An Overview of Degradation Strategies for Amitriptyline.

Antidepressant drugs play a crucial role in the treatment of mental health disorders, but their efficacy and safety can be compromised by drug degradation. Recent reports point to several drugs found in concentrations ranging from the limit of detection (LOD) to hundreds of ng/L in wastewater plants around the globe; hence, antidepressants can be considered emerging pollutants with potential consequences for human health and wellbeing. Understanding and implementing effective degradation strategies are essential not only to ensure the stability and potency of these medications but also for their safe disposal in line with current environment remediation goals. This review provides an overview of degradation pathways for amitriptyline, a typical tricyclic antidepressant drug, by exploring chemical routes such as oxidation, hydrolysis, and photodegradation. Connex issues such as stability-enhancing approaches through formulation and packaging considerations, regulatory guidelines, and quality control measures are also briefly noted. Specific case studies of amitriptyline degradation pathways forecast the future perspectives and challenges in this field, helping researchers and pharmaceutical manufacturers to provide guidelines for the most effective degradation pathways employed for minimal environmental impact.

Drug-Modified Contact Lenses-Properties, Release Kinetics, and Stability of Active Substances with Particular Emphasis on Cyclosporine A: A Review.

The following review focuses on the manufacturing and parameterizing of ocular drug delivery systems (DDS) using polymeric materials to create soft contact lenses. It discusses the types of drugs embedded into contact lenses, the various polymeric materials used in their production, methods for assessing the mechanical properties of polymers, and techniques for studying drug release kinetics. The article also explores strategies for investigating the stability of active substances released from contact lenses. It specifically emphasizes the production of soft contact lenses modified with Cyclosporine A (CyA) for the topical treatment of specific ocular conditions. The review pays attention to methods for monitoring the stability of Cyclosporine A within the discussed DDS, as well as investigating the influence of polymer matrix type on the stability and release of CyA.

Chemical Stability of Lorazepam Oral Solution Repackaged in Plastic Oral Syringes at Room and Refrigerated Temperature.

Purpose: Generic lorazepam oral solution is supplied in a 30 mL multi-dose bottle requiring protection from light and refrigeration, with a beyond use date of 90 days once the bottle is opened. The repackaging of 1 mL doses of lorazepam oral solution into oral syringes allows for facilitated dispensing, yet no available data supports repackaging and storing lorazepam oral solution in syringes. The validation and application of a stability-indicating high-performance liquid chromatography with ultraviolet detection (HPLC-UV) method for the quantification of lorazepam allowed for the determination of the stability of lorazepam oral solution when stored in oral syringes. Methods: A stability-indicating HPLC-UV method was developed for the quantification of lorazepam in oral solution. The method was validated using guidance from USP < 1225 >. For the stability investigation, 2 mg/mL lorazepam oral solution was aliquoted into clear plastic oral syringes in 1 mLmilliliter doses from 2 multi-dose stock bottles and randomly allocated for storage in room temperature or refrigerated environment. Baseline lorazepam concentrations were measured on the day the study was initiated and designated as 100% initial concentration samples. Subsequent samples were analyzed in triplicate at time points of 24, 48, and 96 hours and 7, 10, 14, 21, 30, and 60 days. Results: The calibration curves on three non-consecutive days met the linearity criteria of R 2 > 0.99. Inter- day and intra-day precision and accuracy (percent relative standard deviation and percent error) were ≤2% over three days. During the stability investigation, percent initial concentration of lorazepam from room and refrigerated syringes remained above 90% for the duration of the study. Conclusion: The stability-indicating HPLC-UV method was successfully applied to the investigation of lorazepam oral solution stability when stored in syringes at room and refrigerated temperatures. The emergent need for use of lorazepam concentrate for inpatients and the restrictions of how the medication is supplied necessitated a need for the evaluation of repackaging into unit dose syringes for immediate availability from automated dispensing cabinets. Lorazepam oral solution stored in clear plastic syringes maintained greater than 90% initial concentration at both room and refrigerated temperatures for 60 days.

Mitigating Drug Stability Challenges Through Cocrystallization.

