Caffeoylquinic acid profiling: comparative analysis in yerba mate, Indian camphorweed, and stevia extracts with emphasis on the influence of brewing conditions and cold storage in yerba mate infusion.

Herbal infusions exhibit diverse pharmacological effects, such as antioxidant, anti-inflammatory, anticancer, antihypertensive, and antineurodegenerative activities, which can be attributed to the high content of phenolic compounds (e.g., caffeoylquinic acids (CQAs)). In this study, we used ultraperformance liquid chromatography to determine the content of CQAs in the methanolic extracts of model herbs, namely, yerba mate (Ilex paraguariensis), stevia (Stevia rebaudiana), and Indian camphorweed (Pluchea indica (L.) Less.). The results revealed that yerba mate had the highest total CQA content (108.05 ± 1.12 mg/g of dry weight). Furthermore, we evaluated the effect of brewing conditions and storage at 4 °C under dark and light conditions on the antioxidant property and total phenolic and CQA contents of a yerba mate infusion. The analysis of the yerba mate infusions prepared with different steeping times, dried leaf weights, and water temperatures revealed that the amount of extracted CQAs was maximized (∼175 mg/150 mL) when 6 g of dried leaves were steeped in hot water for 10 min. A total of 10-day refrigerated storage resulted in no significant changes in the antioxidant activity and total phenolic and CQA contents of an infusion kept in a brown container (dark). However, the antioxidant properties and total phenolic and CQA contents were negatively affected when kept in a clear container, suggesting the detrimental effect of light exposure. Our study provides practical recommendations for improving the preparation and storage of herbal infusions, thus catering to the needs of consumers, food scientists, and commercial producers. Moreover, it is the first study of the influence of light exposure on the content of crucial quality attributes within plant-based beverages.

Bracketed Stability Evaluation of Methimazole USP in PLO Gel Mediflo™30 Pre-Mixed.

Extemporaneously compounded Methimazole 1% and 10% in PLO Gel Mediflo™30 Pre-Mixed were studied to assess physical, chemical and microbial stability over time. The formulations were stored at room temperature in tightly closed, light resistant plastic containers. Chemical stability was evaluated using a validated, stability indicating HPLC analysis and physical stability was evaluated through observation of organoleptic appearance and pH measurement at predetermined time points. Lastly, antimicrobial effectiveness testing was conducted per USP <51> guidelines. The results indicate that compounded Methimazole remained within the stability criteria for the duration of the study and can be assigned an extended beyond-use-date of 120 days under the studied conditions.

Unused, expired pharmaceuticals and their disposal practices among the general public in Burdur-Türkiye: a cross-sectional study.

BACKGROUND: Unused pharmaceuticals are currently a public health problem. This study aimed to identify unused pharmaceuticals, research practices about the disposal methods, classify the medicines according to Anatomical Therapeutic Chemical codes (ATC) and, to determine the number of unused medicines. METHODS: The study was designed as a cross-sectional study. Data were collected between April and August 2023 in Burdur-Türkiye by non-probability sampling technique (convenience method). Pharmaceuticals were classified according to ATC. Statistical Package for Social Science SPSS (V.24) package program was used for data analysis. RESULTS: A total of 1120 people, 1005 in the first sample group and 115 in the second sample group, participated in the study. Findings of first sample group: A total of 4097 boxes of unused pharmaceuticals (4.7 ± 4.3 boxes/per capita) were detected. It was found that pharmaceuticals were stored in areas such as kitchens (59.1%) and refrigerators (38.6%), the reason for keeping them was reuse (41%), and the disposal practice was household garbage (81%). Paracetamol (648 boxes), Other cold preparation (303 boxes), Dexketoprofen (239 boxes), Diclofenac (218 boxes), Amoxicillin and beta-lactamase inhibitor (190 boxes) were found to be the most frequently unused pharmaceuticals. Using the unused medicines at home without consulting a physician was 94.1% (self-medication). Findings of second sample group: Of the 6189 dosage forms in 265 boxes pharmaceutical, 3132(50.6%) dosage forms were used and 3057(49.4%) were found to be unused. CONCLUSION: There is a significant amount and number of unused medicines in households, and self-medication is common. Medicines are not properly disposed of and some of them expire. Public information is needed. A "drug take-back system" for unused medicines can be useful in solving this problem.

