f actorS  i nfluencing  D iSSolution  r ate

The main biopharmaceutical and physiological factors that influence the dissolution rate of a drug can be summarized as follows:

1. Drug solubility. Greater the drug solubility, greater the drug’s dissolution rate. This is evident in the Noyes–Whitney equation. The solubility and dissolution rate of acidic drugs is low in acidic gastric fluids, while that of basic drugs is high. Similarly, the solubility and dissolution rate of basic drugs is low in basic intestinal fluids, while that of acidic drugs is high.

2. Viscosity of the dissolving medium. Greater the viscosity of the dissolving liquid, lower the diffusion coefficient of the drug, lower the dissolution rate.

Viscosity of the dissolving bulk medium and/or the unstirred layer on the surface of the dissolving formulation can be affected by the presence of hydrophilic polymers in the formulation, which dissolve to form a viscous solution. In vivo, the viscosity may be affected by the food intake.

3. Diffusion layer thickness. Greater the diffusion layer thickness, slower the dissolution rate. The thickness of the diffusion layer is influenced by the degree of agitation of the dissolving medium both in vitro and in vivo.

Hence, an increase in gastric and/or intestinal motility may increase the dissolution rate of poorly soluble drugs. For example, food and certain drugs can influence gastrointestinal (GI) motility.

4. Sink conditions. Removal rate of dissolved drugs by absorption through the GI mucosa and the GI fluid volume affect drug concentration in the GI tract.

5. pH of the dissolving medium. Drug dissolution rate is determined by the drug solubility in the diffusion layer surrounding each dissolving drug par-ticle. The pH of the diffusion layer has a significant effect on the solubility of a weak electrolyte drug and its subsequent dissolution rate. The disso-lution rate of a weakly acidic drug in GI fluid (pH 1–3) is relatively low because of its low solubility in the diffusion layer. If the pH in the diffusion layer could be increased, the solubility exhibited by the weak acidic drug in this layer (and hence the dissolution rate of the drug in GI fluids) could be increased. The potassium or sodium salt form of the weakly acidic drug has a relatively high solubility at the elevated microenvironmental pH in the diffusion layer due to the strong counterion bases, KOH or NaOH, respec-tively. Thus, the dissolution of the drug particles takes place at a faster rate.

6. Particle size and surface area. An increase in the specific surface area (sur-face area per unit mass) of a drug in contact with GI fluids would increase its dissolution rate. Generally, the smaller a drug’s particle size, the greater its specific surface area, and higher the dissolution rate. However, particle size reduction may not always be helpful in increasing the dissolution rate of a drug, and thus its oral bioavailability. For example:

a. Porosity of drug particles plays a significant role. Thus, smaller par-ticles with lower porosity may have lower surface area compared to larger particles with greater porosity. The dissolution rate depends on the “effective” surface area, which includes the influence of particle porosity.

b. In some cases, particle size reduction may cause particle aggregation, thus reducing the effective surface area. To prevent the formation of aggregates, small drug particles are often dispersed in polyethylene gly-col (PEG), polyvinylpyrrolidone (PVP), dextrose, or surfactants such

46 Pharmaceutical Dosage Forms and Drug Delivery as polysorbates. For example, micronized griseofulvin is dispersed in PEG 4000.

c. Also, certain drugs such as penicillin G and erythromycin are unstable in gastric fluids and do not readily dissolve in them. For such drugs, particle size reduction may increase not only the rate of drug dissolu-tion in gastric fluids, but also the extent of drug degradadissolu-tion.

7. Crystalline structure. Amorphous (noncrystalline) form of a drug may have faster dissolution rate compared to the crystalline forms. Some drugs exist in a number of crystal forms or polymorphs. These different forms may have significantly different drug solubility and dissolution rates.

a. Dissolution rate of a drug from a crystal form is a balance of the energy required to break the intermolecular bonds in the crystal and the energy released upon the formation of the drug–solvent intermolecular bonds.

Thus, stronger crystals may have lower intrinsic dissolution rate.

b. Intrinsic dissolution rate reflects the dissolution rate of a drug crystal or powder normalized for its surface area. It is expressed in terms of mass per unit time per unit surface area. Drug forms that have higher intrinsic dissolution rate are expected to have higher dissolution rates.

c. The greater strength of a crystalline polymorph, sometimes evident by its high melting point, sometimes rank order correlates with its lower intrinsic dissolution rate.

d. Similarly, amorphous solids, which lack a long range order that defines crystalline structure, tend to have higher intrinsic dissolution rates.

8. Temperature. An increase in temperature leads to greater solubility of a solid with positive heat of the solution. Heat of solution indicates release of heat upon dissolving. Positive heat of solution is indicative of greater strength of solute–solvent bonds formed (which release energy) compared to the solute–solute bonds broken (which take in energy). The solid will therefore dissolve at a more rapid rate if the system is heated. Therefore, in vitro dissolution studies are carried out at 37°C, to simulate body tempera-ture and in vivo dissolution condition

9. Surfactants. Surface-active agents increase the dissolution rate by (a) low-ering the interfacial tension, which lowers the contact angle of solvent on the solid surface, increases wetting of the drug particle, and penetra-tion of the solvent inside the dosage form; and (b) increasing the satu-ration solubility of the drug in the dissolution medium. Surfactants such as sodium lauryl sulfate (SLS) and Triton X-100, are frequently used to achieve sink conditions and rapid dissolution during in vitro dissolution method development.

3.4 ABSORPTION

Bioavailability is the fraction of an ingested dose of a drug that is absorbed into the systemic circulation, compared to the same dose of the compound injected intrave-nously—which is directly injected into the systemic circulation. Bioavailability of a drug is determined during new product development.

Bioequivalence, on the other hand, is comparison of relative bioavailability of two dosage forms in terms of the rate and extent of drug levels achieved in the sys-temic circulation, and the maximum drug concentration reached. Generic drugs are required to satisfy statistical criteria of bioequivalence to the branded version before they can be considered equivalent.

In the case of oral dosage forms, drug bioavailability depends on the rate and extent of drug absorption from the GI tract. Drug absorption from the gut depends on many factors, such as the drug’s solubility and intrinsic dissolution rate in the GI fluids, which are influenced by GI pH and motility, and drug’s particle size and surface area. Thus, an interplay of physicochemical properties of drug and physi-ological properties of the GI tract determine the outcome of factors that determine drug absorption.

Drug absorption is affected not only by the properties of drug and its dosage forms, but also by the nature of the biological membranes. Drugs pass through living membranes by (Figure 3.4)

1. Passive diffusion a. Simple diffusion b. Facilitated diffusion

i. Channel-mediated transport ii. Carrier-mediated transport 2. Active transport

Passive diffusion can also be classified as paracellular or transcellular depending on the route of drug absorption across the epithelial cell barrier. The surface lining of the GI tract consists of epithelial cells attached to each other by tight junctions formed through their membranes. Drug transport across the tight junctions between cells is known as paracellular transport. It involves both diffusion and the convective flow

Simple diffusion Cytoplasm Lipid bilayer

Extracellular space

Channel-mediated diffusion

Carrier-mediated diffusion Channel

protein Carrier

protein

Energy

Passive transport

(facilitated diffusion) Active transport Transported molecule

Electrochemical gradient

FIGURE 3.4 An illustration of main transport processes across cellular membranes.

48 Pharmaceutical Dosage Forms and Drug Delivery of water accompanying water-soluble drug molecules. Drug transport by absorption into the epithelial cell from the gut lumen side, followed by release of the drug mol-ecule from the epithelial membrane on the other side of the epithelial cell into the systemic circulation is known as transcellular transport.