Solubility is an essential and extensively studied preformulation parameter. It focuses on drug-solvent system that could occur during drug delivery. Such information is important to the formulator, for it enables him to select the best solvent medium for a drug, identify and overcome certain challenges that arise in the formulation of pharmaceutical solutions, and, furthermore, estimate the level of all known and significant impurities and contaminants in the drug molecule under evaluation.
The solubility of a candidate drug molecule is the amount of the drug (solute) that dissolves in a given solution (solvent) to produce a saturated solution at constant temperature and pressure. A candidate drug molecule, especially drugs for oral administration must possess some aqueous solubility for optimum absorption into the systemic circulation. Poorly soluble drug molecules (less than 10 mg/ml) may dissolve slowly and thus, suffer from bio absorption problems.
- 1 Factors affecting the solubility of candidate drug molecules
- 2 Criteria for solubility determination
- 3 Techniques for solubility enhancement
- 4 Parameters evaluated during solubility analysis.
Factors affecting the solubility of candidate drug molecules
- Molecular structure of solute
- Nature of solvent/ co-solvents
- Crystal characteristics: polymorphism and solvation
- Particle size of the solid
- Complex formation
- Common ion effect
- Effect of indifferent electrolytes on the solubility product
- Effect of electrolytes on the solubility of non-electrolytes
Criteria for solubility determination
- The solute and the solvent must be pure.
- A saturated solution must be obtained before any sample is removed for analysis.
- The method of sample collection must be satisfactory.
- The method of analysis must be reliable.
- Temperature must be properly controlled.
Techniques for solubility enhancement
- Chemical modification of drug molecule
- Addition of surfactant/ solubilizing agent
- Use of co-solvent.
- Ionization and pH optimization/adjustment.
- Particle size reduction
- Temperature change
Parameters evaluated during solubility analysis.
a. Ionization constant/ Drug Pka
Many drugs are either weak acids or weak bases. In Solutions, these drugs equilibria exist between undissociated molecules and their ions depending on the pH value of the containing medium. It is important to fully understand the ionization or dissociation characteristics of drug substances as their absorption is greatly dependent to a large extent on their degrees of ionization. The un-ionized species are more lipid-soluble, and thus are presented and transported across the membrane barriers by passive diffusion unlike the ionized species that are lipid insoluble with slow permeability.
Pka of weakly acidic or basic drug substances in a solution at a given pH can be calculated using the Henderson-Hasselbalch equations:
For acidic drugs:
pH = pKa + log [ionized drug] / [unionized drug].
For basic drugs:
pH = pKa + log [unionized drug] / [ionized drug].
Various analytical techniques, e.g. spectrophotometric determination, potentiometric titration, dissolution rate method and liquid-liquid partition method, may be used to determine ionization constants of a drug molecule, but the temperature at which the determination is performed should be specified because the values of the constants vary with temperature.
b. Partition co-efficient
Partition coefficient (P) also known as distribution coefficient (D), is the ratio of unionized drug distributed between organic (n-octanol) and aqueous (water) phase at equilibrium. Mathematically it is represented as
Po/w = (Conc. of drug in organic phase/ Conc. of drug in water) equilibrium.
Knowledge of how drug substances partition in hydrophilic or lipophilic phase is therefore very useful to the formulator in selecting appropriate extraction solvents, carrying out drug stability studies, absorption of drug from dosage forms (e.g., ointments, suppositories, transdermal patches), measuring the hydrophobic bonding ability of drug substances to serum albumin and also permeation of drug substances across biological membrane etc.
Solubilization is the process by which apparent solubility of an otherwise sparingly soluble substance is increased by incorporation into micelles to form a thermodynamically stable solution. The ability of surfactant solution to dissolve or solubilize water-insoluble or partly soluble substances starts at the critical micelle concentration (CMC) and increases with the increase of the micelles. There is need to fully understand the solubility behavior and possible mechanism for solubilization of a candidate drug molecule over the pH range encountered in the gastrointestinal tract to achieve a stable dosage form with effective absorption and enhanced bioavailability.
d. Thermal effect
The effect of temperature on a candidate drug molecule can be determined by measuring heat of solution. Heat of solution, also known as enthalpy of dissolution or enthalpy of solution, represents the heat released or absorbed when a solute dissolves completely in a large quantity of solvent. This is important as the solubility of a drug substance in a given solvent is influenced by changes in temperature. The heat of solution can either be positive (endothermic) or negative (exothermic) depending on the amount of energy required to break the bonds present in the solutes, as well as, how much energy is generated from the solid-solvent bond formation. Increased drug solubility can be achieved by increasing temperature of solutions with positive heat of solution (endothermic process).
e. Common ion effect (Ksp)
Common ion effect describes the effect on equilibrium that occurs when a common ion i.e., an ion that is already present in a solution is added to the solution. The addition of common ion significantly decreases the solubility of a sparingly soluble electrolyte by shifting the equilibrium towards the reactant and causing the solute to precipitate (salting out). This shift in equilibrium/ salting out, results from the removal of water molecules as solvent owing to the competing hydration of other ions. The reverse process, ‘salting in’, arises with larger anions (hydrotropes) which improves the solubility of poorly water-soluble candidate drug molecules by opening the water structure.
This study enables a preformulation scientist to study the influence of particle size, surface area and excipients on dissolution of candidate drug molecule. It also enables him predict if dissolution would be a rate limiting step in the absorption process of drug substances. Apart from intravenous route which offers direct access of drug substances into the systemic circulation, other routes of drug administration require an absorption step before drugs reach the systemic circulation. The extent to which drug substances are absorbed into systemic circulation depends on their dissolution rates. This is true for oral solid dosage forms (e.g., tablet, capsule, and suspension) as well as those administered intramuscularly in form of pellets or suspension. Dissolution rate also affect the onset and intensity of drug action, the duration of response and controls the overall bioavailability of drug substances.
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