Physical-chemical Stability of the Extemporaneous Paracetamol Oral Suspension in Puccini Base.

This study describes a new method for the preparation of extemporaneous paracetamol-based suspensions for pediatric and adult patients. This method allows the preparation of extemporaneous suspensions up to concentrations of 50 mg/mL by using a liquid base, named "Puccini". A high-pressure liquid chromatographic method was developed and validated for the determination of chemical stability of paracetamol when the formulations were stored at 4°C and 25°C. The chemical stability of the active pharmaceutical ingredient in the base was demonstrated for more than 90 days. Visual analyses of the formulations showed a phenomenon of precipitation at both storage temperatures, but the simple agitation of the formulations before its use re-established the formation of homogeneous suspensions.

Effectiveness of the online-eLearning program KeepCoool at improving the vaccine cold chain in general practices.

BACKGROUND: Protecting vaccines from freeze damage is a poorly addressed problem. We describe the effectiveness of the eLearning KeepCoool on cold chain maintenance in general practices. METHODS: For this intervention study, temperatures of vaccine refrigerators were logged at one-minute intervals. Personnel from practices with cold chain breaches was offered the eLearning. The primary outcome was the intervention's effectiveness to achieve temperatures in the target range (2 to 8°C) in the sixth week (follow-up) compared to the first (baseline). Using continuous temperature data, a generalized additive model for location, scale and shape was estimated. RESULTS: The practice response rate was 38% (64 of 168). At baseline, 73% of the practices and 68% of the refrigerators (51 of 75) showed cold chain breaches. 47% of the practices (n = 22 with 24 refrigerators) participated in the eLearning (55 physicians and practice assistants). At follow-up, 17% of those refrigerators were in the target range continuously, 38% reached targets 95% of the time while always >0°C, and temperatures ≤0°C decreased by 63%. Based on 2 million temperature data, the average Euclidian distance based on regression showed a significant improvement (p<0.05). CONCLUSION: The eLearning KeepCoool improved the practices´ vaccine cold chain. It is freely available at https://keepcoool.ukbonn.de.

Psychotropic medicine use without current or prior medical advice, storage at home and association with perceived stress in a primary health care setting in Greece / Uso de medicamentos psicotrópicos sin consejo médico actual o previo, almacenamiento en el hogar y asociación con estrés percibido en un entorno de atención primaria en Grecia

Objective: Psychotropic medicines use alters according to socio-economic factors and perceived stress. The study aimed to assess the prevalence of use of psychotropic medicines and supplements (PMS) without medical advice, including storage at home, and its relationship with socio-demographic characteristics and perceived stress in primary care patients. Materials and methods: A cross-sectional sample of adult attendees in an urban primary care unit in Crete, Greece, were surveyed during regularly scheduled appointments during a three-week period in October 2020. A questionnaire was distributed to investigate PMS use during the last 12 months. The validated Greek version of Perceived Stress Scale (PSS-14) was adopted to measure perceived stress. Results: Of 263 respondents (mean age 46.3±14.5 years; 66.5% females), 101 (38.4%; 95%CI 33.1–43.7%) recalled having psychotropic medicines stored at home cabinets and 72 (27.4%; 95%CI 22.4–32.3%) reported using PMS without medical advice in the last 12 months. Conclusions: This study revealed a high prevalence of PMS use without medical advice, including storage at home. People>59 years of age, experiencing irregular sleep and scoring high in PSS, displayed increased prevalence of storing PMS at home or using them without medical advice. The findings could potentially inform primary care providers to focus on patients most likely to be users of PMS without medical advice.(AU)

