1. Introduction

The preferred route of oral administration is limited to those drug molecules that are poorly permeable across the gastric mucosa and are at least sparingly soluble. A large majority of the new chemical entities (NCE) and many existing drug molecules are poorly soluble, thereby limiting their potential uses and increasing the difficulty of formulating bioavailable drug products.

The growing percentage of NCE displaying solubility demands that technologies for enhancing drug solubility be developed to reduce the percentage of poorly soluble drug candidates eliminated from the development.

Novel technologies like nanosizing by media milling, supercritical processing, homogenization, cryogenic technology, lipid based technologies, micellar technology and some novel carrier like inulin glass, different polymeric micelle or matrix system of solubilization that may allow greater opportunities in the delivery of poorly soluble drugs.

2. Novel Technologies

Newer and novel drug delivery technologies developed in recent years for bioavailability enhancement of insoluble drugs are described below.

2.1. Size Reduction Technologies

The particle size reduction techniques enhance the dissolution rate of the poorly water soluble drugs due to the enormous surface area that is generated. The drug particles are reduced to micron or nanosize by nanosizing, precipitation, cryogenic and super critical fluid technologies

Compared with formulation efforts using traditional processes such as wet-granulation (WG), roller-compaction (RC), or direct compression (DC), development of nanoformulations is one of the more complex formulation works. Not only must the drug particles be rendered into nanosized domains via technically demanding processes, but they must also be stabilized and formulated rigorously to retain the nature and properties of the nanoparticles. This review will focus on Elan's nanomilling technology for oral formulation applications. Before delving in, a snapshot of other nanoparticle technologies is provided.

The definition of “nanoparticles” will be confined to crystalline particles with a monolithic core. There are two main approaches to making nanoparticles: ‘top down’ and ‘bottom up’ technologies ^{1, 2}. The ‘top down’ approach is by far the more popular; it will be referred to as ‘nanosizing’. The approach basically relies on mechanical attrition to render large crystalline particles into nanoparticles. Examples of the ‘top down’ approach include Elan's NanoCrystal® wet-milling technology ³ and SkyePharma's Dissocubes® high-pressure homogenization technology ^{1, 4}. The ‘bottom up’ approach relies on controlled precipitation/crystallization ². The process involves dissolving the drug in a solvent and precipitating it in a controlled manner to nanoparticles through addition of an anti-solvent (usually, water). This technology is available from DowPharma ( Midland, MI, USA)and BASF Pharma Solutions (Florham Park, NJ, USA). A hybrid approach is also feasible. Baxter's NANOEDGE® technology employs both ‘bottom up’ and ‘top down’ approaches through microprecipitation and homogenization ¹. The focus and examples of this review will be based on the application of the NanoCrystal® technology to the development of nanoformulations. However, most of the discussion on properties and characterization of nanoparticles, selection of stabilizers, and considerations in nano formulation development is relevant to the other technologies.

2.1.1. Theoretical Aspects for Increasing Dissolution Rate through Nanosization

The solid API dissolution rate is proportional to the surface area available for dissolution as described by the Nernst– Brunner/Noyes–Whitney equation ^5–7:

dX/dt = A.D (Cs - Xd/V) / h

Where, dX/dt=dissolution rate, Xd=amount dissolved, A=particle surface area, D=diffusion coefficient, V=volume of fluid available for dissolution, Cs=saturation solubility, h=effective boundary layer thickness.

Based on this principle, API micronization has been extensively used in the pharmaceutical industry to improve oral bioavailability of drug compounds. It is evident that a further decrease of the particle size down to the sub-micron range will further increase dissolution rate due to the increase of the effective particle surface area ⁸. For example in the case of aprepitant, the nanocrystal dispersion of 120-nm particle size exhibits a 41.5-fold increase in surface area over the standard 5 μm suspension ⁹. Furthermore, as described by the Prandtl equation, the diffusion layer thickness (h) will also be decreased thus resulting in an even faster dissolution rate ¹⁰.

In addition to the dissolution rate enhancement described above, an increase in the saturation solubility of the nanosized API is also expected ¹¹, as described by the

Freundlich–Ostwald equation:

S = S_∞ exp (2γ M / rρRT)

Where,

S=saturation solubility of the nanosized API, S∞=saturation solubility of an infinitely large API crystal, γ is the crystal- medium interfacial tension, M is the compound molecular weight, r is the particle radius, ρ is the density, R is a gas constant and T is the temperature.

Assuming a molecular weight of 500, ρ=1 g/mL and a γ value of 15–20 mN m-1 for the crystal-intestinal fluid interfacial tension, the above equation would predict an approximately 10–15% increase in solubility at a particle size of 100 nm. However a more significant increase in solubility appears to occur in reality.

