Amber Polyethylene Terephthalate Research Articles

Losartan potassium liquid formulation for paediatric hospital use: development and stability evaluation

ObjectivesThis study aimed to develop a liquid oral formulation containing losartan potassium, an angiotensin II receptor antagonist drug used for its antihypertensive activity, and to perform a preliminary stability assessment...

Development and Stability Control of Pediatric Oral Tizanidine Hydrochloride Formulations for Hospital Use.

Tizanidine hydrochloride is a centrally acting skeletal muscle relaxant used in the treatment of spasticity. This drug is sold only as tablets or capsules, which highlights the need to develop oral liquid formulations that allow administration to children and adults with impaired swallowing. This study aim was to develop and improve tizanidine hydrochloride liquid formulations from raw material and to evaluate their stability. A stability-indicating high performance liquid chromatography method was validated for two formulations developed. Fifteen formulations were developed containing syrup and fifteen containing sodium carboxymethyl cellulose as vehicles, to select the two most suitable for stability testing. The formulations were prepared in triplicate and placed in amber polyethylene terephthalate and glass bottles, which were stored under three different conditions: at room temperature (15-30°C), under refrigeration (2-8°C), and at 40°C. The physicochemical and microbiological stability of formulations were evaluated, applying high performance liquid chromatography and microbiological count. The studied formulations at 15-30°C, 2-8°C, and 40°C can be used for a period of 70days, and all parameters are inside of recommended specifications, enough to allow its use in the context for which it was developed, the application in hospital. The formulations developed in this work have simple components to avoid adverse reactions in vulnerable populations. Results of this study could be applied as a reference for hospital use; once it demonstrated the reliability of storage time interval and proper conditions for use.

Stability of extemporaneously compounded temozolomide 10 mg/mL suspensions in Oral Mix SF® in glass and plastic bottles and plastic syringes.

Temozolomide oral suspension is not commercially available. To evaluate the stability of three temozolomide 10 mg/mL suspensions prepared in Oral Mix SF® in three container types stored at 4°C and 23°C. Using commercial capsules, three separate batches of three different temozolomide 10 mg/mL formulations (Oral Mix SF® with PK-30; PK-30 and citric acid; and neither PK-30 nor citric acid) were made and stored in three container types (amber glass bottles, amber polyethylene terephthalate bottles, and polypropylene oral syringes). The aliquots in each container type were stored protected from light, half at 25°C and half at 4°C. On study days 0, 5, 8, 14, 21, 28, 35, 42, and 56, physical properties of samples from each container type at each temperature were assessed, and the temozolomide concentration was determined using a stability-indicating method. The beyond-use-date (time to achieve 90% of initial concentration calculated using the lower limit of the 95% confidence interval of the observed degradation rate) was calculated. Samples stored at 25°C turned from white to orange within seven days. Temozolomide crystals were observed in all samples. Concentration changes due to study day and temperature (p < 0.001) were observed but not due to container (p = 0.991) or formulation (p = 0.987). The beyond-use-date of all formulations in all container types was 56 days at 4°C and 6 days at 23°C. We recommend that these temozolomide 10 mg/mL formulations be stored at 4°C and be assigned a beyond-use-date of 30 days.

A New Generation of Dihydropyridine Calcium Channel Blockers: Photostabilization of Liquid Formulations Using Nonionic Surfactants.

The stability profile of a new 1,4-dihydropyridine derivative (DHP), representative of a series with a hexahydroquinoline ring, was studied to design light-stable liquid formulations. This molecule, named M3, has been shown among the analogs to have a high capacity to block both L- and T-type calcium channels. The ethanol solution of the drug was subjected to a photodegradation test, in accordance with standard rules. The concentrations of the drug and its byproducts were estimated using multivariate curve resolution, applied to the spectral data collected during the test. The improvement of both the photostability and water solubility of M3 was investigated by adding the surfactant polysorbate 20 in a 1:5 ratio to aqueous solutions of the drug. These formulations were exposed to stressing light in containers of bleu polyethylene terephthalate (PET), amber PET, and covered amber PET. The best results were obtained when using the covered amber PET container, reaching a degradation percentage of the drug less than 5% after 12 h under an irradiance power of 450 W/m2. The stability of the compound was compared to that of nimodipine (NIM) under the same conditions.

