Solubility of drugs:
Solubility expressions, mechanisms of solute solvent interactions, ideal solubility parameters, solvation & association, quantitative approach to the factors influencing solubility of drugs, diffusion principles in biological systems. Solubility of gas in liquids, solubility of liquids in liquids, (Binary solutions, ideal solutions) Raoult’s law, real solutions. Partially miscible liquids, Critical solution temperature and applications. Distribution law, its limitations and applications
Solubility is the ability of one substance to fully dissolve in another substance under specified conditions. The word soluble comes from the fourteenth century, from the Latin word ‘solvere’ meaning to dissolve. The concentration of a solution is usually quoted in terms
of mass of solute dissolved in a particular volume of solvent. The solubility is generally expressed in gram per litre. Therefore, solubility of a solute in a solvent at a particular temperature is the number of grams of the solute necessary to saturate 100 grams or mL of the solvent at that temperature. Most commonly encountered solutions are solids dissolved in liquids. The solid that dissolve in a liquid is the solute and the liquid in which it dissolves is solvent. A solute is the dissolved agent usually the less abundant part of solution whereas
solvent is more abundant part of solution. If a solid can dissolve in a liquid, it is said to be soluble in that liquid, if not it is said to be insoluble. As we add more solids to a liquid the
solution becomes more concentrated. The greater the solubility of a substance the more concentrated it is possible to make the solution. Solubility is measured after solute of interest
has had sufficient contact time (however long it takes) with the solvent. There are two types of solubility: one is called intrinsic solubility and the other one is apparent solubility. Intrinsic solubility is defined as the maximum concentration to which a solution can be prepared with
a specific solute and solvent. It is often derived from calculation, and is a single numeric
number (for example, 0.5 µg/mL) that is independent of the environmental factors. The
apparent solubility is dependent on the environmental factor such as pH and ionic strength
and is obtained from the experimental measurements. The rate of solubility is affected by
many factors such as type of solvent, size and amount of solute particles, stirring speed and
temperature. The concept of solubility is very important because it governs the preparation
of solutions as dosage forms and a drug must be in solution before it can be absorbed by
the body or have any biological activity. Since activity of drug depends on solubility, it is
equally important to control environmental conditions which impact various types of solution.
SOLUBILITY EXPRESSIONS
The solubility of a drug or other substance in a solvent can be expressed quantitatively in numerous terms viz. percent by mass, percent by volume, molality (m), molarity (M), mole fraction (x), and parts per million (ppm), etc. The particular terminology we use depends largely on the use to which we will put it. Solubility of substance is defined as the amount of solute dissolved in a specific amount of solvent at specific temperature. The British Pharmacopoeia and other official chemical and pharmaceutical compendia frequently use the term parts per parts of solvent (for example, parts per million, ppm). The expressions ‘insoluble’, ‘very highly soluble’ and ‘soluble’ also can be used to express solubility of solutes but being inaccurate often not found to be helpful. For quantitative work specific concentration terms must be used. Most substances have at least some degree of solubility in water and while they may appear to be ‘insoluble’ by a qualitative test, their solubility can be measured and quoted precisely. In aqueous media at pH 10, chlorpromazine base has a
solubility of 8 × 10−6 mol/dm3. It is very slightly soluble and it might be considered as ‘insoluble’ upon visual inspection due to lack of disappearance of solid. In many solutions the concentration has a maximum limit that depends on various factors, such as temperature, pressure, and the nature of the solvent. Relative concentrations of a solute/solvent system can often be expressed by the terms dilute and concentrated, or by the terms unsaturated, saturated, and supersaturated. Solutes in water are often categorized as either strong electrolytes, if completely ionized in water or weak electrolytes, if only partially ionized or non-electrolytes when non-ionized. In regard to solubility, general terms can be used when describing whether a compound is soluble or not. These terms are given in and are based on the part of solvent needed to dissolve 1 part of the solute for example, testosterone is considered insoluble in water but soluble in alcohol, ether or other organic solvents. Fortunately, when injected to body, insoluble testosterone is diluted and the larger volume of body water permits testosterone to go into solution.