Objetivo: El uso de medicamentos psicotrópicos cambia según los factores socioeconómicos y el estrés percibido. El estudio tuvo como objetivo evaluar la prevalencia de uso de medicamentos y suplementos psicotrópicos (MSP) sin consejo médico, incluido el almacenamiento en el hogar y su relación con las características sociodemográficas y el estrés inferido en pacientes de atención primaria. Materiales y métodos: Se encuestó a una muestra transversal de asistentes adultos en una Unidad de Atención Primaria Urbana en Crete, Grecia, durante citas programadas regularmente durante un periodo de tres semanas en Octubre de 2020. Se distribuyó un cuestionario para investigar el uso de MSP durante los últimos 12 meses. Se adoptó la versión griega validada de la Escala de Estrés Percibido (Perceived Stress Scale 14, PSS-14) para medir el estrés percibido. Resultado: De 263 encuestados (edad media 46,3 ± 14,5 años; 66,5% mujeres), 101 (38,4%; IC 95%; 33,1-43,7%) recordaban tener medicamentos psicotrópicos almacenados en los armarios de sus casas y 72 (27,4%; IC 95%; 22,4-32,3%) informó haber usado MSP sin consejo médico en los últimos 12 meses. Conclusiones: Este estudio reveló una alta prevalencia de uso de MSP sin consejo médico, incluido el almacenamiento en el hogar. Las personas mayores de 59 años, que experimentaron sueño irregular y puntuaron alto en PSS, mostraron una mayor prevalencia de almacenar MSP en casa o usarlos sin consejo médico. Los hallazgos podrían informar potencialmente a los proveedores de atención primaria para que se centren en los pacientes con mayor probabilidad de usar MSP sin consejo médico.(AU)

Freeze-drying of bupivacaine lipospheres: preparation, characterization, and evaluation of anti-microbial properties.

PURPOSE: To prepare freeze-dried bupivacaine lipospheres intended for topical application in burn injuries. The aim was improving the storage stability and developing a prolonged release pattern to tackle the adverse reactions resulting from the frequent administration of bupivacaine. METHODS: The lipospheres were prepared by hot-melt dispersion method employing bupivacaine base at 1.5 and 3%w/w, tristearin 6% w/w as the core while dipalmitoyl phosphatidylcholine (DPPC) and soy phosphatidylcholine (SPC) as the coat at 0.75, 1.5 and 3% w/w. The lotion was then freeze-dried and cryoprotected by sucrose 3% w/w. Evaluation was carried out through loading and release analysis, storage study, particle characterization including morphology, zeta potential and particle size as well as anti-microbial assessment. RESULTS: The highest loading, (87.6 ± 0.1%), was achieved using bupivacaine 3% and SPC 0.75%. After 6 months of storage at 4 ͦC, the loading in the lotion and the freeze-dried samples were 17.4 ± 0.2 and 87.2 ± 0.3%, respectively. In vitro dissolution test demonstrated 94.5% and 95% of bupivacaine release from lotion and freeze-dried samples, after 24 h. The respective zeta potential of -1.30 and 26 mV was recorded for lotion and solid-state bupivacaine. Micromeritic evaluation of freeze-dried powder exhibited particle size of 35.23 ± 2.02 µm and highly-wrinkled-irregular morphology without detectable needle structures related to drug free crystals. The powder had rapid reconstitution property and antibacterial activity. CONCLUSION: Freeze- drying holds a promising potential to improve the storage stability of bupivacaine lipospheres with well- preserved release pattern and particle properties for further topical application.

The effect of emulgel preparation on the stability of Kojic acid in the topical anti-hyperpigmentation products.

