Praveen Tyle

Degradation mechanism and kinetic studies of a novel anticancer agent, AG2034

Abstract AG2034 is an anticancer drug designed using protein structure-based techniques. As demonstrated in preformulation studies [ Wang et al., 1997 . Preformulation studies of a novel glycinamide ribonucleotide formyl transferase inhibitor, AG2034 (in preparation)], hydrolysis and oxidation were the two major degradation pathways for AG2034. AG2034 was initially formulated as a lyophilized powder for injection for parenteral administration. The hydrolysis was an unusual problem because of the erratic degradation kinetics. Further investigation in this study suggested that the hydrolysis of AG2034 was not through chemical degradation pathway, rather it was enzymatic—caused by the microbial growth in the solution. The enzymatic mechanism was supported by the observations that hydrolysis was dependent on temperature and pH, and could be effectively inhibited by the presence of EDTA, some preservatives, as well as by aseptic filtration. Due to the sensitivity of AG2034 to enzymatic degradation, sterility was crucial in maintaining the solution stability. Oxidation was the other degradation pathway which was found to be more significant at higher pH range. The pH-oxidation profile was studied in the pH range of 6–9, and the results indicated that the optimization of pH alone could not effectively minimize oxidation rate and result in a sufficiently stable liquid formulation. Consequently, a number of antioxidants and chelating agent EDTA were evaluated. It was observed that the effect of EDTA on oxidation was minimal. Sodium thiosulfate could slightly stabilize AG2034 against oxidation, while monothioglycerol, sodium sulfite and cysteine had no positive effects. Oxidation of AG2034 was shown to be sensitive to the presence of oxygen. The replacement of headspace gas with nitrogen significantly reduced the amount of oxidation product formation. Based on the kinetic study, it was estimated that liquid formulation could be stabilized with the headspace nitrogen control and the use of appropriate antioxidant.

Effect of Size, Shape and Hardness of Particles in Suspension on Oral Palatability

AbstractThe size, shape. and hardness of particles in suspension can influence the oral sensory perception and palatability. This information can be used in the design of a suspension dosage form or to define optimal parameters for a reconstitutible oral delivery system. The report summarizes the effect of garnet, polyethylene and mica suspension on texture, taste and consistency. Significant differences in sensory perception exist between different samples based on the size, shape or hardness of the particles.

Phytosterol Stabilized Emulsions: Interpacial Complexation and Structural Investigations

AbstractMechanisms operative in phytosterol (Generol 122®) stabilized oil-in-water emulsions have been described by studying the behavior of Generol 122® in the presence of an amphoteric surfactant, Deriphat 160C® (sodium lauriminodipropionate). Interfacial intermolecular complexation of Generol 122® as cosurfactant with the amphoteric Deriphat 160C®, has been proposed from NMR and IR studies. Such association complexes appear to form liquid crystalline phases at the oil-water interfaces. A ternary phase diagram of Generol 122®:Deriphat 160C®:water was constructed and the presence of various liquid crystalline phases has been demonstrated.

PHYTOSTEROL STABILIZED EMULSIONS: CORRELATION BETWEEN RHEOLOGIC AND CALORIMETRIC STUDIES

AbstractMechanisms responsible for the stability of phytosterol stabilized emulsions have been determined. The emulsions were non-Newtonion in behavior with considerable degrees of thixotropy and with static yield values at low shear rates on the upcurves of the rheograms. Both of these properties signify the presence of a three-dimensional gel-like stabilizing network. The enthalpies determined by differential scanning calorimetry correlate linearly with the static yield values obtained by rheologic measurements. Relationships exist therefore between the energies required to fluidize the emulsions and the gel-like structures of the systems.

Preformulation Studies on ag-392, a Novel Antitumor Compound

AG-392, a novel antitumor agent, was synthesized using a technology described as “Protein Structure-based Drug Design”. A validated HPLC analytical method was developed to quantitate AG-392. Solubility studies conducted on the AG-392 free base, its glucuronate salt and mesylate salt showed solubilities less than 0.8 mg/mL in D5W. However, the solubility in propylene glycol for the free base was 24 mg/ml and was 7 and 27 mg/mL for the glucuronate and mesylate salts of AG-392, respectively. Based on the results of preformulation studies, a formulation of glucuronate salt of AG-392 in propylene glycol at a concentration of 5 mg/mL was developed for the parenteral delivery. This formulation is compatible with D5W and WFI, but not saline solution. The dilute solutions in WFI show pH values ranging from 4.7 to 5.5. The proposed formulation was tested for in vivo efficacy in a murine lymphoma model and was found to display antitumor activity.