Use of Sodium Alginate

Sodium Alginate Use in Extended-Release Tablet Formulations

Abstract

Extended-release tablets are typically based on semi-synthetic cellulose ethers such as hypromellose (HPMC), hydroxyethyl cellulose (HEC), or hydroxypropyl cellulose (HPC). Alginates offer a completely natural alternative to these polymers. The objective of this study was to investigate the effects of sodium alginate particle size, concentration, and viscosity at various grades on the performance of modified-release tablets. Extended-release caffeine tablets with release over 8-10 hours were successfully prepared via direct compression (DC) using VIVAPHARM® Sodium Alginate.

Introduction

Therapeutic requirements and patient compliance make the introduction of dosage forms with long-term active ingredient release desirable. Among current formulation techniques, the so-called hydrophilic matrix is the simplest and most cost-effective approach. The main components of hydrophilic matrices are the active ingredient(s) and a sufficient quantity (typically 20-30%) of a hydrophilic polymer. Upon contact with water, the polymer will form a gel layer at the interface between the release medium and the tablet core. Subsequently, drug release will occur through diffusion within the gel layer and/or through its erosion. A series of excipient properties are critical for the performance of extended-release systems: The viscosity of the polymer affects the strength of the gel layer that controls release. Therefore, it has a significant impact on the release rate. The concentration of the extended-release polymer in a hydrophilic matrix must exceed a certain level to ensure reproducible formation of a robust gel structure [1]. The particle size distribution (PSD) of the release-controlling polymer will have an effect on the rate of gel formation. That is, when larger particle sizes are involved, gel formation takes longer than with finer PSD material. The more time that passes before consistent gel formation occurs, the more API can uncontrollably leach from the tablet. This phenomenon is typically called the "burst effect."

Study Objective

The objective of this study was to understand the criteria for selection of sodium alginate grades for extended-release tablets prepared via direct compression (DC)—namely the interactions of parameters such as viscosity, concentration, and particle size. Additionally, suitable formulations were compared with corresponding formulations based on HPMC, the most commonly used release-controlling polymer in hydrophilic matrix tablets.

Materials and Methods

Modified-release caffeine tablets were produced via direct compression (DC) using caffeine as the model active ingredient, different levels of VIVAPHARM® Sodium Alginate or HPMC as the release-controlling polymer, silicon-treated microcrystalline cellulose (SMCC) as filler-binder, and magnesium stearate as lubricant. For comparison, immediate-release tablets were produced by direct compression (DC) of caffeine with PROSOLV® EASYtab Nutra CM—an all-in-one excipient containing filler-binder, flow aid, disintegrant, and lubricant. Dissolution profiles were recorded either with a pH change from 1.0 to 6.8 after two hours (Method 1) or at a constant pH of 6.8 (Method 2).  

Results and Discussion

Effect of Viscosity

The viscosity of release-controlling polymers is related to polymer chain lengths and consequently the robustness of gels they form at higher concentrations. The effect of viscosity is shown in Figure 1 for three grades of sodium alginate having the same particle size but covering a viscosity range of 100–750 mPa*s. All formulations contain 20% alginate. Sodium alginate PH 175 type (548 mPa*s) demonstrated stronger API release retardation compared to PH 172 type (137 mPa*s). On the other hand, a further increase from 548 to 682 mPa*s (type 176) did not result in a significant change in the release rate.

Effect of Concentration

The strength of the release-controlling gel, and therefore the release rate, was found to depend on the polymer concentration in the formulation. Figure 2 shows the effect of polymer concentration on drug release. For a formulation containing 20% VIVAPHARM® Sodium Alginate PH 175, approximately 80% API release was reached after about six hours, while for the corresponding formulation with 50% polymer content, t was approximately nine hours. Although this suggests a wide range of formulation options, certain limitations must be considered: reducing polymer content below 20% will typically result in loss of consistency in the release rate [1]. Therefore, it is not an appropriate tool for achieving faster dissolution. Instead, lower viscosity grades should be considered while maintaining a minimum 20% concentration. In cases requiring stronger retardation, the poor flowability of sodium alginate powder, particularly when direct compression (DC) formulations are involved, sets an upper limit on the use level (see Table 3).

Effect of Particle Size Distribution

For directly compressible (DC) formulations, the powder flowability of the tablet mixture is critical. Both the concentration and particle size of the sodium alginate used will affect powder flow. As shown in Table 3, powder flow can be improved from "poor" (Angle of Repose: 47°) to "acceptable" (41°) by selecting a coarser grade of sodium alginate of the same viscosity type. Figure 3 shows the effect of polymer particle size on release profiles for tablets containing the same concentration and viscosity of sodium alginate but differing in particle size. A much faster initial drug release ("burst effect") is observed for tablets containing the coarser grade (PH 125). Since these tablets contain fewer but larger sodium alginate particles, more time passes before a consistent diffusion barrier is formed. During this lag period, the API can leach from the tablet with little or no control. Although PH 125 appears favorable in terms of improved powder flowability (see Table 3), the coarse particle size leads to delayed formation of the release matrix and consequently a significant burst effect.

Comparison with HPMC

Today, HPMC (hypromellose, substitution type 2208) is the most commonly used release-controlling polymer in hydrophilic matrix formulations. Therefore, the ability of sodium alginate to extend caffeine release was compared to a formulation containing an equivalent amount of HPMC K4M. Both formulations showed significant delay in drug release when compared to the immediate-release formulation used as control. The effect was more pronounced in the case of HPMC, which provided incomplete dissolution during the observed time frame. Sodium Alginate demonstrated significant retardation effect, supporting its suitability as a natural alternative to semi-synthetic polymers in the formulation of extended-release tablets.

Conclusion

Sodium alginate was found to be a suitable release-controlling polymer for directly compressed (DC), extended-release tablets. The behavior of Sodium Alginate followed the same rules commonly accepted for semi-synthetic polymers such as HPMC. That is, the same formulation constraints were established: Particle size must be balanced between adequate flowability (large particles) and rapid hydration (small particles). Concentration must be set at a level that prevents inconsistent release behavior (too low concentration) and poor powder flow (too high concentration). The only freely selectable variable is viscosity; this allows design of release profiles within formulation parameters that are otherwise fixed. In summary, a general recommendation for formulating an alginate-based extended-release tablet corresponds to a usage level of 20-30% of alginate with an average particle size of approximately 50 μm. Direct-compressed caffeine tablets formulated according to this guideline using 30% concentration of VIVAPHARM® Alginate PH 175 with PROSOLV 90 SMCC as filler/binder and magnesium stearate as lubricant consistently achieved 8-hour extended-release profiles.

Note

Unlike HPMC, alginates are anionic polymers that are sensitive to pH changes. This study employed different dissolution methods with and without pH change. Some interesting effects of the pH of the release medium on early-phase dissolution behavior were observed and analyzed. These highly complex findings will be reported separately in an additional article.   *For details, please contact our Pharmaceutical Department at JRS Turkey. Reference: [1] Leuenberger et al., Int. J. Pharm., 38 (1987) 109-115   Review and Translation: Seda Tüntaş Şenel Sales Manager Pharmaceuticals, Cosmetics and Home Care JRS Rettenmaier Turkey Natural Fibre Tic. Ltd. Co.