BACKGROUND: The emulgel, a novel drug delivery system, merges emulsion and gel, offering advantages like enhanced stability, precise control over drug release kinetics, and increased drug absorption compared to emulsions alone. Kojic acid (KA) demonstrates potent inhibition of the tyrosinase enzyme, a crucial player in the melanin synthesis pathway. AIMS: The main objective of this experimental study is to formulate KA within an emulgel framework and assess its stability under various environmental conditions. METHODS: One percent of KA emulgel and 1% simple gel, serving as the control product, were supplemented with varying concentrations of sodium metabisulfite (SMBS) for its antioxidant properties. The formulations were segregated into four groups and subjected to diverse maintenance and stress conditions over a three-month period. Monthly evaluations of physicochemical alterations were conducted, initially employing digital photography, followed by the extraction of KA and subsequent quantification of its concentration through high performance liquid chromatography (HPLC). RESULTS: The best formulations for retaining KA among the prepared ones were the 0.25% SMBS KA emulgel and the 0.1% SMBS KA simple gel, capable of retaining 86% and 76% of the initial KA content under stress conditions, respectively (p < 0.0001). CONCLUSIONS: Regarding to this study, ideal storage condition for KA emulgel and simple gel is in the refrigerator temperatures. Moreover, optimal SMBS concentrations for stability enhancement are 0.25% for emulgel and 0.1% for the simple gel. A significant statistical difference was observed between refrigerated emulgel and simple gel in the retention of KA in the presence of optimum concentration of antioxidants (p < 0.0001).

Extended physicochemical stability of cetuximab in opened vials and infusion bags when stored at 4°C and 25°C.

INTRODUCTION: This study aimed to determine the stability of cetuximab: (1) under "in-use" conditions after dilution to 1 mg/mL in 0.9% sodium chloride in polyolefin bags and (2) as an undiluted solution (5 mg/mL) repackaged in polypropylene bags or kept in the vial after opening. METHODS: Ready-to-use 500 mg/100 mL vials of cetuximab solution were diluted to 1 mg/mL in 100 mL bags of 0.9% sodium chloride or repackaged as a 5 mg/mL solution into empty 100 mL bags. Bags and vials were stored at 4°C for 90 days and 25°C for 3 days. A syringe sample of 7 mL was taken from each bag for the initial determinations. The sampled bags were weighed to determine their initial weight and placed under the planned storage conditions. The physicochemical stability of cetuximab was estimated using validated methods. RESULTS: No changes in turbidity, no protein loss, and no changes in cetuximab tertiary structure were observed after 30 days of storage or when subjected to a temperature excursion of 3 days at 25°C and when stored at 4°C for up to 90 days, regardless of the concentrations and batches. The colligative parameters did not change under any of the tested conditions. No evidence of microbial growth was found in bags after 90 days of storage at 4°C. CONCLUSION: These results support the extended in-use shelf-life of cetuximab vials and bags, which can be cost-effective for healthcare providers.

Container Closure Integrity of a Glass Prefillable Syringe in Deep Frozen Storage Conditions.

Development of novel pharmaceutical drug modalities has created a need for frozen storage and transportation. Accurate and easy assessment of container closure integrity (CCI) in frozen conditions remains a challenge. Thus, container closure systems (CCS) suitable for low temperatures have been primarily restricted to vials despite the growing popularity of prefillable syringes (PFS) for parenteral administration. A new dye ingress test method, suitable for testing at low temperatures, was developed and applied to PFS across a range of deep-frozen temperatures. The method is versatile and can easily be extended to other common CCS formats over a wide range of temperatures including storage on dry ice (-80 °C). This new method was paired with an orthogonal technique, laser-based CO2 headspace gas analysis, to evaluate the CCI of a glass PFS at temperatures from -50 °C to -80 °C. Both test methods showed comparable results and consistent CCI failure below a temperature of -70 °C. The primary mode of failure was the plunger-to-barrel interface, likely attributable to dimensional changes and loss of elasticity. This study demonstrates the temperature dependent CCI behavior of glass PFS and underscores the importance of thorough characterization of package integrity for deep frozen drug products.

Application of Accelerated Predictive Stability Studies in Extemporaneously Compounded Formulations of Chlorhexidine to Assess the Shelf Life.