Stability of Extemporaneously Compounded Domperidone 5 mg/mL Suspension in Oral Mix in Plastic and Glass Bottles and Plastic Syringes

Domperidone liquid for oral administration is not commercially available in Canada, but is needed for patients who cannot swallow intact tablets. To evaluate the stability of domperidone 5 mg/mL suspensions prepared in Oral Mix vehicle and stored, for up to 91 days, in amber polyvinylchloride (PVC) bottles, amber glass bottles, or amber polyethylene terephthalate (PET) bottles at 4°C or 25°C or in polypropylene oral syringes at 25°C. Three separate 300-mL batches of domperidone suspension 5 mg/mL were prepared with Oral Mix vehicle. Fifty-millilitre aliquots of the suspension were stored in 100-mL bottles (amber PVC, amber glass, or amber PET). Half of the bottles of each type were stored at 25°C and half at 4°C. On study days 0, 1, 2, 4, 7, 10, 14, 21, 28, 35, 42, 49, 63, 77, and 91, domperidone concentration was determined, with a validated reverse-phase, stability-indicating liquid chromatographic method, in samples drawn from each type of container stored at each temperature. In addition, 1.5-mL aliquots of a fourth 100-mL batch of suspension were stored in 3-mL oral syringes at 25°C and were tested on the same study days. The concentration of domperidone in all study samples remained above 93% of initial concentration after storage for 91 days. The percent remaining on day 91, based on fastest degradation rate (as represented by the lower limit of the 95% confidence interval [CI]), was at least 92.3% for suspensions stored at 4°C in PVC, glass, and PET bottles. With storage at 25°C, suspensions in PVC and glass bottles retained more than 90% of initial concentration, whereas suspensions in PET bottles and plastic syringes retained 88.9% and 88.0% of initial concentration, respectively. Because suspensions of domperidone in PET bottles and oral syringes retained less than 90% of their initial concentration on day 91 (based on the 95% CI), it is suggested that such suspensions be stored at 4°C or 25°C in any bottle type or syringe with an assigned beyond-use date not exceeding 75 days.

Determination of Antimony in Pharmaceutical Formulations and Beverages Using High-Resolution Continuum-Source Graphite Furnace Atomic Absorption Spectrometry.

A sensitive and accurate method, employing high-resolution continuum source atomic absorption spectrometry, for the determination of antimony (Sb) was developed. Conditions such as pyrolysis and atomization temperatures, the use of chemical modifiers, and sample pretreatment were optimized for the determination of Sb in pharmaceutical preparations and beverages stored in polyethylene terephthalate (PET) containers. In addition to container analysis, the influence of time of contact, temperature, and content composition on the migration of Sb was investigated. Twenty-six samples were periodically analyzed until finalize 1 year bottling. Eight mineral water samples were analyzed after storage at temperatures from 40 to 80°C for 48 h. Five different-colored PET samples were stored at 80°C for 20 days and periodically analyzed. Bottles, containing from 46.4 mg/kg Sb (amber PET) to 91.6 mg/kg Sb (colorless PET), leached Sb depending on the content ingredients, time of contact, and temperature. Although drinking water itself did not promote Sb migration at room temperature, juices and medicines did. After 1 year of storage, the Sb level in the samples ranged from 5 to 50 μg/L. The rate of leaching depended on the temperature, which was slow below 60°C, but rapidly increased at 60-80°C. The higher the Sb content in the bottle, the higher the amount of migration. Because Sb is a possible carcinogen to humans, containers for pharmaceutical use should be better controlled, and factors that increase Sb leaching in products that are widely consumed should be avoided.

