Co-amorphous formation of piroxicam-citric acid to generate supersaturation and improve skin permeation

Hirakawa, Yuya; Ueda, Hiroshi; Takata, Yasumitsu; Minamihata, Kosuke; Wakabayashi, Rie; Kamiya, Noriho; Goto, Masahiro

doi:10.1016/j.ejps.2020.105667

Cited by 33 publications

(20 citation statements)

References 47 publications

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“…The co-amorphous systems involve combining drug and low molecular weight organic excipient (the co-former) in an equimolar ratio using suitable methods to yield a homogenous amorphous single phase [27][28][29]. It should be noted that several studies have established the ability of citric acid and tartaric acid to form co-amorphous systems with weakly basic drugs [30][31][32][33], which corroborates our results on the formation of BX795-tartaric acid/citric acid co-amorphous systems. Furthermore, our PXRD analyses showed that BX795-tartaric acid/citric acid co-amorphous mixtures were stable for at least 1 month at room temperature (Figure S18).…”

Section: Discussionsupporting

confidence: 89%

BX795-Organic Acid Coevaporates: Evaluation of Solid-State Characteristics, In Vitro Cytocompatibility and In Vitro Activity against HSV-1 and HSV-2

et al. 2021

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BX795 is a TANK binding kinase-1 inhibitor that has shown excellent therapeutic activity in murine models of genital and ocular herpes infections on topical delivery. Currently, only the BX795 free base and its hydrochloride salt are available commercially. Here, we evaluate the ability of various organic acids suitable for vaginal and/or ocular delivery to form BX795 salts/cocrystals/co-amorphous systems with the aim of facilitating pharmaceutical development of BX795. We characterized BX795-organic acid coevaporates using powder X-ray diffractometry, Fourier-transform infrared spectroscopy (FT-IR), Raman spectroscopy, 1H-nuclear magnetic resonance spectroscopy, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) to elucidate the interaction between BX795 and various organic acids such as taurine, maleic acid, fumaric acid, tartaric acid, and citric acid. Furthermore, using human corneal epithelial cells and HeLa cells, we evaluated BX795-organic acid coevaporates for in vitro cytocompatibility and in vitro antiviral activity against herpes simplex virus-type 1 (HSV-1) and type-2 (HSV-2). Our studies indicate that BX795 forms co-amorphous systems with tartaric acid and citric acid. Interestingly, the association of organic acids with BX795 improved its thermal stability. Our in vitro cytocompatibility and in vitro antiviral studies to screen suitable BX795-organic acid coevaporates for further development show that all BX795-organic acid systems, at a concentration equivalent to 10 µM BX795, retained antiviral activity against HSV-1 and HSV-2 but showed differential cytocompatibility. Further, dose-dependent in vitro cytocompatibility and antiviral activity studies on the BX795-fumaric acid system, BX795-tartaric acid co-amorphous system, and BX795-citric acid co-amorphous system show similar antiviral activity against HSV-1 and HSV-2 compared to BX795, whereas only the BX795-citric acid co-amorphous system showed higher in vitro cytocompatibility compared to BX795.

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Section: Discussionsupporting

confidence: 89%

BX795-Organic Acid Coevaporates: Evaluation of Solid-State Characteristics, In Vitro Cytocompatibility and In Vitro Activity against HSV-1 and HSV-2

et al. 2021

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“…For the drug–excipient category, the excipient, i.e., the co-former, is a low molecular weight substance such as an amino acid or carboxylic acid (e.g., citric acid). The co-amorphous formulations between a drug and citric acid can achieve higher drug solubility and dissolution rates compared to the drug alone in its crystalline form [ 111 ]. Citric acid, having hydrogen bonding ability due to the three carboxylic groups and one hydroxyl group and a low molecular weight, is useful as a co-former to form co-amorphous structures [ 112 ].…”