2.1.2. Media Milling/ Nanocrystal Technology

Nanometer size drug crystals are produced by using high shear media mills with the nanocrysal technology. The milling chamber is charged with milling media, water drug and stabilizer if required other excipients like buffer and salt  may be used High energy generated shear forces and the force generated during impaction on the milling media with the drug provide the energy input to fracture the drug crystals into nanosize particles. The stabilizer promotes size reduction   process and generates physically stable suspensions.  The generated nanoparticles possess high surface energy and tend to agglomerate. The stabilizer wets the surface of the drug and provides static or ionic barrier. The size of nanocrystal particles (typically less than 200 nanometers (nm) in diameter) allows for safe and effective passage through capillaries.

Nanocrystal technology can be incorporated in a variety of oral dosage presentations including:

Tablets-immediate-release film coated, modified-release, orally disintegrating tablet

Capsules-immediate-release, modified-release, Liquid dispersions, Powders

Nanocrystal particles of active drug substance have rapid dissolution rates, and may then enable the following differentiated advantages:

• Increased oral bioavailability
• More rapid absorption of active drug substance
• Elimination of fed-fasted effects

2.1.3. Nanosuspension by Homogenization Techniques

2.1.3.1. Homogenization In Water ¹²

Disso-cubes and Nanoedge Technology lead to the formation of aqueous suspension of nanosized drug particles. The nanosuspensions are prepared by dispersion of drug powder by high speed stirring, in water containing stabilizers like anionic and non-ionic surfactants and polymers. This macrosuspension is then passed through high pressure homogenizer under optimized condition. The nanosuspension so formed can be processed to yield a solid dosage form.

2.1.3.2. Homogenization in Non-Aqueous Media ¹²

Nanopure uses non-aqueous media or water miscible liquids to disperse and homogenize the drug. PEGs are usually employed. The drug if dispersed in a liquid PEG (PEG 400) yields a nanosuspension on homogenization. The nanosuspension in liquid PEG can be filled into hard or soft gelatin capsules, in the case of solid PEG (PEG 1000}, the PEG is heated upto 85° and melted. The drug is dispersed in this molten medium and homogenized at the same temperature. This hot nanodispersion yields a solid dispersion of drug nanocrystals in solid PEG. The solid dispersion in PEG can be milled to a powder and compressed to tablets or filled in capsules.

2.1.4. Cryogenic Technology¹²

2.1.4.1.Spray Freezing into Liquid (SFL)

This is a novel technology to produce particles with greatly enhanced particle surface area. An organic or organoaqueous solution of drug with stabilizers is injected into a cryogenic liquid such as liquid nitrogen. The droplets of drug solution that form on spraying, freeze at a rate sufficient to minimize particle growth and crystallization. The particles are then obtained by removal of solvent and liquid nitrogen by freeze drying carefully, to avoid agglomeration. Significantly enhanced dissolution is due to amorphous and highly porous particles. The drug can be incorporated into the solvent along with hydrophilic excipients to produce micro particulate powders containing the drug molecularly embedded in excipients matrix.

2.1.5. By Using Supercritical Fluid Technology

The application of supercritical fluids (SCF) for the precipitation of pharmaceuticals and natural substances has attracted great attention due to the peculiar properties of these fluids ¹³.

Supercritical fluid is any substance at a temperature and pressure above its thermodynamic critical point. It has the unique ability to diffuse through solids like a gas, and dissolve materials like a liquid. Additionally, it can readily change in density upon minor changes in temperature or pressure. Carbon dioxide and water are the most commonly used supercritical fluids.

Table No.1: Some SCF Along with Their Properties

Solvent	Molecular weight	Critical temperature	Critical pressure	Density
	g/mol	K	MPa (atm)	g/cm³
Carbon dioxide (CO2)	44.01	304.1	7.38 (72.8)	0.469
Water (H2O)	18.02	647.3	22.12 (218.3)	0.348
Methane (CH4)	16.04	190.4	4.60 (45.4)	0.162
Ethane (C2H6)	30.07	305.3	4.87 (48.1)	0.203
Propane (C3H8)	44.09	369.8	4.25 (41.9)	0.217
Ethylene (C2H4)	28.05	282.4	5.04 (49.7)	0.215
Propylene (C3H6)	42.08	364.9	4.60 (45.4)	0.232
Methanol (CH3OH)	32.04	512.6	8.09 (79.8)	0.272

For every substance there is a temperature above that it can no longer exists as a liquid no matter how much pressure is applied. Like wise, there is a pressure above which the substance can no longer exists as a gas no matter how high the temperature is raised. These points are called supercritical temperature and supercritical pressure respectively. Beyond which the substance has properties intermediate between a liquid and gas and is called a supercritical fluid. So supercritical fluids are gases and liquids, which are at temperatures and pressures above the critical points. Supercritical fluids (SF) having good solvating power and high diffusivity. They differ greatly in viscosity, similar to gases and lower than liquids. So diffusion of solutes in SF is higher than that of liquids, which results in a decrease in resistance to mass transfer i.e. facilitates mass transfer. The diffusion coefficients of SF are in between gas and liquid. The solvating power of SF depends upon their density. As pressure increased, the SF density increases and correspondingly their solvating power also increases. Therefore, the solvating power of the supercritical fluid can be altered by small changes in operating conditions (i.e. temperature and pressure) according to the need.

