Critical Tools in Tableting Research: Using Compaction Simulator and Quality by Design (QbD) to Evaluate Lubricants' Effect in Direct Compressible Formulation.

As commonly known, the product development stage is quite complex, requires intensive knowledge, and is time-consuming. The selection of the excipients with the proper functionality and their corresponding levels is critical to drug product performance. The objective of this study was to apply quality by design (QbD) principles for formulation development and to define the desired product quality profile (QTPP) and critical quality attributes (CQA) of a product. QbD is a risk- and science-based holistic approach for upgraded pharmaceutical development. In this study, Ibuprofen DC 85W was used as a model drug, Cellactose® 80 along with MicroceLac® 100 as a filler, and magnesium stearate, stearic acid, and sodium stearyl fumarate as lubricants. By applying different formulation parameters to the filler and lubricants, the QbD approach furthers the understanding of the effect of critical formulation and process parameters on CQAs and the contribution to the overall quality of the drug product. An experimental design study was conducted to determine the changes of the obtained outputs of the formulations, which were evaluated using the Modde Pro 12.1 statistical computer program that enables optimization by modeling complex relationships. The results of the optimum formulation revealed that MicroceLac® 100 was the superior filler, while magnesium stearate at 1% was the optimum lubricant. A design space that indicates the safety operation limits for the process and formulation variables was also created. This study enriches the understanding of the effect of excipients in formulation and assists in enhancing formulation design using experimental design and mathematical modeling methods in the frame of the QbD approach.

Outcomes of a Postoperative Data-Extraction Questionnaire After Adenotonsillectomy in Children.

OBJECTIVES/HYPOTHESIS: To evaluate outcomes of a postoperative telephone questionnaire for children who underwent adenotonsillectomy (T&A). To determine whether episodes of postoperative hemorrhage were not captured until the call, and whether this impacted knowledge of physician rates of hemorrhage. STUDY DESIGN: Retrospective database analysis. METHODS: Retrospective analysis of outcomes of an 11-question data extraction tool utilized at a tertiary care children's hospital for follow-up in T&A patients <18 years of age over a 2-year period. Sub-analysis of positive responses to the question asking about incidence of postoperative hemorrhage. RESULTS: During the study period, 1,068/3,142 (34.0%) parents responded to the phone call. Median age was 6.0 years (interquartile range [IQR] 4.0-8.2), and 566 (53.0%) were male. Ninety (8.4%) noted that the child was still snoring, but only 9 (0.84%) reported signs of obstructed breathing. A total of 402 (37.6%) reported a voice change after surgery. Most children (n = 885, 82.9%) did not receive opioid analgesics, and 252 (23.6%) received acetaminophen/ibuprofen 7 days postoperatively. Return visits to the emergency department were reported in 149 patients; primarily for hemorrhage in 46 (30.8%). In 7 (15.2%) patients, the hemorrhage event was not recorded until the call. The majority-of respondents (n = 1,031, 96.5%) were satisfied with the outcome of the procedure. CONCLUSIONS: The postoperative T&A tool provided a means of gathering information on success and satisfaction with surgical outcomes. Children were able to be managed primarily with acetaminophen and ibuprofen. Most complications were captured in the electronic record, although some episodes of hemorrhage were not noted until the call, emphasizing the importance of follow-up. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E2821-E2826, 2021.

Ibuprofen Better than Acetaminophen for Reducing Fever, Pain in Young Children.

According to this study: In children younger than age two, treatment with ibuprofen was associated with reduced fever and less pain within the first 24 hours compared with acetaminophen.The incidence of adverse events was low with both treatments.

Fever response to ibuprofen in viral and bacterial childhood infections.

OBJECTIVE: to compare the antipyretic effects of ibuprofen in febrile children with serious bacterial infections (SBI), and children with a presumed viral infection. METHODS: A prospective cross- sectional study was conducted in a pediatric Emergency department between October 2018 and March 2020 for children aged 3 months to 4 years with a rectal temperature ≥ 38.5 °C. Patients received 10 mg/kg of ibuprofen oral suspension. Rectal temperature was measured 60 and 120 min after administration. Laboratory and imaging evaluations were performed for each study participant in order to identify serious bacterial infection. RESULTS: Ninety patients were included, of which 18 were diagnosed with serious bacterial infections. There was no significant difference in age, fever at presentation and duration of fever between the groups. No significant difference was noted in body temperature reduction at 60 and 120 min after ibuprofen administration (1.09 ± 0.75 °C vs 0.89 ± 0.58 °C, mean difference -0.12 °C, 95% CI -0.54-0.15 °C; 1.85 ± 0.53 °C vs 1.78 ± 0.83 °C, mean difference - 0.07 °C, 95% CI -0.49-0.36 °C, in the SBI and non-SBI groups respectively). CONCLUSION: Fever response to Ibuprofen administration is not indicative of serious bacterial infections in children under 4 years of age. Larger prospective studies are required to define whether the lack of response to Ibuprofen has any impact on the management of febrile children.

