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1、Effect of Additives on the Transformation Behavior ofL-Phenylalanine in Aqueous SolutionRajeev Mohan,Kee-Kahb Koo,Christine Strege,and Allan S. Myerson*,|Andrx Pharmaceuticals, Inc., 4955 Orange Drive, Fort Lauderdale, Florida 33314, Department of Chemical Engineering, Sogang University, Seoul 121-7
2、42, Korea, Institut fur Verfahrenstechnik TVT, Martin-Luther-Universita t, Halle D-06099, Germany, and Department of Chemical Engineering, Illinois Institute of Technology, 3301 S. Dearborn, Chicago, Illinois 60616The solution-mediated transformation of anhydrousL-phenylalanine in a saturated soluti
3、on of monohydrateL-phenylalanine has been studied and the transformation rate quantified using the powder X-ray diffraction technique. It has been demonstrated that the anhydrous form is not stable below 37 C (transition point) in the presence of additives, as previously reported (Sato, T.; Sano, C.
4、 European Patent 0703214A2, 1995), and that the additives (ammonium sulfate and dextrose) affect only the transition rate but not the thermodynamic stability or the transition point.1. Introduction and BackgroundPolymorphism is the phenomenon of a chemical species having more than one possible cryst
5、al structure. Numerous organic materials including amino acids and pharmaceutical and food substances are known to have polymorphs. In addition, many of these materials can crystallize as hydrates or solvates where solvent is present as an integral part of the crystal lattice. Solvates and hydrates
6、of a given compound are often called pseudopolymorphs. The crystallization of polymorphs/ pseudopolymorphs occurs as a result of different mo- lecular conformations or packings. It is a function of crystal growth conditions such as temperature, pres- sure, impurity content, and growth rate, along wi
7、th intra/intermolecular forces and interactions of the solute with solvents and additives. In many cases, crystallization leads to the formation of a metastable polymorph, which will eventually trans- form into a more stable form. This transformation can occur in solution or in a dry state. The tran
8、sformations from one polymorph to another are usually rapid when crystals are suspended in solutions and are termed solution-mediated transformations. Solution-mediated transformations have been reported for stearic acid,2,3 magnesium phosphate hydrate,4L-glutamic acid,5theo- phylline,6carbamazepine
9、,7ammonium nitrate,8calcium sulfate,9and calcium phosphates.10The phase trans- formations of several organic and inorganic hydrate salts have been studied.11,12These studies indicate that the stable crystals grow, whereas the less stable crystals dissolve. Typically, for a given substance, there exi
10、sts a transition temperature below which one polymorph is stable and above which another form is stable. Reversible transformations between these forms can be effected by temperature manipulations. Sometimes transformation is not certain even though a systementers a condition that will theoretically
11、 allow it. Transformation can only be ensured if a more stable solid phase is already present, is introduced (by seed- ing), or makes its appearance by nucleation. The rate of transformation can also be affected by the addition of additives or specific impurities.13 Materials crystallizing in differ
12、ent polymorphs show a wide range of physical and chemical properties, including different melting points, spectral properties, thermal conductivities, heat capacities, and densities.14-24 For example, the most stable structure has the lowest solubility and the lowest dissolution rate. Polymorphism i
13、s particularly important in pharmaceutical industries, where the polymorph present can alter the dissolution rate, bioavailability, chemical stability, and/or physical stability. Furthermore, during the manufacturing pro- cess of dosage forms or the storage of products, phase transition has been fre
14、quently observed.19,25-27Because of the different properties of polymorphs, it is advanta- geous to choose the proper polymorph for the desired application. Several factors need to be addressed, in- cluding the number of polymorphs; the solubilities of the different forms; the methods for preparing
15、pure stable forms; the methods for preventing the transfor- mation of forms during several unit operations such as drying, grinding, or tableting, etc.; and the chemical and physical stabilities of each form. Haleblain and Mc- Crone17reviewed the numerous activities that require the consideration of
16、 polymorphism. Crystal habit plays an important role during downstream processing. Plate- like forms of tolbutamide cause powder bridging and capping problems during tableting.28In suspensions, it has been shown that transformation of a material to a stable form results in caking. This was due to the growth of crystals of the stable form with the concurrent dissolution of crystals of a less stable form.29The dissolution and bioavailability due to different poly- morphs has been well-documen