Table No. 2: Comparison between SCF, Liquids & Gases

Solvent Phase	Density(gm/cm)	Viscosity(gm/cm/s)	Diffusion Coefficient	Comments
Gas	0.001	0.0001	0.1	Viscosity like SCF
Liquid	1.0	0.01	<0.00001	High viscosity than gas and SCF
SCF	0.1-1.0	0.0001-0.001	0.001-0.0001	Similar to gas in viscosity

The advantages of SCF process include;  

• No degradation due to mechanical stress as evident in crushing, milling,
• Suitable for thermo labile moieties,
• No extensive usage of organic solvents as needed for recrystallizaton processes.
• The organic solvent used is removed along with the SCF
• Light, oxygen and possibly moisture free atmosphere during processing.

Choice of supercritical fluid

Supercritical CO₂ is commonly used for pharmaceutical purpose due to the following reasons

• Its critical temperature is 31.3°C, so by using this, operations can be carried out at near room temperature
• It is non-toxic, non -flammable and approved by FDA for use in food and pharmaceutical operations and is inexpensive.

The different particle generating processes are

2.1.5.1. Rapid Expansion of Supercritical Solutions (RESS) or Supercritical Fluid

Nucleation (SFN) ¹⁴

This process is applicable to the substances those are soluble in supercritical fluids. In this process, first the solute is dissolved in a supercritical fluid then it is passed through a nozzle at supersonic speed. Pressure reduction of solution in a nozzle leads to a rapid expansion. This rapid expansion of supercritical solutions leads to super saturation of the solute and subsequent precipitation of solute particles with narrow particle size distributions.

Fig, No.1: RESS process

Fig.no.1 explains the principle of RESS process. The solid solute is incorporated in to an extraction unit and the supercritical fluid is pumped through a pre heater into the vessel, at a particular temperature and pressure. The supercritical fluid dissolves solute and the resultant solution is introduced in to precipitation unit by expansion through a capillary or laser drilled nozzle. The precipitation unit is maintained at conditions where the solute has much lower solubility in the supercritical fluid. Temperature is the same as that of in the extractor but the pressure is reduced. During expansion the density and the solubilizing power of the supercritical fluid decreases dramatically, resulting in a high degree of solute super saturation and subsequent precipitation. The morphology and size distribution of the precipitated material is a function of its pre expansion concentration and expansion conditions. The higher the pre expansion concentration, the smaller the particles and narrower will be the particle size range.

2.1.5.2. Anti Solvent Processes

While the RESS process can only be applied to products, which can be dissolved by the supercritical solvent and it cannot be used for substances like organic acids and proteins. For such substances an anti solvent crystallization process can be applied. The principle involved in the anti solvent process is dissolution of solid material in a more suitable solvent followed by addition of large amount of a poor solvent. This results in the precipitation of the solute. Here, super critical solvents can be used as anti solvents.

2.1.5.2.1. Gas Anti Solvent Recrystallization (GAS) ^15–17

In the GAS technique, first solute is dissolved in a good solvent followed by the introduction of supercritical fluid in the gaseous state (anti solvent gas) into that solution. Their precipitation of the solute takes place and this process is known as GAS (fig.no.2). In this process, the size distribution of precipitate depends on the rate of addition of the supercritical fluid. The most important requirement for this technique is that the carrier solvent and the supercritical fluid anti solvent must be at least partially miscible.

Fig.No.2: GAS process

2.1.5.2.2. Supercritical Anti Solvent (SAS) Technique¹⁸

In this technique, first solute is dissolved in a good solvent then the solution is fed into a pressure vessel under supercritical conditions, through a nozzle (i .e. sprayed into supercritical fluid anti solvent) when the solution is sprayed in to supercritical fluid anti solvent the anti solvent rapidly diffuses in to that liquid solvent as the carrier liquid solvent counter diffuses in to the anti solvent. Because the supercritical fluid expanded solvent has lower solvent power than the pure solvent, the mixture becomes supersaturated resulting in the precipitation of the solute and the solvent is carried away with the supercritical fluid flow.

