Extemporaneously Compounded Research Articles

Prevalence, Scope and Quality of Extemporaneous Medications in Selected Healthcare Facilities and Implications for Pharmacy Practice.

Background: Extemporaneous compounding is the preparation of medicines for individual patients when no commercially available authorized form exists. Unlike registered medications, these products are not subjected to various tests for quality by Regulatory Authorities. Data on compounded medications in Ghana is currently inadequate or unavailable. There is the need to collate data that can be used to influence policy and to regulate preparation of extemporaneous products. Aim: To establish the prevalence, scope and quality of extemporaneously compounded medicines at selected hospitals in Accra, Ghana. Methodology: Prescriptions presented at the pharmacies in selected hospitals were reviewed to determine the requests that needed to be extemporaneously prepared as well as the prevalence and the scope of formulations. Three of the most frequently compounded medications were procured and subjected to microbial contamination tests using the pour plate method followed by differential tests if microbes were present. Content analysis of the active ingredients was determined using High Performance Liquid Chromatography (HPLC). Results: 641 requests comprising 49 different extemporaneous products were collated from the hospitals studied. Hydroxyurea, furosemide and spironolactone suspensions were the three most frequently prescribed. Patients aged from 0-2 years had majority of the prescriptions. Conclusion: A population of patients still exist who depend on compounding for their drug needs. 49 different formulations were prepared at one of the hospitals visited. Samples of products analyzed were of good quality.

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

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

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.

Extemporaneous Compounding: Prevalence, Risks and Quality Assurance

Extemporaneously compounded products are designed for an individual patient based on a licensed physician’s prescription in response to an identified need. Compounding provides medications for unique medical needs for which commercially manufactured products are unavailable. Compounding practice includes activities such as formulating, mixing, or repacking products. Extemporaneous preparations are not licensed by Drug Regulatory Authorities and hence, are not evaluated for quality, efficacy, and stability. Also, adverse event reporting is not mandatory for these products. The need for extemporaneous preparations is precipitated by a lack of commercially available products for all the medicines and dosage forms that are required by patients. Products intended for topical and pediatric use are the majority. Extemporaneous preparations are generally considered as high-risk products. Common risks of compounded products include calculation errors, microbial contamination, therapeutic failure, and adverse reactions. To reduce the risks, Drug Regulatory Authorities havedeveloped guidelines that describe the minimum standards to be followed when preparing for extemporaneous compounding to ensure product quality and fitness. A comprehensive assessment is performed to justify the need for these products. The preparation process should comply with all the Good Manufacturing Practices including design of compounding areas. Pharmacists performing compounding activities require appropriate knowledge, skills, and competence to undertake the task. The ingredients used in compounding are subject to pharmacopeial quality standards and should be sourced from approved vendors. The final compounded product in some countries is controlled as stipulated in the components standard. Extemporaneous compounding remains an important part of pharmacy practice. Comprehensive risk assessment, adherence to the prescribed manufacturing practices, and use of national formularies are necessary for quality assurance of these preparations.

Quality and Stability Evaluation of Extemporaneously Compounded Losartan Potassium Oral Suspension at the Hospital Pharmacy

Aims: The purpose of this study was to evaluate the quality of an extemporaneous formulation of losartan potassium oral suspensions from crushed losartan potassium tablets to ensure that the compounded suspension maintained its quality attributes during its storage period.
 Methodology: Losartan potassium suspensions were compounded extemporaneously in the same way they are prepared for patients at a hospital pharmacy. The suspensions were kept in the refrigerator at 4°C and evaluated immediately and after 9, 18, and 28 days. Suspension ease of redispersion, color, odor, pH, particle size, zeta potential, viscosity, and sedimentation volume were all evaluated. In addition, microbiological stability, drug content, and drug dissolution were assessed.
 Results: During the study period, the extemporaneously compounded suspension retained its color and odor, and the pH profile remained consistent. Moreover, all suspensions were easily resuspended in a homogeneous liquid with gentle shaking, and no caking was detected. Furthermore, the results of the microbiological test revealed no microbial growth. The content uniformity and dissolution test results met the pharmacopeial requirements. The findings revealed that the losartan potassium compounding procedure was reliable and capable of producing 2.5 mg/mL of losartan potassium suspension using commercially available tablets and Ora-Blend as a suspending vehicle. Furthermore, after 28 days in the refrigerator (4°C), the suspension had acceptable quality features.
 Conclusion: Extemporaneously compounded suspension allows physicians to prescribe a variable dose that adjusts to each patient’s needs, providing treatment when the liquid dosage form is unavailable.

