Physicochemical and microbiological stability of 40 mg/mL amiodarone hydrochloride oral suspension.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Amiodarone hydrochloride is an antiarrhythmic drug used to treat supraventricular tachycardia. However, there are currently no commercial pediatric forms available to treat young patients. Various oral formulations were previously reported in the literature, but the concentration was lower than the doses prescribed in clinical practice (a loading dose of 500 mg/m2/day for 7-10 days followed by a maintenance dose of 250 mg/m2/day). The objective of this study was to develop an oral liquid formulation of amiodarone hydrochloride at an optimal concentration for use in children and to evaluate its physicochemical and microbiological stability. METHODS: No commercial suspension vehicle was used, allowing the choice of excipients. Compounding was performed using hydroxypropylmethylcellulose as thickener, potassium sorbate preservative, citric acid/sodium citrate buffer, sodium saccharin as a , and a strawberry flavoring agent. A concentration of 40 mg/mL was selected based on a 5-year compilation of prescribed doses. Analyses performed were the following: visual and microscopic inspection, testing for antimicrobial preservation, osmolality and pH measurements, quantification of amiodarone hydrochloride by a stability-indicating liquid chromatography method, and a microbiological count. RESULTS: At least 95% of the initial amiodarone hydrochloride remained stable during the 60-day study period under refrigeration. All other tested parameters remained stable at 5 °C. A targeted log reduction of the microorganism inoculum by day 14 and no microbial growth by day 28 were demonstrated in the test for antimicrobial preservation. CONCLUSION: The stability of 40 mg/mL amiodarone hydrochloride oral suspension was maintained under refrigeration for 60 days before opening bottles and for 1 month after opening bottles.

Effect of Food on the Pharmacokinetics, Safety, and Tolerability of Budesonide Oral Suspension in Healthy Adult Participants: A Randomized Phase 1 Study.

Budesonide oral suspension (BOS) is a swallowed corticosteroid indicated for 12-week therapy in eosinophilic esophagitis with minimal systemic exposure following administration. We aimed to assess the relative bioavailability of a single dose of BOS administered under fasting and fed (high-fat/high-calorie meal) conditions. Healthy adult volunteers (N = 20) were enrolled in an open-label, single-center, crossover study and were randomized (1:1) to receive a single oral dose of BOS 2.0 mg under fasting or fed conditions, with a 48-h washout period before crossover to the alternative conditions. Serial plasma samples were collected before and up to 24 h after dosing. Pharmacokinetic (PK) parameters were calculated from plasma budesonide concentration-time profiles by noncompartmental analysis. The mean peak budesonide concentration (Cmax) was ∼13% lower under fed than under fasting conditions (604.1 vs 692.9 pg/mL). Areas under the concentration-time curves from dosing to the last measurable budesonide concentration and from dosing to infinity were ∼26% higher and ∼27% higher under fed than fasting conditions (3529 vs 2811 pg h/mL and 3892 vs 3075 pg h/mL, respectively). The median time to peak plasma budesonide concentration was significantly longer (∼1 h) under fed than fasting conditions (2.516 vs 1.286 h, P < .001). Safety and tolerability were also assessed throughout the study; all adverse events were mild or moderate in severity. Despite slight differences in budesonide PK parameters between fed and fasting conditions, the effect of food on systemic exposure to budesonide (BOS formulation) is not expected to be clinically meaningful.

Non-destructive Raman Method Development for Quantifying Active Pharmaceutical Ingredient in an Oral Suspension Through Plastic Dosing Syringes.

For liquid drug products, e.g., solutions or suspensions for oral or parenteral dosing, stability needs to be demonstrated in primary packaging during storage and in dosing devices during in-use periods per quality guidelines from the International Conference on Harmonisation (ICH) and the European Agency for the Evaluation of Medicinal Products (EMEA). One aspect of stability testing for liquid drug products is in-use stability, which typically includes transferring the liquid samples into another container for further sample preparation with extraction diluent and necessary agitation. Samples are then analyzed with traditional chromatography methods, which are laborious, prone to human errors, and time-consuming, especially when this process needs to be repeated multiple times during storage and in-use periods. Being able to analyze the liquid samples non-destructively would significantly improve testing efficiency. We investigated different Raman techniques, including transmission Raman (TRS) and back scatter Raman with a non-contact optic (NCO) probe, as alternative non-destructive tools to the UHPLC method for API quantitation in in-use liquid samples pulled into plastic dosing syringes. The linearity of the chemometric methods for these two techniques was demonstrated by cross-validation sample sets at three levels over an API concentration range of 60 to 80 mg/mL. The accuracy of the chemometric models was demonstrated by the accurate prediction of the API concentrations in independent samples from four different pilot plant batches manufactured at different sites. Both techniques were successful in measuring a signal through a plastic oral dosing syringe, and predicting the suspension API concentration to within 4% of the UHPLC-measured value. For future work, there are opportunities to improve the methodology by exploring additional probes or to expand the range of applications by using different sample presentations (such as prefilled syringes) or formulation matrices for solutions and suspensions.