The experimental set up is shown in fig.no.3 where the liquids containing solute and the supercritical phase are fed continuously in to the precipitator. The effect of processing variables such as temperature, pressure, stirring rate, conc. of the injecting solution, rate and temperature of the carrier solution, nature of liquid solvents and choice of supercritical fluid on the physical properties of the end product are to be studied and optimizes for any product.

Fig. No.3: Supercritical Anti Solvent (SAS) Technique

2.1.5.2.3. Precipitation with Compressed Fluid Anti Solvents(PCA)

Conventional techniques for particle size reduction including milling, recrystalization from liquid anti solvents, freeze drying and spray drying may result in excessive use of organic solvent, thermal and chemical degradation of products, trace residues in the drug and inter batch particle size variability. Precipitation with compressed anti solvents or PCA is a promising alternative form of micronization. In PCA, the drug is first dissolved in an organic solvent and then the solution is sprayed in to a liquid or supercritical CO₂, which causes the drug to precipitate as the solvent dissolves in the CO₂.

e.g. insulin powder was successfully formed from a PCA process using dimethylsiloxide (DMSO) as the solvent and spraying the solution through a capillary in to supercritical CO₂. The precipitated powder averaged 2-3 μm in diameter, with 90% <4 μm (number distribution).Another variant of PCA involves complexation of drug with surfactant prior to dissolution in organic solvent and spraying in to supercritical CO₂.

Fig. No.4 -Precipitation with Compressed Fluid Anti Solvents (PCA)

The complexation termed hydrophobic ion pairing (HIP). This process helps to preserve the native structure of the compound and increases its solubility in organic solvents. Chymotrypsin, insulin and ribonuclease were precipitated using PCA with HIP.

2.1.5.3. Solution Enhanced Dispersion With Supercritical Fluids (SEDS)

This technique was developed at the University of Bradford, U.K. It is a version of PCA involving ternary systems of water/ organic/CO_2. SEDS involves the precipitation of solute from a conventional solvent by a supercritical anti solvent, notably supercritical CO₂. Mixing takes place in a co-axial nozzle and the precipitated solute is retained on a filter.

The experimental arrangement of the SEDS process is shown in fig.no.5 the key component is the two channeled co-axial nozzle with internal mixing chamber. Liquid CO₂ is supplied at constant flow rates and the state of the CO₂ is changed from liquid to supercritical by passing the liquid CO₂ through a heat exchanger in the air oven, which is maintained at a temperature above the critical temp of CO₂. Drug solution is introduced in to the nozzle using a pump, together with the supercritical CO₂. The streams contact with in the nozzle, where the high velocity supercritical CO₂ disperse the liquid streams. The pressure in the system is maintained by a backpressure regulator. The drug powder formed by dispersion and extraction process is collected in the pressure vessel, and the supercritical solution is vented via the backpressure regulator outlet. This process provides uniform solvent free particles with low batch-to-batch variation and good control in recovering the supercritical fluid and organic solvents used in particle formation.

Fig. No.5: Solution Enhanced Dispersion with Supercritical Fluids (SEDS)

2.1.6. Stabilizers Used in Nanosization Process

Common pharmaceutical excipients that are suitable for use as polymeric stabilizers include the cellulosics, such as hydroxyl propyl cellulose (HPC) and hydroxyl propyl methyl cellulose (HPMC), povidone (PVP K30), and pluronics (F68 and F127) ^3,19–21. The molecular weights of these polymers are usually between 50 k and 100 kDa. The chains should be long enough to provide a steric layer, but not too big to slow down dissolution. The surfactant stabilizers can be non-ionic, such as polysorbate (Tween 80), or anionic, such as sodium laurylsulfate (SLS) and docusate sodium (DOSS). Cationic surfactants are typically not used as stabilizers for oral formulation due to their antiseptic properties. Smaller surfactant molecules can also stabilize nanoparticles, but are usually more prone to Ostwald ripening and particle growth. Several groups have reported the use of the above stabilizers in their work ³. Also, surfactants often help in the wetting and dispersion of the drug particles which are usually very hydrophobic. In marketed products based on Elan's NanoCrystal® technology, stabilizers such as HPMC E3, Povidone, HPC-SL, DOSS, and SLS have been used. Nanosuspensions are typically converted to a solid dosage form for clinical formulations. Prior to drying, redispersants need to be added to the nanosuspension to ensure complete redispersion of nanoparticles into their primary, pre-drying state ²². Sugars, such as sucrose, lactose, and mannitol, are commonly used as redispersants in oral formulations. The sugar molecules serve as “protectants” and prevent nanoparticles from aggregating as they are concentrated during drying ²².