Drug stability plays a significant role in the pharmaceutical industry from early-phase drug discovery to product registration as well as the entire life cycle of a product. Various formulation approaches have been employed to overcome drug stability issues. These approaches are sometimes time-consuming which ultimately affect the timeline of the product launch and may further require formulation optimization steps, affecting the overall cost. Pharmaceutical cocrystal is a well-established route to fine tune the biopharmaceutical properties of drugs without covalent modification. This article highlights the role of cocrystallization in mitigating the stability issues of challenging drug molecules. Representative case studies wherein the drug stability issue is addressed through pharmaceutical cocrystals have been discussed briefly and are summarized in tabular form. The emphasis has been made on the structural information of cocrystals and understanding the mechanism that improves the stability of the parent drug through cocrystallization. Besides, a guided strategy has been proposed to modulate the stability of drug molecules through cocrystallization approach. Finally, the stability concern of fixed-dose or drug combinations and the challenges associated with cocrystals are also touched.

In Vitro Assessment of Compounded Lurasidone Suspensions for Enteral Feeding Tubes.

Purpose: Extemporaneously compounded drug suspensions are often necessary for patients who are intubated or receiving nutrition through enteral feeding tubes. Lurasidone is a relatively new antipsychotic medication available only as oral tablets (Latuda®), and there is no data to support its use in this patient population as a compounded liquid formulation. This study was designed to assess the feasibility of preparing lurasidone suspensions from tablets and their compatibility with enteral feeding tubes. Methods: Representative nasogastric tubes were selected for this study, including polyurethane, polyvinylchloride, and silicone tubes with a range of 8 to 12 Fr (2.7-4.0 mm) in diameter and 35 to 55″ in length. Two strengths of lurasidone suspensions, 1 and 8 mg/mL, were prepared by the standard mortar-pestle method. Latuda® tablet 120 mg was used as the drug source, and a 1:1 mixture of Ora-Plus®:water was used as the suspension vehicle. The drug suspensions were delivered through the tubes mounted on a peg board to simulate patient position in a hospital bed. The ease of administration through the tubes was evaluated visually. The drug concentration before and after the tube delivery was analyzed by high performance liquid chromatography (HPLC). In addition, a 14-day stability study of the compounded suspensions was performed at room temperature to support the beyond-use dating. Results: Freshly prepared lurasidone suspensions, 1 and 8 mg/mL, met the potency and uniformity requirements. Both strengths of suspensions exhibited satisfactory flowability through all the tube types studied with no signs of clogging. The HPLC results confirmed that greater than 97% of drug concentration was retained after tube delivery. During the 14-day stability study, the suspensions retained greater than 93% of their original concentration. There was no significant change in pH or visual appearance. Conclusions: The study demonstrated a practical procedure to prepare 1 and 8 mg/mL lurasidone suspensions that are compatible with commonly used enteral feeding tube materials and dimensions. A beyond-use date of 14-day was established for the suspensions stored at room temperature.

Extended Stability of Isoproterenol Hydrochloride Injection in Polyvinyl Chloride Bags Stored in Amber Ultraviolet Light Blocking Bags.

Purpose:Evaluate the stability of isoproterenol hydrochloride injection in 0.9% sodium chloride in polyvinyl chloride bags for up to 90 days. Methods: Dilutions of isoproterenol hydrochloride injection to a concentration of 4 µg/mL were performed under aseptic conditions. The bags were stored in amber ultraviolet light blocking bags at room temperature (23°C-25°C) or under refrigeration (3°C-5°C). Three samples of each preparation and storage environment were analyzed on days 0, 2, 14, 30, 45, 60, and 90. Physical stability was performed by visual examination. The pH was assessed at baseline, each analysis day, and upon final degradation evaluation. Sterility of the samples was not assessed. Chemical stability of isoproterenol hydrochloride was evaluated using liquid chromatography with tandem mass spectrometry. Samples were considered stable if there was <10% degradation of the initial concentration. Results: Isoproterenol hydrochloride diluted to 4 µg/mL with 0.9% sodium chloride injection was physically stable throughout the study. No precipitation was observed. At days 2, 14, 30, 45, 60, and 90 all bags diluted to 4 µg/mL had <10% degradation when stored under refrigeration (3°C-5°C) or stored at room temperature (23°C-25°C). Conclusion: Isoproterenol hydrochloride diluted to a concentration of 4 µg/mL with 0.9% sodium chloride for injection in ultraviolet light blocking bags was stable for 90 days at room temperature and under refrigeration.

Extended Stability of Vasopressin Injection in Polyvinyl Chloride Bags and Polypropylene Syringes and Its Impact on Critically Ill Patient Care and Medication Waste.

