In liquid pharmaceuticals solutions sometimes the active drug is poorly soluble or insoluble in the desired solvent and could not able to achieve the required concentration of formulation. In such cases, it is required to increase the solubility of that material in the solvent by a suitable technique. Solubilization is the technique by which the desired solubility of a poorly water-soluble substance is achieved. Since water is the most commonly used solvent in pharmaceutical liquids, the following techniques have been aimed at increasing the solubility of a drug substance in water.
Pharmaceutical Approach
1. pH Adjustments
Most of the drugs are either weak acids or weak bases.
The aqueous solubility of a weak acid or a weak base is greatly influenced by
the pH of the solution. Hence, the solubility of a drug that is either a weak
base or a weak acid may be altered by adjusting the pH of the solution. The
solubility of a weak base can be increased by lowering the pH of its solution whereas
the solubility of a weak acid can be improved by increasing the pH. pH
adjustment for improving the solubility can be achieved in two ways:
(a) Salt formation.
(b) Addition of buffers to the formulation.
However, pH adjustments should be done judiciously
since other factors such as stability, bioavailability, etc. can also be
affected by a change in pH.
e.g. Gatifloxacin is insoluble in water at higher pH
but the same drug gets solubilized at the lower pH and attends maximum
solubility below the pH of 5. Hence the parenteral preparation of Gatifloxacin
is formulated at a pH of 3.5 to 5.5.
e.g. The solubility of various chemotherapeutic agents such as
Methotrexate, Fluorouracil, Cytarabine, etc. also gets affected by the
alteration in pH changes.
2. Cosolvency
Cosolvency is the technique of increasing the
solubility of poorly soluble drugs in a liquid by the addition of a solvent
miscible with the liquid in which the drug is also highly soluble. Cosolvents
such as ethanol, glycerol, propylene glycol, or sorbitol decrease the interfacial
tension or alter the dielectric constant of the medium and increase the
solubility of weak electrolytes and non-polar molecules in water. Example:
Formulation of Diazepam injection using propylene glycol as cosolvent.
3. Complexation
In certain cases, it may be possible to increase the
solubility of a poorly soluble drug by allowing it to interact with a soluble
material to form a soluble intermolecular complex. It is however essential that
the complex formed is easily reversible so that the free drug is released
readily during or before contact with biological fluids. Several compounds, such
as nicotinamide and Beta-cyclodextrin, have been investigated as possible
agents to increase the solubility of water-insoluble drugs.
e.g. Interaction of Iodine with Povidone to form a water-soluble
complex and preparation of Itraconazole injection by forming inclusion complex
of itraconazole with hydroxy propyl beta-cyclodextrin.
4. Surface active agent
A surface active agent is a substance that reduces the
interfacial tension between the solute and the solvent to form a thermodynamically
stable homogeneous system. The mechanism involved in this solubilization
technique involves micelle formation and due to the formation of a stable
system, it is widely used in pharmaceutical formulations. When a surfactant
having a hydrophilic and a lipophilic portion is added to a liquid, it first accumulates
at the air/solvent interface; further addition leads to its dispersion
throughout the liquid bulk. At a certain concentration known as the Critical
Micelle Concentration (CMC), the dispersed surfactant molecules tend to
aggregate into groups of 100 to 150 molecules known as a micelle.
In an aqueous medium, the surfactant molecule orients
in such a manner that its hydrophilic portion faces the water while the
lipophilic portion resides in the micelle interior. An insoluble compound added to the surfactant
liquid either enters the micelle interior, gets adsorbed onto the micelle
surface, or sits at some intermediate point depending on its polarity, thus affecting
solubilization.
Surface active agents should be non-toxic and stable,
possess good solubilizing power, and be compatible with other formulation
ingredients. If they are intended for oral use, they should also have an
agreeable taste and odor. Surfactants that are used as solubilizing agents
generally have HLB values over 13. Examples include polysorbate-80, polyoxyl 40
stearate, sodium lauryl sulfate, and PEG-40-Castor oil (Cremophor).
e.g.: Fat-soluble vitamins A, D, E, and K, antibiotics
like griseofulvin and chloramphenicol, and analgesics such as aspirin and
phenacetin have been solubilized by using surface active agents.
5. Hydrotropism
Hydrotropism is the term used to describe the increase
in aqueous solubility of a drug by the use of large concentrations (20% to 50%)
of certain additives. The exact mechanism for hydrotropism is not clear
although complexation, solubilization, or cosolvency have been suggested as the
probable mechanisms. Hydrotropism is rarely applied to pharmaceutical formulations,
as the increase in aqueous solubility is generally inadequate.
e.g.: An increase in solubility of caffeine and
theophylline by the addition of sodium benzoate and sodium salicylate
respectively.
6. Micronization
Surface area and particle size are inversely related
to each other. The smaller the drug particle, the larger the surface area and the
greater the solubility. A decrease in particle size achieved through
micronization will result in higher solubilization of the drug.
e.g.: Micronization of poorly aqueous soluble, but non-hydrophobic
drugs such as griseofulvin and chloramphenicol results in enhanced
solubility.
7. Solid Solutions
Solid solutions are prepared by melting of physical
mixture of solute, a poorly water-soluble drug, and solid solvent, a highly
water-soluble compound or polymer followed by rapid solidification. Solid
solutions are also called molecular dispersions or mixed crystals. When such a binary system comprising of drugs
dispersed in a solid solvent is exposed to water, the soluble carrier dissolves
rapidly leaving the poorly water-soluble drug in a state of microcrystalline
form with increased surface area resulting in enhanced solubility.
e.g.: Griseofulvin from succinic acid solid solution
dissolves 6 to 7 times faster than pure griseofulvin and Digitoxin-PEG 6000
solid solution showed enhanced solubility.
Chemical Modification: The
solubility of a substance can be improved by chemically modifying the
substance. For example, aqueous solubility can be improved by increasing the
number of polar groups in a molecule. This is often achieved by salt formation;
for instance, alkaloids are poorly soluble in water whereas alkaloidal salts
are freely soluble in it. Alternatively, a molecule may be modified to produce
a new chemical entity or prodrug. The aqueous solubility of chloramphenicol
sodium succinate, for example, is about 400 times greater than that of chloramphenicol.
Prodrugs, however, must revert to the parent molecule after
administration.
Stability: In
addition to the solubility of the medicament, other considerations regarding the
physical, chemical, and microbiological stability of the preparation will need
to be taken into consideration.