Identification, preparation, and characterization of several polymorphs and solvates of terazosin hydrochloride.

The phenomenon of polymorphism is prevalent in pharmaceuticals, yet it is unusual to identify more than three or four forms for any particular drug. Terazosin hydrochloride has been found to exist at room temperature in four solvent-free forms that can be isolated directly, one solvent-free form that can be prepared by desolvation of a methanolate, a methanol solvate, and a dihydrate. This study presents characterization and methods for preparation of each of these forms. Data are also presented demonstrating the relative stability of these forms.

Ritonavir: an extraordinary example of conformational polymorphism.

PURPOSE: In the summer of 1998, Norvir semi-solid capsules supplies were threatened as a result of a new much less soluble crystal form of ritonavir. This report provides characterization of the two polymorphs and the structures and hydrogen bonding network for each form. METHODS: Ritonavir polymorphism was investigated using solid state spectroscopy and microscopy techniques including solid state NMR, Near Infrared Spectroscopy, powder X-ray Diffraction and Single crystal X-ray. A sensitive seed detection test was developed. RESULTS: Ritonavir polymorphs were thoroughly characterized and the structures determined. An unusual conformation was found for form II that results in a strong hydrogen bonding network A possible mechanism for heterogeneous nucleation of form II was investigated. CONCLUSIONS: Ritonavir was found to exhibit conformational polymorphism with two unique crystal lattices having significantly different solubility properties. Although the polymorph (form II) corresponding to the "cis" conformation is a more stable packing arrangement, nucleation, even in the presence of form II seeds, is energetically unfavored except in highly supersaturated solutions. The coincidence of a highly supersaturated solution and a probable heterogeneous nucleation by a degradation product resulted in the sudden appearance of the more stable form II polymorph.

The use of near-infrared spectroscopy to monitor the mobility of water within the sarafloxacin crystal lattice.

Near-infrared spectroscopy (NIRS) is proposed as a technique to study the mobility of water within the sarafloxacin crystal lattice. An investigation of two samples of sarafloxacin revealed that NIRS can distinguish between acceptable and unacceptable batches for formulation purposes. X-ray powder diffraction (XRPD), mid-infrared (mid-IR) spectroscopy, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) could not detect any differences between the two samples. NIRS detected differences in the location or orientation of the water molecules within the crystal lattices.

Non-invasive determination of ethanol, propylene glycol and water in a multi-component pharmaceutical oral liquid by direct measurement through amber plastic bottles using Fourier transform near-infrared spectroscopy.

Fourier transform near-infrared (FT-NIR) spectroscopy was used to quantify rapidly the ethanol (34-49% v/v), propylene glycol (20-35% v/v) and water (11-20% m/m) contents within a multi-component pharmaceutical oral liquid by measurement directly through the amber plastic bottle packaging. Spectra were collected in the range 7302-12,000 cm-1 and calibration models set-up using partial least-squares regression (PLSR) and multiple linear regression. Reference values for the three components were measured using capillary gas chromatography (ethanol and propylene glycol) and Karl Fischer (water) assay procedures. The calibration and test sets consisted of production as well as laboratory batches that were made to extend the concentration ranges beyond the natural production variation. The PLSR models developed gave standard errors of prediction (SEP) of 1.1% v/v for ethanol, 0.9% v/v for propylene glycol and 0.3% m/m for water. For each component the calibration model was validated in terms of: linearity, repeatability, intermediate precision and robustness. All the methods produced statistically favourable outcomes. Ten production batches independent of the calibration and test sets were also challenged against the PLSR models, giving SEP values of 1.3% v/v (ethanol), 1.0% v/v (propylene glycol) and 0.2% m/m (water). NIR transmission spectroscopy allowed all three liquid constituents to be non-invasively measured in under 1 min.

Role of an isomorphic desolvate in dissolution failures of an erythromycin tablet formulation.

The investigation of dissolution failures for erythromycin dihydrate tablet formulation over a 12-month period using a near-infrared spectroscopy technique revealed the role of a desolvated dihydrate in the retardation of dissolution. Near infrared spectroscopy (NIR) indicated a dehydrated dihydrate of erythromycin is produced during formulation and gradually binds with Mg(OH)2. The binding delays the process of dissolution. NIR was used to successfully predict that humidifying the tablets would reverse the binding and increase the dissolution rate.