Quality Assessment of Extemporaneously Compounded Carvedilol Oral Suspension for Pediatric Patients at the Hospital Pharmacy

Aims: The aim of this study was to evaluate different quality control parameters and the stability of the carvedilol compounded extemporaneous suspensions over three months at room temperature.
 Methodology: The carvedilol compounded extemporaneous suspensions were prepared in our lab in a manner consistent with how they are prepared for pediatric patients at the hospital pharmacy. The suspensions were stored at room temperature and analyzed immediately and at 1, 2 and 3 months. Suspensions were monitored for changes in organoleptic properties, pH, particle size, zeta potential, viscosity, sedimentation volume, drug content and drug dissolution.
 Results: The results demonstrated that the carvedilol compounding protocol used in this study was reliable and able to prepare 1.67 mg/mL of carvedilol suspension by using carvedilol commercially available tablets and Ora-blend as a suspending vehicle. Also, the extemporaneously compounded suspension maintained acceptable quality attributes when stored for three months at room temperature.
 Conclusion: The extemporaneously compounded suspension enables pediatricians to administer a variable dose, which adapts to every patient’s needs, and gives the possibility of treatment when the liquid dosage form is not available.

Stability-study-of-an-extemporaneous-isoniazid-oral-suspension-prepared-using-commercially-available-tablets-with-x-temp-oral-suspension-system

Isoniazid (INH) is a hydrazine derivative that is routinely used for the treatment of pulmonary and extrapulmonary tuberculosis. It is used with other anti-tuberculosis drugs usually in regimes including rifampicin, ethambutol, and pyrazinamide. As there is no access to commercial oral solution in Malaysia, there is a requirement to prepare this product by extemporaneous compounding. This study is initiated to identify an easy-to-prepare formulation for compounding and to select product storage condition and establish beyond-use date. INH tablets were used to mix into X-Temp® Oral Suspension System to compound the 10 mg per mL and 40 mg per mL solution. For the stability studies, the finished products were packed into amber HDPE bottles and stored at refrigeration (5°C ± 3°C) or room temperature (30°C ± 2°C) for up to 90 days. The samples were evaluated by visual inspection, pH measurement, high-performance liquid chromatography (HPLC) assay at predetermined testing intervals for 90 days. The samples were submitted for microbiology testing at each time point. An HPLC method validation was also carried out to ensure that the system provides accurate, precise and reliable analytical data. The results showed that INH suspension at concentration of 10mg/mL and 40mg/mL remained unchanged in physical, chemical and microbiological evaluations for up to 90 days. The HPLC results demonstrated that all the samples retained the drug concentration within the specification. It could be suggested that INH tablet can be extemporaneously compounded in X-Temp® Oral Suspension System at a concentration of between 10mg/mL to 40mg/mL with the resulting product stable for up to 90 days when packed in HDPE bottles and stored at either refrigeration or room temperature.

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

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. 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. 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. 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. 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.

Stability of N-Acetylcysteine 60 mg/mL in Extemporaneously Compounded Injectable Solutions.

