Various methods have been employed to improve the solubility and dissolution rates of poorly water-soluble drugs:

1. Particle Size Reduction: This method involves crushing the drug to achieve the desired particle size. Hammer mills and roller mills are commonly used in the feed industry. Factors such as the type of ingredient, energy usage, and grinding capacity are considered when selecting a mill. Multi-stage grinding combining different mills can be employed to achieve optimal particle size reduction at a reasonable cost (Lyu et al. 2020).
2. Nanonization: Nanonization refers to using a drug in the form of nanoparticles, which are particles smaller than one micron. Various definitions of nanomaterial have been put forth by regulatory organizations, with a general consensus that the average size should fall between 1 and 100 nm. Nanonization techniques offer the potential for improved solubility and bioavailability of drugs (Da Silva et al. 2020).
3. Cosolvency: Cosolvency is a commonly used technique to enhance solubility. It involves using aqueous-organic solvent combinations during the manufacturing of liquid dosage forms, solution preparation, or crystallization processes. The cosolvency approach can also be applied to generate medicinal nanosuspensions by utilizing solubility data in cosolvent-water mixtures (Jouyban 2019).
4. Hydrotropy: Hydrotropy involves the addition of a significant amount of a second solute to enhance the dissolution of a third solute in water. Hydrotropic solutions, such as sodium benzoate and salicylate, have been reported to increase the aqueous solubility of poorly water-soluble drugs (ALZobaidy et al. 2021).
5. pH Adjustment: Adjusting the pH can potentially increase the water solubility of drugs. The choice of buffer capacity and the tolerability of the selected pH are crucial considerations in this method. Acidic drugs may exhibit increased solubility when excipients soluble in higher pH environments are added, while alkalizing agents can enhance the solubility of basic drugs (Jagtap et al. 2018).
6. Sonocrystallization: Sonocrystallization involves the application of ultrasound (US) during the crystallization process. Research has shown that sonocrystallization offers advantages such as increased product homogeneity, favored polymorph formation, faster crystallization times, and higher crystal purity (Nalesso et al. 2019).
7. Supercritical Fluid (SCF) Process: The supercritical fluid process utilizes carbon dioxide gas under pressure and heat. When carbon dioxide reaches the supercritical point, it transitions from a liquid to a supercritical phase. In this process, carbon dioxide is used to dissolve the intended chemical to be converted into nanoparticles. The mixture is then rapidly expanded by spraying it through a nozzle, causing carbon dioxide to evaporate and resulting in the production of nanoparticles (Hussein et al. 2018).
8. Solid Dispersion: Solid dispersion involves the creation of a mixture by melting, using a solvent, or melting a solvent technique, of one or more hydrophobic active components in an inert hydrophilic carrier. The final product consists of a hydrophilic matrix and a hydrophobic drug (Abbas et al. 2016).
9. Self-Emulsifying (SE) or Self-Micro Emulsifying Systems (SEMS): Self-Emulsifying Drug Delivery Systems (SEDDS) have been developed to enhance drug solubility. SEDDS are characterized as isotropic mixtures of hydrophilic solvents and cosolvents, solid or liquid surfactants, and natural or synthetic oils. Simple binary systems, such as the lipophilic phase and drug or the lipophilic phase, surfactant, and drug, can be employed in SEDDS formulations. Co-surfactants are used to create microemulsions in SEDDS formulations. In vitro lipid droplet sizes of 200 nm to 5 mm and a cloudy appearance of the dispersion distinguish SEDDS formulations (Kanjani et al. 2016).

Nanoemulsion nanoemulsions and sub-micron emulsions (SMEs)

Nanoemulsion Nanoemulsions and sub-micron emulsions (SMEs) are thermodynamically unstable but can be stabilized by surfactant and co-surfactant molecules coating the interface, as illustrated in Fig. 1. Nanoemulsions have gained popularity in the administration of vaccines, DNA-encoded drugs, antibiotics, cosmetics, and topical preparations. These substances can be administered through various routes, including oral, pulmonary, intranasal, ophthalmic, and transdermal (Savardekar and Bajaj 2016).