Comparison of Acetaminophen (Paracetamol) With Ibuprofen for Treatment of Fever or Pain in Children Younger Than 2 Years: A Systematic Review and Meta-analysis.

Importance: Acetaminophen (paracetamol) and ibuprofen are the most widely prescribed and available over-the-counter medications for management of fever and pain in children. Despite the common use of these medications, treatment recommendations for young children remain divergent. Objective: To compare acetaminophen with ibuprofen for the short-term treatment of fever or pain in children younger than 2 years. Data Sources: Systematic search of the databases MEDLINE, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials and the trial registers ClinicalTrials.gov and the Australian New Zealand Clinical Trials Registry from inception to March 2019, with no language limits. Study Selection: Studies of any design that included children younger than 2 years and directly compared acetaminophen with ibuprofen, reporting antipyretic, analgesic, and/or safety outcomes were considered. There were no limits on length of follow-up. Data Extraction and Synthesis: Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline, 2 authors independently extracted data and assessed quality. Data were pooled using a fixed-effects method if I2 was less than 50% and using a random-effects method if I2 was 50% or greater. Main Outcomes and Measures: The primary outcomes were fever or pain within 4 hours of treatment onset. Safety outcomes included serious adverse events, kidney impairment, gastrointestinal bleeding, hepatotoxicity, severe soft tissue infection, empyema, and asthma and/or wheeze. Results: Overall, 19 studies (11 randomized; 8 nonrandomized) of 241 138 participants from 7 countries and various health care settings (hospital-based and community-based) were included. Compared with acetaminophen, ibuprofen resulted in reduced temperature at less than 4 hours (4 studies with 435 participants; standardized mean difference [SMD], 0.38; 95% CI, 0.08-0.67; P = .01; I2 = 49%; moderate quality evidence) and at 4 to 24 hours (5 studies with 879 participants; SMD, 0.24; 95% CI, 0.03-0.45; P = .03; I2 = 57%; moderate-quality evidence) and less pain at 4 to 24 hours (2 studies with 535 participants; SMD, 0.20; 95% CI, 0.03-0.37; P = .02; I2 = 25%; moderate-quality evidence). Adverse events were uncommon. Acetaminophen and ibuprofen appeared to have similar serious adverse event profiles (7 studies with 27 932 participants; ibuprofen vs aceteminophen: odds ratio, 1.08; 95% CI, 0.87-1.33; P = .50, I2 = 0%; moderate-quality evidence). Conclusions and Relevance: In this study, use of ibuprofen vs acetaminophen for the treatment of fever or pain in children younger than 2 years was associated with reduced temperature and less pain within the first 24 hours of treatment, with equivalent safety.

Comparison of ibuprofen and piroxicam gel in the treatment of trauma pain: A randomized double-blind trial of geriatric population.

OBJECTIVE: This study aimed to compare the analgesic efficacy of topical ibuprofen and topical piroxicam for acute musculoskeletal injuries. METHODS: In this prospective, randomized, controlled, double-blinded study, geriatric patients were assigned to groups to receive either topical ibuprofen (n = 70) or topical piroxicam (n = 69). The first dose of gel was applied in the emergency department and the remaining doses were self-administered at home by the patients thrice daily for 72 h. For each patient, the initial baseline visual analog scale (VAS) score (V 0) was compared with the VAS scores at the 60 min (V1), 120 min (V2), 24 h (V3) and 72 h (V4) time points. The decreases in VAS scores, clinical effectiveness of the treatments, and incidence of adverse events were evaluated. RESULTS: In the topical ibuprofen group, the VAS scores were significantly lower at each measurement time point compared to baseline (p < .001). The results were as follows: V0 -V: 1.08, 95% CI: 0.56-1.61; V0 -V2: 1.09, 95% CI: 0.49-1.69; V0 -V3: 1.44, 95% CI: 0.81-2.07; V0 -V4: 1.59, 95% CI: 0.91-2.26. The mean percentage decrease in the VAS scores in the topical ibuprofen group was significantly higher than that in the topical piroxicam group (p < .001). The clinical effect of treatment was found to be significantly higher for the ibuprofen gel group (p < .001). There was no substantial difference in treatment-related adverse events between the groups (p > .05). CONCLUSION: Ibuprofen gel, which is a safe treatment option for geriatric patients, is more clinically effective than piroxicam gel. Response to Reviewers.

