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Review Article
Technological approaches to increase the bioavailability of Ibuprofen
expand article infoViktorio Veselinov Mihaylov‡, Mihaela Tosheva‡, Viktor Petrov‡, Stefka Titeva‡
‡ Medical University - Pleven, Pleven, Bulgaria

Corresponding author: Viktorio Mihaylov ( viktorio.mihaylov@mu-pleven.bg )

Academic editor: Denitsa Momekova
© 2025 Viktorio Mihaylov, Mihaela Tosheva, Viktor Petrov, Stefka Titeva.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation: Mihaylov V, Tosheva M, Petrov V, Titeva S (2025) Technological approaches to increase the bioavailability of Ibuprofen. Pharmacia 72: 1-11. https://doi.org/10.3897/pharmacia.72.e149517
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Abstract

Ibuprofen is a BCS class II drug with poor water solubility and high permeability. The oral bioavailability is limited by the drug dissolution step. This is the reason that high doses of the drug are required in order to reach the therapeutic plasma concentration after oral administration, causing the occurrence of adverse reactions, mostly related to the gastrointestinal tract in the case of Ibuprofen. This necessitates the investigation of various methods to increase the solubility and hence bioavailability of Ibuprofen, thereby also aiming to reduce the dose and side effects. The present review describes the main technologies used to enhance the solubility and thereby reduce the dose included. These technologies include micronization, nanosizing, crystal engineering, solid dispersions, cyclodextrins, solid lipid nanoparticles, microemulsions, self-emulsifying, and self-microemulsifying drug delivery systems, as well as the results obtained by a number of scientists who conducted research on the methods in question.

Keywords

Ibuprofen, solubility, bioavailability, microemulsions, SEDDS

Pharmacological and physicochemical characteristics of Ibuprofen

Ibuprofen is a widely used non-steroidal anti-inflammatory drug (NSAID). It’s mainly used as a racemic mixture and is a non-selective inhibitor of the cyclooxygenase enzymes COX-1 and COX-2. Cyclooxygenase enzymes are a key part in the synthesis of prostanoids – prostaglandin (PG) E2, PGD2, PGF2α, PGI2 (also known as prostacyclin), and thromboxane (Tx) A2 – from arachidonic acid, and thus Ibuprofen exerts its anti-inflammatory, analgesic, and antipyretic effects. Inhibitory action on neutrophil aggregation and degranulation, as well as proinflammatory cytokine production by immune cells, is also suggested for Ibuprofen by several researchers. Increased levels of the endocannabinoid anandamide, an activator of the antinociceptive axis through the cannabinoid receptors (CB1 and CB2) in the CNS, are also observed. It is mainly used in the treatment of mild to moderate pain associated with dysmenorrhea, headache, migraine, postoperative and dental pain, and in the treatment of spondylitis, osteoarthritis, rheumatoid arthritis, and soft tissue disorders. Ibuprofen is considered one of the safest NSAIDs available (Potthast et al. 2005; Bushra and Aslam 2010; Mazaleuskaya et al. 2015).

Ibuprofen has lipophilic properties and is poorly soluble in water. The solubility of Ibuprofen is pH-dependent and is particularly low in the acidic environment of the stomach. As the pKa (in the range of 4.5–4.6) is reached and at pH values above the pKa, an increase in the solubility of Ibuprofen is observed as a result of ionization, which has been proven by various authors. Ibuprofen does not exhibit genuine polymorphism, but it tends to slightly modify the crystal lattice, which may also affect its solubility. (Higgins et al. 2001; Janus et al. 2020) For the octanol-water partition coefficient log P values of 3.7, 3.6, 2.1, and 1.2 are obtained at pH values of 1, 4, 6, and 7, respectively. Using different atomic contributions to lipophilicity-based methods, other authors have estimated log P and Clog P values of 3.68 and 3.14, respectively (Higgins et al. 2001; Kasim et al. 2004).

