Quantifying cross-linking strength in sodium starch glycolate and its impact on tablet disintegration and dissolution

Abstract

The development of a robust oral solid dosage form requires knowledge of all the sources of variation that could impact the dosage form’s performance and stability, in line with Quality-by-Design (QbD). This requires a deep understanding of the relationships between raw material properties, the process parameters and the final product quality. This paper presents a method to quantify the strength of cross-links (SXL) in SSG grades by comparing the sediment volume of precipitation after gelling before and after exposure to alkaline conditions. It is demonstrated that SSG grades with phosphorous cross-links are more resistant to hydrolysis than ester cross-links. The developed method can help formulators to assess the SXL of SSG before use in a formulation. The SXL was quantified for seven marketed SSG grades, showing a clear difference between SSG grades with phosphorous cross-links (SXL ≈ 1) and ester cross-links (SXL 0.4 – 0.7). The tablet disintegration and API dissolution of these SSG grades were evaluated for a wet granulation formulation with atenolol. Results show that all SSG grades with phosphorous cross-links realized 80 % atenolol dissolution within 25 min, whereas all grades with ester cross-links reached this threshold only after 45 min or more. This shows that the type of cross-link is a critical attribute that can result in dissolution success or failure. An excellent correlation was observed between the SXL and the time at which 80 % of the atenolol was dissolved. The findings of this study show that understanding the type of cross-link and the SXL of SSG can support formulators with the development of good, robust formulations, in line with a quality-by-design approach. The provided case study shows that formulators can make their formulations more robust to stress exposure before, during or after tablet manufacturing by using an SSG grade with phosphorous cross-links, thereby limiting the risk of product failure.

Introduction

The development of a robust oral solid dosage form requires knowledge of all the sources of variation that could impact the dosage form’s performance and stability, in line with Quality-by-Design (QbD) [[1], [2], [3]]. This requires a deep understanding of the relationships between raw material properties, the process parameters and the final product quality.

Disintegrants are well-known excipients that can be used in the formulation of oral solid dosage forms to promote the disintegration of tablets and capsule slugs when placed in aqueous environments or body fluids. Disintegration refers to the process of breaking up a dosage form into smaller particles, to increase the surface area of the active pharmaceutical ingredient available for dissolution and subsequently absorption. Disintegrants are commonly classified in literature as traditional disintegrants and superdisintegrants [4]. Superdisintegrants have improved efficiency and facilitate faster disintegration in smaller quantities. Superdisintegrants include croscarmellose sodium, crospovidone and sodium starch glycolate (SSG).

SSG was the first superdisintegrant introduced on the market. SSG allows for rapid water penetration into the dosage form and powerful swelling results in disintegration. Swelling is defined as the multi-dimensional expansion of particles. This internal pressure separates adjoining components, and breaks the matrix when the adhesion and cohesion of ingredients is overcome [5].

SSG is synthesized from starch polymers that are modified by the introduction of carboxymethyl groups and cross-links [6]. The degree of carboxymethyl substitution and the degree of cross-linking are important factors for the effectiveness of SSG as a superdisintegrant [7,8]. Unmodified starch consists of amylose and amylopectin chains. It hardly swells or dissolves in cold water because of strong inter- and intra- molecular hydrogen bonds [9]. Carboxymethylation is the substitution of hydroxyl groups by anionic, strong hydrophilic carboxymethyl ester groups. Carboxymethyl ester groups weaken the internal structure by reducing the hydrogen bonding between the polymer chains. They allow for swelling of the starch structure when brought into contact with water. Carboxymethylation increases the solubility of the starch and the viscosity of the starch solution. Carboxymethylated starch however hardly takes up any water in the starch structure, due to the viscous barrier that is created which inhibits further water uptake [10]. Cross-linking is the formation of covalent bonds between the polymer chains and is performed to prevent dissolution of the modified starch particles into a viscous solution (gel formation), while maintaining hydrophilicity [[11], [12], [13]]. Cross-links decrease the swelling capacity, solubility, and viscosity. The degree of cross-linking should be high enough to avoid the detrimental effect of the viscous barrier but should be low enough to retain sufficient water uptake [10]. Bolhuis et al. found optimal performance for SSG when 1 in 4 anhydroglucose units was carboxymethylated, and 1 in ∼ 500 anhydroglucose units was cross-linked [10,14].

Multiple types of SSG are described in the United States Pharmacopeia (USP) and the European Pharmacopeia (Ph.Eur.), as shown in Table 1 [[15], [16], [17]]. Both pharmacopeia describe sodium starch glycolate type A and B in their monographs, which differ in the pH and sodium content. The Ph.Eur. describes one additional type of SSG, namely type C. For type C, the Ph.Eur. specifies that the cross-linking is obtained by physical dehydration.