Figure 1. 

Structure of nanoemulsion (Mushtaq et al. 2023).

The order of mixing the various components during formulation is crucial when creating nanoemulsions. Combining the oily phase with surfactants as the initial step promotes favorable conditions for nanoemulsion development. Conversely, preparing surfactants and water as the initial step would favor the formation of “macroscopic” emulsions (Che Marzuki et al. 2019).

Figure 2. 

Ultrasonication techniques (Vaibhav et al. 2019).

Since an emulsifier reduces the surface energy per unit area between the oil and water phases of the emulsion, it is essential for the production of fine droplets. Through repellent electrostatic interactions and steric hindrance, the emulsifier also contributes to the stabilization of nanoemulsions (Mushtaq et al. 2023).

Surfactants are often the emulsifier employed, but proteins and lipids have also been successful in the creation of NEs. The preparation of NEs using diverse techniques, broadly categorized into two main categories: high-energy and low-energy procedures, has been the focus of research over the past ten years. Ultrasonication and high-pressure homogenization (HPH) are high-energy processes that use a lot of energy. (~10⁸–10¹⁰ W kg^-1) to create tiny drops, On the other hand, low-energy techniques take advantage of particular system characteristics to create tiny droplets without expending a lot of energy (~10³ W kg^-1) (Mushtaq et al. 2023).

Figure 3. 

Production of nano emulsions using high pressure homogenization (Kumar et al. 2019).

Partitioning from oil into the surfactant layer and ultimately into the aqueous phase is how drugs are released from NEs. Nanoprecipitation occurs when the drug’s solubilized moiety contacts nearby water while diffusing out of oil. This significantly increases the drug’s surface area, hastening the drug’s disintegration in accordance with Noyes-equation. Whitney’s Thus, to create a sustained/controlled release device, the dynamics of drug release can be changed at each of these steps by subtly changing the composition of NEs (Dave et al. 2017).

The characteristics of the aqueous phase, such as pH, ionic concentration of the aqueous phase, and electrolytes, has an impact on the droplet size and stability of NEs. Ringer’s solution, simulated stomach fluid (pH 1.2), simulated intestinal fluid (pH 6.8), phosphate buffered saline, and plain water can all be employed as the aqueous phase when evaluating spontaneous Nano emulsification of NEs. Among the aqueous phase’s other characteristics, pH can significantly impact how NEs behave in phases when a medication with a pH-dependent solubility is added to the system (Sarkeret al. 2015).

Figure 4. 

Micro fluidization method for the manufacture of nano emulsions (Talegaonkar and Negi 2015).

The second most important transport medium after water due to its capacity to solubilize lipophilic drug molecules and improve absorption through the body’s lipid layer. Oil is incredibly useful for administering medications with lipophilic active ingredients because of its extraordinary capacity to penetrate cell membranes. The oil phase also affects the swelling of the surfactant’s tail group region (Kaleet al. 2017). The preparation of NEs uses a variety of oils (Table 3).

The selection of a suitable surfactant is critical for the formulation of nanoemulsions. The surfactant should possess a strong solubilizing capacity for hydrophobic drug molecules and be capable of micro-emulsifying the oily phase (c). In nanoemulsion (NE) formulations, the choice of surfactant plays a vital role. A hydrophilic surfactant that forms an oil-in-water (O/W) nanoemulsion with a hydrophilic-lipophilic balance (HLB) value of 10 is preferred. The hydrophobic core of the surfactant improves drug entrapment and enhances solubility. When the oil concentration is high, the surfactant concentrates at the oil-water interface, resulting in emulsions where the drug is solubilized in the internal oil phase. Conversely, when the oil level is low, tiny oil-entrapped surfactant globules, known as NEs, are formed (Savardekar and Bajaj 2016).

Figure 5. 

Phase inversion temperature method for the manufacture of nanoemulsions (Rai et al. 2018).