Ibuprofen is most commonly administered orally. Following oral administration of Ibuprofen, it is rapidly and completely absorbed, and maximum plasma concentrations are reached within 1–2 h in humans with an absolute bioavailability (BA) of about 100%. It is rapidly bio-transformed with a serum half-life of 1.8 to 2 hours. Rapid and complete absorption suggests a high permeability through the GI membrane, which has been proven by conducting scintigraphic studies with sustained-release products in humans as well as studies on mice (Parr et al. 1987; Reuter et al. 1997; Bushra and Aslam 2010). Consistent with the high degree of plasma protein binding (>99%), Ibuprofen exhibits a low apparent volume of distribution that approximates plasma volume (0.1–0.2 l/kg). It is able to penetrate into the central nervous system (CNS) and accumulate at peripheral sites where its analgesic and anti-inflammatory effects are required. Ibuprofen is present in a free, unbound form in cerebrospinal fluid and is retained in the synovial fluid in the inflamed joints of arthritic patients. The therapeutic concentration range for Ibuprofen is in the range of ̴ 10–50 mg/l. Its relatively short plasma half-life (t1/2, ̴ 1–3h) determines the necessity of frequent administration to maintain therapeutic plasma concentrations (Bushra and Aslam 2010; Mazaleuskaya et al. 2015). There are no known metabolites of Ibuprofen that are pharmacologically active. Hepatic biotransformation results in two inactive main metabolites, which are excreted either free or as conjugates in urine. Total urinary recovery of Ibuprofen and its metabolites is about 70–90% of the administered dose. There is almost no unchanged Ibuprofen detected in the first 24 hours in urine. About 10% of the administered dose is eliminated via feces. Neither Ibuprofen nor the metabolites accumulate after multiple doses (Davies 1998; Potthast et al. 2005).

Pharmaceutical technologies for enhancing oral bioavailability of Ibuprofen

Ibuprofen is a Biopharmaceutical classification system class II drug with low solubility and high permeability through the cell membranes, which necessitates the study of different methods to increase solubility and hence bioavailability (Fig. 1). The main technologies to achieve the enhanced oral bioavailability of drugs with poor aqueous solubility include the use of micronization, nanosizing, crystal engineering, solid dispersions, cyclodextrins, solid lipid nanoparticles, and other colloidal drug delivery systems such as microemulsions, self-emulsifying drug delivery systems, self-microemulsifying drug delivery systems, and liposomes (Krishnaiah 2010).

Figure 1. 

Technological approaches for enhancing oral bioavailability of Ibuprofen.

Micronization and nanosizing

Nanotechnology has opened new avenues for bioavailability enhancement, with nanocrystal formulations standing at the forefront. By reducing drug particles to nanoscale dimensions, typically through techniques like wet-milling or high-pressure homogenization, nanocrystal formulations can dramatically increase the specific surface area of drug particles, enhancing the dissolution rates (Parmar et al. 2021).

The field of nanocrystal technology has also seen significant enhancement. Sophisticated milling processes, including combination approaches of wet- and cryo-milling, have enabled the production of nanocrystals with enhanced stability and narrow size distributions. The sizing of a drug to the submicron range increases its surface area and consequently its dissolution rate and bioavailability (Al-Kassas et al. 2017). Particle sizes in the range of 100 to 200 nm are achieved through different methods, with the following being researched for Ibuprofen: solvent/antisolvent precipitation, spray drying, particles from gas-saturated solution, supercritical antisolvent technique, supercritical fluid technique, and wet milling (Table 1).

Table 1.
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Micronization and nanosizing studies on Ibuprofen.

Manufacturing method Achieved particle size Results Ref.
Solvent/antisolvent precipitation with isopropyl alcohol as solvent 200–450 nm compared to 90–425 micron for the raw Ibuprofen Ibuprofen dissolves mostly in the first 30 minutes for the nanoparticles and approximately 2.33 times better than the raw Ibuprofen. Mansouri et al. 2011
Spray drying of nano-suspensions 5–10 µm compared to range of 20–30 µm to 80–120 µm initial size of Ibuprofen The dissolution studies show almost complete Ibuprofen release after 2 min, similar to the nanosuspension. Plakkot et al. 2011
PGSSTM (Particles from gas-saturated solution) – based method on Ibuprofen-PEG6000 mixtures 20–50 nm compared to 1–6 µm for Ibuprofen particles After 2 hours: 53% for the Ibuprofen raw particles, 71% for the Ibuprofen particles from direct mixing, and 79% for the Ibuprofen nanoparticles. Chen et al. 2013
Supercritical anti-solvent technique 87–264 nm compared to original particle size of 144 ± 87 µm Increased dissolution rate of the drug and hence better bioavailability. Mezzomo et al. 2015
Supercritical fluid technique 2.8–7.3 µm compared to 180 µm for the raw Ibuprofen Particles of the micronized Ibuprofen show better solubility in the first 40 min of the test, as well as better results in the permeability test. Sosna et al. 2019
Wet milling technique 1.7 µm compared to 71.3 µm for the raw Ibuprofen 147.4 µm/ml saturated solubility in PBS solution has been achieved. Micronized Ibuprofen shows 100% release in 120 min compared to 55.9% for the original drug particles. Sharif et al. 2022

Mansouri et al. (2011) receive 200–450 nm particle size using solvent/antisolvent precipitation with isopropyl alcohol as solvent and approximately 2.33 times better Ibuprofen release. Chen et al. (2013) receive 20–50 nm particle size using the PGSSTM (particles from gas-saturated solution) – based method on Ibuprofen-PEG6000 mixtures. The drug release from the nanoparticles is around 50% better than that of the raw particles. Using the wet milling technique, Sharif et al. (2022) receive a 1.7 µm particle size and almost 2 times better Ibuprofen release with 100% released after 2 hours compared to 55.9% for the raw Ibuprofen.