Evaluation of stability of melatonin in extemporaneously compounded oral suspensions

AbstractBackgroundMelatonin is commonly used to treat insomnia, sleep disturbance or hyperactivity disorders. It can be administered in paediatric patients as oral formulations prepared using either bulk powder or commercial products. Few studies have evaluated the stability of these oral formulations, but some storage conditions information may be lacking and a need has been identified for additional stability studies.AimThe aim of this research was to study the stability of extemporaneously prepared oral suspensions of melatonin (2 mg/mL), prepared from pure drug powder or commercial tablets using a proprietary dye‐free oral vehicle: Oral Mix SF (Medisca Pharmaceutique Inc.).MethodTwo melatonin oral liquid preparations were formulated: (a) tablets in Oral Mix SF and (b) pure drug powder in Oral Mix SF. Preparations were stored at room temperature (23–27°C) as well as under refrigeration (3–5°C) in amber plastic syringes (PreciseDose Dispenser™, Medisca Pharmaceutique Inc.) and amber polyethylene terephthalate (PET) bottles with appropriate closures for a period of 90 days. Preparations were assessed using a validated stability‐indicating high‐performance liquid chromatography method. Beyond use dates were evaluated by statistical analysis of the overall degradation trend.ResultsAll preparations were physically and chemically stable for at least 90 days in all storage conditions at room temperature and under refrigeration.ConclusionResults showed that compared to other vehicles, these suspensions had equivalent stability, indicating that Oral Mix SF is a viable dye‐free and sugar‐free alternative for extemporaneous compounding of melatonin.

Nutritional value of cold-pressed rapeseed oil during long term storage as influenced by the type of packaging material, exposure to light & oxygen and storage temperature.

The effect of various conditions (storage temperature, exposure to light, access of oxygen) and different packaging material (amber glass, amber polyethylene terephthalate) on the nutritional value of cold-pressed rapeseed oil during 12months of storage was investigated. Quantified quality parameters included: acidity, peroxide value, spectrophotometric indices (K 232 , K 268 ), fatty acid composition, tocopherols and sterols. Storage of oil at 4°C was found to be most appropriate for maintaining the quality of cold-pressed rapeseed oil. Exposure of oil samples stored at room temperature to light in combination with the access of oxygen caused the most pronounced losses in the total tocopherols (ca. 90-91% of α-T, and ca. 80-81% of γ-T), total phytosterols (ca. 15-16%) and substantial deterioration in oil qualitative properties. Although storage at room temperature is common for use in households, storage of at low temperatures (4°C) significantly increases the possibility of prolonged shelf life of cold-pressed rapeseed oil.