N-Acetylcysteine (NAC) administered by the IV route is the current treatment of choice for acetaminophen overdose. However, the protocol approved by health authorities in most countries has a complex dosing regimen, which leads to dosage errors in one-third of cases. Therefore, the Canadian Antidote Guide in Acute Care Toxicology and individual poison centres have begun to recommend a simplified regimen using continuous IV infusion. Unfortunately, no study has demonstrated the stability of IV solutions of NAC at concentrations above 30 mg/mL or in solutions other than 5% dextrose. To evaluate the stability of solutions of NAC 60 mg/mL in 0.9% sodium chloride, 0.45% sodium chloride, or 5% dextrose, stored for up to 72 hours in polyvinyl chloride (PVC) bags at 25°C. Solutions of the desired concentration were prepared from a commercial solution of NAC 200 mg/mL, with dilution in 0.9% sodium chloride, 0.45% sodium chloride, or 5% dextrose, and were then stored at room temperature in PVC bags for up to 72 hours. At predetermined time points (0, 16, 24, 40, 48 and 72 h), samples were collected and analyzed using a stability-indicating high-performance liquid chromatography method. A solution was considered stable if it maintained at least 90.0% of its initial concentration. Particulate matter count was also evaluated to confirm chemical stability. Finally, organoleptic properties, such as odour and colour, were evaluated to assess the stability of the solutions. All solutions maintained at least 98.7% of their initial concentration. No obvious changes in odour or colour were observed. Moreover, particle counts remained acceptable throughout the study, according to the criteria specified in United States Pharmacopeia (USP) General Chapter <788>. NAC 60 mg/mL, diluted in 0.9% sodium chloride, 0.45% sodium chloride, or 5% dextrose and stored in PVC bags at 25°C, was chemically and physically stable for a period of at least 72 hours.

Preparation and Evaluation of Extemporaneously Compounded Aspirin Capsules from Crushed Aspirin Tablets

Aims: Extemporaneous preparations of medications might bring about technical and clinical consequences due to formulation failures. Therefore, all such prepared formulas should undergo valid and reliable procedures supported by solid data. Otherwise, patients can experience significant risk due to microbial contamination or physical or chemical changes during the preparation process. Thus, effective extemporaneous preparation relies on correct calculations to avoid extra and serious harm. Therefore, because 50-mg aspirin capsules are not available in Saudi Arabia, this study aimed to formulate 50-mg capsules from available 100-mg aspirin tablets.&#x0D; Methodology: Quality control tests of the preparations were carried out at the time of preparation and after one month of storage at 25 °C and at 40 °C and 75% relative humidity. All tests were carried out according to the British and United States pharmacopeia monograph of aspirin.&#x0D; Results: The drug content assay and uniformity test indicated that the aspirin capsules were within the pharmacopeial limits. The disintegration time for all aspirin capsules was within the pharmacopeial limits of 30 minutes. The aspirin release profile showed that approximately 90% of the aspirin dissolved after 10 minutes.&#x0D; Conclusion: The results indicated that the extemporaneous preparation of ASA capsules complied with the quality control tests for freshly prepared capsules and after one month of storage at room temperature and at 40 °C and 75% relative humidity. The dissolution profile of these capsules indicates immediate and high release of ASA, which is essential to ensure the required absorption. This study is of great importance for patients who need to take this dose of ASA. Pharmacists can prepare good-quality capsules with the desired ASA content using a 100-mg ASA tablet as a source of the active ingredient.

Stability-indicating LC-MS Method for Determination of Stability of Extemporaneously Compounded Buprenorphine Oral Syringes for Neonatal Abstinence Syndrome.

