Forty Percent New Drug Candidates Low Solubility Water Biology Essay


In drug discovery, about 40% of new drug candidates display low solubility in water, which leads to poor bioavailability, highintrasubject/intersubject variability and lack of dose proportionality. Furthermore, oral delivery of numerous drugs is hinderedowing to their high hydrophobicity . Therefore, producing suitable formulations is very important to improve the solubility and bioavailability of such drugs.One of the most popular and commercially viable formulationapproaches for solving these problems is self-emulsifying drugdelivery systems . SEDDS have been shown to be reasonably successful in improving the oral bioavailability of poorlywater-soluble and lipophilic drugs . Traditional preparationof SEDDS involves dissolution of drugs in oils and their blending with suitable solubilizing agents. However, SE formulations are normally prepared as liquids that produce some disadvantages, for example, high production costs, low stability and portability, lowdrug loading and few choices of dosage forms. . More importantly,the large quantity (30-60%) of surfactants in the formulations can induce gastrointestinal (GI) irritation.To address these problems, S-SNEDDS have been investigated, asalternative approaches. Such systems require the solidification ofliquid self-emulsifying (SE) ingredients into powders/nanoparticles to create various solid dosage forms (SE tablets and SEpellets , and so on. Thus, S-SNEDDS combine the advantages of SNEDDS (i.e. enhanced solubility and bioavailability) with those ofsolid dosage forms (e.g. low production cost, convenience ofprocess control, high stability and reproducibility, better patient compliance.).To date, there have been some studies that mainly focus on the preparation and characterization of a solid SE dosage

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self-emulsifying drug delivery systems (SEDDSs) is recently used method to increase solubility and bioavailability of poorly soluble drugs. SEDDSs are isotropic mixtures of oils , surfactants,and cosurfactants , and can be used in order to improve the oral absorption of highly lipophilic compounds. SEDDSs spontaneously form fine oil-in-water emulsions when it introduced into an aqueous phase under gentle agitation...In recent years, the formulation of poorly soluble compounds presented interesting challenges for formulation scientists in the pharmaceutical industry. Up to 40% of new chemical entities discovered by the pharmaceutical industry are poorly soluble or lipophilic compounds, which leads to poor oral bioavailability and lack of dose proportionality .In the oral formulation of such compounds, a number of attempts such as decreasing particle size, use of wetting agents, coprecipitation, and preparation of solid dispersions have been made to modify the dissolution profile and thereby improve the absorption rate. Recently, much attention has focused on lipid-based formulations to improve the bioavailability of poorly water soluble drugs. Among many such delivery options, like incorporation of drugs in oils , surfactant dispersion , emulsions and liposomes , one of the most popular approaches are the self-emulsifying drug delivery systems (SEDDSs).


The utility of solubilizing lipid based formulations for improving the gastrointestinal absorption of poorly water soluble drugs.while the primary mechanism by which these formulations are thought to improve drug absorption is through elimination of the need for preabsorptive drug solubilization by the gastrointestinal tract, other mechanisms may include protection from chemical and enzymatic degradation localized in the aqueous environment and promotion of lymphatic drug transport which circumvents hepatic first pass metabolism.


SEDDSs are mixtures of oils and surfactants, and sometimes containing cosolvents/co-surfactants. which emulsify spontaneously to produce fine oil-in-water emulsions when introduced into an aqueous phase under gentle agitation. Self-emulsifying formulations spread readily in the gastrointestinal (GI) tract, in the stomach and the intestine provide the agitation necessary for selfemulsification. These systems advantageously present the drug in dissolved form and the small droplet size provides a large interfacial area for the drug absorption . SEDDSs typically produce emulsions with a droplet size less than 300 nm


self-nano emulsifying drug delivery systems (SNEDDSs) form transparent nanoemulsions with a droplet size of less than 150 nm. When compared with emulsions, which are sensitive and metastable dispersed forms, SEDDSs are physically stable formulations that are easy to manufacture. Thus, for lipophilic drug compounds that exhibit dissolution rate-limited absorption, these systems may offer an improvement in the rate and extent of absorption and result in more reproducible blood-time profiles .

Composition of SEDDSs

The self-emulsifying process is depends on:

The nature of the oil-surfactant pair

The surfactant concentration

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The temperature at which self-emulsification occurs.

Oils. Oils can solubilize the lipophilic drug in a specific amount. It is the most important excipient because it can facilitate self-emulsification and increase the fraction of lipophilic drug transported via the intestinal lymphatic system, thereby increasing absorption from the GI tract . Long-chain triglyceride and medium-chain triglyceride oils with different degrees of saturation have been used in the design of SEDDSs. Modified or hydrolyzed vegetable oils have contributed widely to the success of SEDDSs owing to their formulation and physiological advantages . Novel semisynthetic medium-chain triglyceride oils have surfactant properties and are widely replacing the regular medium- chain triglyceride

Surfactant. Nonionic surfactants with high hydrophilic-lipophilic balance (HLB) values are used in formulation of SEDDSs (e.g., Tween, Labrasol, Labrafac CM 10, Cremophore, etc.). The usual surfactant strength ranges between 30-60% w/w of the formulation in order to form a stable SEDDS. Surfactants have a high HLB and hydrophilicity, which assists the immediate formation of o/w droplets and/or rapid spreading of the formulation in the aqueous media. Surfactants are amphiphilic in nature and they can dissolve or solubilize relatively high amounts of hydrophobic drug compounds. This can prevent precipitation of the drug within the GI lumen and for prolonged existence of drug molecules

Cosolvents. Cosolvents like diehylene glycol monoethyle ether (transcutol), propylene glycol, polyethylene glycol, polyoxyethylene, propylene carbonate, tetrahydrofurfuryl alcohol polyethylene glycol ether (Glycofurol), etc., may help to dissolve large amounts of hydrophilic surfactants or the hydrophobic drug in the lipid base. These solvents sometimes play the role of the cosurfactant in the microemulsion systems.