Exploring paediatric oral suspension development: Challenges, requirements, and formulation advancements.

Oral suspension is the most preferred dosage form for the paediatric population because of the difficulties related to solid medications, such as the swallowing limitations, bitter taste, and poor oral bioavailability, which can cause serious impairment to attain a successful treatment. Given the importance of successful therapies, there is a need for safe and effective commercially-available paediatric oral suspension and their characterization. For the latter, it is important to identify safe excipients and preservatives. The paediatric group is a diverse category which includes infants and teenagers, with major pharmacokinetics and pharmacodynamics differences, mainly because of physiological and behavioral variations. Therefore, finding a single formulation for paediatric population remains a challenge, as well asthe formulation of stable-in-time suspension. In addition, drug's dissolving characteristic and permeation, are the main determinants for oral absorption, which are closely related to drug release kinetics from the pharmaceutical form. In this context, drug release profile is an important and limiting step in oral bioavailability, particularly for BCS class II drugs; thus, it is possible to increase bioavailability and minimize adverse effects by changing the release rate of such drugs. This review covers all the aspects for paediatric oral suspension development, and analyses the considerations for excipients selection as a crucial task for effectively choosing a safe and effective pharmaceutical form and correctly dosing paediatric patients.

Reconstitution of oral antibiotic suspensions for paediatric use in households: a cross-sectional study among caregivers of 3-5-year-old children from a selected district, Sri Lanka.

INTRODUCTION: Reconstitution of oral pediatric antibiotic suspension by primary caregivers plays an essential role in determining the overall health outcome of the child. Incorrect reconstitution techniques could lead to underdosing, overdosing, or introduction of infection. Underdosing could lead to non-resolving infection and antimicrobial resistance. OBJECTIVES: To assess the practice and associated factors on reconstitution of oral pediatric antibiotic suspensions (OPAS) among primary caregivers of 3-5-year-old children in a selected district in Sri Lanka. METHODS: A cross-sectional study was carried out among 835 primary caregivers selected using two-stage cluster sampling at field clinics to assess practices for the reconstitution of OPAS. A live demonstration of the reconstitution of the OPAS was assessed by a checklist. Associated factors with caregiver practices on reconstitution were assessed using Chi-square with the statistical significance level set at 0.05. RESULTS: A total of 820 respondents were recruited and completed the study (response rate = 98.2%). Overall, 56.0% displayed good performance in the demonstration of reconstitution of oral pediatric antibiotic suspension. Poorest performances were observed in shaking the bottle to loosen the powder (Correct: 53.7%), topping up the bottle with water up to the marked line (Correct: 58.0%), and filling the water below the marked line in the bottle (Correct: 59.0%). Caregivers in urban areas compared to rural and estate regions (45.6% vs. 22.7% and 26.5% respectively) and caregivers aged 35 years or above compared to less than 35 years age group (31.5% vs. 22.5%) performed the reconstitution of OPAS poorly. Parental factors, namely age, gender, level of education, and geographical region (urban/rural/estate) were significantly associated with the performance in reconstituting the oral paediatric antibiotic suspension (p = 0.002, p < 0.001, p < 0.001, and p < 0.001 respectively). Factors related to the child, specifically whether they attend preschool and whether they have an older sibling, were found to have a significant association with the correct execution of the reconstitution of OPAS (p = 0.017, and p = 0.030 respectively). CONCLUSIONS AND RECOMMENDATIONS: A significant number of primary caregivers displayed poor practice in key steps during the reconstitution of OPAS, which could have a negative impact on the health of the child. Targeted place-based behavioural change health programs with the use of infographic leaflets/ posters may correct the practices of caregivers.