In the hospital settings, buprenorphine is used for the treatment of patients with neonatal abstinence syndrome. It is extemporaneously compounded and stored in oral plastic syringes. However, limited information exists about the stability of buprenorphine and its compounded formulations when stored under specific conditions. Hence, we developed a stability-indicating high-performance liquid chromatography-mass spectrometry (LC-MS) method to analyze the stability of buprenorphine over time. A stability-indicating LC-MS method was developed to map the potential degradation peaks of buprenorphine when exposed to acidic, basic, and oxidative conditions. This method was used to study the stability of compounded buprenorphine oral syringes stored under refrigeration (2°C-8°C) and room temperature (25°C ± 2°C with 60% relative humidity). Syringes from each storage condition were assessed for stability using pH meter and stability-indicating LC-MS assay for 30 days. Buprenorphine gets completely degraded in the presence of acid at the end of 1 hour of exposure. Various degradation peaks were identified using LC-MS assay for buprenorphine under acidic, basic, and peroxide conditions. Stability study of oral buprenorphine syringes showed no precipitation, cloudiness, or color change during this study at all storage conditions. The LC-MS assay revealed that buprenorphine oral syringes retained greater than 90% of the initial concentrations for 30 days. Highly sensitive stability-indicating LC-MS method was developed for studying the stability of extemporaneously compounded buprenorphine oral syringes. This study demonstrates that buprenorphine extemporaneous formulation prepared according to the manufacturers' recommendations is stable under refrigerated or room temperature conditions for 30 days in oral plastic syringes.

Stability Determination of an Extemporaneously Compounded Ambrisentan Suspension by High Performance Liquid Chromatography Analysis

Ambrisentan, an endothelin receptor antagonist FDA-approved for the treatment of pulmonary arterial hypertension in adult patients, lacks an acceptable pediatric dosage form. The objective of this investigation was to determine the stability of an extemporaneously compounded ambrisentan suspension. Ambrisentan suspension was compounded to a concentration of 1 mg/mL using commercially available suspending agents. The suspension was then evenly split into 2 plastic amber prescription bottles. One bottle was stored at room temperature and under continuous fluorescent light while the other bottle was stored under refrigeration and protection from light. A fast and selective reversed-phase high-performance liquid chromatography (HPLC) method was developed and validated for the analysis of ambrisentan. HPLC analysis was performed on samples withdrawn from the stock bottles at predetermined time intervals, up to 90 days. The developed HPLC method enabled the elution and detection of ambrisentan peak at 4.4 minutes. HPLC analysis revealed that all samples from both storage conditions retained >90% potency throughout the study timeframe. There were no signs of any ambrisentan breakdown products on HPLC analysis. Color and odor of the final product was also consistent throughout the 90-day storage period. Ambrisentan suspension, compounded to 1 mg/mL, is stable at room temperature or under refrigeration for up to 90 days.

Stability Evaluation of Extemporaneously Compounded Vancomycin Ophthalmic Drops: Effect of Solvents and Storage Conditions.

Vancomycin is the drug of choice for methicillin-resistant Staphylococcus aureus keratitis and other ocular infections. Vancomycin ophthalmic drops are not commercially available and require compounding. The present study was designed to investigate the stability of vancomycin ophthalmic drops in normal saline, phosphate-buffered saline (PBS), and balanced salt solution (BSS) while stored at room temperature or under refrigeration. Vancomycin ophthalmic drops (50 mg/mL) were aseptically prepared from commercially available intravenous powder using PBS, BSS, and saline. Solutions were stored at room temperature and in a refrigerator for 28 days. The vancomycin stability was tested by a microbiology assay and high-performance liquid chromatography HPLC analysis immediately after formulation and at days 7, 14, and 28 after storage at room temperature or under refrigeration. The pH, turbidity was also tested. Vancomycin formulations in PBS, BSS and normal saline had initial pH of 5; 5.5; 3 respectively. The formulation in PBS developed turbidity and a slight decrease in pH upon storage. Microbiological assay did not show any change in zone of inhibition with any of the formulation upon storage either at room temperature or under refrigeration. HPLC analysis did not detect any decrease in vancomycin concentration or the accumulation of degraded products in any of the formulations upon storage either at room temperature or under refrigeration. Vancomycin ophthalmic drops prepared using PBS, BSS, and normal saline were stable up to the tested time point of 28 days, irrespective of their storage temperature.

Influence of Different Concentrations of Surfactants on Dissolution Profiles of Extemporaneously Compounded Pessaries with Clindamycin Phosphate

Influence of Different Concentrations of Surfactants on Dissolution Profiles of Extemporaneously Compounded Pessaries with Clindamycin Phosphate

Standardization of Concentrations for Extemporaneously Compounded Oral Liquid Medications.

