Understanding ph-dependent inclusion complexation of cinnarizine with β- cyclodextrin via nmr spectroscopy

Sakoman, Franjo; Galić, Nives; Čikoš, Ana (2025) Understanding ph-dependent inclusion complexation of cinnarizine with β- cyclodextrin via nmr spectroscopy. In: Held Gotfredsen, Charlotte, (ed.) SMASH 2025 Conference Program. Porto, Portugal, SMASH 2025 Conference, .

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Abstract

Cinnarizine (CIN) is a piperazine-based antihistamine used in the treatment of vestibular disorders and motion sickness. According to the Biopharmaceutical Classification System (BCS), it’s a class II drug defined by high permeability but low aqueous solubility, limiting its absorption and therapeutic potential. Additionally, its pH-dependent dissolution presents a significant challenge for formulation and clinical use, especially in variable gastrointestinal environments.[1,2] Cyclodextrins (CDs) can form inclusion complexes by noncovalently encapsulating hydrophobic drug molecules, thereby possibly enhancing their solubility and bioavailability. Among them, β-cyclodextrin (β-CD) is the most commonly used due to its suitable cavity size and low cost.[3] Previously (4), we established the formation of the CIN:β-CD complex through chemical shift perturbations, investigated the orientation of CIN within β-CD via intermolecular interactions (ROESY), and performed an acid titration to identify the optimal pH that maximizes CIN solubility without compromising complex stability. After defining these conditions (pD 3.4 for the CIN:β-CD complex), in which CIN exists in a mixed mono-/bi-protonated state, DOSY experiments revealed approximately 91% complexation. To further explore the influence of CIN’s protonation state on its inclusion behaviour, but also provide some insight into the complex stoichiometry, a new titration of CIN with β-CD was performed at pD 3.4 and pD < 1. Our results not only confirm the formation of a 1:1 inclusion complex under mildly acidic conditions but also suggest the possible formation of some portion 1:2 complex, as previously proposed by Tokumura et al. (5). In contrast, under strongly acidic conditions, where CIN is fully bi-protonated, inclusion is significantly reduced. These findings provide new insight into the influence of pH on binding behaviour, contributing to the understanding of cyclodextrin-based formulation strategies for poorly soluble drugs.

Item Type:	Conference or workshop item published in conference proceedings (UNSPECIFIED)
Uncontrolled Keywords:	NMR spectroscopy; cinnarizine; β-cyclodextrin; inclusion complex; pH
Subjects:	NATURAL SCIENCES > Chemistry > Analytic Chemistry
Divisions:	NMR Center
Projects:	Project title Project leader Project code Project type Priprava, karakterizacija i biokompatibilnost novih supramolekulskih kompleksa lijek/ciklodekstrin i lijek/dekstrinske nanospužve s poboljšanim svojstvima Nives Galić IP-2022-10-6033 HrZZ
Depositing User:	Franjo Sakoman
Date Deposited:	22 Jan 2026 09:34
URI:	http://fulir.irb.hr/id/eprint/10896

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