Solubilization in Pharmaceutical Sciences: Concepts, Mechanisms & Enhancement Strategies

This presentation provides an in-depth understanding of solubilization and its critical role in pharmaceutical formulations. It covers:

Definition & Mechanisms of Solubilization

Role of surfactants, micelles, and bile salts in drug solubility

Factors affecting solubilization (pH, polarity, particle size, temperature, etc.)

Methods to enhance drug solubility (Buffers, Co-solvents, Surfactants, Complexation, Solid Dispersions)

Advanced approaches (Polymorphism, Salt Formation, Co-crystallization, Prodrugs)


This resource is valuable for pharmaceutical scientists, formulation experts, regulatory professionals, and students interested in improving drug solubility and bioavailability.

1. SOLUBILIZATION Khushal H. Chavan

2. Content:

3. Introduction Solubilization can be defined as ‘the preparation of a thermodynamically- stable solution of an insoluble or very slightly-soluble substance by the use of amphiphilic components. Solubilization has been defined by McBain as the spontaneous passage of poorly water-soluble solute molecules into an aqueous solution of a soap or a detergent, in which a thermodynamically stable solution is formed. A relationship between the extent of solubilization and the lipophilicity of the compound has been observed by Collett and Koo . They found a linear relationship between the π- values of functional groups on substituted benzoic acids and their aqueous/micellar partition coefficients in polysorbate 20 .

4. In the small intestine, drug solubility can be enhanced by amphiphilic bile components such as bile salts, monooleins and lecithin. Increase in solubility of up to 100-fold upon the addition of physiological concentrations of bile salts to aqueous media has been observed. When amphiphilic bile components are present in concentrations higher than their critical micelle concentration (CMC), micellar solubilization of the drug can occur. Solubilization via simple bile salt micelles has been reported for many poorly soluble drugs, including glutethimide , griseofulvin, digoxin and gemfibrozil .

5. For drug candidates with either poor water solubility or insufficient solubility for projected solution dosage forms, preformulation studies should include limited experiments to identify the possible mechanisms for solubilization. The mechanism for this phenomenon has been studied quite extensively and involves the property of surface-active agents to form colloidal aggregates known as micelles. When surfactants are added to a liquid at low concentrations, they tend to orient at the air-liquid interface. As additional surfactant is added, the interface becomes fully occupied, and the excess molecules are forced into the bulk of the liquid. At still higher concentrations, the molecules of surfactant in the bulk of the liquid begin to form oriented aggregates or micelles; this change in orientation occurs rather abruptly, and the concentration of surfactant at which it occurs is known as the critical micelle concentration (CMC).

6. Solubilization: An important property of association colloids in solution is the ability of the micelles to increase the solubility of materials that are normally insoluble, or only slightly soluble, in the dispersion medium used. This phenomenon, known as solubilization . Solubilization has been used with advantage in pharmacy for many years; as early as 1892, Engler and Dieckhoff 25 solubilized a number of compounds in soap solutions. Knowing the location, distribution, and orientation of solubilized drugs in the micelle is important to understanding the kinetic aspect of the solubilization process and the interaction of drugs with the different elements that constitute the micelle. These factors may also affect the stability and bioavailability of the drug.

7. Figure depicts a spherical micelle of a nonionic, polyoxyethylene monostearate, surfactant in water. The figure is drawn in conformity with Reich's suggestion 28 that such a micelle may be regarded as a hydrocarbon core, made up of the hydrocarbon chains of the surfactant molecules, surrounded by the polyoxyethylene chains protruding into the continuous aqueous phase. Benzene and toluene, nonpolar molecules, are shown solubilized in the hydrocarbon interior of the micelle. Salicylic acid, a more polar molecule, is oriented with the nonpolar part of the molecule directed toward the central region of the micelle and the polar group toward the hydrophilic chains that spiral outward into the aqueous medium. Parahydroxybenzoic acid, a predominantly polar molecule, is found completely between the hydrophilic chains.

