Poor Solubility Of Drug Substance Major Obstacle Biology Essay

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Poor solubility of drug substance is a major obstacle in the development of drug formulations. One of the most persistent problems faced by drugs with poor aqueous solubility is that their oral delivery is frequently associated with implications of low bioavailability and lack of dose proportionality. More than 40% drugs coming from high through output screening are poorly soluble in water. Currently only 8% of new drug candidates have both high solubility and permeability

According Biopharmaceutic classification system the class II and class IV drugs shows low solubility showing variable absorption. One determinant factor for absorption is drug dissolution, which is influenced by solubility of drug in GI fluids. Bioavailability can be defined as the rate and extent (amount) of drug absorption of unchanged drug from its dosage form. Drug absorption is defined as the process of movement of unchanged drug from the site of administration to systemic circulation. The two critical slower rate determining processes in the absorption of orally administered drugs are,

(1) Rate of dissolution

(2) Rate of drug permeation through the biomembrane

Dissolution is the rate determining step for hydrophobic, poorly aqueous soluble drugs. So it is necessary to enhance the dissolution poorly soluble drugs to enhance the therapeutic effectiveness of the drug. Dissolution is a process in which a solid substance solubilises in a given solvent; mass transfer from the solid surface to liquid phase. According to Noyes and Whitney equation the rate of drug dissolution is directly proportional to the saturation or maximum drug solubility. Rate of drug dissolution is affected by various factors like solubility, particle size, polymorphism, salt form of drug, psuedopolymorphism, complexation and wettability, etc.

Consideration of modified Noyes-Whitney equation provides some hints as to how the dissolution rate of even poorly soluble compounds might be improved to minimize the limitations to oral availability.

dC = DAK (Cs-Cb)

dt Vh

From this equation it is clear that larger the surface area, higher the dissolution rate. Since the surface area increases with decreasing particle size, a decrease in particle size will improve the dissolution rate. The surface of such particles has energy higher than the bulk of the solid resulting in an increased interaction with the solvent. A fundamental step in the solubilisation of drug compounds is the selection of an appropriate salt form, or for liquid drugs, adjustment of pH of the solution.

Poorly soluble drugs have motivated the development of drug delivery technologies to overcome the obstacles to their solubilisation through either chemical or mechanical modification of the environment surrounding the drug molecule, or physically alerting the macromolecular characteristics of aggregated drug particles. These technologies include both traditional methods of solubility enhancement, such as particle size reduction via comminution and spray drying, addition of surfactants and inclusion in cyclodextrin-drug complexes, and the use of more novel mechanisms such as self-emulsifying system, micronisation via nanoparticles, pH adjustment and salting in processes.


The various techniques available for improving the solubility of poorly soluble drugs are,

Physical modifications:

Particle size reduction:



Modification of crystal habit



Drug dispersion in carriers

Eutectic mixtures

Solid dispersions

Solid solutions


Solubilization by surfactants


Self emulsifying drug delivery systems

Chemical Modifications:

Soluble prodrugs


Particle size reduction:

The bioavailability of low solubility drugs is often related to drug particle size. By reducing particle size, the increased surface area may improve the dissolution properties of the drug to allow a wider range of approaches and delivery technologies. Conventional method of particle size reduction, such as comminution and spray drying, rely upon mechanical stress to disaggregate the active compound. The mechanical forces inherent to comminution often impart significant amounts of physical stress upon the drug product which may induce degradation. Recrystallisation of poorly soluble materials using liquid solvents and antisolvents also used to reduce particle size.

Particle size reduction through the traditional methods of comminution, such as grinding and milling, are often incapable of reducing the particle size of nearly insoluble drugs. Other methods have been developed to impart less physical stress upon the particles to impart less physical stress upon the drug particles, such as piston gap homogeniser to create nanoparticles through hydrodynamic cavitation. Another novel and nanosizing and solubilisation technology is supercritical fluid processes. Through manipulation of the pressure of SCF processing, the favorable characteristics of gases-high diffusivity, low viscosity and low surface tension-may be imparted upon liquids to precisely control the solubilization of a drug with a supercritical fluid. Several methods of SCF processing have been developed, such as precipitation with compressed antisolvents process, solution enhanced-dispersion by SCF, supercritical antisolvents processes and aerosol supercritical extraction system.

Modification of crystal habit:

Polymorphism is the ability of an element or compound to crystallize in more than one crystalline form. Different polymorphs of drugs exhibit different physicochemical properties including solubility, melting point, density, stability. The amorphous form of drug is always more suited than crystalline form because of increased surface area. Generally the anhydrous form of a drug has greater solubility than the hydrates. The order for dissolution of different solid forms of drug is Amorphous > Metastable polymorph > Stable polymorph.

