Stability Evaluation of Bracketed Diclofenac Sodium USP in VersaPro™ Cream Base, VersaPro™ Gel Base and PLO Gel Mediflo™ 30 Compound Kit.

Diclofenac Sodium is a nonsteroidal anti-inflammatory drug (NSAID) that has analgesic, anti-inflammatory, and antipyretic properties, and has been found to be effective in treating a variety of acute and chronic pain and inflammatory conditions. A stability study was designed to assess the physical, chemical, and antimicrobial stability of three extemporaneously compounded bracketed Diclofenac Sodium formulations over time using a validated, stability indicating HPLC method. Diclofenac Sodium 1% and 15% were compounded in Medisca VersaPro™ Cream Base, VersaPro™ Gel Base and PLO Gel Mediflo™30 Compound Kit and stored at room temperature, in tightly closed, light resistant, plastic containers for 180 days. The organoleptic properties, pH, viscosity, and Diclofenac Sodium concentration of each formulation were evaluated at predetermined time points. Antimicrobial effectiveness testing of the compounded formulation according to USP <51> was also evaluated at the initial time point and after 180 days. The results demonstrated that all formulations remained within the specified stability criteria for the duration of the study. Therefore, an extended beyond-use-date of 180 days may be assigned to these compounded formulations under the studied conditions.

Y-site simulation compatibility study of 10% calcium salts with various injectable solutions during toxicological resuscitation.

PURPOSE: To determine the physical compatibility of 10% calcium chloride and 10% calcium gluconate in combination with injectable solutions, administered in the paediatric and adult intensive care unit setting during toxicological resuscitation involving calcium channel blockers and beta-blockers. METHODS: Forty-eight combinations were prepared at room temperature, including the following products: calcium chloride, calcium gluconate, insulin, epinephrine, norepinephrine, highly concentrated dextrose solution, sodium chloride, Plasma-Lyte A and Ringer's lactate. A visual evaluation at times 0, 1, 4, 24, 48 and 72 hours and a particle count test with the LS-20 particle counter at times 0, 4, 24 and 72 hours were performed. The admixtures were considered incompatible if there was a precipitate, a colour change, turbidity, viscosity or a gas formation. The stability of calcium salts was also tested in empty IV bags and syringes by the particle count test. RESULTS: All drug mixtures were found to be compatible by visual evaluation and using the particle counter based on United States Pharmacopoeia chapter 788 (USP<788>) specifications. Calcium salts were compatible with insulin and vasopressors in the tested combinations. The stability of 10% calcium salts in empty IV bags and polypropylene syringes was demonstrated for up to 48 hours at room temperature. CONCLUSION: All the combinations tested were physically compatible for up to 72 hours at room temperature. Clinical use of calcium salt infusions, at an undiluted concentration, in combination with these injectable solutions in a toxicological resuscitation context is considered clinically acceptable.

Stability evaluation of compounded hydroxyurea 100 mg/mL oral liquids using a novel analytical method involving chemical derivatization.

This study assessed the stability of six extemporaneously compounded hydroxyurea oral liquids stored at room temperature. Hydroxyurea oral liquids (100 mg/mL) were prepared using three different mixing methods (mortar, mixer or QuartetRx) from either bulk powder, capsule content, or whole capsules. Two brands of capsules were tested in this study. All formulations were stored at room temperature (25°C / 60% RH) in amber plastic bottles for 90 days and amber plastic syringes for 14 days. Physical stability was assessed visually, while chemical stability was evaluated using a stability-indicating high-performance liquid chromatography method. Chemical derivatization with xanthydrol allowed the retention of hydroxyurea on a reverse-phase column. At least 93.9% and 97.0% of the initial concentration of hydroxyurea remained after 90 days in bottles and 14 days in syringes, respectively. There were no visual changes in formulations over the study period. Changes in pH up to 1.6 units were observed after 90 days of storage and were explained most likely by an ammonium generating degradation pathway. Ammonium was quantified and remained within safe levels in each HU 100 mg/mL oral preparations. Hydroxyurea oral liquids were all stable for 90 days in amber plastic bottles and 14 days in amber plastic syringes.

