Solubility as well as Bioavailability Enhancement Techniques


Priyanka R. Patil*, Mr. Rohan R. Vakhariya, Dr. C. S. Magdum

Rajarambapu College of Pharmacy, Kasegaon, Tal.- Walwa, Dist.- Sangli, Maharashtra

*Corresponding Author E-mail:



Solubility is a solvent property. The word 'solubility' is a defined as the maximum number of disruptions possible. It can also be quantitatively defined as well as qualitatively. Quantitatively, it is defined as the ratio of solute to saturated solutions at a particular temperature. In qualitative condition, consistency can be defined as random interactions between two or more substances, which create uniform molecular dispersal. Solubilization involves the breaking of inter-ionic or intermolecular Solvent molecules, Solution between soluble molecules or ions, Space for spatial interaction. Drug, temperature, Pressure and pH Solubility is an important component get the desired concentration of medicines to systemic circulation, This is a bioavailability.  Most medicines are weak acidic or weak fundamental with poor aqueous solubility. This review highlights various techniques of dissolving medicines or increase solubility of medicines. These techniques include Physical and chemical changes like particle size reduction, micronization, density, Dispersion, complexity, self-emulsification, including complex, prodrug and salt Creation.The larger the surface, the higher the dissolution rate. Since surface area is reduced due to particle size, conventional method can be accomplished through methods such as grinding, ball milling, fluid energy micronization, salt formation and control promenade. Therefore, formulization methods are being invented to increase the biological availability of bad density medicine.


KEYWORDS: solubility, bioavailability, solution, formulations, Techniques.




Parkinsonism The compound density depends on its structure and the solution terms. The structure determines lipophilicity, hydrogen bonding, molecular volume, and crystal energy and ability. The word 'solubility' is a defined as the maximum number of disruptions possible. It can also be quantitatively defined as well as qualitatively. Quantitatively, it is defined as the ratio of solute to saturated solutions at a particular temperature.




In qualitative condition, consistency can be defined as random interactions between two or more substances, which create uniform molecular dispersal. A saturated solution is where the equilibrium is balanced Fluid is commonly expressed as fluid by mass (usually solvent per-a-solvent, per-ll (100mL) solvent mass) morality, mole fraction or other similar descriptive concentration. [1]


Biopharmaceutical Classification System (BCS) US Food and Drug Administration is a guide to estimate the concentration of intravenous intervals. This system prevents estimates using fluid and internal permeability parameters. Solubility is based on the high-dosage capacity of the immediate release product. When high dose strength is denser in 250 ml or pH range of 1 to 7.5, It is considered to be very soluble when there is less water conservative. A 250-mL volume estimate of bioequivalence study protocol has been created, which allows human volunteers to administer the drug administration to glass water [2].


All drugs have been divided into four classes

1. Class I    — high soluble and high permeable

2. Class II  — low soluble and high permeable

3. Class III — low soluble and high permeable

4. Class IV — low soluble and low permeable


Descriptive terms Parts of solvent required to dissolve one part of solute[3]

1. Very soluble           - Less than 1

2. Freely soluble        - More than 1 but less than 10

3. Soluble                   - More than 10 but less than 30

4. Sparingly soluble   - More than 30 but less than 100

5. Slightly soluble      - More than 100 but less than 1000

6. Very slightly soluble - More than 1000 but less than 10,000

7. Very very slightly soluble or practically Insoluble - More than 10,000



Solubilation involves the breaking of inter-ionic or intermolecular Solvent molecules, Solution between soluble molecules or ions, Space for spatial interaction.


Step 1: Holes opens in the solvent Step 2


Step 2: Molecules of the solid breaks away from the bulk


Step 3: The free solid molecule is separated into the hole in the solvent


Factors Affecting Solubility

1. Nature of the solute and solvent,

2. Molecular size polarity

3. Polymorphs physical form of the solid

4. Nature of solvent medium

5. Composition of solvent medium

6. Particle size

7. Temperature

8. Pressure


Need of Solubility [5]:

