**4. Solid self-emulsifying drug delivery systems**

*Current and Future Aspects of Nanomedicine*

*Transmission electron microscope photograph shows spherical nanoemulsion droplets without any signs of* 

in temperature. Cloud point is determined as the temperature above which the emulsion clarity turns into cloudiness which is attributed to the dehydration of polyethylene oxide moiety of non-ionic surfactants [69]. Cloud point values should be sufficiently higher than 37°C (i.e., normal body temperature) to avoid phase

*3.4.5 Determination of zeta potential, mean droplet size and polydispersity index*

size provides large interfacial area for drug absorption and ensures the kinetic stability of the resulting emulsion. Small value of polydispersity index suggests good uniformity of droplet size distribution. High zeta potential values confirm the

The morphology of emulsion droplets could be determined by transmission electron microscopy after appropriate dilution of SEDDS preconcentrate (about 1000-fold) using 2% solution of either phosphotungstic acid or uranyl acetate for negative staining. Droplets should possess a spherical shape without any signs of

Drugs incorporated into lipid-based formulations are already present in a dissolved form. Thus, the assessment of the applicability of these formulations should be more properly based on the rate of drug precipitation over time. On the other hand, the drug solubilization capacity of lipid-based formulations is not a function of formulation characteristics alone. Rather, formulation dispersion and digestion result in the formation of colloidal species that account for the intestinal solubilization capacity [71]. Consequently, possible changes to solubilization capacity that could be attributed to digestion of formulation ingredients or interaction with biliary solubilizing agents should be assessed. *In vitro* lipolysis models simulate the GI environment and better predict the *in vivo* behavior of lipid-based formulations

electrical stability of emulsion droplets and absence of aggregation [66].

Mean droplet size affects the *in vivo* performance of SEDDS. Small mean droplet

*aggregation. Reprinted with permission from Ref. [20]. © Elsevier (2017).*

aggregation or drug precipitation as shown in **Figure 2**.

**54**

**Figure 2.**

separation in the GI tract [70].

*3.4.6 Droplet morphology*

*3.4.7 In vitro lipolysis*

It was reported that ~70% of newly discovered drug molecules and ~ 40% of marketed drugs for oral administration are classified as practically insoluble in water. Therefore, various strategies have been explored to enhance the aqueous solubility and thus oral bioavailability of these drugs. SEDDS have been investigated as an efficient strategy that allows drug administration in pre-solubilized form ready for absorption. Consequently, drugs loaded into SEDDS preconcentrates avoid the dissolution step that frequently limits their absorption. However, the widespread application of liquid SEDDS is challenged by low stability during handling or storage [73] and irreversible drug and/or excipient precipitation [74]. Thus, the majority of marketed liquid SEDDS are filled into soft gelatin (e.g., SandimunneNeoral®, Norvir®, Fortovase®, and Convulex®) or hard gelatin capsules (e.g., Gengraf® and Lipirex®) to be administered as a unit dosage form [75]. However, this approach still possesses the possibility of drug precipitation upon exposure to aqueous media. Additionally, capsule technologies have some limitations such as high production cost and the risk of interaction between the active pharmaceutical ingredient and excipients with the capsule shell. Also, the possibility of drug leakage out of the capsule shell and capsule aging represent further obstacles [76]. Further, the storage temperature is an important consideration since the drug and/or excipients could undergo precipitation at lower temperatures [75]. The tendency of volatile excipients to evaporate into the capsule shell results in drug precipitation and a consequent alteration of drug release [77].

Thus, to address these limitations solid self-emulsifying drug delivery systems (s-SEDDS) were developed by converting the conventional liquid SEDDS into powders which are subsequently filled into capsules or formulated as solid dosage forms such as self-emulsifying tablets, granules, pellets, beads, microspheres, nanoparticles, suppositories and implants [74, 78]. Various solidification techniques for converting liquid SEDDS into s-SEDDS are discussed below.

### **4.1 Solidification techniques for converting liquid or semisolid SEDDS to s-SEDDS**

#### *4.1.1 Adsorption to solid carriers*

Adsorption to highly porous and/or high specific area solid carriers is the most intensively explored approach to obtain s-SEDDS [75]. This technique could be effectively used to produce s-SEDDS by simple mixing of solid carriers with the liquid formulation in a blender [74]. The most frequently employed carriers for adsorption of liquid SEDDS formulations are: (i) silicon dioxide such as Aerosil® (fumed silica) and Sylysia® (micronized amorphous silica); (ii) Neusilin® (magnesium aluminometasilicate) which is available in different surface properties and particle size; (iii) Fujicalin® (porous dibasic calcium phosphate anhydrous) and (iv) calcium silicate [75].

Advantages of this solidification technique include:( i) good content uniformity of the produced powders [79]; (ii) high drug loading efficiency (up to 80% *w/w* without affecting flow properties) [80]; (iii) absence of organic solvents [81]; (iv) cost effectiveness because small number of excipients and basic equipment are required for the final formulation and (v) production of free-flowing powders that can be filled into capsule or compressed into other solid dosage form [82].

During the formulation of s-SEDDS by adsorption technique, careful consideration should be given to the possible interactions between the solid carrier and the drug or other excipients in liquid SEDDS which could result in delayed or incomplete release of loaded drug [83]. Additionally, the particle size, specific surface area, tortuosity of pores as well as type and liquid SEDDS: carrier ratio should be considered [75].

