A comparative study of disintegration actions of various disintegrants using Kohonen's self-organizing maps

doi:10.1016/j.jddst.2017.10.002

Journal of Drug Delivery Science and Technology

Volume 43, February 2018, Pages 141-148

https://doi.org/10.1016/j.jddst.2017.10.002 Get rights and content

Abstract

To gain a better understanding of disintegration actions, 11 different disintegrants were tested. Model tablets were prepared with various preparation conditions, and their disintegration time and tensile strength were measured. The present study also investigated various physicochemical properties of the model tablets and disintegrant powders, including wetting time, water absorption ratio, particle size, morphological observation, swelling property, and T₂ relaxation time (T₂). The experimental data were thoroughly analyzed using self-organizing map (SOM) clustering. The test disintegrants were classified into four distinct clusters. It is worth noting that superdisintegrants, including croscarmellose sodium (Ac-Di-Sol), sodium starch glycolate (Glycolys), and crospovidone (Kollidone CL-F and Polyplasdon XL-10), were assigned to clusters different from those of normal disintegrants. Furthermore, SOM clustering suggested the latent contributions of factors to the disintegration actions. The disintegrant content had a significant impact on the disintegration actions. Furthermore, the T₂ measurements indicated that the interaction mode of crospovidone with water was different from those of cellulose- and starch-based disintegrants. The evidence obtained is valuable information for the formulation design of tablets.

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.

References (24)

P.M. Desai et al.
Review of disintegrants and the disintegration phenomena
J. Pharm. Sci.
(2016)
Y. Onuki et al.
Evaluation of the reliability of nonlinear optimal solutions in pharmaceuticals using a bootstrap resampling technique in combination with Kohonen's self-organizing maps
J. Pharm. Sic.
(2008)
Y. Onuki et al.
Contribution of the physicochemical properties of active pharmaceutical ingredients to tablet properties identified by ensemble artificial neural networks and Kohonen's self-organizing maps
J. Pharm. Sci.
(2012)
J.E. Aguilar-Diaz et al.
The use of the SeDeM Diagram expert system to determine the suitability of diluents-disintegrants for direct compression and their use in formulation of ODT
Eur. J. Pharm. Biopharm.
(2009)
A. Abdelbary et al.
Comparative effects of different cellulosic-based directly compressed orodispersable tablets on oral bioavailability of famotidine
Carbohyd. Polym.
(2009)
P. Hooper et al.
A new modified wetting test and an alternative disintegration test for orally disintegrating tablets
J. Pharm. Biomed. Anal.
(2016)
Y. Iwao et al.
An easy-to-use approach for determining the disintegration ability of disintegrants by analysis of available surface area
Int. J. Pharm.
(2013)
Y.R. Kim et al.
Effect of sugars and sugar alcohols on freezing behavior of corn starch gel as monitored by time domain 1H NMR spectroscopy
Carbohyd. Polym.
(2004)
M.E. Aulton et al.
Aulton's Pharmaceutics: the Design and Manufacture of Medicines
(2013)
R.C. Rowe et al.
Handbook of Pharmaceutical Excipients
(2003)

M. El-Barghouthi et al.

A novel superdisintegrating agent made from physically modified chitosan with silicon dioxide

Drug Dev. Ind. Pharm.

(2008)

J. Quodbach et al.

A critical review on tablet disintegration

Pharm. Dev. Technol.

(2016)

Cited by (27)