Industrially fabricated medicines have a well-defined shelf life supported by rigorous studies before their approval for commercialization. However, the shelf life of extemporaneous compounding topical formulations prepared at hospitals tends to be shorter, especially when no data are available to prove a longer stability period. Also, the storage conditions are unknown in many circumstances. Accelerated Predictive Stability (APS) studies have been shown to be a useful tool to predict in a faster and more accurate manner the chemical stability of extemporaneously compounded formulations requiring a minimum amount of formulation, thereby reducing the chemical drug waste per study. Shelf life will be allocated based on scientific data without compromising drug efficacy or safety. In this work, the APS approach was applied to the commercially available Cristalmina® (CR) and an extemporaneously compounded formulation of chlorhexidine (DCHX). A different degradation kinetic was found between DCHX and CR (Avrami vs. zero-order kinetics, respectively). This can explain the different shelf life described by the International Council for Harmonisation of Technical Requirements Registration Pharmaceuticals Human Use (ICH) conditions between both formulations. A predicted stability for the DCHX solution was obtained from the extrapolation of the degradation rate in long-term conditions from the Arrhenius equation. The estimated degradation from the Arrhenius equation for DCHX at 5 °C, 25 °C, and 30 °C at 365 days was 3.1%, 17.4%, and 25.9%, respectively. The predicted shelf life, in which the DCHX content was above 90%, was 26.67 months under refrigerated conditions and 5.75 and 2.24 months at 25 and 30 °C, respectively. Currently, the Spanish National Formulary recommends a shelf life of no longer than 3 months at room temperature for DCHX solution. Based on the predicted APS and confirmed by experimental long-term studies, we have demonstrated that the shelf life of DCHX extemporaneously compounded formulations could be prolonged by up to 6 months.

Thermal stability and storage of human insulin.

BACKGROUND: Health authorities stress the temperature sensitivity of human insulin, advising protection from heat and freezing, with manufacturers suggesting low-temperature storage for intact vials, and once opened, storage at room temperature for four to six weeks, though usage time and maximum temperature recommendations vary. For human insulin, the recommendations of current shelf life in use may range from 10 to 45 days, and the maximum temperature in use varies between 25 °C and 37 °C. Optimal cold-chain management of human insulin from manufacturing until the point of delivery to people with diabetes should always be maintained, and people with diabetes and access to reliable refrigeration should follow manufacturers' recommendations. However, a growing segment of the diabetes-affected global population resides in challenging environments, confronting prolonged exposure to extreme heat due to the climate crisis, all while grappling with limited access to refrigeration. OBJECTIVES: To analyse the effects of storing human insulin above or below the manufacturers' recommended insulin temperature storage range or advised usage time, or both, after dispensing human insulin to people with diabetes. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 12 July 2023. SELECTION CRITERIA: We included clinical and laboratory studies investigating the storage of human insulin above or below manufacturers' recommended temperature storage range, advised usage time, or both. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used GRADE to assess the certainty of evidence for the clinical study. Most information emerged from in vitro studies, mainly from pharmaceutical companies. There is no validated risk of bias and certainty of evidence rating for in vitro studies. We thus presented a narrative summary of the results. MAIN RESULTS: We included 17 eligible studies (22 articles) and additional information from pharmaceutical companies. Pilot clinical study One pilot clinical study investigated temperature conditions for insulin stored for six weeks in an unglazed clay pot with temperatures ranging between 25 °C and 27 °C. The mean fall in plasma glucose in eight healthy volunteers after clay pot-stored insulin injection was comparable to refrigerator-stored insulin injection (very low-certainty evidence). In-vitro studies Nine, three and four laboratory studies investigated storage conditions for insulin vials, insulin cartridges/pens and prefilled plastic syringes, respectively. The included studies reported numerous methods, laboratory measurements and storage conditions. Three studies on prefilled syringes investigating insulin potency at 4 °C up to 23 °C for up to 28 days showed no clinically relevant loss of insulin activity. Nine studies examined unopened vials and cartridges. In studies with no clinically relevant loss of insulin activity for human short-acting insulin (SAI), intermediate-acting insulin (IAI) and mixed insulin (MI) temperatures ranged between 28.9 °C and 37 °C for up to four months. Two studies reported up to 18% loss of insulin activity after one week to 28 days at 37 °C. Four studies examined opened vials and cartridges at up to 37 °C for up to 12 weeks, indicating no clinically relevant reduction in insulin activity. Two studies analysed storage conditions for oscillating temperatures ranging between 25 °C and 37 °C for up to 12 weeks and observed no loss of insulin activity for SAI, IAI and MI. Four studies, two on vials (including one on opened vials), and two on prefilled syringes, investigated sterility and reported no microbial contamination. Data from pharmaceutical companies Four manufacturers (BIOTON, Eli Lilly and Company, Novo Nordisk and Sanofi) provided previously unreleased human insulin thermostability data mostly referring to unopened containers (vials, cartridges). We could not include the data from Sanofi because the company announced the permanent discontinuation of the production of human insulins Insuman Rapid, Basal and Comb 25. BIOTON provided data on SAI after one, three and six months at 25 °C: all investigated parameters were within reference values, and, compared to baseline, loss of insulin activity was 1.1%, 1.0% and 1.7%, respectively. Eli Lilly and Company provided summary data: at below 25 °C or 30 °C SAI/IAI/MI could be stored for up to 25 days or 12 days, respectively. Thereafter, patient in-use was possible for up to 28 days. Novo Nordisk provided extensive data: compared to baseline, after three and six months at 25 °C, loss of SAI activity was 1.8% and 3.2% to 3.5%, respectively. Loss of IAI activity was 1.2% to 1.9% after three months and 2.0% to 2.3% after six months. Compared to baseline, after one, two and three months at 37 °C, loss of SAI activity was 2.2% to 2.8%, 5.7% and 8.3% to 8.6%, respectively. Loss IAI activity was 1.4% to 1.8%, 3.0% to 3.8% and 4.7% to 5.3%, respectively. There was no relevant increase in insulin degradation products observed. Up to six months at 25 °C and up to two months at 37 °C high molecular weight proteins were within specifications. Appearance, visible particles or macroscopy, particulate matter, zinc, pH, metacresol and phenol complied with specifications. There were no data for cold environmental conditions and insulin pumps. AUTHORS' CONCLUSIONS: Under difficult living conditions, pharmaceutical companies' data indicate that it is possible to store unopened SAI and IAI vials and cartridges at up to 25 °C for a maximum of six months and at up to 37 °C for a maximum of two months without a clinically relevant loss of insulin potency. Also, oscillating temperatures between 25 °C and 37 °C for up to three months result in no loss of insulin activity for SAI, IAI and MI. In addition, ambient temperature can be lowered by use of simple cooling devices such as clay pots for insulin storage. Clinical studies on opened and unopened insulin containers should be performed to measure insulin potency and stability after varying storage conditions. Furthermore, more data are needed on MI, insulin pumps, sterility and cold climate conditions.