Background. Vasopressin is frequently utilized for a variety of shock states in critically ill patients. Short stability (≤24 hours) after intravenous admixture with current manufacturer labeling requires just in time preparation and may lead to delays in therapy and increased medication waste. We aimed to evaluate vasopressin stability in 0.9% sodium chloride stored in polyvinyl chloride bags and polypropylene syringes for up to 90 days. Additionally, we evaluated the impact of extended stability on the time to administration and cost savings from reduced medical waste at an academic medical center. Methods. Dilutions of vasopressin to concentrations of 0.4 and 1.0 unit/mL were performed under aseptic conditions. The bags and syringes were stored at room temperature (23°C-25°C) or under refrigeration (3°C-5°C). Three samples of each preparation and storage environment were analyzed on days 0, 2, 14, 30, 45, 60, and 90. Physical stability was performed by visual examination. The pH was assessed at each point and upon final degradation evaluation. Sterility of the samples was not assessed. Chemical stability of vasopressin was evaluated using liquid chromatography with tandem mass spectrometry. Samples were considered stable if there was <10% degradation of the initial concentration. Results. Vasopressin diluted to 0.4 and 1.0 unit/mL with 0.9% sodium chloride injection was physically stable throughout the study. No precipitation was observed. At days 2, 14, 30, 45, 60, and 90 all bags and syringes diluted to 0.4 units/mL had <10% degradation. Vasopressin diluted to 1 unit/mL and stored under refrigeration had <10% degradation at all measured days, but when stored under room temperature was found to have >10% degradation at day 30. Implementation of a batching process resulted in reduced waste ($185 300) and improved time to administration (26 vs 4 minutes). Conclusion. Vasopressin diluted to a concentration of 0.4 units/mL with 0.9% sodium chloride injection is stable for 90 days at room temperature and under refrigeration. When diluted to 1.0 unit/mL with 0.9% sodium chloride injection it is stable for 90 days under refrigeration. Use of extended stability and sterility testing to batch prepare infusions may lead to improved time to administration and cost savings from reduced medication waste.

Surrounded by ligands: the reactivity of cisplatin in cell culture medium.

The reactivity of platinum-containing drugs such as cisplatin, carboplatin, and oxaliplatin is essential for its mechanism of action as an anticancer agent. This inherent reactivity means that molecules in tools used to study these metal-based drugs such as solvents (DMSO), cell culture media, and other buffer additives can ligate to and inactivate or activate them. This Commentary considers these cautionary tales in the context of a new report that cisplatin can also react with penicillin, reiterates best practice in creating Pt drug stock solutions, and highlights the significant work that remains to fully characterize the fate of cisplatin in cell culture media.

Vehicles for Drug Administration to Children: Results and Learnings from an In-Depth Screening of FDA-Recommended Liquids and Soft Foods for Product Quality Assessment.

PURPOSE: Mixing with liquids or soft foods is a common procedure to improve acceptability of oral medicines in children but may affect drug stability and the in vivo performance of the administered drug product. The aim of the present study was to obtain an overview of the variability of critical attributes of commonly used vehicles and to identify which vehicle characteristics need to be considered when developing in vitro methods for evaluating product quality. METHODS: One product of each vehicle listed in the FDA draft guidance "Use of Liquids and/or Soft Foods as Vehicles for Drug Administration" was analyzed with regard to composition, calorific content and physicochemical properties. RESULTS: The studied vehicles show wide variability, both in composition and physicochemical properties. No correlation was observed between vehicle composition and physicochemical properties. Comparison of results of the present study with previously published data also provided variability in physicochemical properties within individual vehicle types. CONCLUSIONS: To identify acceptable (qualified) vehicles for global drug product labeling, it is important that the vehicles selected for in vitro compatibility screening reflect the variability in composition and essential physicochemical properties of the vehicles recommended on the product label, rather than relying on results obtained with a single vehicle of each type. Future activities will focus on the development of standardized dosing vehicles that can represent key vehicle characteristics in all their variability to ensure reliable risk assessment.

Compatibility and stability of an admixture of multiple anaesthetic drugs for opioid-free anaesthesia.