Common setbacks for the nanosizing technique are the deterioration of the flow properties and wettability of particles and development of electrostatic forces, leading to problematic formulations. Neurological and respiratory damage, circulatory problems, and toxicity are also reported (Dizaj et al. 2015).

The nanoparticles should be stabilized and formulated rigorously to retain their nature and properties in standard dosage forms such as capsules or tablets suitable for oral administration (Al-Kassas et al. 2017).

Crystal engineering

Crystal engineering has been used for improving the solubility, dissolution rate, and subsequent bioavailability of Ibuprofen. The resulting materials have suitable dissolution characteristics while maintaining their chemical and physical stability over long periods of time. Controlled crystallization of drugs results in the production of high-purity powders with well-defined particle size distribution, crystal habit, crystal form (crystalline or amorphous), surface nature, and surface energy (Blagden et al. 2007).

Different methods for crystallization of Ibuprofen such as the solvent change technique, solvent evaporation technique, and crystallization technique in the presence of disintegrants, have been used (Table 2). Rasenack and Muller (2002) and Nokhodchi et al. (2010) find that using the solvent change technique in the presence of different water-soluble additives, except PEG chains, improves the dissolution performance. Crystallization technique in the presence of starch and sodium starch glycolate is studied by Nokhodchi et al. (2015), and significantly improved properties for Ibuprofen are achieved. On the other hand, the highest concentrations of disintegrants show slower dissolution. Vaghela and Tank (2010) receive an increase in Cmax, Tmax, and AUC using the solvent evaporation process in the presence of saccharin sodium.

Table 2.
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Crystal engineering studies on Ibuprofen.

Manufacturing method Results Ref.
Solvent change technique Improvement of the dissolution rate is observed when the crystallization is conducted in the presence of a water-soluble additive. Rasenack and Muller 2002
Solvent change technique The dissolution studies show that in the absence of additive and in the presence of 5% w/w PEG 8000 and PEG 6000, crystallized Ibuprofen shows poorer dissolution performance than the commercial Ibuprofen. Nokhodchi et al. 2010
Crystallization technique in the presence of starch and sodium starch glycolate The dissolution test shows significantly improved properties for Ibuprofen crystallized in both 1 or 5% starch and 0.25–5% sodium starch glycolate. The highest concentrations of disintegrants show slower dissolution due to the formation of a viscous layer around the Ibuprofen particles. Nokhodchi et al. 2015
Solvent evaporation process in presence of saccharin sodium Increase in the pharmacokinetic parameters like Cmax, Tmax, and AUC for the Ibuprofen crystals compared to the standard group. Vaghela and Tank 2020

The resulting polymorphs of the same drug may differ in their physicochemical properties, such as solubility, dissolution rate, melting point, and stability (Blagden et al. 2007).

Solid dispersion

Solid dispersions have been used by a number of authors as an effective method for enhancing the dissolution rate and thus the bioavailability of Ibuprofen (Table 3). The method is based on the preparation of an Ibuprofen-polymer two-component system with water-soluble polymers such as PEG, PVP, PVA, Eudragit, HPMC, as well as others. Solid dispersions are usually prepared by heating mixtures of the drug and carrier to a molten state, followed by resolidification by way of cooling. Another method used for the preparation of solid dispersions is the solvent evaporation method, which involves dissolving the components in a mutually volatile solvent followed by evaporation (simple solvent evaporation, spray drying, lyophilization, electrostatic spinning, fluid-bed coating). Other methods, such as microwave irradiation, fusion method, kneading method, spray drying, electrospinning, and rotary evaporation, have also been used (Vasconcelos et al. 2007; Malkawi et al. 2022).

Table 3.
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Solid dispersions studies on Ibuprofen.