Drug dispersion in carriers:

The solid dispersion techniques was used to reduce particle size and therefore increase the dissolution rate and absorption. The term solid dispersion refers to the dispersion of one or more active ingredients in an inert carrier in a solid state, frequently prepared by melting method, solvent method, fusion solvent method. The most commonly used hydrophilic carriers for solid dispersions include polyvinyl pyrrolidine, polyethylene glycol.

Inclusion complexes and microemulsions:

Complexation is the association between two or more molecules to form a nonbonded entity, and relies on relative weak forces such as London forces, hydrogen bonding and hydrophobic interactions. In case of high dose products and those compounds with higher melting points solubilisation via drug-cyclodextrin inclusion complexes may be more appropriate. Cyclodextrin complexes also employed in conjunction with hydrophilic polymers such as HPMC, to improve the solubilising effects. Drug-cyclodextrin complexes are commonly formed through either supersaturating a cyclodextrin solution with drug and mildly agitating the solution for an extended period of time.

Solubilization by surfactant:

Surfactants are molecules with distinct polar and nonpolar regions and presence of this may lower the surface tension and increases the solubility of the drug within in an organic solvent. Microemulsions and self-emulsifying systems have emerged as potential solubility technologies, whose solubilising and absorption promoting effect is thought to lay in the reactivity of triglycerides and surfactants with the walls of gastro intestinal tract. Traditionally long and medium chain triglycerides have been employed with surfactants to incorporate drugs into self emulsifying system. Co-surfactants are frequently employed to increase the amount of drug capable of being dissolved in to the lipid base. These co-surfactants are often organic solvents suitable for oral administration, such as ethanol, propylene glycol and poly ethylene glycol.

Chemical Modifications:

For organic solvents that are ionizable, changing the pH may be the simplest and most effective means of increasing aqueous solubility. The weakly acidic drug with low pKa or a weakly basic drug with high pKa can be efficiently solubilized by pH control. The use salt of forms is most common and effective method of increasing solubility and dissolution rate of acidic and basic drug.

Other techniques:


The solubilsation of drugs in co-solvents is another technique for improving the solubility of poorly soluble drug. When electrolytes and nonpolar molecules have poor water solubility and it can be improved by altering polarity of the solvent. This can be achieved by addition of another solvent, and process is known as cosolvency. Cosolvent system works by reducing the interfacial tension between the aqueous solution and hydrophobic solute.


The hydrotrophy process involves increasing solubility of drug in water by adding large amount of additives. The mechanism involves the complexation process, that is a weak interaction between hydrotrophic agents..


Nanotechnology mainly refers to the study of materials and structures at the nanosized level. In micronization process of drugs the chance for agglomeration is high, so in order to avoid that nanoscale systems are used. A nanocrystal is material with dimensions measured in nanometers, and particle size ranging from 1 -1000 nanometers. The transfer of drug microparticles to drug nanoparticles improves the bioavailability of poorly soluble drugs. There are basically three formulation principles:





Hydrosols are prepared by precipitation, addition of solvent to the nonsolvent or fast mixing of both. Production of hydrosols in lab scale is performed by mixing solvent and nonsolvent in a static blending. The basic problem associated with hydrosol is the physical stabilization of suspension to avoid particle aggregation and crystal growth due to Ostwald ripening and can be overcome by spray drying of suspension.


The reduction of drug particle size by milling process also used to improve the solubility of poorly soluble drugs. Basic problem associated with milling technique is that the product contains fraction of particles in the micrometer range.


Nanosuspensions are defined as colloidal dispersion of nano-sized particles stabilized by surfactants. It is also defined as a biphasic system consisting of pure drug particles dispersed in an aqueous vehicle in which the diameter of suspended particle is less than 1µm in size. Nanosuspensions consist of the poorly water-soluble drug without any matrix material suspended in dispersion. Nanosuspension can be used to enhance the solubility of drugs that are poorly soluble in aqueous as well as lipid media. As a result rate of flooding of the active compound increases and the maximum plasma level reached faster. It is useful for molecules with poor water solubility, poor permeability or both. The nanosuspension can also be lyophilized or spray dried and the nanoparticles of a nanosuspension can also incorporated in to solid matrix.

Advantages of Nanosuspension:

They are offering increase in the dissolution velocity and saturation solubility of the drug.

They are having improved biological performance.

Ease of manufacture and scale-up.

They possess long-term physical stability.

They are capable of targeting a drug to specific site in body.

Disadvantages of nanosuspension:

Require stabilizers.

Lack of controlled release.

High energy input.