Stability of Compounded Digoxin Solution 0.05 mg/mL for Injection.

Background: In 2015, commercial pediatric digoxin injection 0.05 mg/mL was discontinued, leaving only one adult concentration (0.25 mg/mL) for injection on the Canadian market. No published studies have documented the chemical stability over a long period of time of a diluted solution of digoxin for injection. Objective: The aim of this study was to assess the chemical stability of 2 digoxin injection formulations 0.05 mg/mL diluted in 2 vehicles stored at 5°C or a 25°C. Methods: The compounded solution of digoxin 0.05 mg/mL for injection was prepared with digoxin 0.25 mg/mL after dilution in 2 different vehicles, normal saline, and a compounding of the commercial vehicle. Half of the compounding products were stored in 2 mL transparent glass vials at 25°C and the other half at 5°C. Chemical stability was evaluated by HPLC-UV analysis on days 0, 14, 30, 60, 90, 120, 150, 180 for each temperature conditions. In addition, samples were tested for organoleptic change, presence of particular matter as well as sterility. Results: For all tested preparations, the concentration of digoxin remained above 90.0% of the initial concentration throughout the 180-day study. Furthermore, no organoleptic change was observed; particulate matter assessment was in acceptable range; and sterility specifications were met. Conclusions: Digoxin 0.05 mg/mL obtained with a dilution of digoxin 0.25 mg/mL by normal saline or a copy of the commercial vehicle remained stable for at least 180 days at 5°C and 25°C.

Stability evaluation of compounded clonidine hydrochloride oral liquids based on a solid-phase extraction HPLC-UV method.

The present study aimed to assess the stability of clonidine hydrochloride oral liquids (20-µg/mL) prepared from two different generic tablets in Ora-Blend and stored in amber plastic bottles. Physical and chemical stabilities were evaluated over a period of 90 days at 25°C. Analytical challenges were overcome with the development of a new extraction procedure based on solid phase extraction to ensure efficient clonidine hydrochloride quantification. The absence of physical instabilities, evaluated by qualitative and quantitative measurements (static multiple light scattering), as well as the absence of chemical instabilities, evidenced by a stability-indicating HPLC-UV method, confirmed that a beyond-use date of 90 days was appropriate for these compounded oral liquids.

Compatibility of Lactated Ringer's Injection With 94 Selected Intravenous Drugs During Simulated Y-site Administration.

Objective: To test the compatibility of intravenous (IV) lactated Ringer's injection (LR) with 94 injectable (IV) drugs during simulated Y-site administration. Methods: Ninety-four IV drugs were investigated for compatibility with LR (Baxter). Each sample was prepared in duplicate and performed at room temperature. Two observers performed visual evaluation independently immediately upon mixing and then 15 minutes, 1 hour, 2 hours, 3 hours, and 4 hours after admixture. Another observer performed a particle counting test on 1 of the 2 duplicates of each admixture that did not immediately show incompatibility and then after 4 hours by a light obscuration particle count test. Results: Of the 94 tested drugs, 86 were found to be compatible with LR. A total of 8 drugs were found to be physically incompatible. Of these incompatible drugs, 7 were directly identified visually and 1 was confirmed by the light obscuration particle count test. Conclusion: Lactated Ringer's injection was physically compatible for 4 hours with 86 tested drugs during simulated Y-site administration. Eight drugs, ciprofloxacin, cyclosporine, diazepam, ketamine, lorazepam, nitroglycerin, phenytoin, and propofol, were found to be incompatible and should not be administered with LR.

Stability of Extemporaneously Prepared Acetazolamide Oral Suspensions at Two Temperatures.

