Formulation and stability of an extemporaneously compounded propafenone hydrochloride oral suspension for children with arrhythmia.

OBJECTIVES: In children, supraventricular tachycardia is the most common form of arrhythmia, and propafenone is an effective class Ic antiarrhythmic agent used in this population. No suitable paediatric-specific, dosing-flexible preparation is available in Taiwan. The objective of this study was to develop a formulation of propafenone oral suspension prepared from commercially available propafenone tablets and commercially available oral syrup vehicles for related patients. METHODS: An oral suspension of propafenone hydrochloride at a concentration of 10 mg/mL was prepared by mixing finely grounded propafenone hydrochloride tablets and a 1:1 mixture of Ora-Plus and Ora-Sweet. The beyond-use date was determined by analysing the samples stored at room temperature or 2-8℃ at time 0 and on days 7, 14, 21, 28, 35, 42, 56, and 90. Parameters to be inspected included appearance, pH measurement, high-performance liquid chromatography analysis, and microbial limit tests. RESULTS: On the basis of the physicochemical and microbial stability results, the 10 mg/mL oral suspension of propafenone hydrochloride was stable at 2-8℃ and room temperature for at least 90 days. The suspension did not exhibit significant changes in drug concentration or pH level at any time point. Moreover, no apparent changes or microbial contaminations were observed for at least 90 days. CONCLUSIONS: Propafenone hydrochloride in a 10 mg/mL oral suspension prepared by diluting fine powder with a 1:1 mixture of Ora-Plus and Ora-Sweet and stored in high-density polyethylene bottles and has a beyond-use date of 90 days when stored at 2-8℃ or room temperature. This finding enables us to improve the accuracy of dosage administration and reduce the risk of medication errors affecting the paediatric population.

Use of sodium glycerophosphate in neonatal parenteral nutrition solutions to increase calcium and phosphate compatibility for preterm infants.

BACKGROUND: Preterm infants require higher calcium and phosphate intake than term infants to facilitate adequate bone growth, but this is rarely met in parenteral nutrition (PN) solution because of the limited solubility of calcium and phosphate. This study aimed to evaluate the solubility of organic phosphate with calcium gluconate in neonatal PN solutions, simulating its clinical use. METHODS: PN solutions were composed of calcium gluconate at 50 mEq/L and sodium glycerophosphate (NaGP) at 25 mmol/L. Another component included 1% or 4% amino acid and 10% or 20% dextrose. For comparison, PN solution composed of potassium phosphate was also evaluated. Each solution was evaluated using the following methods: visual inspection, light obscuration particle count test, and pH measurement. To simulate the clinical condition, the solution was tested after compounding, after being stored at 25 °C for 24 h, and after being stored at 2°C-8°C for 2 or 9 days and subsequently at 25 °C for 24 h. RESULTS: There was no visual deposition in PN solution using NaGP in any of the concentrations and under any stored condition. The solution fulfilled the criteria of physical compatibility as < 25 particles/mL measuring ≥10 µm in diameter and <3 particles/mL measuring ≥25 µm in diameter. On the contrary, visual deposition was evidently noted in PN solution using potassium phosphate after its formulation, and the particle count significantly exceeded the range of physical compatibility. CONCLUSION: NaGP and calcium gluconate have significantly good compatibility in PN solution. The use of NaGP in neonatal PN prevents calcium and phosphorus precipitation, hence increasing their supply to preterm infants in meeting their growth requirement.

Formulation and stability of an extemporaneous 0.02% chlorhexidine digluconate ophthalmic solution.

BACKGROUND/PURPOSE: Acanthamoeba keratitis is difficult to treat because Acanthamoeba cysts are resistant to the majority of antimicrobial agents. Despite the efficacy of 0.02% chlorhexidine in treating Acanthamoeba keratitis, a lack of data in the literature regarding the formulation's stability limits its clinical use. The objective of this study was to develop an optimal extemporaneous 0.02% chlorhexidine digluconate ophthalmic formulation for patients in need. METHODS: With available active pharmaceutical ingredients, 0.02% chlorhexidine digluconate sample solutions were prepared by diluting with BSS Plus Solution or acetate buffer. Influences of the buffer, type of container, and temperature under daily-open condition were assessed based on the changes of pH values and chlorhexidine concentrations of the test samples weekly. To determine the beyond-use date, the optimal samples were stored at 2-8°C or room temperature, and analyzed at time 0 and at Week 1, Week 2, Week 3, Week 4, Week 5, Week 8, Week 12, and Week 24. RESULTS: Despite chlorhexidine exhibiting better stability in acetate buffer than in BSS solution, its shelf-life was < 14 days when stored in a light-resistant low-density polyethylene container. The acetate-buffered 0.02% chlorhexidine digluconate solution stored in light-resistant high-density polyethylene eyedroppers did not exhibit significant changes in pH or strength at any time interval. CONCLUSION: The acetate-buffered 0.02% chlorhexidine digluconate ophthalmic solution stored in light-resistant high-density polyethylene eyedroppers demonstrated excellent stability at 2-25°C for 6 months after being sealed and for 1 month after opening. This finding will enable us to prepare 0.02% chlorhexidine digluconate ophthalmic solutions based on a doctor's prescription.

Simultaneous determination of triazole antifungal drugs in human plasma by sweeping-micellar electrokinetic chromatography.