8. O'Malley et al.30 investigated the solubilizing action of Tween 20 on peppermint oil in water and presented their results in the form of a ternary diagram as shown in Figure 16-15. They found that on the gradual addition of water to a 50:50 mixture of peppermint oil and Tween 20, polysorbate 20, the system changed from a homogeneous mixture (region I) to a viscous gel (region II). On the further addition of water, a clear solution (region III) again formed, which then separated into two layers (region IV). This sequence of changes corresponds to the results one would obtain by diluting a peppermint oil concentrate in compounding and manufacturing processes. Analyses such as this therefore can provide important clues for the research pharmacist in the formulation of solubilized drug systems. Determination of a phase diagram was also carried out by Boon et al.31 to formulate a clear, single phase liquid vitamin A preparation containing the minimum quantity of surfactant needed to solubilize the vitamin. Phase equilibrium diagrams are particularly useful when the formulator wishes to predict the effect on the phase equilibria of the system of dilution with one or all of the components in any desired combination or concentration.

9. Factors Affecting Solubilization: The solubilization capacity of surfactants for drugs varies greatly with the chemistry of the surfactants and with the location of the drug in the micelle. If a hydrophobic drug is solubilized in the micelle core, an increase of the lipophilic alkyl chain length of the surfactant should enhance solubilization. At the same time, an increase in the micellar radius by increasing the alkyl chain length reduces the Laplace pressure, thus favoring the entry of drug molecules into the micelle

10. Solutions and Solubility A solution is a chemically and physically homogeneous mixture of two or more substances. The term solution generally denotes a homogeneous mixture that is liquid, even though it is possible to have homogeneous mixtures that are solid or gaseous. Thus, it is possible to have solutions of solids in liquids, liquids in liquids, gases in liquids, gases in gases, and solids in solids. The first three of these are most important in pharmacy, and ensuing discussions will be concerned primarily with them. In pharmacy different kinds of liquid dosage forms are used, and all consist of a dispersion of one or more substances in a liquid phase. Depending on the size of the dispersed particle, they are classified as true solutions, colloidal solutions , or disperse systems . If sugar is dissolved in water, it is supposed that the ultimate sugar particle is of molecular dimensions and that a true solution is formed. On the other hand, if very fine sand is mixed with water, a suspension of comparatively large particles, each consisting of many molecules, is obtained. Between these two extremes lie the colloidal solutions, the dispersed particles of which are larger than those of true solutions but smaller than the particles present in suspensions. Colloidal solutions, in general, are considered to be thermodynamically stable.

11. Solutions of solids in liquids Reversible Solubility Without Chemical Reaction: From a pharmaceutical standpoint, solutions of solids in liquids, with or without accompanying chemical reaction in the solvent, are of the greatest importance, and many quantitative data on the behavior and properties of such solutions are available. This discussion will be concerned with definitions of solubility, with the rate at which substances go into solution, and with temperature and other factors that control the rate and extent of solubility.

12. Solubility: When an excess of a solid is brought into contact with a liquid, molecules of the former are removed from its surface until equilibrium is established between the molecules leaving the solid and those returning to it. The resulting solution is said to be saturated at the temperature of the experiment, and the extent to which the solute dissolves is referred to as its solubility. The extent of solubility of different substances varies from almost imperceptible amounts to relatively large quantities, but for any given solute the solubility has a constant value at a given constant temperature. Under certain conditions it is possible to prepare a solution containing a larger amount of solute than is necessary to form a saturated solution. This may occur when a solution is saturated at one temperature, the excess of solid solute is then removed, and the solution cooled. The solute present in solution, even though it may be less soluble at the lower temperature, does not always separate from the solution, and there is produced a supersaturated solution. Such solutions, formed by sodium thiosulfate or potassium acetate, for example, may be made to deposit their excess of solute by vigorous shaking, scratching the side of the vessel in contact with the solution, or introducing into the solution a small crystal of the solute. Supersaturated solutions are considered to be thermodynamically unstable systems and, therefore, usually return to a saturated solution by excluding the excess solute.

13. Factors Affecting Solubility: pH Levels —  pH measures the amount of hydrogen content in a solution—the more hydrogen ions, the lower the pH and vice versa. Solutions with strong pH levels fully dissociate and those with weak pH levels only partially dissociate. The pKa value is one method used to measure the strength of an acid. A lower pKa value means the drug substance is a stronger acid, which more fully dissociates in water. Polarity of Drug and Solvent —  Ionization is important for a drug to be soluble for oral drug consumption. In addition, ion trapping is important for the drug to work properly. In the stomach or intestines, the drug is non-ionized so it can be absorbed. When it enters the bloodstream, it needs to become ionized again to prevent it from going back to the GIT and to ensure it is absorbed by the body. Lipid soluble substances contain non-ionized molecules (NaCl), and hydrophilic substances contact ionized molecules (Na+, CL-), meaning the more lipid soluble a drug is, the more absorption there will be. The more water soluble (hydrophilic) a drug is, the less absorption there is.

