Effects of Phosphate Buffer in Parenteral Drugs on Particle Formation from Glass Vials

Abstract

The characteristics of inorganic particles generated in glass vials filled with phosphate buffer solutions were investigated. During storage, particles were visually detected in the phosphate buffer solution in particular glass vials which pass compendial tests of containers for injectable drugs. These particles were considered to be different from ordinal glass delamination, which has been reported in a number of papers because the particles were mainly composed of Al, P and O, but not Si. The formation of the particles accelerated at higher storage temperatures. Among the surface treatments tested for the glass vials, sulfur treatment showed a protective effect on the particle formation in the vials, whereas the SiO 2 coating did not have any protective effects. It was found that the elution ratio of Al and Si in the solution stored in the glass vials after the heating was similar to the ratio of Al and Si in borosilicate glass. However, the Al concentration decreased during storage (5°C, 6 months), and consequently, particle formation was observed in the solution. Adding citrate, which is a chelating agent for Al, effectively suppressed the particle formation in the heated solution. When 50 ppb and higher concentrations of Al ion were added to the phosphate buffer solution, the formation of white particles containing Al, P and O was detected. It is suggested that a phosphate buffer solution in a borosilicate glass vial has the ability to form particles due to interactions with the Al that is eluted from the glass during storage.Key words aluminum; borosilicate glass; tubing vial; aluminum phosphate complex The primary packaging system for a sterile drug product should provide adequate protection against any contamination from the external environment, and this protection should be assured during the entire shelf life of the product. In contrast, particularly for liquid, injectable drugs, components of the drugs are always in contact with the surface of the packaging component during storage. Therefore, during the course of formulation development of injectable drugs, it is essential to evaluate the physicochemical compatibility between the drug formulation and the packaging components to select appropriate primary packaging systems. 1,2) Among the packaging materials that are compatible with injectable drug solutions, glass containers, such as vials or ampoules, have been widely chosen and used. For parenteral drug products, borosilicate glasses (Type I) composed principally of silicon dioxide and boric oxides and soda-lime glasses composed of relatively high levels of sodium oxide and calcium oxide are used. Borosilicate glasses in particular are known to have a good chemical durability and are used commonly in the pharmaceutical industry as the primary container. However, these glass containers, even when made from borosilicate glasses, will unavoidably suffer some undesirable events from being in contact with the drug solutions in longterm storage. In certain cases, insoluble particle formation occurs in g...

Comparisons of Aluminum and Silica Elution from Various Glass Vials

“…Since the shape and transparency was similar to those formed in phosphate buffer stored at 40°C as reported previously, 12) it is suggested that the particles were aluminum-phosphate complexes.…”

“…The phosphate buffer solution (16 mM, pH 7, containing 0.9% sodium chloride) was referred to in our previous report. 12) Under the storage condition of 25°C for three months, particles were detected only in the 51-1 vial which was manufactured by Supplier A, and no particles were detected from the other vials for up to 6 months. After 12 months, particles were detected in all of the samples stored at 25°C.…”

“…These results are consistent with the previous report which was conducted using a higher storage temperature. 12,13) In the case of these study conditions, Al itself would be stable as long as its concentration is below approximately 0.5 ppm and Al would precipitate when its concentration surpasses 0.5 ppm. In other words, Al would start precipitating when Si elutes more than approximately 5 ppm because Si elutes ten times as much as Al does.…”

“…8) Other than delamination, some mechanisms are also known as causes for particles forming in glass containers. We demonstrated that phosphate buffer solution in a borosilicate glass vial has a higher possibility of forming particles due to interactions with the aluminum (Al) that is eluted from the glass during storage, 12) and we also found that citrate buffer, acetate buffer and histidine buffer have less possibility of forming particles with Al than phosphate buffer. 13) Considering only the risk of particle formation from the interaction of phosphate buffer and Al, avoiding the use of phosphate buffer is desirable.…”

“…Treating Particles with Citric Acid To confirm whether the particle contained Al in the phosphate buffer solution, according to our previous study 12) a 1 mol/L citric acid aqueous solution was added to each sample solution, and the sample solutions were stored at 40°C for 2 d in plastic tubes. The final citrate concentrations in the vials were 20 mM.…”