Interactions between carbamazepine and polyethylene glycol (PEG) 6000: characterisations of the physical, solid dispersed and eutectic mixtures.
The influence of a hydrophilic carrier (PEG 6000) on the polymorphism of carbamazepine, an antiepileptic drug, was investigated in binary physical mixtures and solid dispersions by means of differential scanning calorimetry (DSC), thermal gravimetry, hot-stage microscopy (HSM), and X-ray diffractometry, respectively. This study provides also an attempt to develop a method to calculate more precisely the eutectic composition. In rather ideal physical mixtures, carbamazepine was found as monoclinic Form III. In solid dispersions, the drug was found to crystallize as trigonal Form II; a eutectic invariant in the PEG 6000-rich composition domain (6% of carbamazepine mass) was evidenced by DSC experiments and confirmed by HSM observations. In the binary phase diagram the ideal carbamazepine liquidus curve was located at temperatures higher than the respective experimental ones. This suggests that drug can be maintained in the liquid state in the temperature-mass fraction (T--x) region between the two carbamazepine liquidus curves. This indicates in turn that attractive interactions occur between carbamazepine and PEG 6000-chains. These interactions have been also claimed to prevent carbamazepine from degradation into iminostilbene (a compound resulting from the chemical degradation of carbamazepine which is postulated to be responsible for the idiosyncratic toxicity of the drug) and thought to lead to the crystallization of metastable Carbamazepine II from melt. The negative excess entropy for eutectic mixtures indicated that the drug crystals are finely dispersed in the bulk of polymer chains.
Laboratoire de Pharmacotechnie et de Biopharmacie, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, 4 Avenue de l'Observatoire, 75270 Paris Cedex 06, France. azerrouk@cybercable.fr
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Naima
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Siro
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Juan-Manuel
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Chantal
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René
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Jerome
D000927:Anticonvulsants / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002220:Carbamazepine / Q000737:chemistry*; D003460:Crystallization; D004055:Differential Thermal Analysis; D004337:Drug Carriers / Q000737:chemistry*; D004347:Drug Interactions; D011092:Polyethylene Glycols / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry*; D014961:X-Ray Diffraction
D000927:Anticonvulsants; D004337:Drug Carriers; D012997:Solvents; D002220:Carbamazepine; D011092:Polyethylene Glycols