A dissolution analyzer is an instrument used to measure the degree of drug dissolution. It is an effective alternative method for studying and evaluating the bioavailability of drugs in vivo, and an important means of ensuring and measuring the rationality and stability of the manufacturing process and quality of solid oral dosage forms. It replaces the past disintegration time limit test with a scientifically advanced measurement method, thereby improving the scientific nature of drug quality control methods and ensuring the clinical efficacy of drugs.

A dissolution analyzer is an instrument used to measure the drug release rate, commonly used in drug quality control and quality assurance during the manufacturing process. Its working principle is based on simulating the in vivo environment. By immersing drug samples in different media such as simulated gastric juice or intestinal juice, the drug release rate is recorded, thereby evaluating the drug's dissolution characteristics and release kinetic parameters.

Specifically, a dissolution analyzer typically consists of two main parts: a sample chamber and a collector. Drug samples are usually placed in the sample chamber in solid or tablet form. The sample chamber is then placed in a predetermined dissolution medium (such as simulated gastric juice or simulated intestinal juice) and stirred at a certain rate. The solute in the drug sample will gradually dissolve and enter the collector through the orifice, and finally enter the fluorescence spectrophotometer or other detection instruments for analysis.

Disintegration Time Relationship

For a drug to exert its effect, it must reach its site of action. Whether a drug can reach the site of action, and the speed and extent of that reach, are influenced by many factors. Taking tablets as an example, after administration, the drug must first disintegrate and disperse before it can dissolve and be absorbed to produce its therapeutic effect. Therefore, pharmacopoeias of various countries conduct disintegration time tests on some tablets, which plays a certain role in ensuring drug efficacy. However, many experiments have raised new questions. For example, G. Levy and Hayes, in their aspirin experiments, found that in vitro disintegration time cannot indicate in vivo efficacy. Disintegration time testing can only control the initial stage of drug dissolution; the subsequent dispersion and dissolution processes are beyond the control of disintegration time. Therefore, it is proposed that the rate and extent of drug dissolution are more closely related to in vivo absorption.

Bioavailability

Bioavailability is the measurement of drug concentration in blood or urine after administration to humans and animals, reflecting the extent to which a drug formulation can be absorbed and utilized in the body, and thus inferring its efficacy. Theoretically, in vivo experiments and clinical studies are the most fundamental and reliable basis for evaluating drug formulations. However, bioavailability testing is extremely labor-intensive and expensive. Screening and evaluating each sample, and controlling product quality, can only be accomplished through in vitro testing methods. While dissolution is not necessarily related to in vivo bioavailability, it is in most cases related; it is a method that uses in vitro testing to replace animal experiments.

Influencing Factors

1. Degassing of the medium, liquid temperature, instrument vibration, stirring speed, sampling point location, filtration rate, and the position of the drug in the container or basket.

2. Drug-related factors, such as solubility, surface area, structure, and crystal form.

3. Formulation-related factors, such as dosage form, formulation, excipients, process, drug interactions, surfactants, particle size and total surface area after formulation disintegration or drug release.

Why do we perform dissolution testing?

Understanding the motivations behind dissolution testing helps ensure the strongest possible foundation for test method development. So let's examine its practical significance and criticality.

When it comes to studying the interaction between the human body and administered drugs, or "pharmacokinetics" (PK), important processes include "absorption, distribution, metabolism, and excretion" (ADME). These define how a drug enters, passes through, and leaves the body, and the controlled drug concentrations that need to be maintained in the body to achieve clinical efficacy and avoid toxicity. For OSD, disintegration and dissolution are the first and foremost steps in this mechanical chain, as absorption depends on the release process after the drug is delivered in a specific form and dissolved. Therefore, dissolution behavior is related to bioavailability, the drug's ability to produce therapeutic effects, and even the risk of toxicity. Thus, measuring dissolution behavior is one of the simplest ways to gain valuable insights into drug performance, drug performance consistency, and safety.

However, it is important to recognize that absorption is not solely dependent on dissolution. As reflected in the Biopharmaceutics Classification System (BCS, a system that classifies drug combinations according to solubility and permeability, see the diagram below), the permeability of a drug to cell membranes (typically gastrointestinal cell membranes) is an equally important factor.

Class 1 and 2 drugs possess high permeability, thus entering the human circulation relatively easily once dissolved. Class 2 drugs currently dominate drug development pipelines, indicating that dissolution rate is likely a limiting factor for their bioavailability. In recent years, Class 2 drugs as defined by the BCS have been a focus of solubilization research, and various formulation methods have been developed for these drug combinations.

Conversely, Class 3 and 4 drugs, due to their low permeability, are not easily absorbed even after dissolution. For these drugs, there may be a situation where the drug concentration is high at the cell membrane "supply" end, while the drug concentration in the circulatory system remains at a very low level.

Also, note the use of the term "solubility" on the bottom axis. When dealing with dissolution behavior, we can simultaneously study the dissolution rate and the degree of drug solubility in different media. Both are important.

How do we use dissolution test data?

Data from dissolution studies can drive decision-making and accelerate formulation development, allowing us to differentiate between APIs (active pharmaceutical ingredients), excipients, formulations, and manufacturing strategies based on their ability to improve bioavailability. This data can also support increasingly complex pharmacokinetic models, thereby efficiently advancing drug launches and ensuring the quality of drugs throughout their entire lifecycle (through generic drug development and any transition to over-the-counter drugs).

What factors determine dissolution testing methods?

First, we obviously need to make some decisions, including the dissolution medium to be used, whether to simulate a feeding or fasting state (e.g., changing the pH of the dissolution medium or other aspects to reflect dissolution in different regions of the gastrointestinal tract), and/or the appropriate degree of agitation required for representative testing.

Second, there are issues regarding local drug concentration. Dissolution testers are relatively large, meaning tests are often conducted in a "sinking" state, where local drug concentrations remain low enough to have no effect on dissolution behavior. This may be a preferred strategy. However, if, for various reasons (such as meeting sustained-release targets or low drug permeability (Class 3 and 4 drugs)), the drug will inevitably dissolve into a relatively high-concentration solution, then alternative strategies are theoretically more practical.

Thirdly, the growing number of Class 2 drug candidates intensifies the need for sensitive dissolution testing. Large test volumes combined with poorly soluble drugs often require measuring extremely low concentrations, necessitating complex assays. Reducing test volumes can alleviate this problem, and there are off-the-shelf solutions specifically designed for this purpose; however, in general, such tests require improved accuracy in both instrumentation and methodology.

Last but equally important, the wide applicability and value of dissolution testing highlight the importance of high-productivity testing equipment and methods. Therefore, purchasing equipment that makes dissolution testing as accurate, efficient, and simple as possible is a worthwhile investment.

In conclusion, dissolution testing, as a crucial step in drug development and quality control, profoundly impacts not only the assessment of drug bioavailability, the prediction of efficacy, and the control of safety, but also provides solid data support for formulation optimization, pharmacokinetic model construction, and drug lifecycle management. Given the diverse characteristics of drugs and the complex in vivo environment, precise selection of dissolution media, optimization of testing conditions, and improvement of instrument and method accuracy are essential to ensuring the accuracy and reliability of test results. Therefore, continuous investment in efficient and accurate dissolution testing technologies and equipment is an inevitable path to promoting drug innovation, ensuring drug quality, and accelerating the drug launch process.