Interactions of ketoprofen and ibuprofen with β-cyclodextrins in solution and in the solid state

doi:10.1016/S0378-5173(98)00035-0

International Journal of Pharmaceutics

Volume 166, Issue 2, 18 May 1998, Pages 189-203

https://doi.org/10.1016/S0378-5173(98)00035-0 Get rights and content

Abstract

The complexing, solubilizing and amorphizing abilities towards ketoprofen and ibuprofen of native β-cyclodextrin and some randomly substituted amorphous derivatives (methyl, hydroxyethyl, and hydroxypropyl β-cyclodextrin with an average substitution degree per anhydroglucose unit, respectively of 1.8, 1.6 and 0.9) were determined and compared with those already observed for naproxen. Drug-carrier interactions were studied in aqueous solution by means of phase-solubility analysis and ¹³C NMR spectroscopy, and in the solid state using differential scanning calorimetry (DSC), X-ray powder diffractometry and infrared spectroscopy. The strength of the inclusion complexes with β-cyclodextrins (K_1:1,ibu>K_1:1,nap>K_1:1,keto) was directly related to the hydrophobic character of the guest (log P values) and depended on its molecular features. The presence in physical mixtures of a high-energy state of crystalline drug molecularly dispersed in the amorphous carrier was assumed from DSC behaviour. Dissolution rates (dispersed amount method) of the active ingredient from equimolar drug-cyclodextrin physical mixtures and amorphous colyophilized products showed that methyl β-cyclodextrin was the most effective carrier also for ketoprofen and ibuprofen.

Introduction

Pharmaceutical applications of cyclodextrins are widespread mainly for their effectiveness as solubilizing and stabilizing agents in various drug formulations (Fromming and Szejtli, 1994). The drawback of the anomalously low aqueous solubility of β-cyclodextrin (16 mg ml⁻¹ at 25°C) which limits the increase in solubility of poorly water soluble drugs as a result of inclusion complexation can be overcome by random substitution of the hydroxyl groups with alkyl or hydroxyalkyl groups (Uekama and Irie, 1987, Yoshida et al., 1988, Irie et al., 1992). Such chemically modified β-cyclodextrins are excellent solubilizers owing to their amorphous character which can be transferred to crystalline drugs in solid combinations, and stronger or weaker complexing agents than the parent crystalline β-cyclodextrin depending upon the influence of the substituent (nature, degree of substitution, etc.) on the molecular features (enlargement or obstruction of the macrocycle cavity, etc.). The performance of randomly substituted β-cyclodextrins as dissolution rate enhancers of crystalline, hydrophobic drugs has therefore to be evaluated in terms of drug-carrier interactions in both aqueous solution (inclusion complexation) and solid state (crystallinity, physical and chemical stability).

As follow-up of our studies on naproxen (Bettinetti et al., 1990, Bettinetti et al., 1991, Bettinetti et al., 1992) we have investigated the performance of methyl, hydroxyethyl and hydroxypropyl β-cyclodextrin with an average substitution degree per anhydroglucose unit, respectively, of 1.8, 1.6 and 0.9 towards ketoprofen and ibuprofen. The drugs, respectively, 2-(3-benzoylphenyl)propionic acid and 2-(4-isobutylphenyl)propionic acid, are slightly soluble in water (respectively, 0.13 mg ml⁻¹ and 0.05 mg ml⁻¹ at 25°C) as naproxen (0.03 mg ml⁻¹). Interactions with cyclodextrins were studied in aqueous solution by means of phase solubility analysis and ¹³C nuclear magnetic resonance, and in the solid state using differential scanning calorimetry, X-ray powder diffractometry and infrared spectroscopy. The dissolution rates of ketoprofen and ibuprofen from the respective equimolecular combinations with each cyclodextrin as physical mixture or colyophilized product were also determined according to the dispersed amount method. The overall results are compared with those obtained for naproxen to shed light on possible contributions of the molecular features of the guest (drug) to the performance of the host (β-cyclodextrin derivative) as a drug carrier.

Section snippets

Materials

Ibuprofen (IBU) and Ketoprofen (KETO) (see structures in Fig. 2, Fig. 3, respectively) and β-cyclodextrin (βCd) were purchased from Sigma (St. Louis, MO). β-Cyclodextrin amorphous derivatives, i.e. methyl (MeβCd), hydroxyethyl (HEβCd) and hydroxypropyl (HPβCd) with an average substitution degree per anhydroglucose unit DS 1.8, MS 1.6, and MS 0.9, respectively, were kindly donated by Wacker-Chemie GmbH (Hanns Seidel Platz 4, D-8000 München 70, Germany) and used as received. All other materials

Solution studies

A_L-type (Higuchi and Connors, 1965) equilibrium phase-solubility diagrams were displayed by both drugs in the respective combinations with each amorphous βCd derivative (Fig. 1a). In the systems with crystalline βCd, the pattern was the same for KETO, but of B_S-type for IBU, because of precipitation of an insoluble complex at high concentrations of the carrier (Chow and Karara, 1986). For both drugs and at each temperature MeβCd brought about the highest relative increase in drug solubility,

Conclusion

Analogies among the IBU–βCds, KETO–βCds and naproxen–βCds interactions in aqueous solution and in the solid state suggest similar basic complexation mechanism and inclusion modes of the guest molecule in the host cavity. MeβCd, the best dissolution rate enhancer for naproxen, is the optimal partner also for IBU and KETO conferring a dissolution efficiency of about 100% to the respective colyophilized products. Outer than forming the relatively most stable inclusion complex, MeβCd is the most

Acknowledgements

Financial support from the MURST is gratefully acknowledged.

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Interactions of ketoprofen and ibuprofen with β-cyclodextrins in solution and in the solid state

Abstract

Introduction

Section snippets

Materials

Solution studies

Conclusion

Acknowledgements

J. Pharm. Sci.

Int. J. Pharm.

J. Pharm. Sci.

J. Pharm. Sci.

Int. J. Pharm.

J. Pharm. Sci.

Int. J. Pharm.

Thermal behaviour and dissolution properties of naproxen in combinations with chemically modified β-cyclodextrins

Drug Dev. Ind. Pharm.

Ketoprofen

Acta Crystallogr. C, Cryst. Struct. Commun.

pH–Solubility relationship and partition coefficients for some anti-inflammatory arylaliphatic acids

Arch. Pharm.

Mechanism of drug dissolution rate enhancement from β-cyclodextrin-drug systems

J. Pharm. Pharmacol.

Cyclodextrin-adamantanecarboxylate inclusion complexes. Studies of variation in cavity size

J. Phys. Chem.

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