Manufacturing method Carrier/s Results Ref.
Solvent and fusion-solvent methods PEG, PVP, Eudragit RS PO, Eudragit RL PO, HPMC Solid dispersions containing Eudragit or HPMC as carriers show retarded dissolution of Ibuprofen. Dabbagh and Taghipour 2007
Microwaves irradiation method PVP/VA 60/40 (PVP/VA 64), hydroxypropyl-β-cyclodextrin The systems containing hydroxypropyl-β-cyclodextrin show 90% release of drug within 5 min. Moneghini et al. 2008
Melt dispersion technique Macrogol 4000, Macrogol 6000 in 1:0.5, 1:1 and 1:1.5 ratios Faster and higher drug release is shown by the SDs containing Macrogol 6000 at the ratio of drug:carrier of 1:1.5. Al Masum et al. 2012
Solvent evaporation technique PEG 6000, PVP K30 More than 80% of Ibuprofen is released in 60 min from Ibuprofen solid dispersions using the PEG6000-PVP K30 combination in a 1:2:2 ratio. Hasnain and Nayak 2012
Solvent evaporation technique, fusion method and kneading method PEG 6000 in drug:carrier ratios of 1:1, 1:2 and 1:3 The formulation of the 1:2 ratio prepared by the fusion method shows drug release at 98.58%. Gawai et al. 2013
Solvent evaporation technique Glucosamine HCl in drug:carrier ratios of 1:1, 1:2 and 1:3 The percentage of Ibuprofen released in 120 minutes reaches over 40% for a solid dispersion with a ratio of 1:3 compared to about 20% for pure Ibuprofen. Wahab et al. 2013
Fusion (melt) method PEG 8000 in drug:carrier ratios of 1:1, 1:2, 1:3 and 1:4 Increased dissolution rate of Ibuprofen from the solid dispersions, with the best results being obtained at the Ibuprofen:PEG 8000 ratio of 1:4 Ofokansi et al. 2016
Spray-drying HPMCP-HP55, Kollidon VA 64 in 1:1 ratio and Ibuprofen:excipient ratios of 1:1, 1:2 and 2:3 Over 80% of the drug is released from all spray-dried samples in less than 10 minutes compared with less than 20% released at the same time from pure Ibuprofen Ziaee et al. 2017
Spray-drying, electrospinning and rotary evaporation HPMCAS or HPMCP-HP55 in Ibuprofen:excipient ratios of 1:9, 3:7, 5:5, 7:3 and 9:1 The fastest release profile is observed in the electrospun samples, where over 65% of the drug is released in the first 5 minutes. Ziaee et al. 2019

A retarded release of Ibuprofen is achieved by Dabbagh and Taghipour (2007) using the solvent and fusion-solvent methods with Eudragit or HPMC as carriers. A study conducted by Gawai et al. (2013) compares the solvent evaporation technique, fusion method, and kneading method for the preparation of solid dispersions with PEG 6000 as а carrier. The best results are achieved using the fusion method with a drug:carrier ratio of 1:2 with 98.58% Ibuprofen released after 2 hours. The spray-drying method is studied by Ziaee et al. (2017, 2019), resulting in more than 80% Ibuprofen released from all spray-dried samples in less than 20 minutes compared to 20% from pure Ibuprofen.

Solid dispersions are not commonly used because the exposure to moisture during storage can lead to phase separation and instability, resulting in the conversion of the amorphous drug into a less soluble crystalline form. Their preparation is relatively expensive, and reproducibility cannot be guaranteed. Incorporating solid dispersions into some dosage forms could also be a challenge (Ghasemiyeh and Mohammadi-Samani 2018).

Cyclodextrin complexes

Cyclodextrins have long been recognized for their ability to form inclusion complexes with poorly soluble drugs, effectively increasing their apparent solubility. Recent research has expanded on this concept, developing modified cyclodextrins with enhanced complexation efficiency and reduced toxicity (Wu et al. 2024). Cyclodextrin complexes are frequently used for enhancing the solubility or absorption of Ibuprofen. Hydrophobic molecules have greater affinity for the cyclodextrin cavity when they are in a water solution. They are resulting in better stability, high water solubility, increased bioavailability, or decreased undesirable side effects. Cyclodextrins are able to form non-covalent dynamic inclusion complexes in solution (Cheirsilp and Rakmaj 2016; Shalaby et al. 2021). The Ibuprofen-cyclodextrin complexes have been prepared through different methods, including freeze-drying, which is found by Khan et al. (2001) to achieve the best results compared to others, with 96.5% Ibuprofen released after 2 hours. Other methods studied are spray-drying and co-precipitation of a cyclodextrin/drug solution or simply grinding the slurry of drug and cyclodextrin (Table 4).

