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Ipratropium bromide (IPR) and fenoterol hydrobromide (FEN) have recently been combined in a promising inhaler to treat two prevalent inflammatory illnesses of the airways: bronchial asthma and chronic obstructive pulmonary disease (COPD). The necessity for a single, sensitive, and trustworthy analytical approach to cover the diverse and necessary tests of in-vitro and in-vivo studies is greatly grown with the rising production of new fixed combinations. Two novel, selective and environmentally friendly LC techniques were developed in order to guarantee precise measurement of IPR and FEN in their challenging formulation. The initial technique involved high-performance thin-layer chromatography (HPTLC) in conjunction with densitometric quantification. Chromatographic separation was attained on HPTLC plates utilizing ethyl acetate - ethanol - acetic acid (5.0:5.0:0.1, by volume) as a developing system. Densitometric quantification of the separated bands was carried out at 220.0 nm over concentration ranges of 0.50-15.0 µg/band for IPR and 0.50-12.0 µg/band for FEN. High-performance liquid chromatography (HPLC) paired with diode array detection (DAD) was the core of the second technique. The optimized separation was achieved on a Zorbax SB C18 (150 × 4.6 mm, 5 µm) column with a combination of 10.0 mM potassium dihydrogen orthophosphate, pH 5.0 ± 0.1, adjusted with o-phosphoric acid and methanol (70:30, v/v) as the mobile phase and pumped at flow rate of 1.0 mL/min. The peaks were monitored at 220.0 nm using diode array detection, achieving linearity range of 5.0-200.0 µg/mL for both drugs. The ICH criteria have been verified and both methods have been confirmed to be valid, and successfully applied for assay the cited drugs in the Atrovent® comp HFA metered dose inhaler as well as delivered dose uniformity testing of the final product. Finally, whiteness appraisal and several state-of-the-art green evaluation metrics were applied to evaluate the sustainability of the proposed methods. The suggested approaches produced promising results and are the first simple and sustainable methodologies for the simultaneous quantification of both drugs in different real samples, all of which strongly suggest their application in quality control laboratories.

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Compressed mini-tablets in sachets or capsules are an increasingly prevalent oral solid dosage form for pediatric products. While resembling adult tablets, additional care is required to control weight and potency (blend uniformity) variation due to their small size (≤2.5 mm average diameter). Additionally, sachet fill count errors complicate dose accuracy as they are difficult to resolve with weight-checking equipment. This study quantified the probability of failing content uniformity (CU) specifications (which results in the inability to release a batch) defined in USP <905> using a Monte Carlo computational model. Failure risk was modeled as a function of sachet fill count, mini-tablet weight, potency distribution, and fill error frequency. The model allows product developers to (1) determine appropriate fill counts based on anticipated product weight and potency relative standard deviation (RSD), (2) set fill error probability tolerances for sachet filling processes, (3) identify CU improvement opportunities, and (4) quantify the probability of CU failure informing risk management activities and risk disclosure for regulatory agencies. A representative product with weight and potency RSD no greater than 5%, fill count of 1-4 mini-tablets per sachet, and fill error probability per mini-tablet filled of 0.1% may experience CU batch failure probabilities as high as 8.23%, but only 0.283% if the fill count is increased to 5-10 mini-tablets per sachet. Generally, fill counts of less than five mini-tablets per sachet should be avoided where possible.

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The determination of the variability of critical dosage form attributes has been a challenge in establishing the quality of pharmaceutical products. During the development process knowledge is minimal. Consequently, ad hoc statistical tools such as hypothesis or significance tests, with calibrated decision error rates are often used in an effort to vet CQAs (Critical Quality Attributes) and keep their levels "between the curbs". As progress moves towards product launch, process and mechanistic understanding grows considerably and there are opportunities to leverage that knowledge for predictive modeling. Bayesian models offer a coherent strategy for integrating prior knowledge into both experimental design as well as predictive analysis for optimal risk-based decision making. This is because the Bayesian paradigm, unlike the frequentist paradigm, can assign probabilities to underlying states of nature that directly impact safety and efficacy such as the population distribution of tablet potencies or dissolution profiles in a batch. However, there are challenges and reluctance in switching to a predictive modeling quality framework once regulatory approval has been attained. This paper offers encouragement to make this switch. In this paper, we review a joint Long Island University - Purdue University (LIU-PU) FDA funded project whose purpose was to further integrate the concepts of this adaptive approach to lot release with the rationale and methods for data generation and curation and to extend the testing of this approach. We discuss the utility of the approach in product development. We consider the regulatory compliance implications, with examples, and establish a potential way forward toward implementation of this approach for both industry and regulatory stake-holders.

