The main objective of the present study was to develop formulations of noscapine hydrochloride hydrate with enhanced solubility and bioavailability using co-solvent- and cyclodextrin-based approaches. Different combinations of co-solvents, which were selected on the basis of high-throughput solubility screening, were subjected to in vitro intestinal drug permeability studies conducted with Ussing chambers. Vitamin E tocopherol polyethylene glycol succinate and propylene glycol based co-solvent formulations provided the maximum permeability coefficient for the drug. Inclusion complexes of the drug were prepared using hydroxypropyl-β-cyclodextrin and sulphobutylether cyclodextrins. Pharmacokinetic studies were carried out in male Sprague-Dawley rats for the selected formulations. The relative bioavailabilities of the drug with the co-solvent- and cyclodextrin-based formulations were found to be similar.
Tablet Formulation of an Active Pharmaceutical Ingredient with a Sticking and Filming Problem: Direct Compression and Dry Granulation Evaluations
To develop a tablet formulation for an active pharmaceutical ingredient for which sticking and filming problems occurred during tablet punching.
Direct compression and dry granulation tableting techniques were evaluated using factorial experimental design. The effects of chrome-coated punch tips, filler types and active percent in the tablet formulation by direct compression were evaluated. Similarly, for dry granulation using the roller compaction technique, three formulation factors – roller compaction pressure, intragranular filler percent and filler type – were studied. Tablets prepared by both techniques were characterized in regard to their compressibility index, tablet hardness, disintegration time, friability index and stickiness-filming index (an arbitrary index). Ten formulations were prepared by each technique. Using multiple response optimizations and estimated response surface plots, the data were analyzed to identify optimum levels for the formulation factors.
Compressibility index values for all the formulations prepared by direct compression exceeded 25%, unlike the blends prepared by dry granulation. Both tablet hardness and disintegration time for direct compression formulations were significantly lower than for dry granulation formulations. The friability index values were significantly higher for direct compression formulations than for dry granulation formulations. All the direct compression formulations, unlike the dry granulation formulations, had a high stickiness-filming index.
Statistical analysis helped in identifying the optimum levels of formulation factors, as well as the method for eliminating sticking and filming. Unlike the direct compression technique, dry granulation yielded tablets for which sticking and filming were completely eliminated.
Permeability Enhancing Lipid-Based Co-Solvent and SEDDS Formulations of SQ641, an Antimycobacterial Agent
Abstract Context: Tuberculosis (TB) is a common and often deadly infectious disease caused by strains of Mycobacteria. Development of new anti-tubercular drugs is essential to control the emergence and severity of multidrug-resistant TB. Objective: The objective of this study was to develop an oral preclinical liquid formulation of SQ641 and to determine the permeability across rat intestinal tissue by Ussing chamber. Methods: Thermal and chemical characterization of SQ641 was performed by differential scanning calorimetric analysis, thermogravimetric analysis and high performance liquid chromatography. A high throughput solubility screening technique was utilized to determine the solubility of SQ641 in different solvents and co-solvents. Several co-solvent and self-emulsifying drug delivery system (SEDDS) formulations were selected for Ussing chamber permeability studies. Results and discussion: Calculated average apparent permeability coefficients of SEDDS formulations of SQ641 (ranging from 0.03 × 10-6 to 0.33 × 10-6) were found to be higher than the permeability coefficients of co-solvent formulations (ranging from 0.00 × 10-6 to 0.09 × 10-6) and those of the neat drug SQ641 in buffer (0.00 × 10-6). Conclusion: SEDDS formulations with superior permeability characteristics may provide a useful dosage form for oral intake of anti-tubercular drug SQ641, possibly due to the increase in solubility and immediate dispersion of drug.
Hydroxyurea, a chemically hydroxylated derivative of the symmetrical urea is currently under investigation for administration to pediatric patients suffering from sickle cell anemia. The PIB clinical formulation contains sodium benzoate as a preservative and needed to be changed because the commercial syrup diluent has replaced sodium benzoate with methylparaben. A 23 screening factorial design matrix with nine different combinations was used to study the compatibility of methylparaben with hydroxyurea and excipients in open cap storage condition (40°C/75%RH) for 4 weeks. The compatibility of hydroxyurea with excipients in closed cap conditions at 30°C/65%RH and 40°C/75%RH storage for up to 6 weeks was also studied. The nine different hydroxyurea blend combinations were tested for physical appearance, thermal properties (differential scanning calorimetry), pH (blend reconstituted in Humco® simple syrup), moisture content, microbial limit testing (MLT), and antimicrobial effectiveness testing (AET). An HPLC method was developed for assaying hydroxyurea.