Many children require medications in oral liquid dosage forms when their dose does not conform to a manufactured tablet or capsule size. Liquid medications are also needed for children who are unable to swallow solid dosage forms. This statement from the PPAG is in support of standardizing the concentrations of extemporaneous formulations of liquid medications for the benefits of safety, accuracy, and overall communication between providers.

Stability of Extemporaneously Compounded Domperidone 5 mg/mL Suspension in Oral Mix in Plastic and Glass Bottles and Plastic Syringes

Domperidone liquid for oral administration is not commercially available in Canada, but is needed for patients who cannot swallow intact tablets. To evaluate the stability of domperidone 5 mg/mL suspensions prepared in Oral Mix vehicle and stored, for up to 91 days, in amber polyvinylchloride (PVC) bottles, amber glass bottles, or amber polyethylene terephthalate (PET) bottles at 4°C or 25°C or in polypropylene oral syringes at 25°C. Three separate 300-mL batches of domperidone suspension 5 mg/mL were prepared with Oral Mix vehicle. Fifty-millilitre aliquots of the suspension were stored in 100-mL bottles (amber PVC, amber glass, or amber PET). Half of the bottles of each type were stored at 25°C and half at 4°C. On study days 0, 1, 2, 4, 7, 10, 14, 21, 28, 35, 42, 49, 63, 77, and 91, domperidone concentration was determined, with a validated reverse-phase, stability-indicating liquid chromatographic method, in samples drawn from each type of container stored at each temperature. In addition, 1.5-mL aliquots of a fourth 100-mL batch of suspension were stored in 3-mL oral syringes at 25°C and were tested on the same study days. The concentration of domperidone in all study samples remained above 93% of initial concentration after storage for 91 days. The percent remaining on day 91, based on fastest degradation rate (as represented by the lower limit of the 95% confidence interval [CI]), was at least 92.3% for suspensions stored at 4°C in PVC, glass, and PET bottles. With storage at 25°C, suspensions in PVC and glass bottles retained more than 90% of initial concentration, whereas suspensions in PET bottles and plastic syringes retained 88.9% and 88.0% of initial concentration, respectively. Because suspensions of domperidone in PET bottles and oral syringes retained less than 90% of their initial concentration on day 91 (based on the 95% CI), it is suggested that such suspensions be stored at 4°C or 25°C in any bottle type or syringe with an assigned beyond-use date not exceeding 75 days.

Stability of Dapsone in Extemporaneously Compounded Oral Suspensions

-

Stability of Extemporaneously Compounded Tacrolimus in Glass Bottles and Plastic Syringes.

-

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.

Stability of an Extemporaneously Compounded Oral Suspension of Bosentan

To assess the stability of an extemporaneously compounded oral suspension of bosentan from commercially available tablets for a period of 1 month. A 6.25 mg/mL oral suspension of bosentan monohydrate was prepared from Tracleer tablets. The bosentan suspension was then evenly divided between 2 light-resistant prescription bottles and stored in the dark either under refrigeration (4-8°C) or at controlled room temperature (21-26°C). The suspensions were assessed for physical changes (ease of resuspendability, change in color, change in odor), and samples were drawn immediately after preparation and on days 0, 1, 3, 7, 10, 14, 21, 28, and 31. Samples were analyzed at each time point by high-performance liquid chromatography (HPLC) utilizing a reversed-phase column with chemical stability defined as the retention of at least 90% of the initial intact bosentan concentration measured. No change in suspendability, color, or odor of the compounded bosentan suspensions was noted throughout the storage period. Furthermore, regardless of storage conditions, the oral suspension of bosentan retained at least 94% of the active pharmaceutical ingredient for 31 days after preparation. The results of our study indicate that a 6.25 mg/mL bosentan oral suspension stored in the dark under refrigeration and at room temperature maintains physical and chemical stability for 1 month.