Important Note
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When dissolution conditions are modified, (such as a change in the spindle speed or a change in temperature or volume of dissolution media) it will invariably result in a change in the volume of the dissolution rate constant.
Features of Dissolution Testing
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Features of dissolution testing are listed below.

Click the numbered buttons for further information about each of the features.

  • 1Requirements
  • 2Apparatus
  • 3Importance
  • 4Recommendations
  • 5Medium
  • 6Industry Guidance
  • 7Solubility
Requirements

The Dissolution profiles of at least 12 individual dosage units from each batch must be determined. There must be a suitable distribution of sampling points to adequately define the profile. The coefficient of variation (CV) for mean dissolution of a single batch should be less than 10%.

Apparatus

It is expected that USP Apparatus 1 (basket) and USP Apparatus 2 (paddle) will be used at compendially recognized rotation speeds; 100 rpm for the basket and 50 - 75 rpm for the paddle.
In other cases, dissolution properties of some modified release formulations may be determined with USP Apparatus 3 or 4.

Importance

Dissolution testing is now indispensible in industry for the following reasons.

  • Dissolution testing provides neccessary QA
  • It provides quality control testing for the manufacturing process and determines stability of relevant characteristics of the product
  • It serves as an indica tor of how well a formulation will perform in vivo
  • IVIVC empowers the dissolution test to serve as a surrogate marker for human bioequivalence studies
  • Dissolution testing minimizes the number of human studies needed for approving and maintaining a drug product on the market
  • It reduces the time and cost of drug development by reducing the number of studies required to demonstrate adequate bioavailability
  • Dissolution testing facilitates initial approval as well as scale-up and post approval changes
  • Dissolution testing develops dissolution specifications based on the performance of the bio/clinical lots
Recommendations

Consult the Office of Pharmaceutical Sciences (OPS) prior to the use of any other type of apparatus.

Medium

In vitro testing requires an initial aqueous medium, either water or a buffered solution preferably not exceeding pH 7.4. Sufficient data should be submitted to justify pH greater than 7.4.

Industry Guidance

Industry guidance is available including:

  • Immediate and Extended Release Scale-Up and Post Approval Change (SUPAC)
  • Chemistry Manufacturing Controls Coordinating Committee (CMCCC) of the Center for Drug Evaluation and Research at the Food and Drug Administration

Solubility

Poorly soluble drugs may need the addition of a surfactant (~1% sodium lauryl sulphate) to dissolve entirely. However, nonaqueous and hydro-alcoholic systems are widely discouraged unless all attempts with aqueous media are unsuccessful. In this case, the CDER (FDA Center for Drug Evaluation and Research) should be consulted.

In Vitro Dissolution Rate Testing

Dissolution testing was first introduced in the early 1960s as the problems associated with the biological availability of drugs became more apparent. Bioavailability rate testing in industry became increasingly widespread as a means of distinguishing between two competitive drugs that were otherwise pharmaceutically identical in their physical properties, according to all other tests at that time.

Features of Dissolution Testing

Intrinsic dissolution rate is described as the time taken to dissolve a specified mass of Active Pharmaceutical Ingredient (API) with a constant surface area in a solvent. It is characteristic of each solid compound in a given solvent under fixed experimental conditions and is useful in predicting probable bioavailability problems due to dissolution rate.

The value is generally expressed as mg/min/cm². Intrinsic rates of 1.0 mg/min/cm² have negligible problems with dissolution rate limitations.

However, rates of less than 0.1mg/min/cm² suggest that the drug is dissolution rate limited.

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Show Anatomy of Apparatus

Particulate dissolution rate is measured by observing the time taken for a suspension of the API to dissolve in a fixed amount of solvent without fixed control of the dose surface area. It is used to study the influence of particle size, surface area and excipients upon the active agent.

Particulate dissolution rate is used, along with intrinsic dissolution, to measure the dissolution rates of chemical compounds. Typically, a weighed amount of powdered sample is added to the dissolution medium in a constant agitation system.

Note
Noyes and Whitney Equation (1897)

Modified Wood's Apparatus

Longitudinal Section

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Note

Equations

This is the first fundamental equation established by Noyes and Whitney to determine the rate of dissolution. The dissolution constant is unique for each material under test and can be determined by measuring the dissolution rate of the material in a defined solvent while keeping the surface area of the material constant at a fixed temperature.

Equations

Brunner and Tollockzo modified the Noyes and Whitney equation to predict the dissolution rate constant under sink conditions when the volume and surface area is kept constant. Sink conditions can be approximated by keeping the volume of the solvent five to ten times larger than the saturation volume of the medium. They are one of the main experimental parameters that need to be controlled during dissolution testing.

Equations

Nernst and Brunner slightly modified the Brunner and Tollockzo Equation to produce a more comprehensive description of the relationship. The elements that comprise the equation can be varied by a number of different external factors (eg. paddle speed, temperature and vibration). Slight changes in any of these factors can actually change the rate at which the product passes into solution.