2.2.Lipid Based Delivery Systems

Lipid-based formulations have been shown to enhance oral absorption of lipophilic drugs ²³. Although the exact mechanisms responsible for this enhanced absorption are not fully known, it is believed that factors including improved drug solubilisation, increased membrane permeability and lymphatic transport may make significant contributions ^{24, 25}. In spite of this, there has been a general reluctance, until recently, to advance such formulations to the market. This reticence is largely due to an absence of clear guidelines on formulation design and a paucity of information regarding vehicle effects in vivo ²⁶. However, in light of the increasing trend towards highly potent, lipophilic drug candidates and the clinical and commercial successes of several lipid-based formulations incorporating lipophilic drugs—such as cyclosporine (Neoral®), ritonavir (Norvir®) and saquinavir (Fortovase®) there has been a renewed interest in this research field.

The lipid based delivery systems include Lipid Solutions, Lipid Emulsions. Micro emulsions and Self Dispersing Lipid Formulations (SDLF). Bioavailability enhancement with lipids occurs due to the solubilizaton of the poorly soluble drugs.

In the case of lipid solutions the solubilized phase arises from the intraluminal digestion of the lipids. Co administration of drugs with lipids influences their path of absorption. The high lipophilicity facilitates absorption into the intestinal lymphatic and then to the systemic circulation thus avoiding first-pass metabolism. Digestion of lipids is an important step for the bioavailability enhancement for the lipid solutions. Lipid solutions consist of drug dissolved in vegetable oil or medium chain triglycerides.

Figure No.6:Schematic representation of the critical steps in oral drug absorption and the possible influences of lipid-based formulations.

2.2.1. Lipid Emulsion Technology

The lipid emulsions are potential carriers for hydrophobic drugs. Their basic structure is a neutral lipid core stabilized by a monolayer of amphiphilic lipid. Addition of a non-ionic surfactant increases the stability of the emulsion. The formulations are produced by the application of high shear, cavitations or impaction (homogenization, ultrasonication, etc.) to reduce the drug particle size in the presence of phospholipids {with or without surface modifiers) that associates at the freshly generated drug surface. Globule size of 50 nm and less can be obtained.

2.2.1.1. Microemulsion Technology

Microemulsions can be defined in general as thermodynamically stable, isotropically clear dispersions of two immiscible liquids stabilized by interfacial films of surface-active molecules. The microemulsions are formed by simple agitation of oil, water, surfactant and co-surfactant. Microemulsions are of two types, O/W and W/O. W/0 microemulsions are formed by emulsifiers of HLB in the range 3-6, while O/W microemulsions are formed by emulsifiers of HLB in the range 8-18. The co-surfactant is usually a medium chain fatty alcohol/ acid/amide. The co-surfactant together with the surfactant reduces the interfacial tension to very low and even transient negative values. At such low interfacial tension the interface would expand to form fine dispersed droplets and subsequently adsorb more surfactant until their bulk condition is depleted enough to make interfacial tension positive. This process known as "Spontaneous Emulification" forms microemulsions.

The Lipophilic Solubilization Technology (LST) is a drug solubilization technology that improves the bioavailability of water insoluble drugs by micro emulsion drug delivery system. CROMETM (Controlled Release Oral Micro emulsion) is a lipid based delivery system that enhances oral absorption and a so prolongs the duration of action.

2.2.1.2. Self Dispersing Lipid Formulations (SDLF)

The SDLFs is one of the promising approaches to overcome the formulation difficulties of various hydrophobic/lipophilic drugs and to improve the oral bioavailability of poorly absorbed drugs. The SDLFs contain oil and a surfactant mixture into which the drug is incorporated. They emulsify when mixed with aqueous environment .The self-emulsification process is specific to the particular pair of oil and surfactant, surfactant concentration, oil/surfactant ratio, and the temperature at which self-emulsification occurs, After self-dispersion, the drug is rapidly distributed throughout the GIT as fine droplets. The droplets formed are either positively charged or negatively charged. As the mucosal lining is negatively charged it was observed that positively charged particles penetrated deeper into the ileum. A cationic emulsion has greater bioavailability than an anionic emulsion.

Lipid Formulation Classification System (LFCS) was established by Pouton in 2000 and recently updated (2006) to help stratify formulations into those with similar component parts ^{27, 28}. Briefly classifies lipid-based formulations into four types according to their composition and the possible effect of dilution and digestion on their ability to prevent drug precipitation (Table no.3).