Drug abuse from GI tract can be limited by various factors. Important breakdown Rebel is poor eruptions of  bad water solubility and drug molecules. When an active agent is administered verbally, they should first dissolve in gastric and / Intestinal fluid so that the GIT screen can reach systemic circulation before it can reach.
That is why, in two parts of pharmaceutical research, focusing on bioavailability of active agents; dissolving medicines and increase disruption rate. BCS is a scientific framework for classifying drug substances based on medicinal fluid and internal permeability.
Due to the reduction of limit on BCS class II and IV drugs, Drug form and solution has been released from gastric fluid and hence the increase in bioavailability. According to the biological availability, a medicinal bad product with bio-product is dissolved, the slow dissolution rate in biological fluid, the poor stability of the deteriorating drugs in the body PH, the bad flow of water through biomembrane, the broadest restrictive metabolism. The larger the surface, the higher the dissolution rate. Since surface area is reduced due to particle size, conventional method can be accomplished through methods such as grinding, ball milling, fluid energy micronization, salt formation and control promenade. Therefore, formulization methods are being invented to increase the biological availability of bad density medicine.
Methods of Solubility Enhancement:

1.      Particle Size Reduction:

a.       Conventional methods

b.      Micronization

c.       Nanosuspension

2.      Co solvency

3.      Hydrotropy

4.      Solid Dispersion

5.      Solubilization by Surfactants

6.      High Pressure Homogenization

7.      PH adjustment

8.      Supercritical fluid recrystallization (SCF)

9.      Sonocrystallisation

10.    Complexation

a.       Physical Mixture

b.      Kneading method

c.       Co-precipitate method

11.    Inclusion Complex Formation-Based Techniques

a.      Kneading Method

b.      Lyophilization/Freeze-Drying Technique

c.       Microwave Irradiation Method

12.  Spray Drying

13.  Liquisolid technique

14.  Micro-emulsion

15.  Cryogenic Method

16.  Neutralization

17.  Self-Emulsifying Drug Delivery Systems



Disposal of drugs is usually related to particle size particles in the shape of bacteriogram, the surface increases. The larger surface area allows for more interaction with the exchange, which increases the solubility.  By reducing the particle size, the dissolving properties improve due to the increased surface area[6].



Conventional methods: 
Conventional methods of particle size reduction, such as assimilation and spray drying, depend on mechanical strength to reduce the active tension. The reduction of particle size thus allows to be economical, reproducible and efficient in improving the disposal. However, the strength to weaken the mechanical strength, Such as milling and grinding, often gives a large amount of physical stress on drug products, which can lead to decreases. Thermal stress due to thermal sensitivity activating active agents is also considered for thermal stress during fever and stress. Using traditional solvents instead of solubility enhancements, poorly dissolving medicines cannot be increased to the desired level of solubility.
Micronization is another tradition for particle size of nanoscale size. Micronization increases the disruption rate of the drug due to increased surface area; By reducing the size of the particle, it does not raise the solution. Microscopic drugs are used by using technology like Jet Mill, Rotor Stator, Colloid Mills, and further Drugs are not suitable for high dose numbers because they do not change the saturation of the medication[6].
Recently, several nanotechnology strategies have been developed to increase the dissolution rate and bioavailability of numerous medicines dissolving in water. Expand nanonization for the study and use of materials and structures at a level of around 100 nm or less. The resulting pharmacological fluid and pharmacokinetics, which result from the development of nanonization, can also reduce systemic side effect. For many new chemical agents with very low resolution, it is not enough to increase oral compulsion by microphone, because micronogenic production has a tendency to be wormwood, which reduces the effective surface to dissolve, the next step is nanonization. Oat milling, homogenizing, emulsification-solvent evaporation technique, peer milling, spray drying etc. Various technologies are used for nanotechnology of similar medicine. There are many examples of drugs nanonization.



A mixture of water-mixable or partially recombinant organic fluid (i.e. co-bankrupt water) is a common and effective way. So that the solution of non-polar increases. This technique is called cosolvancy. Examples of solvents used in the co solvent. The mixture is achieved using PEG 300, propylene glycol or ethanol solubility enhancement Ashes 500-fold, using 20% ​​2-2 Pyrolidone[6].



