Simple to Use

You´ve received a complimentary 20 g sample of CAPTISOL^®. Now, how do you set up studies to get the most information out of the sample?

Twenty grams doesn´t seem like much material, how am I going to get any information out of this? Sound familiar? To many product development scientists, 20 grams of material isn´t enough to start up their equipment. However, early stage development scientists consider 20 grams almost "scale-up quantities". The early formulations they prepare for preclinical studies are typically developed with a few hundred milligrams of material. With that amount, you can also set up a phase solubility study to determine if, and how well, the drug candidate will complex with CAPTISOL. Not only will you know if your solubility can be improved, but you will know by how much, and what amount of CAPTISOL will be required for various formulation targets.

The study involves adding excess drug candidate to aqueous CAPTISOL solutions of varying concentration. The resulting suspensions are agitated at a constant temperature for up to several days, then analyzed for the amount of drug candidate in solution. This can easily be performed on a microscale as illustrated in Table 1.

 THE SIMPLE DETAILS...

• Prepare a 40% solution of CAPTISOL in water by dissolving 400 mg (corrected for water content) into a total volume of 1 mL. 
• Serially dilute the sample as in Table 1. 
• To six small vials, add sufficient drug candidate to exceed the potential amount that could be taken into solution by the CAPTISOL. (See THE FINE PRINT)
• To each vial, add ½ mL of the corresponding CAPTISOL solution, cap the vials, sonicate and place on a tumbling apparatus at controlled (or room) temperature. Let the vials agitate for 1 to 3 days (depending on the stability of your drug candidate).
• Remove the vials at the end of the agitation period and either centrifuge or filter the suspensions to obtain clear solutions.
• Analyze the solutions for drug content.

 INTERPRETING THE DATA...

The results are typically plotted as moles of drug in solutions vs. moles of CAPTISOL added.  A typical phase solubility plot is shown in Figure 1.  If the solubility increases with the addition of CAPTISOL, complexation has occurred.  The strength of the complex, quantitated as a complexation constant (K1:1), can be calculated from the slope and intercept (SO or intrinsic solubility) of a line drawn through the points on the graph.

This equation is valid for the 1-to-1 complexes that are typically formed between drugs and CAPTISOL.  These data can then be used to develop formulations where a required solubility must be maintained.

THE POSSIBILITIES...

By following a procedure such as listed here, a 20 gram sample of CAPTISOL can be used to screen the solubility of 40 to 50 drug candidates.  The screening is also done with, depending on the molecular weight, only 60 to 175 mg of the drug candidate.

THE FINE PRINT...

The amount of drug to add to each vial needs to be in excess of the amount that may be solubilized.  Typically 2 to 3 fold excesses are used.  However, to minimize material use, one may calculate the target maximal solubility and add slightly more.  With an infinitely large complexation constant, one mole of CAPTISOL will solubilize 1 mole of drug.  Thus multiply the molecular weight of the drug by the molar concentration listed in Table 1 and correct for ½  mL total volume.  Add to this number the amount of the drug that is normally solubilized by ½ mL water without any additive.  Repeat this procedure for each of the vials.  This process gives the minimum amount to add to the vials.  In sufficient drug is available, excess drug can be placed in each vial to make the weighing and handling aspects more practical.

What if my phase solubility plot is not linear?

The above equation for calculating K1:1 is only applicable to type AL (linear) plots.  Although rarely seen, it is possible to generate Type AP (positive) and AN (negative) plots.  Type B plots, where the solubility of the complex is reached, has never been observed with CAPTISOL solutions.  Type AP plots are of particular concern because improper formulation can lead to precipitation upon dilution.  Methods for calculating K values for non-linear plots are available in the literature[1] or give us a call and we´ll be happy to assist you with your formulation.