OBJECTIVES: Some drugs need to be compounded by the pharmacist before being administered to the patient. A study was conducted to determine the stability of acetazolamide suspensions in 2 different vehicles (Oral Mix and Oral Mix Sugar Free [SF]) from bulk drug and tablets at 2 different temperatures and in 2 different containers (amber plastic bottles and clear plastic syringes). METHODS: Acetazolamide suspensions (25 mg/mL) were prepared from bulk drug or tablets. Each suspension, using Oral Mix or Oral Mix SF, was split between 2 types of containers-amber plastic bottles and clear plastic syringes-and stored either at room temperature (23°C-27°C) or under refrigeration (3°C-7°C). Samples were drawn from the suspensions right after preparation and on days 7, 14, 30, 45, 60, 75, and 90. They were then analyzed by high-performance liquid chromatography (HPLC) using a reverse-phase column. A validated stability-indicating HPLC with ultraviolet detection method was developed. A visual inspection and a pH measurement were also completed at each time point. Stability was defined as retention of at least 90% of the initial concentration of acetazolamide suspension. RESULTS: At least 91.2% of the initial acetazolamide concentration in suspensions remained throughout the 90-day study period for both vehicles, both containers, and both temperatures. Assays varied between 91.2% and 105.0% of the initial concentration for all 112 tested conditions but 2 (105.2% and 109.0%). Linear regression was calculated for each time profile and remained above 95.0% at the end of the study in all cases. Similarly, pH remained within 0.1 unit of the initial pH, which was 4.2 for Oral Mix and 4.3 for Oral Mix SF. Furthermore, no changes in organoleptic properties were observed because the preparations remained as white fluid suspensions without sedimentation. CONCLUSIONS: Acetazolamide suspensions were stable for at least 90 days in all tested conditions because the average drug concentration was not less than 90% of the initial concentration. The beyond-use date could be extended from 60 to 90 days.

Validation of a stability-indicating HPLC-UV method for the quantification of acetazolamide in Oral-Mix and Oral-Mix SF.

This manuscript details the modifications made to the HPLC assay method described in the USP monograph for Acetazolamide Compounded Oral Suspension.•The method was modified to allow the quantification of acetazolamide in two new suspension vehicles: Oral Mix and Oral Mix SF;•It was validated for linearity, accuracy, precision and specificity;•It was demonstrated stability-indicating and suitable for use in a stability study using these vehicles.

Stability of gabapentin in extemporaneously compounded oral suspensions.

This study reports the stability of extemporaneously prepared gabapentin oral suspensions prepared at 100 mg/mL from bulk drug and capsules in either Oral Mix or Oral Mix SF suspending vehicles. Suspensions were packaged in amber plastic bottles and amber plastic syringes at 25°C / 60%RH for up to 90 days. Throughout the study period, the following tests were performed to evaluate the stability of the preparations: organoleptic inspection to detect homogeneity, color or odor changes; pH measurements; and gabapentin assay using a stability-indicating HPLC-UV method. As crystallization was observed at 5°C, storage at this temperature condition is not recommended. All preparations stored at 25°C / 60%RH remained stable for the whole study duration of 90 days.

Stability of Diazoxide in Extemporaneously Compounded Oral Suspensions.

The objective of this study was to evaluate the stability of diazoxide in extemporaneously compounded oral suspensions. Oral suspensions of diazoxide 10 mg/mL were prepared from either bulk drug or capsules dispersed in either Oral Mix or Oral Mix Sugar Free. These suspensions were stored at 5°C and 25°C/60%RH in bottles and oral syringes for a total of 90 days. At predetermined time intervals, suspensions were inspected for homogeneity, color or odor change; the pH was measured and the concentration of diazoxide was evaluated by ultraviolet detection using a stability-indicating high pressure liquid chromatography method. All preparations were demonstrated to be chemically stable for at least 90 days.

Novel self-assembled mesalamine-sucralfate complexes: preparation, characterization, and formulation aspects.