Ionic or non-ionic surfactants can be used in NE production; however, ionic surfactants are not recommended due to potential toxicological effects. It is essential to accurately determine the surfactant concentration since high levels of surfactants can cause irritation in the gastrointestinal (GI) tract. Therefore, there is a relationship between the surfactant concentration and the size of the droplets. In some cases, increasing the surfactant content, such as with a mixture of saturated C8–C10 polyglycolized glycerides, may result in smaller droplets. However, in certain situations, increasing surfactant concentrations may lead to an increase in the mean droplet size (Ee et al. 2008). Common forms of surfactants are listed in Table 4.

Some of the desirable properties of a surfactant are:

1. It must be capable of lowering surface tension to less than 10 dynes/cm.
2. To avoid coalescence, it must be quickly adsorbed around the dispersed phase globule to form a complete and coherent film.
3. It should contribute to the system’s development of an acceptable zeta potential and viscosity in order to bestow stability.
4. It ought to work well at relatively low concentrations. Surfactants enclose the dispersed globules in monomolecular, multimolecular, or particulate films (Islam et al. 2023).

These substances are added to surfactants to strengthen the interfacial film because they fit well between structurally weaker locations (Mushtaq et al. 2023). Co-surfactants are utilized when surfactant fails to reduce the interfacial tension between oil and water to produce a stable NE. Co-surfactant disrupts the liquid crystalline phase by permeating the surfactant monolayer and additionally adds fluidity. (Wilson et al. 2022) Several varieties of co-surfactants are utilized, such as (Table 5).

Figure 6. 

A schematic illustration of the Phase Inversion Composition (PIC) method’s NE creation (Al-hussaniy et al. 2022).

The advantages of the NEs are as follows:

1. Because they have a larger surface area and more free energy than macro emulsions, NEs are an efficient delivery mechanism.
2. NEs are safe for skin and mucosal membranes because they are neither poisonous nor irritating.
3. The formulation is administered orally using bio-compatible surfactants.
4. It can be used to treat both humans and animals.
5. It aids in the solubilization of lipophilic medications.
6. Increases bioavailability by increasing the rate of absorption.
7. It must transport substances that are both lipophilic and hydrophilic.
8. Reduces adverse effects due to a lower overall dose.

There’s several disadvantage:

1. Stability issues.
2. Thermodynamic not stable.
3. Possibility of Ostwald ripening.
4. Flocculation.
5. Coalescence.
6. Creaming/Sedimentation.
7. Expensive and tedious preparations hinder the scale-up of operation.

Uses mechanical tools that may produce powerful disruptive forces that combine and disturb the phases of oil and water, causing the creation of the small oil droplets. Intense energies are needed to generate disruptive forces greater than the restoring forces to keep the droplets in spherical shapes (Karthiket al. 2015).

Any type of oil can be used to manufacture NEs using high energy methods; however these techniques are most commonly preferred for highly viscous and high molecular weight oils. By using this strategy, fewer surfactants are used, and choosing a surfactant is simpler. Due to heat-sensitive components, this approach appears to be problematic for drug delivery systems (Safaya and Rotliwala 2020).

The low-energy techniques create dispersions by utilizing the chemical potential of the system’s internal parts. Phase transitions that happen in reaction to changes in temperature and composition are used in low-energy emulsification and condensation techniques (Basha et al. 2020).

Techniques for low-energy emulsification result in thermodynamically stable NE. Because they utilise the system’s stored energy to generate tiny droplets, low-energy technologies are becoming increasingly popular. Since they are “soft,” enclosed molecules are supposed to be unharmed by them. These techniques also use less energy, making them more desirable for large-scale production (Sheth et al. 2020).

Utilizing a UV visible spectroscopic technique, the drug content of the drug NE formulation was determined. The NE formulation was used to prepare the 2 g/ml aliquot, which was then diluted with a solvent. The samples were examined using a UV/VIS spectroscopic technique at 278.2 nm. Results were evaluated in triplicate, with the average being taken into account (Hammodi and Abd Alhammid 2020).

The viscosity of NEs was determined using the Brookfield viscometer (Spindle LV-1, Model DV-E; Brookfield Engineering Laboratories, Inc., Middleborough, MA). For NE-1 and NE-2, the NE samples were sheared at a rate of 30 and 50 rpm, respectively. When the reading was stable, measurements (n 14 3) were made (Hamed and Abd Alhammid 2021).

