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.

Ritonavir (Kempf, D. J.; Marsh, K. C., Denissen, J. F.; McDonald, E.; Vasavanonda, S.; Flentge, C. A.; Green, B. E.; Fino, L.; Park, C. H.; Kong, X. P.; Wideburg, N. E.; Saldivar, A.; Ruitz, L.; Kati, W. M.; Sham, H. L.; Robins, T.; Stewart, K. D.; Hsu, A.; Plattner, J. J.; Leonard, J. M.; Norbeck, D. W. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 2484) is Abbott's novel protease inhibitor, for human immunodeficiency virus (HIV), the causative organism of acquired immunodeficiency syndrome (AIDS). It is marketed as Norvir. From the discovery of ritonavir until the new drug application (NDA) filing, only one crystalline form was known to exist. Attempts to identify other possible crystal forms were unsuccessful. Two years after the launch of Norvir to the market, some lots of Norvir capsules failed a dissolution specification. Investigation of this phenomena revealed the existence of a crystal form of ritonavir other than the one already known (Form I). This new crystal form was designated as Form II. The two crystal forms are polymorphs and differ substantially in their physical properties such as solubility. In this article, we will discuss the challenges these polymorphs created for the bulk drug substance as well as for the formulation, and how we dealt with these challenges.

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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.

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.