Journal of pharmaceutical science and technology : the official journal of PDA最新文献

The chemical stability of an Asn-hexapeptide (Val-Tyr-Pro-Asn-Gly-Ala) in lyophilized formulations was evaluated as a function of the pH of the bulk solution, temperature, and residual moisture content in a factorial study. Degradation pathways and product distribution in solid state were determined and characterized. It was shown in this study that the pH of the starting solution had a significant effect on the rate of deamidation and product distribution. In general, better stability for the Asn-hexapeptide was achieved at a slightly acidic pH range (3-5) in the solid state. The effects of residual moisture level and temperature on peptide stability proved to be less significant. A statistically significant two-factor interaction indicated that the pH of formulation solution determined the extent to which the peptide stability depends on moisture level and temperature. In general, the degradation of the Asn-hexapeptide in the solid state was similar to that observed in solution, except for the observation that no isoAsp-hexapeptide was detected at pH 5.0 in the solid state, whereas this was the major degradation product in solution.

Use of saturated steam for sterilization-in-place (SIP) is limited by factors effecting displacement of air from deadlegs. Effects of tube diameter, length, orientation and position within a deadleg were quantitatively studied by examining temperature profiles and rates of kill of Bacillus stearothermophilus spores. Tube diameter had the greatest effect on sterilization. For small diameter tubes, 0.4 cm inside diameter (ID), air displacement was minimal and due mainly to diffusion. 8.8 cm long tubes with 0.4 cm IDs could not be sterilized at 121 degrees C. As tube diameter was increased and buoyant driven convective flow became dominant over viscous forces, sterilization was achieved and tube orientation became critical. Sterilization time, as defined by a twelve log reduction in spore population, was 75 minutes in a 19.0 cm long vertical tube with 1.7 cm ID, whereas 167 minutes were required for an 8.8 cm long tube with 1.0 cm ID. For 8.8 cm long tubes, only the 1.7 cm ID tube could be sterilized when orientated 5 degrees above horizontal. Data show that length to diameter ratios, L/Ds, do not provide a general guideline which can be used to predict sterilization. In the absence of steam bleeders, equipment should be designed to assure strong buoyancy driven convective flow to assure adequate air removal. This requires elimination of small diameter deadlegs (0.4 cm ID and less) and vertical positioning of deadlegs.

The prerequisites for estimating the effect of signal coincidence on both particle undercounting and the injection of false counts in the implementation of U.S.P. 788 contaminating particle assays by light extinction particle counters are defined. These include a particle concentration measure that varies with particle size and a new model of the counting process. Both prerequisites have been verified empirically: a single normalized equation describes the coincidence effect in all single particle counters. The single parameter of the normalized equation is the number of effective detector volumes per milliliter. A maximum undercount limit of 5% is proposed based on adequately suspended particles. Using the SVP U.S.P. XXII acceptance limits of 10,000 particles per container or the PMA propose 6,000 particles per container maximum for particles > 10 microns in U.S.P. XXIII, undercount errors are estimated for the smallest container sizes. The large concentration of particles below the controlled 10 microns particle size, that has been documented in injectable solutions, can pose an additional 788 measurement hazard. A Poisson model is used to estimate and control the injection of false particle counts into the mandated measurement through particle coincidence. Acceptable counting accuracy limits with present particle counting systems can be achieved by understanding the capabilities of the particle counter measurement system and using a dilution technique when appropriate. The new model of the counting process and the new particle concentration measures can result in standard, conservative, instrument specifications for use in Pharmacopeial contamination testing and in GLP user evaluation tests. Part I of this paper includes the theory of the coincidence effect on particle counting and the particle size distribution measured. A summary of the experimental verification employed to determine coincidence count loss as a function of particle concentration for single particle counters is reported. Part II of this paper describes a practical protocol for the determination of operating limits to achieve a selected coincidence undercount limit for single particle counters.

