This literature review is a compilation of the composition and, in most cases, the preparation instructions for simulated biological fluids that may be used as dissolution media in the evaluation of dissolution profiles and amount of drug released from pharmaceutical dosage forms. The use of simulated biological fluids can give a better understanding of the release mechanisms and possible in vivo behavior of a product and enhance the predictive capability of the dissolution testing. A summary of the major characteristics of the most used routes of administration that may affect dissolution and absorption of drug substances is presented. The routes and simulated biological fluids covered by this review are:• Parenteral: simulated body fluid and simulated synovial fluid.• Oral: fasted-state simulated gastric fluid, fed-state simulated gastric fluid, fasted-state simulated intestinal fluid, fed-state simulated intestinal fluid, simulated colonic fluid, fasted-state simulated colonic fluid, and fed-state simulated colonic fluid.• Buccal and sublingual: simulated saliva.• Pulmonary: simulated lung fluid.• Vaginal: simulated vaginal fluid and simulated semen.• Ophthalmic: simulated tears.Simulated sweat is also included. Some examples of how these simulated biological fluids are used to evaluate dosage forms are included in each route of administration.
In this study, we determined the pH and buffer capacity of human gastrointestinal (GI) fluids (aspirated from the stomach, duodenum, proximal jejunum, and mid/distal jejunum) as a function of time, from 37 healthy subjects after oral administration of an 800 mg immediate-release tablet of ibuprofen (reference listed drug; RLD) under typical prescribed bioequivalence (BE) study protocol conditions in both fasted and fed states (simulated by ingestion of a liquid meal). Simultaneously, motility was continuously monitored using water-perfused manometry. The time to appearance of phase III contractions (i.e., housekeeper wave) was monitored following administration of the ibuprofen tablet. Our results clearly demonstrated the dynamic change in pH as a function of time and, most significantly, the extremely low buffer capacity along the GI tract. The buffer capacity on average was 2.26 μmol/mL/ΔpH in fasted state (range: 0.26 and 6.32 μmol/mL/ΔpH) and 2.66 μmol/mL/ΔpH in fed state (range: 0.78 and 5.98 μmol/mL/ΔpH) throughout the entire upper GI tract (stomach, duodenum, and proximal and mid/distal jejunum). The implication of this very low buffer capacity of the human GI tract is profound for the oral delivery of both acidic and basic active pharmaceutical ingredients (APIs). An in vivo predictive dissolution method would require not only a bicarbonate buffer but also, more significantly, a low buffer capacity of dissolution media to reflect in vivo dissolution conditions.
The
use of flubendazole (FBZ) in the treatment of lymphatic filariasis
and onchocerciasis (two high incidence neglected tropical diseases)
has been hampered by its poor aqueous solubility. A material consisting
of binary flubendazole/maleic acid crystals (FBZ/MA), showing considerably
improved solubility and dissolution rate relative to flubendazole
alone, has been prepared in this work through solvent assisted mechanical
grinding. The identification of FBZ/MA as a binary crystalline compound
with salt character (proton transfer from MA to FBZ) relied on the
combined results of powder X-ray diffraction, Raman spectroscopy,
attenuated total reflection Fourier transform infrared spectroscopy
(ATR-FTIR), X-ray photoelectron spectroscopy (XPS), thermogravimetry
(TG), and differential scanning calorimetry (DSC). Isothermal solution
microcalorimetry studies further suggested that the direct formation
of FBZ/MA from its precursors in the solid state is thermodynamically
favored. A comparison of the in silico pharmacokinetic
performance of the FBZ/MA with that of pure FBZ based on a rat fasted
physiology model indicated that the absorption rate, mean plasma peak
concentration, and absorption extension of FBZ/MA were ∼2.6
times, ∼1.4 times, and 60% larger, respectively, than those
of FBZ. The results here obtained therefore suggest that the new FBZ/MA
salt has a considerable potential for the development of stable and
affordable pharmaceutical formulations with improved dissolution and
pharmacokinetic properties. Finally, powder X-ray diffraction studies
also led to the first determination of the crystal structure of FBZ.
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