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Factors that Affect the Solubility of Drugs

Amount of force between solute and solvent, Electronic factors, Solute-solvent interactions, Steric factors, Nature of solute, Nature of solvent etc.
Drugs are dissolved in solvents according to their intended use when preparing liquids. However, the dissolution of the drug is affected by:
  1. Amount of force between solute and solvent
  2. Electronic factors
  3. Solute-solvent interactions
  4. Steric factors
  5. Nature of solute
  6. Nature of solvent
Factors that affect the solubility of drugs are mentioned below;


Weak acids and bases are the most common types of drugs. Water does not dissolve them or only slightly dissolves them, while their salts do. In addition to pH, these agents are strongly affected by their environment in terms of solubility.

It is usual in the literature to report values for solubility constants and dissociation constants for drugs dissolved in distilled water. However, these values may not always be useful. Because dosage formulations such as elixirs contain a higher proportion of solids and cosolvents, these values are different. The solubility constant of cosolvents like alcohol and glycerine is generally greater and the dissociation constant is decreasing.

Certain points should be considered when adjusting the drug's pH environment.
  • Formulations are prepared with the help of a solvent.
  • The concentration of drug needed for the formulation.
  • Product stability shouldn't be affected by the pH level.
  • Physiological compatibility should be encouraged by pH.
The following factors must be accounted for when formulating acidic or basic pharmaceutical solutions.
  • Intoxicating drugs are chemically stable depending on the pH and the buffer components.
  • Drugs in the ionized and unionized forms are solubilized differently.
  • Effectiveness of the drug in treating or treating disease.
It is essential to choose the right buffer pH and type to achieve a proper balance between these variables.


To ensure that the formulation maintains a pH level throughout its life, the pH levels of the drug's environment must be fixed before supplying it. In some cases, pH may change. When that occurs, it is necessary to add a buffer to avoid the consequences of pH change. These criteria should guide the selection of a buffer:
  • pH buffers must be able to handle buffers with adequate capacity.
  • It is possible that the buffer can affect the stability of the final product negatively.
  • The buffer should also be biologically safe for the intended application.
  • It should be possible for the product to be flavored and colored after the buffer has been added.
  • To ensure that the final dosage form's pH is close to the pH of the buffer used, the acid's pKa should be close to its pH.
Borate-boric acid, acetate -acetic acid, bicarbonate-carbonate, and Na2HPO4 - Na2H2PO4 are commonly employed buffer systems in pharmaceutical preparations.


Some drugs cannot be dissolved in water due to their low solubility. The solubility of these drugs is increased when they are dissolved in water-miscible solvents. The solvent used for this purpose is called the cosolvent. The co-solvency process is known as co-solvency.


  • By altering the solvent polarity, you can try to change the polarity of the solution.
  • It occurs when a completely new mixture of solvents is formed whose interactions cannot be predicted easily from those of the individual solvent components.

Compounds that dissolve in 20% ethanol in water can be predicted more easily than compounds that dissolve in water-ethanol-glycerine sorbitol solvents.

The sum of the solubility values of an aqueous solution in each solvent usually does not equal the solubility value in a blend of solvents.

Auxiliary use: A cosolvent can also facilitate the addition of volatile oils to formulations, thus giving them an odor.

Example: The most common liquid oral cosolvents are ethanol, sorbitol, glycerine, syrups, propylene glycol, and PEGs.

Because ethanol has a pharmacological effect, a burning taste in high concentrations, and is expensive, it is kept at a minimum as a cosolvent.

Dielectric constant

It is well known that molecules with an equal distribution of charges dissolve together according to the rule "like dissolves like". Polar molecules, that is, molecules with asymmetric charge distribution, can be dissolved in polar media, and non-polar molecules can be dissolved in non-polar media without being observed.

Dielectric constant refers to the degree of the polarizability of a molecule. Dielectric constants determine which materials belong to the polar, semipolar, or nonpolar categories.

We should therefore keep in mind that a dielectric constant is not necessarily a reliable and adequate determinant of solubility. Despite its dielectric constant of 3.3, sucrose is extremely soluble in water. The dielectric constants of dioxane (2.26), mineral oil (2.5), and water (2,6) are similar, but mineral oil and water are distinct in that dioxane is a miscible liquid.

Due to its higher dielectric constant, water becomes more soluble when its temperature rises. Nevertheless, the water dielectric constant decreases with increasing temperatures. Due to this, solubility cannot be determined by a combination of dielectric constant and temperature.

Combining two solvents yields dielectric constants between those for the components alone. Blends of solvents with the same dielectric constant do not have the same solvent properties. Even though ethanol, at 70% w/w, has a dielectric constant very similar to sucrose, at 40% w/w, which has a dielectric constant of 59.9%, these two solvents have different solvent properties. Hence, the dielectric constant of a solvent provides only a qualitative estimate of the solvent properties and the degree to which polar and nonpolar compounds are soluble in the solvent.