Water-mediated phase transformations of posaconazole: An intricate jungle of crystal forms.

Posaconazole is a broad-spectrum antifungal agent exhibiting rich polymorphism. Up to now, a total of fourteen different crystal forms have been reported, sometimes with an ambiguous nomenclature, but less is known about their properties and stability relationships. Investigating the solid-state of a drug compound is essential to identify the most stable form under working conditions and to prevent the risk of undesired solid-phase transformations under processing and storage. In this paper, we study posaconazole polymorphism by providing a description of its polymorphs, hydrates, and solvates. Powder X-ray diffraction (PXRD), dynamic vapor sorption (DVS), spectroscopic and thermal techniques were employed to characterize the different forms. In addition, the solid-phase transformations of posaconazole in aqueous suspensions were studied by means of Raman microscopy. Surprisingly, we found that Form S, the crystal form contained in the marketed oral suspension, is not the most stable form in water. Form S readily converts to a more stable hydrate, i.e. Form A, after storage in water for two weeks. In the commercial oral formulation the conversion between the two forms is prevented by the presence of polysorbate 80. Such insights into the stabilizing excipient effects beyond particle dispersion are critical to formulators.

What to consider for successful administration of oral liquids via enteral feeding tubes? a case study with paediatric ibuprofen suspensions.

Administration of medications via enteral feeding tubes (EFTs) is a common practice for children who cannot swallow properly. Although liquid formulations are the preferred dosage forms for this route of administration, little attention has been paid to the amount of drug that reaches the site of absorption after administration via an EFT. This systematic in vitro study aimed to identify formulation parameters and administration approaches that are critical for successful dose delivery via EFTs. For this purpose, drug recovery after administration of three different paediatric ibuprofen suspensions via different types of EFTs was studied using derivative UV spectrophotometry for quantification. Study results indicate that in addition to formulation parameters, feeding tube characteristics and the administration process can have a significant impact on the administered dose. The ratio between the total administered fluid volume (TAV), represented by the sum of dose- and flushing volume, and the feeding tube volume (FTV) proved to be a valuable indicator for assessing successful administration. Incorrect dosing and complications could be avoided if the TAV/FTV ratio was greater than 4. This and other knowledge gained in the study will help to make the administration of liquid paediatric medicines via EFTs both more effective and safer.

A Multicenter Randomized Bioequivalence Study of a Novel Ready-to-Use Temozolomide Oral Suspension vs. Temozolomide Capsules.

BACKGROUND: Temozolomide (TMZ) oral suspension (Ped-TMZ, KIZFIZO®) is being developed for the treatment of relapsed or refractory neuroblastoma, a rare cancer affecting infants and young children. The study assessed the safety and the bioequivalence of this novel pediatric formulation with existing TMZ oral capsules. METHODS: In vitro dissolution profiles and the bioequivalence were evaluated following the European Medicines Agency "Guidelines on the investigation of Bioequivalence". The phase I, multicenter, randomized, open-label, crossover, single-dose bioequivalence study enrolled 36 adult patients with glioblastoma multiforme or lower-grade glioma. Each patient received 200 mg/m2 Ped-TMZ suspension and TMZ capsules (Temodal®) on 2 consecutive days, with the order being randomly assigned. Fourteen blood samples were collected up to 10 h post-dosing. Bioequivalence was assessed by comparing the 90% confidence interval for the ratio of the geometric means of maximum TMZ plasma concentration (Cmax) and the area under the curve (AUCt). Other endpoints included further pharmacokinetic parameters and safety. RESULTS: Both formulations exhibited a fast in vitro dissolution profile with more than 85% of TMZ dissolved within 15 min. For the bioequivalence study, thirty patients completed the trial as per the protocol. The ratio of Ped-TMZ/TMZ capsule geometric means (90% CI) for AUCt and Cmax were 97.18% (95.05-99.35%) and 107.62% (98.07-118.09%), respectively, i.e., within the 80-125% bioequivalence limits. No buccal toxicity was associated with Ped-TMZ liquid formulation. CONCLUSIONS: This study showed that Ped-TMZ oral suspension and TMZ oral capsule treatment are immediate release and bioequivalent medicines. There were also no unexpected safety signals or local toxicity (funded by ORPHELIA Pharma; ClinicalTrials.gov number, NCT04467346).

Bioequivalence of Different Formulations of Zonisamide Oral Suspensions: A Short Review.

