Crystal modification of phenytoin using different solvents and crystallization conditions

Nokhodchi, Ali; Bolourtchian, N.; Dinarvand, Rassoul

doi:10.1016/s0378-5173(02)00488-x

Cited by 97 publications

(73 citation statements)

References 18 publications

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“…Treated phenytoin powder showed more peaks in the XRD pattern than the untreated drug powder (32). This could be due to an alteration of the powder to a completely crystalline form or a difference in crystal orientation due to a change in crystalline habit.…”

Section: X-ray Diffraction Studiesmentioning

confidence: 91%

Enhancement in Dissolution Rate of Piroxicam by Two Micronization Techniques

Varshosaz¹,

Khajavinia²,

Ghasemlu³

et al. 2013

Dissolution Technol.

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Piroxicam is a nonsteroidal anti-inflammatory drug that is practically insoluble in water. The oral absorption rate of piroxicam is dependent on its dissolution rate in the GI tract. The aim of this study was to enhance the dissolution of piroxicam by a microcrystallization technique. The preparation of microcrystals of piroxicam was done by two methods, solvent change and pH shift. In the solvent-change method, the drug was dissolved in acetone, and the stabilizer was dissolved in water. The aqueous phase was added to acetone under homogenization in an ice bath for 1 min. In the pH-shift method, the drug and stabilizer were both dissolved in 0.1 N NaOH (pH 12) using homogenization. The pH was adjusted to 3 using 0.1 N hydrochloric acid. Dissolution testing was carried out in a hydrochloric acid medium using the rotating basket method. Particle size and morphology, FTIR, DSC, XRD, and surface area of the microcrystals were studied. The effects of drug and stabilizer concentration and homogenization rate on particle size and dissolution efficiency were studied statistically using a D-optimal design. The dissolution efficiency in both methods was increased about 3-to 4-fold. The particle size in both methods was decreased in comparison with untreated drug. Maximum dissolution and minimum particle size were obtained by the solvent-change method. According to the results, both microcrystallization methods are effective in the modification of the crystalline the habit of piroxicam.

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Section: X-ray Diffraction Studiesmentioning

confidence: 91%

Enhancement in Dissolution Rate of Piroxicam by Two Micronization Techniques

Varshosaz¹,

Khajavinia²,

Ghasemlu³

et al. 2013

Dissolution Technol.

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“…It is well known that the crystalline habit of phenytoin is significantly influenced by the physical conditions of formation and growth rate. 21) However, to the best of our knowledge, there is no report that phenytoin has polymorphic crystals. In accordance with this, the XRD spectral pattern of the precipitate collected from the glucose infusion fluid admixture was the same as that from the HCl solution admixture, suggesting that they only differ in terms of crystal habit (Fig.…”

Section: Discussionmentioning

confidence: 95%

A 5% Glucose Infusion Fluid Provokes Significant Precipitation of Phenytoin Sodium Injection via Interruption of the Cosolvent Effect of Propylene Glycol.

Onuki

Ikegami-Kawai

Ishitsuka

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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The precipitation of phenytoin sodium injection provoked by mixing with infusion fluids renders its use in clinical practice difficult, as rapid intravenous (i.v.) push and i.v. infusion are supposed to be avoided. As some of its aspects remain unclear, this study tried to elucidate this precipitation mechanism. In particular, this study focused on the significant precipitation induced by glucose infusion fluid. The precipitation provoked by 5% glucose infusion fluid was obviously different from the precipitation that accompanied simple pH reduction, in terms of the growth mode and morphology of crystals. In addition, the effect of glucose was partially unrelated to pH reduction. NMR measurements including a two-dimensional nuclear Overhauser effect spectroscopy (2D-NOESY) spectrum indicated the specific interaction between glucose and propylene glycol, which is incorporated into phenytoin sodium injection as a solubilizing agent. These results led to the conclusion that this interaction was crucial for the precipitation of phenytoin, as it diminished the solubilizing effect of propylene glycol, resulting in the enhancement of the crystallization of phenytoin. The determination of phenytoin solubility in aqueous solutions at different pH values revealed that phenytoin incorporated in the admixture could be dissolved completely, as long as the injection was diluted with saline or water. These findings offer a profound insight into the formulation design of phenytoin sodium injection and its use in clinical practice.Key words phenytoin; precipitation; glucose infusion fluid; propylene glycol; 2-dimensional nuclear Overhauser effect spectroscopy Phenytoin sodium injection is indicated for the control of status epilepticus of the grand mal type and for the prevention and treatment of seizures that occur during neurosurgery. As phenytoin is a weak-acid drug (pK a =8.3) 1) with low solubility at biological pH values, 2,3) phenytoin sodium injection is prepared using an organic cosolvent consisting of 40% (v/v) propylene glycol and 10% (v/v) ethanol, with the pH adjusted to 12.The intravenous (i.v.) administration of phenytoin sodium has long represented a dilemma. The rate of administration is strictly limited; the delivery of the injection is recommended at a rate not exceeding 50 mg/min, 4) as a rapid i.v. push has a risk of serious adverse effects on the cardiorespiratory system.5-7) In contrast, the addition of phenytoin sodium injection to an i.v. infusion is not recommended because of its low solubility and resultant precipitation; this means that continuous infusion should be avoided.Many reports in the literature describe precipitation occurring by mixing phenytoin sodium injection with various infusion fluids. [8][9][10][11][12][13][14][15] The reduction in pH that accompanies the dilution with the infusion fluids is widely recognized as the principal cause of the precipitation; 16,17) the pH of the admixture is reduced once the phenytoin sodium injection is diluted in an excessive amount of infusion fluids. ...

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“…Although the crystallization medium had central effect on phenytoin crystal habit modification, altering crystallization temperature had no effect on crystal habits except a change in size of crystals. In the case of compaction, the crystals produced from alcohol or acetone showed high crushing strengths as a result of lower porosity and lower elastic recoveries (Nokhodchi et al, 2003).…”

Section: Compaction and Flowabilitymentioning

confidence: 99%

“…Considering the results, nature of recrystallization solvents in this case had no effect on dissolution profiles. It was suggested that the differences in dissolution rates for phenytoin was related to the surface area of various crystals with different shapes (Nokhodchi, Bolourtchian et al, 2003). Wettability and the changes in intrinsic dissolution rate of doped phenytoin crystals were evaluated by Chow et al They stated that the differences in dissolution rates of phenytoin crystalline powders with different morphology were mainly because of the changes in surface area rather than the improvements in the wetting of more polar surface moieties.…”

Section: Wwwintechopencommentioning

confidence: 99%