An Insight into Different Stabilization Mechanisms of Phenytoin Derivatives Supersaturation by HPMC and PVP

Otsuka, Naoto; Ueda, Keisuke; Ohyagi, Naoko; Shimizu, Kozue; Katakawa, Kazuaki; Kumamoto, Takuya; Higashi, Kenjirou; Yamamoto, Keiji; Moribe, Kunikazu

doi:10.1002/jps.24527

Cited by 33 publications

(21 citation statements)

References 56 publications

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“…Recently, some polymers with solubilization effect, such as PVP, have been found to decreases the apparent permeability. 46 In our studies, we obtain the similar result that L100-55 with good solubilization role on Pip sacrice apparent intestinal membrane permeability, which may be attributed to the encapsulation of the drug into L100-55 and the change of the molecular state of Pip in the presence of the acid-base interaction. 46…”

Section: Effect Of Supersaturation On Permeabilitysupporting

confidence: 78%

The inhibiting role of hydroxypropylmethylcellulose acetate succinate on piperine crystallization to enhance its dissolution from its amorphous solid dispersion and permeability

et al. 2019

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Section: Effect Of Supersaturation On Permeabilitysupporting

confidence: 78%

The inhibiting role of hydroxypropylmethylcellulose acetate succinate on piperine crystallization to enhance its dissolution from its amorphous solid dispersion and permeability

et al. 2019

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“…In contrast, the results presented in this study show that some polymers, i.e., HPMCAS-L or PVPVA64, can enable supersaturation of some of the GFA class 1 drugs and consequently, it appears that GFA class 1 drugs can supersaturate, but would on their own very rapidly recrystallize from a supersaturated solution. A similar result was found in a previous study in which the supersaturation propensity of phenytoin with and without polymer using a solvent shift method was investigated [31]. They found that phenytoin on its own would not supersaturate, whereas supersaturation of the drug was enabled in the presence of either HPMC or PVP (1.0% ( w / v )).…”

Section: Resultssupporting

confidence: 85%

The Influence of Polymers on the Supersaturation Potential of Poor and Good Glass Formers

et al. 2018

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The increasing number of poorly water-soluble drug candidates in pharmaceutical development is a major challenge. Enabling techniques such as amorphization of the crystalline drug can result in supersaturation with respect to the thermodynamically most stable form of the drug, thereby possibly increasing its bioavailability after oral administration. The ease with which such crystalline drugs can be amorphized is known as their glass forming ability (GFA) and is commonly described by the critical cooling rate. In this study, the supersaturation potential, i.e., the maximum apparent degree of supersaturation, of poor and good glass formers is investigated in the absence or presence of either hypromellose acetate succinate L-grade (HPMCAS-L) or vinylpyrrolidine-vinyl acetate copolymer (PVPVA64) in fasted state simulated intestinal fluid (FaSSIF). The GFA of cinnarizine, itraconazole, ketoconazole, naproxen, phenytoin, and probenecid was determined by melt quenching the crystalline drugs to determine their respective critical cooling rate. The inherent supersaturation potential of the drugs in FaSSIF was determined by a solvent shift method where the respective drugs were dissolved in dimethyl sulfoxide and then added to FaSSIF. This study showed that the poor glass formers naproxen, phenytoin, and probenecid could not supersaturate on their own, however for some drug:polymer combinations of naproxen and phenytoin, supersaturation of the drug was enabled by the polymer. In contrast, all of the good glass formers—cinnarizine, itraconazole, and ketoconazole—could supersaturate on their own. Furthermore, the maximum achievable concentration of the good glass formers was unaffected by the presence of a polymer.

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“…The physical properties of phenytoin were previously reported by Stella et al . Commonly used polymer excipients such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and polyvinylpirrolidone (PVP) were not able to maintain maximum phenytoin supersaturation due to rapid crystallization, despite moderate solubility enhancement. − In this study, a near full release of phenytoin with sustained supersaturation over 6 h was achieved using PNIPAm nanogels that were loaded with phenytoin by spray drying from solution into a solid amorphous powder of roughly micron-sized particles. During dissolution, nanoparticles were observed and quantified by a combination of cryogenic transmission electron microscopy (cryo-TEM) and small-angle X-ray scattering (SAXS) experiments.…”

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confidence: 60%

Polymer Nanogels as Reservoirs To Inhibit Hydrophobic Drug Crystallization

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et al. 2019

ACS Nano

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The effects of cross-link density and composition on the loading and in vitro dissolution of the drug phenytoin as amorphous solid dispersions in emulsion polymerized poly(N-isopropylacrylamide) (PNIPAm) and poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) nanogels were investigated near the lower critical solution temperature (LCST). Nanogel size and particle density in phosphate buffered saline were quantified by dynamic light scattering (DLS) and viscometry experiments, while drug−nanogel interactions were revealed by cross peaks in aqueous-state nuclear Overhauser effect spectroscopy measurements. Spray-dried dispersions (SDDs) of drugloaded PNIPAm nanogel particles (R ≈ 43 nm) were directly visualized by cryogenic transmission electron microscopy and further quantified by small-angle X-ray scattering during in vitro dissolution. SDD dissolution profiles were highly dependent on the nanogel cross-link density and directly correlated with the state of dispersion of the drug-loaded nanogel particles. A balance between net particle hydrophobicity and hydrophilicity along with the distance in temperature from the LCST are shown to dictate the in vitro dissolution of the amorphous solid dispersions. Solubility enhancement mechanisms disclosed in this study provide essential guidance for the design of effective nanogels for oral drug delivery applications.

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An Insight into Different Stabilization Mechanisms of Phenytoin Derivatives Supersaturation by HPMC and PVP

Cited by 33 publications

References 56 publications

The inhibiting role of hydroxypropylmethylcellulose acetate succinate on piperine crystallization to enhance its dissolution from its amorphous solid dispersion and permeability

The inhibiting role of hydroxypropylmethylcellulose acetate succinate on piperine crystallization to enhance its dissolution from its amorphous solid dispersion and permeability

The Influence of Polymers on the Supersaturation Potential of Poor and Good Glass Formers

Polymer Nanogels as Reservoirs To Inhibit Hydrophobic Drug Crystallization

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