Crystallization of Carbamazepine Pseudopolymorphs from Nonionic Microemulsions Anna Kogan, †,‡ Inna Popov, § Vladimir Uvarov, § Shmuel Cohen, || Abraham Aserin, † and Nissim Garti* ,† Casali Institute of Applied Chemistry and Department of Inorganic and Analytical Chemistry, The Institute of Chemistry, and The Unit for Nanoscopic Characterization, The Center for Nanoscience and Nanotechnology, The Hebrew UniVersity of Jerusalem, Jerusalem 91904, Israel ReceiVed September 6, 2007. In Final Form: October 14, 2007 Crystallization of carbamazepine (CBZ), an antiepileptic drug, precipitated from confined spaces of nonionic microemulsions was investigated. The study was aimed to correlate the structure of the microemulsion [water-in-oil (W/O), bicontinuous, and oil-in-water (O/W)] with the crystalline structure and morphology of solid CBZ. The precipitated CBZ was studied by DSC, TGA, powder XRD, single-crystal XRD, SEM, and optical microscopy. The results suggest that the microstructure of the microemulsions influences the crystallization process and allows crystallizing polymorphs that exhibit different crystal structure and habits. W/O nanodroplets orient the crystallizing CBZ molecules to form a prismlike anhydrous polymorphic form with monoclinic unit cell and P2 1 /n space group. Bicontinuous structures lead to platelike dihydrate crystals with orthorhombic unit cell and Cmca space group. The O/W nanodroplets cause the formation of needlelike dihydrate crystals with monoclinic unit cell and P2 1 /c space group. The morphological features of solid CBZ remain predetermined by the basic symmetry and parameters of its unit cell. Precipitation of CBZ pseudopolymorphs from supersaturated microemulsion is discussed in terms of oriented attachment that provides perfect packing of numerous separately nucleated ordered nuclei of CBZ into microscale platelets and then into macroscopic crystals. Crystallization from microemulsion media enabling one to obtain the drug (CBZ) with predicted structure and morphology should be of great significance for pharmaceutical applications. 1. Introduction Preparation or processing of pharmaceutical solids frequently results in formation of polymorphs or solvates. 1 Polymorphs are crystalline substances having the same chemical composition but different internal crystal structure. 2 Solvates, also known as pseudopolymorphs, are crystalline solid adducts containing solvent molecules within the crystal structure. 3 If the incorporated solvent is water, the solvate is termed a hydrate. 2,3 Polymorphic modifications and various hydration states of a compound have different crystal structures, giving rise to unique differences in the physical and pharmaceutical properties of the drug. Different polymorphs and solvates will differ in their lattice energy and entropy, as well as in their density, vapor pressure, refractive index, melting point, and heat of fusion. The differences between polymorphs could result in significant differences in solubility and dissolution rate and as a result affect the drug release rate and its bioavailability. 2,4-6 Crystallization within confined space is a new trend in crystallization of a variety of organic 7-9 and inorganic materials. 10-12 One way to achieve a controlled crystallization process is by precipitating the compound from a confined liquid- phase such as microemulsion media. Microemulsions are clear, stable, isotropic mixtures of oil, water, and surfactant, frequently in combination with a cosurfactant. Microemulsions are nanosized droplets characterized by thermodynamic stability and high surface areas. 13-17 In recent years, we have conducted studies related to controlled crystallization and polymorphism of drugs and nutraceuticals from confined reservoirs of dispersed liquid systems. Such controlled crystallization may lead to the formation of nonstable polymorphic structures with unusual crystal habits and proper- ties. 7,18,19 A strong correlation between the microemulsion droplet size and shape and phase structure of the drug was found. Formation of a new polymorph of the artificial sweetener * Corresponding author. Tel: +972-2-658-6574/5. Fax: +972-2-652- 0262. E-mail: garti@vms.huji.ac.il. † Casali Institute of Applied Chemistry. ‡ The results presented in this paper are part of A.K.’s PhD dissertation in Applied Chemistry, The Hebrew University of Jerusalem, Israel. § The Unit for Nanoscopic Characterization. || Department of Inorganic and Analytical Chemistry. 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