Hydrootopy is a Solubilization event. The number of second solution results in the increase in the number of hydrogen bridges in the water clusters as the existing solution hydrotropic substances increase in aqueous solution. This makes the water more hydrophobic and thus it is a good bankrupt for the polar drugs. However, the use of hydro toxic substances such as sodium benzoate, nicotine amide, urea, caffeine, orbital etc. is limited to the following factor[11],

        A slight increase of saturated solution with high concentrations excipients

        Isotonicity is not available.

        Personal effects of expansions. Hydrotropic Solubilation is one of them.


4. Solid Dispersion:

Solid dispersion as a group of solid foods containing at least two Various components, usually hydrophilic metrics and hydrophobic drug. The matrix may be either crystalline or indecent. The drug can be isolated at the reactor, amorphous or crystalline particles. Solid dispersion can be referred to as an inverter matrix or as a more active element in the density of the density created by the leak, solvent and the twining solution. 


Carriers for Solid Dispersions:

1.      Acids: – Citric Acid, Tartaric Acid, Succinic Acid.

2. Sugars: – Sucrose, Dextrose, Sorbitol, Maltose, Galactose, and Xylitol.

3. Polymeric Materials: – Poly-vinylpyrollidone, EG 4000 and 6000, Carboxy-mythyl cellulose, Hydroxypropyl-cellulose, Guar gum, Xanthangum, Sodium Alginate, Dextrin, Cyclodextrin.

4.      Surfactants – Poly ox ethylene stearate, poloxamer, Deoxycholic acid, Tweens and Spans, Glacier 44/14, Vitamine E TPGS NF.

5. Miscellaneous - Urea, Urethane Hydroxyl alkyl Xanthene Pentaerythritol


Surface-active agents are substances that at low concentrations Adsorb on to the surfaces or interfaces of system and alter the surface or interfacial free energy and the surface and the interfacial tension.


Dissolve mechanism enhanced by solid dispersion

1       Reduction of particle size.

2       Solubilization effect (use of carriers).

3       Increased elasticity and dispersion by

4       Prepare a metastable dispersion with low heat for faster immersion.

5       Ex. Disruption power for Furs Chemed is 17 kg / mol and disruption power for 1: 2 furraside: PVP co-projection 7.3 Kg / Mol[8].


5. Solubilization by Surfactants:

The traditional approach to dissolving a poorly soluble substance is to reduce the intra-regional tension between the wet and the commercial surface, for better grilling and salvation. Different types of surfactants like poly globalized  glycerides, twins, spoons, synthetic block copolymers like poly oxythylene sterile and poly (propylene) oxide) -Poly (ethylene oxide) -poly (propylene oxide) such as poloxamers-based muscles, Poly (beta-benzyl-el-aspatate) -biploy (ethylene oxide), poly (caprolactone) -bi-poly (ethylene oxide) etc. are very successful as emitters and carriers for immersion growth. Due to the improvement of medicinal fluid through medicinal fluid, surface tension is reduced due to the combination of medicines and solvent, moisture properties and molecular solubilization [7].


6. High Pressure Homogenization:

High-pressure homogenizing has been used to create Nanoscopulation of many disintegration drugs. In this process, the Suspension of Drugs and Surfactant is suppressed by the pressure of the high pressure homogenizer's nanosized aperture valve. The theory of this method is based on hydroelectricity.  In the particles is high enough to convert strength Drug micro particles in nanoparticles. This requires the need for small sample particles and many cycles of homogenization before loading the anxiety.  Disruption rates and bioavailability of solid foods such as spironolactone and omeprazole, high pressure homogenization by reducing their particle size [9].


7. pH adjustment:

Poor water dispersion is likely to be applied by water Changed a pH to dispose of this approach, it is necessary to consider the buffer capacity and tolerance of the chosen pH. Solubilized Expectant, which extends environmental pH to a pH as a dose in the form of Weekly Acidic Medicines. Disposal of that drug, the accidents that act as alkalizing agents, can increase instability of weekly basic medicines.



Preparation and analysis are easy.
Produce easy to make and fast track.

Emboli, which can cause verbally. Tolerance and poisoning related to using (local and systematic) Non-physiological pH and extreme pH. Solid solubilized and dissolved system, a dissolved drug. The aqueous environment is comparatively less stable than the chemical relative Formulas crystalline cube.The selected pH can increase the speed Hydrolysis or other system catalysts [1o].