Table 4.
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Cyclodextrin studies on Ibuprofen.

Manufacturing method Results Ref.
Homogenous coprecipitation-evaporation, coprecipitation-centrifugation, spray drying and freeze drying methods Greatly enhanced solubility and dissolution rates of the complexes compared to that of the physical mixture. The freeze-drying method shows the best results, with up to 96.5% Ibuprofen released after 2 hours. Khan et al. 2001
Direct compression and extrusion/spheronization of powders containing inclusion complexes (Ibuprofen with β-cyclodextrin) The Ibuprofen released from the tablets and the two pellet formulations reaches almost 100% at 24 hours. Salustio et al. 2012
Physical mixture of Ibuprofen with β-cyclodextrin and hydroxypropyl-β-cyclodextrin in different pH The dissolution studies show increased aqueous solubility of Ibuprofen by the inclusion complexation with β-cyclodextrin and hydroxypropyl-β-cyclodextrin. Bagal and Joshi 2017
Spray-drying technique with a 1:1 molar ratio of Ibuprofen and β-cyclodextrin, followed by direct compression The in vitro dissolution tests show more than 50% Ibuprofen released in the first 3 min from the five orally disintegrating tablet formulas. Purnamasari and Saputra 2020

Direct compression and extrusion/spheronization of powders containing inclusion complexes of Ibuprofen with β-cyclodextrin are used by Salustio et al. (2012), resulting in almost 100% released Ibuprofen after 24 hours from the tablets and pellet formulations. More than 50% Ibuprofen released is achieved by Parnamasari and Saputra using the spray-drying technique, followed by direct compression.

A possible problem with cyclodextrins is the difficulty in stabilizing them due to the dependence on a number of factors, such as the nature of the used substances as well as their orientation within the cyclodextrin cavity, the type and degree of substitution of the cyclodextrins, and the reaction medium (Aiassa et al. 2023).

Lipid-based nanoparticles

Lipid-based nanoparticles are a group that includes emulsified systems, such as microemulsions, solid lipid nanoparticles, self-emulsifying and self-microemulsifying drug delivery systems, as well as liposomes, and have gained significant attraction for enhancing the bioavailability of lipophilic drugs. However, conventional emulsions are associated with the presence of many problems, most often related to stability. With more modern methods such as microemulsions, solid lipid nanoparticles, self-emulsifying and self-microemulsifying drug delivery systems, these drawbacks are largely avoided (Krishnaiah 2010).

Solid lipid nanoparticles (SLNs)

Solid lipid nanoparticles are another technological approach studied for increasing the bioavailability of Ibuprofen by avoiding insufficient drug concentration due to poor absorption, rapid metabolism and elimination, poor drug solubility, and high fluctuation of plasma levels due to unpredictable bioavailability after peroral administration (Mehnert and Mader 2012; Yadav et al. 2013; Lingayat et al. 2017). Ibuprofen SLNs have been prepared through different methods, with high-pressure homogenization and microemulsion technology considered the most feasible methods for large-scale production of SLNs (Table 5).

Table 5.
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Solid lipid nanoparticle studies on Ibuprofen.

Lipid phase Results Ref.
Precirol ATO 5 (Glycerol distearate) Complete release of Ibuprofen from dextran hydrogels after 1 hour in HCl solution. About 75% of the drug is released from the SLNs after 2 hours in acid medium. Almost 60% of Ibuprofen is released from the SLN-hydrogel system after 2 hours in acid medium. Casadei et al. 2006
Stearic acid, trilaurin or tripalmitin as well as various stabilizers SLNs consisting of a trilaurin lipid matrix show almost 100% released Ibuprofen after 30 minutes. Tripalmitin SLNs also show increased dissolution rates, and 100% of Ibuprofen is released after 2 hours. Stearic acid SLNs show slower dissolution rates, with 100% released after 5 hours. Potta et al. 2011
Cetyl alcohol, polyvinyl alcohol (surfactant) and colloidal silicon dioxide Complete release of Ibuprofen is achieved with t50% = 1h when colloidal silicon dioxide is introduced in the aqueous phase. With the incorporation of colloidal silicon dioxide by the organic phase and Aerosil® R974 by the aqueous or organic phase, the kinetics are decreased with t50% = 5h. Perge et al. 2012
Stearic acid with Phospholipon-80H (Hydrogenated lecithin) as surfactant and Tween 80 as stabilizer in different proportions Ibuprofen release from different formulations is much higher than the pure drug. 1.5% Tween 80 concentration is considered optimal as it gives 75.58% Ibuprofen release up to a 6-hour period with a higher dissolution rate in the initial period. De Pintu et al. 2012
Stearic acid, Compritol 888 ATO (Glyceryl dibehenate) and Tripalmitin with surfactants (Poloxamer 188 and Tween 80) 40% of the Ibuprofen is released within the first 2 hours, and sustained release is observed for the next 90 hours in pH 7.4 phosphate buffer at 37 °C. Thakkar et al. 2015
Stearic acid 35.6% and 69% released Ibuprofen after 30 min and 300 minutes, respectively, compared to 19% and 26% for the Ibuprofen suspension. Akbari et al. 2015
Capmul GMS 50K (Glyceryl monostearates) with Gelucire 50/13 (Stearoyl polyoxyl-32 glycerides) as surfactant Short burst release with 10% Ibuprofen released, followed by a slow, steady, and sustained release with around 90% released after six days. Kumar et al. 2018
Stearic acid as a carrier matrix and polyvinyl pyrrolidone as a surfactant 94% and 96% of the Ibuprofen is released at the end of 7 hours and 8 hours, respectively. Initial burst release is not shown. Omwoyo and Moloto 2019

