(T1530-06-39) Development and Evaluation of Stable 24-Hour Sustained-Release Tablet Formulations with Alcohol-Induced Dose Dumping Prevention

Purpose: Sustained release (SR) formulations are designed to prolong drug release and maintain therapeutic plasma concentrations over extended periods, thereby enhancing patient adherence and outcomes. These formulations offer advantages over immediate-release products, especially when the latter require multiple daily doses that may lead to subtherapeutic or toxic plasma levels¹. This study aimed to develop and evaluate the accelerated stability of direct compression (DC) SR formulations designed to deliver a soluble model drug, caffeine, over 24 hours. A coprocessed matrix of polyvinyl acetate (PVAc) and povidone 30 (PVP) was selected as the primary release-modulating agent. The impact of additional matrix adjuvants was assessed to fine-tune the dissolution profile and evaluate formulation robustness, including resistance to alcohol-induced dose dumping.

Methods: Sustained release tablets were formulated using caffeine granular (Sigma) at a fixed 60% drug load. Kollidon® SR (BASF), a PVAc-based, non-erodible matrix with PVP as a pore-former, served as the primary SR excipient². Additional matrix formers included hydrogenated castor oil (Kolliwax® HCO, BASF), a hydrophobic agent³, and Carbopol® 71G NF (Lubrizol), a hydrophilic-gelling polymer⁴. Mesoporous silica (Syloid® 63 FP, Grace) was evaluated as a moisture scavenger to enhance stability and mitigate humidity impact during 6 months (6M) of accelerated stability testing (40 °C/75% RH)⁵. Magnesium stearate (Spectrum-Chemical) was used as the lubricant. Based on the initial screening study, matrix formulations containing Kollidon® SR were developed and evaluated. The composition details are shown in Figure 1. Tablets were prepared via direct compression by first sifting Kollidon® SR through a #40 mesh, followed by co-sifting caffeine and other excipients (excluding the lubricant). The sifted mixture was blended in a V-blender at 20 rpm for 15 minutes, then lubricated for 5 minutes. Tablets were compressed using a Korsch XL100 rotary press with 10 mm concave punches at 20 rpm. Tablet compression parameters are shown in Figure 1. Dissolution testing of SR tablets (n=6) was conducted using USP Apparatus II (paddle) at 100 rpm in 900 mL of water at 37 °C ± 0.5 °C. The concentration of the dissolved drug was accessed through an UV–VIS spectrometer⁶⁻⁷. Results are shown in Figure 2. Accelerated stability study was conducted on tablets packed in high-density polyethylene (HDPE) bottles with induction sealing, and two grams of MiniPax® desiccant (Multisorb Filtration) were added per container for additional moisture protection. Dissolution testing was repeated after 6M under accelerated conditions. Dissolution profiles before and after stability testing were compared using the similarity factor (f₂), with values ≥50 indicating comparable profiles⁸. To assess alcohol-induced dose dumping, dissolution was also conducted in a hydroalcoholic medium (60% v/v 0.1N HCl and 40% v/v ethanol) for 2 hours, complying with FDA guidelines⁹.

Results: All formulations exhibited suitable powder flow and compressibility due to the excellent flowability and plastic deformation of Kollidon® SR¹⁰. Tablets from all three formulations achieved a 24-hour SR profile, and dissolution remained stable after 6M storage in accelerated conditions when compared to the initial profile, with f₂ values of 54.31, 51.05, and 85.10 for formulations 1, 2 and 3 respectively, indicating statistically similar profiles. The addition of functional excipients influenced release kinetics. Compared to the pure polymer (Formulation 1), Formulation 2, which contains Kolliwax® HCO (hydrophobic polymer) and Syloid® 63 FP, decreased the drug release. In contrast, Formulation 3, which contains Carbopol® 71G (hydrophilic polymer) and Syloid® 63 FP, slightly accelerated the drug release. These results demonstrate that SR drug release can be modulated using hydrophilic (accelerating) or hydrophobic (retarding) matrices. Notably, Formulation 3 showed the highest f₂ value, indicating the least susceptibility to accelerated stability conditions. No alcohol-induced dose dumping was observed in any SR formulation, either on initial samples or 6M stability samples (Figure 3). Kollidon® SR and Carbopol® appeared to retard drug release in hydroalcoholic medium, partly due to reduced caffeine solubility in ethanol and the lack of solubility of these polymers in this media⁴^,¹¹. Formulation 2 containing Kolliwax® HCO showed similar drug release in 0.1N HCl and hydroalcoholic medium with an f2 value of 81.57.

Conclusion: Stable 24-hour sustained-release tablets were successfully developed using Kollidon® SR via direct compression at high drug loading. These formulations demonstrated robust performance under accelerated storage conditions, particularly when packaged with desiccant in sealed HDPE containers. No alcohol-induced dose dumping was observed, supporting the suitability of Kollidon® SR for sustained release formulations of soluble drugs such as caffeine.

References: 1. Florence, A.T., & Attwood, D. (2016). Physicochemical Principles of Pharmacy (6th ed.). Pharmaceutical Press.
2. Sakr, W., Alanazi, F., & Sakr, A. (2011). Effect of Kollidon® SR on the release of albuterol sulfate from matrix tablets. Saudi Pharmaceutical Journal, 19(1), 19–27.
3. Amaral, M.H., Lobo, J.M.S., & Ferreira, D.C. (2001). Effect of hydroxypropyl methylcellulose and hydrogenated castor oil on naproxen release from sustained-release tablets. AAPS PharmSciTech, 2(2), 20.
4. Lubrizol Advanced Materials, Inc. (n.d.). Carbopol® 71G NF Polymer. https://www.lubrizol.com/Health/Pharmaceuticals/Excipients/Carbopol-Polymer-Products/Carbopol-71G-NF-Polymer
5. Grace W.R. (n.d.). SYLOID® 63 FP. https://www.chempoint.com/products/grace/syloid-silicas/syloid-silica-excipients/syloid-63-fp
6. U.S. Pharmacopeia. General Chapter The Dissolution Procedure: Development and Validation.
7. Kumawat, M.K., Tewatia, S., Ajmal, G., & Mittal, P. (2022). Caffeine in Tablet Dosage Form: Analytical Method Development and Validation by Using U.V. Spectroscopy: Pharmaceutical Science-Pharmaceutics. International Journal of Life Science and Pharma Research, 13(1), 107–115.
8. Stevens, R.E., Gray, V., Dorantes, A., Gold, L., & Pham, L. (2015). Scientific and Regulatory Standards for Assessing Product Performance Using the Similarity Factor, f2, 17, 301–306.
9. U.S. Food and Drug Administration. (2022). Bioavailability Studies Submitted in NDAs or INDs- General Considerations: Guidance for Industry. https://www.fda.gov/media/121311/download.
10. BASF Pharma Solutions. Kollidon® SR. https://pharma.basf.com/products/kollidon-sr
11. Bustamante, P., Navarro, J., Romero, S., & Escalera, B. (2002). Thermodynamic origin of the solubility profile of drugs showing one or two maxima against the polarity of aqueous and nonaqueous mixtures: niflumic acid and caffeine. Journal of Pharmaceutical Sciences, 91(4), 874–883.


Figure 1: Caffeine SR formulations and tableting process results


Figure 2: Dissolution profile of Formulation 1, 2 and 3. Initial and after 6M of accelerated stability


Figure 3: Dissolution profile of Initial and stability samples of Formulations 1, 2 and 3 in 0.1N HCl and 0.1N HCl + 40% ethanol