A comparative study of disintegration actions of various disintegrants using Kohonen's self-organizing maps
Graphical abstract
Introduction
To manufacture orally administered compacted tablets, in addition to the active pharmaceutical ingredient (API), a wide variety of excipients is normally incorporated into the tablets [1]. According to the intended main functions, excipients to be incorporated into tablets are subcategorized into different groups. These include disintegrants, fillers, binders, glidants, lubricants, matrix formers, antiadherents, flavoring agents, and colorants [1]. Among these, a disintegrant is the most important excipient for determining the disintegration property of tablets. Tablet disintegration can be understood as the first stage in the bioavailability cascade including drug release and absorption from the gastrointestinal tract.
Excipients that have a hydrophilic but insoluble nature in water or gastrointestinal fluids are considered suitable as disintegrants [2]. Currently, a wide variety of excipients, especially starch- and cellulose-based substances, are used as disintegrants [2], [3]. For example, corn starch, partially pregelatinized starch, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose have traditionally been incorporated into tablets as disintegrants. Furthermore, chemical modification of starch, cellulose, and povidone enables us to create excellent disintegrants. In particular, croscarmellose sodium, sodium starch glycolate, and crospovidone are referred to as superdisintegrants because they can achieve excellent disintegration action at much lower concentrations.
To date, various theories have been proposed as the mechanism of disintegration action, including swelling of particles, exothermic wicking reaction, particle deformation recovery, particle repulsion, and heat of interaction [1], [2], [4], [5]. Swelling is commonly accepted as the most important mechanism for tablet disintegration. Swollen disintegrant particles push apart the adjacent components, thereby initiating the breakup of the tablet matrix. Wicking is the ability to draw water into the tablet matrix. It is an essential element for disintegrant activation. Water penetrates the tablet not only through pores, but also along a hydrophilic network by wicking of the incorporated disintegrant particles. It might cause weakening of the tablet structure. It is worth noting that these mechanisms are not independent, and each one can influence or be influenced by the other mechanisms. For instance, the wicking can be considered as the pre-request for swelling, deformation recovery, and other proposed disintegration mechanisms [2], [5]. Although there are quite a few studies on the mechanisms of disintegrates [2], [4], [5], they are still complicated, and it therefore remains difficult to fully understand their actions.
Against this background, the present study conducted a comparative study of various disintegrants to gain a better understanding of their disintegration actions. To prepare samples, 11 different test substances were selected from popular disintegrants, and then their model tablets were prepared using different conditions (i.e., change in disintegrant content and compression force in the tabletting process). Afterwards, their properties were measured, and the observed data were thoroughly analyzed using Kohonen's self-organizing map (SOM). Thereby, the disintegrants were ultimately summarized into several clusters to reveal latent relationships between the factors. The present study offers profound insight into disintegration actions of the test disintegrants.
Section snippets
Materials
The disintegrants tested in this study are summarized in Table 1. Low-substituted hydroxypropyl celluloses (L-HPCs) [LH-11 (L11), LH-21 (L21), LH-31 (L31), and NBD-021(NBD)] were purchased from Shin-Etsu Chemical (Tokyo, Japan). Croscarmellose (CMC) [NS-300 (NS)] and croscarmellose calcium (CMC-Ca) [ECG-505 (ECG)] were purchased from Gotoku Chemical (Tokyo, Japan). Croscarmellose sodium (CMC-Na) [Ac-Di-Sol (AC)] was purchased from FMC Health and Nutrition (Philadelphia, PA). Sodium starch
Changed behavior of DT and TS with changing factors
The DT and TS of standard tablets are presented in Fig. 1 and shown in supplemental material (see Table s1). Various DT values were observed for the test tablets. AC-, GLY-, and KO-containing tablets disintegrated within a short period; 59.3 ± 4.2 s for AC, 99.7 ± 3.1 s for GLY, and 62.3 ± 0.6 s for KO, respectively. By contrast, the DT of the CS-containing tablet was integral for markedly longer than that of the other tablets, taking over one thousand seconds to disintegrate (1304 ± 174 s).
Discussion
The present study sought to gain a better understanding of the disintegration actions of various disintegrants. The test substances were selected from disintegrants popularly used for commercial products. GLY (sodium starch glycolate), KO and PP (crospovidones), and AC (CMC-Na) are referred as “superdisintegrants” [3], [8].
To characterize their disintegration actions, the present study made use of SOM analysis. SOM is a feedforward-type neural network model regarded as a powerful tool for data
Conclusions
The present study provides enhanced technical knowledge concerning the disintegration actions of different disintegrants. Using SOM clustering, we could classify the disintegration actions of test disintegrants into four distinct clusters. The actions of the superdisintegrants were sharply distinguished from those of standard disintegrants. Furthermore, the latent relationships between the disintegration actions and physicochemical properties were suggested from the SOM feature maps. This study
Conflict of interest
The authors declare that they have no financial or noncompeting interests concerning this manuscript. The Department of Pharmaceutical Technology, University of Toyama, is an endowed department, supported by an unrestricted grant from Nichi-Iko Pharmaceutical Co (Toyama, Japan).
Acknowledgments
This work was supported by JSPS KAKENHI Grant Number JP16K08192 and Tamura Science Foundation. We thank Mr. Hirofumi Furuya at Nichi-Iko Pharmaceutical Co for technical support.
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