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

based on size are often inconsistent and the upper end of the nanoscale at 100 nm is an arbitrary cut‐off (Boverhof et al. 2015). Thus, the 100‐nm limit is often considered constraining and, according to a more‐inclusive definition, particles <1,000 nm in each dimension (submicron particles) is designated as NPs (Keck and Müller 2006). The latter more‐inclusive definition is particularly applicable in the pharmaceutical field since the particle size in the nanometer range can lead to increased dissolution rates because of the increase in surface area and increased saturation solubility (Junghanns and Müller 2008). In this respect, the generation of nanometer range particles from the API molecule itself is coming under NPs with a nomenclature of API nanocrystals or API nanosuspensions. On the other hand, encapsulating the API into a preformed or in situ forming nanosized API delivery carrier is also grouped under NPs. Now the question will arise, at an industrial environment, which type of API is going for API nanocrystals/nanosuspensions formation and which type of API needs to go as cargo in a nanosized carrier? To clarify this confusion, the following discussion is devoted wherein the poorly soluble API is grouped into two categories.

       1.1.1.1. Poorly Water‐Soluble Grease Ball and Brick Dust Molecules

It is now well known that the poor API solubility is an issue for approximately 70–90% of new APIs (Merisko‐Liversidge and Liversidge 2011; Müller and Keck 2012). According to Lipinski (2005) there are two different classes are available within the poorly soluble APIs viz. (i) grease ball and (ii) brick dust molecules.

      Hydrophobic APIs have a limited capacity to interact with the water phase, in accordance with “similia similibus solvuntur” (like dissolves like), and these APIs are solubility‐limited by poor hydration. The poorly soluble APIs restricted in solubility by poor hydration are described in the popular scientific jargon as “grease ball” molecules, due to their high hydrophobicity and lack of interaction with water. Although they possess poor water solubility (insolubility is probably due to the salvation extreme), the grease ball molecules are easily soluble to lipids or oils and therefore these molecules can plausibly be formulated into lipid‐or oil‐based formulations. In contrast, the brick dust molecules are poorly soluble due to crystal packing interactions being insoluble to both aqueous solvents and lipids or oils. So, the aqueous solubility of brick dust molecules could be enhanced by the formation of amorphous materials or particle size decrease, e.g., nanocrystallization. Thus, formulating APIs as nanocrystals should be mainly used as a solubility enhancement formulation approach to brick dust molecules rather than to grease balls.

      In other words, Yalkowsky and coworkers established the General Solubility Equation (GSE), in which the solubility of a compound is expressed as a function of the melting point (T_m) and its lipophilicity (in the form of the octanol‐water partition coefficient, log K_o/w or simply the log P value) (Jain and Yalkowsky 2001). The GSE states the following relationship:

(1.1)

      where S₀ is the intrinsic solubility, i.e., the solubility of the non‐ionised (neutral species).

Specifically, “grease balls” represent highly lipophilic compounds (log K_o/w > 3), which are poorly hydrated and their solubility is solvation limited, whereas “brick dust” compounds display lower lipophilicity and higher melting points (T_m > 200°C) and their solubility is limited by the strong intermolecular bonds within the crystal (Bergström et al. 2007), therefore, they said to have solid‐state‐limited solubility. Collectively, the APIs with solvation‐limited solubility are lipophilic, relatively large molecules and lack conjugated systems. Most of these grease ball molecules have been developed as oral dosage forms, however, the developed dosage forms typically include several different excipients that may improve dissolution (disintegration and dispersion) and solubilization. This indicates that an extensive API development process would be required to bring these grease ball molecules to the market. In contrast, the APIs with solid‐state‐limited solubility (brick dust molecules) are often flat, typically with an extended ring structure and display high aromaticity. These molecular features are important for forming a more stable crystal lattice. Hence, brick dust molecules have been found to benefit from formulation approaches such as particle size reduction and amorphization, whereas grease balls can be formulated as lipid or oil‐based formulations (Tuomela et al. 2016). Table 1.1 shows the various properties of brick dust and grease ball APIs.

It should be noted, however, that while compounds described as solvation‐limited (grease ball) often display intrinsic solubility values in the lower nanomolar scale, none of the compounds included in the solid‐state‐limited (brick dust) category had intrinsic solubility values even in this lower nanomolar scale (Wassvik et al. 2008). Interestingly, griseofulvin which has a solubility of approximately 15 μM was the least soluble compound found in the dataset published by Wassvik et al. (2008). Two fundamental explanations may be given for why this is the case. First of all, after using the GSE relationship [Eq. (1.1)] along with the knowledge that compounds with a log P value of 2 or less will tend to have solid‐state‐dependent solubility, the estimated or expected intrinsic solubility value of compounds having extraordinarily high melting points (of about 325°C) would be about 30 μM. Secondly, most of the solely solubility‐limited compounds because of their solid‐state are terminated relatively early in the API development process. So, in the quest of affordable APIs for therapeutic activity, the grease ball molecule looks competitively better than the brick dust molecule during the API or dosage form development process.

TABLE 1.1. Typical Differences Between Grease Ball and Brick Dust Molecules

      Extracted from Bergström and Larsson (2018).

Grease Ball API	Brick Dust API
Highly lipophilic compound with high log P (>3 or 4) and a low melting point (<200°C)	Compound with high log P (<2) and high melting point (>200°C)
Poorly soluble compounds restricted in solubility by poor hydration are described as grease ball molecule	Compound with strong intermolecular bonds and/or complex interaction patterns with large number of interaction points between the molecules in the crystal lattice which often shows a limited capacity to dissociate from the solid form. This type of compounds are called as brick dust (stone‐like)
These compound cannot form bonds with water molecules, thus their solubility is limited by the solvation process	The solubility of compounds in water is restricted due to strong intermolecular bonds within the crystal structure
Usual formulation approaches do not work, solubility enhancement through the use of a polar promoiety may prove useful	If the molecule has brick dust nature, a polar promoiety may work as this strategy which might disrupt the intermolecular interactions that led to the high crystallinity
Grease ball APIs are the candidates for entrapment into various lipid‐and oil‐based nanoformulations	Brick dust fraction that dissolves neither in oil nor in water cannot be administered as self‐emulsifying API delivery system

Preparing the pulverized API suspended in aqueous or non‐aqueous medium (is termed as API nanosuspensions) is being suggested as a universal delivery approach for those group of orally administrable APIs that fall into class II (low solubility and high permeability) and class IV (low solubility and low permeability) of