Statistical considerations on real time and extended controlled temperature conditions (ECTC) stability data analysis of vaccines.

BACKGROUND: Although maintaining vaccines in a strict cold chain has cost and logistical implications in low- and middle-income countries, only a few vaccines have obtained approval for extended controlled temperature conditions (ECTC) application, which permits the administration of vaccines after storage outside of the cold chain for a defined period. We developed a methodology to evaluate stability data and calculate minimum release potency (MRP) in support of ECTC application. METHODS: The methodology is focused on statistical considerations consisting of stability data collection, statistical analysis plan, statistical modelling, and statistical report. It uses mock stability data from a hypothetical product and may serve as a helpful guide for other products. The statistical data analysis is performed using the R program which is an open-source program and validated using the SAS software. RESULTS: We developed a stability data testing scheme that included 24 lots with six-time points for up to 24 months under real-time and real condition (RT) in the cold chain samples stored at 2-8 °C and 12 lots with six timepoints for 14 days under ECTC samples stored at 40 °C. The log-transformed stability data met the linear regression assumptions and were poolable from representative lots with no significant lot variation. The linear regression analysis model with a common slope and intercept confirmed the stable antigen content over time under RT and ECTC by the mean regression line and 95% confidence interval. Based on the fitted models and the estimated coefficients, the antigen content value of 966 was derived as the MRP under RT for 24 months followed by 14 days under ECTC. CONCLUSION: The presented framework of statistical considerations, with practical methods and R program codes to perform statistical analysis, may serve as a guide for developing the CTC data for a vaccine's stability evaluation prospectively.