Two well-known active agents, mesalamine (MES) and sucralfate (SUC), were investigated for possible utilization as fixed-dose combination product. The anti-inflammatory action of MES in association with bioadhesiveness and mucosal healing properties of SUC were considered promising for the development of a new compound containing both molecules, aimed as an improved treatment of ulcerative colitis. The present study investigates the capacity of the two active agents to interact and generate a new and stable entity via self-assembling. Spray-drying was used to co-process the two active principles from an aqueous mixture where the ratio MES:SUC was in the range 25:75, 50:50, and 75:25. The structural data (X-Ray, FTIR, SEM, DSC, and (1)H NMR) have shown that MES and SUC are interacting leading to complexes with properties differing from those of each separate active agent and from their physical blends. (1)H NMR results indicated that complexation occurred when the aqueous suspensions of drugs were mixed, prior to spray-drying. Drug-drug self-assembling was the driving mechanism in the formation of the new entity. Based on the structural data, a hypothetical structure of the complex was proposed. Co-processing of MES and SUC represents a simple and useful procedure to prepare new self-assembled compounds by valorizing the ionic interactions between the two entities. Preliminary studies with oral solid dosage forms based on MES-SUC complexes tested in vitro have shown a controlled MES release, opening the perspective of a new colon-targeted delivery system and a novel class of compounds with therapeutic application in inflammatory bowel diseases.

Stability of Prednisone in Oral Mix Suspending Vehicle.

The stability of prednisone (5 mg/mL) formulated as a suspension in Oral Mix vehicle was evaluated. Oral Mix is a novel oral, dye-free suspending vehicle developed by Medisca Pharmaceutique Inc. for preparation of extemporaneous dosage forms. This drug was chosen based on its high frequency of prescription among the pediatric population. Suspensions were prepared from both pure active and commercial tablets utilizing two different container closures: amber glass bottles and polypropylene syringes (PreciseDose Dispenser Medisca Pharmaceutique Inc.). Formulations were stored at 5°C or 25°C and organoleptic properties, pH, and concentration were evaluated at predetermined time points up to 90 days. Validated stability-indicating high-performance liquid chromatography methods were developed. Beyond-use date was evaluated by statistical analysis of the overall degradation trend. Prednisone was stable for at least 90 days at 25°C. No changes in organoleptic properties or pH were observed for either of the formulations, and the global stability was roughly equivalent and sometimes superior to the stability of the same drugs in other previously used vehicles. Thus, Oral Mix was found to be a suitable dye-free vehicle for extemporaneous formulations.

Stability of penicillin G sodium diluted with 0.9% sodium chloride injection or 5% dextrose injection and stored in polyvinyl chloride bag containers and elastomeric pump containers.

PURPOSE: The stability of penicillin G sodium solutions stored in polyvinyl chloride (PVC) bags or elastomeric pump containers was studied. METHODS: Test samples were prepared by diluting powdered penicillin G sodium (10 million units/10-mL vial) to solutions of 2,500 or 50,000 units/mL with 0.9% sodium chloride injection or 5% dextrose injection. The preparations were transferred to 250-mL PVC bags and elastomeric pump containers. All samples were prepared in triplicate and stored at 5°C. Chemical stability was measured by a stability-indicating high-performance liquid chromatographic (HPLC) assay and by pH evaluation. Particulate matter was evaluated according to compendial standards using a light-obscuration particle count test. Preparations were visually examined throughout the study. RESULTS: After 21 days of storage, all test samples remained chemically stable, with an HPLC assay recovery value of more than 90% of the initial value. After 28 days, all samples prepared with either diluent and stored in PVC bags, as well as the samples diluted to 2,500 units/mL with sodium chloride injection and stored in elastomeric pump containers, did not meet the recovery acceptance limit. For all test samples, the mean pH consistently decreased during storage, from about 6.4 to about 5.5. Particle counts remained acceptable throughout the study, and no change in appearance was observed. CONCLUSION: Penicillin G for injection (2,500 and 50,000 units/mL) diluted in 0.9% sodium chloride injection or 5% dextrose injection and stored at 5°C in PVC containers or elastomeric pump containers was physically and chemically stable for a period of at least 21 days.