Commercially available SSG grades type A differ chemically from each other through the type of cross-link that is used [18]. Two types of cross-links are available, being phosphorous (phosphate-ester) cross-links and ester (internal, carboxyl or non-phosphorous) cross-links, as visualized in Fig. 1. Phosphorous cross-links are produced using a chemical cross-linking agent. Phosphoryl chloride (POCL3), sodium trimetaphosphate (STMP), and sodium tripolyphosphate (STPP) are agents approved by the FDA that are used to create phosphorous cross-links in SSG [[18], [19], [20], [21]]. Ester cross-links can be formed by dehydration or by employing cross-linking agents such as epichlorohydrin,1 citric acid, a mixture of adipic acid/acetic anhydride, a mixture of succinic anhydride/vinyl acetate, and genipin [18,19]. The relevance of the type of cross-links is acknowledged by the USP, which specifies that commercially available SSG should be labeled to indicate the cross-linking agent (if used) [16].

Both phosphorous and ester cross-links are effective in preventing the formation of a viscous barrier when going into solution. The main difference in application between the two types of cross-links is however related to their chemical stability. Phosphorous cross-links are chemically stronger than ester cross-links, which may be susceptible to hydrolysis [22]. Storage at high humidity, shear stresses and alkaline conditions can be risk factors that increase the likelihood of cross-link hydrolysis [23]. When cross-links hydrolyze, the hydrophilic chains of the starch particles become more soluble, increasing the viscosity and gelling [24]. Such gelling allows the formation of a viscous barrier that slows down water penetration into the tablet and retard the activation of the disintegrant within the core of the tablet [25], as visualized in Fig. 2.

This paper describes a new method to assess the strength of cross-linking (SXL), by comparing the sediment volume of precipitation of SSG gelling before and after exposure to alkaline conditions. Reduced levels of cross-linking are quantified by evaluating changes in the sediment volume of the gel. Understanding cross-link type and SXL of SSG can support formulators with the development of reliable and robust formulations. A low SXL indicates a high risk for cross-link hydrolysis, while an SXL of 1 suggests a low risk for hydrolysis. The SXL is quantified for seven marketed SSG grades and linked to the type of cross-linking in the chemical structure. It is hypothesized that SSG grades with phosphorous cross-links have an SXL close to 1, while SSG grades with ester cross-links have substantially lower SXL.

The SSG grades are also evaluated in a wet granulation formulation with atenolol to investigate the relation between SXL on the one hand and tablet disintegration and active pharmaceutical ingredient (API) dissolution performance on the other hand. Lower SXL is expected to correlate to slower tablet disintegration and API dissolution in the model formulation, due to the reduced wicking caused by the formation of a viscous barrier. Wet granulation with atenolol serves as a representative formulation example to evaluate the susceptibility of SSG to hydrolytic degradation Wet granulation involves exposure to moisture and thermal stress, which can compromise the stability of SSG. Additionally, atenolol, a weak base with a pKa of 9.6 [29,30], may contribute to alkaline conditions during processing, further increasing the risk of degradation of the cross-links. Direct compression formulations, in contrast, serve as a control to isolate intrinsic performance differences among various SSG grades.

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Materials

Table 2 provides details of the materials used in this study. Additionally, the type of cross-linking of the seven commercial SSG grades included in this study is specified. The chemical structure of phosphorous and ester cross-linked SSG is visualized in Fig. 1A and 1B respectively.

Table 2. Overview of the materials used in this study. the type of cross-links is specified for the seven commercial SSG grades.

Grade denotification	Grade	Supplier	Type of cross-links
Atenolol	2288–0500	Ofipharma
MCC-101	Pharmacel® 101	DFE Pharma
Povidone	Kollidon® K30	BASF
MCC-102	Pharmacel® 102	DFE Pharma
Magnesium Stearate	STB K5280	Sigma Aldrich
Anhydrous lactose	SuperTab® 21AN	DFE Pharma
SSG-A	Primojel®	DFE Pharma, the Netherlands	Phosphorous [26]
SSG-B	Explotab	JRS, Germany	Phosphorous [26]
SSG-C	Vivastar P	JRS, Germany	Ester [26,27]
SSG-D	Glycolys	Roquette, France	Phosphorous [25]
SSG-E	Glycolys Maize	Roquette, Brazil	Ester*
SSG-F	Glycolys low solvent	Roquette, Brazil	Ester*
SSG-G	DST	YungZip, Taiwan	Ester [28]

* based upon indication on Certificate of Analysis “cross-linking agent: none”.

Pauline H.M. Janssen, Willem Rijpkema, Kathleen Stout, Marlijn Orbons, Arpan Patel, Bastiaan H.J. Dickhoff, Quantifying cross-linking strength in sodium starch glycolate and its impact on tablet disintegration and dissolution, European Journal of Pharmaceutics and Biopharmaceutics, 2025, 114803, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2025.114803.