Solubility of Drugs Introduction Solubility Expressions Mechanisms of Solute Solvent Interactions Ideal Solubility Parameters Solvation Association Quantitatve Approach to the Factors Influencing Solubility of Drugs Diffusion Principles in Biological Systems Solubility of Gas in Liquids Solubility of Liquids in Liquids Binary Solutions Ideal Solutions Raoult’s Law Real Solutions Partially Miscible Liquids Critical Solution temperature and its Applications Distribution Law Limitations of Distribution Law Applications of Distribution Law
1. Define solubility and give general principles of solubility.
2. Define following terms.
(a) Solubility parameter (b) Tie line
(c) Insolubility (d) Saturated solution
(e) Solute (f) Solvent
(g) Supersaturated solution (h) Saturated solution
(i) Dilute solution (j) Concentrated solution
(k) Apparent solubility (l) Conjugate temperature
(m) Blending (n) Intrinsic solubility
(o) True partition coefficient (p) Critical solution temperature
(q) Ideal solution (r) Real solution.
3. What is a solution? List the multitude of solution types that exist. Give some examples of
pharmaceutical solutions.
4. Classify solutions on the basis of concentration of solutes.
5. Distinguish between solutes, solvents, and solutions.
6. Differentiate between solutions and colloids.
7. Explain solubility in ideal and real solutions.
8. Explain principle of solubility with example using dissolution process.
9. Describe in detail energetics of solubility.
10. Explain mechanisms of solvent actions for solubility.
11. Write notes on
(a) Miscibility of liquids (c) Nernst distribution law
(b) Partition coefficient (d) Solubility of electrolytes
12. Explain factors affecting solubility of gases in liquids.
13. Explain the temperature dependence of gas solubility in liquid solutions.
14. Describe relationship between dielectric constant and solubility.
15. Describe preparation of saturated solution for determination of solubility.
16. Describe analysis of saturated solution to determine solubility of solids.
17. The pharmacist must take precautionary measures to avoid the inappropriate findings
while determining solubility of solids in liquids’. Explain this statement.
18. Enlist factors affecting solubility of solids in liquids.
19. ‘Although in many cases solubility increases with the rise in temperature and decreases
with the fall of temperature but it is not necessary in all cases’. Explain with suitable
examples.
20. What is solubility curve? Explain continuous and discontinuous solubility curves with
suitable examples.
21. What is importance of solubility enhancement? Explain different methods for the same.
22. Explain Raoult’s law. Give its limitations.
23 Solubility of majority of the drugs in water is influenced by the pH of the system. Explain
with suitable example.
24. Altering chemical structure of the molecule changes solubility of solute in the same
solvent. Explain.
25. Define partition coefficient. Deduce partition law thermodynamically. Give some
examples or partition coefficient of drugs with respective solvent systems.
26. Explain partition coefficient of ionizable solute in solvent system.
27. What are limitations of distribution law?
28. Enlist conditions essential for partition coefficient.
29. How partition coefficient help to determine equilibrium constant of a chemical reaction?
30. Enlist and explain in brief pharmaceutical applications of partition coefficient.
31. A 100 mg of a non-polar drug X (mol. weight = 510) was shaken with 100 mL of 1 : 1 v/v of octanol/water mixture for a K-value determination. The concentration of the drug in the aqueous layers was found to be 5.2 × 10−4 M. Calculate,
(a) The partition coefficient P of the drug.
(b) log K
(c) K’
(d) Will the partition coefficient change if the pH of the aqueous layer is changed?
32. The log K value of the Sulindac was experimentally determined to be 3.34. Calculate K’ of
the drug at pH 4.9 assuming that pKa = 3.88.
