Amorphisation of Free Acid Ibuprofen and Other Profens in Mixtures with Nanocellulose: Dry Powder Formulation Strategy for Enhanced Solubility

Mantas, Athanasios; Labbe, Valentine; Loryan, Irena; Mihranyan, Albert

doi:10.3390/pharmaceutics11020068

Cited by 15 publications

(14 citation statements)

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“…We have recently shown that the formulation of ibuprofen and other arylpropionic acid derivatives with nanocellulose can result in enhanced solubility and rapid dissolution rate due to amorphization of the drug [30]. Ordinary MCC, which has a low surface area, fails to produce this effect.…”

Section: Introductionmentioning

confidence: 99%

Immediate-Release Nifedipine Binary Dry Powder Mixtures with Nanocellulose Featuring Enhanced Solubility and Dissolution Rate

Mantas

Mihranyan

2019

Pharmaceutics

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Nifedipine (NIF) is a 1,4-dihydropyridine-based calcium channel blocker with poor solubility, whose bioavailability is highly dependent on the type of formulation. Dry powder mixtures of 20% w/w NIF with microcrystalline cellulose (MCC) and its high surface area nanocellulose analogue, which is namely Cladophora (CLAD) cellulose, were produced by heating at the melting temperature of the drug for 1 h. Non-heated samples were used as a reference. The solid-state properties of the mixtures were characterized by scanning electron microscopy, differential scanning calorimetry and X-ray diffraction. The drug release was studied in biorelevant media, including simulated gastric fluid (SGF), fasted-state simulated intestinal fluid (FaSIF) and fed-state simulated intestinal fluid (FeSIF). An enhanced apparent solubility and faster dissolution rate of NIF were observed in the heated mixture of NIF with CLAD-H in all tested biorelevant media (i.e., SGF, FaSIF and FeSIF), which was due to NIF amorphization in the high surface area nanocellulose powder. Ordinary MCC, which is essentially non-porous, did not produce an enhancement of a similar magnitude. The results of the study suggest that dry powder formulation using high surface area nanocellulose is a facile new strategy for formulating calcium channel blocker drugs, which could potentially be a viable alternative to currently used soft gel liquid capsules.

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Section: Introductionmentioning

confidence: 99%

Immediate-Release Nifedipine Binary Dry Powder Mixtures with Nanocellulose Featuring Enhanced Solubility and Dissolution Rate

Mantas

Mihranyan

2019

Pharmaceutics

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“…The cellulose batches used in this study were identical to those used previously [12,13]. Notably, the pore volume of CLAD was 276 times and the specific surface area of CLAD was about 108 times larger than that for MCC as derived from N 2 gas sorption analysis.…”

Section: Resultsmentioning

confidence: 92%

“…We have previously shown that heat-assisted mixing of poorly soluble drugs from varying pharmacological classes with high surface area nanocellulose results in enhanced solubility and dissolution rate in biorelevant media. In particular, the latter effect was shown for NSAIDs from arylpropionic acid derivatives, e.g., ibuprofen, flurbiprofen, ketoprofen, and naproxen [12], as well as dihydropyridine-type calcium channel blockers, e.g., nifedipine, felodipine [13]. In this article, we extend this strategy and demonstrate improved formulation for a model problem drug featuring both poor solubility and unusually high number of polymorphs.…”

Section: Introductionmentioning

confidence: 84%

Dissolution Behavior of Flufenamic Acid in Heated Mixtures with Nanocellulose

Mantas

Mihranyan

2020

Molecules

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Flufenamic acid (FFA) is a problem drug that has up to eight different polymorphs and shows poor solubility. Variability in bioavailability has been reported in the past resulting in limited use of FFA in the oral solid dosage form. The goal of this article was to investigate the polymorphism and amorphization behavior of FFA in non-heated and heated mixtures with high surface area nanocellulose, i.e., Cladophora cellulose (CLAD). As a benchmark, low surface area microcrystalline cellulose (MCC) was used. The solid-state properties of mixtures were characterized with X-ray diffraction, Fourier-transform infrared spectroscopy, and differential scanning calorimetry. The dissolution behavior of mixtures was studied in three biorelevant media, i.e., fasted state simulated gastric fluid, fasted state simulated intestinal fluid, and fed state simulated intestinal fluid. Additional thermal analysis and dissolution tests were carried out following 4 months of storage at 75% RH and room temperature. Heated mixtures of FFA with CLAD resulted in complete amorphization of the drug, whereas that with MCC produced a mixture of up to four different polymorphs. The amorphous FFA mixture with CLAD exhibited rapid and invariable fasted/fed state dissolution in simulated intestinal fluids, whereas that of MCC mixtures was highly dependent on the biorelevant medium. The storage of the heated FFA-CLAD mixture did not result in recrystallization or changes in dissolution profile, whereas heated FFA-MCC mixture showed polymorphic changes. The straightforward dry powder formulation strategy presented here bears great promise for reformulating a number of problem drugs to enhance their dissolution properties and reduce the fasted/fed state variability.

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“…This results in a loss of dissolution and solubility advantage of the amorphous state. Mainly, an amorphous dosage form of ibuprofen sodium was proved to have long-term stability issue and alteration of dissolution profile as determined by Mantas et al ( 58 ).…”

Section: Discussionmentioning

confidence: 99%

Influence of Polyvinyl Alcohol (PVA) on PVA-Poly-N-hydroxyethyl-aspartamide (PVA-PHEA) Microcrystalline Solid Dispersion Films

et al. 2020

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This study was conducted to formulate buccal films consisting of polyvinyl alcohol (PVA) and poly-N-hydroxyethyl-aspartamide (PHEA), to improve the dissolution of the drug through the oral mucosa. Ibuprofen sodium salt was used as a model drug, and the buccal film was expected to enhance its dissolution rate. Two different concentrations of PVA (5% w/v and 7.5% w/v) were used. Solvent casting was used to prepare films, where a solution consisting of drug and polymer was cast and allowed to dry. Attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM) were used to investigate the properties of films. In vitro dissolution studies were also conducted to investigate drug release. SEM studies showed that films containing a higher concentration of PVA had larger particles in microrange. FTIR studies confirmed the presence of the drug in films and indicated that ibuprofen sodium did not react with polymers. DSC studies confirmed the crystalline form of ibuprofen sodium when incorporated within films. In vitro dissolution studies found that the dissolution percentage of ibuprofen sodium alone was increased when incorporated within the film from 59 to 74%. This study led to the development of solid microcrystalline dispersion as a buccal film with a faster dissolution rate than the drug alone overcoming problem of poor solubility.

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Amorphisation of Free Acid Ibuprofen and Other Profens in Mixtures with Nanocellulose: Dry Powder Formulation Strategy for Enhanced Solubility

Cited by 15 publications

References 50 publications

Immediate-Release Nifedipine Binary Dry Powder Mixtures with Nanocellulose Featuring Enhanced Solubility and Dissolution Rate

Immediate-Release Nifedipine Binary Dry Powder Mixtures with Nanocellulose Featuring Enhanced Solubility and Dissolution Rate

Dissolution Behavior of Flufenamic Acid in Heated Mixtures with Nanocellulose

Influence of Polyvinyl Alcohol (PVA) on PVA-Poly-N-hydroxyethyl-aspartamide (PVA-PHEA) Microcrystalline Solid Dispersion Films

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