Table No. 3: Lipid Formulation Classification System (LFCS) as described by Pouton showing typical compositions and properties of lipid-based formulations ^{28, 29}

Increasing hydrophilic content →
	Type I	Type II	Type IIIA	Type IIIB	Type IV
Typical composition (%)
Triglycerides or mixed glycerides	100	40–80	40–80	<20	-
Water-insoluble surfactants (HLB<12)	-	20–60	-	-	0–20
Water-soluble surfactants (HLB>12)	-	-	20–40	20–50	30-80
Hydrophilic co-solvents	-	-	0–40	20–50	0–50
Particle size of dispersion (nm)	Coarse	100–250	100–250	50–100	<50
Significance of aqueous dilution	Limited importance	Solvent capacity unaffected	Some loss of solvent capacity	Significant phase changes and potential loss of solvent capacity	Significant phase changes and potential loss of solvent capacity
Significance of digestibility	Crucial requirement	Not crucial but likely to occur	Not crucial but may be inhibited	Not required	Not required

Self Emulsifying Drug Delivery Systems (SEDDS) i.e type II and Self Microemulsifying Drug delivery systems (SMEDDS) i.e type III are stable preparations and improve the dissolution of the drug due to increased surface area on dispersion. Therefore, this combination is not dependent on bile secretion for absorption. The emulsified form itself is readily absorbable. This ensures a rapid transport of poorly soluble drug into the blood. The preparation involves incorporation of the drug into a suitable oil-surfactant mix until a clear solution is formed. This can be filled into hard or soft gelatin capsule. ^{9, 30, 31}

PORT (Programmable Oral Release Technology) Systems formulate poorly soluble drugs as proconcentrates (concentrates) that will form microemulsion in vivo leading to enhanced bioavailability of such drugs. IDD-SE® technology constitutes a SEDDS where surface stabilized sub micron sized particles or droplets are self generated when the dosage form is exposed to the aqueous environment of the GIT. Macromed developed a system for oral application ReSolv™, which will spontaneously emulsify in situ. Alpha Rx uses its proprietary BCD (Bioadhesive Colloidal Dispersion) drug delivery technology for the development of novel drug formulations for compounds that are otherwise insoluble or poorly soluble in water. BCD drug delivery technology consists of two different approaches which improve the effectiveness of insoluble drugs and enable new methods of drug delivery. These are CLD (Colloidal Lipid Dispersion System) for transdermal drug delivery and SECRET (Self Emulsifying Controlled Release Tablet System) for oral drug delivery. BCD drug delivery technology is unique in that its utility is dependent upon the physico-chemical properties (i.e. insolubility and surf ace properties) of a drug rather than its chemical structure and reactivity.

The advantages of lipid-based systems include:

§Manufacturing is easy and cheap.

§Scale up is simple.

§The formulation can be administered orally as capsules.

§Enhanced oral bioavailability.

§Reproducible drug levels can be obtained.

2.2.2. Lipid-based excipients

Lipids are fatty acids and their derivatives, and substances related biosynthetically or functionally to these compounds ³².Vegetable oils contain mixtures of triglycerides (90 to 95% w/w) but also free fatty acids, phospholipids, and non-saponifiable products such as pigments and sterols or fat soluble vitamins like tocopherols and carotenoids that act as natural antioxidants against the rancidity of oils. It should be noted that a unique excipient derived from vegetable source tocopherols is d-alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS). It is a water-soluble source of tocopherol and an absorption enhancer for poorly-soluble drugs. ^33–36

Hydrogenated cottonseed oil (Lubritab™, Akofine™ or Sterotex™); hydrogenated palm oil (Dynasan™ P60, Softisan™ 154, Suppocire®); hydrogenated castor oil (Cutina™ HR) or hydrogenated soybean oil (Sterotex™ HM, Hydrocote™ or Lipo™). Hydrogenation is often a step in the derivation of vegetable oils before other reactions (polyglycolysis, ethoxylation, etc.) in order to increase the chemical stability of these excipients. Glyceryl monocaprylocaprate (Capmul® MCM); glyceryl monostearate (Geleol™, Imwitor® 191, Cutina™GMS or Tegin™); glyceryl distearate (Precirol™ ATO 5); glyceryl monooleate (Peceol™); glyceryl monolinoleate (Maisine™ 35-1); glyceryl dibehenate (Compritol® 888 ATO). Monoglycerides can also be acetylated on their two free hydroxyl groups (Myvacet® 9-45). ³⁷

2.3. Micellar Technologies

Figure No.7: Schematic representation of lipid digestion and drug solubilisation in the small intestine. ³⁸

The presence of exogenous lipid in the duodenum therefore stimulates the secretion of biliary lipids (BS, PL and Ch) which combine with lipid digestion products to generate a series of colloidal species including micelles, mixed micelles, vesicles and emulsion droplets. Importantly, whilst most of the data describing an elevation in intestinal bile salt levels in the presence of lipid have been generated after ingestion of the relatively large quantities of lipid typically contained in food, recent studies have also shown that lipid quantities as low as 2 g, are capable of stimulating gallbladder contraction and biliary secretion (at least in the case of long chain lipid), and as such suggest that increased luminal BS concentrations may occur even after administration of e.g. two capsules of a lipid-based formulation in the fasted state ³⁹.

