Itraconazole suspension for intravenous injection: determination of the real component of complete refractive index for particle sizing by static light scattering.

The purpose of this study is to assess the impact of real refractive indices, using different itraconazole suspensions, on the associated particle size distributions. Instrumental particle size measurement remains the practical option for determining the particle size distribution of a suspension. In this study, the suspension particle size distribution was measured by static light scattering, which requires knowledge of both the real and imaginary components of the complete refractive index. The real refractive indices of micronized itraconazole raw material, as well as vacuum-dried itraconazole suspension samples obtained from different formulations, polymorphs, manufacturing methods and particle size distributions, were determined using the Becke line method. Identical samples were analyzed by two contract laboratories in order to assess consistency. For the static light scattering equipment used in this study, the complete relative refractive index (RRI = n(particte) / n(dispersant) - ik) input required for software calculation is denoted by a refractive index kernel (RRI input) comprising a relative real component and an imaginary component. The reported real refractive indices for the itraconazole raw material as well as vacuum dried itraconazole suspension samples were different, ranging from 1.608 to 1.65 (selected kernel range of 120A010I to 124A010I). The imaginary component of itraconazole suspension was determined in a previous study to be 010I. The average real refractive index was calculated to be 1.62 (122A010I). The particle size distributions obtained using 120A010I and 124A010I were in good agreement with one generated using 122A010I. Therefore, itraconazole suspensions that were produced using different manufacturing methods/formulations or exhibited different particle size distributions/polymorphic forms may use 122A010I in determining particle size distribution. The particle size distributions determined using RRI input outside the range of 120A010I to 124A010I may not be reliable. However, it is recommended that similar investigations be conducted for other drug suspensions on a case-by-case basis.

Effect of terminal sterilization by irradiation on amber Type I and Type III glass containers containing veterinary oxytetracycline suspension.

The purpose of this study is to determine the effect of terminal sterilization by gamma irradiation on 500-mL amber Type I and Type III glass containers (bottles) containing oxytetracycline (OTC) (25% W/V) suspension formulated using 20% (W/V) phospholipids syrup. The formulation was developed for veterinary parenteral administration. The results of terminal sterilization were used to assess the acceptability for this suspension product. OTC is light-sensitive and needs to be stored in amber glass containers. Amber Type I and Type III glass containers were considered for this formulation during development. Type I is a highly resistant, borosilicate glass (oxidized glass). Type III, which is soda-lime glass (reduced glass, see Materials and Methods), may also be used for parenteral products. The amber Type I and Type III glass containers, containing the suspension, were irradiated at 20-40 kGy for 150 min. In order to determine the sterility of the suspension, ampoules of the biological indicator, Bacillus pumilus, were placed in a number of bottles of the suspension. The bottles with the biological indicators were then positioned among the rest of the production bottles as per a radiation dose-mapping study conducted at the sterilization facility. Potency determination and stability evaluations for OTC were performed using high pressure liquid chromatography (HPLC). The results indicate that the gamma irradiation dose of 20-40 kGy for 150 min was able to inactivate 10(6) Bacillus pumilus spores in ampoules. After gamma sterilization, OTC concentration, pH, particle size, endotoxins, and sterility were evaluated. The assay results were comparable for the suspension in amber Type I and Type III glass containers. Sterility and pyrogenicity were measured by the USP Membrane Filtration Method and USP Bacterial Endotoxins Test, respectively. The suspension in the amber Type III glass container was also chemically (HPLC) and physically (suspension mean particle size, viscosity, density, and syringeability) stable for at least 12 months at room temperature. However, amber Type I glass darkened following irradiation, leading to a substantial reduction in glass transparency. The appearance of amber Type III glass was acceptable. Thus, the "reduced" glass, such as soda-lime, was found to be much less susceptible to darkening than the highly oxidized borosilicate amber. Due to the potential aesthetic concerns with Type I glass, the amber Type III glass container was selected for this suspension formulation.

Modeling of heat and mass transfer processes for the gap-lyophilization system using the mannitol-trehalose-NaCl formulation.

Gap freezing (GF) is a new concept that was developed to reduce the primary drying time using an alternative freezing process. The purpose of this investigation was to determine the gap-tray heat transfer coefficient, Kgtr , and to investigate the effect of gap lyophilization on cycle reduction of a mannitol-trehalose-NaCl (MTN) formulation. The values of Kgtr were measured using the product temperature profiles in three different configurations: (1) shelf freezing followed by shelf drying (denoted as SF-SD), (2) GF followed by SD (denoted as GF-SD), and (3) GF followed by gap drying (denoted as GF-GD). For the lyophilization cycle using shelf drying (SF-SD), 80% of the heat transferred during primary drying was from the bottom shelf to the vial, versus 20% via radiation from the top shelf. For the lyophilization cycle using gap drying (GF-GD), only 37% of the heat transferred during primary drying was from the bottom shelf to the vial versus 63% via radiation from the top shelf. Furthermore, GF in conjunction with annealing significantly reduces the dry layer resistance of the MTN formulation, which is the opposite of what was observed with a conventional freezing cycle.

Gap-freezing approach for shortening the lyophilization cycle time of pharmaceutical formulations-demonstration of the concept.

During gap freezing, vials are placed on a metal tray, which is separated from the shelf surface with a small air gap that eliminates significant conductive heat transfer from the shelf to the bottom of the vial. The purpose of this freezing approach is to reduce the lyophilization cycle time of various amorphous formulations by nearly isothermal freezing. Such isothermal freezing promotes the formation of large ice crystals, and thus large pores throughout the cake, which subsequently accelerates the primary drying rate. The nucleation temperature using gap freezing, for the experimental conditions tested, was in the range of -1°C to -6°C, much higher than the range of -10°C to -14°C found using conventional shelf freezing. Isothermal freezing becomes effective when the gap is greater than 3 mm. The pore sizes and cake resistance during primary drying for various formulations were determined using the pore diffusion model developed by Kuu et al. (Pharm Dev Technol, 2011, 16(4): 343-357). Reductions in primary drying time were 42% (for 10% sucrose), 45% (for 10% trehalose), and 33% (for 5% sucrose).

Solid-phase extraction and HPLC analysis of methylparaben and propylparaben in a concentrated antibiotic suspension.

An accurate and precise solid-phase extraction coupled with high performance liquid chromatography (SPE/HPLC) method developed for the quantification of antimicrobial preservatives (methylparaben and propylparaben) in oxytetracycline injectable suspension is described in this article. The SPE technique was necessary to quantify the preservatives since the high concentration of the drug and excipients was masking low levels of preservatives, making quantification difficult. This developed HPLC method was stability-indicating and found to be linear between 1.3 to 2.4 mg/mL for methylparaben and 0.15 to 0.27 mg/mL for propylparaben in this concentrated antibiotic suspension formulation. The extraction recoveries were 98.8-101.6%. System precision and sample extraction precision (RSD) were less than 1%.