#### *4.1.2 Spray drying*

Spray drying is also a promising technique for transforming liquid SEDDS to s-SEDDS using different carriers (i.e., hydrophobic or hydrophilic carriers) which preserve the self-emulsifying properties of the formulation. It is a simple and economical technique which involves mixing of lipids, surfactants, drug and solid carriers followed by solubilization and spray drying. The solubilized mixture is atomized into a spray of fine droplets that are introduced into a drying chamber where the volatile phase evaporates forming dry particles under controlled conditions of temperature and airflow [74]. The type of carrier can affect the rate of release and thus the oral bioavailability of loaded drug by affecting the droplet size of the nano or microemulsion formed after reconstitution [84]. Also, careful consideration should be given to the atomizer, the airflow pattern, the temperature and the design of the drying chamber which should be selected according to the powder specifications. Low yield is a disadvantage of solidification by spray drying technique which could be attributed to the removal of non-encapsulated drug with the exhausted air [85].

#### *4.1.3 Extrusion/spheronization*

Extrusion/spheronization is the most explored technique for the production of uniformly sized self-emulsifying pellets [75]. Extrusion is a procedure of converting a raw material with plastic properties into a spaghetti-shaped agglomerate having uniform density. Extrusion is followed by spheronization where the extrudate is broken into spherical pellets (spheroids) of uniform size [86]. The produced pellets have good flowability and low friability. Before pellet production, the wet mass is composed of liquid SEDDS, lactose, microcrystalline cellulose (MCC) and water. A disintegrating agent could be added to enhance drug release [87]. MCC acts as adsorbent for the liquid SEDDS to ease pellet formation and avoid problems such as poor flow properties, pellet agglomeration and low hardness. Larger amount of liquid SEDDS can be loaded into the pellets when a greater quantity of MCC on the account of lower amount of lactose is employed in the formulation. The ratio of lactose: MCC and liquid SEDDS: water affects the pellets' disintegration time and surface roughness as well as the extrusion force [88].

#### *4.1.4 Microencapsulation*

Co-extrusion technique is a promising strategy for microencapsulation of liquid SEDDS into polymeric matrices. This technique employs a vibrating nozzle device equipped with a concentric nozzle. The formed microcapsules are then hardened by ionotropic gelation. Ionotropic gelation is based on the gel formation ability of polysaccharides (e.g., pectin, alginate, carrageenan, and gellan) in the presence of multivalent ions (e.g., Ca+2) [89]. Alginate and pectin are the most intensively investigated natural ionic polysaccharides for formation of microcapsule shell. However, Ca-alginate microcapsules clog the nozzle during the microencapsulation process. On the other hand, pectin microcapsules lack sufficient hardness. Thus, microcapsules composed of an alginate-pectin matrix could be more acceptable than those composed solely of one polymer. Various hydrophilic filling agents

**57**

*Self-Emulsifying Drug Delivery Systems: Easy to Prepare Multifunctional Vectors for Efficient…*

(e.g., lactose) could be added to the shell formation phase in order to prevent core leakage and microcapsule collapse during the drying process. Advantages of microcapsules include predictable GI transit time and large surface area that allow faster drug dissolution. Additionally, they are composed of biocompatible, non-toxic and

Different carriers (e.g., Aerosil® 200) were employed to prepare the self-emulsifying granules where the liquid SEDDS acts as a binder. However, granulation with SEDDS produces a broader size distribution and difficult to control aggregation compared with

In this process, powder agglomeration is attained by the addition of binding agent which melts at relatively low temperature such as Gelucire®, lecithin, partial glycerides or polysorbates [92]. While the liquid SEDDS is adsorbed to neutral carriers such as silica and magnesium aluminometasilicate [93]. Melt granulation is advantageous compared to wet granulation since it is a 'one-step' process in which the addition of granulating liquid and the following drying phase are absent [74].

SEDDS are combinations of SEDDS and solid dosage forms. Therefore, the characterization of s-SEDDS is the sum of the corresponding evaluation criteria of

DSC is mainly employed to ensure drug incorporation into the s-SEDDS as well as the absence of drug-solid carrier interaction. It is also used to investigate the physical state (i.e., crystalline or amorphous) of the incorporated drug in the final formulation [94]. Transition from the crystalline to amorphous state is common in SEDDS formulations which lowers the drug melting point and improves its solubil-

XRD is employed to investigate the physical state of the incorporated drug

and the raw materials as well as to confirm the physical state of loaded drug [96].

incorporated drug and the solid carrier or other formulation excipients [76].

SEM is employed to elucidate the structural and morphological features of s-SEDDS

FT-IR is usually employed to investigate any potential interaction between the

granulation procedure where water is employed as granulating agent [91].

*DOI: http://dx.doi.org/10.5772/intechopen.88412*

biodegradable natural polymers [90].

*4.1.5 Wet granulation*

*4.1.6 Melt granulation*

**4.2 Characterization of s-SEDDS**

both SEDDS and solid dosage forms.

*4.2.1.1 Differential scanning calorimetry (DSC)*

because it affects both *in vitro* and *in vivo* performance.

*4.2.1.4 Fourier-transform infrared spectroscopy (FT-IR)*

*4.2.1 Solid state characterization*

ity and dissolution rate [95].

*4.2.1.2 X-ray diffractometry (XRD)*

*4.2.1.3 Scanning electron microscopy (SEM)*

### *Self-Emulsifying Drug Delivery Systems: Easy to Prepare Multifunctional Vectors for Efficient… DOI: http://dx.doi.org/10.5772/intechopen.88412*

(e.g., lactose) could be added to the shell formation phase in order to prevent core leakage and microcapsule collapse during the drying process. Advantages of microcapsules include predictable GI transit time and large surface area that allow faster drug dissolution. Additionally, they are composed of biocompatible, non-toxic and biodegradable natural polymers [90].