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Background and Purpose: Total skin electron beam therapy (TSEBT) is an important skin-directed radiotherapeutic procedure done in the treatment of cutaneous T-cell lymphomas, namely, mycosis fungoides (MF). This procedure is usually done at larger source-to-surface distances with the patient standing on a rotatory platform. As the patient has to stand in different positions without any rigid immobilization devices, there are chances that the total skin may not get uniformly irradiated which could lead to nonuniform dose distributions. Therefore, all the necessary arrangements should be made to evaluate the dose for different regions of the skin using suitable in vivo dosimeters at the radiotherapy centers offering these treatments. This study aimed to evaluate the consistency between the delivered and planned doses in vivo during TSEBT using Gafchromic EBT3 film dosimetry. Materials and Methods: The surface dose for the six MF patients treated for TSEBT at our hospital from 2018 to 2022 was measured and evaluated. 2 cm × 2 cm Gafchromic® EBT3 films were used to measure skin dose at reference body positions of clinical interest. All the patients were treated with the modified Stanford technique. The irradiated film strips were analyzed for the dose using the IMRT OmniPro software. The doses at respective positions were expressed as mean dose ± standard deviation and the deviation was calculated as the percentage of the prescribed dose. Results: One hundred and fifty-four Gafchromic® EBT3 film strips irradiated on six TSEBT patients showed a maximum dose variation of 2.00 ± 0.14 Gy, in the central body regions. The dose variation in the peripheral areas such as hands and ears was larger. A variation of 2 ± 0.32 Gy was observed on the hands and ears. The uniformity of the dose delivered to maximum body parts was within -7% and +16% for the peripheral areas like hands. The American Association of Physicists in Medicine recommends a dose uniformity of 8% and 4% in the vertical and horizontal patient plane for direct incident beam; however, for oblique incidences like in the modified Stanford technique, the dose variation is about 15%. Conclusion: In vivo dosimetry using Gafchromic EBT3 film dosimetry for TSEBT yields objective data to find the under or overdose regions. That can be useful to provide quality treatment, especially when treatments tend to be as complex as TSEBT.

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INTRODUCTION: Loteprednol etabonate (submicron) ophthalmic gel 0.38% (LE SM gel 0.38%) is a corticosteroid formulation designed to retain the nonsettling characteristics of loteprednol etabonate ophthalmic gel 0.5%, but with reduced drug particle size to improve ocular penetration, allowing for reduced dosing frequency. This study compared the dose uniformity of LE SM gel 0.38% with branded and generic prednisolone acetate (PA) 1% suspensions under simulated in-use dosing conditions. METHODS: Drug concentrations in drops of LE SM gel 0.38% and PA 1% suspensions, expressed from bottles that were shaken or not shaken, were determined during 2 weeks of simulated on-label dosing (LE SM gel 0.38%: three times daily; PA suspensions: four times daily). Sedimentation of drug particles was assessed for each product using dispersion analysis. RESULTS: The mean (SD) percent declared drug concentration of LE SM gel 0.38% over 2 weeks was 103.2% (1.3%) when the drug was dispensed from shaken bottles and 103.3% (1.5%) when dispensed from unshaken bottles. However, for branded and generic PA suspensions, mean (SD) percent declared concentrations were 102.2% (1.4%) and 98.3% (2.9%), respectively, when dispensed from shaken bottles; and 89.2% (18.6%) and 78.3% (13.5%), respectively, when dispensed from unshaken bottles. Dispersion analysis showed that drug particles in LE SM gel 0.38% remained fully suspended under accelerated sedimentation conditions, whereas both branded and generic PA suspension drug particles settled out of suspension. CONCLUSIONS: LE SM gel 0.38% delivered the drug consistently at the declared concentration over the entire 2 weeks of simulated in-use dosing conditions, regardless of whether the drug was dispensed from shaken or unshaken bottles. However, both branded and generic PA suspensions required the bottle to be shaken to provide a consistent drug concentration.

