| Περίληψη: | Several active pharmaceutical ingredients (API) exhibit polymorphism i.e. the ability of a solid material to exist in more than one form or crystal structure (polymorphs). The polymorphs differ somewhat in physical and, sometimes, chemical properties, although their solutions and vapours are identical. Among the different physical properties that are affected by polymorphism are solubility and dissolution rate which have great impact on the bioavailability of the drug. Frequently an API polymorph transforms to another, more thermodynamically stable, phase. When such transformation takes place then a pharmaceutical industry faces problems related to bioavailability of an API as well as litigation problems due to patent protection of specific polymorphs.
The pharmaceutical substance that was studied in this current work was, Aripiprazole, an antipsychotic drug. API crystallizes in a large number of polymorphic and solvatomorphic phases. Μore specific 9 polymorphic and 9 solvatomorphic phases have been positively identified, from which Form III and Form V are currently tested as possible candidates for drug formulations. The objective of the present work was to establish methods capable of identification and quantification of Apiprazole crystal forms and their possible transformation to hydrate phase in Aripiprazole powders as well as in the tested tablets. Stability test were also performed on Aripiprazole crystal forms III and V.
The analytical techniques applied were X-ray Powder Diffraction (XRPD), Infrared spectroscopy (IR) and Raman spectroscopy. Calibration lines of mixtures of API Form III and Monohydrate were constructed. Results show that all three techniques were capable of identifying and quantifying the monohydrate phase however XRPD is probably the method of choice due to the lower detection limit (0.34%) of monohydrate in Phase III-monohydrate mixtures. Quantitative analysis of these polymorphs in the presence of excipients (tablets) is difficult due to the rather low API percentage in tablets (8%) and the high detection limits of monohydrate in mixtures of III and monohydrate. An effort to increase the low API content was made by dissolving in water a large percentage of excipients at alkaline pH. Even though the stability tests show that no transformation of pure Phase III occurs under these conditions, in tablets with some presence of monohydrate, rapid transformation of the remaining Phase III was observed during the dissolution process of the excipients. Thus, the only way was to apply directly the analytical techniques that were used for the pure mixtures to tablets.
It was found that Raman and IR spectra cannot be used due to heavy overlapping with excipients bands. By increasing the scan time the identification of anhydrate phase and the hydrate was possible by using XRPD.
In order to avoid any possible transformation of both Form III and Form V (stability tests show transformation to hydrate phase) it was decided to build the calibration line using only the hydrate phase and the placebo. The constructed calibration line was constructed exhibit low detection limit (0.1156%). Based on this calibration line and the calibration lines that were build using pure Form III and hydrate mixtures a methodology was proposed and the polymorphs were determined in finished formulations.
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