8. Supercritical fluid recrystallization (SCF):

The fluid is known as supercritical fluid, in which the temperature and pressure are more than the pressure of its critical temperature and pressure over pressure, so that they get both gas and liquid properties. D. The best example of this is carbon dioxide. SCFs are extremely compressed at critical temperatures and allow changes in density and mass transport features, so that due to mid-pressure pressures, its bankruptcies are determined. Drugs are dissolved in SCFs so that they can be recycled for less particle size[11].
The most common process techniques involving supercritical fluids are:
1       Supercritical anti-delivery (SAS)
2       Quick expansion of severe problem (decrease).


9. Sonocrystallisation:

Re-structuring of solid materials using liquid Solvents and antisolventes are also working successfully to reduce particle size. Novel approach to minimize particle size based on crystallization using ultrasounds. To stimulate crystallization, the frequency of 20-100 KHz use ultrasound power, known by frequency range, to induce crystallization. This increases the focal point rate but controls the size of the effective size of the device and the size of the active drug-use components. Most applications use ultrasound in the 20KH-5MHz range[12].


10. Complexation:

Integration is the association between two or more molecule to become a binding with a defined stoichiometry. Two types of complexity which are useful for dissolving medicines. Including stacking in water media and inclusion.


a. Self-Association and Stacking Complexation

Non-polar Moiety escapes from the water through strong Hydrogen binding water regulator. This is due to some reason Molecule to reduce contact with water through the combination of their hydrocarbon. Stacked complexes can be homogenous or mixed Former self-organization and then in completeness is known.


b. Inclusion Complex

Integration involves the later-polar part of a non-polar molecule or molecule (which is known Guest) in a non-polar cave of atomic or atomic mass.


Techniques of complexation:

a.       Physical Mixture

b.      Kneading method

c.       Co-precipitate method


11. Inclusion Complex Formation-Based Techniques:

Solubility Enhancement Technologies, including the complex composition technique is working more and more perfect solution for improving resolution, dissolution rate, And bioavailability of  bad water dissolving drugs Including Complexes are built by non-polar access. A molecule or non polar area (known as Guests) in another molecule or group (known as host). Major structural requirements. There is a snug fit in the guest for inclusion integration Host cavity The host's cave must be large Sufficient enough to accommodate guests and small enough remove the water, so that water and total wealth. The non-polar area of ​​the host and guest is reduced. Different techniques are used to prepare for inclusion. Due to improving their complex medicines for bad supplements aqueous solution is listed here: [13]


A. Kneading[13]

This process involves the preparation of cyclodextrin paste Guest molecules can either be used for less water Ethanol to create mass. It can be dried in the month of June 45 degrees Celsius and pulverized.


B. Lyophilization/Freeze-Drying Technique:

To get a porous, unrelated powder high level interactions between drugs and CDs, Freeze Drying techniques. In this technology, the solvent system is removed by the primary friction and with minimal pressures drying solutions of medicines and CDs. Through this method thermocouple can be successfully made in complex form. The limitations of this technique are the use of specialized equipment, time consuming process and poor powder products. The  freeze drying technique is considered as an alternative to bankrupt evaporation and incorporates the molecular mix of drugs and carriers in common commons.


C. Microwave Irradiation Method:

The reaction of the microwave bacteria in this technology is the response from drug and complex agents using microwave ovens. Depending on certain donors, the drug and the CD are dissolved by a mixture of water and organic fluids specified in a round bottom flask. The microwave oven reduces to about one to two minutes of mixture in 60 degrees Celsius. Upon completion of the reaction, sufficient solvent mixture is added to the above reaction mixture to remove the remaining, uncompressed free drug CD. Separation obtained by using the Whitman filter paper is isolated and the vacuum oven is dried at 40 ° C intervals of 48 hours.