A combination of raised levels of endogenous BS, PL and Ch and the presence of exogenous, formulation-derived lipid and surfactant species therefore provides a continuum of lipidic microenvironments from lipid solution to emulsion droplets to the core of vesicular and micellar phase ^40–42 into which co administered PWSD may partition. In turn this provides for a reservoir of solubilised drug at the absorptive site ³⁷ and generates the concentration gradient required to drive improved absorption (Fig.No.7). Luminal amphiphilies such as BS may also enhance the solubilisation of PWSD by improving wetting at concentrations below the critical micellar concentration (CMC) ^{43, 44}.

2.3.1. Mixed micelles

As long chain phospholipids are known to form bilayers when dispersed in water the preferred phase of short chain analogues is the micellar phase. The prediction of the arrangement keeps demanding, because it is related with chemical structure, temperature and water content. In general, amphiphilic ionic, anionic or ampholytic molecules, which are able to decrease the surface tension of a solvent, arrange in micelles, as Tween or sodium dodecylsulfonate above a certain critical concentration. Mixed micelles have a hydrophobic core in which low soluble compounds can dissolve. Also for this group of particles different compounds can be chosen to increase solubilization. However, compared to liposomes, mixed micelles offer a little less flexibility in the choice of their physico-chemical characteristics.  A micellar solution is a thermodynamically stable system formed spontaneously in water and also in organic solvents. The latter is of less interest in pharmaceutical technology. Micelle formation can only occur above a certain solute concentration, the critical micellar concentration (CMC), and at solution temperatures above the critical micellar temperature (CMT), the small colloidal aggregates (micelles) are in rapid thermodynamic equilibrium with a measurable concentration of monomers. The size (mostly around 5 to 10 nm) and shape of micelles depend, ultimately on the chemical, structure of the detergent. According to small spherical, rod-shaped, and discoidal micelles exist in water.

Micellar solutions exhibit solubilization phenomena. The micelle solubilizes host molecules (i.e. drugs) in ally zone or the micelle volume, but the penetration into the micelle depends over all on the inner space of the micelle (as mentioned, diameter of entire micelle often below 10nm), on the hydrophohicity of the drug and on the charge of the incorporated molecule. The interaction between micelles and lipophilic drugs leads to the formation of mixed micelles (MM), often called swollen micelles, too. The addition of salt, alcohol etc. can vary the degree of penetration into the micelle (co-solubilization). In mixed micelles, the mobility of the micellar phase was found to be decreased due incorporated molecules. Considerably, swollen micelles are larger than the analogous "free micelles" because solubilization may result mostly from the increase in micellar size.

Micelles of common surfactants usually have relatively high CMC and are unstable upon strong dilution. e.g. in the blood volume. Toxic side effects of some tensides on human cells have to be considered beside bad taste or tensides in per oral liquids further more, investigations have to be used on drug tenside incompatibilities and on initial over saturation what would lead 10 later drug expulsions from the micelle. The kinetics of micelles is driven by both rapid micelle- monomer exchanges and by dissolution and new formation of micelles, but nevertheless the extent of water-amphiphile contact between water and methylene and methyl groups and an extreme disorder of the micelle interior. But swollen micelles arc fluid systems, hut sufficiently stable to he used as delivery systems for stable drugs. Now a day, polymeric micellar pharmaceutical carriers with solubilization capacity and rather low CMC value are proposed.

Fig. no. 8: Mixed Micelle Formation Process

2.3.2. Polymeric Micelles

Amphiphilic polymers assemble into nanoscopic supramolecular core-shell structures, termed polymeric micelles, which are under extensive study for drug delivery. There are several reasons for this growing interest. Polymeric micelles may be safe for parenteral administration relative to existing solubilizing agents (for instance, Cremophor EL), permitting an increase in the dose of potent yet toxic and poorly water soluble compounds. Polymeric micelles solubilize important poorly water-soluble compounds, such as amphotericin B (AmB), propofol, paclitaxel, and photosensitizers. A major factor in drug solubilization is the compatibility of a drug and a core of a polymeric micelle. It may consider Pluronics®, poly (ethylene glycol) (PEG)-phospholipid conjugates, PEG-b-poly (ester) s, and PEG-b-poly (L-amino acid)s for drug delivery. Polymeric micelles may circulate for prolonged periods in blood, evade host defenses, and gradually release drug. Thus, they may show a preferential accumulation at sites of disease such as solid tumors. Polymeric micelles inhibit p-glycoprotein at drug-resistant tumors, gastrointestinal tract, and blood/brain barrier, perhaps providing a way to overcome drug resistance in cancer and increase drug absorption from the gut and drug absorption into the brain. Lastly, polymeric micelles may reduce the self-aggregation of polyene antibiotics, key membrane-acting drugs used to combat life threatening systemic fungal diseases. In this way, they may reduce its dose-limiting toxicity without a loss of antifungal activity.

