Pharmaceutical Dosage Forms and Coarse Dispersions

Coarse Dispersions

• Coarse dispersions are heterogeneous mixtures with dispersed particles larger than 1000nm.
• These particles settle rapidly due to gravity or other forces.
• Dispersed phases in coarse dispersions can be easily separated from the continuous phase through filtration.

Pharmaceutical Dosage Forms

• Aqueous solutions containing sugar are classified as syrups.
• Sweetened hydroalcoholic solutions are termed elixirs.
• Solutions of aromatic materials are called spirits if the solvent is alcohol and aromatic waters if the solvent is aqueous.
• Solutions prepared by extracting active constituents from crude drugs are termed tinctures or fluid extracts, depending on their preparation and concentration.
• Tinctures can also be solutions of chemical substances dissolved in alcohol or hydroalcoholic solvents.
• Sterile and pyrogen-free solutions intended for parenteral administration are classified as injections.

Advantages of Suspensions Over Solutions

• Suspensions can provide increased stability for the drug.
• They allow for altering the taste of the drug.
• A larger quantity of the drug can be present in the dispersed form, preventing precipitation.

Solutes in Pharmaceutical Solutions

• Solutes other than the medicinal agent are often included in orally administered solutions.
• These additives provide color, flavor, sweetness, or stability.

Formulation Considerations for Solutions

• Pharmacists must consider the solubility and stability of each solute in the chosen solvent or solvent system when formulating or compounding pharmaceutical solutions.

Solutions: One-Phase Systems

• Solutions are one-phase systems consisting of two or more substances.
• The addition of sucrose to water creates a single-phase system, resulting in a true solution, which is physically homogenous.
• Solutions can be solid, liquid (most commonly used by pharmacists), or gas.

Liquid Solutions

• The solvent in a liquid solution is a liquid, while the solute can be liquid, solid, or gas.
• If water is a component of the system, it is considered the solvent.
• The larger component is usually the solvent, however, when a solid is dissolved in a liquid, the solid is the solute and the liquid is the solvent regardless of the proportion.

True Solutions

• True solutions are a type of dispersion (molecular dispersion) where the particle size is less than 1nm.

Types of Solutions

• Liquid in liquid:
  • Two liquids, like water/alcohol, water/glycerin, and water/acetone, form homogenous mixtures regardless of proportions. These liquids are called miscible.
  • Liquefied phenol/water or ether/water form homogenous systems only when mixed in specific proportions. Such liquids are said to be miscible in specific proportions.
  • Water/mineral oil are insoluble in each other in any proportion, making them immiscible.
• Gas in liquid:
  • The solubility of gas in liquid is described by Henry's Law, which states that the solubility of a gas is directly proportional to the pressure at a constant temperature, provided the gas is only slightly soluble.
  • The high solubility of certain gases, like ammonia and hydrogen chloride, may be due to chemical reactions between the gas and solvent or cohesive influences exerted by the molecules. Increasing pressure has a minimal effect on their solubility.
  • Increasing temperature decreases the solubility of gases. For example, CO2 is twice as soluble at 0°C compared to 20°C. Gaseous solutions should be stored in a cool place (refrigerator).
  • Containers holding strong ammonia solutions should be cooled before opening to reduce gas liberation and expansion, as the solubility of gases increases with cooling.
  • Adding a salt to a liquid containing a dissolved gas can cause gas liberation due to the decrease in solubility. This is referred to as "salting out" of the gas.
• Solid in liquid:
  • Most true solutions are examples of solid in liquid solutions.

Solubility

• Solubility refers to the maximum concentration a solution can achieve with a specific agent and solvent at a given temperature.
• A solvent is said to be saturated when it has dissolved all possible solute at a given temperature.
• When excess solid (solute) is shaken with liquid (solvent) for a period, a maximum amount will dissolve, resulting in a saturated solution at that temperature.
• Adding excess solute to a saturated solution and increasing the temperature will lead to further solute dissolution.
• If such a solution is filtered and cooled to the original temperature, it often retains the extra solute dissolved at higher temperatures. This resulting solution is called a supersaturated solution (e.g., Na thiosulfate and K acetate solutions).

