Factors affecting solubilization of a poorly soluble novel tubulin-binding agent.

JCA112 is a novel tubulin-binding agent with limited aqueous solubility and high hydrophobicity. Three strategies; cyclodextrin inclusion complexation, solid dispersion (SD) formation, and liposome incorporation were evaluated to enhance the solubility of JCA112. Phase-solubility studies were carried out with hydroxypropyl β-cyclodextrin (HPβCD), SDs were prepared by solvent evaporation method and liposomes were prepared by thin-film hydration method.

Physico chemical characterization of a novel anti-cancer agent and its comparison to Taxol(®).

Every year several thousand compounds are screened for their anti-cancer activity by a general test procedure amongst which only few selected move past the in vitro screening process. This may be due to the intrinsic property of the drug substance. Therefore, a complete physicochemical characterization of a New Chemical Entity (NCE) is essential to understand the effect of these properties on the in vitro and possibly in vivo behavior of these compounds.

Physicochemical characterization of NPC 1161C, a novel antimalarial 8-aminoquinoline, in solution and solid state.

NPC 1161C is a novel antimalarial drug of interest because of its superior curative and prophylactic activity, and favorable toxicity profile against in vivo and in vitro models of malaria, pneumocystis carinii pneumonia, and leishmaniasis. The preformulation studies performed included determination of pK(a)s, aqueous and pH solubility, cosolvent solubility, log P, pH stability, thermal analysis, and preliminary hygroscopicity studies. The mean pK(a1), pK(a2), and pK(a3) were determined to be 10.

Wax-based sustained release matrix pellets prepared by a novel freeze pelletization technique I. Formulation and process variables affecting pellet characteristics.

A novel freeze pelletization technique was evaluated for the preparation of wax-based matrix pellets. Pellets containing either theophylline or diltiazem HCl were prepared using various waxes. In this technique, molten waxes along with a dispersed active ingredient were introduced as droplets into an inert and immiscible column of liquid to form pellets.

Wax-based sustained release matrix pellets prepared by a novel freeze pelletization technique II. In vitro drug release studies and release mechanisms.

A novel freeze pelletization technique was evaluated for the preparation of wax-based sustained release matrix pellets. Pellets containing water-soluble drugs were successfully prepared using a variety of waxes. The drug release significantly depended on the wax type used and the aqueous drug solubility.

Development and validation of a stability-indicating reversed-phase high performance liquid chromatography method for NPC 1161C, a novel 8-aminoquinoline anti-malarial drug.

NPC 1161C (+/-8-[(4-amino-1-methylbutyl)amino-5-(3,4-dichlorophenoxy)-6-methoxy-4-methylquinoline succinate]) is a novel investigational antimalarial drug of interest for its in vivo oral potency, activity against blood and tissue stage parasites, favorable toxicity profile, long duration of action, and utility in both prophylaxis and treatment models. The pharmaceutical development of NPC 1161C warranted the availability of an assay for the detection and quantification of the drug and its separation from the impurities and degradation products. A simple and rapid stability-indicating reversed-phase HPLC method was developed and validated according to ICH guidelines.

A mathematical model to predict the size of the pellets formed in freeze pelletization techniques: parameters affecting pellet size.

A mathematical model was developed based on the theory of drop formation to predict the size of the pellets formed in the freeze pelletization process. Further the model was validated by studying the effect of various parameters on the pellet size such as viscosity of the pellet forming and column liquids, surface/interfacial tension, density difference between pellet forming and column liquids; size, shape, and material of construction of the needle tips and temperatures maintained in the columns. In this study, pellets were prepared from different matrices including polyethylene glycols and waxes.

Content analysis and stability evaluation of selected commercial preparations of St. John's wort.

Content analysis and stability studies were performed for the commercial products of St. John's wort. Six marketed formulations were analyzed for their hypericin and pseudohypericin content.

Rheology of Microcrystalline Cellulose and Sodiumcarboxymethyl Cellulose hydrogels using a controlled stress rheometer: part II.

Rheological properties of two different commercial grades of Microcrystalline Cellulose/Sodiumcarboxymethyl Cellulose (MCC/NaCMC) hydrogels were investigated. Viscoelastic characterization of the hydrogels using a controlled stress rheometer revealed that structure formation in the gels could be detected at a concentration as low as 1.0% w/w MCC/NaCMC in purified water.

Rheological characterization of Microcrystalline Cellulose/Sodiumcarboxymethyl cellulose hydrogels using a controlled stress rheometer: part I.

Rheological properties of two different commercial grades of Microcrystalline Cellulose/Sodiumcarboxymethyl Cellulose (MCC/NaCMC) hydrogels were investigated. A controlled stress rheometer fitted with parallel plate geometry was used. Application of the Cross Model relating the viscosity and shear rate data indicated the gels are extremely shear thinning.