Chemical Stability of Epinephrine 10 mcg/mL Diluted in 0.9% Sodium Chloride and Stored in Polypropylene Syringes at 4 degrees C and 25 degrees C.

Studies have evaluated epinephrine stability in higher concentrations and shorter durations than we require. The objective of this study was to evaluate the chemical stability of epinephrine in syringes at concentrations of 10 mcg/mL in 0.9% sodium chloride at 4°C and 25°C. Solutions of 10 mcg/mL epinephrine in 0.9% sodium chloride were prepared and stored in 10-mL Becton, Dickinson and Company syringes. Three units of each container were stored at 4°C and 25°C. Concentration analysis was completed on study days 0, 2, 7, 14, 21, 28, 42, 56, 72, and 91 using a validated stability-indicating liquid chromatographic method with ultraviolet detection. Chemical stability was based on the intersection of the lower limit of the 95% confidence interval of the observed degradation rate and the time to achieve 90% of the initial concentration (T-90). The analytical method separated degradation products from epinephrine to measure concentration specifically, accurately, and reproducibly. During the study period, all solutions at 4°C retained more than 89.62% of the initial concentration for 91 days. Solutions stored at 25°C retained more than 90% for 21 days. Multiple linear regression revealed significant differences in percent remaining due to study day (P<0.001) and temperature (P=0.002). The calculated T-90, with 95% confidence, was 71.40 days for solutions stored at 4°C but only 12.77 days for solutions stored at 25°C. We conclude that 10 mcg/mL epinephrine solution diluted in 0.9% sodium chloride stored at 4°C is chemically and physically stable for 64 days, with 95% confidence. The syringe may be held at room temperature for up to 24 hours during this period and still retain more than 90% of the initial concentration.

Physiochemical and Microbiological Stability of Azathioprine Suspensions in PCCA Base, SuspendIt.

Azathioprine is used to treat the symptoms of rheumatoid arthritis and for the prevention of transplant rejection. A review of the therapeutic uses of Azathioprine reveals the need for flexibility in dosing. This flexibility is readily achieved using an oral liquid dosage form. However, no commercial liquid dosage form of Azathioprine currently exists. Azathioprine is commercially available only as a 50-mg tablet. An extemporaneously compounded suspension from pure drug powder would provide a flexible, customizable option to meet unique patient needs with convenient and accurate dosing options. The purpose of this study was to determine the physicochemical and microbiological stability of extemporaneously compounded Azathioprine suspensions in the PCCA Base, SuspendIt. This base is a sugar-free, paraben free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. The study design included two Azathioprine concentrations to provide stability documentation over a bracketed concentration range for eventual use by compounding pharmacists. A robust stability-indicating high-performance liquid chromatographic assay for the determination of the chemical stability of Azathioprine in PCCA SuspendIt was developed and validated. Suspensions of Azathioprine were prepared in PCCA SuspendIt at 10-mg/mL and 50-mg/mL concentrations, selected to represent a range within which the drug is commonly dosed. Samples were stored in amber plastic prescription bottles at two temperature conditions (5°C and 25°C). Samples were assayed initially, and on the following time points (days): 7, 14, 28, 49, 63, 90, 119, and 182. Physical data such as pH, viscosity, and appearance were also noted. Microbiological stability was tested. All measurements were obtained in triplicate. A stable extemporaneous product is defined as one that retains at least 90% of the initial drug concentration throughout the sampling period and is protected against microbial growth. The study showed that Azathioprine concentrations did not go below 96.8% of the label claim (initial drug concentration) at both temperatures studied. No microbial growth was observed. The pH values remained constant. The viscosity of the suspensions allowed easy re-dispersal of the drug particles upon shaking. This study demonstrates that Azathioprine is physically, chemically, and microbiologically stable in PCCA SuspendIt for 182 days in the refrigerator and at room temperature, thus providing a viable, compounded alternative for Azathioprine in a liquid dosage form, with an extended beyond-use date to meet patient needs.

Graphene Hollow Micropatterns via Capillarity-Driven Assembly for Drug Storage and Neural Cell Alignment.