Fig. No.9: A- Micelle (non-polymeric) composed of amphiphilic surfactants,

                  B- Polymeric micelle composed of amphiphilic block copolymers

2.4. Porous Microparticle Technology

In this technology, poorly water soluble drug is embedded in microparticles having a porous, water soluble, sponge like matrix. When mixed with water, the matrix dissolves wetting the drug and leaving a suspension of rapidly dissolving drug particles)

This is the core technology applied as HDDS™ (Hydrophobic Drug Delivery System). These particles provide large surface area for increased dissolution rate. The firm has a proprietary spray drying technology that allows the size and porosity of the particles to be engineered as des-red. Alliance Inc of USA and Nektar Therapeutics is also in the process of incorporating this technology.

2.5. Solid Dispersion Technology

The application of dispersions is one of the strategies applied to increase the dissolution rate of lipophilic drugs in aqueous environments. They consist of a hydrophilic carrier incorporating very small particles of the lipophilic drug, preferably in the amorphous state ^45–47. The expected increase in bioavailability (up to 600%) by using solid dispersions is confirmed in many in-vivo studies ^{48, 49}.

2.5.1 Inulin glasses/Sugar glasses

Inulin is a novel excipient offering unique advantages to increase the solubility of lipophilic compounds. Inulin is a naturally occurring fructose polymer; the compound has a long history of safe parenteral use in medicine as the gold standard to measure the glomerular filtration rate. Furthermore, the compound has obtained GRAS status (Generally Recognized As Safe) from regulatory authorities, facilitating use in oral applications.

Mixing an inulin solution with a drug solution followed by freeze-drying under appropriate conditions, results in the formation of a sugar glass. Uniquely for inulin, the dissolution profile of the lipophilic compound incorporated is closely related to the dissolution of this sugar glass. This leads to a strongly enhanced, reliable dissolution for the low soluble active component.

The sugar glasses that emerge from this process also protect the compound against physical and chemical degradation, thereby increasing stability. The inulin formulation technology is suitable for oral and pulmonary application.

Table no. 4: List of poorly soluble drugs along with methods for increasing solubility.

Sr. No.	Poorly soluble Drugs	Methods for  increasing solubility
1.	Dolargin	Nanoparticulation
2.	Loperamide	Nanoparticulation
3.	Tubocurarine	Nanoparticulation
4.	Doxorubicin	Nanoparticulation
5.	Ibuprofen	Nanoparticulation
6.	Diazepam	Nanoparticulation
7.	Naproxen	Nanoparticulation
8.	Carbamazepine	Nanoparticulation
9.	Griseofulvin	Nanoparticulation
10.	Nifedipine	Nanoparticulation
11.	Phytosterol	Nanoparticulation
12.	Omeprazol	Nanosuspension
13.	Domperidone	Nanosuspension
14.	Zidovudine	Nanosuspension
15.	Cyclosporin	Inulin Glass
16.	Diazepam	Inulin Glass
17.	Amoxacilline	Inulin Glass
18.	Bacitracin	Inulin Glass
19.	D9tetra hydro cannabinol	Inulin Glass
20.	Adriamycin	Mixed micelle
21.	Doxorubicin	Mixed micelle
22.	Paclitaxel	Mixed micelle
23.	Aspirin	RESS
24.	Ibuprofen	RESS
25.	Nifedipine	RESS
26.	β-Estradiol	RESS
27.	Lovastatin	RESS
28.	Stigmasterol	RESS
29.	Salicylic acid	RESS
30.	Lysozyme	SAS
31.	Trypsin	SAS
32.	Insulin	PCA
33.	Hydrocortisone	PCA
34.	Dexamethasone	GAS

Summary

The growing percentage of new chemical entites displaying solubility demands that technologies for enhancing drug solubility be developed to reduce the percentage of poorly soluble drug candidates eliminated from the development.

Novel technologies like nanosizing by media milling, supercritical processing, homogenization, cryogenic technology, various precipitation technologies, lipid based technologies, micellar technology & some novel carrier like inulin glass, different polymeric micelle or matrix system of solubilization that may allow greater opportunities in the delivery of poorly soluble drugs.

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About Author:

Malpani A. S
Department of Pharmaceutics, Roland Institute of Pharmaceutical Sciences, Berhampur, Orissa, India.