Isothermal titration calorimetry method for determination of cyclodextrin complexation thermodynamics between artemisinin and naproxen under varying environmental conditions.

A novel isothermal titration calorimetry method was used to determine the complexation thermodynamics for hydroxypropyl-beta-cyclodextrin with artemisinin and naproxen at varying temperature and pH. The new method is very useful for studying complexation reactions between cyclodextrin and drugs with poor solubility and all the thermodynamic parameters of the cyclodextrin complexation were determined. The analysis of the thermodynamic data reveals involvement of hydrophobic bonding in the cyclodextrin complexes studied.

Interaction of artemisinin and its related compounds with hydroxypropyl-beta-cyclodextrin in solution state: experimental and molecular-modeling studies.

Hydroxypropyl-beta-cyclodextrin (HPBCD) was investigated as a possible solubilizer for a series of poorly water-soluble antimalarial drugs. The solubilities of artemisinin, artether, dihydroartemisinin, and 10-deoxoartemisinin in HPBCD solutions were studied. The phase-solubility profile of these drugs in HPBCD solutions, in the concentration range studied, can be classified as type A(L) or soluble 1:1 complexes.

Carrier-mediated partitioning of artemisinin into Plasmodium falciparum-infected erythrocytes.

The purpose of the present study was to characterize the partitioning of artemisinin into both uninfected and Plasmodium falciparum-infected red blood cells (RBCs). The partitioning of [(14)C](+)-artemisinin into RBCs was studied at four different hematocrit levels and eight time periods. At the optimum time of 2 h, the partitioning process was investigated with eight different drug concentrations ranging from 0.

Anxiolytic properties of botanical extracts in the chick social separation-stress procedure.

Rationale: The recent growth in sales of natural products labeled as dietary supplements in the United States has renewed scientific interest in the study of the therapeutic effects of multi-component botanical products.

Objectives: This study sought to determine whether botanical extracts derived from the Rutaceae family, Acori graminei, the Magnoliaceae family, Alchemilla vulgaris and Primula veris, which had previously been identified in bioassays as having potential anxiolytic activity, were active in the chick social separation-stress procedure.

Methods: Eight-day-old chicks received IP injections of test articles 30 min before being tested in the presence of two social companions or in isolation for a 3-min observation period.

Release of bovine serum albumin from preformed porous microspheres of poly(L-lactic acid).

Preformed porous microspheres of poly(L-lactic acid) (Accurel have been shown to sustain the release of highly water soluble solutes, like dextran and mannitol, for a time period of more than 4 months. The purpose of this investigation was to mechanistically characterize the release of a model protein, bovine serum albumin (BSA), from these highly porous microspheres. The microspheres were loaded with [14C]BSA in three different concentrations of 0.

Characterization of drug release from liposomal formulations in ocular fluid.

The successful application of liposomes in topical ophthalmic drug delivery requires knowledge of vesicle stabilization in the presence of tear fluid. The release of procaine hydrochloride (PCH) from large unilamellar liposomes in the presence of simulated tear fluid was studied in vitro as a function of bilayer lipid content and tear protein composition. Reverse-phase evaporation vesicles were prepared from egg phosphatidylcholine, stearylamine or dicetyl phosphate, and cholesterol.

Sustained release of acetaminophen from heterogeneous matrix tablets: influence of polymer ratio, polymer loading, and co-active on drug release.

The aim of this research was to investigate the effect of pseudoephedrine (PE), polymer ratio, and polymer loading on the release of acetaminophen (APAP) from hydroxypropyl methyl cellulose (HPMC)/polyvinylpyrrolidone (PVP) matrices. Granules formulated with APAP or both APAP and PE, and various blends of HPMC and PVP were compressed into tablets at varying compression forces ranging from 2000 to 6000 Ib. In vitro drug release from the matrix tablets was determined and the results correlated with those of tablet water uptake and erosion studies.

Structure-activity relationships of the antimalarial agent artemisinin. 2. Effect of heteroatom substitution at O-11: synthesis and bioassay of N-alkyl-11-aza-9-desmethylartemisinins.

A novel class of artemisinin analogs, N-alkyl-11-aza-9-desmethylartemisinins 17-29, were synthesized via ozonolysis and acid-catalyzed cyclization of precursor amides 5-16. These amides were prepared through condensation of an activated ester of the known intermediate acid 2 with the corresponding primary amine. The analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum and found in some cases to be more active than artemisinin.

Development and evaluation of a novel dissolution apparatus for medicated chewing gum products.

A novel dissolution apparatus was developed for medicated chewing gum products. A prototype gum product containing phenylpropanolamine hydrochloride (PPA) was used to evaluate the apparatus. The apparatus consists of a conical Teflon base and a rotating, ribbed Teflon plunger suspended in a dissolution vessel.