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Mediterranean fly pest (Ceratitis) is one of the most destructive pests of fruit species in Morocco. The sterile insect technique (SIT) is an environmentally friendly strategy that uses ionizing radiation to sterilize adult insects. Morocco has a panoramic gamma irradiator used to irradiate agri-food products. This irradiator is not dedicated to SIT programs due to its geometry that does not allow to obtain a dose uniformity ratio (DUR) recommended for such applications. This article presents a Monte Carlo study to investigate the feasibility of using the panoramic gamma irradiator at the National Institute for Agronomic Research (NIAR) of Tangier, Morocco, to setting up SIT methods and contributing to Ceratitis control programs. The Monte Carlo method was used to simulate the concrete bunker in which the panoramic gamma irradiator is installed. To obtain a recommended DUR required for SIT programs, two cells similar of the Gammacell-220 irradiator, which is mainly used in the SIT programs around the world, were simulated inside the concrete bunker. The simulation and calculations were performed using the MCNPX-2.7e Monte Carlo simulation code. It is demonstrated that at both investigated positions, the spatial distribution of dose rates in the two modeled irradiation cells, which were similar to a gammacell-220 irradiator cell, are uniform enough that the cells can be used for SIT programs. It is concluded that the panoramic irradiator at NIAR can be used to contribute to the control of Mediterranean fly pest and other insect pests in Morocco.

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In this work, a novel risk-based methodology for lot release is proposed. Its objective is to assess the risk that a lot declared to have passed truly meets product specifications. The methodology consists of 3 parts: adaptive sample size determination, estimation of the probability that the product was within specifications, and the lot-release decision. The methodology provides a probabilistic statement about the true quality of the batch. Having a probability estimate is the essential condition of risk-based decision-making. We demonstrate the proposed methodology on experimental data generated from 17 immediate-release solid oral drug products from a number of different manufacturers with 5 to 10 lots per manufacturer.

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The present investigation is to study the effect of two different induction ports (IP), i.e., USP IP and USP-modified IP equipped with andersen cascade impactor on in vitro aerodynamic performance along with the impact of USP-modified glass sampling apparatus on delivered dose uniformity of fluticasone propionate (FP) dry powder inhaler (DPI). FP DPI was fabricated by spray drying technique using engineered mannitol microparticles (EMP) with different force controlling agents, i.e., leucine and magnesium stearate. Additionally, commercially available two DPI inhaler devices namely Handihaler® and Breezhaler® were used to aerosolize the FP blends. Spherical smooth surface of EMP showed good powder flow properties and acceptable percentage content uniformity (> 95%). Amounts of FP deposited in cascade assembly using USP-modified IP with the Breezhaler® device was significantly higher (1.32-fold) as compared with the Handihaler® device. Moreover, USP-modified IP showed better deposition as compared with USP IP. Additionally, both inhaler devices showed a satisfactory delivered dose (> 105%) for FP using modified glass sampling apparatus at a flow rate of 60 L/min for 2 s. It was interesting to note that not only formulation properties but also IP geometry and device resistance have significant impact on DPI deposition pattern. This study is a first detailed account of aerodynamic performance of FP using USP-modified IP and USP-modified glass sampling apparatus. Thus, it can be of potential importance for both the academic and industry perspective.

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Objective To explore the feasibility of application of the Monte Carlo method to simulate the whole body dose distribution in patients with total body X (γ) ray irradiation by comparing the actual measurement results.Methods A Monte Carlo model of a 6 MV Elekta Synergy Clinical linear accelerator was established by MCNPX.According to the relationship between the CT value and the density of the material,the CT of the ATOM physical phantom was converted into a voxel phantom for MCNPX calculation.The dose distribution of the whole body was simulated in the total body X (γ) ray irradiation.The simulated results were compared with the measurement values of the thermoluminescence dosimetry at different positions in the ATOM physical phantom to analyze the differences.Results The difference between the depth dose curve and the off-axis dose curve and the actual measurement values calculated by the 6 MV accelerator treatment head model in the water tank was less than 2％,with the maximum dose depth of approximately 1.5 cm and field size of 10 cm× 10 cm,which were consistent with the actual measurement values.The maximum difference between the simulated results at different locations in the body and the thermoluminescence dosimeter was approximately 4％,and the simulated results of MCNPX were almost in good agreement with the results of thermoluminescence.Conclusions The whole body dose distribution in patient with total body X (γ) ray irradiation can be accurately simulated by MCNPX.Monte Carlo simulation makes it possible to optimize the uniformity of the total body dose during the total body irradiation process.

