INTRODUCTION:

Curcumin, a polyphenolic derivative from turmeric (Curcuma longa), has garnered great interest in pharmaceutical research because of its broad spectrum of therapeutic actions¹. Curcumin, a polyphenolic derivative from turmeric (Curcuma longa), has garnered great interest in pharmaceutical research because of its broad spectrum of therapeutic actions², These are anti-inflammatory, antioxidant, anti-cancer, and neuroprotective activities, so Curcumin may be a potential therapeutic agent for numerous chronic diseases such as arthritis, cardiovascular diseases, neurodegenerative disorders, and cancer. Despite its potent pharmacological effects³. When administered orally Curcumin shows very low absorption, rapid metabolism, and poor systemic availability that limit its therapeutic effect. Solubility and dissolution rate of a drug are important for its absorption and bioavailability, especially for oral administration. Drugs with low water solubility generally have poor absorption, resulting in suboptimal therapeutic results, such as erratic or incomplete absorption⁴. Since curcumin is hydrophobicity, its solubility in water is below 0.01 mg/mL, so it's a critical limiting factor for its bioavailabity⁵. Consequently, there is a growing interest in developing solubility enhancement techniques for Curcumin to improve its dissolution rate and oral bioavailability. A number of approaches have been used to overcome the solubility limitations of insoluble drugs such as Curcumin. These techniques are devised to speed up the dissolution rate either by changing the physicochemical state of the molecule or by modifying the surrounding in which the molecule dissolves⁶. This work explores ten different methods for solubility enhancement to assess their ability to enhance the dissolution rate of Curcumin and compares those solutions based on dissolution profiles and calculations of dissolution efficiency (DE)⁷.

Solid dispersion is one of the best strategies for solubility enhancement, which consists in dispersing the drug into a hydrophilic carrier matrix⁸. Solid dispersions can be prepared by techniques such as solvent evaporation or melting (fusion) method. Dispersing Curcumin in carriers such as Polyvinylpyrrolidone (PVP) or Polyethylene Glycol (PEG 6000) converts the drug into an amorphous form with improved dissolution properties compared to its crystalline form. Also, Mannitol, a sugar alcohol, is employed as a solvent for its hydrophilic nature and for its capability to improve drug solubilization as a carrier. Micronization, one of the most frequently employed, methods, is to decrease the size of the drug to the micron or nanometer dimension^9–11. From decreasing particle size, the surface area offering dissolution is greater, giving higher drug dissolution rate. This approach is especially valuable for hydrophobic drugs such as Curcumin, for which slow dissolution is associated with poor interaction of the surface with water. Cyclodextrin complexation is another popular strategy of enhancing the solubility of poorly soluble drugs^1,12. Cyclodextrins are cyclic oligosaccharides with a hydrophobic core and hydrophilic exterior which can form inclusion complexes with hydrophobic drugs such as Curcumin. The hydrophobic drug is housed in the cyclodextrin cavity, therefore protected from the aqueous phase and dramatically enhanced solubility is achieved¹³. The application of surfactants is also a highly-established approach to solubility enhancement. Surfactants, like Sodium Lauryl Sulfate (SLS), lower the surface tension between the drug particles and the dissolution medium, making the drug better wetted and dispersed in aqueous conditions¹⁴. Also in this regard, Pluronic F-127, an amphiphilic block copolymer, can self-assemble into micelles in solution, and solubilize hydrophobic drugs, such as Curcumin, by encapsulating them into the hydrophobic center of the micelles. Nanoformulations in the area of drug delivery have been attracting considerable interest among researchers because of their potential to enhance the solubility of poorly soluble drugs¹⁵. When the drug particles are made down to the nanometer scale, nanoformulations not only increase the surface of the drug but also solubilize the drug through nanocarriers, like lipid-based nanoparticles. These nanoparticles offer a hydrophobic core enclosing the drug and increasing solubility and stability. PH modification is a simple, but practical tool for enhancing solubility of ionic drugs. Altering the pH of the dissolution medium allows the ionization state of the drug to be changed, and consequently, solubility can be increased. For Curcumin, solubility is enhanced at alkaline (pH 8.0) conditions, because the drug is ionized and thus more soluble in water. The co-solvent method exploits the synergistic effect of co-solvent solvents, such as ethanol and water, to improve the water solubility of hydrophobic drugs¹⁶. Ethanol possesses solubilizing properties for Curcumin, making it easier to dissolve in aqueous conditions. This method is highly suitable for drugs of lowwater solubility but soluble in organic solvents. Last, the hydrophilic matrix systems, comprised of the use of Hydroxypropyl Methylcellulose (HPMC), are extensively employed in the controlled-release formulations. A water-soluble polymer (HPMC) expands in the presence of aqueous conditions, forming a gel-like network, which regulates drug release, increases wettability, and improves solubility¹⁷.