Factors Affecting Solubility

• Temperature:
  • Solids are generally more soluble in hot water than cold water.
  • There are three cases for the solution process:
    • Endothermic reaction: Increased temperature leads to increased solubility.
    • Exothermic reaction: Increased temperature leads to decreased solubility, e.g., methyl cellulose and Ca salts are more soluble in cold water than hot water. Solutions of methyl cellulose become cloudy when heated and form a flaky precipitate that redissolves as the solution cools.
    • When heat is neither absorbed nor released during the solution process: Increases or decreases in temperature have no effect on solubility, e.g., NaCl has the same solubility in water at 25 °C and boiling water.
• Rate of Solution:
  • The rate of solution is the speed at which the solute dissolves, measured in units of concentration/time (mg/ml/min).
  • Factors affecting the rate of solution:
    • Particle size of the solute: Reducing particle size increases the surface area and the rate of solution. (1/particle size ∝ surface area). The finer the powder, the greater the surface area in contact with the solvent, leading to faster dissolving.
    • Agitation: Increasing agitation increases the rate of solution by removing more concentrated solution from the solute surface and bringing fresh, less concentrated solvent. Agitation reduces the thickness of the stagnant layer, increasing solvent penetration and solubility.
    • Heating: Increases the frequency of solvent molecule collisions with the dissolving material's surface, increasing solubility.
• Effect of Molecular Structure:
  • The more similar the molecular structures of solute and solvent, the greater the solubility of one in the other.
  • Solubility in water is related to the dipolar nature of the water molecule:
    • Water molecules are described as polar structures with strong dipole characteristics (negative and positive regions).
    • Molecules with dipoles tend to form groups and associate with other polar substances. This attraction in water molecules is through hydrogen bonding.
  • Polar solvents like water dissolve salts and other electrolytes readily, making them poor solvents for non-polar substances.
  • Polar liquids can act as solvents when they can form complexes with the solute through hydrogen bonding (e.g., water and low molecular weight alcohols).
  • As the molecular weight of alcohols increases, polarity decreases, leading to decreased solubility in water.
  • Carbon tetrachloride (CCl4) is non-polar. It cannot solvate salt ions like NaCl since it doesn't provide the attractive force (solvent force) required to overcome the forces holding the ions of the salt together. Therefore, non-polar liquids do not dissolve polar or slightly polar substances.
  • Ethyl alcohol molecules have:
    • 5 non-polar carbon-hydrogen bonds
    • 1 C-C bond (non-polar)
    • C-O bond & H-O bond (polar)
  • Ethyl alcohol is considered a good solvent for some polar and non-polar substances due to the presence of distinct polar and non-polar regions.
  • While there are exceptions to any specific rules for solvent selection, the following generalizations can be helpful in predicting solubilities:
    • Solvents and solutes with similar structures dissolve more readily.
    • Polar liquids dissolve electrovalent compounds readily but are poor solvents for non-polar substances. Non-polar liquids are required for non-polar solutes.
    • Polar liquids should be miscible with other polar liquids. Conversely, non-polar liquids dissolve only slightly in polar solvents but readily dissolve in non-polar solvents.
    • Complex organic compounds with both polar and non-polar groups in their molecules can dissolve in polar liquids, but their solubility decreases proportionally to the number of non-polar groups.
    • Semi-polar liquids like ethyl alcohol exhibit properties of both polar and non-polar solvents.
• Effect of pH on Solubility:
  • Organic substances are either weak acids or weak bases. Their aqueous solubility is dependent on the pH of the solvent.
  • These substances dissociate slightly, and the undissociated forms are slightly soluble in water.
  • Within a specific pH range, they exist in ionic or dissociated forms, which are very soluble in water.
  • The solubility of weak organic acids like barbiturates and sulfonamides in water increases with increased pH (addition of base) due to the formation of water-soluble salts.
  • For example, Phenobarbital (free acid) has a solubility of 1.25 g/1000 mL in water at 25 °C with a pH of 5.5. Phenobarbital sodium (salt) has a solubility of 1000 g/1000 mL in water at 25 °C with a pH of 9.3. Therefore:
    • Increasing the pH of a Phenobarbital solution above 5.5 by adding a strong base increases the solubility.
    • Decreasing the pH of a Phenobarbital solution by adding a strong acid leads to the precipitation of Phenobarbital (free acid).
  • The solubility of weak organic bases (alkaloids and local anesthetics) in water increases with decreased pH (addition of acid) due to the formation of water-soluble salts.
  • For example:
    • Temperature | Solubility | pH
    • Atropine (free base) | 25 °C | 2.2 g/1000 mL | >10
    • Atropine Sulfate (Salt) | 25 °C | 2500 g/1000 mL | 5.4
  • Increasing the pH of an aqueous solution of the salt by adding a base leads to the precipitation of atropine (free base).
  • At a given pH, the degree of ionization of a weakly acidic or basic drug depends on its pKa value, which is the negative logarithm of its dissociation constant.
  • For weak acidic drugs:
    • pH = pKa + Log ( (S - So) / So )
    • S = molar concentration of the drug (dissociated and undissociated) species in solution.

This quiz covers the properties and classifications of coarse dispersions and various pharmaceutical dosage forms. It includes information on syrups, elixirs, spirits, tinctures, and injectable solutions. Test your knowledge on the characteristics and advantages of suspensions over solutions in the pharmaceutical context.