Polyethylene Terephthalate: Sax Responds

In his letter Vasami reminds readers that phthalates are not used in the manufacture of PET. Indeed, I emphasized precisely this point in my commentary (Sax 2010), for example, when I stated that “phthalates are not used as substrates or precursors in the manufacture of PET.” Vasami also asserts that “it is not chemically plausible for PET to produce these phthalate esters”; however, I never suggested that virgin PET gives rise to phthalate esters via degradation of PET itself. I did cite multiple studies in which phthalates were recovered from the contents of PET bottles—as contaminants leaching from the PET bottle wall. How did the phthalates come to be there? As I noted, one possibility is that some of the PET used in manufacturing the bottles may have been recycled PET, and some of this recycled PET might have been contaminated with phthalates. Again, as I noted in my commentary, PET is commonly used for bottling a variety of products (e.g. shampoo) that are known to contain phthalates; these phthalates can then sorb into the PET bottle. Other researchers have previously documented that various organic substances readily migrate into PET (e.g., Komolprasert and Lawson 1997). Indeed, previous investigators have documented the presence of phthalates in PET bottles marketed for consumer use (e.g., Kim et al. 1990); Nerin et al. (2000) reported that the concentration of phthalates was much higher in recycled PET material than in virgin PET. There are good environmental arguments for recycling plastics rather than disposing of them in landfills. The potential for tension between the desire to recycle plastics, on the one hand, and the desire to protect human health, on the other hand, has long been recognized (e.g., Castle 1994). Reconciling these two objectives requires a better understanding of the origin of endocrine disruptors in PET. Vasami notes that although Choe et al. (2003) reported antimony chloride as showing high estrogenicity, “antimony oxides—not antimony chloride—are used as catalysts in the manufacture of PET.” Although Vasami asserts that antimony oxides “are chemically and toxicologically distinct from antimony chlorides,” the toxicological literature does not provide strong support for this assertion. Antimony chloride, when combined with water, readily forms antimony oxide (National Research Council 2000), and both antimony chloride and antimony oxide ionize in vivo. Merski et al. (2008) reported that when animals were fed ground PET, antimony was recovered from their urine in a dose-dependent fashion. Toxicologically, what seems to matter is the antimony and its oxidation state [trivalent (III) or pentavalent (V)], not the anion (chloride or oxide). Antimony(III) is the ionization state in the antimony oxide used in the production of PET; the same ionization state (III) is found in antimony chloride. Using X-ray spectrometry, Martin et al. (2010) confirmed that the antimony in PET bottle walls is in fact trivalent antimony. The toxicological literature clearly establishes that trivalent antimony is far more toxic to humans than is pentavalent antimony (e.g., Chulay et al. 1988; De Boeck et al. 2003; Phillips and Stanley 2006). Vasami’s implication that antimony(III) oxide, when ingested, might be free of the risks demonstrated for antimony(III) chloride, is without evidentiary basis. Vasami concludes by reminding readers that PET bottles meet all applicable safety requirements. However, he neglects to note that these safety requirements were developed largely in the 1980s and 1990s, when the chief concern about antimony and other metalloids had to do with carcinogenicity (e.g., De Boeck et al. 2003) and organ toxicity (e.g., Poon et al. 1998). The standards were developed based on doses believed to be carcinogenic and/or directly toxic. The ability of inorganic metalloids such as antimony to act as xenoestrogens has only recently been recognized (Darbre 2006). More research is needed to determine whether the regulatory requirements for antimony in foods and beverages should be adjusted in order to minimize the risk of endocrine-disrupting effects. Certainly there is a paucity of research on the endocrine-disrupting effects of antimony. But surely the remedy for this deficiency is more research, not a stubborn insistence that what we don’t know can’t hurt us.

Stability of codeine phosphate in an extemporaneously compounded syrup

The stability of codeine phosphate in an extemporaneously compounded syrup is described. Codeine phosphate 3-mg/mL syrup was prepared using commercially available Codeine Phosphate, USP, Sterile Water for Irrigation, USP, and Ora-Sweet syrup vehicle. Samples were stored in amber polyethylene terephthalate bottles with child-resistant caps. A second batch of codeine phosphate 3-mg/mL syrup was prepared and drawn into amber polyethylene oral syringes with silicon elastomer tips. All samples were stored at room temperature and in the dark. Samples were analyzed immediately and at 7, 14, 28, 42, 56, 70, and 98 days. Codeine phosphate concentrations were measured using a modified stability-indicating high-performance liquid chromatographic method. At each test interval, the density of the syrup was determined gravimetrically using a 10-mL amber oral syringe. Excessive degradation was defined as a greater than 7% loss of the initial concentration. The stock internal standard was stable for at least 98 days at room temperature. The compounded syrup retained more than 93% of the initial codeine phosphate concentration for at least 98 days at 22-25 degrees C. No changes in color, clarity, or odor and no visible solids or microbial growth were observed in any sample. The pH of the syrup was initially 4.2 and remained unchanged throughout the study. Codeine phosphate 3 mg/mL in Ora-Sweet syrup vehicle was stable in both amber polyethylene terephthalate bottles and amber polyethylene oral syringes for at least 98 days when stored at 22-25 degrees C and protected from light.