Due to the broad spectrum of feasible techniques, this work presents an overall assessment of these ten methods in solubility enhancement of Curcumin ¹⁸. Through comparing the dissolution profiles and dissolution efficiency, we intend to find the optimal strategies of enhancing Curcumin's solubility and bioavailability. The lessons learned in this work can be used to develop other poorly soluble drugs, thereby moving towards the creation of better oral medications.

MATERIALS AND METHODS:

Materials:

Curcumin (99% pure) was obtained from Sigma-Aldrich. In this work, the hydrophilic carriers employed were Polyvinylpyrrolidone (PVP K30), Polyethylene Glycol (PEG 6000), and Mannitol, all of which are available from commercial suppliers. Additionally, β-cyclodextrin (Sigma-Aldrich) was used for inclusion complexation. Surfactants (Sodium Lauryl Sulfate (SLS) and Pluronic F-127) were added to improve wettability and solubility. Hydroxypropyl Methylcellulose (HPMC) was chosen for the hydrophilic matrix composition. Ethanol and water were employed as the solvents, and phosphate buffer (pH 6.8) was done for the dissolution experiments. All chemicals and reagents used were of analytical grade.

Methods:

Preparation of Solid Dispersions: Two solid dispersion methods were used: solvent evaporation method and melting method. Curcumin was prepared with the solvent evaporation method in the 1:4 drug-to-carrier ratio of PVP, PEG 6000, or Mannitol. The mixture was dissolved in ethanol and the solvent was evaporated in a rotary evaporator under reduced pressure¹⁹. Dry films were obtained and then ground into fine powders by means of a mortar and pestle. Melting method, Curcumin was doped into the molten carriers (PEG 6000 or Mannitol) at the melt temperatures and drop out into fine powders after rapid cooling and grinding²⁰.

Micronization: Curcumin was micronized by high-energy ball milling to reduce particle size and to increase the surface area. This was achieved for increasing the dissolution rate by means of the principle of enhanced surface-to-volume ratio²¹.

Cyclodextrin Complexation: The co-precipitation method enabled the preparation of Curcumin/β-cyclodextrin inclusion complex. Curcumin and β-cyclodextrin were dissolved in ethanol and water, respectively. The two solutions were combined and homogenized at room temperature. Following stirring for hours, the solvent was removed and the precipitate was collected, dried and pulverized to a fine powder.

Use of Surfactants: Surfactant solutions were made with Sodium Lauryl Sulfate (SLS) and Pluronic F-127. Curcumin was dispersed in these surfactant solutions, which decrease interfacial tension between Curcumin and water and hence enhance its solubility and wettability.

Nanoformulation: A lipid-based nanoformulation of curcumin was synthesized by encapsulating curcumin in solid lipid nanoparticles. Lipid nanoparticles were prepared by hot homogenization technique. The lipid (Compritol) was melted and Curcumin was dispersed into the molten lipid phase. The lipid phase was then diluted in hot water and emulsified with a surfactant using a high-speed homogenizer. After cooling, the resulting nanoformulation was collected.

pH Adjustment: The solubility of Curcumin was improved by dissolving it in a medium with an adjusted pH of 8.0. The alkaline environment enhanced the ionization power of Curcumin, resulting in its enhanced aqueous solubility.

Co-solvent Method: Curcumin was dissolved in a co-solvent ethanol-water (1:1) mixture by utilizing the solubilizing property of ethanol for hydrophobic drugs. This approach was designed to enhance the solubility of Curcumin in aqueous systems.²².