14. Drug Particle Size —   The solubility of a drug is directly tied to the particle size. Typically, larger particles are less soluble, especially if the temperature, pressure and polarity for the solutes is the same. The ability for a drug to be soluble allows for simple diffusion of the drug with no energy or carrier protein needed to enter and be absorbed by the bloodstream. Solution Process  — Most substances are endothermic, or absorb heat in the process of dissolution, meaning an increase in temperature from room-temperature storage to oral consumption and moving into body heat results in an increase in solubility. In addition to temperature, agitation helps increase the speed at which the drug dissolves.

15. Methods of Expressing Solubility : When quantitative data are available, solubility may be expressed in several ways. For example, the solubility of sodium chloride in water at 25°C may be stated as 1 g of sodium chloride dissolves in 2.786 mL of water. (An approximation of this method is used by the USP.) 35.89 g of sodium chloride dissolves in 100 mL of water. 100 mL of a saturated solution of sodium chloride in water contains 31.71 g of solute. 100 g of a saturated solution of sodium chloride in water contains 26.47 g of solute. 1 L of a saturated solution of sodium chloride in water contains 5.425 moles of solute. This also may be stated as a saturated solution of sodium chloride in water is 5.425 molar with respect to the solute. In order to calculate item 3 above from items 1 or 2, it is necessary to know the density of the solution, which in this case is 1.198 g/ mL. To calculate item 5, the number of grams of solute in 1000 mL of solution (obtained by multiplying the data in item 3 by 10) is divided by the molecular weight of sodium chloride, name 58.45.

16. Rate of Solution: It is possible to define quantitatively the rate at which a solute goes into solution. The simplest treatment is based on a model depicted in Figure 13-1. A solid particle dispersed in a solvent is surrounded by a thin layer of solvent having a finite thickness, l , in units of length e.g. centimeters. The layer is an integral part of the solid and, thus, is referred to characteristically as the stagnant layer . This means that, regardless of how fast the bulk solution is stirred, the stagnant layer remains a part of the surface of the solid, moving wherever the particle moves. The thickness of this layer may get smaller as the stirring of the bulk solution increases, but it is important to recognize that this layer will always have a finite thickness, however small it may get.

17. Solubility of a nonelectrolyte in water is generally either decreased or increased by the addition of an electrolyte; it is only rarely that the solubility is not altered. When the solubility of a nonelectrolyte is decreased, the effect is referred to as salting out ; if it is increased, it is described as salting-in . Inorganic electrolytes commonly decrease solubility, though there are some exceptions to the generalization. Salting-out occurs because the ions of the added electrolyte interact with water molecules, and thus, in a sense, reduce the amount of water available for dissolution of the nonelectrolyte. (See Thermodynamics of the Solution Process for another view.) The greater the degree of hydration of the ions, the more the solubility of the nonelectrolyte is decreased. If, for example, one compares the effect of equivalent amounts of lithium chloride, sodium chloride, potassium chloride, rubidium chloride, and cesium chloride (all of which belong to the family of alkali metals and are of the same valence type), lithium chloride decreases the solubility of a nonelectrolyte to the greatest extent, and the salting-out effect decreases in the order given. This is also the order of the degree of hydration of the cations; lithium ion—being the smallest ion and, therefore, having the greatest density of positive charge per unit of surface area— is the most extensively hydrated of the cations, whereas cesium ion is hydrated the least. Salting-out is encountered frequently in pharmaceutical operations.

18. Salting-in commonly occurs when either the salts of various organic acids or organic-substituted ammonium salts are added to aqueous solutions of nonelectrolytes. In the first case, the solubilizing effect is associated with the anion; in the second, it is associated with the cation. In both cases the solubility increases as the concentration of added salt is increased. The solubility increase may be relatively great, sometimes amounting to several times the solubility of the nonelectrolyte in water.

19. Methods to increase solubility of poorly soluble drugs A large number of promising drug candidates do not make it to the market because of poor bioavailability, due primarily to their poor solubility in aqueous medium. Recently, several strategies have been used to improve solubility profile of these drugs and include the following: Use of buffers Use of cosolvents Use of surfactants Complexation S olid dispersions.

