04-11-2016, 10:51 AM
1464334921-bmffinal.doc (Size: 1.77 MB / Downloads: 5)
Solubility is defined in quantitative terms as the concentration of the solute in a saturated solution at a certain temperature and in qualitative terms, it may be defined as the spontaneous interaction of two or more substances to form a homogeneous molecular dispersion. A saturated solution is one in which the solute is in Equilibrium with the solvent. The Solubility of a drug may be expressed as parts, percentage, molarity, molality, volume fraction, and mole fraction1.
Drug Solubility is the maximum concentration of the drug solute dissolved in the solvent under specific condition of temperature, pH and pressure. The drug Solubility in saturated solution in a static property where as the drug dissolution rate is a dynamic property that relates more closely to the bioavailability rate. The pharmacopoeia lists Solubility in term of milliliter of solvent required to 1gm of solute. If exact solubilities are not known the pharmacopoeia provides general terms to describe a given range
1 Process of Solubilization4:-
The process of Solubilization involves the breaking of inter-ionic or intermolecular bonds in the solute, the separation of the molecules of the solvent to provide space in the solvent for the solute, interaction between the solvent and the solute molecule or ion.
1.1.2 Need of Solubility5,6:-
Therapeutic effectiveness of a drug depends upon the bioavailability and ultimately upon the Solubility of drug molecules. Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown. Currently only 8% of new drug candidates have both high Solubility and permeability.
As a matter of fact, more than one-third of the drugs listed in the U.S. Pharmacopoeia fall into the poorly water-soluble or water-insoluble categories. It was reported a couple of decades ago that more than 40% of the failures in new drug development have been attributed to poor biopharmaceutical properties, including water in Solubility, while it was still indicated recently that about 50% failure of drug candidates was due to poor ―drug-like‖ properties. It is commonly recognized in the pharmaceutical industry that on average more than 40% of newly discovered drug candidates are poorly water-soluble. Poor ―drug like‖ properties of lead compounds led to ineffective absorption from the site of administration, which has been designated as an important part of the high clinical failure due to poor pharmacokinetics. 4
1.1.3 Factors affecting Solubility 6:-
1. Particle size:-
The size of the solid particle influences the Solubility because as a particle becomes smaller, the surface area to volume ratio increases. The larger surface area allows a greater interaction with the solvent. 7,8
S is the Solubility of infinitely large particle. So is Solubility of fine particles
V is molar volume
Ŷ is the surface tension of the solid. R is the radius of the fine particle
2. Temperature:-
Temperature will affect Solubility. If the solution process absorbs energy then the Solubility will be increased as the temperature is increased. If the solution process releases energy then the Solubility will decrease with increasing temperature7. Generally, an increase in the temperature of the solution increases the Solubility of a solid solute. A few solid solutes are less soluble in warm solutions. For all gases, Solubility decreases as the temperature of the solution increases.
3. Pressure:-
For gaseous solutes, an increase in pressure increases Solubility and a decrease in pressure decrease the Solubility. For solids and liquid solutes, changes in pressure have practically no effect on Solubility.
4. Nature of the solute and solvent:-
The solubility of solute in solvent depends on the nature of both solute and solvent.
That means ―like dissolves like‖.
5. Molecular size:-
Molecular size will affect the Solubility. The larger the molecule or the higher its molecular weight the less soluble the substance. Larger molecules are more difficult to surround with solvent molecules in order to solvate the substance. In the case of organic compounds the amount of carbon branching will increase the Solubility since
more branching will reduce the size (or volume) of the molecule and make it easier to solvate the molecules with solvent.
6. Polarity:-
Polarity of the solute and solvent molecules will affect the Solubility. Generally non-polar solute molecules will dissolve in non-polar solvents and polar solute molecules will dissolve in polar solvents. The polar solute molecules have a positive and a negative end to the molecule. If the solvent molecule is also polar, then positive ends of solvent molecules will attract negative ends of solute molecules. This is a type of intermolecular force known as dipole-dipole interaction. All molecules also have a type of intermolecular force much weaker than the other forces called London Dispersion forces where the positive nuclei of the atoms of the solute molecule will attract the negative electrons of the atoms of a solvent molecule. This gives the non-polar solvent a chance to solvate the solute molecules.
7. Polymorphs:-
A solid has a rigid form and a definite shape. The shape or habit of a crystal of a given substance may vary but the angles between the faces are always constant. A crystal is made up of atoms, ions, or molecules in a regular geometric arrangement or lattice constantly repeated in three dimensions. This repeating pattern is known as the unit cell. The capacity for a substance to crystallize in more than one crystalline form is polymorphism. It is possible that all crystals can crystallize in different forms or polymorphs. The two polymorphs cannot be converted from one another without undergoing a phase transition. Polymorphs can vary in melting point. Since the melting point of the solid is related to Solubility, so polymorphs will have different solubilities. Generally the range of Solubility differences between different polymorphs.
1.1.4 Techniques for Solubility Enhancement9:-
1. Micronization:-
The process involves reducing the size of the solid drug particles to 1 to 10 microns commonly by spray drying or by use of attrition methods (fluid energy or jet mill).The process is also called micro-milling.