Intrinsic Dissolution Testing Is Here， Are You Ready?

For the new inherent dissolution testing, we find ourselves both familiar and unfamiliar. We are familiar with it because it falls within the realm of dissolution, yet unfamiliar due to its differences from traditional dissolution testing. Next, let me guide you through understanding inherent dissolution.

1. Concept of Inherent Dissolution Rate

The inherent dissolution rate refers to the rate at which a pure solid substance dissolves under conditions of constant surface area. It is expressed as the amount of substance dissolved per unit time per unit area, typically in milligrams per minute per square centimeter (mg•min⁻¹•cm⁻²).

Inherent dissolution is an important parameter of the physicochemical properties of a drug, representing the drug's intrinsic dissolution characteristics.

In contrast, dissolution rate refers to the rate and extent to which an active drug is released from conventional dosage forms like tablets, capsules, or granules under specified conditions, usually expressed as a percentage (%).

Dissolution rate is influenced by excipients, formulation type, manufacturing process, purity, and medium, and does not reflect the intrinsic properties of the drug itself.

Therefore, compared to traditional dissolution, inherent dissolution differs not only in the subject of study but also in its method of calculation.

2. Significance of Intrinsic Dissolution Study

So why study the intrinsic dissolution of drugs? The reasons can be summarized as follows:

1. Intrinsic dissolution can to some extent reflect the purity of the drug.

2. It is used to evaluate the consistency of active pharmaceutical ingredients from different sources, batches, different crystallization conditions, or different crystal forms.

3. It is used to investigate the effects of factors such as different salt bases, crystal forms, particle sizes, surfactants, and pH values on dissolution.

4. It can predict to some extent the dissolution behavior of drug formulations, thereby predicting the bioavailability and efficacy of the drug.

Therefore, the intrinsic dissolution rate of drugs can provide data support for the evaluation of the quality of active pharmaceutical ingredients and the selection of production processes, and provide guidance for the selection of drug dosage forms and the design of prescriptions.

III. Regulations Related to Intrinsic Dissolution

The United States Pharmacopeia (USP) includes the rotating disk method and the fixed disk method, and specifies the test methods, experimental apparatus, experimental parameters, and data processing methods, including parameters for drug tabletting, sample positioning, paddle positioning, and stirring speed range.

The European Pharmacopoeia (EP) 9.0 only includes the rotating disk method, and does not provide recommendations or requirements for rotation speed.

Since the first publication of the "Guiding Principles for Intrinsic Dissolution Determination" in China in April 2023, it has not been formally implemented. Its content refers to the US Pharmacopeia. Next, we will roughly understand the instrument setup based on the content included in the guidance:

Method I (Rotating Disk Method)

Except for replacing the basket shaft-rotating basket assembly with a mold-shaft assembly, the other apparatus and requirements are the same as those for the dissolution and release test method (General Chapter <711>).

The tabletting device for the rotating disk method is composed of a punch and die made of hard steel. The bottom of the die has three threaded holes for connecting a polishing steel bottom plate, which makes the pressed tablets have a mirror-like smooth surface. The die contains a cavity (diameter approximately 0.2~1.0 cm) for holding the pre-weighed sample. After loading the sample, insert the punch into the die cavity and press the tablets. There is a hole at the top of the punch for easy insertion of a rod after the test to remove the punch from the die. Finally, a single-sided pressed tablet with a certain surface area can be produced at the bottom of the die. The top of the die has threads for connection to the shaft. Schematic diagrams of the tabletting device and mold-shaft assembly in the rotating disk method in the dissolution cup are shown in Figure 1.

Figure 1: Schematic Diagram of the Tabletting Device and Mold-Shaft Assembly for the Rotating Disk Method in the Dissolution Cup 

From the description of the rotating disk method apparatus, we can highlight several key points:

a) The surface of the compressed sample tablet should be smooth.

b) The inner diameter of the mold should be 0.2~1.0 cm.

c) The sample should be weighed.

Method II (Fixed Disk Method)

A schematic diagram of the tabletting device and mold-shaft assembly for the fixed disk method in the dissolution cup is shown in Figure 2.

Figure 2: Schematic Diagram of the Tabletting Device and Fixed Disk Assembly for the Fixed Disk Method in the Dissolution Cup

The principles of the fixed disk method and the rotating disk method are the same, but there are a few differences in the apparatus:

a) The placement position of the drug mold is different.b) The shape of the dissolution cup is different.c) The source of the dissolution surface liquid flow is different. In the rotating disk method, the liquid flow is driven by the rotation of the mold, while in the fixed disk method, the liquid flow is driven by the rotation of the paddle or other stirring devices.

IV. Factors Affecting Intrinsic Dissolution

1. Contact Area with the Solvent

The first method for intrinsic dissolution specifies that the diameter of the cavity inside the mold should be approximately 0.2~1.0 cm. This size, along with the instrument's rotation speed, determines the duration from the start to the end of the experiment. Regulations state that the entire validation process should ensure coverage of at least five sampling points. Therefore, choosing an appropriate diameter for the mold is our primary consideration:

• 1) If the diameter is too large, some samples may experience tablet collapse (non-disintegration) during the dissolution process.
• 2) If the diameter is too small, the dissolution rate will be relatively slow and more susceptible to external factors such as bubbles.

 Copley DSi Series Dissolution Tester Intrinsic Dissolution Punch and Die Set (Diameter 7 mm) 

On the other hand, after the sample is compressed into a tablet in the mold, it has two surfaces: one in contact with the solvent and the other needing to be sealed off from the solvent by a sealing gasket/silicone pad.

2. Punch Pressure and Time

The first step of intrinsic dissolution testing is to compress the sample into tablets. The density of the tablet greatly affects its dissolution rate, and this density is influenced by the pressure applied during tabletting. Therefore, it is best to ensure consistent tabletting pressure and time.

3. Amount of Sample

For those familiar with infrared spectroscopy, it's known that the addition of KBr and sample can affect the thickness and transmittance of pressed pellets. Similarly, for intrinsic dissolution sample tablets, this issue exists as well. In our experiments, it's best to ensure consistent and sufficient sample amounts for parallel samples to maintain consistency among samples.

4. Number of Parallel Samples

Given that the reproducibility of sample tabletting is not always optimal, it's preferable to conduct multiple parallel samples (at least three) simultaneously when studying the intrinsic dissolution of samples to quickly and accurately identify their dissolution characteristics. Copley's intrinsic dissolution testing protocol allows for testing of 6-8 parallel samples simultaneously.

5. Sampling Volume

Automated sampling is crucial for multi-sampling dissolution experiments because the accuracy of sampling and replenishment directly affects the sample concentration for subsequent sampling. The DissoMate AS series dissolution autosampler introduced by YMX Technology, with its precise sampling advantages (1 mL: ±0.007; 5 mL: ±0.03; 10 mL: ±0.05) and features like needle tracking, dual-pump drive, and adaptive sampling speed, is perfectly tailored for intrinsic dissolution testing.

Copley DiS800i Dissolution Tester + Welch DissoMate AS Dissolution Autosampler (Copley DiS800i Dissolution Tester is only available for sale in Hong Kong, Macau, and Taiwan regions).

Of course, in addition to the above, factors such as temperature and stirring speed in traditional dissolution methods also have an impact on intrinsic dissolution. Everyone should also pay attention to these factors in future experiments.