Hydrophilic Matrix System: Curcumin was introduced into a hydrophilic matrix system based on Hydroxypropyl Methylcellulose (HPMC). HPMC was immersed in water and Curcumin was dispersed in solution. After drying, the mixture was milled and the resulting fine powder was used for dissolution testing²³.

Dissolution Studies: Dissolution studies for all formulations were carried out using a USP Dissolution Apparatus II (paddle) in 900mL of phosphate buffer (pH 6.8) at 37 0.5°C. The paddle rotation speed was maintained at 50rpm. Samples of 5mL were taken in intervals (5, 10, 15, 30, 45, 60, and 90min) and filtered at a 0.45µm filter²⁴. The concentration of dissolved Curcumin was determined at 421nm by a UV spectrophotometer. The volume of dissolution medium was kept constant by replenishing the extracted substrates with fresh buffer to provide sink conditions.

Data Analysis: Dissolution profiles were plotted by the relative percentage of Curcumin dissolved at each time point. Dissolution efficiency (DE) was also determined for each method at 45min to reflect the performance of the solubility enhancement methods. Graphs of accumulative drug release were constructed and used to compare the performance of each method.

RESULTS:

Dissolution Profiles:

The dissolution profiles of Curcumin obtained by using the various approaches to solubility enhancement are illustrated in Figure 1. All the methods demonstrated a significant enhancement in dissolution rate in comparison with pure Curcumin, which showed unsatisfactory dissolution as it yielded only 35% dissolved in 90 min.

Figure 1, as demonstrated, all of the solubility enhancement methods significantly accelerated the dissolution of Curcumin in comparison to it in its pure form. Across all compared methods, cyclodextrin complexation and nanoformulation (lipid based) produced the most rapid dissolution rates (more than 90% dissolution within 90minutes). Solid dispersion with PVP by the solvent evaporation method also demonstrated significant enhancement with the same dissolution rate, 94% at 90 minutes.

Figure 1: Dissolution Profiles of Curcumin Using Various Solubility Enhancement Techniques

Micronization facilitated a dissolution enhancement through increased surface area producing an 80% dissolved Curcumin, when surfactant-based formulations (SLS) and Pluronic F-127 improved the wettability and dissolution of Curcumin, yielding approximately 88% of the dissolved form. Alternatively, the pH modification and HPMC hydrophilic matrix approaches led to moderate enhancements, with around 75% dissolution.

Dissolution Efficiency (DE):

The dissolution efficiency (DE) values were calculated to further compare the effectiveness of each method (see Table 1).

Table 1: Dissolution Efficiency (DE) of Curcumin Using Different Solubility Enhancement Methods

Method	Dissolution Efficiency (%)
Pure Curcumin	35
PVP (Solvent Evaporation)	87
PEG 6000 (Solvent Evaporation)	75
Mannitol (Solvent Evaporation)	65
Micronization	80
Cyclodextrin Complexation	92
Surfactant (SLS)	88
Pluronic F-127	88
Nanoformulation (Lipid-Based)	94
pH Adjustment	75
Co-solvent (Ethanol-Water)	85
HPMC Matrix	72

DISCUSSION:

Based on the findings of this research, it is shown that the solubility and dissolution rate of Curcumin can be greatly enhanced by employing a number of the solubility enhancement methods. Among the methods evaluated, cyclodextrin complexation, nanoformulation, and solid dispersion with PVP (solvent evaporation) emerged as the most effective in enhancing Curcumin's dissolution rate, each achieving over 90% dissolution within 90 minutes. In comparison, pure Curcumin showed a low dissolution rate, with only 35% of it dissolved after 90 min, indicating a sharper contrast and significantly superior performance of the investigated procedures. The results align with previous literature findings. E.g, Curcumin solid dispersion using PVP (solvent evaporation) demonstrated significantly enhanced dissolution with 87% dissolution efficiency (DE%, which is consistent with Curcumin solid dispersion using PVP (solvent evaporation), as reported by Leuner and Dressman²⁵, Who showed PVP's high potentiality for developing amorphous dispersions for hydrophobic drugs, increasing their wettability and suppressing phase separation and precipitation. Similar findings were reported by Serajuddin²⁶, Who demonstrated that solvent evaporation is more effective for stabilization of amorphous forms than techniques such as melt extrusion. Nevertheless, the solid dispersion, PEG 6000 based, although a good candidate, led to 75% DE%, a less effect probably by the poor hydrogen bonding of PEG and the limited storage capacity of PEG for the drug amorphous state as stated earlier by Loftsson²⁷. In contrast, cyclodextrin complexation was the most efficient in this work, producing 92% dissolution efficiency, as was reported by Loftsson²⁷, who showed that cyclodextrins can notably increase the solubility of hydrophobic drugs through inclusion complex formation. The high solubility improving effect observed for cyclodextrins owing to the ability of covering the hydrophobic part of Curcumin from water and allowing its hydrophilic part to contact with water is explained. This finding agrees with further investigations, e.g., Stella²⁸, who reported that β-cyclodextrin enhances Curcumin solubility by more than tenfold. Although β-cyclodextrin was employed in this study, Tønnesen et al⁷, who also pointed out that the application of derivatives such as hydroxypropyl-β-cyclodextrin might lead to even better improvement, and, therefore, provided a direction for subsequent optimization²⁹. Nanoformulations also a highly efficient approach yielded 94% dissolution, as with Pouton and Porter³⁰, who showed that lipid-based delivery systems such as solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are an efficient delivery system for enhancing the bioavailability of hydrophobic drugs by delivering a hydrophobic protective core. This finding is also supported by Aggarwal et al³⁰, reported improved bioavailability (bioavailability as a consequence of encapsulation) and resistance to degradation with Curcumin encapsulation in nanoparticles. Micronization also resulted in a dramatic improvement, an 80% dissolution, which is in agreement with Zimmerman et al ³¹, demonstrated that, by increasing the surface area of poorly soluble hydrophobic drugs for dissolution, particle size reduction improves their solubility. Yet, micronization may not be protective against recrystallization as effectively as techniques modifying the molecular state of the drug, e.g., solid dispersions, as previously reported by Serajuddin²⁶. Incorporation of surfactants such as Sodium LaurylSulfate (SLS) and Pluronic F-127 resulted in significant solubility enhancement with both achieving 88% dissolution³². This is consistent with Rangel-Yagui et al³³, Who reported the effect of surfactants on solubility by decreasing interfacial tension and enhancing micelle formation, but which might be less efficient than solid dispersions in preventing recrystallization. Finally, the pH adjustment and the co-solvent method further enhanced the Curcumin solubility, but to a much smaller extent than the other methods. PH control achieved 75% dissolution by increasing the ionization of Curcumin, although at highly basic conditions Curcumin is reported to be unstable as derived by Aggarwal et al³⁴, could limit this method's long-term use. Ethanol/water co-solvent system, yielded 85% dissolution, which is in line with Patel et al³⁵, Showed that cosolvent systems enhance solubility by decreasing the solvent polarity through a solvation mechanism. Yet, the Curcumin excipiable precipitating in the presence of ethanol evaporation, as shown in this and in the previous work, is still a problem ^36,37. Compared to the literature available, this work it is confirmed that solubility improvement methods, i.e., solid dispersions, cyclodextrin complexation, and nanoformulations, are very effective in increasing the Curcumin dissolution rate, but their applicability may also vary depending on the desired application and formulation stability^38,39 . Integration of these techniques may potentially provide further advantages that could serve as a spring board for future studies with a goal of optimizing Curcumin formulations with increased bioavailability and therapeutic potential.

Study Limitations:

Laboratory Constraints: The experiment was carried out in controlled laboratory environment using a USP Dissolution Apparatus II and a UV spectrophotometer. These conditions may not fully replicate the complex in vivo environment where variables such as gastrointestinal pH variations, enzymatic interactions, and food effects may influence drug solubility and bioavailability.

Single-Point Solubility Enhancement Assessment: The study focused on evaluating dissolution rates and efficiencies over a 90-minute time frame. Timely short-term assessment does not take into account the long term stability of formulations that may be an important consideration for on-market pharmaceutical use. Additional studies are required to investigate the stability of these enhanced formulations over time.