By measuring the interfacial tension, it is possible to study the genesis and characteristics of NEs. When the presence of a surfactant phase or middle phase NEs is in equilibrium with an aqueous or an oil phase, ultra-low values of interfacial tension are connected with phase behavior. It is possible to test the extremely low interfacial tension of NEs using a spinning-drop technique (Rashid and Abd-Alhammid 2019).

Using a pH meter, the pH of the formulation was determined (Eutech instrument, Landsmeer, the Netherlands). A micro-osmometer autocal type 13 based on the freezing-point method (Roebling, Berlin, Germany) was used to measure the osmolarity of the emulsions. Measurements were taken after 100 mL of each native NE was added to a microtube (Jasim et al. 2020).

• Heating Cooling Cycle
• Centrifugation: at 3500 RPM
• Freeze Thaw Cycle: In this experiment, the formulation underwent three freeze-thaw cycles among twenty-one °C and +25 °C held under typical laboratory conditions.

Three months were spent doing these studies. At ambient humidity and accelerated temperatures of 30 °C, 40 °C, 50 °C, and 60 °C, three batches of formulations were maintained. The samples were taken out on a regular basis at intervals of 0, 1, 2, and 3 months, and the drug content was determined using an HPLC method that indicates stability (Hamed and Hussein 2020).

Semipermeable membrane utilized in a dissolution equipment can be used to evaluate the in vitro release studies of drugs containing NE. Instead of the basket, a glass tube with a cylindrical shape and a length of 6 cm is added. This tube must be tightly covered in the semi-permeable membrane. The cylindrical tube containing the drug-loaded NE is positioned at the semi-permeable membrane surface. To produce sink conditions and maintain permanent solubilization, the cylindrical tube should be submerged in 100 ml of buffer while preserving pH. At 32C, the release study can be performed for 24 hours. The speed of the stirring shaft should be 100 revolutions per minute. The UV spectrometer can be used to determine the samples’ absorbance (Chaudhari and Kuchekar 2018).

Using a Keshary Chien diffusion cell, in vitro skin permeation investigations are performed on abdomen skins taken from male rats weighing (25010 g). The vertical diffusion cell’s donor and receptor chambers are separated by skin. A 20% ethanol solution of fresh water is used to fill the receptor chamber. The solution in the receiver chamber is constantly agitated at 30RPM while the receiver chamber’s temperature is set at 37 °C. The formulations are put in the donor chamber, and the solution in the receiver chamber is taken out for Glass Chromatography (GC) analysis at various times and promptly replaced with a fresh solution of the same volume. The same sample is used three times. To determine the overall amounts of medicines penetrated at each time interval, cumulative adjustments are made. Plotted as a function of time are the total amounts of medication that have passed through the skin of rats. The slope of the linear component of the cumulative amount of drug permeated through the rat skins per unit area vs time plot is used to compute the steady-state drug permeation rates through rat skins (Chaudhari and Kuchekar 2018).

To ascertain a NE’s shelf life, accelerated stability studies are carried out. The formulations are kept at three different temperatures and humidity levels (30 °, 40 °, and 50 0.5 °) for almost three months. After a predetermined amount of time (0, 30, 60, and 90d), samples are taken out and examined using HPLC at max to determine how much medication is still there. For samples withdrawn at zero time, checks are used. Following the calculation of the reaction rate constant (K) for the degradation from the line slope using the equation slope = K/2.303 at each elevated temperature, this establishes the order of the reaction. The logarithm values of K are then plotted against the reciprocal of absolute temperature at various elevated temperatures (Arrhenius plot).

This plot value for K at 25 °C is used to determine it, and the value is then used to predict shelf life by entering the value into the following equation: t(0.9)=0.1052/K25. Where t 0.9 is the amount of time needed for a medicine to lose 10% of its effectiveness, also known as shelf life (Chaudhari and Kuchekar 2018; Hamed and Hussein 2020; Jasim et al. 2020).