Questions and Answers – Webinar Rational Selection of Cyclodextrins for the Solubilization of Poorly Soluble Oral Drugs
On Nov. 8th we had a really interesting webinar with Speakers from CycloLab and BASF:
Rational Selection of Cyclodextrins for the
Solubilization of Poorly Soluble Oral Drugs
If you missed the very interesting presentations and more than 17 questions answered live by the speakers you can view the recording of the webinar.
We could not answer all questions in the webinar as there were so many and the webinar time was limited.
Therefore the speakers answered all remaining questions and we show the answers here:
Q: Using solubility study to determine stability constant has its limitation because it consumes large amount of API, how about other in silico technique like docking?
A: Yes, in silico techniques such as docking simulations or molecular modeling can be applied to evaluate the interaction between drug and API and account for steric effects.
Q: What’s the water solubility of Gamma-CD and HP-gamma-CD? Why HP-gamma-CD is not suitable for oral dose?
A: The water solubility of gamma-CD is ~ 230 g/L, for HP-gamma-CD the solubility is approximately doubled (~450 g/L). HP-gamma-CD would require additional toxicology studies to be applied also in oral products after approval by the regulatory agencies.
Q: How to manage the stability for ready to use solution of glycoproteins drugs?
A: There exists an ICH guideline (ICH Q1A (R2)) to follow. Both physical (aggregation, adsorption to container wall, etc.) and chemical integrity should be addressed.
Q: What is the pH of HP-beta cyclodextrin in water? Can cyclodextrins change injectable solution pH?
A: HP-beta cyclodextrin would not be expected to significantly change the pH in water due to the absence of acidic or basic functional groups. Pharmaceutically approved cyclodextrins are either neutral or in a non-buffering salt form (SBECD is sodium salt of a sulfonic acid), therefore alike HP-beta cyclodextrin, pH shifting is not expected.
Q: Can you explain that how (or if) the self-assembly behavior of cyclodextrins affects the formation of inclusion complex with the drugs?
A: Self-assembly of cyclodextrins was observed especially at high cyclodextrin concentrations. This means that non-inclusion complexes or aggregates are formed that do not contribute to a further linear increase in solubility of the drug with increasing amount of cyclodextrin. Negative deviation from a linear solubilization isotherm can be a consequence.
Q: Do we need to perform albumin absorption studies for drug-cyclodextrin complex?
A: In some studies that address bioequivalence issues of injectable drug-cyclodextrin complexes, protein binding experiments (with e.g., whole plasma or serum albumin) are sometimes performed.
Q: Have you observed any limitation in the molar weight of API it can capture?
A: The limitation for complexation in the cavity of cyclodextrins is the inner diameter which ranges from 0.45 nm (alpha-CD) to 0.85 nm (gamma-CD). Depending on the 3d shape of the guest molecule, the limitation regarding molecular weight can vary. Assuming an ideal spherical shape, the molar weight cutoff would be somewhere ~300 g/mol depending on the cyclodextrin type. Most molecules however are not ideal spheres, but somewhat elongated. This results in even larger molecules such as itraconazole (MW ~ 700 g/mol) being suitable for complexation. Larger guest molecules (e.g., peptides) are partially encapsuled, preferably interacting with their most hydrophobic and sterically matching moieties.
Q: Are there any software to study linearity of complex formation?
A: If solubility isotherms are obtained experimentally, deviation from linearity can be explored by fitting various equations (e.g., curve fitting with a quadratic equation to evaluate the possible existence of a complex of higher order). A possible in silico technique can be molecular dynamics or docking simulations that can predict the interaction behavior of the drug with cyclodextrins at different concentrations.
Q: How can a large molecule like itraconazole be encapsulated in a CD cavity?
A: The interaction between itraconazole and cyclodextrins like HPB-CD shows positive deviation from linearity, indicating the formation of higher order complexed (e.g., drug-CD in 1:2 complexes). This would mean that not the complete molecule of itraconazole is located within the cavity of a single cyclodextrin, but rather that some part of the drug molecule is located within the cavity.
Q: Are there any cyclodextrins that have been approved for i.v. administration?
A: Yes, Hydroxypropyl-beta cyclodextrin and Sulfobutylether beta cyclodextrin
Q: Based on your experience can K11 predict complex stability in ICH conditions in liquid form?
A: In a chemical sense, the stabilization is unpredictable, since the successful complexation may result in conformational changes of the guest molecule which can make them less prone to degradation (typically) but sometimes even more sensitive (e.g., beta-lactams). Sometimes the observed API-stabilization effect of cyclodextrins is rather due to interactions with non-API components (i.e., other excipients, like benzalkonium chloride).
Thanks very much again for participating so actively in the webinar!