The ethylene oxide sterilization process control should take into account several parameters, so that only the biological monitor can integrate in all of them, presenting a biological challenge similar to the product under sterilization conditions. The authors evaluated spore resistance on several different carriers: paper, aluminum foil and plastic. The influence was studied through the challenge of sub-lethal cycles, followed by the lethality study and the D-value calculation. There was a significant statistical difference in spore resistance between paper and plastic carriers.

Water miscible cosolvents in parenteral products generally increase pain and/or local irritation post injection. The goal of this study was to validate the usefulness of the rat paw lick model (Cleozzi et al., J. Pharmacol. Meth., 4, 1980, 285-289) in screening pain and local irritation with parenteral formulations. Paw licks were counted in 3 min. intervals, over a total period of 15 min., following subplantar injection of test formulations in the hind paw of rats. A dose-response relationship following the injection of solutions containing increasing concentrations of a known painful compound was used to validate the model. The results obtained from additional experiments were found to correlate closely to those obtained using other tests (e.g. in vitro hemoglobin release test, and in vivo creatine kinase release test in rabbits). It was found that: (a) the model is responsive to changes in the sensation of pain and/or irritation due to drug or non-active components; (b) the increase in propylene glycol or ethanol concentrations results in increased pain and/or local irritation, (c) the increase in the apparent pH of cosolvent-based formulations from 7.2 to > or = 10 may increase pain and/or local irritation, and (d) there is generally a "thresh-hold limit" between the concentration of painful component and the paw licks, which should be established for the component under evaluation. The data overall suggest that the rat paw lick model is a rapid and simple method for rapid screening of formulations for pain/irritation following local administration.

Pentamidine isethionate is a lyophilized antiprotozoal drug. Its solutions, when lyophilized, have been found to exhibit a range of properties that depend on its concentration and the manner in which it is allowed to freeze. These properties were examined by Differential Scanning Calorimetry (DSC), freeze-drying microscopy and X-ray powder diffraction. In DSC studies, the drug exhibited eutectic behavior with a eutectic temperature of -2.8 degrees C. Freeze-drying microscopic examination of a sample of solution after cooling at about 1 degrees C/min showed that the sample dried with retention up to -4 degrees C, where melting was observed. By using the appropriate drug concentration and manipulating the freezing stage, crystallization of the drug from solution could be induced during cooling to yield a crystalline end-product.

The adsorption characteristics of insulinotropin, a 31-amino acid peptide, to several different sterilizing filters were investigated in the present report. The 0.2 micron filters used in the study were a Nylon-66 filter, a hydroxyl-modified polyamide (BioInert) filter, a polyvinylidene fluoride (PVDF) filter, and a polyhydroxy-propyl-acrylate-grafted polyvinylidene fluoride (GV) filter. The results indicate a rank ordering of adsorption (low to high) of GV, BioInert, Nylon-66, and PVDF. Based on these results, it is possible to predict the amount of solution which must be passed through the specific filter to saturate the binding sites per unit area.

Abbott-72517 is an inhibitor of human renin and is being investigated for the treatment of hypertension. It is an orally bioavailable candidate which is being developed for oral as well as intravenous use. The preclinical development of this molecule involved studies to evaluate irritation at the site of injection in an animal model. Several formulation variables such as drug concentration, types of buffer (citrate or acetate), addition of cosolvent (ethanol) to enhance drug solubility, and tonicity modifiers such as glycerin or mannitol were evaluated. Additionally, in vitro formulation--whole blood hemolysis and plasma precipitation studies were conducted. Based on these studies, a liquid formulation containing 1.2 mg/mL Abbott-72517.HCl as base, 0.01M citrate buffer, pH 3.7, in 0.45% sodium chloride containing 2.5% mannitol was recommended for preclinical studies. Various processing and administration parameters were evaluated including filter qualification and compatibility of the drug with typical infusion fluids and administration sets. The liquid formulation was further characterized for physical and chemical stability. It was shown that it has acceptable stability at ambient temperature. Based on the accelerated temperature storage results, T90 at 25 degrees C is > 1 year for the ready-to-use liquid formulation. Additionally, a lyophilized version of the liquid formulation was evaluated.