(W1130-07-45) Solubility Enhancement of Ibuprofen via Crystalline Solid Dispersions: A Comparative Study of Carriers and Optimization Using DoE

Purpose: Poor aqueous solubility remains a major limitation for the oral bioavailability of many drugs, including Ibuprofen, a BCS Class II compound. Solid dispersion (SD) techniques, particularly crystalline solid dispersions (CSDs), offer a strategy to enhance solubility while retaining the physical stability of the drug. Compared to amorphous solid dispersions (ASDs), which may suffer from recrystallization, CSDs preserve the crystalline nature of the drug, providing better long-term stability. This study aimed to develop and optimize CSD formulations of Ibuprofen using various pharmaceutical carriers and a Twin-Screw Granulator, applying a Box–Behnken design to identify critical formulation and process parameters influencing drug solubility and release. The objective was to achieve enhanced solubility and dissolution rates while maintaining the drug’s crystalline state for improved stability.

Methods: Initial screening of pharmaceutical carriers such as Mannitol, Xylitol, Sorbitol, Maltitol, Lactose monohydrate, Microcrystalline Cellulose (MCC), and Starch 1500 was conducted based on their ability to improve drug solubility, dissolution rate in purified water, and compatibility with Ibuprofen. Crystalline solid dispersions were prepared using Hot-Melt Extrusion (HME) with 30% drug load, 2.5% superdisintegrant (sodium starch glycolate), and 1% magnesium stearate as a lubricant before tablet compression. A three-factor, three-level Box–Behnken design was employed to study the effect of drug loading (20–50%), feed rate (0.5–1.3 g/min), and processing temperature (85–115 °C) on two responses: solubility and drug release. Formulations were characterized by Differential Scanning Calorimetry (DSC) to evaluate crystallinity, X-ray Diffraction (XRD) for solid-state confirmation, and Scanning Electron Microscopy (SEM) for morphological assessment. Drug-carrier interactions were analyzed using Fourier-Transform Infrared Spectroscopy (FTIR) and Proton Nuclear Magnetic Resonance (¹H-NMR) in DMSO-d₆. Solubility studies were conducted for the pure API, physical mixtures, and CSD extrudates in purified water, 0.1N HCl, pH 4.5 acetate buffer, and pH 7.2 phosphate buffer. Dissolution profiles were generated in these four media for the pure drug, physical mixtures, CSD extrudates, and marketed formulations. Final formulations were compressed into tablets, and physical characterization included weight variation, hardness, friability, disintegration time, drug content analysis, and dissolution testing.

Results: Screening studies showed that all seven carriers improved solubility and dissolution rates compared to the pure drug, with Lactose monohydrate demonstrating the highest enhancement. This was attributed to improved wettability and hydrogen bonding interactions with Ibuprofen, supported by FTIR and NMR findings. FTIR spectra showed a shift in the carboxylic acid peak (~1700 cm⁻¹), while NMR analysis revealed the disappearance of the carboxylic proton peak at δ = 12.34 ppm in the CSD, confirming strong drug–carrier interaction. DSC results indicated that approximately 83.6% of Ibuprofen retained its crystalline state in the optimized CSD, confirming crystallinity and eliminating the risk of complete amorphization. SEM images showed uniform dispersion and reduced particle size in the extrudates. Solubility studies showed significant improvement with optimized CSDs compared to the pure drug and physical mixtures. Dissolution testing across multiple pH conditions revealed that the optimized formulation provided enhanced drug release profiles compared to the pure drug, physical mixture, and marketed formulation. The Box–Behnken design revealed that lower drug loading and higher processing temperatures improved solubility, while a slower feed rate enhanced drug release. Based on the desirability function, the optimized formulation was achieved at 20% drug loading, 115 °C processing temperature, and 0.5 g/min feed rate. This optimized formulation demonstrated improved solubility and dissolution in all media tested and maintained its physical and chemical stability upon storage. Stability studies (1 month at 40°C/75% RH) confirmed that 79.8% of the drug remained in crystalline form, compared to the initial 83.6%, indicating that only 3.8% had converted to the amorphous form. Drug release profiles remained consistent with initial results.

Conclusion: Crystalline solid dispersions offer an effective and stable strategy to enhance the solubility and dissolution of poorly water-soluble drugs like Ibuprofen. Lactose monohydrate was identified as the most suitable carrier due to its hydrophilicity and ability to form hydrogen bonds with the drug. The Box–Behnken design provided insights into critical process parameters affecting formulation performance. The optimized CSD formulation showed significant improvement in solubility and drug release across a range of physiological media and retained its crystalline structure, as confirmed by DSC and XRD. The formulation remained stable over one month in terms of both crystallinity and dissolution. Compared to ASDs, the CSD formulation demonstrated superior stability and processability. These findings highlight the potential of CSDs as a robust platform for enhancing the oral bioavailability of poorly soluble APIs.

References: 1. Jaywant N. Pawar, Ritesh A. Fule, Mohammed Maniruzzaman, Purnima D. Amin, Solid crystal suspension of Efavirenz using hot melt extrusion: Exploring the role of crystalline polyols in improving solubility and dissolution rate, Materials Science and Engineering: C, Volume 78, 2017, Pages 1023-1034, ISSN 0928-4931, https://doi.org/10.1016/j.msec.2017.04.055
2. Bárdos, V., Szolláth, R., Tőzsér, P., Mirzahosseini, A., Sinkó, B., Angi, R., & Takács-Novák, K. (2025). Study of the Influence of Pharmaceutical Excipients on the Solubility and Permeability of BCS Class II Drugs. Scientia Pharmaceutica, 93(2), 19. https://doi.org/10.3390/scipharm93020019


Solubility and drug release study of pure drug, and CSD formulations with different carriers with 30% drug loadings in purified water.


3D response surface plots of CSD (DoE runs) formulations for solubility and dissolution in purified water


DSC thermogram, Solubility and Drug release study of Ibuprofen, Physical Mixture, Optimized CSD formulation and Marketed formulation in Water, 0.1N HCl, pH 4.5 Acetate buffer, pH 7.2 Phosphate buffer.