Real-time quantification of low-dose cohesive formulations within a sampling interface for flowing powders.

This study investigates the performance of a sampling interface for monitoring cohesive, flowing powder formulations with Hausner's Ratio and Carr's Index higher than 1.5 and 35%, respectively. The sampler device was operated in combination with near-infrared (NIR) spectroscopy to quantify ibuprofen concentrations between 1.5 and 4.5% w/w. NIR spectra also provided essential information to study the process dynamics within the sampler. The 200 spectra per blend obtained demonstrated a continuous powder flow with no evidence of agglomerates or segregation within the sampler for a blend of 6 kg. A NIR calibration model was optimized to predict independent test blends, delivering root mean square error of predictions and bias under 0.1% w/w. The test blends were within specifications according to the requirements of European Pharmacopeia. Variographic analysis demonstrated that the sampler device may determine low drug concentration in cohesive powder blends, presenting sampling errors below 0.011 (%w/w)2. This analysis also demonstrated that an increase in the blend compressibility leads to a slight rise in sampling errors within the sampler device. The sampler device offers statistical robustness in the evaluation of blend uniformity, providing greater confidence in the quality determination of the cohesive powder blends without significantly affecting its flow properties.

Dexibuprofen: Statistical assessment of drug release kinetics and investigative quality perspective.

Healthcare professionals including physicians and pharmacists have been trying since long to come across and work out regarding the issue of generic alternatives, which is highly affected by factors like therapeutic efficacy, cost effectiveness, aesthetic and elegant appearance and implementation of packaging number over the drug product. However, the community pharmacist professionals are also facing difficulty in making decision regarding selection and dispensing the most efficacious brand to the patients. In this regard, the initiation of recent approaches for the development of amenable drug products has led to evolve the concept of generating new avenues for achieving higher patient compliance. Hence, the objective of this study was to evaluate the quality attributes and make comparisons regarding different brands of Dexibuprofen available in market of Karachi, Pakistan. The study is based on evaluation of physical chemical parameters of five different brands. Moreover, a comparative dissolution profile of selected brands of Dexibuprofen was also performed by applying numerous approaches. DEX-1was selected as reference while DEX-2- DEX-5 was selected as test brands. Results of all the selected brands met all the compendial requirements. Interpretation of the entire aforementioned test was evaluated using model independent, model- dependent and one - way ANOVA. The work presented in this study has been designed to provide quality standard products easily accessible in Pakistani market.

Particulate Study on NeoProfen, a Neonatal Injectable Product.

UNLABELLED: NeoProfen or sterile ibuprofen L-lysine at 10 mg/mL ibuprofen, in 2 mL single-use Type I glass vials is often a first choice medication used to close a patent ductus arteriosus in neonatal patients from 500 to 1500 g body weight. Visible particulate matter was found in vials that were placed on a commercial stability program prior to the approved expiration date of 2 years. A combination of instrumental techniques including inductively coupled plasma-mass spectrometry, x-ray photoelectron spectroscopy, scanning electron microscopy energy dispersive x-ray spectrometry, and Raman and Fourier transform infrared microspectroscopy was used to evaluate stability, pilot batch and packaging samples in a root cause investigation. The particulate matter was shown to consist largely of ibuprofen aluminum salts of various stoichiometries. It developed over time by a substitution mechanism, in which the ibuprofen anion in solution reacts with the aluminum oxide network of the borosilicate glass giving the ibuprofen aluminum salt with =Al-OH remaining in the network. For corrective action an alternate Type I borosilicate glass vial with interior coating, not found in the original vial, was chosen for the product to prevent this occurrence. LAY ABSTRACT: NeoProfen (sterile preservative-free ibuprofin L-lysine at 17 mg/mL in a single-use glass vial) is used to close a clinically significant patent ductus arteriosus in premature infants no more than 32 weeks gestational age. The neonatal population is especially sensitive to outside chemical, physical and environmental conditions because of incompletely developed organ systems, low birth weight and other underlying conditions. Two batches of this product were voluntarily recalled by the manufacturer, Lundbeck, and investigated for the source of particulate matter observed during a commercial stability testing program. This was found to result from an interaction between the product and the Type I borosilicate glass vial where ibuprofen substitutes for the aluminum oxide network in the glass, forming an ibuprofen aluminum hydroxide salt as particulate. In order to prevent this salt formation an alternate glass vial was chosen which had interiors treated using a chemical vapor deposition technique. These vials were found to preserve NeoProfen quality properties during short term stress and medium term stability studies.

