ABSTRACT
A recent intriguing finding that a helical network arrangement forms the bicontinuous cubic phase is attracting great attention for the possibility of new routes to asymmetric synthesis by achiral molecules. However, the design of the molecular structure for the cubic phase is still unrevealed. In this work, a nonsymmetric core molecule with larger naphthalene and smaller benzene moieties at each side of the central linkage and the same disiloxanyldecyloxy terminal at both terminals is shown to be the first example of molecule forming both single-layered and double-layered core assembly modes in the Ia3d phase as a single molecule system. The molecule forms the former mode at high temperatures as a thermodynamically stable phase, similarly to the symmetric naphthalene core system, whereas, on cooling below a temperature (â¼350â K), a metastable Ia3d phase forms a double-layered core state down to room temperature, which is common to the benzene core system. As another effect of the nonsymmetric core, the cubic phase is maintained at room temperature for more than 100â days with slight distortion. Infrared spectral studies and quantum chemical calculations suggested the easy transformation between the two core assembly modes. The core nonsymmetry can be a versatile fine-tuning of the core assembly mode and phase stability for the cubic phase molecules.
ABSTRACT
The performance of transmission Raman spectroscopy (TRS) for quantifying a cocrystal and its dissociation in solid dosage form was investigated. Some tablets containing 0%-20% (w/w) of a cocrystal of carbamazepine (CBZ)/succinic acid (SUC), 0%-4% of CBZ, 0%-4% of SUC, and 75%-99% of D-mannitol were prepared. The Raman spectra of these tablets were preprocessed using the standard normal variate (SNV) or multiplicative scatter correction (MSC) as well as the Savitzky Golay second derivative, and then, these were used to generate calibration models using partial least squares (PLS) regression. The performance of the model was superior when the MSC preprocessing spectra of the cocrystal between 200 and 1800â¯cm-1 were used for calibration. The determination coefficient of the PLS calibration curve for the CBZ/SUC cocrystal between 200 and 1800â¯cm-1 with MSC was 0.97, root mean square error of cross validation (RMSECV) was 1.16, and root mean square error of prediction (RMSEP) was 1.10. As in the case of the CBZ/SUC cocrystal, the performance of the model was superior when the MSC preprocessing spectra of CBZ and SUC between 200 and 1800â¯cm-1 were used for calibration. These data suggest that TRS is useful for quantifying a cocrystal and its dissociation compounds in solid dosage forms.
Subject(s)
Carbamazepine/chemistry , Drug Compounding/methods , Spectrum Analysis, Raman/methods , Succinic Acid/chemistry , Biological Availability , Calibration , Carbamazepine/pharmacokinetics , Chemistry, Pharmaceutical/methods , Crystallization , Feasibility Studies , Least-Squares Analysis , Succinic Acid/pharmacokinetics , TabletsABSTRACT
In recent years, to guarantee a quality-by-design approach to the development of pharmaceutical products, it is important to identify properties of raw materials and excipients in order to determine critical process parameters and critical quality attributes. Feedback obtained from real-time analyses using various process analytical technology (PAT) tools has been actively investigated. In this study, in situ monitoring using low-frequency (LF) Raman spectroscopy (10-200â¯cm-1), which may have higher discriminative ability among polymorphs than near-infrared spectroscopy and conventional Raman spectroscopy (200-1800â¯cm-1), was investigated as a possible application to PAT. This is because LF-Raman spectroscopy obtains information about intermolecular and/or lattice vibrations in the solid state. The monitoring results obtained from Furosemide/Nicotinamide cocrystal indicate that LF-Raman spectroscopy is applicable to in situ monitoring of suspension and fluidized bed granulation processes, and is an effective technique as a PAT tool to detect the conversion risk of cocrystals. LF-Raman spectroscopy is also used as a PAT tool to monitor reactions, crystallizations, and manufacturing processes of drug substances and products. In addition, a sequence of conversion behaviors of Furosemide/Nicotinamide cocrystals was determined by performing in situ monitoring for the first time.