To satisfy the needs of pediatric and other patients with focal onset seizures who cannot swallow solid dosage forms of zonisamide, an oral liquid form of this drug is necessary in clinical practice. Although there are two oral suspensions of zonisamide with marketing authorization (MA), there are issues of availability and high cost which limit their use and inspire extemporaneous compounding. Extemporaneously compounded oral suspensions of zonisamide are prepared according to different formulas and vary in stability; therefore it is essential to test this characteristic. Bioequivalence of extemporaneously compounded oral suspensions has never been tested, and the efficacy and safety of zonisamide oral suspensions have generally not been demonstrated in clinical trials. As a narrow therapeutic window drug, zonisamide requires precision in dosing, which could be achieved only with dosage forms with established bioavailability, efficacy, and safety. In order to avoid underdosing and toxicity with zonisamide oral suspensions and utilize their full therapeutic potential, it is necessary to perform bioequivalence studies with each variation of extemporaneously compounded oral suspension and also clinical trials with both commercial and extemporaneous oral suspensions of zonisamide.

Study UNICO: Perception of Urologists and Andrologists, in Spain, about the Use of Sildenafil Oral Suspension in Patients with Erectile Dysfunction.

OBJECTIVE: To describe the profile of patients with erectile dysfunction (ED), attending to consultation and satisfaction using sildenafil oral suspension, from the specialist's perception. MATERIALS AND METHODS: This is a nationwide multicenter, epidemiological, descriptive and observational study, with the studied population as the unit of study. Thirty urologists and/or andrologists completed a questionnaire with questions about ED patients' profile attending to their practice, sildenafil oral suspension perception of effectiveness and safeness, and their opinion about patients' satisfaction after sildenafil oral suspension treatment. Aggregate data were collected for the last 6 patients treated or on treatment with sildenafil oral suspension. RESULTS: Overall, 40.9% and 24.9% of patients had moderate or severe ED, respectively. Among the patients, 73.6% were older than 50 years. The disease progression was approximately one year (11.8 months). ED etiology was mostly organic (38.1%) and mixed (31.8%). Cardiovascular comorbidities were present in 57.4%, mental health problems in 16.4% and hormonal disorders in 10.2% of the patients. The main reason for choosing sildenafil oral suspension was the ease of dose adjustment. The specialists considered that 73.4% of the patients responded satisfactorily to treatment. They also rated the perceived effectiveness and safeness of the product as very good or good. CONCLUSIONS: Urologists and andrologists consider that most patients with ED achieve a high degree of satisfaction with sildenafil oral suspension. The main advantage of the treatment is the possibility of adjusting the dose according to patient's needs and circumstances.

Efficacy of Amphetamine Extended-Release Oral Suspension in Children with Attention-Deficit/Hyperactivity Disorder: Effect Size Across the Day.

Objective: To evaluate the treatment effect size throughout the day of amphetamine extended-release oral suspension (AMPH EROS; Tris Pharma, Inc., Monmouth Junction, NJ, USA) in a laboratory classroom study conducted in children aged 6-12 years with attention-deficit/hyperactivity disorder (ADHD). Methods: A post hoc analysis was performed to assess the overall effect size as well as the effect size at each time point from early morning through evening (1, 2, 4, 6, 8, 10, 12, and 13 hours postdose) for each efficacy measure evaluated in a 5-week, randomized, dose-optimized, double-blind, placebo-controlled, laboratory classroom assessment, efficacy, and safety study of AMPH EROS (N = 99). Change from baseline of the primary (Swanson, Kotkin, Agler, M-Flynn, Pelham [SKAMP]-C) and key secondary (secondary efficacy assessments included the SKAMP attention [SKAMP-A], SKAMP-deportment subscale [SKAMP-D], Permanent Product Measure of Performance-number of problems attempted [PERMP-A], PERMP-number of problems correct [PERMP-C]) efficacy measures were analyzed using a linear mixed model repeated-measures analysis model. Comparisons among treatments were adjusted for multiple comparisons using the Bonferroni method. The effect size was estimated using Cohen's d, to determine "small," (0.2), "medium," (0.5), or "large" (0.8) magnitudes of treatment effects. Results: Large overall effect sizes were observed for all primary and key secondary efficacy assessments. Moreover, the SKAMP-C, PERMP-number of problems attempted, and PERMP-C scores showed large effect sizes at each time point evaluated across the day, from 1 to 13 hours postdose. The SKAMP-A and SKAMP-D scores showed a medium to large effect size at each time point. Conclusions: AMPH EROS demonstrated a large and consistent effect size across the day, including early in the morning, in the treatment of symptoms of ADHD in children aged 6-12 years. Trial Registration: clinicaltrials.gov identifier: NCT02083783.

