetics screening, creature dosage form selection for efficacy, pharmacokinetics (PK) and toxicity, and choosing compounds for 10-ray co-crystallization studies to guide structure-based design (see Affiliate 7). Although information technology is convenient to presume that all the compound added to an experiment is dissolved, precipitation is not unusual and it decreases the compound's bodily concentration in solution. This results in lower apparent activity, absorption, and toxicity. Therefore, we need to measure solubility.

While it may seem that solubility measurement is simple, the compound'southward physical state and the solution'south physical and chemic conditions can touch the concentration of compound that actually dissolves and the amount that precipitates. There is not merely one solubility value for a chemical compound, only it tin can differ with the aqueous solution. To complicate matters, a lot of depression solubility compounds are encountered in modern drug discovery.

Solubility measurements require well-developed and advisedly performed methods. This chapter provides an overview of the key aspects of in silico and in vitro solubility methods.

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Extraction and Other Downstream Procedures for Evaluation of Herbal Drugs

Pulok K. Mukherjee , in Quality Control and Evaluation of Herbal Drugs, 2019

six.4.4.four Solubility Expressions

The solubility of a drug may exist expressed in a number of ways. The U.S. pharmacopeia lists the solubility of drugs as the number of milliliters of solvent in which 1  1000 of solute will dissolve. For instance, the solubility of boric acid is given in the U.S. pharmacopeia as follows: i   grand of boric acid dissolves in xviii   mL of water, in 18   mL of booze, and in 4   mL of glycerin. Solubility is also quantitatively expressed in terms of molality, molarity, and percentage. For substances whose solubilities are non definitely known, the values are described in pharmaceutical compendia by the employ of certain full general terms. Solubilities of drugs are plant expressed in various units in the Merck Index. For exact solubilities of many substances, the reader is referred to the works of Seidell, Landolt-Bornstein, International Critical Tables, and Lange's Handbook of Chemical science.

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Raw Materials for Wood Coatings (two) – Solvents, Additives and Colorants

Franco Bulian , Jon A. Graystone , in Forest Coatings, 2009

2.1.1 Solvency

Solubility is a physical procedure where the 'affinity' of the molecules plays the most important role. A general rule is that the similarity in the chemic composition can determine a good analogousness and thus solubility ('like dissolves like'). Hydrocarbon solvents, being not-polar substances, are ordinarily suitable to deliquesce relatively not-polar film formers like oils or alkyds.

Polar solvents like alcohols are more suitable for dissolving relatively polar film formers such as cellulose nitrate or the urea–formaldehyde resins.

There are a number of theoretical treatments of solubility but the most widely used in the coatings industry is the solubility parameter. This can be related to the second law of thermodynamics:

$\Delta G=\Delta H-T\Delta S,$

where One thousand is the free energy, H is the enthalpy (heat of vaporisation), T is the temperature and Due south is the entropy.

Essentially something tin can be expected to dissolve if there is a subtract in free energy. Since molecules will become more mixed on dissolution, at that place will be an increase in entropy and costless energy should decrease, hence solubility is favoured. However, information technology can be resisted by the enthalpic term. Hildebrand defined a solubility parameter to judge the enthalpic term. The solubility parameter is the square root of the cohesive energy density and is a measure of the molecular attraction:

$\partial ={(E/V)}^{1/2},$

where ∂ is the solubility parameter, E is the cohesive energy/mole and V is the molar book.

The concept was further developed by Hansen and others, to business relationship for contributions from dispersion, polar and hydrogen bonding molecular forces. Three-dimensional solubility maps may be used to make up one's mind solvent and resin solubility. For an introduction, see Ho and Glinka [1].