Potta et al. (2011) have established almost 100% Ibuprofen released after 30 minutes for solid lipid nanoparticles consisting of a trilaurin lipid matrix and 100% released after 5 hours for stearic acid SLNs. Complete release of Ibuprofen with t50% = 1 hour is achieved by Perge et al. (2012) with cetyl alcohol as the lipid phase, polyvinyl alcohol as the surfactant, and colloidal silicon dioxide introduced in the aqueous phase. Sustained release of Ibuprofen is achieved using SLNs by Thakkar et al. (2015), Kumar et al. (2018), and Omwoyo and Moloto (2019).

Difficulties encountered in the development of SLNs are low drug loading efficiency because of their perfect crystalline structure and the possibility of drug expulsion due to the crystallization process during the storage conditions. Another disadvantage is the initial burst release, which usually occurs with these formulations (Ghasemiyeh and Mohammadi-Samani 2018).

Microemulsions

Microemulsions containing Ibuprofen have been studied to increase its solubility and stability (Table 6). They are characterized by thermodynamic stability, solubilization capacity, structural morphology, physical property, and applicability. They avoid the disadvantages of classic emulsions. Microemulsions are composed of oil and water stabilized by an interfacial film of surfactant molecules, typically in conjunction with a co-surfactant. Oil-in-water microemulsions are preferred as a method for enhancing the solubility and dissolution rate of Ibuprofen (Moulik and Rakshit 2006).

Table 6.
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Microemulsion studies on Ibuprofen.

Oil phase Surfactants Co-surfactants Results Ref.
Peanut oil, Labrafac Lipophile WL1349 (Medium chain triglycerides), Labrafil M 1944CS (Oleoyl polyoxyl-6 glycerides) Tween 80, Labrasol (Caprylocaproyl Polyoxyl-8 glycerides), Cremophor RH40 (PEG-40 Hydrogenated Castor Oil), Span 80 Transcutol P, propylene glycol, ethanol Fast release of Ibuprofen, and the cumulative amount of drug released after 30 minutes is above 80% in pH 6.8 phosphate buffer, 0.1M HCl, and distilled water. Hu et al. 2011
Olive oil Sucrose ester L-1695 (Sucrose Laurate) Glycerol Improved absorption profile of the nanoemulsion compared to microemulsions and drug-in-oil systems, which is further confirmed by in vivo studies using rat models. Anuar et al. 2020

The optimal ratio of the components attained by Hu et al. (2011) is 17% oil (Labrafil M 1944 CS), 21% surfactant (Cremophor RH40), 7% co-surfactant (Transcutol P), and 55% water, achieving more than 80% released Ibuprofen after 30 minutes in pH 6.8 phosphate buffer, 0.1M HCl, and distilled water.

Possible factors that would make the development of microemulsions difficult are the relatively short shelf life, influence on the stability by environmental parameters like temperature and pH, limited solubilizing capacity for high melting substances, and requirement for non-toxicity of the used surfactant (Raut and Khandre 2022).

Self-emulsifying drug delivery systems (SEDDS) and self-microemulsifying drug delivery systems (SMEDDS)

Self-emulsifying drug delivery systems consist of the drug dissolved in a mixture of oils, surfactants, and co-solvents, which form fine oil-in-water emulsions upon contact with gastrointestinal fluids (Fig. 2). Typically, emulsions formed by SEDDS have a droplet size of 100 to 300 nm, while microemulsions formed by SMEDDS are transparent with a droplet size of less than 50 nm. SEDDS are physically stable formulations compared to conventional emulsions and are easy to manufacture. These systems provide an improvement in the rate and extent of absorption and lead to more reproducible blood-time profiles for lipophilic drug compounds that exhibit dissolution rate-limited absorption (Gursoy and Benita 2004).