Bioconcentration of ibuprofen in fathead minnow (Pimephales promelas) and channel catfish (Ictalurus punctatus).

Pharmaceutical products and their metabolites are being widely detected in aquatic environments and there is a growing interest in assessing potential risks of these substances to fish and other non-target species. Ibuprofen is one of the most commonly used analgesic drugs and no peer-reviewed laboratory studies have evaluated the tissue specific bioconcentration of ibuprofen in fish. In the current study, fathead minnow (Pimephales promelas) were exposed to 250 µg L(-1) ibuprofen for 28 d followed by a 14 d depuration phase. In a minimized bioconcentration test design, channel catfish (Ictalurus punctatus) were exposed to 250 µg L(-1) for a week and allowed to depurate for 7 d. Tissues were collected during uptake and depuration phases of each test and the corresponding proportional and kinetic bioconcentration factors (BCFs) were estimated. The results indicated that the BCF levels were very low (0.08-1.4) implying the lack of bioconcentration potential for ibuprofen in the two species. The highest accumulation of ibuprofen was observed in the catfish plasma as opposed to individual tissues. The minimized test design yielded similar bioconcentration results as those of the standard test and has potential for its use in screening approaches for pharmaceuticals and other classes of chemicals.

Effect of grewia gum as a suspending agent on ibuprofen pediatric formulation.

The purpose of this work was to evaluate the potential of grewia gum (GG) as a suspending agent in pharmaceutical oral formulation using ibuprofen as model drug. Ibuprofen pediatric suspension (25 mg/5 mL) was formulated with grewia gum (0.5% w/v) as the suspending agent. Similar suspensions of Ibuprofen containing either sodium carboxymethylcellulose (Na-CMC) or hydroxymethylpropylcellulose (HPMC) were also produced. The suspensions were evaluated for ease of redispersion, sedimentation, rheological properties, and the effect of aging on the rheological properties at 25°C. The particle size and particle size distributions of the dispersed solute were determined. The redispersion time was 19, 11, and 0.5 min, respectively, for formulation containing Na-CMC, HPMC, and GG .The sedimentation volumes were 0.05, 0.05, and 0.125 mL, respectively, for Na-CMC, HPMC, and GG . Viscosities of suspensions at spindle speed of 25 rpm were of the order: GG > HPMC > Na-CMC when freshly prepared and of the order: HPMC > GG > Na-CMC within 6 months of storage. The particles size was 72.72, 73.82, 81.93, and 83.41 µm, respectively, for suspensions containing Na-CMC, ibuprofen alone, HPMC, and GG. Greatest hysteresis was observed in formulation containing HPMC. All the formulations were stable. It was our conclusion that the difference in the physicochemical properties of ibuprofen pediatric formulations was influenced more by the suspending agent used in the formulations than the drug. GG combined better redispersion with minimal changes in viscosity on storage compared to Na-CMC and HPMC as suspending agent. Thus GG may serve as a good suspending agent requiring no further aid in suspension redispersibility.

HPLC determination of ciprofloxacin, cloxacillin, and ibuprofen drugs in human urine samples.

This paper reports, for the first time, a liquid chromatographic method for the simultaneous determination of three frequently co-administered active principles, two antibiotics, ciprofloxacin (CIPRO) and cloxacillin (CLOXA) belonging to the fluoroquinolones and beta-lactam families, respectively, and ibuprofen (IBU), a non-steroidal anti-inflammatory drug. The chromatographic separation was performed on a C-18 analytical column, using isocratic elution with methanol-acetonitrile-pH 3 formate buffer (CT = 0.1 M) (15:12:73, v/v/v) for 3 min and, after that, a linear gradient with methanol-acetonitrile (88:12, v/v) for 8 min. Several absorption spectra were obtained for each peak using a DAD detector. Chromatograms at the maximum absorption wavelength for each analyte, 220 nm for both IBU and CLOXA, and 280 nm for CIPRO were selected as the most suitable. The proposed chromatographic method requires about 15 min per sample. The presence of a urine background was tested and no interference was found. The method was satisfactorily applied to the determination of CIPRO, CLOXA, and IBU, in fortified urine, and in urine samples from a patient undergoing treatment with these three active principles, among others. Limits of quantification in urine were 1.00, 1.70, and 2.87 microg/mL for CIPRO, CLOXA, and IBU, respectively.