To increase the water solubility of poorly water-soluble drugs, solubilization can be used. Solubilization is the process of molecule-to-molecule passage between poorly soluble solute molecules and an aqueous soap or detergent solution, in which a thermodynamically stable solution forms.

A surfactant that is added to a liquid at a low concentration tends to orient itself toward the air-liquid interface. Increasing the concentration of surfactants forces the molecules into the liquid bulk, increasing concentrations of surfactant cause micelles to form in liquid bulk. Micelles form at certain surfactant concentrations, known as critical micelle concentrations (CMC).

Solubilization occurs as a result of micelle entrapping or adsorbing solute molecules. Surface-active agents, therefore, need to be present at or above the CMC. Typically, surfactants comprise polysorbates used for orally administered products.

Example -
  1. Increased CMC formation improves cresol solubility when combined with the soap solution and cresol
  2. Compared with pure water, aqueous soap solutions contain more soluble cholesterol.


It is generally the case in the solution that organic compounds tend to associate with one another. In every solvent and at every temperature, every substance has specific and reproducible equilibrium solubility. Whenever there is a deviation from this inherent solubility, this is proof that new species (complexes) have formed in the solution causing its instability.

The interaction between an insoluble compound and a soluble ingredient can result in a soluble complex. Iodine solutions are a typical example. A soluble KII2 compound is formed when the soluble iodine (I2) reacts with the soluble iodine (I2).

A weakened acid or a weakly basic compound has a total solubility equal to the inherent solubility of the undissociated compound plus its dissociation concentration. If the compound is complexed, the solubility of the compound in solution equals the inherent solubility of the primary compound into solution plus the concentration of the compound in solution. The idea of increasing solubility of a compound with this approach must meet certain standards, such as reversibility, dis-sociability, and release of the active ingredient, otherwise, the compound becomes ineffective.


In general, hypertrophy refers to an increase in the solubility of different ingredients in water due to a high concentration of additives.

Mechanism - A weak interaction between a solute and a hydrotropic agent results in the formation of a complex.

Limitations -
  • To achieve this effect, a substantial amount (between 20 and 50 percent) of additive is required.
  • The effect cannot be produced by simply increasing solubility.
  • Several of the compounding agents are biologically active compounds or have unknown biological properties.
Examples -
  • The solubility of caffeine is increased by sodium benzoate.
  • Theophylline is more easily dissolved by sodium acetate.
  • Moreover, PVP increases Iodine's solubility.
  • A solution of sodium benzoate makes benzoic acid more solubilized.

Chemical modification of drug

By modifying the drug chemically, poorly soluble drugs can become more soluble.

Examples - In water, betamethasone alcohol dissolves at a solubility of 5.8 mg/100 ml at room temperature. It is 10 grams per 100 milliliters of water solubility for betamethasone alcohol 21 disodium phosphates, a chemically modified drug.

Limitations - As with the parent compound, chemically modified drugs must undergo the same extensive testing protocol including bioactivity studies, acute and chronic toxicity, pharmacodynamics evaluation, and clinical studies. Time and money are spent on this lengthy and expensive procedure. Thus, it should only be considered when there are no other options.


With an increase in temperature, many drugs/additives become more soluble.

Salting out

Organic compounds can become precipitated or separated when excess salt content is added to aqueous solutions of organic compounds. There is a phenomenon known as salting out which occurs because water molecules compete with salts to dissolve in them. In terms of salting-out power, the size and importance of its ions play a role.

Salting in

It is the process of making an organic compound more soluble through the addition of salt. For example, globulins (proteins) in water are saline when salt is present.

Particle size

If the particle size is decreased below submicron levels, it becomes insoluble, an increase of about 10% taking place. Because small particles have a higher surface free energy, they are less soluble.

The molecular size of solvent molecules

A large proportion of water's solvent properties come from its small molecular size. Liquids with similar properties to water, including polarity, dielectric constant, and hydrogen bonding, may not be suitable for ionic compounds. Liquid molecules are much larger than water molecules, hence the difference in size. These liquid molecules have trouble penetrating and dissolving crystals.

The molecular size of solute molecules

A substance's solubility is affected by its shape. Water simply fits perfectly around ammonia inside its structure, which is why ammonia is highly soluble in it. A molecule's shape has a significant influence on its solubility in a given solvent, primarily due to entropy.


The molecular weight ranges from 10,000 to millions for these compounds. PVP, carbazole, enzymes, plasma proteins, and natural polysaccharides are a few examples. Macromolecular solubility is influenced by ionic character, molecular weight, shape, pH, temperature, and salt addition. At low concentrations, water solutions have the characteristic of being vicious and forming gels. Due to these properties, macromolecules are used extensively to thicken and suspend dosage forms.
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Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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