Volatile Compounds and Chemical Changes in Ultrapasteurized Milk Packaged in Polyethylene Terephthalate Containers

ABSTRACTThe volatile compounds profile and chemical stability of ultrapasteurized 2% milk bottled in amber polyethylene terephthalate (PET) were studied along with its shelf life of 60 d at 5 °C. Identification of volatile compounds using a solid‐phase microextraction (SPME) technique with gas chromatography‐mass spectrometry was performed in situ in the commercial product. Chemical stability was determined by measuring dissolved oxygen, free sulfhydryl groups, ascorbic acid, and headspace oxygen. The classes of volatile compounds identified were ketones, aldehydes, hydrocarbons, fatty acids, alcohol, and miscellaneous compounds. Volatile compounds found consistently during the storage period were 2‐heptanone, methoxy‐phenyl‐oxime, decane, 1‐ethyl‐2,4‐dimethyl‐benzene, D‐limonene, 2‐nonanone, octanoic acid, dodecane, and 4‐(1,1,3,3, ‐tetramethylbutyl) phenol. Possible products of lipid oxidation, such as hexanal, octanal, and nonanal, were also positively identified. Chemical stability of PET‐bottled milk was demonstrated by the insignificant changes in pH or TA, with the exception of ascorbic acid concentration, which degraded in the product at 60 d of refrigerated storage. Sensory evaluation of the milk samples revealed that there is no noticeable oxidized or rancid off‐flavor at 60 d of storage.

Characterization of an extemporaneous liquid formulation of lisinopril.

The stability of lisinopril in an extemporaneously prepared suspension stored at or below 25 degrees C for 28 days under ambient light exposure was studied. A formulation of 1-mg/mL oral suspension was prepared from commercially available 20-mg lisinopril tablets, using Bicitra and Ora-Sweet SF as the compounding vehicles to make a final volume of 200 mL. Individual samples, stored in 8-oz amber polyethylene terephthalate bottles, were used for each test performed. All samples were stored at 25 degrees C. Appropriateness of the extemporaneous preparation method was performed by shaking three lots of each suspension for 30, 60, and 90 seconds. To test the robustness and reproducibility of the method, two chemists prepared the suspensions from the same three lots of lisinopril tablets. Chemical and physical stability were established by analyzing duplicate samples at time zero and after one, two, four, and six weeks. The solubility of lisinopril was tested from suspensions stored for four weeks. In-use stability was also examined over four weeks. Photochemical stability was examined by exposing three batches of the suspension to maximum light stress in accordance with the International Conference on Harmonization. Antimicrobial-effectiveness testing was also conducted with freshly prepared suspensions and suspensions stored for six weeks. The preparation method used was appropriate and effective. Lisinopril is fully dissolved in the suspension matrix. Satisfactory chemical, physical, and microbiological results were obtained after the suspensions were stored for six weeks at 25 degrees C and 35% relative humidity. Lisinopril suspensions extemporaneously prepared from tablets are stable for at least four weeks when stored at or below 25 degrees C under ambient light exposure.

Stability of ganciclovir in extemporaneously compounded oral liquids.

The stability of ganciclovir in extemporaneously prepared sugar-containing and sugar-free oral liquids was studied. The contents of 80 250-mg capsules of ganciclovir were combined with Ora-Sweet or Ora-Sweet SF (sugar free) (Paddock Laboratories) to produce 200 mL of suspension with a ganciclovir concentration of 100 mg/mL. Five 1-mL samples were analyzed immediately, and the rest of the suspension was poured into five 60-mL amber polyethylene terephthalate bottles and stored at 23-25 degrees C. Samples were removed and analyzed with stability-indicating high-performance liquid chromatography on days 15, 35, 60, 91, and 123. The suspensions retained at least 96% of the initial ganciclovir concentration for 123 days. The pH of the suspensions was initially 4.5 and remained unchanged throughout the study. There was no detectable change in color or odor and no visible microbial growth in any sample. Ganciclovir 100 mg/mL was stable for 123 days in sugar-containing and sugar-free oral liquids stored at 23-25 degrees C in amber polyethylene terephthalate bottles.

