Oil-in-Water Nanosized Emulsions for Drug Delivery and Targeting. Tamilvanan Shunmugaperumal

and Müller 2010). Another elegant way proposed by Butler and Dressman (2010) to classify the API molecules is the Developability Classification System (DCS) as this way of categorizing the API molecules is in a more biorelevant manner. According to the DCS, the API molecules can further be sub‐categorized into two types to distinguish between dissolution rate‐limited (DCS Class IIa) and solubility‐limited (DCS Class IIb) API molecules (as shown in Flowchart 1.1). More importantly, the intrinsic solubility and the related intraluminal API concentration for API molecules belonging to Class IIb and IV are too low to achieve sufficient flux over the epithelial membrane. Therefore, the API molecules belonging to DCS Class IIb and IV often utilize the complexation or other formulation approaches based on solid‐state modifications and even these approaches might be preferable compared with nanocrystals or nanosuspensions (Chen et al. 2017; Möschwitzer 2013; Shah et al. 2016).

Flowchart 1.1. API sub‐categorization.

After understanding the clear‐cut difference between the grease ball and brick dust API molecules, the oil‐based heterogeneous, dispersion (liquid‐retentive) system, like emulsion, is the main centre of focal point to solve the solubility (and thus the intestinal permeability) problems of grease ball API molecules.

1.1.2. Nanosized Emulsions

      An emulsion is a biphasic liquid preparation consisting of two immiscible liquids, one of which (the dispersed phase) is finely and uniformly dispersed as globules throughout the second phase (the continuous phase) (Barkat et al. 2011). If the amount of oil phase is significantly low when compared to the amount of water phase, then, the final emulsion is termed as oil‐in‐water (o/w) emulsion. Conversely, when the amount of water phase is significantly lower than the oil phase, the resulting emulsion system appears to be somewhat more viscous and is called as water‐in‐oil (w/o) emulsion. Both o/w and w/o type of emulsion systems are stabilized against the aggregation, coalescence and separation of dispersed oil or water phase by the addition of a third component called as emulsifying agent or emulgent or emulgator. In fact, the therapeutic emulsions are being stabilized by the addition of more than one emulgent molecules in order to prevent random collision of‐and then the coalescence of‐dispersed oil or water phase of the o/w or w/o emulsion. Mixing of appropriate amounts of oil, water and emulgent leads to the formation of an emulsion and this whole process is being named as emulsification. Apart from the amount of dispersed oil or water phase which will determine the type of final emulsion formed (whether o/w or w/o), the amount of single or multiple emulgent molecule added during the emulsification process will obviously control the type of emulsion produced. In addition, the size‐reduction equipments such as high‐energy or low‐energy homogenizer used to mix the oil and water phases along with single or multiple emulgent molecules will also direct the final emulsion produced in terms of mean size of the dispersed phase in the final emulsion. Interestingly, both high‐and low‐energy homogenizers will generate emulsions with nano‐range droplets particle sizes of the dispersed phase.

The emulsion generated by the low‐energy or spontaneous emulsification process is termed as microemulsion. On the other hand, the emulsion produced by means of the high‐energy homogenizers is called as nanoemulsion or nanosized emulsion. Again there are few basic differences between microemulsion and nanosized emulsion. Firstly, the microemulsion possesses the dispersed phase droplet diameter value well below the range of 100 nm, typically even below 10 nm as well. But the dispersed phase droplet diameter of the nanosized emulsion lies above 100 nm that too in between 300 to 500 nm level. Secondly, the notable difference between these two emulsions is being their physical appearances. While the microemulsion creates solution like transparent appearance, the nanosized emulsion looks like slightly bluish‐coloured white milk. Thirdly, a moderately higher amount of single or multiple emulgent molecules is used for producing the microemulsion when compared to the emulsifier molecules' amount which is being utilized to prepare the nanosized emulsion. Table 1.2 depicts the basic differences between microemulsion and o/w nanosized emulsion. In spite of these basic differences between microemulsion and o/w nanosized emulsion, these two terms (micro‐ and nano‐emulsions) are, however, used interchangeably in many medical and pharmaceutical literatures.

TABLE 1.2. Typical Differences Between Microemulsion and Oil‐in‐Water Nanosized Emulsion

Microemulsion	Oil‐in‐Water Nanosized Emulsion
Emulsifier concentration is high, i.e., 30–40%	Emulsifier concentration is comparatively less, preferably 2–5% and can be increased up to 10%
It is a thermodynamically stable isotropic mixture	It is thermodynamically unstable but kinetically stable for some time with the help of emulsifier molecule's coverage onto the dispersed oil droplet surface
Particle size ranges below 10 nm or below 100 nm	Particle size ranges from 200 to 700 nm
It is toxic for parenteral application but oral dosage form is possible. Any water‐soluble API can be used	All routes of application are possible

       1.1.2.1. Nanosized Emulsions: Prime Candidates for Nanoparticle Engineering

As discussed above, emulsions exist as two types often reported as being the same, thermodynamically stable (microemulsion) and thermodynamically unstable or metastable (MS) varieties (nanosized emulsion), the prevailing form is a function of surface tension that is related to dispersion entropy. The factors that are critical in long‐term product stability are presented in flowchart form (Flowchart 1.2). The MS or nanosized emulsions are considerably more susceptible to the destabilization phenomena than thermodynamically stable variety. Destabilization does occur due to aggregation or coalescence of dispersed oil droplets of o/w nanosized emulsion and Ostwald ripening phenomena. Whereas the aggregation or coalescence destabilization phenomena are related to the mechanics of the droplet surface, the Ostwald ripening describes the change of an inhomogeneous structure or size in the dispersed oil droplets of emulsion over time. The presence of inhomogeneous sizes in the dispersed oil droplets allow the smaller particles to dissolve and deposit on the larger particles in order to reach a more thermodynamically stable state wherein the surface to area ratio is minimized, i.e., the formation of larger‐sized dispersed oil droplets at the expense or unison of smaller‐sized oil droplets. This is accentuated by the smaller particle dimensions because of the increased internal Laplace pressure that is related to droplet surface curvature. The Ostwald ripening is otherwise termed as particle coarsening. This causes interfaces with low curvature to grow at the expense of interfaces with high curvature and the average size‐scale of the domains to increase in size with time. The driving force for this process is the minimization of the total interfacial energy of the system. Coarsening typically occurs under conditions where the volume fractions of the phases are nearly at their equilibrium values. The coarsening process has a profound effect on the properties of materials. For example, the Ostwald ripening or particle coarsening impacts directly on continuous phase solubility of the dispersed phase components and encapsulated API.

Flowchart