A theoretical and spectroscopic study of co-amorphous naproxen and indomethacin

Löbmann, Korbinian; Laitinen, Riikka; Grohganz, Holger; Strachan, Clare J.; Rades, Thomas; Gordon, Keith C.

doi:10.1016/j.ijpharm.2012.05.016

Cited by 97 publications

(82 citation statements)

References 35 publications

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“…Co-amorphouses are amorphous complexes with specific interactions, which are seemed to be synthon, between drugs and counters or other drugs, i.e., have both features of solid dispersion and co-crystal. [16][17][18][19] Thus, co-amorphouses have been studied for their improvement of the physicochemical properties of drugs, especially the solubility. 20,21) In certain cases, a co-amorphous was physically more stable because of the presence of a synthon compared with the stability of each single, non-interacting amorphous molecule.…”

Section: )mentioning

confidence: 99%

Physicochemical Evaluation and Developability Assessment of Co-amorphouses of Low Soluble Drugs and Comparison to the Co-crystals

Yamamoto

Kojima

Karashima

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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To judge the developability and analyze functional mechanism of co-amorphouses, we investigated the physicochemical properties of co-amorphouses and compare the properties with the co-crystals having the same drug and counters. Co-amorphous compounds are a novel approach to improve the physicochemical properties of drugs. A co-amorphous is in an amorphous solid state allowing non-ionic interactions between drug molecules and counter molecules. The co-amorphous compounds composed of itraconazole (ITZ) with the organic carboxyl acid, fumaric acid (FA) or L-tartaric acid (TA), were prepared by mechanical grinding. Potential interactions within ITZ-FA co-amorphous were assessed by Raman spectroscopy. ITZ-FA coamorphous was not crystallized as the co-crystal or as a single ITZ crystal, suggesting that the amorphous state, like the amorphous solid dispersion, was physically stable and that ITZ-FA co-amorphous was also chemically stable. In contrast, no clear interactions were observed within ITZ-TA co-amorphous, and the coamorphous was physically stable but chemically unstable. The solubility of the co-amorphous state was much higher than those of ITZ crystal and the co-crystals and was almost identical to that of amorphous ITZ. A co-amorphous compound like ITZ-FA co-amorphous might be feasible to implement in the development of solid drug products and bring some merits compared to the co-crystals, and the function is governed by the interaction between a drug and a counter. The co-amorphous approach may be an effective strategy for drug development and can contribute to the production of novel drugs with improved functions.Key words co-amorphous; co-crystal; stability; solubilization; interaction; itraconazole Solubility improvement is one of the most important challenges for drug development of poorly soluble drugs. Amorphization of drugs is a major effective strategy to prepare solubilized formulations, because the crystal packing effect on a drug substance significantly decreases its solubility. 1-3)An amorphous compound is in a higher energy state and has a higher mobility than a crystalline compound, improving its solubility and dissolution properties. However, due to the higher energy state, the physical and chemical stability of amorphous compounds are relatively lower than those of a crystal. 4,5) In many cases, an amorphous drug is formulated by solid dispersion with hydrophilic polymers to improve the amorphous drug stability. [6][7][8] The complex formed with polymers can prevent the drug's crystallization and maintain the physical stability of the amorphous state. Generally, weak interactions cannot sufficiently stabilize amorphous drugs. 9)The prediction and design leading to the interactions between the drug and the polymer are still difficult to accomplish. Therefore, solid dispersions combined with several kinds and amounts of polymers need to be tested.As another approach to enhance a drug's solubility, pharmaceutical co-crystals have been investigated and adapted to the drug development processes in...

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Section: )mentioning

confidence: 99%

Physicochemical Evaluation and Developability Assessment of Co-amorphouses of Low Soluble Drugs and Comparison to the Co-crystals

Yamamoto

Kojima

Karashima

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Dissolution experiments revealed that the two drugs indomethacin (Ind) and naproxen (Nap) were likely to be released as pairs from the co-amorphous system, as identical dissolution profiles were observed (termed synchronized release) (8)(9)(10). This was explained by the formation of Ind-Nap heterodimers in the co-amorphous mixtures prepared at various molar ratios (11). For binary systems with a molar ratio different from 1:1, a modified approach of using the Gordon-Taylor equation was suggested.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to polymer-based glass solutions, co-amorphous formulations are based on the combination of at least two species of low molecular weight components that all are crystalline before being processed. The preparation of co-amorphous systems is mostly done by ball milling, and the fact that single Tgs are found by DSC indicates that the obtained systems were homogeneous mixtures (8)(9)(10)(11)(12)(13)(14)(15)(16). One advantage of ball milling is that it is inflicting only very limited chemical degradation (17), specifically for some indomethacin systems degradation levels of less than 1.5% were found (13).…”

Section: Introductionmentioning

confidence: 99%

Influence of variation in molar ratio on co-amorphous drug-amino acid systems

Jensen

Larsen

Löbmann

2016

European Journal of Pharmaceutics and Biopharmaceutics

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“…In this context, the presence of molecular interactions was investigated and identified as peak shifts in the FTIR spectra. The presence of two carboxylic acid groups in both drugs and their possibility to form a carboxylic acid heterodimer was taken as starting point for the calculation of theoretical FTIR spectra using quantum mechanical tools, i.e., density functional theory (Löbmann et al 2012a). The theoretical spectrum of the co-amorphous 1:1 indomethacin-naproxen heterodimer was compared to the theoretical spectra of the drug homodimers and the experimentally obtained FTIR spectra.…”

Section: Co-amorphous Indomethacin-naproxen Systemsmentioning

confidence: 99%