Edaravone Administered Orally and Via Nasogastric Tube in Healthy Adults: A Comparative Bioavailability Phase 1 Study.

Intravenous edaravone is used to treat patients with amyotrophic lateral sclerosis. This randomized, open-label, two-way crossover, single-dose phase 1 study compared the relative bioavailability of a newly developed edaravone oral suspension when administered orally and via a nasogastric tube (NGT) as a model of percutaneous endoscopic gastrostomy tube administration in healthy adult subjects. Thirty-six subjects were randomly assigned to one of two groups, with 18 per group. Blood was collected pre- and post-dose for pharmacokinetic assessments; safety was evaluated. Plasma concentration-time profiles of unchanged edaravone were similar between administration routes. Comparative bioavailability analysis revealed that geometric least squares mean ratios (NGT/oral) for maximum plasma concentration and area under the plasma concentration-time curve from time zero to infinity of unchanged edaravone were 1.052 and 0.981, respectively. No serious adverse events or adverse drug reactions were reported. These results suggest that oral edaravone suspension can be administered directly to the stomach without dose adjustment via feeding tubes; both oral and NGT administration are well tolerated.

Characterization of two excipient interaction degradation products in oseltamivir phosphate powder for oral suspension by MS and NMR.

Oseltamivir phosphate is widely used to treat and prevent influenza, and is available in the form of capsules, powder for oral suspension, pediatric solutions, and granules. Because of the amino group, oseltamivir is easy to react with the excipients of the formulation to generate drug-excipient interaction impurities. In this research, two degradation products in a commercial oseltamivir phosphate powder for oral suspension due to interaction between API and citrate were investigated. They were characterized to be 3-((-6-acetamido-3-(ethoxycarbonyl)-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)carbamoyl)-3-hydroxypentanedioic acid and 2-(2-((-6-acetamido-3-(ethoxycarbonyl)-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)-2-oxoethyl)-2-hydroxysuccinic acid by MS and NMR, respectively. Furthermore, the formation mechanisms of these impurities were verified, and the method of analysis of covariance was used to assess the rate of impurities' degradation. HIGHLIGHTS: Two excipient interaction degradation products in commercial oseltamivir phosphate powder for oral suspension were studied and elucidated in detail via LC-MS/MS and NMR. The incompatibility risk of pH conditioners such as citrate and citric acid with formulations that contain an amino group was disclosed in this article. Analysis of covariance was demonstrated to assess the impact of various formulations and preparation techniques on the rate of impurity degradation.

Development of a Hospital Compounded, Taste-Masked, Temozolomide Oral Suspension and 5-Year Real-Life Experience in Treating Paediatric Patients.

The development of oral pediatric forms by pharmaceutical companies is still insufficient. In fact, many drugs used in paediatric oncology, such as temozolomide, are not labeled and adapted for paediatric use. Temozolomide (TMZ) is an alkylating agent used as the standard of care for many adult and pediatric brain tumours, such as neuroblastoma, glioblastoma and medulloblastoma. The present study was carried out to propose a suitable and palatable formulation of the oral liquid preparation of TMZ. The suspension is composed of TMZ suspended in SyrSpend SF pH 4, as well as TMZ crystallization stabilizing agents and sweetening agents. To reach this formulation, several taste-masking agents were evaluated. Here, we describe the method of preparation of the formation as well as the monocentric population treated with the formulation over a 5-year period. A 20 mg/mL TMZ suspension was developed. TMZ suspension is stable for 6 weeks, stored between 2 and 8 degrees, protected from light, and compatible with nasogastric tubes. Thirty-eight patients participated in the palatability study and choose cola flavour, and 104 patients were treated in Gustave Roussy with the developed suspension; no unexpected event was reported. To conclude, we propose here a new TMZ liquid formulation which is stable for at least 6 weeks and well-tolerated with extensive feedback.

Formation and Characterisation of Posaconazole Hydrate Form.

