(M1230-07-38) Improved Ibuprofen Tablet Formulation Using Co-Processed Excipients Containing Polyethylene Glycol 8000

Purpose: Ibuprofen is a widely used non-steroidal anti-inflammatory drug (NSAID) to reduce fever, treat mild to moderate pain, and manage inflammation associated with conditions like arthritis. Ibuprofen requires particle size reduction to improve solubility, followed by granulation to improve powder flow and compressibility characteristics^1,2. Consequently, commercialized ibuprofen tablets typically contain eight to ten excipients, making it challenging for finished drug product manufacturers to qualify, manage, and maintain excipient suppliers. Direct compression is the preferred method for tablet manufacturing due to its cost-effectiveness and ease of scale-up. Recently, co-processed excipients (CPE) have gained attention due to their ability to reduce the number of excipients needed while addressing challenges related to direct compression, such as flowability, compressibility, capping, lamination, and weight uniformity³. This study aimed to develop and optimize an ibuprofen tablet formulation by direct compression using co-processed excipients, focusing on key factors such as powder flowability, compressibility, weight uniformity, and hardness.

Methods: Over fifty formulations comprising various blend compositions and ratios of mannitol, sorbitol, microcrystalline cellulose (MCC), dibasic calcium phosphate, colloidal silicon dioxide (SiO₂), polyethylene glycol (PEG) 8000 were co-processed using spray-drying. Each co-processed formulation was tested for flowability, mixability, disintegration, and hardness. The four most favorable CPEs (CPE A – CPE D) were then characterized and evaluated in tablet formulations containing ibuprofen. All tablets were made by direct compression on a Korsch STYL’One Nano with comparable attributes to a benchmark 200-mg ibuprofen tablet (9 mm round, 300 mg weight, 141 N hardness). Each formulation was tested for compressibility, weight uniformity, and hardness. Tablet weights were measured using a Mettler Toledo XSR Excellence Precision Balance, and hardness was measured with a Sotax MT50 Hardness Tester. The CPEs were screened for flowability per USP-NF General Chapter < 616 > Bulk Density of Powders (Table 1). Each CPE’s physical characteristics were evaluated after dry blending with ibuprofen and/or silica gel. Half of the required amounts of ibuprofen and silica gel were mixed with each CPE using a Hauschild SpeedMixer for 10 s at 800 rpm. The remaining half of the ibuprofen and silica gel were added into the mixture and mixed for an additional 30 s at 800 rpm. After tableting, only the most promising CPE was retained for formulation optimization. The formulation containing CPE C was optimized by varying the amounts of silica gel and magnesium stearate. Additionally, a vibration/shock frequency of 10 Hz was introduced to the Korsch STYL’One Nano hopper to further improve powder flow.

Results: The compressibility index and Hausner ratio were calculated using the tap density of each CPE (Table 1). CPE B, C and D exhibited passable powder flow, while CPE A was excluded from the study due to poor powder flow. CPE B and D required external addition of silica gel to improve overall flowability. CPE C was chosen for formulation optimization as it already contained SiO₂. The external addition of 2% silica gel and the introduction of 10 Hz vibration/shock frequency to the hopper (V4 – Table 2) improved mixability, powder flow and weight uniformity without compromising hardness. However, the V4 scale-up process revealed sticking issues. Further refinements with magnesium stearate (V5 and V6 – Table 2) resulted in lower hardness values, even at higher compression forces, and were therefore abandoned. V7, with an increased amount of silica gel (3%), proved to be the most successful based on the flowability, weight uniformity, and hardness results. No sticking was observed during scale-up, and uniform weight and hardness distribution were maintained throughout the batch (Figure 1).

Conclusion: The purpose of this study was to create an optimized ibuprofen tablet formulation with attributes comparable to a benchmark 200-mg ibuprofen tablet. Multiple co-processed excipient blends were produced and evaluated for suitable physical properties, including powder flowability, compressibility, weight uniformity, and hardness. CPE C V7 was the most promising, providing an optimized tablet formulation after dry blending ibuprofen and silica gel followed by direct compression. Formulation V7 bypassed the wet granulation steps typically used in the industry and reduced the total number of excipients needed in the formulation.

References: 1. Ofokansi, K. C., Kenechukwu, F. C., Ezugwu, R. O. & Attama, A. A. Improved dissolution and anti-inflammatory activity of ibuprofen-polyethylene glycol 8000 solid dispersion systems. Int. J. Pharm. Investig. 6, 139–147 (2016).
2. Le, V. N. P., Leterme, P., Gayot, A. & Flament, M. P. Influence of granulation and compaction on the particle size of ibuprofen—Development of a size analysis method. Int. J. Pharm. 321, 72–77 (2006).
3. Thulluru, A., Madhavi, C., Nandini, K., Sirisha, S. & Spandana, D. Co-Processed Excipients: New Era in Pharmaceuticals. Asian J. Res. Pharm. Sci. 9, 1 (2019).

Acknowledgements: Disclaimer: This research material is provided in good faith for informational purposes only. Dow or Univar Solutions USA LLC assume no obligation or liability for the information disclosed herein.

Table 1. Co-Processed Excipients (CPE) A – D Flowability

Table 2. CPE C Ibuprofen Formulation Optimization

Figure 1. CPE C Ibuprofen Formulations Optimization and Scale Up – Weight Uniformity