12. Spray Drying:

Evaporation of Drug and Polymer Solutions is done in a variety of ways with the help of a spray dryer. These solutions are dissolved by dissolving the solution in the water released in methanol and polymers, and both mix in solution, which create clear solutions. Evaporation using evaporation. A spray mixture with polymer gets in 20-30 minutes [14]


13. Liquisolid technique:

When dissolved medicine is included in the fluid vehicle Carrier content that has a porous surface and almost Cellulose as its inner leak fibers, absorption and both Exploitation happens. That is, the liquid was absorbed in the beginning the inner side of the particles is under its internal structure and captured the absorption of the liquid, after the saturation of this process on the surface of the coriander and on the outer surface Particles arise. Then, the coating material is high Offers absorbent properties and a large specific surface area Delirium flow characteristics of liquid immune system. Liquidize the solid system is acceptable conducive and compressed powder Forms of liquid medicines [14].
In the concept of fluid, The system dissolving liquid drugs with reduced aqueous solution Converting to the right non-volatile solvents, free vehicles And usually radically compressed powder by a simple admixture excipients of selected powder referred to as carriers and coating Ingredients Amorous Cellulose and Silica Powder can be used as coating material.
14. Micro-emulsion:
Micro emulsion is an optical clear pre-centered, isotopic, Thermo Dynamically Transparent system contains a mixture of oil, hydrophilic surfactants and hydrophilic solvents that distribute bad water dissolving drugs. After contact with water, formulas disperse automatically. Creates a very clear emulsion of very small and uniform oil droplets poor dissolving drugs are solubilized. Micro-emulsion has been used to increase the use Dispose of many medicines which are practically inappropriate in water Protein for oral, parents and transdermal use.


15. Cryogenic Method:

Cryogenic techniques have been developed to increase the rate of dissolution of drugs by producing high amount of nano-structured amorphous drug particles in very low temperature conditions. Cryogenic invention can be defined by the form of injection equipment (capillary, rotary, pneumatic, ultrasonic nozzle), location of the nose  and cryogenic fluid ( N2, R, O2, organic solvents). After cryogenic processing, dry powder can be obtained through various medicinal processes such as spray freeze drying, atmospheric freeze drying, vacum freeze drying and filtration[15]. 


16. Neutralization:

Medicines are added to alkaline solutions such as sodium hydroxide, Ammonium hydroxide. The β-cyclodextrin is then added to dissolve the solution. The clear resolution received after few seconds under the movement is unqualified to reach the equivalent point of use of HCL solution. At this moment, the white line was not able to understand the appearance; the compound involved is related to the creation of the compound. It is then transmitted and dry.


17. Self-Emulsifying Drug Delivery Systems:

A mixture of oil, surfactant, co-surfactant, more hydrophilic solvents, and co-sol venture creates a transparent isotropic solution called self-emulsifying drug delivery system (SEDDS). Emulsions or in a flammable condition, it mildly improves micro-emulsion and is used for improving lympholysis and absorption of improving lymph node.[3] The self-emulsification process is specific to the temperature of oil/surfactant joint, surfactant concentration, oil/surfactant ratio and self-emulsification temperature. Immersion facility can be easily separated from the water which is accessible in various liquid crystalline or gel steps created on the surface of the liquid.[7] Some parameters are proposed to show self-emulsifying performance, including the rate of amplification, in-flight size distribution and in conjunction with the resulting comments. Among them, the emulsion drip shape is considered to be a critical factor in self-reliance/exposure performance, because it determines the degree of freedom from the drug and the extent to which the absorption is determined.



Through this article, we conclude that the solubility is highest important physical features for Bioavailability, formulation, development of various doses, Therapeutic effect of the drug and the nature of drug and certified analysis. The Solubility method of growth is for the purpose of determining good formulation, such as good oral biology, Good patient adherence with dosing and low cost Production. Different techniques described on the stand alone or in combination can be used to increase the dynamics of Drug solubility can be enriched by many technologies. Increase the number of folds in the solution. Due to the problem of many medicines, they get bioavailability affected and therefore require increase the solubility. Now it is possible reduces problem related to the solubility And Enhancement of drug solubility is achieved with the help of various techniques mentioned above.



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Received on 19.01.2019         Modified on 16.03.2019

Accepted on 04.04.2019       ©A&V Publications All right reserved

Res.  J. Pharma. Dosage Forms and Tech.2019; 11(2):105-110.

DOI: 10.5958/0975-4377.2019.00016.8