RAMAN SUPPLEMENT


SOLID STATE TRANSFORMATIONS OF APIs


DURING MANUFACTURING BY RAMAN ANALYSIS OF PHARMACEUTICAL MOLECULES AND DOSAGE FORMS


Alain Hédoux University Lille Nord de France


Molecular organic compounds go through several stages of processing (milling, freeze-drying, spray-drying, pressurising) for packaging as solid-dosage form. Moreover, during their storage, drugs may be exposed to a wide range of temperatures and humidities which can lead to different kinds of phase transformations (crystallisation from an amorphous state or crystal – crystal transitions). It is well known that the physical properties of the condensed phases are closely related to solubility and bioavailability of Active Pharmaceutical Ingredients (APIs). Consequently, the constant monitoring of the physical state of the compound is needed because phase transformations often occur unexpectedly and can take a long time (crystallisation). In addition, information on stability conditions of the polymorphs and the amorphous state have to be determined, and polymorph selection and control is crucial. We show in this paper that Raman investigations on APIs and solid-dosage forms bring out crucial information for predicting process induced transformation by packaging and storage of the drug.


The use of high-dispersive Raman spectro - meters gives the original opportunity to analyse the three kinds of molecular motions that exist in the organic molecular compounds, in the


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framework of the rigid body model. The intramolecular motions, the semi-inter - molecular motions corresponding to large amplitude rotations of a group of atoms within


the molecule or the whole of the molecule and the intermolecular motions, i.e. lattice vibrations in the crystalline state, and consisting in a vibrational density of states (VDOS) in the solid amorphous state. The pronounced contrast between strong covalent intramolecular interactions and soft van der Waals intermolecular attractions or H-bonding association is reflected in the Raman spectra by a spectral gap between external and internal peaks. Internal vibrational modes are sensitive to the molecular environment and then the Raman spectrum of intramolecular motions can be used as a probe of local order to determine various kinds of disorder. At low frequencies (ν < 80 cm-1


), the Low-Frequency


Raman Spectrum (LFRS) of disordered molecular systems results from the overlapping contributions of semi-intermolecular motions,


European Pharmaceutical Review 11 Volume 16 | Issue 5 | 2011


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