Contemporary Issues in Pharmaceutical Sciences

Structure-Activity Relationship of Cimetidine or Ranitidine

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1. Describe the structure-activity relationship of cimetidine or ranitidine; accounting for the API’s properties and biotransformations.

2. Use the Molecular Pharmaceutics article by A M Stewart et al., to advocate for efficiency of screening for intestinal permeability.

3. Account for the concern and implications about potential nitrosodimethylamine (NDMA) contamination in medicines such as ranitidine, valsartan and metformin.

Many current small molecule drug candidates have very low solubility. By some estimates, as many as 90% of current small molecule drugs in the development pipeline are BCS class II or IV (low solubility).1 Many such compounds require modifications for bioavailability enhancement, such as salt forms,2−4 cocrystals,5,6 particle size reduction,7 inclusion complexes,8−10 lipid formulations,11,12 and amorphous solid dispersions.13−15 These formulation approaches are developed in order to increase dissolution rate, solubility, and/or increase “carriers” such as micelles, vesicles, complexes, or colloids in the intestine.

An understanding of the mechanism of bioavailability enhancement of these drug products is crucial for selecting and optimizing formulations to carry forward to clinical trials and to the market. In vitro dissolution tests are designed to compare the relative rates of dissolution and extent of active pharmaceutical ingredient (API) concentration achieved using different formulations. The results of such tests, however, depend on several factors, including (a) apparatus type, (b) dose-to-volume ratio, (c) type of agitation and (d) dissolution medium/media composition(s), and (e) how the media is sampled.

Flux Apparatus. The vertical membrane flux cell consists of a donor compartment and a receiver compartment, separated by an Accurel PP 1E (55% porous, 100 μm thickness) polypropylene membrane (3M, Maplewood, MN) (Figure 1).32 The membrane is impregnated with 50 μL of Pion GIT-0 lipid solution consisting of 20% w/w phospholipid dissolved into dodecane (Pion Inc., Billerica, MA) and attached to the receiver vessel. Both the donor and receiver compartments are agitated by magnetic stirring. The receiver compartment contains a plastic spacer and grating to elevate the stir bar above the membrane. Samples are introduced to the donor vessel by preweighing directly into the donor vessel and subsequently adding dissolution medium. Once the dissolution medium has been added to the donor vessel, the receiver vessel is inserted into the donor vessel and suspended vertically 5 mm above the donor compartment by a plastic sleeve. For the experiments herein, the donor vessel contained 5 mL of dissolution medium, buffered at pH 5, 6.5, or 8 as indicated.

The receiver vessel contained 10 mL of buffer at the same pH as the donor solution with 2% sodium lauryl sulfate (w/w). The surface area of the membrane is 4.90 cm2 . The temperature for all experiments was maintained at 37 °C by circulating water through a heating block mounted to a μDiss Profiler (Pion Inc.). UV probes (10 mm path length) connected to a Rainbow UV spectrometer (Pion Inc.) system were used to determine the apparent drug concentration in the receiver vessels. Samples of the donor compartment were removed with a disposable pipet for centrifugation followed by HPLC and DLS analysis of the supernatant.