Posaconazole is an API added as Form I for the production of oral suspensions, but it is found as Form-S in the final formulation. In this study, it was found that this polymorphic conversion, which may affect the bioavailability, is due to an interaction with water. However, the relatively poor wettability of posaconazole Form I renders the complete wetting of its particles and production of pure Form-S challenging. Consequently, for its isolation, Form I should be dispersed in water followed by application of sonication for at least 10 min. Pure posaconazole Form-S was characterised using X-ray powder diffraction (XRPD), Raman spectroscopy, attenuated total reflection (ATR) spectroscopy, thermogravimetric analysis (TGA) and optical microscopy. From these techniques, posaconazole Form-S was characterised as a hydrate form, which includes three molecules of water per API molecule.

Design and stability of pediatric oral formulation of imatinib.

BACKGROUND: Imatinib is a protein-tyrosine kinase inhibitor which is currently only commercially available as a tablet dosage form in the strength of 100mg and 400mg. The elaboration of new oral liquid formulations is suitable in pediatrics and for patients who have difficulties to swallow, notably in the absence of commercial forms. This enables the adaptation of dosage and secure the administration. OBJECTIVES: The formulation of an oral pediatric solution of imatinib at a concentration of 30 mg/mL and the evaluation of its stability for the treatment of pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia. METHODS: The physicochemical stability parameters: appearance, pH, osmolality, and drug content of formulation were evaluated for 30 days when stored at 2-8°C. Concentration of solution was measured with a validated method using high performance liquid chromatography (HPLC) coupled with an absorbance UV detector. Equally, microbiological stability was performed. RESULTS: The remaining imatinib concentration was at least 95% of the initial concentration after 30 days stored in fridge temperature. No changes were observed regarding the physical properties of the formulation during the study period. CONCLUSIONS: The stability study showed that the imatinib oral solution at a concentration of 30 mg/mL provides an alternative option at the commercial tablet dosage forms for pediatric patients and patients who have difficulties to swallow.

Hospital compounding to face shortage: A case study of the development of a lopinavir-ritonavir oral suspension during the first wave of SARS-COV-2 in France.

The potential usefulness of lopinavir-ritonavir on Covid 19 infection during the first wave of contamination in France had boosted Kaletra® syrup prescription to the point of causing its national shortage. In the intensive care units of Parisian hospitals in charge of patients with life-threatening viral contamination, caregivers had to resort to lopinavir-ritonavir-based tablets, crushing them and then dispersing the powder in milk to facilitate administration by nasogastric tube. The difficulties and poor control of this degraded mode, which does not always ensure control of the amount of the drug in the prepared dose and may induce insufficient antiviral exposure, led us to develop in a very short time, while ensuring quality control proportional to the risk, a liquid form as an alternative to Kaletra® oral solution shortage. For this purpose, we describe this compounding formulation and its preparation process, while justifying the quality control strategy adapted to the risk as well as its chemical and physical stability. Based on the chemical and physical studies, the preparation was showed to be stable during at least 2 months between +2°C and +8°C and 1 week at room temperature. This has resulted in the design of kits that include multi-dose packaging and a measuring device and contain the appropriate quantities of drugs to ensure at least one week's treatment for each patient, during which time the kit in use can be stored at room temperature. The intensive care team used this treatment under conditions that they considered well adapted until the imported specialty became available.

Warfarin Sodium Stability in Oral Formulations.

Warfarin sodium is a low-dose pharmaceutical blood thinner that exists in two forms: the clathrate form and the amorphous form. In commercially available warfarin sodium oral suspension, the active pharmaceutical ingredient (API) is added in the amorphous state. This study investigates the apparent instability of the commercially available warfarin liquid oral formulation using Raman and IR spectroscopy, X-ray diffraction, differential scanning calorimetry, UV spectroscopy, and optical microscopy. Warfarin, not its sodium salt, was identified as the undissolved solid existing in the suspension. This was found to be due to the dissociation of sodium salt and the protonation of the warfarin ion in the liquid phase, which triggered the crystallization of the sparingly soluble unsalted form. The coexistence of protonated and unprotonated warfarin ions in the supernatant, as detected by Raman and UV spectroscopy, confirmed this assumption. Study of the dissolution of warfarin sodium amorphous salt and crystalline sodium clathrate in the placebo and pure water verified the results. The effect of pH and temperature on warfarin precipitation was also explored.