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In Vivo Environments Affect Drug Exposure

Li Di , Edward H. Kerns , in Drug-Like Properties (Second Edition), 2016

3.4.ii Solubility

Higher solubility produces a greater concentration of free drug molecules at the intestinal membrane for absorption. Equally the concentration gradient across the membrane increases, the flux of drug molecules across the membrane too increases. Solubility varies throughout the length of the intestine, considering information technology is greatly affected past the solution pH and the pThou _a of the molecule (see Chapter 7). Almost basic molecules are in the charged cationic (protonated) state throughout the tum and intestine. This favors skillful solubility, because the charged form is more soluble than the neutral grade. Virtually acid molecules are neutral in the tum and upper intestine, thus limiting solubility to the intrinsic solubility of the neutral molecules. As the pH increases throughout the intestine, the relative amount of the anionic form of the acrid increases, resulting in higher solubility. These behaviors are examples of the solubility differences amidst compounds in different regions of the intestine. The fundamentals and effects of pK _a on solubility are discussed in Chapter half dozen. Solubility can be enhanced with structural modifications that introduce a solubilizing functional group, such every bit one that is ionizable (meet Chapter vii).

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Handbook of Modern Pharmaceutical Assay

Edward Lau (Deceased) , in Separation Science and Engineering science, 2001

c. Method of Solubility Determination

Solubility is typically determined by placing an backlog amount of solute into a screw-capped test tube of proper size. An appropriate quantity of solvent is added, and the tube is capped securely. Tubes are placed in a bath kept within 0.five°C of the desired temperature. Sample tubes are rotated end over terminate mechanically until equilibrium is reached.

Periodic samples are taken for analysis to ensure stability and the attainment of equilibrium. Circumspection must be taken to prevent leakage. After equilibration, the sample is immune to stand up for settling of the excess solids. The solution is carefully withdrawn, filtered, and diluted accordingly. The solution may be analyzed gravimetrically or with suitable analytical methods such as UV or HPLC.

Solubility may be determined according to the function of the study as follows.

i. Solubility as a Function of Temperature.

Solubility may exist determined at several temperatures and plotted confronting the reciprocal of the absolute temperature (temperature in °C + 273), resulting in a direct line. This plot is based on the van't Hoff equation,

$ln{X}_2/X_1=\Delta H°/R\left(T_2-T_1/T_{\mathrm{ane}}{T}_2\right)$

where X ₁ is the solubility at temperature T ₁, Ten _ii is the solubility at temperature T _ii, ΔH° is the standard estrus of reaction, and R is the gas constant. From the van't Hoff equation, the solubility at a given temperature can be estimated.

two. Aqueous Solubility with Varying Buffered pH Values.

Solubility may be determined in various pH values with buffer solutions at constant temperature. For convenience of assay, buffer systems without UV chromophores are desirable. The solubilities may be determined past UV spectroscopy later proper dilution or by HPLC. Plotting pH versus its related solubility according to the Henderson–Hasselbalch equation includes

pH = pK a + log(B/BH+)	for base
pH = pThou a + log(A− /HA)	for acrid

Thus, pThou _a may be obtained, and solubility at a given pH may also exist calculated (Fig. v).

Figure 5. Determination of pThou _a by solubility.

three. Solubility in Organic Solvents.

Solvents such as alcohols, acetonitrile, tetrahydrofuran, and chlorinate solvents are unremarkably used for drug conception or analytical determination. Solubility in organic solvents is useful for the evolution of chromatographic methods or co-solvent systems for less soluble drugs. Determination may exist made gravimetrically afterwards evaporation under an IR lamp, or with HPLC.

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Mercury Production☆

Fathi Habashi , in Reference Module in Materials Scientific discipline and Materials Engineering science, 2017

four Amalgams

The solubility of metals in mercury at room temperature varies greatly; the highest is that of indium (57%), and the everyman is that of chromium (4×ten ⁻⁷%). Solubility increases with increased temperature. The following types of solubilities can exist identified:

1.

Metals deliquesce with formation of compounds at room temperature, for instance, the alkali and alkaline metal earth metals. The reaction is exothermic.

ii.

Metals with depression solubilities that do not course compounds, for example, aluminum, chromium, cobalt, and fe.

3.

Metals with depression solubilities that do course compounds, for example, uranium.

Due to its loftier surface tension, mercury has the ability to wet metals. When the solubility limit of a metal is exceeded, mercury still tin wet the metal, forming a thick amalgam paste. Strictly speaking, an amalgam is a solution of a metal in mercury and a quasi-amalgam is a metal wetted by mercury after the solubility limit has been exceeded.

