https://onlinelibrary.wiley.com/doi/pdf/10.1021/js950534b

Pharmaceutical Applications of Cyclodextrins. 1. Drug Solubilization and Stabilization

The Stability of Cyclodextrin Complexes in Solution.

Cyclodextrins as pharmaceutical solubilizers.

Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

Objectives Drug pipelines are becoming increasingly difficult to formulate. This is punctuated by both retrospective and prospective analyses that show that while 40% of currently marketed drugs are poorly soluble based on the definition of the biopharmaceutical classification system (BCS), about 90% of drugs in development can be characterized as poorly soluble. Although a number of techniques have been suggested for increasing oral bioavailability and for enabling parenteral formulations, cyclodextrins have emerged as a productive approach. This short review is intended to provide both some basic science information as well as data on the ability to develop drugs in cyclodextrin-containing formulations.

Key findings  There are currently a number of marketed products that make use of these functional solubilizing excipients and new product introduction continues to demonstrate their high added value. The ability to predict whether cyclodextrins will be of benefit in creating a dosage form for a particular drug candidate requires a good working knowledge of the properties of cyclodextrins, their mechanism of solubilization and factors that contribute to, or detract from, the biopharmaceutical characteristics of the formed complexes.

Summary  We provide basic science information as well as data on the development of drugs in cyclodextrin-containing formulations. Cyclodextrins have emerged as an important tool in the formulator's armamentarium to improve apparent solubility and dissolution rate for poorly water-soluble drug candidates. The continued interest and productivity of these materials bode well for future application and their currency as excipients in research, development and drug product marketing.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.2042-7158.2010.01030.x

Pharmaceutical applications of cyclodextrins: basic science and product development.

Solution calorimetry has been employed to evaluate the stability constants and enthalpy changes associated with complex formation between α-, β, or -γ-cyclodextrin (CD) and a group of amine compounds having the diphenylmethyl functionality. Data from thermal titrations of the compounds were analyzed using nonlinear least squares. The standard free energy decrease accompanying the formation of inclusion complexes is generally due to a negative standard enthalpy change (ΔH°). The standard entropy change (ΔS°) was negative, except in the case of complexes formed with γ-CD. Of the 13 compounds studied, only 2 formed complexes with 1:2 (compound: (β-CD) stoichiometry, terfenadine · HC1 and cinnarizine · 2HC1. All the others formed 1:1 complexes. The structural effect on the stability constants, thermodynamics, and inclusion geometry was explored by relating the calorimetric results to the chemical structures of the guest molecules and the cavity sizes of the CD molecules. The results suggest that one of the phenyl groups of the diphenylmethyl functionality resides in the CD cavity and is in van der Waals contact with the inside wall of the CD cavity. In the case of α- and β-CDs, van der Waals interaction dominates in the stabilization. On the other hand, the interaction between these compounds and γ-CD is largely entropically driven. Adiphenine · HC1 forms a more stable complex with β-CD than proadifen · HC1, suggesting that hydrogen bonding to the carbonyl oxygen by the hydroxyl group on the rim of the CD ring can influence the strength of the binding interaction.

Structural effects on the binding of amine drugs with the diphenylmethyl functionality to cyclodextrins. I. A microcalorimetric study.

Microcalorimetric investigation of the complexation between 2-hydroxypropyl-β-cyclodextrin and amine drugs with the diphenylmethyl functionality

Molecular modeling has been used to study the complexation between α, β, or γ-cyclodextrin (CD) and a group of amine compounds having the diphenylmethyl functionality. The computer program SYBYL 5.3 and the Tripos force field (version 5.2) were used for all the calculations. Three-dimensional structures of 13 amine compounds were built individually from their atoms, and CDs were built based on the X-ray crystallographic coordinates. The diphenylmethyl derivative-CD complexes were constructed and optimized. Based on the calculated binding energies accompanying the inclusion process, the preferred method of approach of the compounds to the cavities of the CD molecules, and the structural effects on the binding between amine compounds and three CDs were explored. The calculated binding energies exhibited a good correlation with the stability constants obtained from solution calorimetric titrations. The present study shows that for similar ligand molecules, the molecular modeling technique should enable us to visualize the structure of the inclusion complexes and will also assist us in determining the ability of a potential drug molecule to form a stable complex with CDs.

Wei-Qin Tong

Papers

Structural effects on the binding of amine drugs with the diphenylmethyl functionality to cyclodextrins. I. A microcalorimetric study.

Microcalorimetric investigation of the complexation between 2-hydroxypropyl-β-cyclodextrin and amine drugs with the diphenylmethyl functionality

Structural effects on the binding of amine drugs with the diphenylmethyl functionality to cyclodextrins. II. A molecular modeling study.