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Budesonide Easyhaler® multidose dry powder inhaler is approved for the treatment of asthma. Objectives were to determine the delivered dose (DD) uniformity of budesonide Easyhaler® in simulated real-world conditions and with different inspiration flow rates (IFRs). Three dose delivery studies were performed using 100, 200, and 400 µg/dose strengths of budesonide. Dose uniformity was assessed during in-use periods of 4-6 months after exposure to high temperature (30°C) and humidity (60% relative humidity) and after dropping and vibration testing. The influence of various IFRs (31, 43, and 54 L/min) on the DD was also investigated. Acceptable dose uniformity was declared when mean DD were within 80-120% of expected dose; all data reported descriptively. DD was constant (range: 93-109% of expected dose) at all in-use periods and after exposure to high temperature and humidity for a duration of up to 6 months. DD post-dropping and -vibration were unaffected (range 98-105% of expected dose). Similarly, DD was constant and within 10% of expected dose across all IFRs. Results indicate that budesonide Easyhaler® delivers consistently accurate doses in various real-life conditions. Budesonide Easyhaler® can be expected to consistently deliver a uniform dose and improve asthma control regardless of high temperature and humidity or varying IFR.

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There is as yet no commercialized preparation for oral administration of flecainide acetate (FA) to children. In such cases, manipulation of commercial tablets is the usual practice in pharmacy services of hospitals and compounding pharmacies, to provide a suitable dosage form for this vulnerable pediatric population group. In this study, we have formulated FA as an oral solution, as an alternative to the suspension elaborated from commercial tablets. Due to this sensitivity of young patients, we have used the pure active pharmaceutical ingredient (API) and the lowest permitted levels of pediatric excipients. Despite being a highly soluble API, only one of the formulations appears as a transparent solution due to complete FA solubilization. The proposed formulation is physico-chemically and microbiologically stable and the mass and dose uniformity is appropriate for 30 days' storage at 25 °C.

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This study aimed to evaluate dose uniformity for 192Ir and 60Co stepping sources. High dose rate 192Ir and 60Co stepping sources were simulated by the MCNPX Monte Carlo code. To investigate dose uniformity, treatment lengths of 30, 50, 100, and 150 mm with stepping distances of 3, 5, 7, and 10 mm were considered. Finally, dose uniformity for the 192Ir and 60Co stepping sources with increasing distances from the source were assessed at these treatment lengths and steps. The findings showed that the dose distribution was non-uniform for regions in close vicinity of the source, especially in the high source steps, but for most points at distances >10 mm from the center of the source, the dose distribution was uniform. For most points, the dose uniformity increased with reduction of the source steps and increments of the transverse distance from the source. The dose non-uniformity was similar for most of the corresponding points of 60Co and 192Ir sources with the same treatment lengths and source steps, except at the distance of 150 mm. When using stepping technique for the treatment of tumors, more attention should be focused on treatment planning, especially with higher stepping distances and lower transverse distances from the source.

