Cosolvent, drug solubilization

One potential risk that formulators run when using cosolvents as drug solubilizers is the possibility of vehicle toxicity. Each cosolvent is characterized by an acceptable concentration range, which cannot be exceeded without incurring biological damage. To avoid the requirement for in vivo testing, several in vitro models have been advanced to evaluate the relative safety of cosolvent excipients. The most useful in vitro procedure follows the hemolysis of red blood cells, which has been correlated with in vivo animal tests [87,88]. 

The choice of solubilization method will depend upon how efficiently the drug can be solubilized, stability in the system, and upon the biocompatibility of the vehicle for a given delivery route. For solid dosage forms, it may be possible to alter the solid phase to enhance dissolution. For parenterals, the four most commonly used techniques for solubilization are pH adjustment cosolvent addition micelle inclusion through surfactant addition and complexation. The following chapter is designed to summarize the theoretical as well as practical use of each of the above techniques. More extensive discussion on techniques for drug solubilization can be found in books dedicated to the subject. ... 

The ability of a cosolvent to solubilize a given solute can be related to the properties of both the solute and cosolvent. The solubilization slope, a, for a given cosolvent system is dependent upon the polarity of the drug and the polarity of the cosolvent and can be related by,... 

The permissible amount of a given cosolvent will be dependent upon the dosage form. Table 7 gives some examples of products that contain cosolvents. The introduction of new, safe cosolvents would greatly enhance the technique of using cosolvents for solubilization. However, even with the limited number of acceptable cosolvents, cosolvancy is clearly a valuable methods by which to solubilize poorly water soluble drugs. 

Dimethylacetamide is used as a solvent in oral and injectable pharmaceutical formulations. It has been used as a cosolvent to solubilize poorly soluble drugs. The use of dimethylacetamide has also been investigated as a vehicle for the parenteral delivery of relatively small peptides. ... 

The main formulation challenge with HFA pMDI has been the poor solubility of the surfactants that were used in CFC products. Most pMDI formulations are suspensions of fine powder in propellant, and in order to obtain acceptable dose uniformity these suspensions usually require surfactants to stabilize them. The inability to use conventional surfactants has therefore led to a range of diverse formulation approaches. These encompass drug solubilization using cosolvents (Qvar is an example), new surfactants, coating particles with surfactant, and particle engineering (Fig. 3). However, as is the case with most... 

Cosolvents are often nsed in the formnlation of microemulsions to increase the solnbility of drug by cosolvency and to stabilize the dispersed phase. In addition to making the environment more hydrophobic by redncing the dielectric constant of water, cosolvents also increase the amount of molecularly dispersed snrfactant in the aqueous phase. Availability of free surfactant aids in drug solubilization by creating pockets of hydrophobic regions within the aqueous phase. " ... 

Recent years have witnessed an unceasing interest and substantial progress in drug solubilization by different techniques, such as complexaiion, use of surfactants and cosolvents, etc. (77). Hius, novel and more efficient ocular delivery systems for scarcely soluble drugs might be in store for the future. 

Figure 5 Solubilization and effect of dilution drug-cyclodextrin complex or drug cosolvent formulation.

Similarly to the solubility of active drugs, the solubility of surfactants that were used in CFC systems has significantly changed. Surfactant solubility in HFA 134a ranges from 0.005% to 0.02% w/v, much lower than the concentration required to stabilize suspensions (0.1-2.0% w/v) (24,42). The surfactants can be solubilized with the addition of cosolvents such as ethanol. However, it is most likely that cosolvents will be incompatible with suspension formulations because drug solubility will also be promoted and crystal growth will occur. 

S/v is the solubility in water, and f is the fraction of organic solvent in the cosolvent mixture. If the cosolvent mixture contains more than two organic solvents (i.e., a ternary or higher cosolvent mixture), the total drug solubility can be approximated by a summation of solubilization potentials as... 

Li, P, L. Zhao, and S. H. Yalkowsky (1999). Combined effect of cosolvent and cyclodextrin on solubilization of nonpolar drugs journal of pharmaceutical sciende harm. Sci., 88 1107-1111. 

Trivedi, J. S. and M. L. V fells (2000). Solubilization using cosolvent approach. In Liu, R.l( felt r-lnsoluble Drug Formulation, Interpharm Press, Denver, CO, pp. 141-168. 

When delivered parentally or orally, a drug in solution is more rapidly bioavailable compared to a solid dosage form. The cosolvent approach also has some limitations as pointed out for other solubilization techniques. When solubilization of a drug is achieved by use of cosolvent, it must meet certain requirements, such as nontoxicity, compatibility with blood, nonsensitizing, nonirritating, and above all physically and chemically stable and inert. 

Rubino et al. [64-66] studied solubilization by cosolvents in binary and ternary systems. They determined that the solubility of poor water-soluble drugs was approximately described by the log-linear solubility equation as applied to multiple solvent systems ... 

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