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NS-300

Mechanism of cellulose derivative disintegrants

Two different types of carboxymethylcellulose were originally developed by
GOTOKU CHEMICAL CO., LTD. in Japan. One is a calcium chelate type "ECG-505" and the other is a free acid type "NS-300."
Fig-1 shows the chemical structure of ECG-505 and NS-300.

Fig-1 Chemical structure
Molecular formula of ECG-505 Molecular formula of NS-300

It is necessary to consider the following three conditions to investigate the mechanism of cellulose derivative disintegrants.

  1. The examination of disintegrative ability should be evaluated on the basis of the distinction between the powder form and the tablet form. As disintegrants are often used in the form of tablets, the evaluation in the form of tablets is more important than that of powders.
  2. There are two kinds of water uptake mechanism for disintegration. One is generally known as swelling based on the water uptake ability of the disintegrant, and the other is wicking based on the rapid penetration of water into tablets due to good wetting of the disintegrant.
  3. The mechanism of disintegration is dependent on physicochemical property caused by hydrogen bonding of hydroxyl groups in cellulose.

EX-1: Disintegrative ability in the form of powders

Avicel PH101, L-HPC, and Ac-Di-Sol were supplied as samples to be compared with ECG-505 and NS-300 for the purpose of examining the mechanism of cellulose derivative disintegrants.

Max swelling force of five disintegrants above-mentioned in the form of powders was examined.

As shown in Fig-2, the max swelling force levels of Avicel PH101 and NS-300 are lower than those of Ac-Di-Sol, L-HPC, and ECG-505.





EX-2: Swelling behavior of the tablets made of single disintegrant powders

Fig-3 is the photographs of shape changes in water uptake of the tablets made by compressing single disintegrant powders. ECG-505, L-HPC, and Ac-Di-Sol swell with expansion, but NS-300 and Avicel PH101 volumetrically swell without expansion. The absorption and swelling abilities of the former three samples are superior to those of the later two samples in the form of powders as shown in Fig-2 and Fig-3.


EX-3: Disintegrative ability in the form of tablets

Fig-4 shows the rate of water uptake and disintegration time of Aspirin tablets containing 5% each disintegrant.

Though NS-300 shows a low value of the max swelling force in the form of powder as shown in Fig-2, Fi-4 shows that the disintegration time of tablet including NS-300 is very short and accordingly the disintegrative ability of NS-300 in the form of tablet is very high.

Four types of disintegration mechanisms (swelling, deformation, wicking, and repulsion) are proposed in the review by Joseph (Pharmaceutical Technology April 1984). Judging from the review and the results from Fig-2~4, Ac-Di-Sol, L-PHC, and ECG-505 belong to the swelling type, while NS-300 is classified into the wicking type that exhibits the fast rate of water uptake.


EX-4: Application of disintegrants to rapidly disintegrating oral tablets

NS-300 shows a faster disintegrant time than Ac-Di-Sol, L-HPC, ECG-505, and Polyplasdone as shown in Fig-5. For NS-300 has the property of the shortest wetting time as shown in Fig-6.


A consideration for the relation between hydrogen bond and disintegration

From the foregoing study, it is supposed that the mechanism of cellulose derivative disintegrants described above may be influenced by inter/intra molecular hydrogen bonding of cellulose derivatives.
For example, Avicel PH101 has a crystalline part by a strong hydrogen bonding, and the hydroxyl groups at the C6 position in the original cellulose mainly govern the inter/intra molecular hydrogen bonds.
Therefore, Avicel PH101 exhibits little water uptake due to the inactive hydroxyl groups. As these hydroxyl groups are bound each other, they are expressed by the made-up name of "close state."
To possess the disintegrative ability, it is necessary to make hydroxyl groups activate by cutting the hydrogen bonding through alkaline treatment and introducing some substituents into the C6 position to inhibit the aggregation or binding of the hydroxyl groups.
These hydroxyl groups of disintegrants have a good activity to water uptake.
Therefore the hydroxyl groups of swelling type such as Ac-Di-Sol, L-PHC, and ECG-505 are expressed by the made-up name of "open state" contrary to "close state." In case of NS-300, the carboxymethylcellulose sodium is adjusted with mineral acid to form a carboxylic acid at the end of substituted function, which has a tendency to form a loose hydrogen bonding or aggregation with hydroxyl groups that exist near by.
The hydroxyl groups of NS-300 are supposed to convert the "open state" to some "close state."
This changing affects some physicochemical properties such as wetting, contact angle, and capillary action, resulting in occurrence of wicking action.

In conclusion, these examinations of the five disintegrants above-mentioned show that ECG-505 is a good disintegrant as a swelling type, while NS-300 is superior to the other disintegrants as a wicking type.

ECG-505 has been on sale as a disintegrant of swelling type and NS-300 also on sale as a disintegrant of wicking type by GOTOKU CHEMICAL CO., LTD.
Besides ECG-505 was registered in JP in 1966, USP and US-NF in 1985, and EP in 1994.
NS-300 was also registered in JP in 1986.


Reference:
Fig-1~Fig-4: The 121st Annual Meeting of the Pharmaceutical Society of Japan Sapporo: March 2001
Y.Takashima and H.Yuasa:Tokyo University of Pharmacy
Fig-5~Fig-6:The 17th Symposium on Particulate Preparation and Design
Ohtsu City:October 2000
E.Yonemochi:Toho University of Pharmaceutical Science
J.Fukami:Kyoto Pharmaceutical Industries, Ltd.
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