Pharmacology Chapter on Oral Drug Absorption

Oral route is the preferred way of dosing because it is the easiest and most convenient way of noninvasive administration.
For an orally administered drug to exert its effect systematically, it has to become bioavailable (i.e. available at the site of action). This means that the drug has to permeate through the GI mucosal membrane into the general circulation.
The availability of a drug in the body depends on its ability to dissolve in the gastrointestinal (GI) fluids.
The solubility of a drug in the GI fluids is affected by both physiological and physicochemical factors.
The Biopharmaceutics Classification System (BCS) combines physicochemical properties of compounds and physiological factors to predict the fraction dose absorbed from the gastrointestinal transit.
The permeability of a given drug determines the upper limit of its extent of absorption.
A change in the solubility/dissolution properties of a drug/formula may significantly affect its biological availability.

### Dissolution Testing of Immediate Release Products

Dissolution tests are designed to assure the pharmaceutical quality.
The goals of dissolution testing are to ensure the ability to manufacture a drug product reproducibly, ensure that it maintains its release properties throughout the shelf life, and rely on the stability of the biopharmaceutical properties of the dosage form (rate and extent of absorption).
Dissolution testing is important for establishing IVIVC’s (In Vitro In Vivo Correlation).
Dissolution tests are used to predict the in vivo performance of the dosage form, especially important for drugs with slow release from the dosage form, instability in the GIT, poor permeability of the GI mucosa, or extensive first pass metabolism.
Dissolution testing can be used to assess the in vivo performance of the dosage form when the release of the drug is the limiting factor in the absorption process, such as controlled release dosage forms and immediate release dosage forms containing poorly soluble drugs.
Selection of dissolution test media is based on the BCS:
- Class 1: High Solubility - High Permeability
- Class 2: Low Solubility - High Permeability
- Class 3: High Solubility - Low Permeability
- Class 4: Low Solubility - Low Permeability

### Dissolution Testing of Immediate Release Products - Class I Drugs

Class I drugs have good aqueous solubility and easy transport properties through the GI mucosa.
Bioavailability after oral dosing is usually close to 100% provided they are not decomposed in the GI tract and do not undergo extensive first pass metabolism.
Acetaminophen and metoprolol are typical examples of Class I drugs.
The FDA recommends a one point test in a simple medium, with 85% or more of the drug to be released within 30 minutes for immediate release dosage forms of class I drugs.
Simulated gastric fluid without enzymes is the first choice dissolving medium because Class I drugs have high solubility throughout the physiological pH range.
Pepsin can be added to ensure timely dissolution of hard gelatin capsules in some cases.
Simulated intestinal fluid without enzymes can be used for weakly acidic drugs whose dissolution may be hampered by the low pH of the SGF.
Water is unsuitable for Class I drugs due to its nominal buffer capacity.
More complex biorelevant media are not necessary for class I drugs.

Class II drugs are characterized by low solubility but are easily transported across the GI mucosal membrane.
An aqueous solubility less than 100 ug/ml or a dose number more than 1 is often a signal that the dissolution of the drug will control the rate of its introduction to the general circulation.
The FDA uses a D/S value of 250 in the SUPAC guidance as the cutoff value for compounds with good solubility.
Biorelevant media are usually recommended for class II drugs including:
- SGF plus surfactant to simulate a fasted state in the stomach
- Ensure or milk 3.5% fat to simulate a fed state in the stomach
- FaSSIF to simulate a fasted state in the small intestine
- FeSSIF to simulate a fed state in the small intestine
SGF plus surfactant is particularly suitable for weak bases because they are most soluble under acidic conditions.
The surfactant added must be able to reduce the surface tension to an appropriate value (35-40 mNm-1).
The volume of the gastric fluid is an important issue in developing a bio-relevant dissolution testing since the volume of gastric fluid in the fasting state is 30-50 ml.

FaSSIF and FeSSIF are two dissolution media that were developed to simulate the fed and fasting conditions in the intestinal content.
The two media are particularly useful for forecasting the in vivo performance of poorly soluble drugs from different formulations and assessing the food effects on the in vivo dissolution.
They are more suitable for IVIVC than the regular compendial media.
These media are intended for development rather than QC applications.

If the standard curve is in % or mg%, convert it to g/mL or mg/mL.
Convert to the amount dissolved (mg) by multiplying by the volume of the medium.
Calculate the corrected factor by multiplying the sampling volume by the concentration and adding it to the previous corrected factor.
Calculate the total amount dissolved by adding the dissolved amount to the corrected factor.
Calculate the % drug release by dividing the total amount dissolved by the initial amount of drug.

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