Coamorphous Drug Systems: Enhanced Physical Stability and Dissolution Rate of Indomethacin and Naproxen

Abstract

One of the challenges in drug development today is that many new drug candidates are poorly water-soluble, and one of the approaches to overcome this problem is to transfer a crystalline drug into its amorphous form, thus increasing dissolution rate and apparent solubility of the compound. In this study, a coamorphous drug/drug combination between the two nonsteroidal anti-inflammatory drugs, naproxen and γ-indomethacin, was prepared and investigated. At molar ratios of 2:1, 1:1 and 1:2, the drugs were quench cooled in order to obtain a coamorphous binary phase. Physical stability was examined at 277.15 and 298.15 K under dry conditions (phosphorus pentoxide) and analyzed with X-ray powder diffraction (XRPD). Intrinsic dissolution testing was carried out to identify dissolution advantages of the coamorphous form over its crystalline counterparts or amorphous indomethacin. Fourier transform infrared spectroscopy (FTIR) was used for analyses at the molecular level to detect potential molecular interactions. Differential scanning calorimetry (DSC) thermograms were employed to assess the glass transition temperatures (T(g)), and the results were compared with predicted T(g)s from the Gordon-Taylor equation. Results showed that naproxen could be made amorphous in combination with indomethacin while this was not possible with naproxen alone. Peak shifts in the FTIR spectra indicated molecular interactions between both drugs, and it is suggested that the two drugs formed a heterodimer. Therefore, samples at the 1:2 and 2:1 ratios showed recrystallization of the excess drug upon storage whereas the 1:1 ratio samples remained amorphous. Intrinsic dissolution testing showed increased dissolution rate of both drugs in the coamorphous form as well as a synchronized release for the 1:1 coamorphous blend. All T(g)s displayed negative deviations from the Gordon-Taylor equation with the 1:1 ratio showing the largest deviation. In a novel approach of predicting the glass transition temperature, the 1:1 drug ratio was inserted as an individual component in the Gordon-Taylor equation with the excess drug representing the second compound. This approach resulted in a good fit to the experimentally determined T(g)s.

In vitro/in vivo evaluation of an optimized fast dissolving oral film containing olanzapine co-amorphous dispersion with selected carboxylic acids

“…These results indicated that the COAD used to prepare the films greatly enhanced the extent and rate of dissolution of OL from the prepared OFDF. This enhancement was a result of the synchronized dissolution of OL and ascorbic acid brought about by the co-amorphous dispersion (Löbmann et al, 2011). The cumulative percentage of drug released after 10 min (Q 10min ) was evaluated among different films.…”

Dissolution behavior of co-amorphous amino acid-indomethacin mixtures: The ability of amino acids to stabilize the supersaturated state of indomethacin

“…By the definition of Dengale et al, these systems contain two or more small molecular weight compounds that are homogenously mixed to form an amorphous single phase system [19]. For example, two active compounds have been combined to produce co-amorphous mixtures [20,21], but finding compatible drug-drug pairs may, however, be challenging, which has increased the interest in combining a pharmacologically active molecule with an inactive low molecular weight excipient, such as an amino acid (AA) [22][23][24].…”

Coamorphous Atorvastatin Calcium to Improve its Physicochemical and Pharmacokinetic Properties

“…These systems show molecular interaction between two components (17) or without evidence of intermolecular interactions (13). In this investigation, ATC in the presence of NIC was completely converted to the coamorphous form, as it is evident from disappearance of typical pattern of ATC in PXRD and melting endotherm in DSC thermogram (32)(33).…”

“…Amorphous small molecule mixtures (coamorphous or amorphous cocrystals) is an example of one such recent method developed to produce amorphous drugs in the presence of a second compound which could either be another active pharmaceutical agent or an excipient, resulting in improved stability (10). Cimitidineindomethacin (11), ranitidine hydrochlorideindomethacin (12), simvastatin-glipizide (13), cimetidine-diflunisal (14), acyclovir-citric acid (15), naproxen-cimetidine (16) and indomethacinnaproxen (17) are examples of coamorphous systems from the literature.…”