Polymorphism of Phenylbutazone: Properties and Compressional Behavior of Crystals

Drugs with low water solubility are predisposed to poor and variable oral bioavailability and, therefore, to variability in clinical response, that might be overcome through an appropriate formulation of the drug. Polymorphs (anhydrous and solvate/hydrate forms) may resolve these bioavailability problems, but they can be a challenge to ensure physicochemical stability for the entire shelf life of the drug product. Since clinical failures of polymorph drugs have not been uncommon, and some of them have been entirely unexpected, the Food and Drug Administration (FDA) and the International Conference on Harmonization (ICH) has required preliminary and exhaustive screening studies to identify and characterize all the polymorph crystal forms for each drug. In the past, the polymorphism of many drugs was detected fortuitously or through manual time consuming methods; today, drug crystal engineering, in particular, combinatorial chemistry and high-throughput screening, makes it possible to easily and exhaustively identify stable polymorphic and/or hydrate/dehydrate forms of poorly soluble drugs, in order to overcome bioavailability related problems or clinical failures. This review describes the concepts involved, provides examples of drugs characterized by poor solubility for which polymorphism has proven important, outlines the state-of-the-art technologies and discusses the pertinent regulations.

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“…Phenylbutazone is a potent anti-rheumatic drug existing in different polymorphic and solvated forms [110][111][112][113].…”

Section: Phanylbutazonementioning

confidence: 99%

“…Phenylbutazone is a potent anti-rheumatic drug that exists in different polymorphic [110][111][112] and solvated forms [113]. Different solubilities, dissolution rates and oral absorption were highlighted between two different polymorphic forms [114].…”

Section: Phenylbutazonementioning

confidence: 99%

Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs

2015

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“…Phenylbutazone has at least five polymorphic forms, α, β, δ, ε, and γ [12][13][14][15][16][17]. Among these polymorphs, δ is most stable at room temperature and α is most stable at lower temperatures.…”

Section: Introductionmentioning

confidence: 97%

Effect of supersaturation on the crystallization of phenylbutazone polymorphs

Datta

Grant²

2005

Cryst. Res. Technol.

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The article describes the effect of degree of supersaturation, σ, on the crystallization of specific polymorphs of phenylbutazone from its methanolic solution at 20°C. At low initial supersaturation, σ ≤ 2.0, the fraction of the metastable α polymorph in the crystallized product exceeds that of the δ polymorph, while at σ ≥ 5.0, the fraction of the stable δ polymorph increases in the crystallized product. The results are explained by the effect of supersaturation on the relative rates of nucleation and crystal growth of the polymorphs. Furthermore, the mechanism of nucleation and crystal growth also change with supersaturation. Supersaturated methanolic solutions of phenylbutazone exhibit a critical temperature at which the nucleation rates of the polymorphs decrease drastically. This effect is partly explained by the decreased mobility of phenylbutazone molecules at lower temperatures. Nucleation is most rapid when the crystallization temperature is close to the transition temperature, T t (α↔δ), between the polymorphs, α and δ. The nucleation rate decreases as the temperature difference between T t (α↔δ) and the crystallization temperature increases.

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“…Some authors [6,7] also studied the melt crystallized phenylbutazone. According to Miiller [7], Form fl can be prepared "by melting and recrystallization of the commercial products, which were always available as form 6".…”

mentioning

confidence: 99%

Thermal behaviour of melt crystallized phenylbutazone

Forni

Coppi

Iannuccelli

et al. 1990

Journal of Thermal Analysis

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In the DSC curves, the melting point of phenylbutazone Form A was affected by the heating rate (first heat cycle). The DSC curves of the melt crystallized phenylbutazone (second heat cycle) showed the endothermic peaks of both Form C and Form A. The change in the first heat cycle of either the heating rate, the upper temperature limit, or the isothermal hold period at the upper temperature limit affected the value of the area ratio between the endothermic peaks of the two polymorphs in the DSC curves of the melt crystallized phenylbutazone. It was therefore suggested that the value of the area ratio is related to the energy supplied to the melt phenylbutazone in the first heat cycle. According to this hypothesis, the energy level that the melt should reach to crystallize as the metastable Form C should be higher than the essential one to crystallize as the stable Form A.

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Polymorphism of Phenylbutazone: Properties and Compressional Behavior of Crystals

Cited by 75 publications

References 14 publications

Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs

Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs

Effect of supersaturation on the crystallization of phenylbutazone polymorphs

Thermal behaviour of melt crystallized phenylbutazone

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