The ability to combine and use drugs in a single infusion device may be useful in resource-limited settings. This study examined the chemical stability of an opioid-sparing mixture of ketamine, lidocaine and magnesium sulphate when combined in a single syringe. High-performance liquid chromatography and atomic absorption spectrophotometry were performed on six syringes containing the three-drug mixture. Since most opioid-sparing techniques typically rely on a 24-hour infusion regime, we tested stability at the initial admixing and 24 hours later. Stability was defined as a measured drug concentration within 10% of expected, with the absence of precipitation or pH alterations. Pharmacokinetic simulations were conducted to further show that the achieved plasma drug concentrations were well within an effective analgesic range. All mixed drug concentration measurements were within the required 10% reference limit. No obvious precipitation or interaction occurred, and pH remained stable. Drug stability was maintained for 24 hours. Pharmacokinetic simulations showed that ketamine and lidocaine were within their minimum analgesic effect concentrations. Our results show that this three-drug mixture is chemically stable for up to 24 hours after mixing, with a pharmacokinetic simulation illustrating safe, clinically useful predicted plasma concentrations when using the described admixture.

Interaction of letrozole and its degradation products with aromatase: chemometric assessment of kinetics and structure-based binding validation.

Letrozole is one of the most prescribed drugs for the treatment of breast cancer in post-menopausal women, and it is endowed with selective peripheral aromatase inhibitory activity. The efficacy of this drug is also a consequence of its long-lasting activity, likely due to its metabolic stability. The reactivity of cyano groups in the letrozole structure could, however, lead to chemical derivatives still endowed with residual biological activity. Herein, the chemical degradation process of the drug was studied by coupling multivariate curve resolution and spectrophotometric methodologies in order to assess a detailed kinetic profile. Three main derivatives were identified after drug exposure to different degradation conditions, consisting of acid-base and oxidative environments and stressing light. Molecular docking confirmed the capability of these compounds to accommodate into the active site of the enzyme, suggesting that the sustained inhibitory activity of letrozole may be at least in part attributed to the degradation compounds.

Anticancer Drugs: Recent Strategies to Improve Stability Profile, Pharmacokinetic and Pharmacodynamic Properties.

In past decades, anticancer research has led to remarkable results despite many of the approved drugs still being characterized by high systemic toxicity mainly due to the lack of tumor selectivity and present pharmacokinetic drawbacks, including low water solubility, that negatively affect the drug circulation time and bioavailability. The stability studies, performed in mild conditions during their development or under stressing exposure to high temperature, hydrolytic medium or light source, have demonstrated the sensitivity of anticancer drugs to many parameters. For this reason, the formation of degradation products is assessed both in pharmaceutical formulations and in the environment as hospital waste. To date, numerous formulations have been developed for achieving tissue-specific drug targeting and reducing toxic side effects, as well as for improving drug stability. The development of prodrugs represents a promising strategy in targeted cancer therapy for improving the selectivity, efficacy and stability of active compounds. Recent studies show that the incorporation of anticancer drugs into vesicular systems, such as polymeric micelles or cyclodextrins, or the use of nanocarriers containing chemotherapeutics that conjugate to monoclonal antibodies can improve solubility, pharmacokinetics, cellular absorption and stability. In this study, we summarize the latest advances in knowledge regarding the development of effective highly stable anticancer drugs formulated as stable prodrugs or entrapped in nanosystems.

Stability Studies of UV Laser Irradiated Promethazine and Thioridazine after Exposure to Hypergravity Conditions.

Pharmaceuticals carried into space are subjected to different gravitational conditions. Hypergravity is encountered in the first stage, during spacecraft launching. The stability of medicines represents a critical element of space missions, especially long-duration ones. Therefore, stability studies should be envisaged before the implementation of drugs for future deep space travel, where the available pharmaceuticals would be limited and restocking from Earth would be impossible. Multipurpose drugs should be proposed for this reason, such as phenothiazine derivatives that can be transformed by optical methods into antimicrobial agents. Within this preliminary study, promethazine and thioridazine aqueous solutions were exposed to UV laser radiation that modified their structures and generated a mixture of photoproducts efficient against particular bacteria. Subsequently, they were subjected to 20 g in the European Space Agency's Large Diameter Centrifuge. The aim was to evaluate the impact of hypergravity on the physico-chemical and spectral properties of unirradiated and laser-irradiated medicine solutions through pH assay, UV-Vis/FTIR absorption spectroscopy, and thin-layer chromatography. The results revealed no substantial alterations in centrifuged samples when compared to uncentrifuged ones. Due to their stability after high-g episodes, laser-exposed phenothiazines could be considered for future space missions.

Opioid-Free Anesthesia: Physico Chemical Stability Studies on Multi-Analyte Mixtures Intended for Use in Clinical Anesthesiology.