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PURPOSE: To achieve stereotactic radiosurgery (SRS) dose distributions with sharp gradients using orthovoltage energy fluence modulation with inverse planning optimization techniques. METHODS: A pencil beam model was used to calculate dose distributions from an orthovoltage unit at 250 kVp. Kernels for the model were derived using Monte Carlo methods. A Genetic Algorithm search heuristic was used to optimize the spatial distribution of added tungsten filtration to achieve dose distributions with sharp dose gradients. Optimizations were performed for depths of 2.5, 5.0, and 7.5 cm, with cone sizes of 5, 6, 8, and 10 mm. In addition to the beam profiles, 4π isocentric irradiation geometries were modeled to examine dose at 0.07 mm depth, a representative skin depth, for the low energy beams. Profiles from 4π irradiations of a constant target volume, assuming maximally conformal coverage, were compared. Finally, dose deposition in bone compared to tissue in this energy range was examined. RESULTS: Based on the results of the optimization, circularly symmetric tungsten filters were designed to modulate the orthovoltage beam across the apertures of SRS cone collimators. For each depth and cone size combination examined, the beam flatness and 80-20% and 90-10% penumbrae were calculated for both standard, open cone-collimated beams as well as for optimized, filtered beams. For all configurations tested, the modulated beam profiles had decreased penumbra widths and flatness statistics at depth. Profiles for the optimized, filtered orthovoltage beams also offered decreases in these metrics compared to measured linear accelerator cone-based SRS profiles. The dose at 0.07 mm depth in the 4π isocentric irradiation geometries was higher for the modulated beams compared to unmodulated beams; however, the modulated dose at 0.07 mm depth remained <0.025% of the central, maximum dose. The 4π profiles irradiating a constant target volume showed improved statistics for the modulated, filtered distribution compared to the standard, open cone-collimated distribution. Simulations of tissue and bone confirmed previously published results that a higher energy beam (≥ 200 keV) would be preferable, but the 250 kVp beam was chosen for this work because it is available for future measurements. CONCLUSIONS: A methodology has been described that may be used to optimize the spatial distribution of added filtration material in an orthovoltage SRS beam to result in dose distributions with decreased flatness and penumbra statistics compared to standard open cones. This work provides the mathematical foundation for a novel, orthovoltage energy fluence-modulated SRS system.

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PURPOSE: The purpose of the study was to determine the concentrations of Flarex® and Lotemax® when shaken and not shaken. Many patients fail to shake or inappropriately shake suspensions of corticosteroids before instillation as directed. This study was designed to help determine what concentration of corticosteroid these patients are receiving. In addition, independent confirmation of loteprednol etabonate ophthalmic gel dose uniformity was determined and compared as a possible alternative. METHODS: Drug concentrations of shaken versus unshaken Flarex and Lotemax were determined over a 20-day simulated tapered course in our institutional laboratory. Collected samples were analyzed by reversed-phase high-performance liquid chromatography with photodiode array detection at 240 nm. RESULTS: Flarex had a mean concentration of 93.7% of the declared concentration when shaken and 7.25% when not shaken. The difference between these groups was statistically significant (P = 0.0001). Lotemax had a mean concentration of 96.74% of the declared concentration when shaken and a mean concentration of 98.97% when not shaken. The difference between these groups was not statistically significant (P = 0.194). CONCLUSIONS: Flarex maintains dose uniformity when shaken. When not shaken, it has poor dose uniformity. Lotemax was consistent whether shaken or not in our study and can be considered to eliminate the variability of poor patient compliance with shaking. The manufacturers of both drugs recommend shaking before application.

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CONTEXT: The formulation of an active pharmaceutical ingredient (API) as oral solution or suspension in pediatrics is a habitual practice, due to the non-existence of many commercialized medicines in pediatric doses. It is also the simplest way to prepare and administer them to this vulnerable population. The design of a formulation that assures the dose and the system stability depends on the physico-chemical properties of the API. OBJECTIVE: In this study, we formulate a class IV API, Acetazolamide (AZM) as suspension for oral administration to pediatric population. The suspension must comply attributes of quality, safety and efficacy for this route of administration. MATERIALS AND METHODS: We use simple compounding procedures, as well as fewer pure excipients, as recommended for children. Mass and uniformity content assays and physical and chemical stability studies were performed. To quantify the API an UPLC method was used. RESULTS AND DISCUSSION: We verified the physico-chemical stability of the suspensions and that they passed the mass test of the European Pharmacopeia (EP), but not the dose uniformity test. CONCLUSIONS: This reveals that AZM must be formulated as liquid forms with a more complex system of excipients (not usually indicated in pediatrics), or otherwise solid forms capable of assuring uniformity of mass and dose for every dosage unit.