Formulation of SEDDSs

With a large variety of liquid or waxy excipients available, ranging from oils through biological lipids, hydrophobic and hydrophilic surfactants, to water-soluble cosolvents, there are many different combinations that could be formulated for encapsulation in hard or soft gelatin or mixtures which disperse to give fine colloidal emulsions . The following should be considered in the formulation of a SEDDS:

The solubility of the drug in different oil, surfactants and cosolvents.

The selection of oil, surfactant and cosolvent based on the solubility of the drug and the preparation of the phase diagram .

The preparation of SEDDS formulation by dissolving the drug in a mix of oil, surfactant and cosolvent.

The addition of a drug to a SEDDS is critical because the drug interferes with the self-emulsification process to a certain extent, which leads to a change in the optimal oil-surfactant ratio. So, the design of an optimal SEDDS requires preformulation-solubility and phase-diagram studies. In the case of prolonged SEDDS, formulation is made by adding the polymer or gelling agent .

Mechanism of self-emulsification

According to Reiss, self-emulsification occurs when the entropy change that favors dispersion is greater than the energy required to increase the surface area of the dispersion. The free energy of the conventional emulsion is a direct function of the energy required to create a new surface between the oil and water phases and can be described by the equation:

Where, DG is the free energy associated with the process (ignoring the free energy of mixing), N is the number of droplets of radius r and s represents the interfacial energy. The two phases of emulsion tend to separate with time to reduce the interfacial area, and subsequently, the emulsion is stabilized by emulsifying agents, which form a monolayer of emulsion droplets, and hence reduces the interfacial energy, as well as providing a barrier to prevent coalescence .

Characterization of SEDDSs

The primary means of self-emulsification assessment is visual evaluation. The efficiency of self-emulsification could be estimated by determining the rate of emulsification, droplet-size distribution and turbidity measurements.

Visual assessment. This may provide important information about the self-emulsifying and microemulsifying property of the mixture and about the resulting dispersion

Droplet Size. This is a crucial factor in self-emulsification performance because it determines the rate and extent of drug release as well as the stability of the emulsion Photon correlation spectroscopy, microscopic techniques or a Coulter Nanosizer are mainly used for the determination of the emulsion droplet size . The reduction of the droplet size to values below 50 μm leads to the formation of SMEDDSs, which are stable, isotropic and clear o/w dispersions

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Determination of emulsification time. Self-emulsification time, dispersibility, appearance and flowability was observed and scored according to techniques described in H. Shen et al. (21) used for the grading of formulations.


SEDDS formulation is composed of lipids, surfactants, and cosolvents. The system has the ability to form an oil-in-water emulsion when dispersed by an aqueous phase under gentle agitation. SEDDSs present drugs in a small droplet size and well-proportioned distribution, and increase the dissolution and permeability. Furthermore, because drugs can be loaded in the inner phase and delivered by lymphatic bypass share, SEDDSs protect drugs against hydrolysis by enzymes in the GI tract and reduce the presystemic clearance in the GI mucosa and hepatic first-pass metabolism. Table I shows the SEDDSs prepared for oral delivery of lipophilic drugs in recent years.

LFCS Classification Diagram

Figure 2 | Lipid digestion and drug solubilization in the small intestine. Following ingestion, the digestion of exogenous dietary triglyceride (TG) and formulation TG is initiated in the stomach by gastric lipase. The stomach further contributes to lipid processing by mechanical mixing (propulsion, grinding and retropulsion), which when combined with the presence of the amphiphilic products of initial lipid digestion (diglyceride and fatty acid) facilitates formation of a crude emulsion (lipid digestion by lingual lipase in the mouth might precede gastric digestion; however,

pharmaceutical formulations are typically encapsulated so that their contents are released in the stomach after ingestion). In the small intestine, pancreatic lipase together with its cofactor co-lipase203 completes the breakdown of TG to diglyceride, monoglyceride and fatty acid. Pancreatic lipase acts primarily at the sn-1 and sn-3 positions of TG to produce 2-monoglyceride and free fatty acid203,204. The chemical digestion of formulation- or biliary-derived phospholipid (PL) also occurs in the small intestine in which pancreatic phospholipase A2 hydrolyses a single fatty-acid molecule from the sn-2 position of PL to yield lysophosphatidylcholine and fatty acid205,206. The presence of exogenous lipids in the small intestine also stimulates secretion of endogenous biliary lipids, including bile salt (BS), PL and cholesterol from the gall bladder. In the presence of raised BS concentrations, the products of lipid digestion (monoglyceride, fatty acid and lysophospholipid) are subsequently incorporated into a series of colloidal structures, including multilamellar and unilamellar vesicles, mixed micelles and micelles. Together these species significantly expand the solubilization capacity of the small intestine for lipid digestion products and drugs (D). The oil droplet in the intestine is stylistically represented in different colours to indicate undigested TG in the core (orange) and digested products such as fatty acid (blue) and monoglyceride (green) on the surface of the droplet.


Self-emulsifying drug delivery systems are a promising approach for the formulation of drug compounds with poor aqueous solubility. The oral delivery of hydrophobic drugs can be made possible by SEDDSs, which have been shown to substantially improve oral bioavailability. With future development of this technology, SEDDSs will continue to enable novel applications in drug delivery and solve problems associated with the delivery of poorly soluble drugs.