The number of cases of invasive fungal infections (IFIs) has risen significantly in recent years; therefore, this study developed a sensitive and effective sweeping-micellar electrokinetic chromatography (MEKC) method for the simultaneous determination of the three most frequently used triazole antifungal drugs for the treatment of IFIs, which included voriconazole, itraconazole, and posaconazole. Due to the diverse lipophilicity of the tested drugs, the analytical conditions that resulted in good resolution between itraconazole and posaconazole caused the peak for voriconazole to split. The splitting phenomenon was resolved by incorporating a high-salt stacking mechanism into the sweeping-MEKC method. The optimum background electrolyte was composed of 25 mM phosphoric acid solution (pH 2.2), 100 mM sodium dodecyl sulfate, 13 % acetonitrile, and 13 % tetrahydrofuran. The best peak shape of voriconazole was obtained when the conductivity ratio between the sample matrix and background electrolyte was 2.3. Compared to the conventional MEKC mode, the enhancement factor of the sweeping-MEKC method was 66 for itraconazole, 55 for posaconazole, and 43 for voriconazole. The sweeping-MEKC method was validated in terms of precision, accuracy, linearity, specificity, selectivity, and sensitivity. The linearity ranges of the method covered the commonly used therapeutic ranges of the three drugs. The developed sweeping-MEKC method was successfully applied to the analysis of clinical samples, thus demonstrating its applicability for clinical use.

Using sweeping-micellar electrokinetic chromatography to determine voriconazole in patient plasma.

Invasive fungal infection is a life-threatening condition; its occurrence has increased significantly over the past 20 years. We have developed a sensitive and efficient sweeping-micellar electrokinetic chromatography (sweeping-MEKC) method to quantify voriconazole, a potent triazole antifungal drug, in patient plasma. Solid phase extraction (SPE) conditions were first optimized to minimize plasma interference while maintaining a high recovery; the sweeping-MEKC conditions were then systematically optimized to obtain a high sweeping efficiency with good selectivity. Under the optimal analytical conditions, voriconazole was baseline-separated from endogenous materials within 10.5 min with a limit of detection of 0.075 microg mL(-1). The background electrolyte comprised 40 mM phosphoric acid, 110 mM sodium dodecyl sulfate, and 20% acetonitrile. In terms of method repeatability, the relative standard deviations (RSDs) of the migration time and the peak area (intra-day; n=6) were both less than 5.5%; in terms of intermediate precision, and the RSDs of the peak area and the migration time (inter-day; n=3) were both less than 6.3%. We successfully applied this developed method to the quantitative determination of plasma voriconazole levels in 16 patients; the results correlated well with those obtained through analyses using high-performance liquid chromatography. This sweeping-MEKC method is accurate and efficient and appears to be applicable to therapeutic drug monitoring and clinical research.

Rapid determination of aristolochic acids I and II in herbal products and biological samples by ultra-high-pressure liquid chromatography-tandem mass spectrometry.

Aristolochic acids (AAs) are a mixture of structural-related compounds, in which aristolochic acid I (AA I) and aristolochic acid II (AA II) are reported to be correlated with Aristolochic acid nephropathy (AAN). In this work, a rapid and sensitive ultra-high-pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed to determine AA I and AA II in herbal products and biological fluids. By using gradient elution with a mobile phase composed of a mixture of 10mM ammonium formate buffer (pH 3.0) and acetonitrile, AAs could be determined within 10 min. Under optimum UHPLC-MS/MS conditions, the limit of detections was 0.14 and 0.26 ng mL(-1) for AA I and AA II, respectively. Run-to-run repeatability and intermediate precision of peak area for AA I and AA II were less than 5.74% relative standard deviation (RSD). Accuracy was tested by spiking 10, 100 and 1000 ng mL(-1) in rat serum and the recoveries were within 76.5-92.9%. Matrix effects were within 78.8-127.7%. The developed method was successfully applied to determine AA I and AA II in several herbal products and to investigate their pharmacokinetic behavior in female Wister rats. The result shows that the developed UHPLC-MS/MS method is efficient, sensitive, and accurate for the determination of AA I and AA II in herbal products and biological samples.

Rapid analysis of melamine in infant formula by sweeping-micellar electrokinetic chromatography.

In the present study, an analytical method using capillary electrophoresis with on-line preconcentration technique was developed for rapid determination of melamine in infant formula. Both stacking and sweeping preconcentration techniques had been investigated for the comparison of their effectiveness in melamine analysis. The limit of detection of melamine standard was 0.5 ng/mL for the field amplified sample stacking (FASS) technique and 9.2 ng/mL for the sweeping technique. Although the FASS technique provided better concentration efficacy than the sweeping technique, the matrix effect was more profound with the former. Matrix effect was evaluated by comparing the enhancement factor (EF) of melamine standard and post-extraction spiked infant formula solution. The EF was changed from 429.86 +/- 9.81 to the level less than 133.31 with significant peak distortion in the FASS system, and it was remained unchanged in the sweeping system. Sweeping-micellar electrokinetic chromatography (sweeping-MEKC) was demonstrated to be most suitable for real sample analysis. Under optimum sweeping-MEKC conditions, melamine content in infant formulas could be determined within 6 min. The developed solid phase extraction (SPE) procedures coupled with the sweeping-MEKC method was subjected to method validation. Run-to-run repeatability (n = 3) and day-to-day reproducibility (n = 3) of peak area were within 3.6% and 4.8% RSD, respectively. The accuracy was tested by spiking 0.5 and 2 microg/mL of melamine standard in the melamine contaminated milk powder provided by the European Commission, and the recoveries were 93.4 +/- 0.5% and 98.7 +/- 0.4%, respectively. Results of this study show a great potential for the sweeping-MEKC method as a tool for the fast screening of melamine in infant formulas.