Newswise — When new drugs or drug candidates are introduced in the market, they often have low water solubility, which makes it difficult for them to be absorbed in the body. This limits their effectiveness. To improve solubility, cyclodextrins (CDs) are commonly used as solubilizing agents. CDs have a unique structure with a hydrophilic exterior and a hydrophobic cavity inside that can enclose drug molecules to form inclusion complexes. However, even with enhanced solubility, drugs may not be efficiently absorbed in the body as they cannot easily pass through biological membranes.

Increasing the concentration of drugs in a solution can improve their permeability through biological membranes, but this leads to an unstable supersaturated state where the drug precipitates and forms crystals. To prevent this, effective crystallization inhibitors need to be added. CD derivatives are a useful option as they can solubilize drugs and inhibit crystallization. However, the mechanism by which CD derivatives inhibit crystallization is not well understood.

A recent study conducted by researchers from Chiba University in Japan looked into the effects of 12 different CD derivatives, which have varying hydrophobic cavity sizes, on inhibiting the crystallization of two poorly water-soluble drugs, carvedilol (CVD) and chlorthalidone (CLT).

Their work was made available online on March 22, 2023, and published in Volume 637 of the International Journal of Pharmaceutics on April 25, 2023. It involved contributions from Professor Kunikazu Moribe, Associate Professor Kenjirou Higashi, and Assistant Professor Keisuke Ueda.

The ability of different CD derivatives to dissolve drugs varies, which affects how much of the drug remains dissolved in a solution. This can cause errors in estimating the strength of their ability to stop the drug from crystallizing. Therefore, it is important to analyze the drug crystallization inhibition effect of CD derivatives while also considering their ability to dissolve drugs. This is according to Mengyao Liu, the lead author of the study and a Ph.D. student at the Laboratory of Pharmaceutical Technology at the Graduate School of Pharmaceutical Sciences at Chiba University.

To study the effect of different CD derivatives on two drugs, the researchers conducted two tests. First, they performed phase solubility tests, which involved dissolving the drugs in solutions of different concentrations of CD derivatives to measure how well they dissolve. Second, they measured the crystallization induction time, which is the time it takes for a solution to form crystals, by adding drops of the drugs to create supersaturated solutions and then tracking their concentrations over time.

The researchers found that β-CD and γ-CD derivatives helped improve the solubility of CVD, while β-CD derivative was the only one that enhanced CLT’s solubility. They also discovered that the solubility improvement relied on the ability to form stable inclusion complexes, which was determined by the fit between the drug molecule and the CD cavity size.

The study found that there was no connection between the ability of different CD derivatives to increase solubility and their ability to prevent drug crystallization. The researchers discovered that the methylated CD derivatives were more effective than their unmethylated counterparts in keeping the drug in a supersaturated state, which is important for enhancing drug absorption in the body. The researchers believe this is due to the highly hydrophobic outer surfaces of the methylated CD derivatives, which hinder the formation of crystals and thus maintain the supersaturated state of the drug.

In conclusion, these findings shed light on the potential application of CD derivatives in drug-supersaturated formulations, which, in turn, could facilitate the clinical use of poorly water-soluble drug candidates.

About Professor Kunikazu Moribe

Dr. Kunikazu Moribe is a Professor at the Laboratory of Pharmaceutical Technology at the Graduate School of Pharmaceutical Sciences at Chiba University in Japan. His research focuses on physical pharmacy, pharmaceutical technology, and drug delivery systems. He has published over 183 papers on pharmaceutics, which have been cited over 3,000 times. In recognition of his contributions to the field, he was conferred the Asahi Kasei Pharmaceutical Technology Research Award for Young Scientists in 2013 by the Academy of Pharmaceutical Sciences and Technology Japan.

Chiba University

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