Section: Citric Acid In Formulationsmentioning

confidence: 99%

Citric Acid: A Multifunctional Pharmaceutical Excipient

et al. 2022

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Citric acid, a tricarboxylic acid, has found wide application in the chemical and pharmaceutical industry due to its biocompatibility, versatility, and green, environmentally friendly chemistry. This review emphasizes the pharmaceutical uses of citric acid as a strategic ingredient in drug formulation while focusing on the impact of its physicochemical properties. The functionality of citric acid is due to its three carboxylic groups and one hydroxyl group. These allow it to be used in many ways, including its ability to be used as a crosslinker to form biodegradable polymers and as a co-former in co-amorphous and co-crystal applications. This paper also analyzes the effect of citric acid in physiological processes and how this effect can be used to enhance the attributes of pharmaceutical preparations, as well as providing a critical discussion on the issues that may arise out of the presence of citric acid in formulations.

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“…Amorphization of drugs causes loss of the stable crystalline state or forms a metastable state. Amorphous or metastable drugs provide higher solubility, remain in a high energy state with higher molecular mobility and lead to supersaturation [ 46 ]. The degree of supersaturation increases with the formation of the amorphous or metastable state of the drug, and hence, drug permeation through skin increases.…”

Section: Mechanistic Aspects Of Amorphous Drug Dispersion For Transde...mentioning

confidence: 99%

“…In an amorphous state or supersaturated systems drug exists in a non-equilibrium condition and becomes thermodynamically unstable. Molecular mobility increases within the drug, which initiates nucleation followed by recrystallization [ 46 ]. Crystallization of drugs in the system reduces the degree of saturation, and subsequently, thermodynamic activity is reduced [ 47 ].…”

Section: Amorphous Drug Loaded Transdermal Systemsmentioning

confidence: 99%

“…Recently few coamorphous systems have been reported where the poor soluble API is mixed with another coformer and dispersed in a viscous vehicle, often PEG 400 [ 15 , 46 ]. Intermolecular interaction like hydrogen bonding and ionic interaction between the two drugs or drug and coformer is the primary factor of forming a stable amorphous system.…”

Section: Amorphous Drug Loaded Transdermal Systemsmentioning

confidence: 99%

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Amorphization of Drugs for Transdermal Delivery-a Recent Update

et al. 2022

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Amorphous solid dispersion is a popular formulation approach for orally administered poorly water-soluble drugs, especially for BCS class II. But oral delivery could not be an automatic choice for some drugs with high first-pass metabolism susceptibility. In such cases, transdermal delivery is considered an alternative if the drug is potent and the dose is less than 10 mg. Amorphization of drugs causes supersaturation and enhances the thermodynamic activity of the drugs. Hence, drug transport through the skin could be improved. The stabilization of amorphous system is a persistent challenge that restricts its application. A polymeric system, where amorphous drug is dispersed in a polymeric carrier, helps its stability. However, high excipient load often becomes problematic for the polymeric amorphous system. Coamorphous formulation is another approach, where one drug is mixed with another drug or low molecular weight compound, which stabilizes each other, restricts crystallization, and maintains a single-phase homogenous amorphous system. Prevention of recrystallization along with enhanced skin permeation has been observed by the transdermal coamorphous system. But scalable manufacturing methods, extensive stability study and in-depth in vivo evaluation are lacking. This review has critically studied the mechanistic aspects of amorphization and transdermal permeation by analyzing recent researches in this field to propose a future direction.

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Co-amorphous formation of piroxicam-citric acid to generate supersaturation and improve skin permeation

Cited by 33 publications

References 47 publications

BX795-Organic Acid Coevaporates: Evaluation of Solid-State Characteristics, In Vitro Cytocompatibility and In Vitro Activity against HSV-1 and HSV-2

BX795-Organic Acid Coevaporates: Evaluation of Solid-State Characteristics, In Vitro Cytocompatibility and In Vitro Activity against HSV-1 and HSV-2

Citric Acid: A Multifunctional Pharmaceutical Excipient

Amorphization of Drugs for Transdermal Delivery-a Recent Update

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