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PURPOSE: This U.S. Food and Drug Administration (FDA) laboratory study examines the impact of tablet splitting, the effect of tablet splitters, and the presence of a tablet score on the dose uniformity of two model drugs. METHODS: Whole tablets were purchased from five manufacturers for amlodipine and six for gabapentin. Two splitters were used for each drug product, and the gabapentin tablets were also split by hand. Whole and split amlodipine tablets were tested for content uniformity following the general chapter of the United States Pharmacopeia (USP) Uniformity of Dosage Units <905>, which is a requirement of the new FDA Guidance for Industry on tablet scoring. The USP weight variation method was used for gabapentin split tablets based on the recommendation of the guidance. RESULTS: All whole tablets met the USP acceptance criteria for the Uniformity of Dosage Units. Variation in whole tablet content ranged from 0.5 to 2.1 standard deviation (SD) of the percent label claim. Splitting the unscored amlodipine tablets resulted in a significant increase in dose variability of 6.5-25.4 SD when compared to whole tablets. Split tablets from all amlodipine drug products did not meet the USP acceptance criteria for content uniformity. Variation in the weight for gabapentin split tablets was greater than the whole tablets, ranging from 1.3 to 9.3 SD. All fully scored gabapentin products met the USP acceptance criteria for weight variation. CONCLUSION: Size, shape, and the presence or absence of a tablet score can affect the content uniformity and weight variation of amlodipine and gabapentin tablets. Tablet splitting produced higher variability. Differences in dose variability and fragmentation were observed between tablet splitters and hand splitting. These results are consistent with the FDA's concerns that tablet splitting can have an effect on the amount of drug present in a split tablet and available for absorption. LAY ABSTRACT: Tablet splitting has become a very common practice in the United States and throughout the world. Tablets are often split to modify dose strength, make swallowing easier, and reduce cost to the consumer. To better address product quality for this widely used practice, the U.S. Food and Drug Administration (FDA) published a Guidance for Industry that addresses tablet splitting. The guidance provides testing criteria for scored tablets, which is a part of the FDA review process for drugs. The model drugs selected for this study were amlodipine and gabapentin, which have different sizes, shapes, and tablet scores. Whole and split amlodipine tablets were tested for drug content because of a concern that the low-dose strength may cause greater variability. Whole and split gabapentin tablets were tested for weight variation because of their higher dosage strength of 600 mg. All whole tablets met the acceptance criteria for the Uniformity of Dosage Units based on the guidance recommendations. When unscored amlodipine tablets were split by a splitter, all formulations did not meet the acceptance criteria. When fully scored gabapentin tablets were split by hand and by splitter, they met the acceptance criteria. The findings of this FDA study indicated physical characteristics such as size, shape, and tablet score can affect the uniformity of split tablets.

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Bone allografts have been used widely to fill up essential void in orthopaedic surgeries. The benefit of using allografts to replace and reconstruct musculoskeletal injuries, fractures or disease has obtained overwhelming acceptance from orthopaedic surgeons worldwide. However, bacterial infection and disease transmission through bone allograft transplantation have always been a significant issue. Sterilization by radiation is an effective method to eliminate unwanted microorganisms thus assist in preventing life threatening allograft associated infections. Femoral heads procured from living donors and long bones (femur and tibia) procured from cadaveric donors were sterilized at 25 kGy in compliance with international standard ISO 11137. According to quality requirements, all records of bone banking were evaluated annually. This retrospective study was carried out on annual evaluation of radiation records from 1998 until 2012. The minimum doses absorbed by the bones were ranging from 25.3 to 38.2 kGy while the absorbed maximum doses were from 25.4 to 42.3 kGy. All the bones supplied by our UMMC Bone Bank were sterile at the required minimum dose of 25 kGy. Our analysis on dose variation showed that the dose uniformity ratios in 37 irradiated boxes of 31 radiation batches were in the range of 1.003-1.251, which indicated the doses were well distributed.

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The delivered dose uniformity is one of the most critical requirements for dry powder inhaler (DPI) and metered dose inhaler products. In 1999, the Food and Drug Administration (FDA) issued a Draft Guidance entitled Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products-Chemistry, Manufacturing and Controls Documentation and recommended a two-tier acceptance sampling plan that is a modification of the United States Pharmacopeia (USP) sampling plan of dose content uniformity (USP34<601>). This sampling acceptance plan is also applied to metered dose inhaler (MDI) and DPI drug products in general. The FDA Draft Guidance method is shown to have a near-zero probability of acceptance at the second tier. In 2000, under the request of The International Pharmaceutical Aerosol Consortium, the FDA developed a two-tier sampling acceptance plan based on two one-sided tolerance intervals (TOSTIs) for a small sample. The procedure was presented in the 2005 Advisory Committee Meeting of Pharmaceutical Science and later published in the Journal of Biopharmaceutical Statistics (Tsong et al., 2008). This proposed procedure controls the probability of the product delivering below a pre-specified effective dose and the probability of the product delivering over a pre-specified safety dose. In this article, we further propose an extension of the TOSTI procedure to single-tier procedure with any number of canisters.