Figure 2. 

Behavior of SEDDS in the gastrointestinal tract.

A SEDDS formulation typically consists of drug, oil, surfactant, and co-surfactant. Oil is the most critical excipient in SEDDS because it solubilizes the needed amount of the lipophilic drug. Both natural and/or synthetic oils can be employed. Oils improve lymphatic permeability in the intestines, solubility in gastric and intestinal fluids, protect the drug from biotransformation, and increase the dissolution rate, thereby increasing the bioavailability of Ibuprofen (Gursoy and Benita 2004; Baytok and Saka 2023).

Surfactants facilitate the dispersion process by forming the interfacial film and reducing the interfacial tension to a small value. Emulsifiers with an HLB value above 12 have the highest emulsifying performance. In general, non-ionic surfactants are preferred over ionic surfactants because they are less toxic (Dokania and Joshi 2015).

Co-surfactants reduce the interfacial tension to a negative value and form a flexible interfacial film, thus acquiring different curvatures necessary for microemulsion formulation over a wide range of compositions. Usually medium-chain-length alcohols (C3–C8) are preferred as co-surfactants (Dokania and Joshi 2015).

Many studies have been conducted proving the effectiveness of SEDDS in increasing the solubility and bioavailability of Ibuprofen (Table 7). The optimal ratios of components obtained from Wang et al. (2009) are 45% isopropyl myristate as the oil phase, 10% Span 20 and 22% Tween 80 as the surfactants, and 1,2-octanediol as the co-surfactant, resulting in more than 95% Ibuprofen released after 30 minutes. More than 90% of released Ibuprofen after 60 minutes is achieved from all stable SEDDS formulations containing peanut oil, Tween 80, and n-Octanol by Sharma et al. (2012). Similar results are achieved by Saritha et al. (2014) with more than 90% released Ibuprofen after 30 minutes for SEDDS containing Labrafac, Tween 80, and PEG 200. Fast releases with more than 80% released after 10 minutes (Nicholas et al. 2015) and 90.04 ± 1.764% after 10 minutes (Darusman et al. 2015) are also obtained. 99.87 ± 1.98% released Ibuprofen after 60 minutes is achieved by Penjuri et al. (2017) using Labrafil M2125 as the oil phase, Cremophor RH 40 as the surfactant and Plurol oleique CC as the co-surfactant.

Table 7.
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SEDDS, SMEDDS and S-SEDDS studies on Ibuprofen.

Oil phase Surfactants Co-surfactants Results Ref.
Isopropyl myristate Span 20, Tween 20 1,2-Octanediol The optimal SNEDDS formulation shows more than 95% Ibuprofen released within 30 minutes. A relationship between the emulsion droplet size and the dissolution rate has been observed. Wang et al. 2009
Castor oil Tween 20, Span 20 None Above 90% Ibuprofen is released from self-emulsifying capsules compared to about 61% released from conventional Ibuprofen tablets in pH 6.8 phosphate buffer. Sharma et al. 2011
Peanut oil Tween 80 n-Octanol All stable formulations of SEDDS release above 90% of Ibuprofen after 60 minutes, compared to 61% from the pure drug. Sharma et al. 2012
Labrafac (Medium chain triglycerides) Tween 80 PEG 200 More than 90% of Ibuprofen is released within 30 minutes. All SEDDS formulations show better dissolution profiles than the marketed product. Saritha et al. 2014
Lauroglycol 90 (Propylene glycol monolaurate (Type II)) Labrasol (Caprylocaproyl Polyoxyl-8 glycerides) Peceol (Glyceryl monooleate (Type 40)) More than 80% of Ibuprofen is released after 5 minutes from all formulations. T50 and T85 values are determined to be approximately 3 minutes and 5 minutes, respectively. Nicholas et al. 2015
Oleic acid Cremophor RH 40 (PEG-40 Hydrogenated Castor Oil) Propylenglycol SEDDS reaches 90.04±1.764% Ibuprofen released after 10 minutes compared to 59.33±1.638% for pure Ibuprofen powder. Darusman et al. 2015
Goat fat Tween 60 None SEDDS show good results in the in vitro dissolution test. Higher tween 60:goat fat content ratios give better release profiles. Mohammad et al. 2016
Labrafil M2125 (Linoleoyl Polyoxyl-6 glycerides) Cremophor RH 40 (PEG-40 Hydrogenated Castor Oil) Plurol oleique CC (Polyglyceryl-3 dioleate) The in vitro release profile is found to be significantly higher than that of the marketed formulation and pure drug, reaching 99.87±1.98% after 60 minutes. Penjuri et al. 2017
Labrafil M Cremophor EL PEG 400 100% drug release is achieved within 15 minutes for Ibuprofen self-microemulsifying dispersible tablets compared to 13.12% for plain medication. Bhattacharjee et al. 2021