Objectives: Opioid-free anesthesia is used increasingly often in hospitals around the world. In this type of anesthesia, opioids are replaced by other analgesics, such as ketamine, lidocaine, dexmedetomidine, and magnesium sulfate. Many clinicians prepare these agents as dual, triple, or quadruple admixtures within a single syringe. However, data on the stability of the individual substances within these preparations over time and in different storage conditions is very limited. Here, we aim to investigate various admixture of dexmedetomidine, ketamine, lidocaine, and magnesium sulfate with respect to the stability of the individual agents over time at different storage conditions. Methods: An ultra-high performance liquid chromatography method coupled to mass spectrometric detection was developed and validated to determine the stability of lidocaine, ketamine, and dexmedetomidine. Quantification of magnesium was carried out in parallel by potentiometric titration. Results: Our results demonstrate the stability of dual, triple or quadruple mixtures of selected substances in 0.9% saline under different storage conditions. Under all conditions, analyzed admixtures remain stable for at least 8 weeks. The quadruple mixture of lidocaine, ketamine, dexmedetomidine, and magnesium sulfate was storable for as long as 148 days without a significant loss of analyte. Conclusion: A new chromatographic method was successfully developed to analyze the stability of various pharmacological agents commonly used by clinicians in opioid-free anesthesia. The data we obtained indicate that mixing these agents together in a single syringe is safe and reliable and suggest that hospital pharmacies may prepare these solutions in advance of planned surgeries.

The effect of temperature on the stability of PCSK-9 monoclonal antibody: an experimental study.

BACKGROUND: PCSK9 monoclonal antibody lowers plasma PCSK9 and LDL-cholesterol levels. The manufacturers recommend drug storage at 2-8 °C, and not above 25 °C. This study aimed to investigate drug stability at various temperatures that this drug could be exposed to during medication handling and transportation in tropical countries. METHODS: Alirocumab and evolocumab were tested in 3 study conditions: room temperature (RT), cooler device with cold pack, and freeze-thaw for 9 and 18 h. Heated drugs were used as negative control. Free plasma PCSK9 levels from 9 hyperlipidemia subjects were measured with ELISA. RESULTS: Average subject age was 49.2 ± 18.4 years. Percent PCSK9 inhibition significantly declined in heated drugs compared to baseline. Average RT during the study period was 30.4 ±2.6 °C. Change in percent PCSK9 inhibition of PCSK9 mAb at RT from baseline was - 5.8 ± 4.4% (P = 0.005) and - 11.0 ± 8.9% (P = 0.006) for alirocumab at 9 h and 18 h, and - 9.7 ± 11.8% (P = 0.04) and - 15.1 ± 14.3% (P = 0.01) for evolocumab at 9 and 18 h, respectively. In contrast, there were no significant changes in percent PCSK9 inhibition from baseline when PCSK9 mAb was stored in a cooler. In freeze-thaw condition, changes in percent PCSK9 inhibition from baseline to 9 and 18 h were - 5.2 ± 2.9% (P = 0.001) and - 2.6 ± 4.9% (P = 0.16) for alirocumab, and - 1.8 ± 4.2% (P = 0.24) and 0.4 ± 6.1% (P = 0.83) for evolocumab. CONCLUSION: Proper drug storage according to manufacturer's recommendation is essential. Drug storage at RT in tropical climate for longer than 9 h significantly decreased drug efficacy; however, storage in a cooler device with cold pack for up to 18 h is safe.

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

BACKGROUND: Temozolomide oral suspension is not commercially available. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: We recommend that these temozolomide 10 mg/mL formulations be stored at 4°C and be assigned a beyond-use-date of 30 days.

Stability of calcium levofolinate reconstituted in syringes and diluted in NaCl 0.9% and glucose 5% polyolefin/polyamide infusion bags.

