Recent advances in co-amorphous drug formulations

Dengale, Swapnil J.; Grohganz, Holger

doi:10.1016/j.addr.2015.12.009

Cited by 368 publications

(273 citation statements)

References 69 publications

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“…In a solution, an amorphous form of a drug can be described as a spring that triggers the high initial concentration whereas the polymer acts as a parachute to prevent the recrystallization and precipitation of the drug [18]. However, the use of polymers as stabilizers of the amorphous drugs has some limitations, such as the hygroscopicity of many polymers, and the limited miscibility of drugs to polymers, which results to large polymer consumption [19]. To overcome these formulation challenges, co-amorphous formulations have been introduced and shown to stabilize the amorphous form in the solid state [12,19].…”

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“…However, the use of polymers as stabilizers of the amorphous drugs has some limitations, such as the hygroscopicity of many polymers, and the limited miscibility of drugs to polymers, which results to large polymer consumption [19]. To overcome these formulation challenges, co-amorphous formulations have been introduced and shown to stabilize the amorphous form in the solid state [12,19]. 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].…”

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confidence: 99%

“…To overcome these formulation challenges, co-amorphous formulations have been introduced and shown to stabilize the amorphous form in the solid state [12,19]. 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].…”

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

Ojarinta

Heikkinen

Sievänen

et al. 2017

European Journal of Pharmaceutics and Biopharmaceutics

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Dissolution behavior of co-amorphous amino acid-indomethacin mixtures : The ability of amino acids to stabilize the supersaturated state of indomethacin Ojaranta, Rami; Heikkinen, Aki T.; Sievänen, Elina; Laitinen, Riikka Ojaranta, R., Heikkinen, A. T., Sievänen, E., & Laitinen, R. (2017). Dissolution behavior of co-amorphous amino acid-indomethacin mixtures : The ability of amino acids to stabilize the supersaturated state of indomethacin. European Journal of Pharmaceutics and Biopharmaceutics, 112, 85-95. doi:10.1016/j.ejpb.2016.11 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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

Ojarinta

Heikkinen

Sievänen

et al. 2017

European Journal of Pharmaceutics and Biopharmaceutics

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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.…”

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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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“…An amorphous dispersion of low molecular weight ingredients is defined as a co-amorphous mixture [19]. Coamorphous drug delivery systems have recently attracted the interest in the pharmaceutical field to overcome limitations of solid dispersions and improve bioavailability and stability of the single amorphous components [20].…”

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confidence: 99%

Physico-chemical characterisation of three-component co-amorphous systems generated by a melt-quench method

D’Angelo

Edgar

Hurt

et al. 2018

J Therm Anal Calorim

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The purpose of this work was to evaluate the possibility of creating a ternary co-amorphous system and to determine how the properties of a co-amorphous material are altered by the addition of a selected third component. Piroxicam and indomethacin form a stable co-amorphous with the T g above room temperature. The third component added was selected based on tendency to crystallise (benzamide, caffeine) or form amorphous (acetaminophen, clotrimazole) on cooling. Generated co-amorphous systems were characterised with TGA, HSM, DSC, FTIR and XRD. Stable ternary co-amorphous systems were successfully generated, which were confirmed using XRD, DSC and FTIR analysis. In all cases, T g of the ternary system was lower than the T g of the binary system, although higher than that of the individual third component. Upon storage for 4 weeks, all created ternary systems showed significantly smaller variation in T g compared to the binary system. Stable three-component co-amorphous systems can be generated via melt-quench method using either a crystalline or an amorphous third component. Addition of third component can alter the T g of co-amorphous system and in all cases created more stable co-amorphous system upon storage. Physical parameters may not be sufficient in predicting the resulting T g ; therefore, knowledge of chemical interaction must be brought into equation as well.

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Recent advances in co-amorphous drug formulations

Cited by 368 publications

References 69 publications

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

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

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

Physico-chemical characterisation of three-component co-amorphous systems generated by a melt-quench method

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