Preformulation Studies of the gamma-Cyclodextrin and Montelukast Inclusion Compound Prepared by Comilling


Montelukast (MLK), an oral antiasthmatic drug with growing use, requires special care in formulation and storage to avoid its degradation by action of light and water. This work investigates the increase in the stability of montelukast as the effect of molecular encapsulation with gamma-cyclodextrin (gamma-CD) by means of a solvent-free method, cogrinding. As a first step, a 1:1 preferred stoichiometry is established for this hostguest system using a combination of molecular modeling and the continuous variation method. The solid 1:1 inclusion compound, gamma-CD center dot MLK, is obtained by 2 comilling procedures. For comparison purposes, gamma-CD center dot MLK is also prepared by a classical codissolution procedure and isolated by freeze-drying. Products were characterized by powder X-ray diffraction, C-13{H-1} CP-MAS NMR, scanning electron microscopy, Fourier-transform infrared spectroscopy, thermogravimetry, and differential scanning calorimetry, which confirm inclusion, demonstrate the formation of amorphous products by comilling, and highlight the importance of the amorphous nature of the starting materials for the stability of the comilled final product. The dissolution profile of montelukast when released from the comilled products shows equivalent concentrations to those obtained with the same mass of the pure drug, with the extra advantage of keeping the solution stability (unaltered concentration) for longer periods. (C) 2019 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.




Pharmacology & Pharmacy; Chemistry


Barbosa, JS; Nolasco, MM; Ribeiro-Claro, P; Paz, FAA; Braga, SS

nossos autores


The supply of gamma-CD (pharmaceutical grade Cavamax W8, manufactured by Wacker-Chemie) by Ashland Specialty Ingredients (Dusseldorf, Germany) is gracefully acknowledged. The authors are also grateful to Fundacao para a Ciencia e a Tecnologia (FCT, Portugal), European Union, QREN, European Fund for Regional Development (FEDER), through the program COMPETE, for general funding to the QOPNA research unit (project PEst C-QUI/UI0062/2019; FCOMP-01-0124-FEDER-037296) and to CICECOdAveiro Institute of Materials (FCT Ref. UID/CTM/50011/2019; project POCI-01-0145-FEDER-007679). JSB acknowledges FCT for the PhD grant No. PD/BD/135104/2017.

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