Particle size dependency of dissolution rate and human bioavailability of phenytoin in powders and phenytoin-polyethylene glycol solid dispersions.

Yakou, Shigeru; Umehara, Kumiko; Sonobe, Takashi; Nagai, Tsuneji; Sugihara, Masayasu; Fukuyama, Yukio

doi:10.1248/cpb.32.4130

Cited by 19 publications

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“…2,3) According to a few reports, however, the dissolution rate of phenytoin was improved by reducing its particle size, thereby increasing its concentration in blood to the desired level. [4][5][6] Reducing the particle size makes the increase of surface area and as a result of it, dissolution rate of drug increases according to the Nernst-Brunner and Levich modification of the Noyes-Whitney model of dissolution. 7,8) Solubility problem could be solved by reducing particle size to nanometer range.…”

mentioning

confidence: 99%

Nanosizing of Poorly Water Soluble Compounds Using Rotation/Revolution Mixer

Takatsuka¹,

Endo²,

Yao³

et al. 2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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Synthesis of water soluble compounds with high pharmacological activity is becoming increasingly difficult. Pulverization is one of the methods that can be used to enhance the dissolution rate of poorly water soluble compounds and improve their bioavailability. 1) Pulverization is an important process, especially during the discovery, clinical, and developmental stages of a drug to salvage from the dropout of compound.Phenytoin is a highly crystalline compound with a high melting point of 295-298°C and poor solubility in water. Because of its poor solubility in water, there are very few cases where the concentration of phenytoin in blood reaches the desired levels when administered at a conventional dosage. 2,3) According to a few reports, however, the dissolution rate of phenytoin was improved by reducing its particle size, thereby increasing its concentration in blood to the desired level. [4][5][6] Reducing the particle size makes the increase of surface area and as a result of it, dissolution rate of drug increases according to the Nernst-Brunner and Levich modification of the Noyes-Whitney model of dissolution. 7,8) Solubility problem could be solved by reducing particle size to nanometer range. 9)There are different techniques for pulverizing compounds to obtain nanoparticles-wet-grinding in agitated media milling, stirred media milling, wet co-grinding.10,11) However, in most cases, these techniques are difficult to be carried out. Wet milling is one of the various methods used to obtain nanoparticles of a given compound. The use of the wet mill, NanoCrystal, brought about a remarkable improvement in bioavailability by reducing the size of the particles to the nanometer range.12,13) Conventional beads milling is timeconsuming and requires a large amount of beads for pulverizing a given compound in the grinding chamber. Moreover, troublesome tasks such as the cleaning of balls and machine have to be carried out after the pulverization. The rotation/revolution mixer is used to homogenize materials such as epoxy resins, silicone resins, acrylic resins, metal pastes, inks, cosmetics, pastes, and foodstuff. In the pharmaceutical field, beads milling is used for preparing oral formulations for preclinical safety studies.14) Beads milling helps improve product quality and reduce its manufacturing process. Rotation/revolution mixer does not need much amount of compounds and can pulverize a small amount of them (mg order). It can easily scale up from very small volume to large volume. This paper reports on a method to reduce the size of the particles to the nanometer range by using a rotation/revolution mixer and zirconia balls. ExperimentalManufacturing Instruments A rotation/revolution mixer (Nano Pulverizer NP-100, Thinky Co., Ltd., Tokyo, Japan) was used to pulverize the compounds. Two types of vessels made of polyacetal were used-one was convex and the other was circular, as shown in Figs. 3a, b. Zirconia (zirconium oxide) balls with diameters of 0.05 mm, 0.1 mm, 0.3 mm, 0.5 mm, and 1 mm (YTZ-0.05, -0.1, -0.3...

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confidence: 99%

Nanosizing of Poorly Water Soluble Compounds Using Rotation/Revolution Mixer

Takatsuka¹,

Endo²,

Yao³

et al. 2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…In the melting process, the molecular mobility of carrier is high enough to change the drug's incorporation 36 . A common adaptation to the melting phase consists of suspending the active drug in a previously melted carrier, instead of using both drug and carrier in the melted state, reducing, therefore, the process temperature .To cool and solidify the melted mixture, several processes such as ice bath agitation 37,38 , stainless steel thin layer spreading followed by a cold draught 39 , solidification on petri dishes at room temperature inside a dessicator 40 , spreading on plates placed over dry ice 41 , immersion in liquid nitrogen or stored in a dessicator 42,43 were used.…”

Section: Fig 4: Manufacturing Processes Used To Produce Solid Dispermentioning

confidence: 99%

Untitled

2010

IJPSR

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The solubility behavior of drugs remains one of the most challenging aspects in the formulation development. Although there was a great interest in solid dispersion systems during the past four decades to increase solubility by improving dissolution rate and bioavailability of poorly soluble drugs; there commercial use has been very limited, primarily because of manufacturing difficulties and various stability problems. It can be carried out by reducing drug particle size to the absolute minimum, and hence improving drug wet-ability, bioavailability may be significantly improved. Solid dispersion of drugs was generally produced by melt or solvent evaporation methods. Recently, surfactants have been included to stabilize the formulations, thus avoiding drug recrystallization and potentiating their solubility. New manufacturing processes to obtain solid dispersions have also been developed to reduce the drawbacks of the initial process. In this review, it is intended to discuss the eminent approach to improve the solubility or the dissolution rate and recent revival has been discussed.

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“…n ) Calculated based on the AUC values of tablet and solution formulations assuming that Fa from latter one is 1 [48]. o ) Calculated based on the AUC 0-48 values of tablet formulation in fasted and fed states assuming that Fa from latter one is 1 ( Fa ¼ 0.58) and bioavailability of 59% [38] [41]. p ) Calculated based on the AUC of tablet formulation in the fasted and fed conditions assuming that Fa from latter one is 1 [46].…”

Section: General Absorption Equationmentioning

confidence: 99%

Computational Oral Absorption Simulation for Low‐Solubility Compounds

Sugano

2009

Chemistry & Biodiversity

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Bile micelles play an important role in oral absorption of low-solubility compounds. Bile micelles can affect solubility, dissolution rate, and permeability. For the pH-solubility profile in bile micelles, the Henderson-Hasselbalch equation should be modified to take bile-micelle partition into account. For the dissolution rate, in the Nernst-Brunner equation, the effective diffusion coefficient in bile-micelle media should be used instead of the monomer diffusion coefficient. The diffusion coefficient of bile micelles is 8- to 18-fold smaller than that of monomer molecules. For permeability, the effective diffusion coefficient in the unstirred water layer adjacent to the epithelial membrane, and the free fraction at the epithelial membrane surface should be taken into account. The importance of these aspects is demonstrated here using several in vivo and clinical oral-absorption data of low-solubility model compounds. Using the theoretical equations, the food effect on oral absorption is further discussed.

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Particle size dependency of dissolution rate and human bioavailability of phenytoin in powders and phenytoin-polyethylene glycol solid dispersions.

Cited by 19 publications

References 0 publications

Nanosizing of Poorly Water Soluble Compounds Using Rotation/Revolution Mixer

Nanosizing of Poorly Water Soluble Compounds Using Rotation/Revolution Mixer

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Computational Oral Absorption Simulation for Low‐Solubility Compounds

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