Stability of lamotrigine in two extemporaneously prepared oral suspensions at 4 and 25 degrees C.

The stability of lamotrigine 1 mg/mL in two extemporaneously prepared oral suspensions at 4 and 25 degrees C was studied. Lamotrigine tablets were ground to powder, and the powder was combined with a 1:1 mixture of Ora-Sweet and Ora-Plus or a 1:1 mixture of Ora-Sweet SF and Ora-Plus (Paddock Laboratories) to produce two 1-mg/mL suspensions. One 100-mg lamotrigine tablet was used to prepare one 100-mL batch of each suspension. The suspensions were stored in amber polyethylene terephthalate prescription bottles at 4 or 25 degrees C. Samples were collected on days 0, 7, 14, 28, 42, 56, 70, and 91 for analysis of lamotrigine content by high-performance liquid chromatography; pH was measured, and the samples were visually observed against a black and white background. The mean concentration of lamotrigine was >99% of the initial concentration in all samples throughout the 91-day study period; there was no change in apparent pH, odor, or physical appearance. Lamotrigine 1 mg/mL in two extemporaneously compounded oral suspensions was stable for 91 days in polyethylene terephthalate prescription bottles at 4 and 25 degrees C.

Stability of ramipril in water, apple juice, and applesauce

The stability of ramipril in water, in apple juice, and in applesauce was studied. The contents of a single capsule each of ramipril 1.25, 2.5, and 5 mg were mixed in glass beakers with 120 mL of deionized and filtered water, apple juice, or applesauce. Each mixture was apportioned into 10 120-mL amber polyethylene terephthalate (PET) containers. Five of the containers in each set were stored at 23 degrees C, and samples were taken at 0, 1, 2, 6, 12, and 24 hours. The other five containers were stored at 3 degrees C, and samples were taken at 4, 8, 12, 24, and 48 hours. The samples were analyzed for ramipril concentration by stability-indicating high-performance liquid chromatography (HPLC). The quantity of drug remaining in the PET container after "administration" was determined by mixing the contents of single 5-mg ramipril capsules with 60 mL of apple juice, pouring the mixture into a waste receptacle, rinsing the PET container three separate times with 10 mL of water, and analyzing the pooled fluid from these rinses for ramipril concentration by HPLC. Under no condition did the percentage of ramipril remaining drop below 90%. No peaks for degradation products appeared in the chromatograms. The mean +/- S.D. quantity of ramipril remaining in the PET containers after draining was 0.3 +/- 0.3% for the apple juice. Ramipril from 1.25-, 2.5-, and 5-mg capsules mixed in water, in apple juice, and in applesauce was stable for 24 hours at 23 degrees C and for 48 hours at 3 degrees C.

Methods for Predicting Migration to Packaged Pharmaceuticals

The compatibility of the pharmaceutical product with packaging materials is an important parameter which must be evaluated during the product development process. This paper discusses the possibility that pertinent FDA methodology can be modified in a more efficient way using currently available analytical techniques. Several studies on potential migrants from packaging materials, such as heat-seal adhesives, amber polyethylene terephthalate (PET) containers, and rubber gaskets of aerosol valves, are presented to show that commonly encountered questions with regard to packaging materials used during product stability studies can also be answered in the same way.

Determination of potential migrants from commercial amber polyethylene terephthalate bottle wall.

Potential migrants were isolated from commercial polyethylene terephthalate (PET) bottles using Soxhlet extraction. The concentrated extract was then subjected to GC/MS analysis. A total of 19 migrants has been identified. The majority of compounds appeared to be intermediate reaction products or residual monomers of their dehydration and transesterification products. Several processing aids such as fatty acids and commonly used plasticizers were also identified. The amount of seven compounds present in the major portion of exhaustive extract of the PET bottle wall ranged from 800 micrograms/g polymer to as low as 0.6 microgram/g.