International harmonization of generic drugs: in vitro dissolution tests for Japanese and American generic tablets.

Ibuprofen tablets on the market in Japan and the USA were compared by manual- and automatic-dissolution tests according to USP24 criteria. Dissolution test were performed in 900 ml of phosphate buffer of pH 7.2 at 37.0+/-0.5 degrees C at 50 rpm for 60 min, and the time required for 70% dissolution (T70%) and 5% dissolution after 60 min (A60) were evaluated. The dissolution profiles of both Japanese and American tablets by the automatic-method showed almost the same profiles as those of the manual method. T70% of the American and Japanese tablets by the manual method were not significantly different (p>0.05) from the automatic-method at various sampling positions. The A60 of the American and Japanese tablets by the manual-method was not significantly different (p>0.05) except at one position. The results indicate that the automatic-method was more reproducible than the manual-method, and also that systematic error was negligible. The T70% and A60 of the American tablets were significantly different (p<0.05) from the Japanese tablets. The American tablets were a film-coated over-the-counter drug and the Japanese tablets were a sugar-coated prescription drug. There was a difference in dissolution behavior between the dosage forms of the two countries.

Biowaiver monographs for immediate release solid oral dosage forms: ibuprofen.

Literature data are reviewed on the properties of ibuprofen related to the biopharmaceutics classification system (BCS). Ibuprofen was assessed to be a BCS class II drug. Differences in composition and/or manufacturing procedures were reported to have an effect on the rate, but not the extent of absorption; such differences are likely to be detectable by comparative in vitro dissolution tests. Also in view of its therapeutic use, its wide therapeutic index and uncomplicated pharmacokinetic properties, a biowaiver for immediate release (IR) ibuprofen solid oral drug products is scientifically justified, provided that the test product contains only those excipients reported in this paper in their usual amounts, the dosage form is rapidly dissolving (85% in 30 min or less) in buffer pH 6.8 and the test product also exhibits similar dissolution profiles to the reference product in buffer pH 1.2, 4.5, and 6.8.

Comparison of two ibuprofen formulations in the treatment of shoulder tendonitis.

In order to compare the efficacy and tolerance of two drug formulations of ibuprofen, conventional tablets 600 mg QID (CI) and sustained-release tablets 1200 mg BID (SRI), a total of 147 patients in 7 centres in Denmark with nontraumatic shoulder pain were included in a double-blind dummy study. Initially all patients received a local injection of corticosteroid and local anaesthetic, and were randomly allocated either drug (CI or SRI) for a period of 3 weeks. Complete relief was recorded from significantly more of the patients in the CI group (21%) than in the SRI group (7%) while a similar number of patients improved viz., 67% of the SRI treated group and 77% of the CI treated group. Based on doctor's assessment improvement in the two groups was equal. 44% of the patients recorded side effects, the number and pattern being the same in the two groups. No serious side effects were recorded. It is concluded that the two treatment regimens can be rated as clinically equivalent.

S-ibuprofen versus ibuprofen-racemate. A randomized double-blind study in patients with rheumatoid arthritis.

Ibuprofen (ibu) is a racemic 2-arylpropionic acid non-steroidal anti-inflammatory drug whose activity is due mainly to the S-enantiomer. So far only the racemic compound is in clinical use. A double-blind randomized trial was carried out for a 2-week period in 50 patients with classical rheumatoid arthritis (RA) (Steinbrocker II-III) to compare the effectiveness and tolerance of S-ibu (400 mg T.I.D.) with that of the racemic compound (600 mg T.I.D.). Ritchie-index, limitation of movement, joint pain on pressure and pain at night decreased significantly in both groups. Due to lack of effectiveness, the dose had to be increased in 3 patients from the S-ibu group as well as in 6 patients from the racemic group resulting in mean daily doses of 1220 mg S-ibuprofen and 1870 mg racemic ibu. No statistically significant difference could be found between both groups concerning efficacy and unwanted effects. Therefore, S-ibu given alone may be advantageous because the metabolic load to the human body is reduced and patients are more likely to comply with drug doses of 1.2 g/day as compared to 1.8 g/day.