PURPOSE: Calcium levofolinate (CaLev) for intravenous administration is commercially available as a powder that must be reconstituted for injection or reconstituted and then diluted before administration. The lack of stability data on CaLev solutions renders necessary extemporaneous manual preparation, preventing the use of automated/semi-automated systems, with a consequent loss in terms of quality and safety. METHODS: The present work assessed the chemical-physical and microbiological stability of CaLev prepared in sodium chloride 0.9%, glucose 5% and water for injections and stored in polyolefin/polyamide bags and polypropylene syringes at 2-8°C protected from light. For this purpose, we developed and validated a new rapid High Performance Liquid Chromatography with Ultra Violet Diode-Array Detection (HPLC-UV-DAD) method. RESULTS: The samples tested were stable for 14 days, retaining >95% of their initial concentration and showing no change in colour, turbidity or pH. Microbiological tests performed on the samples were negative. CONCLUSIONS: Our results confirmed the analytical stability of CaLev in NaCl 0.9%, glucose 5% and water for injection at concentrations used in clinical practice at our institute. This enables our centralized laboratory to organize the preparation of this drug in advance and the use of robots rather than manual preparation reduces the workload and the risk of preparation errors.

Stability of Antimicrobial Drug Molecules in Different Gravitational and Radiation Conditions in View of Applications during Outer Space Missions.

The evolution of different antimicrobial drugs in terrestrial, microgravity and hypergravity conditions is presented within this review, in connection with their implementation during human space exploration. Drug stability is of utmost importance for applications in outer space. Instabilities may be radiation-induced or micro-/hypergravity produced. The antimicrobial agents used in space may have diminished effects not only due to the microgravity-induced weakened immune response of astronauts, but also due to the gravity and radiation-altered pathogens. In this context, the paper provides schemes and procedures to find reliable ways of fighting multiple drug resistance acquired by microorganisms. It shows that the role of multipurpose medicines modified at the molecular scale by optical methods in long-term space missions should be considered in more detail. Solutions to maintain drug stability, even in extreme environmental conditions, are also discussed, such as those that would be encountered during long-duration space exploratory missions. While the microgravity conditions may not be avoided in space, the suggested approaches deal with the radiation-induced modifications in humans, bacteria and medicines onboard, which may be fought by novel pharmaceutical formulation strategies along with radioprotective packaging and storage.

Stability screening of pharmaceutical cocrystals.

An efficient protocol for assessing both the chemical and physical stability of cocrystalline forms of active pharmaceutical ingredients (APIs) is proposed. In this protocol, the cocrystalline material is used to prepare two standard formulations, mimicking wet granulations, to make low-dose tablets. After designed stress testing at a range of temperatures and RH conditions, degradant formation is modeled from the data using ASAPprime® to determine if the tablets have a minimum of a one-year shelf-life (25 °C/60% RH open). When the cocrystals provide a kinetic solubility enhancement over the un-complexed API, a physical assessment of the cocrystal stability is carried out using the same tablets at selected stress conditions. For this assessment, kinetic solubility (where the amount of buffer used to dissolve the tablet is adjusted to completely dissolve the cocrystalline form but leave most of the un-complexed form out of solution) changes are used to indicate whether there is a significant risk for physical instability on long-term storage. This process was exemplified using model cocrystals of APIs.

Stability of Ampicillin in Normal Saline Following Refrigerated Storage and 24-Hour Pump Recirculation.

OBJECTIVE: Use of ampicillin in outpatient parenteral antimicrobial therapy (OPAT) has historically been complicated by frequent dosing and limited stability. The purpose of this study was to evaluate stability of ampicillin using high-pressure liquid chromatography (HPLC) in an OPAT dosing model using continuous infusion at room temperature over 24 hours immediately following preparation compared with batches stored under refrigeration for 24 hours, 72 hours, and 7 days. METHODS: An HPLC method was developed and validated as stability indicating using guidance in USP general Chapter <1225>. Four ampicillin batches were prepared for each experimental condition (immediate use and refrigerated storage for 24 hours, 72 hours, and 7 days). A pump was used to recirculate the solutions through medical-grade tubing for 24 hours. Triplicate 1-mL aliquots were removed from each batch at time 0, 4, 8, 12, and 24 hours and analyzed for ampicillin concentration. RESULTS: Each batch was assayed for initial concentration (20.34-21.50 mg/mL), and percent recovery compared with that concentration thereafter. For the duration of infusion, the average recoveries were 96.4%, 95.8%, 94.6%, and 90.3% for immediate use, 24-hour storage, 72-hour storage, and 7-day storage, respectively. The recovery remained above 90% for all batches and time points, except for 7-day storage, which fell below 90% after 4 hours of circulation. CONCLUSION: Ampicillin can be prepared and stored in a refrigerator for up to 72 hours prior to continuously infusing at room temperature over 24 hours with less than a 10% loss of potency over the dosing period. This model supports twice weekly OPAT delivery of ampicillin.