Techniques of Solubilization

Techniques of Solubilization

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.

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