20. Use of Buffers The idea behind the use of buffers to improve solubility is to create and maintain pH conditions in a system that causes the drug to be in its ionized state. The ionized fraction of a drug is much more soluble in water, due to its increased polarity relative to the unionized fraction. Buffers can also help in reducing the likelihood of drug precipitation when drug solution is diluted in an aqueous medium. Consistent with the principles of solubility changes with pH, acidic drugs are formulated under relatively basic conditions while the opposite is true for the basic drugs. Some examples of drugs that are formulated with buffer systems are Amikacin sulfate (pH 3.5–5.5, citrate buffer) and Midazolam hydrochloride (pH 3). The drugs that make good candidates for use of pH variation or buffers are the ones that have the ability to ionize within a pH range of 2–8.

21. Use of Cosolvents A common way to increase drug solubility is through the use of a water-miscible organic solvent. This strategy is based on the fact that poor solubility of drugs in water results from the great difference in polarity of the two components, water being of very high polarity and the drug having low polarity. Addition of a cosolvent with a polarity value of less than that of water reduces the difference between polarity of the drug and water cosolvent system, thereby improving solubility. Commonly used cosolvents for this purpose are the hydrogen bonding organic solvents such as ethyl alcohol, propylene glycol, and glycerin. The polarity scale of solvents is defined by a property known as the dielectric constant. This value for water is 80, and for ethyl alcohol, propylene glycol, and glycerin, it is 24, 32, and 42, respectively. Most poorly soluble drugs have dielectric constant values of less than 20. Examples of some parenteral solution that contain cosolvents include chlordiazepoxide (25% propylene glycol), diazepam (10% ethyl alcohol and 40% propylene glycol), and digoxin (10% ethyl alcohol and 40% propylene glycol). Non-polar and nonionizable drugs are good candidates for cosolvent systems.

22. Use of Surfactants Surfactants are molecules with well defined polar and non-polar regions that allow them to aggregate in solution to form micelles. Non-polar drugs can partition into these micelles and be solubilized. Depending on the nature of the polar area, surfactants can be nonionic (e.g., polyethylene glycol), anionic (e.g., sodium dodecyl sulfate), cationic (e.g., trialkylammonium ), and zwitterionic (e.g., glycine and proteins). Among these, the most commonly used ones are the anionic and non-ionic surfactants. Since the process of solubilization occurs due to presence of micelles, generally high concentrations of surfactants are needed to significantly improve drug solubility. One example of surfactant based solution is Taxol (paclitaxel), an anti-cancer drug that is solubilized in 50% solution of Cremophor. Other examples include valrubicin in 50% Cremophor, and cyclosporin in 65% Cremophor

23. Complexation Complexation is the association between two or more moleculesv to form a noncovalent-based complex that has higher solubility than the drug itself. From the solubility standpoint, complexes can be put into two categories the stacking complexes and inclusion complexes. Stacking complexation is driven by association bof non-polar areas of the drug and complexing agent. This results in exclusion of the non-polar areas from contact with water, thereby reducing the total energy of the system. This aggregation is favored by large, planar, non-polar regions on the molecules. Stacking can be homogeneous or mixed but results in a clear solution. Inclusion complexes are formed by insertion of drug molecule into a cavity formed by the complexing agent. In this arrangement the non-polar area of the drug molecule is excluded from water, due to its insertion in the complexing agent. One requirement for the complexing agent in such systems is that it has a non-polar core and a polar exterior. The most commonly used inclusion complexing molecules are cyclodextrins. The cyclic oligomers of glucose are relatively soluble in water and have cavities large enough to accept non-polar portions of many drug molecules. Cyclodextrins can consist of six, seven, or eight sugar residues and are classified as , respectively. Due to geometric considerations, steroid molecules are very suitable for inclusion into cyclodextrin complexes.  

24. Solid Dispersions Solid dispersion refers to the dispersion of one or more active ingredients in an inert carrier or matrix at solid state, prepared by the melting (fusion), solvent, or the melting-solvent method. It has also been defined as the product formed by converting a fluid drug-carrier combination to the solid state. The term coprecipitate or co-evaporate has also been used frequently when a solid dispersion is prepared by the solvent method. Classification of Solid Dispersions Solid dispersions can be classified as follows: Simple eutectic mixtures Solid solutions Glass solutions of suspensions Compound or complex formation between the drug and the carriers Amorphous precipitations of drug in crystalline carrier