Preparation method for Nanosuspension:

Mainly there are two methods for preparation of nanosuspensions. The conventional methods of precipitation are called Bottom up technology. In Bottom up technology the drug is dissolved in a solvent, which is then added to non solvent to precipitate the crystals. The basic advantage of precipitation technique is the use of simple and low cost equipments. The basic challenge of this technique is that during the precipitation procedure the growing of the drug crystals needs to be controlled by addition of surfactant to avoid formation of microparticles. The limitation of this precipitation technique is that the drug needs to be soluble in at least one solvent and this solvent needs to be miscible with non solvent.

The other is Top down technologies are the disintegration methods and are preferred over the precipitation methods. The Top down technologies include Media Milling (Nanocrystals), High Pressure Homogenization in water (Dissocubes), High Pressure Homogenization in non aqueous media (Nanopure) and combination of Precipitation and High-Pressure Homogenization (Nanoedege). Few other techniques used for preparing nanosuspensions are emulsion as templates and micro emulsion as templates.

Precipitation method:

In this technique the drug is dissolved in an organic solvent and this solution is mixed with a miscible antisolvent. In the water - solvent mixture solubility is low and drug precipitates. Rapid addition of drug solution to an antisolvent leads to sudden supersaturartion of mixed solution, and generation of fine crystalline or amorphous solids. Precipitation of amorphous material favored at high supersaturation when the solubility of amorphous state is exceeded.


Simple process

Low cost equipment

Ease of scale up


Drugs has to be soluble with one solvent and that this solvent needs to be miscible with a non solvent.

Growing of drug crystals need to be limit by surfactant addition.

High-pressure homogenization Method:

The technology was first developed by R.H.Muller (1998). In this process firstly the drug powders are dispersed in a stabilizer solution to form pre-suspension; then pre-suspension was homogenized by the high-pressure homogenizer at a low pressure for several times as a kind of premilling, and finally was homogenized at a high pressure for 10-25 cycles until the nanosuspensions with the desired size were prepared. The instrument can be operated at pressures varying from 100 to1500 bars.


During homogenization, the fracture of drug particle is brought about by cavitation, high shear forces and the collision of particles against each other. The drug suspension, contained in a cylinder of diameter about 3mm, passes suddenly through a very narrow homogenization gap of 25µm, which leads to high streaming velocity.

In the homogenization gap, according Bernoulli's equation the dynamic pressure of the fluid increases with the simultaneous decrease in static pressure below the boiling point of water at room temperature. This leads to formation of gas bubbles, which implode when suspension leaves the gap (Cavitation). This implosion force break down the drug microparticles in to nanoparticles. The process can be affected by factors like, effect of homogenization pressure and number of homogenization cycles.


Drugs that are poorly soluble in both aqueous and organic media can be easily formulated in to nanosuspension.

Ease of scale up and little batch to batch variation.

Allow aseptic production of nanosuspension for parenteral drug administration.


Prerequisite of micronized drug particles

Prerequisite of suspension formation using high speed mixtures before subjecting it to homogenization.

Milling Method:

The method is first developed and reported by Liversidge (1992); the nanosuspensions are prepared by using high-shear media mills or pearl mills. In this method firstly, drug and surfactants were mixed to form a homogeneous mixture and inputted into the milling chamber; secondly, the milling pearls or the milling ball was put into, and certain amount of water was or not added into the milling chamber; thirdly, the miller was turned on for about several to dozens of hours to prepare the nanosuspensions.

Fig.no.5 Agitator bead mill with Dynamic separator gap

1) product inlet; 2) Product Outlet;

3) Cooling jacket; 4) Milling Pearls;

5)Rotor with grinding disks; 6)Dynamic separator gap

Principle: The high energy and shear forced generated as a result of impaction of milling media with the drug provide the energy input to break the microparticulate drug in to nano-sized particles. The milling medium is composed of glass, Zirconium oxide or highly cross-linked polystyrene resin. The process can be performed in batch or recirculation method.


Drugs that are poorly soluble in both aqueous and organic media can be easily formulated in to nanosuspension.

Ease of scale up and little batch to batch variation.

Narrow size distribution of the final nano-sized product.


1) Nanosuspensions contaminated with materials eroded from milling media may be problematic when used in chronic therapy.

2) The media milling technique is time consuming.

3) Scale up is not easy due to mill size and weight.

Emulsion as templates:

The use of emulsion as templates is applicable for those drugs that are soluble in either volatile organic solvent or partially water-miscible solvent. There are two ways of fabricating drug nanosuspension by the emulsification method. In the first method an organic solvent or mixture of solvents loaded with the drug is dispersed in the aqueous phase containing suitable surfactants to form an emulsion. The organic phase is then evaporated to form nanosuspension stabilized by surfactants. Another method is use of partially miscible solvents and drug nanosuspension is obtained by just diluting the emulsion.


Use of specialized equipment is not necessary.

Particle size can be controlled by controlling size of emulsion droplet.