Feature extraction of particle morphologies of pharmaceutical excipients from scanning electron microscope images using convolutional neural networks
2024, International Journal of Pharmaceutics
Scanning electron microscopy (SEM) images are the most widely used tool for evaluating particle morphology; however, quantitative evaluation using SEM images is time-consuming and often neglected. In this study, we aimed to extract features related to particle morphology of pharmaceutical excipients from SEM images using a convolutional neural network (CNN). SEM images of 67 excipients were acquired and used as models. A classification CNN model of the excipients was constructed based on the SEM images. Further, features were extracted from the middle layer of this CNN model, and the data was compressed to two dimensions using uniform manifold approximation and projection. Lastly, hierarchical clustering analysis (HCA) was performed to categorize the excipients into several clusters and identify similarities among the samples. The classification CNN model showed high accuracy, allowing each excipient to be identified with a high degree of accuracy. HCA revealed that the 67 excipients were classified into seven clusters. Additionally, the particle morphologies of excipients belonging to the same cluster were found to be very similar. These results suggest that CNN models are useful tools for extracting information and identifying similarities among the particle morphologies of excipients.
A comprehensive understanding of disintegrants and disintegration quantification techniques: From the perspective of tablet microstructure
2023, Journal of Drug Delivery Science and Technology
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.
Application of unsupervised and supervised learning to a material attribute database of tablets produced at two different granulation scales
2023, International Journal of Pharmaceutics
The purpose of this study is to demonstrate the usefulness of machine learning (ML) for analyzing a material attribute database from tablets produced at different granulation scales. High shear wet granulators (scale 30 g and 1000 g) were used and data were collected according to the design of experiments at different scales. In total, 38 different tablets were prepared, and the tensile strength (TS) and dissolution rate after 10 min (DS10) were measured. In addition, 15 material attributes (MAs) related to particle size distribution, bulk density, elasticity, plasticity, surface properties, and moisture content of granules were evaluated. By using unsupervised learning including principal component analysis and hierarchical cluster analysis, the regions of tablets produced at each scale were visualized. Subsequently, supervised learning with feature selection including partial least squares regression with variable importance in projection and elastic net were applied. The constructed models could predict the TS and DS10 from the MAs and the compression force with high accuracy ( $R^{2} =$ 0.777 and 0.748, respectively), independent of scale. In addition, important factors were successfully identified. ML can be used for better understanding of similarity/dissimilarity between scales, for constructing predictive models of critical quality attributes, and for determining critical factors.
Artificial intelligence applications in pharmaceutical technology
2023, Computer-Aided Applications in Pharmaceutical Technology: Delivery Systems, Dosage Forms, and Pharmaceutical Unit Operations
This chapter presents a review of the possible applications of methods based on neural computing in pharmaceutical products and process development. Some of the methods described are used for classification purposes, whereas others can be applied to modeling and optimization, or even induction of rules. The basic concepts of each method are theoretically described, followed by examples of their application in pharmaceutical technology. A theoretical background aims to provide a better understanding of the methods and is based on their most important features. Examples should encourage the reader to embrace the abovementioned methods and use them to complement conventional statistical methods for classification and regression.
The Molded Tablet, a disintegrant-free orally disintegrating tablet, resists thickening solution-reduced drug dissolution
2022, Journal of Drug Delivery Science and Technology
Citation Excerpt :
Notably, MTs are a disintegrant-free ODT. In addition to their effect on disintegration, disintegrants significantly affect a wide range of tablet properties, including tensile strength (TS) [18], stability of active pharmaceutical ingredients (APIs) [19], and hygroscopic properties [19]. Therefore, MTs exhibit distinct tablet properties from common disintegrant-containing ODTs.
In clinical practice, a thickening solution is frequently coadministered with medicinal tablets to facilitate swallowing by older patients. This study investigated the effect of thickening solutions on the reduction in drug dissolution from orally disintegrating tablets (ODTs) by testing a disintegrant-free ODT, the Molded Tablet (MT), and various disintegrant-containing ODTs. After measurement of the tensile strength of the test ODTs, a drug dissolution test was performed on ODTs treated with or without thickening solutions. Drug dissolution from the common disintegrant-containing ODTs was reduced significantly by treatment with thickening solutions, but the reduction was more moderate for the test MT. The present study also measured the swelling behavior and mechanical strength of the test ODTs after treatment with thickening solution. We observed that the MTs displayed less swelling in the thickening solution and that the swollen tablets had lower mechanical strength than the disintegrant-containing ODTs. This study suggests that the disintegrants contained in ODTs play a key role in reducing drug dissolution accompanied by treatment with a thickening solution, i.e., the disintegrants allow the ODT to interact closely with the thickening solution and this interaction has a substantial impact on the drug dissolution from ODTs.
Downstream processing of spray-dried ASD with hypromellose acetate succinate – Roller compaction and subsequent compression into high ASD load tablets
2021, International Journal of Pharmaceutics: X
Despite wide commercial application of hypromellose acetate succinate (HPMCAS) in spray-dried amorphous solid dispersion (ASD) drug products, little information is available in the references on downstream processing of spray-dried dispersions with HPMCAS. Poor flow and high dilution factor are a challenge in formulating spray-dried ASDs into tablets, leaving little space for other excipients facilitating binding and disintegration. Direct compression is not possible due to the poor powder flow of spray-dried ASDs. Moisture has to be avoided due to the plasticizing properties of water on the ASD, resulting in reduced stability of the amorphous state. Thus, dry granulation by roller compaction and subsequent tablet compression is the preferred downstream process. We report the investigation of downstream processing by roller compaction and tablet compression of a high load formulation with 75% of spray-dried amorphous solid dispersion (Nifedipine:HPMCAS 1:2). A head to head comparison of microcrystalline cellulose/croscarmellose (MCC/cl-NaCMC) as binder/disintegrant vs. MCC and low-substituted hydroxypropyl cellulose (L-HPC) as excipient for binding and disintegration showed improved re-workability of the formulation with MCC/L-HPC after roller compaction. Upon transfer to the rotary press, a 45% higher tensile strength of tablets is observed after dry granulation with MCC/L-HPC.

View all citing articles on Scopus

View full text

A comparative study of disintegration actions of various disintegrants using Kohonen's self-organizing maps

Abstract

Graphical abstract

Introduction

Section snippets

Materials

Changed behavior of DT and TS with changing factors

Discussion

Conclusions

Conflict of interest

Acknowledgments

J. Pharm. Sci.

J. Pharm. Sic.

J. Pharm. Sci.

Eur. J. Pharm. Biopharm.

Carbohyd. Polym.

J. Pharm. Biomed. Anal.

Int. J. Pharm.

Carbohyd. Polym.

Aulton's Pharmaceutics: the Design and Manufacture of Medicines

Handbook of Pharmaceutical Excipients

A novel superdisintegrating agent made from physically modified chitosan with silicon dioxide

Drug Dev. Ind. Pharm.

A critical review on tablet disintegration

Pharm. Dev. Technol.