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Leaching in Chloride Media

Tomáš Havlík , in Hydrometallurgy, 2008

Solubility of chlorides

Solubility of CuCl in cold water is very low, but around threescore  mg/l. However, in concentrated chloride solutions the solubility speedily increases [11]. This fact is very important because the chloride technology of leaching sulphide minerals by CuCl₂ would exist otherwise not feasible for use in do. Another important moment is that the solubility of CuCl depends greatly also on the grade of presence of the chloride ions. These facts are summarised in Fig. 8.i.

Fig. 8.one. Information for the solubility in CuCl–NaCl–H₂O organisation at unlike temperatures in HCl.

The increase of the NaCl concentration results in an almost linear increase of the solubility of CuCl. On the other paw, in more complex systems, the issue of the presence of other chlorides may differ – for example, the improver of FeCl_two at a constant concentration of NaCl and HCl increases the solubility of CuCl, whereas the addition of ZnCl₂ reduces this solubility. Winand [11] relates this to the strength of the resultant complexes. Fe²⁺ forms weak complexes in the chloride medium and, consequently, is a donor of Cl⁻ ions. On the other hand, the Zn²⁺ ion forms strong complexes and therefore acts every bit an acceptor of Cl⁻.

Similarly, the solubility of CuCl_ii is affected to a sure extent by the presence of other chlorides in the solution. However, its solubility in h2o is considerably higher than that of CuCl. The addition of NaCl in the presence of HCl slightly increases the solubility of CuCl₂ merely the presence of FeCl_iii and/or ZnCl2 affects its solubility to a greater extent, specially the presence of FeCl₃. As indicated by Fig. eight.2, in solutions saturated with both NaCl and CuCl₂, the presence of ZnCl₂ leads to the precipitation of CuCl₂  ·   2H_twoO, whereas the presence of FeCl_iii would cause the precipitation of NaCl.

Fig. viii.ii. Solubility in complex Cu²⁺ chloride solutions at 50   °C [eleven]. The system CuCl₂–ZnCl_ii–NaCl–HCl–H₂O: 1) c _Zn2+  =   0.5   M; 2) c _Zn2+  =   1.v   M; the arrangement CuCl₂–FeCl₃–NaCl–HCl–H₂O: 3) c _Fe3+  =   0.v   M; 4) c _Fe3+  =   1   M; 5) c _Fethree+  =   1.five   1000.

Another factor affecting the solubility of individual chlorides is temperature. Its effect is stronger in the case of CuCl₂, as shown by comparing of Figs. 8.3 and eight.4.

Fig. 8.3. Solubility of Cu⁺ in the CuCl–FeCl₂–ZnCl₂–NaCl–HCl–H₂O system.

Fig. 8.4. Temperature dependence of the solubility of CuCl_two in h2o [11].

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Solvent Systems

Laurence W. McKeen , in Fluorinated Coatings and Finishes Handbook, 2006

6.6 Solubility

The solubility of paint materials in the blanket system is particularly important in solution coatings. This behavior is quite complex, but solubility can often exist calculated past the same software described in the previous two sections. A polymer has three experimentally determined solubility parameters. These parameters are chosen dispersive or non-polar, polar or dipole moment, and hydrogen bonding. These parameters are too called Hansen Solubility Parameters. ^[one] A polymer will dissolve in a solvent organisation that has similar solubility parameters. These solubility parameters can be calculated for solvent mixtures. Further, since the solvent composition can as well exist calculated equally a function of evaporation time, the solubility parameters can be calculated as a function of evaporation time. A formulator should wait for major shifts in the solubility parameters as an indication of possible issues related to polymer solubility, such as bumps in the blanket caused by crystallization of one of the raw materials from solution. For example, this tool has helped the writer in solving problems with a new formulation. Particles were discovered in a coating after it had dried which were non present at the time of application.

These particles were a dissolved component of the blanket system that had become insoluble during evaporation of the solvent, essentially forming crystals in the coating. An example of solubility data is shown in Fig. six.6. This effigy shows a significant shift in solubility parameters betwixt the initial awarding and 200 seconds of evaporation. While the shift, in this example, may not actually cause a solubility problem, it should alert the formulator to the possibility.

Figure half-dozen.six. Solubility variation with fourth dimension.

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Does Solubility Increase With Temperature,

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