**5. Equilibrium solubility of diluted nanoformulations**

For lipid nanoformulations, drug solubility determines the maximum drug loading capacity (single unit dose) and is increased when the drug is highly lipid soluble or when the formu‐ lation contains high proportions of surfactant or cosolvent. The solubilization capacity of the nanoformulations (SNEDDS) is likely to decrease when excipients are dispersed and digested in the GI tract. As a result, the drug concentrations in the GI fluids are elevated from the equilibrium solubility and could cause extreme precipitation.

tions as they produce microemulsions/nanoemulsions (SMEDDS and SNEDDS) of lipid‐ surfactant mixtures with particle sizes in the range of 0–250 nm upon dispersion. The microemulsions can be used for many other drug delivery/application systems, such as topical, intra venous, trans‐dermal, etc. There are several marketed products available which were developed as Type III formulations since the drugs may be absorbed from the microemulsions and or nanoemulsions without the digestion of lipids and/or surfactants present. Type III systems further divided into subtype IIIA and IIIB according to the hydrophilic content of the SMEDDS and SNEDDS. Type IV systems are efficient formulations as they also produce SMEDDS and/or SNEDDS and have high drug loading ability but may loss solvent capacity

The excipients commonly used in designing SNEDDS are liquid at room temperature, and their compatibility with semi‐solid and solid dosage forms allows encapsulating into soft/hard gelatin capsules for oral delivery. This could be a great challenge as the interaction between liquid formulation and capsule shell may result in either brittleness or softness of the shell [33]. In addition, the stability of liquid formulations could be another major issue (e.g., leaching and rancidity) since some drugs might suffer significant chemical instability in both aqueous and oily formulations. Apart from that, manufacturing liquid‐filled soft gelatin capsules is a slow process and requires specialized equipment, having risk of formulation components migrating

Therefore, to address this limitation, incorporation of liquid lipid formulations into a solid dosage form is convincing and desirable. Liquid lipid formulations could be transformed into acceptable free flowing fine powder by loading the formulation on a suitable solid carrier as solid SNEDDS [34, 35]. Only few studies have attempted to investigate the conversion of such formulations into free flowing powders by adsorption using various inorganic high surface area materials (i.e., neusilin, syloid, aeroperal and aerosol) that are amenable to encapsulation or tableting [36, 37]. On the other hand, the final powder preparation should have acceptable flow properties to achieve the best content uniformity and weight variation. The current interest in solidification technique by both the industry and academia is raised enormously due to the attractive properties including independence of gastric transit, flexibility in dose dividing, decrease in intra‐ and inter‐subject variability, highest safety profile and physical/

For lipid nanoformulations, drug solubility determines the maximum drug loading capacity (single unit dose) and is increased when the drug is highly lipid soluble or when the formu‐ lation contains high proportions of surfactant or cosolvent. The solubilization capacity of the nanoformulations (SNEDDS) is likely to decrease when excipients are dispersed and digested

upon dilution with aqueous media.

38 Advanced Technology for Delivering Therapeutics

into capsule shell [23].

chemical stability improvement.

**5. Equilibrium solubility of diluted nanoformulations**

**4.2. Solidification of SMEDDS/SNEDDS**

To predict the likely fate of the drug on dispersion effectively, one should investigate its solubility in the formulations during aqueous dilution. The solubility of PWSDs within the diluted nanoformulations can be determined using a shake‐flask method to observe how the drug solubility is changed as water is incorporated into the system. The samples are prepared by adding an excess amount of drug to the formulation, which is then shaken and thoroughly mixed with a vortex mixer. The samples are incubated in a dry heat incubator at 37°C for 7  days and centrifuged to separate excess solid drug from the dissolved drug. An aliquot of the supernatant is weighed and diluted in an appropriate solvent. The dissolved drug concentra‐ tion can be analyzed by UV‐vis spectrophotometer.

**Figure 2.** Effect of aqueous dilution on solubility of fenofibrate in nanoformulations representing LFCS Types IIIB and IV systems. Data are presented as mean ± SD (n = 3).

**Figure 2** shows the fenofibrate solubility in nanoformulations (SMEDDS/SNEDDS) of LFCS Type IIIB and IV systems which was studied over 10–100 dilution with water. The results suggest how fenofibrate solubility decreased markedly, with several Type IIIB and IV nano‐ formulations, as the formulation was diluted with water [12]. After adding only 10% w/w water to the anhydrous formulation (drug dissolved at 80% of its equilibrium solubility), the one‐ third drug solubility had dropped down from the initial solubility of the formulation. The data predict that if fenofibrate was dissolved at its equilibrium solubility in the anhydrous formu‐ lations, its solubility would be exceeded in all cases when the formulation is diluted 1 in 10 or 1 in 100.