Stability of Extemporaneously Compounded Suspensions of Trimethoprim and Sulfamethoxazole in Amber Plastic Bottles and Amber Plastic Syringes.

BACKGROUND: Trimethoprim (TMP) and sulfamethoxazole (SMX) are widely used, in combination, to treat or prevent various infections. Unfortunately, no liquid oral formulation is currently available in Canada for patients who are unable to swallow tablets. OBJECTIVE: To evaluate the stability of suspensions of TMP and SMX (8 and 40 mg/mL, respectively) prepared in Oral Mix or Oral Mix SF vehicle (Medisca Pharmaceutique Inc) and stored for up to 90 days in amber plastic bottles or amber plastic syringes at 5°C or 25°C. METHODS: Suspensions were prepared from bulk powder and from tablets in Oral Mix and Oral Mix SF vehicles, then transferred to amber plastic (polyethylene terephthalate glycol) bottles and plastic oral syringes and stored at 5°C and 25°C. Samples were collected on predetermined study days (0, 7, 14, 23, 45, 60, 75, and 90 days) and analyzed using a validated high-performance liquid chromatography - ultraviolet detection method. A suspension was considered stable if it maintained at least 90% of its initial concentration with 95% confidence. Observations of organoleptic characteristics such as colour and odour, as well as pH, were used to assess physical stability. RESULTS: Suspensions prepared from bulk powder maintained concentrations of TMP and SMX of at least 97% of the initial concentration over the 90-day study period. No obvious changes in colour, odour, or pH were observed. However, acceptable suspensions could not be prepared from the commercial tablets. A persistent foam that developed at the surface of all suspensions prepared from tablets could result in inconsistent dosing. CONCLUSIONS: Extemporaneously compounded oral suspensions of TMP and SMX (8 and 40 mg/mL, respectively) prepared from bulk powder in Oral Mix and Oral Mix SF vehicles and stored in amber plastic bottles or syringes at 5°C or 25°C remained stable for at least 90 days. Suspensions made from tablets produced unacceptable formulations.

CONTEXTE: Le triméthoprime (TMP) et le sulfaméthoxazole (SMX) sont largement utilisés conjointement pour traiter ou prévenir diverses infections. Malheureusement, aucune formulation liquide orale n'est actuellement disponible au Canada pour les patients incapables d'avaler des comprimés. OBJECTIF: Évaluer la stabilité des suspensions de TMP et de SMX (respectivement 8 et 40 mg/mL) préparées dans un véhicule Oral Mix ou Oral Mix SF (Medisca Pharmaceutique Inc.) et stockées pendant 90 jours dans des flacons ou des seringues en plastique ambré à 5 °C ou 25 °C. MÉTHODES: Les suspensions ont été préparées à partir de poudre en vrac et de comprimés dans les véhicules Oral Mix et Oral Mix SF, puis transférées dans des flacons en plastique ambré (polyéthylène téréphtalate glycol) et dans des seringues orales en plastique et stockées à 5 °C et 25 °C. Des échantillons ont été recueillis à des jours prédéterminés (0, 7, 14, 23, 45, 60, 75 et 90 jours) et analysés à l'aide d'une méthode de détection par ultraviolet validée de chromatographie en phase liquide à haute performance. La suspension était jugée stable si elle préservait au moins 90 % de sa concentration initiale avec un seuil de confiance de 95 %. Les observations des caractéristiques organoleptiques, comme la couleur et l'odeur, ainsi que le pH, ont été faites pour évaluer la stabilité physique. RÉSULTATS: Les suspensions préparées à partir de poudre en vrac préservaient au moins 97 % de la concentration initiale de TMP et de SMX pendant la période d'étude de 90 jours. Aucun changement manifeste de couleur, d'odeur ou de pH n'a été observé. Cependant, les suspensions acceptables n'ont pas pu être préparées à partir des comprimés commerciaux. Une mousse homogène se formait à la surface de ces suspensions, ce qui pourrait entraîner un dosage incohérent. CONCLUSIONS: Les suspensions orales composées extemporanées de TMP et SMX (respectivement 8 et 40 mg/mL) préparées à partir de poudre en vrac dans des véhicules Oral Mix et Oral Mix SF et stockées dans des flacons ou des seringues en plastique ambré à 5 °C ou 25°C sont restées stables pendant au moins 90 jours. Les suspensions préparées à partir de comprimés ont donné des formulations inacceptables.