Limited Formulation Stability Analysis:

While dissolution efficiencies were actually determined, the work did not in detail assess the possibility of recrystallization or the long term physical and chemical stability of the formulations, especially of micronized and solid dispersion forms, which may influence drug-performance over time.

Potential for Variability in Manufacturing: Preparation procedures, i.e., high-energy ball milling for micronization and solvent evaporation for solid dispersions, may lead to inhomogeneity of particle size and amorphous stability. Although testing of reproducibility as between batches was not comprehensively performed this could affect scalability and commercial feasibility.

Exclusion of In Vivo Testing:

The study did not include in vivo bioavailability or pharmacokinetic studies. Although vitro dissolution data can be useful guidance of in vivo performance in principle, in vivo bioavailability and therapeutic effects need to be confirmed in animal models or human trials to assess the translational validity of the findings.

Limited Range of Analytical Techniques:

Curcumin concentration was determined only by UV spectrophotometry in the dissolution studies. The inclusion of more analysis methods, such as high-performance liquid chromatography (HPLC) and/or mass spectrometry, can offer more stable and quantitative determination, especially for degradation products or byproducts.

Potential Drug-Carrier Interactions:

The study did not deeply explore the possible interactions between Curcumin and the various carriers or excipients used, which could affect the safety, efficacy, or bioavailability of the final formulation. Specific interaction studies would be required to confirm the absence of any adverse or unanticipated effect.

Specific pH Conditions:

The study utilized a pH of 8.0 for pH modification, which enhanced Curcumin's solubility. Nevertheless, the physiological significance of this pH, in particular within the human gastrointestinal tract, over which pH is not constant, was not discussed. The stability and solubility of Curcumin in the various GI conditions needs to be further explored.

Focus on Single-Drug Model:

The research was restricted to Curcumin as a model compound. While the results are promising, the applicability of these solubility enhancement techniques to other poorly soluble drugs with different chemical properties and dissolution profiles remains to be tested.

Lack of Comprehensive Toxicity Assessment:

The article did not discuss the possible toxicity or biocompatibility of the different excipients and formulations. For instance, the application of surfactants (e.g., sodium lauryl sulfate and lipid-based nanoformulation) may present safety issues that need to be assessed before it can be used clinically.

These restrictions highlight directions for future studies which encompass, long term stability investigations, in vivo bioavailability validation, broader drug applicability, and complete safety assessments to expand the translational reach of the results.

CONCLUSION:

This paper presents a systematic comparative analysis of ten solubility enhancement methods of Curcumin. Nanoformulations, cyclodextrin complexation, and solid dispersions with PVP were the most promising techniques which achieved marked improvements in dissolution rate and dissolution efficiency. These results indicate the applicability of such methods for the enhancement of bioavailability of lipophilic drugs such as Curcumin and its potential relevance for the future design of pharmaceutical formulations.

LIST OF ABBREVIATIONS:

1. CUR - Curcumin

2. PVP - Polyvinylpyrrolidone

3. PEG - Polyethylene Glycol

4. SLS - Sodium Lauryl Sulfate

5. HPMC - Hydroxypropyl Methylcellulose

6. β-CD - Beta-Cyclodextrin

7. SLNs - Solid Lipid Nanoparticles

8. NLCs - Nanostructured Lipid Carriers

9. USP - United States Pharmacopeia

10. DE - Dissolution Efficiency

CONFLICT OF INTEREST:

There are no conflict of interest.

AUTHOR CONTRIBUTION:

The authors confirm contribution to the paper as follows: study conception, design and draft manuscript preparation: Ruba Malkawi. Jawad Tawalbeh; analysis and interpretation of results. Esra Malkawi; data collection, and grammar draft editing. Baraa Jarwan; experimental work and data collection. All authors reviewed the results and approved the final version of the manuscript.

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Received on 23.10.2024 Revised on 07.04.2025

Accepted on 16.07.2025 Published on 05.09.2025

Available online from September 08, 2025

Research J. Pharmacy and Technology. 2025;18(9):4126-4132.

DOI: 10.52711/0974-360X.2025.00593

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.