Using cyclodextrins in pharma formulations

Cyclodextrins can be used to improve solubility in drug formulations, as Sarah Houlton explains

Pharmaceutical actives have to be sufficiently soluble in water for delivery to the cellular membrane, but they also have to be sufficiently hydrophobic to be able to cross the membrane. Most APIs do not have the required solubility in water, and it is the job of the formulator to find a way of balancing the two requirements for successful drug delivery. Techniques can include extremes of pH, surfactants and organic solvents, and another possibility is the use of cyclodextrins to aid solubility. As well as improving delivery, they can increase product stability, reduce volatility and mask unpleasant tastes and smells.

Perhaps most familiar nowadays as the active ingredient in household smell-reducing products like Procter & Gamble's Febreze, cyclodextrins are enzymatically-modified starches. The starch is treated with the enzyme cyclodextrin glucosyltransferase, and three ring-shaped cyclodextrins are typically formed: alpha, with six glucose molecules in the ring, beta, with seven, and gamma, which has eight. The 'hole' in the middle is lined with the electron-dense glycosidic oxygen atoms, and these, along with the hydrogen atoms in the cavity, give the 'hole' its hydrophobic character, making it able to host organic molecules. The hydroxyl groups are on the outside of the ring, and can interact with water, conferring aqueous solubility. The ring is narrower at one end than the other, with the free rotation around the C-6 carbon making this end smaller than that with the C-2 and C-3.

X-ray crystallographic data have shown that the sizes of the cyclodextrins are as shown in Table 1. In all cases, the thickness of the ring is 7.8Ã…. Because the cavities are different sizes, this gives selectivity over the guest molecules that are accommodated. α-Cyclodextrin, for example, is a good fit for a phenyl ring, and larger molecules bind best with γ-cyclodextrin. In a good complex, the guest should both fill the cavity and have contact with its walls.

Solubility of cyclodextrins in water increases with temperature, and differs between the three forms because of hydrogen bonding. The hydroxyls on C-2 and C-3 of adjacent glucose molecules of β-cyclodextrin interact strongly with each other, so cannot interact with water. The increased strain of the γ-cyclodextrin ring means that they cannot interact with each other so strongly, and hence are more available for interaction with water, leading to higher water solubility. The less-constrained γ-cyclodextrin has even lower interaction between C-2 and C-3, and hence an even greater water solubility. Solubility is also affected by the nature of the guest molecule, and in some cases this can mean the γ-cyclodextrin complexes are the least soluble. Cyclodextrins are largely insoluble in organic solvents, though they do dissolve to a degree in some polar, aprotic solvents like acetone and alcohols.

Cyclodextrin inclusion complexes usually include one guest molecule within each cyclodextrin, with a stable complex being formed by a variety of noncovalent forces, such as van der Waals forces and hydrophobic interactions. With some molecules of small molecular weight, more than one guest may be included; similarly, if the guest has a high molecular weight, then it may bind to more than one cyclodextrin molecule at the same time.

Raising the temperature can increase the probability of complex formation, by increasing the solubility of both host and guest. However, heat also destabilises the complex, so the two effects must be balanced against each other.

There are six basic methods by which cyclodextrin complexes can be formed:

Natural cyclodextrins are all suitable for use in oral, nasal, buccal and suppository formulations. However, βcyclodextrin's lower water solubility and the fact that it produces insoluble cholesterol complexes mean it is not suitable for parenteral formulations. Modified cyclodextrins are preferable in parenteral products because of their greater water solubility.

A formulation of piroxicam containing βcyclodextrin was launched by Italian company Chiesa in 1989 to treat dysmenorrhoea. Its benefits are claimed to be reduced irritation and better bioavailability.

Recent work on cyclodextrins is establishing their safety in food and pharmaceutical products, and toxicology studies are under way to prove the safety of chemically-modified cyclodextrins. It is likely that hydroxypropyl-β-cyclodextrin complexes of drugs that cannot be delivered otherwise will be the first to be approved. The great benefits of improved solubility mean that once their safety in humans has been fully established, then they will become a potent weapon in the pharmaceutical formulator's arsenal.