Ease of scale up if formulation is optimized properly.


Drugs that are poorly soluble in both aqueous and organic media cannot be formulated by this technique.

Safety concerns because use of hazardous solvents.

High amount of surfactant /stabilizer is required.

Microemulsions as templates:

Microemulsions are thermodynamically stable and isotropically clear dispersion of two immiscible liquids, such as oil and water, stabilized by an interfacial film of surfactant and co-surfactant. For production nanosuspension oil-in-water microemulsions are used, the suitable dilution of microemulsions yields nanosuspension. The nanosuspension thus formed has to be made free of the internal phase and surfactants by means of diultrafiltration.


Need for less energy input for production of nanosuspension.

Use of specialized equipment is not necessary.


Need for diultrafiltration for purification of drug.

High amount of surfactant/stabilizer is needed.


Nanosuspension are characterized in similar ways as those used for conventional suspensions such as appearance, colour, odor, assay and related impurities, etc. Apart from this nanosuspensions should be evaluated for their particle size, zeta potential, crystalline status, dissolution studies and in vivo studies.

Mean particle size and particle size distribution:

Particle size distribution determines the physicochemical behavior of the formulation, such as saturation solubility, dissolution velocity, physical stability, etc. the particle size distribution can be determined by photon correlation spectroscopy (PCS), laser diffraction (LD), and coutler counter multisizer.

Zeta potential:

Zeta potential is an indication of the stability of the suspension. For a stable suspension stabilized only by electrostatic repulsion, a minimum zeta potential of ±30 mV is required whereas in case of combined electrostatic and steric stabilizer, a zeta potential of ±20 mV would be sufficient.

Crystalline state and particle morphology:

To characterize the polymorphic changes due to the impact of high-pressure homogenization in the crystalline structure of the drug, techniques like X-ray diffraction analysis in combination with differential scanning calorimetry or differential thermal analysis can be used. Nanosuspension can undergo a change in the crystalline structure, which may be to an amorphous form or to other polymorphic forms because of high-pressure homogenization.

Saturation solubility and dissolution velocity:

Nanosuspensions have an important advantage over other techniques, that it can increase the dissolution velocity as well as the saturation solubility. The assessment of saturation solubility and dissolution velocity helps in determining the in vitro behavior of the formulation.

In-vivo biological performance:

The establishment of an in-vitro/in-vivo correlation and the monitoring of the in-vivo performance is important parameter used for characterization nanosuspension. This parameter is important in intravenously injected nanosuspension.


Oral drug delivery:

The poor oral bioavailability of the drug may be due to poor permeability, poor solubility or poor stability in the gastrointestinal tract (GIT). Nanosuspension resolve the problem of poor bioavailability by solving problems like poor solubility and poor permeability across the membrane. The oral administration of gonadotropin inhibitor Danazol as a nanosuspension leads to an absolute bioavailability of 82.3% and the conventional dispersion only to 5.2% .

Parenteral drug delivery:

The parenteral route is an invasive route provides quick onset of action, rapid targeting and reduced dosage of the drug. One of the most important applications of nanosuspension technology is the formulation of intravenously administered products. Clofazimine nanosuspensions for IV use showed that drug concentration in the liver, spleen and lungs reached a comparably higher level, well in excess of the minimum inhibitory concentration for most Mycobacterium avium strains.

Ocular drug delivery:

Nanosuspension can be used for improving bioavailability of drugs that exhibit poor solubility in lachrymal fluids. For sustained release of the drug for a stipulated time period, nanosuspension can be incorporated in a suitable hydrogel base or mucoadhesive base or even in ocular inserts. The polymeric nanosuspension of flubiprofen and ibuprofen prepared using acrylate polymers like Eudragit RS100 and Eudragit RL100 shows better in-vivo performance over the existing formulation.

Pulmonary administration:

Nanosuspension can be used for delivering drugs that exhibit poor solubility in pulmonary secretions. Aqueous nanosuspension can be nebulized using mechanical or ultrasonic nebulizers for lung delivery. They also increases adhesiveness and thus cause a prolonged residence time. Budenoside is poorly water-soluble corticosteroid formulated as a nanosuspension for pulmonary delivery.

Targeted drug delivery:

Nanosuspension can be used for targeted deliver as their surface properties and changing of the stabilizer can easily alter in-vivo behavior. Kayser formulated aphidicolin as nanosuspension to improve targeting against Leishmania-infected macrophages at a concentration in the microgram range.

Mucoadhesive of the nanoparticles:

Nanoparticles orally administered in the form of a suspension diffuse in to the liquid media and rapidly encounter the mucosal surface. The adhesiveness of nanosuspension improves bioavailability and targeting of parasite persisting in the GIT. The bioadhesion can also improved by including a mucoadhesive polymer in the formulation.