Simultaneous Dissolution of Naproxen and Flurbiprofen from a Novel Ternary .GAMMA.-Cyclodextrin Complex

Abstract

A crystalline ternary complex was prepared by sealed-heating of naproxen (NPX) with a flurbiprofen (FBP)/g g-cyclodextrin (g g-CD) inclusion complex. The dissolution rates of NPX and FBP in the ternary complex were almost the same, indicating that FBP and NPX from the complex dissolved simultaneously. The ternary CD complex showing a fascinating dissolution property could be a new formulation for combination therapies.Key words cyclodextrin; dissolution; powder X-ray diffraction; sealedheating; inclusion complex Many drug candidates usually show poor water solubility. Various pharmaceutical techniques such as polymorphic control, co-crystal formation, and nanoparticle preparation are available to improve the physicochemical properties of drugs.1-4) Cyclodextrin (CD) inclusion complex formation is also a useful technique for improving the dissolution property and enhancing the bioavailability of drugs.5-7) Co-precipitation, freeze-drying, evaporation, co-grinding, and processing with supercritical CO 2 are used for the preparation of solid CD inclusion complexes. [8][9][10] We have prepared various types of solid CD inclusion complexes by using the sealed-heating method wherein a mixture of guest and CD molecules is simply heated within an enclosed space. [11][12][13] In the sealed-heating method, vaporized guest molecules are assumed to be included in the cavity of CDs through the gas phase. Crystalline inclusion complexes of poorly water-soluble drugs can be obtained through the sealed-heating method without using solvents. Specific inclusion complexes that are difficult to prepare can also be obtained through this method. In our recent study, it was found that the sealed-heating of salicylic acid (SA) with polyethylene glycol (PEG)/g-CDpolypseudorotaxane induced complex formation.14) In this complex, two SA molecules for each g-CD molecule were incorporated into the intermolecular spaces between the columns of g-CD stacks, while double-stranded PEG chains were included in the g-CD cavity. Although a large number of studies have been carried out on the inclusion complexes of CDs, there are only a few reports on the existence of guest molecules outside the CD cavity. [15][16][17][18] New CD complexes with desired properties can be designed if the interstitial spaces outside the CD cavity are utilized for the incorporation of guest drugs. In this study, a ternary g-CD complex containing two active pharmaceutical ingredients (APIs) was prepared by the sealed-heating method. Using this method, guest drugs could be incorporated into the intermolecular spaces between g-CD columns. The dissolution property of the obtained complex was studied in order to assess its potential for pharmaceutical applications.Flurbiprofen (FBP) and naproxen (NPX) are anti-inflammatory drugs with poor water solubility (Fig. 1). In this study, each drug was used as a model guest molecule either for inclusion in the g-CD cavity or incorporation into the intermolecular spaces. The preparation process of the ternary complex consisted of two st...

Large-ring Cyclodextrins

“…The recent study of an interaction of CD and drug in the solid state found a novel complex. Other drugs existed in the intermolecular space among the regularly threedimensional structures gathering columnar type structures that were assembled from CD alone or an inclusion complex between CD and drug (68)(69)(70). It suggests that CD10 and CD14 can form not only inclusion complexes, but also noninclusion complexes in solid state, since they can form a similar structure with the continuous cavity in the crystal state as shown in Fig.…”

Structural Evaluation of Crystalline Ternary γ-Cyclodextrin Complex

“…In fact, it has already been found that the NPX (FBP/g-CD) ternary complex showed specific dissolution characteristics in which two species of APIs were released simultaneously after being dispersed into a dissolution media. 17 We have been investigating this unique dissolution from the ternary complex. Understanding the structures and molecular state of the ternary complexes described here could help to explain the dissolution mechanism.…”

“…16 A previous study showed that the sealed-heating technique induced the formation of a crystalline ternary g-CD complex containing two pharmaceutical drugs, naproxen (NPX) and flurbiprofen (FBP). 17 The ternary complex exhibited a unique dissolution behavior-NPX and FBP dissolved simultaneously. It has been speculated that, in the complex, FBP was incorporated into the cavity of g-CD and NPX was located in the intermolecular spaces in the g-CD columns.…”

Aplicações Tecnológicas do Polimorfismo Farmacêutico

“…A observação de funcionalidades supramoleculares e características conformacionais dos componentes do cristal é uma etapa decisiva durante a seleção de agentes de co-cristalização e formadores de sais com maior probabilidade de formar modifi cações cristalinas sob condições laboratoriais. Esta prática também permite predizer a compatibilidade de cocristalização de diferentes fármacos dentro de uma fase cristalina 32 , o que, em determinados casos, é desejado do ponto de vista farmacotécnico dado que a incorporação de múltiplos fármacos dentro de uma única fase sólida pode evitar incompatibilidades físicas entre diferentes insumos farmacêuticos 33 , sendo isto, entretanto, algo pouco reportado na literatura 34 .…”