A number of potential mechanisms for enhancing the bioavailability of lipophilic drugs are suggested. SEDDS are reducing the gastric transit and, in this way, increasing the time available for dissolution. Effective luminal drug solubility is also increased by the presence of lipids, forming intestinal mixed micelles and thereby increasing the solubilization capacity of the GI tract. SEDDS enhance the lymphatic transport for lipophilic drugs and increase bioavailability directly or indirectly by reducing the first-pass metabolism. SEDDS also enhance the drug and peptide bioavailability by increasing membrane fluidity, the opening of tight junctions, and inhibition of P-glycoprotein and CYP450. SEDDS/SMEDDS lead to the formulation of chylomicrons, which are absorbed primarily through the lymphatic system, thus avoiding the first-pass metabolism (Fig. 3).

Figure 3. 

Mechanism of absorption of SEDDS.

It is reported that long-chain triglycerides with carbon atoms higher than 12 are transported via intestinal lymphatics. Some lipids are reported to attenuate the activity of intestinal efflux transport and may reduce the enterocyte-based metabolism. For drugs with lower permeability, various combinations of oils and surfactants show permeability-enhancing properties (Kumar et al. 2010; Dokania and Joshi 2015; Kovvasu et al. 2019).

The disadvantages of liquid SEDDS related to their stability and relatively short shelf life can be avoided by developing solid SEDDS. They could be prepared by absorption into solid carriers, spray-drying, freeze-drying, and hot melt extrusion. The additional component that is included in S-SEDDS is the solid carrier. These can be water-soluble (polymer, protein, polysaccharide-based) and water-insoluble carriers (porous and non-porous silica absorbents, aluminosilicates, and carbonates). S-SEDDS are most often found in the form of tablets and capsules, and they are another method for improving Ibuprofen solubility, bioavailability, and stability. They have reduced production costs, as well as improved erratic absorption behavior of drugs with low aqueous solubility. Controlled drug release, prolonged gastric residence time, and improved permeability could also be achieved. The mechanism of absorption of the drug from S-SEDDS includes disintegration of the tablet or capsule and then self-emulsification under mild agitation in the stomach (Maji et al. 2021).

Conclusion

Various methods for increasing the solubility and bioavailability of Ibuprofen have been studied. Through them, better results were achieved in the Ibuprofen release. Many of these methods, such as nanosizing, crystal engineering, cyclodextrins, and solid dispersions, are associated with many drawbacks. Most often, these difficulties are related to low physical and chemical stability, difficulties in the preparation, expensive production, and low reproducibility of the results. Microemulsions have been identified as a method to successfully increase bioavailability associated with fewer setbacks, most often with their physical stability. These difficulties are avoided with the use of self-emulsifying and self-microemulsifying drug delivery systems. SEDDS, SMEDDS, and S-SEDDS appear to be innovative and promising approaches to increasing the solubility and bioavailability of Ibuprofen, and they should be given more attention in the future.

Additional information

Conflict of interest

The authors have declared that no competing interests exist.

Ethical statements

The authors declared that no clinical trials were used in the present study.

The authors declared that no experiments on humans or human tissues were performed for the present study.

The authors declared that no informed consent was obtained from the humans, donors or donors’ representatives participating in the study.

The authors declared that no experiments on animals were performed for the present study.

The authors declared that no commercially available immortalised human and animal cell lines were used in the present study.

Funding

The present study received financial support as part of research project №3/2024 „Technological and biopharmaceutical studies for the preparation and characterization of Ibuprofen loaded self-emulsifying systems (SEDDS)“, funded by Medical University – Pleven.

Author contributions

All authors have contributed equally.

Author ORCIDs

Viktorio Mihaylov https://orcid.org/0009-0008-7463-7596

Mihaela Tosheva https://orcid.org/0009-0007-5683-5989

Viktor Petrov https://orcid.org/0009-0009-3420-1779

Stefka Titeva https://orcid.org/0009-0002-2397-1574

Data availability

All of the data that support the findings of this study are available in the main text.

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