Dissolution Method Development Process
Development of an appropriate dissolution method for quality control purposes requires consideration of many factors and a balance of different needs. The method is typically distinctive to each drug product because of the unique characteristics of the active ingredient, the formulation, and the manufacturing process.
Dissolution testing of solid oral dosage forms has been used for several decades to aid in formulation/ process development and to examine and assure batch-to-batch quality, consistency, and performance of drug products . The USP General Chapter <1092> The Dissolution Procedure: Development and Validation has useful explanations on the development aspects. USP General Chapter <711> Dissolution has the specifics for dissolution testing methodology.
A dissolution method development process is described below:
1. Solubility Based on BCS
The most important data set for dissolution method development is the solubility–pH profile. The solubility profile will indicate whether the compound is considered a highly soluble compound based on the BCS. If the highest proposed strength dosage dissolves in 250 mL of media over the pH range 1–6.8 according to the EMA guidance or pH 1–7.5 according to the United States FDA guidance, then it is considered a highly soluble compound.
If the compound is highly soluble, dissolution profiles should be established using 900 mL of 0.1 N HCl, pH 4.5, and pH 6.8 media, with typically USP Apparatus 2 (paddles) at 50 rpm. The medium that produces the slowest dissolution rate with a standard spindle speed should be selected for the method. A slower dissolution rate will increase the likelihood that the method might be able to discriminate formulation composition, manufacturing process variations, or pharmacokinetics performance. Lastly, the appropriate medium selection would make the method suitable for determining whether the dosage form still would meet BCS Class 3, Class 1, or both criteria for a highly soluble compound over the shelf-life.
2. Apparatus
For immediate-release solid oral dosage forms, USP Apparatus 1 (Basket) or Apparatus 2 (paddle) are typically used. The other USP dissolution apparatus are typically used for controlled-release or non-oral formulations.If an early dosage form (e.g., capsules) floats, the use of a sinker around the capsule should be considered to allow a paddle method to be used.
3. Spindle Speed
With the paddle apparatus, a 50-rpm spindle speed should be used as the starting point based on regulatory guidance from FDA, the European Medicines Agency (EMA), and the Japanese Pharmaceutical and Food Safety Bureau (PFSB). If there are issues with coning (the piling of non-dissolving excipients under the paddle that limits media penetration into the pile), the use of paddles with a 75-rpm spindle speed should be investigated. The FDA and PFSB recommend a 75-rpm paddle as an option.
4. Media and Buffers
The type of medium and the volume are selected to provide sink conditions. USP defines sink condition as “the volume of medium at least three times that required in order to form a saturated solution of drug substance”.
The general pH range of dissolution media is from 1.1 to 6.8. The pH can be higher if needed for solubility reasons. In general, the pH should not exceed 8.0. A medium is chosen based on the desired pH, for example, hydrochloric acid for pH 1.0–3.0, glycine for pH 2.0– 3.0, citrate for pH 2.5–3.5, acetate for pH 4.0–5.5, and phosphate pH 6.0–8.0. These stated buffer pH ranges are by no means limitations.
If the medium over the pH range fails to give adequate dissolution, then surfactants should be evaluated. The first choice for a surfactant is sodium dodecyl sulfate (SDS).
The concentration of the surfactant used for dissolution test should be justified. Typically the lowest concentration required to achieve an acceptable dissolution profile should be used. An SDS concentration range of 0.1–3% or higher has been used. If SDS at a previously approved concentration does not yield at least 85% dissolved by 60 min or interacts with the active/excipients, other surfactants listed on this FDA Web site should be examined.
The effect of medium deaeration should be investigated. When the medium is heated, the dissolved gases have a tendency to form bubbles. These bubbles could have an unpredictable effect on dissolution. The bubbles may cause a dosage form to adhere to the apparatus/vessel, reduce medium access to particles, or increase the tendency for particles to float.
5. Medium Volume
The standard dissolution medium volumes used in the industry and accepted by regulatory agencies are 500 mL and 900 mL.
6. Sampling Time Points
Sampling time points generally range from 5 min to more than 60 min. Typical time points are 15, 30, 45, and 60 min. However, the time points are based on the product’s profile and on the method’s ability of tracking key aspects of the formulation. If there is a desire to better understand or track the disintegration effect, a 5- or 10-min time point would be needed. If there is a significant risk of slowing on stability, a time point may be added beyond 60 min to ensure that at least 85% dissolved average values are achieved.
It is useful to have a sampling time point at 15 min, especially if the compound is dissolved at least 85% within that period of time.
7. Sinkers
As mentioned previously, sinkers can be utilized on capsules to allow use of the USP 2 Apparatus. Sinkers may also aid in other situations, such as sticky tablets or slowly disintegrating tablets. Tablets sticking to vessels may result in high variability in dissolution profiles because they may stick at various off-center locations in the vessels. The non-centered tablets are exposed to a different hydrodynamic environment than those that are centered.
Read also:
- Understanding the Q Value in Dissolution Testing
- Factors Affecting Dissolution of Pharmaceutical Products
Resource Person: Nora Haddouche