25. Solid-State Manipulations: Moving beyond the simple molecule, solid-state manipulations explore the intricate ways drug molecules arrange themselves in the solid state, influencing crucial pharmaceutics parameters. Think of it as deciphering the crystal code: Polymorphism: A Tale of Many Forms Amorphization: Embracing Disorder for Enhanced Solubility Co-crystallization: A Molecular Matchmaker Salt Formation: Ionic Bonds for Enhanced Aqueous Solubility

26. Polymorphism: Like snowflakes adorning winter windows, a drug molecule can exist in multiple polymorphic forms, each with unique crystal structures and, consequentially, distinct physicochemical properties. Identifying and harnessing the optimal polymorph is key to optimizing drug performance. Consider ritonavir, an HIV protease inhibitor: its Form II exhibits significantly higher solubility and bioavailability compared to Form I, paving the way for effective oral therapy. Hydrogen bonds present in ritonavir form I and form II crystal structures. 

27. 2. Amorphization: Shattering the crystalline lattice, amorphization transforms the drug into a non-crystalline state, resembling "molecular glass." This often translates to a dramatic increase in surface area, leading to a ~1000-fold enhancement in dissolution rate compared to the crystalline counterpart. However, the inherent thermodynamic instability of amorphous forms necessitates careful formulation strategies to ensure physical stability.

28. 3. Co-crystallization: Imagine forging alliances between drug molecules and " coformers " to create new crystal structures with superior properties. Co-crystallization offers a versatile approach to fine-tune solubility, stability, and even modify taste or melting point. For example, the co-crystal of carbamazepine with saccharin dramatically improves its aqueous solubility, enabling wider therapeutic applications.  Illustration of the influence of coformer solubility on the spring and parachute effect of cocrystals.

29. 4. Salt Formation: By reacting the drug molecule with an acid or base, we can form ionic salts. These salts often exhibit remarkable water solubility, overcoming the limitations of poorly soluble free acids or bases. Additionally, salts can enhance stability and sometimes modulate the drug's activity profile. Aspirin, for instance, exists as a more soluble and stable salt form compared to its free acid counterpart. Example of Salt Formulation: Degradation reaction of amlodipine in the presence of maleic acid.

30. Drug Derivatization: Beyond rearranging the "crystal puzzle pieces," drug derivatization delves into modifying the molecular structure itself. Chemical alterations can unlock new therapeutic potential or overcome limitations hindering the original drug. Here are some key strategies: Prodrugs: Trojan Horses of Drug Delivery Bioisosterism : Mimicking Nature's Lego Set Analog Design: Beyond Inspiration, Innovation

31. Prodrugs: Prodrugs are cleverly disguised chemical entities that undergo metabolic transformation within the body to release the active drug. This approach can improve targeting, enhance oral bioavailability, and minimize side effects. For instance, the prodrug oseltamivir phosphate, upon absorption, gets converted into the active antiviral agent oseltamivir within the body, effectively targeting influenza virus replication. Prodrug of a drug molecule: Engineering of small-molecule lipidic prodrugs as novel nanomedicines for enhanced drug delivery

32. 2. Bioisosterism : Bioisosterism involves replacing functional groups in the drug molecule with chemically similar but pharmaceutically superior alternatives. This elegant strategy allows scientists to tweak the "molecular lego set," optimizing properties like potency, stability, and metabolism without compromising the core therapeutic effect. A classic example is the replacement of a nitro group in sulfanilamide with an isosteric thiophene group, leading to the development of the potent antibacterial sulfamerazine . Bioisosterism of drug molecule : Hydrogen to fluorine replacement.

33. 3. Analog Design: Taking inspiration from the original drug's blueprint, scientists can design entirely new molecules with enhanced properties. These analogs retain the core activity but offer improved potency, selectivity, or reduced side effects. Consider the development of fluoroquinolones: each generation, starting with nalidixic acid, represents an analog with enhanced potency and broader spectrum of activity against bacterial pathogens.

34. References : Solid-State Pharmaceutical Chemistry by Glenn H. Gordon and James T. Taylor The Polymorphism Handbook by Julio Cesar de Oliveira Silva, José Mauro de Souza Lima, and Antônio Alvarenga ONTIVEROS-CONTRERAS Prodrug Design and Development by V. J. Stella, R. T. Borchardt, M. J. Chickering, C. G. Monaghan, D. M. Powell, and F. H. Schaefer Bioisosterism : Design and Optimization of Drug-like Molecules by Peter I. O'Shea An Introduction to Medicinal Chemistry by Graham L. Patrick