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.

A new quantitation method for mass spectrometry imaging (MSI) with matrix-assisted laser desorption/ionization (MALDI) has been developed. In this method, drug concentrations were determined by tissue homogenization of five 10 µm tissue sections adjacent to those analyzed by MSI. Drug levels in tissue extracts were measured by liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS). The integrated MSI response was correlated to the LC/MS/MS drug concentrations to determine the amount of drug detected per MSI ion count. The study reported here evaluates olanzapine in liver tissue. Tissue samples containing a range of concentrations were created from liver harvested from rats administered a single dose of olanzapine at 0, 1, 4, 8, 16, 30, or 100 mg/kg. The liver samples were then analyzed by MALDI-MSI and LC/MS/MS. The MALDI-MSI and LC/MS/MS correlation was determined for tissue concentrations of ~300 to 60,000 ng/g and yielded a linear relationship over two orders of magnitude (R(2) = 0.9792). From this correlation, a conversion factor of 6.3 ± 0.23 fg/ion count was used to quantitate MSI responses at the pixel level (100 µm). The details of the method, its importance in pharmaceutical analysis, and the considerations necessary when implementing it are presented.

A family of novel compounds has been detected and isolated following an assay for the attenuation of multiple drug resistance in tumor cells from the fermentation broth and mycelia of a strain of Aspergillus fischeri which we have designated var. brasiliensis. The structures of three components were determined employing 1-D and 2-D homonuclear and heteronuclear NMRspectroscopy and mass spectrometry. The structure of 5-7V-acetylardeemin was confirmed by single crystal X-ray diffraction.These compounds are most closely structurally related to asperlicin E1}.In the course of screening for compounds which reverse multi-drug resistance to antitumor antibiotics, the ardeemins were isolated from a newstrain of Aspergillus fischeri (designated var. brasiliensis).A companion paper2) describes the taxonomy and fermentation of the producing organism and the biological activities of ardeemin (1) and 5-7V-acetylardeemin (2). This paper will describe the isolation and structures of these novel heterocyclic compounds.Isolation of the Ardeemins Upon completion of the fermentation, 8 liters of acetone was added to 20 liters of whole broth and the mixture was stirred for 3 hours (See Fig. 1). To this was added 16 liters of ethyl acetate and the resultant mixture was stirred for 1 hour at which time the organic layer was removed. Anadditional 16 liters of ethyl acetate was added to the aqueous acetone and the mixture was stirred for 1 hour. The second ethyl acetate layer was removed and added to the first, and the combined ethyl acetate extracts wereconcentrated to an aqueoussuspension which was partitioned between equal volumes of waterchloroform -methanol (1.5 liters of each). The upper layer from this partition was extracted twice with further volumes of chloroform (0.7 liters each time) and these chloroform extracts were combined with the original lower layer and concentrated to an oil. This oil was chromatographed over a Sephadex LH-20 column (8cmx 80cm) eluted with methanol. Active fractions from this column were combined and concentrated to an oil. This oil was

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