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This paper describes a rational method of characterizing the biopharmaceutical stability of two oral suspensions of ursodeoxycholic acid (UDCA) used in pediatrics. Because there is no commercial presentation of UDCA that can administer appropriate doses for infants and children, an active pharmaceutical ingredient (API) formulation is required. Due to its very low solubility and low dose in the formula (1.5%), two different suspensions with minimal use of excipients were studied, avoiding the use of complex additives and those not recommended by the European Medicines Agency (EMA). Adherence to Standard Operating Procedure (SOP) allows the preparation of formulations with appropriately sized and stable particles, and suitable rheological behavior in withdrawing the dose after stirring. Dose uniformity, expressed as mass and content variability, was determined using the criteria of the European and the United States Pharmacopoeia. Additionally, dose content variation of every mass determined was studied. A rational method was developed for determining the dose uniformity of UDCA in suspensions, whether freshly prepared or after storage under different conditions for 30 and 60 days. This method permits detection of differences between doses taken at different heights in the vessel at various times and storage conditions. UDCA was stable under all conditions studied, requiring the presence of glycerol in the formulation to obtain the declared API value after stirring. Storage of UDCA suspensions in a refrigerator increased variability between doses.

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We compared the impregnation techniques for globules according to the Manual of Technical Norms for Homeopathic Pharmacies (MNTFH) of the Association of Homeopathic Pharmacists (ABFH), Brazilian Homeopathic Pharmacopoeia (FHB) and variations of these techniques. The variables were evaluated in this procedure, three different sizes of globules (N o . 3, 5 and 7), the hydroalcoholic solution of 70% (v/v) Minoxidil 2% (w/v) was used to impregnate the globules in concentrations of 2, 3, 4, 5% (v/w) and the impregnation at 10 %(v/w) was used hydroalcoholic solutions at 70, 80 and 90% (v/v), and four impregnation techniques various ( A -glass, B -paper, C -cup and D -FHB). As the results of content uniformity did not demonstrate a normal distribution, the one way ANOVA and a nonparametric statistical model were used for evaluation. Considering the average, the standard deviation (SD), the individual variance of each group and the principal components analysis graphs (PCA), it was observed that the “A” impregnation of globules technique, with 5% (v/w) of the impregnation concentrations and the No.5 globule presented the best uniformity of dose. As to the drying, there was a need to use a heat source.

Compararam-se as técnicas de impregnação para glóbulos segundo o Manual de Normas Técnicas para Farmácias Homeopáticas (MNTFH) da Associação Brasileira de Farmacêuticos Homeopatas (ABFH), Farmacopeia Homeopática Brasileira (FHB) e variações destas técnicas. As variáveis avaliadas neste processo foram: três tamanhos diferentes de glóbulos (n.º 3, 5 e 7); a solução hidroalcóolica a 70% (v/v) de minoxidil a 2% (p/v) foi utilizada para impregnar os glóbulos nas concentrações de 2, 3, 4, 5% (v/p) e na impregnação a 10% (v/p) utilizaram-se as soluções hidroalcóolicas a 70, 80 e 90% (v/v); e quatro técnicas de impregnação diferentes ( A -vidro, B -papel, C -copo e D -FHB). A impregnação foi validada através da uniformidade de dose por conteúdo, sendo o minoxidil a substância quantificada. Como os resultados da uniformidade de dose por conteúdo não demonstraram distribuição normal, utilizaram-se o One way ANOVA e um modelo estatístico não paramétrico para sua avaliação. Considerando-se a média, o desvio padrão (DP), a variância individual de cada grupo e os gráficos de análise de componentes principais (ACP), observou-se que a impregnação que utilizou o glóbulo nº5, a concentração para impregnação de 5% (v/p), graduação alcoólica de 70% (v/v) e técnica “A” apresentou a melhor uniformidade de dose. Quanto à secagem, verificou-se a necessidade do uso de uma fonte de calor.

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