Once the dosage form reaches the absorption site, it must disintegrate, deaggregate and release its therapeutic agent. The lack of ability of a drug to go into solution is sometimes a more important limitation to its overall rate of absorption than its ability to permeate the intestinal mucosa. For many drugs that cross the intestinal mucosa easily, the onset of drug levels will be dictated by the time required for the dosage form to release its contents, and for the drug to dissolve.
There are many physicochemical and physiological factors which can have a great influence on the dissolution rate. These are:
Particle Size
An important factor determining the dissolution rate is the particle size of the drug. The dissolution rate is directly proportional to the effective surface area of the drug, which may be increased by physically reducing the particle size.
Faster initial dissolution rates obtained by grinding or milling the drug can often be attributed to both an increase in the surface area as well as changes in surface morphology that lead to a higher surface free energy.
However, an increase in edges, corners defects and irregularities on the surfaces of coarse grade drug particles can also influence the effective hydrodynamic boundary layer, and hence the dissolution rate. Micronization to particle sizes of about 3–5 μm is often a successful strategy for enhancing the dissolution rate of poorly water-soluble drugs.
Deaggregation
The rate of disintegration of the dosage form and the size of the resulting aggregates can be the rate-limiting factors step in the dissolution process. Hence, deaggregation is often a prerequisite for dissolution. The formulation that deaggregates rapidly results a larger surface area forms has particles of exposed to dissolution medium.
Manufacturing Processes
Various manufacturing processes can affect dissolution by altering the effective surface area of the drug particles either by addition of hydrophilic diluents or surface-active agents.
Granulation
In terms of achieving higher dissolution rates, wet granulation is considered superior to dry granulation and direct compression procedures. Wet granulation imparts hydrophilic properties to the surface of the granules, and thus improves the dissolution rates of poorly-soluble drugs. Additionally, the use of hydrophilic fillers and diluents such as starch, lactose and microcrystalline cellulose tends to improve the dissolution of the active ingredients.
Compression Force
The high compression force results in an increase in the inter particle bonding, density and hardness, decrease in solvent permeability and inhibition of wettability of the tablet due to the formation of a firmer and more effective sealing layer by the lubricant under the high pressure and temperature generated during compression. All these effects, due to high compression force, decrease the dissolution rate.
Formulation Ingredients
It has been shown that the dissolution rate of a pure drug can be altered significantly when mixed with various excipients that are added to satisfy certain pharmaceutical functions, such as diluents (fillers), dyes, binders, granulating agents, disintegrants and lubricants. Generally, identical tablet and capsule products manufactured by different pharmaceutical manufacturers, are found to exhibit significant differences in dissolution rates of their active ingredients.
Several studies have shown that poor tablet and capsule formulations cause a marked decrease in bioavailability and impairment of the clinical response. Such findings, especially for life-saving drugs like digoxin and tolbutamide tablets, as well as for chloramphenicol and tetracycline were the triggering factors that compelled the drug regulatory and compendial agencies to institute the dissolution test as a legal requirement for most solid dosage forms.
Granulating Agents and Binders
Tablets granulated with gelatin solution provide a faster dissolution rate in gastric fluid than those prepared using sodium carboxymethylcellulose or polyethylene glycol (PEG) 6,000 as a binder.This observation is attributed to the fact that gelatin imparts hydrophilic characteristics to the hydrophobic drug surface and decreases contact, whereas sodium Carboxymethylcellulose is converted to its less soluble acid form at low pH of the gastric fluid, and PEG 6000 forms a poorly-soluble complex.
Even gelatin obtained from various processes and from different origins, has been shown to affect the dissolution rate of dosage forms.
Disintegrating Agents
The type and amount of disintegrating agents employed in a formulation significantly control the overall dissolution profile of dosage form. Increasing the starch content from 2% to 5% results in a three-fold increase in the dissolution rate.
The effect of starch depends on its swelling characteristics when it comes in contact with water, which results in better and quick disintegration. Another disintegrant, Primojel is found to be ineffective, particularly if added after granulation.
Lubricating Agents
Lubricating agents are often added so that the powder mass does not stick to the processing machinery. The nature, quality and quantity of lubricants added can affect the dissolution rate. The effect of lubricants on the dissolution rate of salicylic acid tablet has been studied and it has been concluded that magnesium stearate, a hydrophobic lubricant, tends to retard the dissolution rate, whereas sodium lauryl sulfate enhances it, due to the hydrophobic character and surface activity, of the latter which increases wetting and better solvent penetration into the tablets.
Effect of lubricants on the dissolution rate of drugs from dosage form would also depend on properties of granules, the lubricant itself and the amount of lubricant used. If granules are fast disintegrating and hydrophilic, a water-soluble surface active lubricant will have an insignificant effect on dissolution. Most lubricants, such as magnesium stearate, aluminum stearate, stearic acid and talc, are hydrophobic.
They decrease the effective drug-solvent interfacial area by changing the surface characteristics of the tablets, which results in reduction of its wettability, prolongation of its disintegration time, and decrease the rate of dissolution.
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