A comprehensive understanding of disintegrants and disintegration quantification techniques: From the perspective of tablet microstructure

Abstract

Disintegration is the process where tablets break down into small particles in a liquid medium. Sufficient disintegration of tablets is conducive to the rapid dissolution of drugs and improve bioavailability, thus it is essential to have a full understanding of the disintegration phenomenon of tablets. The addition of disintegrants plays an indispensable role in initiating the disintegration process of tablets. Developing and applying disintegrants with superior performance is the direction that people are committed to exploring. Seeking new disintegrants from the natural field is another major effort. Additionally, the research and application of Chinese medicine tablets have attracted extensive interest due to the safety and efficacy of natural Chinese herbal medicine. However, the problem of delayed disintegration of Chinese medicine tablets poses a challenge in clinical application. The standard disintegration test (SDT) is clearly defined in Pharmacopoeia with limited information on the disintegration process. Therefore, it seems to be worthy and urgent to quantify the disintegration phenomenon and try to reveal the underlying mechanism and tablet microstructure of the disintegration based on the use of advanced technologies and software methods. In this review, we focused specifically on the recent advances in tablet disintegration, including the development of disintegrants, an overview based on the disintegration of Chinese medicine tablets, and the technical methods for quantifying disintegration, hence providing a reference for further understanding of the disintegration phenomenon.

Introduction

Tablet disintegration is the process of break-up of powder compacts into small particles when the tablet is exposed to a liquid medium. As the first stage in the bioavailability cascade, disintegration facilitates the breakage of the tablet into small fragments after being ingested in the gastrointestinal tract, enabling rapid dissolution of the drug, and thereby improving bioavailability. For immediate release tablets, the disintegration and the dissolution are highly correlated [1,2]. The International Conference on Harmonization (ICH) Tripartite Guideline Q6A discusses the employment of disintegration as an alternative test to dissolution [3]. Therefore, ensuring effective tablet disintegration is critical for drug dissolution and subsequent reliable clinical efficacy. In the design of a tablet dosage form, the active pharmaceutical ingredients (APIs) and excipients together make up the tablet formulation. In general, excipients in tablets perform certain important functions, where the addition of disintegrants promotes the penetration of liquid into the tablet matrix and initiates the subsequent disintegration process. Hence, disintegrants are considered to be one of the most important excipients.

Chinese herbal medicine and natural active ingredients are generally considered to be low adverse reactions and good safety, and their role in promoting human health is increasing. Scientists have emerged an intense interest in the research and development of Chinese herbal medicine. Oral disintegrating tablets and dispersible tablets of Chinese medicine rely on rapid disintegration to show effective active effect in Chinese medicine immediate release dosage form [4]. In addition, the phenomenon of delayed disintegration can be observed in some Chinese medicine tablets, which poses a challenge to promote the dissolution of APIs and achieve clinical efficacy. Although there had been a large number of reports on the disintegration mechanism of chemical drugs, few studies have revealed the disintegration phenomenon of Chinese herbal medicine. There are some difficulties in understanding the disintegration process of Chinese herbal medicine: ⅰ) compared with chemical drugs, the composition of Chinese herbal medicine is more diverse, and the properties are more complex; ⅱ) the extensive excipients in the formula have certain characteristics, and its combination with Chinese herbal medicine increases the variability of the complex process of tablet disintegration; ⅲ) the parameters (such as direct compression, wet or dry granulation, and compaction conditions) of the Chinese medicine tablets manufacturing process have a significant impact on disintegration; ⅳ) the sensitivity of APIs to storage conditions (e.g. moisture, temperature) and medium. These factors pose serious challenges for investigators to a thorough understanding of the disintegration of Chinese herbal medicine.

Nowadays, although the standard disintegration test (SDT) to obtain tablet disintegration time (DT) is clearly specified in different pharmacopoeias, and the results are used to characterize the quality attributes of drug product, this conventional method provides little basic information on tablet disintegration and fails to reveal the disintegration mechanism of this disintegration process. Hence, it seems to be significant and exigent to quantitatively study the disintegration phenomenon of tablets and accurately analyze the microstructure of disintegrating particles employing rapidly developing technical approaches and software methods. Efforts have been made to use complex and advanced evaluation methods to study the phenomena that occur at various stages of the disintegration process.

So far, four reviews from Quodbach and Kleinebudde [5], Desai et al. [6], Markl and Zeitler [7], and Berardi et al. [8] have provided scientific insights into complex disintegration phenomena, and it is noteworthy that these articles primarily focus on tablets composed of chemical drugs, and less mentioned the disintegration of Chinese medicine tablets. Moreover, the most recent review of quantitative disintegration technology dates back to 2017. With advances in analytical technology, innovative quantitative methods have been developed to evaluate disintegration. It is necessary to summarize the recent research progress on quantitative disintegration techniques, in the hope of gaining some insights into the disintegration process from the perspective of tablet microstructure.

This review aims to discuss recent advances in tablet disintegration. Here, we focus on three aspects: ⅰ) the development and application of disintegrants in formulation design; ⅱ) challenges and strategies of disintegration in Chinese medicine tablets; ⅲ) Scientific instruments and analytical methods for quantifying disintegration. For the design and development of tablet dosage forms, this review will provide an in-depth description of the different natural sources of disintegrants and their applications in tablet formulation. For the microstructure of tablet disintegration, this paper attempts to reveal the underlying mechanism of the disintegration process from multidisciplinary technical approaches and provides specific information for the continuous process of tablet disintegration and dissolution. Additionally, we analyze the problems existing in the disintegration of Chinese medicine tablets based on the recent advances, in order to provide ideas for future studies on the disintegration of Chinese medicine tablets.

A comprehensive understanding of disintegrants and disintegration quantification techniques: From the perspective of tablet microstructure

Abstract

Introduction

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