**7. Mechanism of drug supersaturation: role of SMEDDS/SNEDDS**

**6. Drug release and the justification of dispersion test for nanoformulations**

*In vitro* release studies assess the ability of lipid‐based nanoformulations to disperse into various types of media and to evaluate whether the drug partitions from the vehicle into the aqueous medium. It can estimate how much drug will be in solution before absorption thus predicts the fate of the drug *in vivo*. A range of biorelevant dissolution test media and experi‐ mental methodologies has been developed by Dressman's group that have established

Technically, it is difficult to characterize drug release from emulsions *in vitro*, particularly under sink condition. Since solubility of the drug in sink phase may be poor, large volumes of aqueous content may be needed to maintain the sink conditions. It is hard to separate the oil droplets due to their smaller size from the dissolved or released drug in the sink solution levy. In a previous study, our group has conducted an *in vitro* dissolution of anti‐histaminic drug, cinnarizine (CN, week base) from various SNEDDS systems and commercial product Stuger‐ on® tablet [4]. Dissolution was carried out in simulated gastric fluid (SGF, pH 1.2) for first 2 h

application in drug release studies from lipid‐based oral formulations [38, 39].

and subsequently shifted into simulated intestinal fluid (SIF, pH 6.8) for another 2 h.

**Figure 3.** Dissolution profiles of cinnarizine SNEDDS 1 [MCT/MCDM/T85 (25/25/50)], SNEDDS 2 [MCT/MCM/T85 (25/25/50)] and Stugeron® tablets. Data are expressed as mean ± S.E, n = 3. \*\*Abbreviations: MCT—medium‐chain tri‐ glycerides (M810); MCDM—mixture of medium‐chain di‐ and monoglycerides (I988); MCM—medium‐chain mono‐

In SGF, all the SNEDDS showed superior dissolution profiles with respect to Stugeron® tablet (**Figure 3**). At 15 min, Stugeron® tablet managed to release only 66.5% drug in solution where the optimal formulations were able to release 84–95% drug in solution. This indicates the ability of these formulations to provide more efficient and rapid release of CN with respect to the marketed tablet. Upon shifting from SGF to SIF, Stugeron® showed significant precipitation (87–92% precipitated), while the SNEDDS were able to hold high amount of CN (78–93%) in solution (**Figure 3**). This finding suggests the immense need for developing a SNEDDS that could enhance the drug dissolution profile and resist the sharp pH‐dependent changes

glycerides (I308); T85—Tween 85.

40 Advanced Technology for Delivering Therapeutics

particularly for week bases.

When the lipid nanoformulations approach to the high volume of gastric fluid, it is dispersed rapidly and reduces solubilization capacity of the drug due to the high content of surfactant/ water soluble cosolvent, thus potentially generates supersaturation. Even though supersatu‐ ration in the stomach is not desirable as most of the drugs are absorbed in the small intestine, it poses threat for drug precipitation before the drug enters to small intestine. Therefore, SMEDDS/SNEDDS should be designed to minimize supersaturation in the stomach or at least to maintain a period sufficient to allow gastric emptying prior to drug precipitation.

Correlations between the investigations of the equilibrium solubility of the drug in the aqueous diluted formulation (10–99% diluted) and corresponding dynamic dispersion tests could help to predict whether precipitation is likely to take place, and whether it would affect bioavaila‐ bility [12]. The imbalance between high initial solubilized drug concentrations and lower equilibrium drug solubilities during lipid dispersion and digestion *in vivo* does not immedi‐ ately result in precipitation but stimulates drug supersaturation. This supersaturation is more likely to occur in the formulations that contain high proportions of water soluble surfactants or cosolvent. In some cases, during the process of lipid (or surfactant) digestion where hydrolysis occurs to form more polar post digestion products also stimulates changes to colloidal structure, thus lead to changes in drug solubility and may facilitate drug precipita‐ tion.

This is why, SNEDDS must contain drugs less than equilibrium solubility (approximately 50– 90% of the equilibrium solubility) to avoid any precipitation. In recent studies, precipitation inhibitors have been introduced in supersaturated SNEDDS to overcome the risk of precipi‐ tations [40]. Supersaturated SNEDDS inhibit and minimize the nucleation process and subsequent drug precipitation in GIT by achieving and then sustaining the metastable supersaturated state. The commonly used water soluble precipitation inhibitors are PVP, HPMC, NaCMC and MC polymers [41].

## **7.1. The risk of drug precipitation from nanoformulations**

Triglycerides alone (LFCS Type I) are poor solvents for most of the hydrophobic drugs but suitable for highly lipophilic compounds. If lipid‐based formulations contain mixed glycer‐ ides, polar oils, surfactants and/or cosolvents (LFCS Type II and III), it is likely to improve the solvent capacity of the formulation. Therefore, formulators are always preferred to add water soluble surfactants and cosolvents against pure oils, ultimately sometimes resulting in the complete exclusion of oily excipients to produce oil‐free formulations (LFCS Type IV). However, the formulator must keep well balance between oils and surfactants/cosolvents in the formulation to avoid risk of drug precipitation on aqueous dispersion. Several studies showed that small changes in formulation compositions are not expected to cause large changes in drug solubility, but there could be a dramatic drop in solvent capacity upon aqueous dilution [4, 12, 42]. Dilution of a cosolvent implies a substantial loss of solvent capacity, while the loss of solvent capacity may not be suffered with the use of surfactant. This could be possible due to the linearity between solubilized drug to the number of micelles present and therefore to the surfactant concentration. Drugs which are more soluble in surfactant or cosolvent than pure oil are at high precipitation risk because solvent capacity of surfactant and cosolvent decreases upon dilution but not pure oil. Hence, increasing the solubility of a drug by including a cosolvent is generally a poor strategy than using a nonionic surfactant [11, 43]. **Figure 4** shows the extreme precipitation of an anticancer drug, paclitaxel using LFCS Types III and IV formulations.

**Figure 4.** Percentage of the original dose of paclitaxel remaining in solution after 1:100 dilutions in the dispersion me‐ dium (paclitaxel was originally dissolved at 80% of the equilibrium solubility in the anhydrous mixture). One gram formulation was dispersed in 100 ml water, and then, the samples were withdrawn periodically over 24 h to examine the drug precipitations. Data are presented as mean ± SD (n = 3).

It is quite difficult to predict the fate of the PWSDs on dispersion of a typical LFCS Type IIIA lipid formulation. The hydrophilic surfactant used in Type IIIA systems is substantially separated from the oily components, forming a micellar solution in the continuous phase. Hence, one might question: does this system lower the overall solvent capacity for the drug or not? However, this may depend on the log *P* of the drug, and to what extent the surfactant was contributing to its solubilization within the formulation. At present, there are no established techniques available to help formulators assessing the risk of precipitation. It is worth men‐ tioning that in some cases, Type III formulations can take several days to reach equilibrium and the drug remains in a supersaturated state for up to 24 h time [12]. It could be argued that such formulations are not likely to cause precipitation in the gut before the drug is absorbed, and possibly the supersaturation acts as an absorption enhancer by increasing the thermody‐ namic stability of the drug [44].