Electrical conductivity, cell-guided surface topology, and drug storage capacity of biomaterials are attractive properties for the repair and regeneration of anisotropic tissues with electrical sensitivity, such as nerves. However, designing and fabricating implantable biomaterials with all these functions remain challenging. Herein, we developed a freestanding graphene substrate with micropatterned surfaces by a simple templating method. Importantly, the raised surface micropatterns had an internal hollow structure. The morphology results showed that the template microgroove width and the graphene nanosheet size were important indicators of the formation of the hollow structures. Through real-time monitoring and theoretical analysis of the formation process, it was found that the main formation mechanism was the delamination and interlayer movement of the graphene nanosheets triggered by the evaporation-induced capillary force. Finally, we achieved the controlled release of loaded microparticles and promoted the orientation of rat dorsal root ganglion neurons by applying an electric field to the hollow micropatterns. This capillarity-induced self-assembly strategy paves the way for the development of high-performance graphene micropatterned films with a hollow structure that have potential for clinical application in the repair of nerve injury.

Technical note: estimating longer drug shelf-life with reliability plotting.

A graphical plot of drug stability-study data can be extrapolated to estimate the drug's percent degradation and therefore its shelf-life beyond the time period of the study. However, after a statistical confidence limit is applied, that shelf-life estimate is significantly reduced. Such a reduction can be minimized by transforming the data so that it plots as close as possible to linearity, a process that is called reliability plotting. Reliability plotting seems to have been rarely if ever used on drug stability data, despite its being mentioned in relevant guidance documents and its ability to justify longer shelf-life at no additional cost. For example, an 18-month stability study resulted in a 19-month shelf-life using standard extrapolation methods but resulted in a 23 month shelf-life using reliability plotting.

Stability of Opened Durvalumab (IMFINZI) Vials. The Beginning of the End of Costly Product Wastage?

Durvalumab is a monoclonal antibody approved for the treatment of lung, urothelial and biliary tract cancers. Durvalumab is supplied in vials as a solution containing no preservatives. Monographs recommend single use of durvalumab vials, and that any leftovers be discarded within 24 h. Thus, significant portions of unused product from opened vials are wasted on a daily basis, generating considerable financial losses. The objective of the present study was to assess the physicochemical and microbiological stability of durvalumab vials kept at 4 °C or room temperature, at 7 and 14 days after opening. Following pH and osmolality measurements, turbidity and submicronic aggregation of durvalumab solution were evaluated by spectrophotometry and dynamic light scattering, respectively. Moreover, steric exclusion high performance liquid chromatography (SE-HPLC), ion exchange HPLC (IEX-HPLC) and peptide mapping HPLC were used to respectively assess aggregation/fragmentation, charge distribution and primary structure of durvalumab. Microbiological stability of durvalumab was evaluated by incubation of vial leftovers on blood agar. All experiments showed physicochemical and microbiological stability of durvalumab vial leftovers for at least 14 days when aseptically handled and kept at either 4 °C or at room temperature. These results suggest the possible extension of utilization of durvalumab vial leftovers well beyond 24 h.

A universal tool for stability predictions of biotherapeutics, vaccines and in vitro diagnostic products.

It is of particular interest for biopharmaceutical companies developing and distributing fragile biomolecules to warrant the stability and activity of their products during long-term storage and shipment. In accordance with quality by design principles, advanced kinetic modeling (AKM) has been successfully used to predict long-term product shelf-life and relies on data from short-term accelerated stability studies that are used to generate Arrhenius-based kinetic models that can, in turn, be exploited for stability forecasts. The AKM methodology was evaluated through a cross-company perspective on stability modeling for key stability indicating attributes of different types of biotherapeutics, vaccines and biomolecules combined in in vitro diagnostic kits. It is demonstrated that stability predictions up to 3 years for products maintained under recommended storage conditions (2-8 °C) or for products that have experienced temperature excursions outside the cold-chain show excellent agreement with experimental real-time data, thus confirming AKM as a universal and reliable tool for stability predictions for a wide range of product types.