Cosolvents, 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]. 

Yalkowsky, S.H. and Roseman, T.J. Solubilization of drugs by cosolvents.Tdohniques of Solubilization of Drugs, Edited by Yalkowsky, S.H., Marcel Dekker Inc., New York, NY, Chapter 3, 1981. 

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. ... 

Riley, C.M. Solubilization of Some Poorly Soluble Drugs by Cosolvents. M.S. thesis, University of Arizona Tucson, AZ, 1990. 

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. 

YaUcowsky, S. H. and T. J. Roseman. 1981. Solubilization of drugs by cosolvents. In Techniques of Solubilization of Drugs, edited by S. H. Yalkowsky. New York Marcel Dekker, p. 91. 

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. 

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