Aqueous suspensions containing crystalline drug in the sub-micron range is a favorable platform for long-acting injectables where particle size can be used to obtain a desired plasma-concentration profile. Stabilizers are added to the suspensions and screened extensively to define the optimal formulation composition. In the initial formulation screening the amount of drug compound can be limited, necessitating milling methods for small-volume screening predictable for scale-up. Hence, adaptive focused ultrasound was investigated as a potential milling method for rapid small-volume suspensions by identifying the critical process parameters during preparation. Suspensions containing drug compounds with different mechanical properties and thereby grindability, i.e., cinnarizine, haloperidol, and indomethacin with brittle, elastic, and plastic properties, respectively, were investigated to gain an understanding of the manufacturing with adaptive focused acoustics as well as comparison to already established milling techniques. Using a DoE-design, peak incident power was identified as the most crucial process parameter impacting the milling process for all three compounds. It was possible to decrease the sizes of drug particles to micron range after one minute of focused ultrasound exposure which was superior compared to other milling techniques (e.g., non-focused ultrasound exposure). The addition of milling beads decreased the drug particle sizes even further, thus to a lower degree than other already established milling techniques such as milling by dual centrifugation. This study thereby demonstrated that adaptive focused ultrasonication was a promising method for rapid homogenization and particle size reduction to micron range for different compounds varying in grindability without altering the crystalline structure.

Clonidine Hydrochloride is a centrally acting alpha-agonist hypotensive agent available as tablets for oral administration in three dosage strengths: 0.1 mg, 0.2 mg and 0.3 mg. A review of the therapeutic uses of clonidine hydrochloride reveals the need for flexibility in dosing. This flexibility is readily achieved using an oral liquid dosage form. However, no commercial liquid dosage form of clonidine hydrochloride currently exists. An extemporaneously compounded suspension from pure drug powder would provide a flexible, customizable option to meet unique patient needs with convenient and accurate dosing options. The purpose of this study was to determine the physicochemical and microbiological stability of extemporaneously compounded clonidine hydrochloride suspensions in the PCCA Base, SuspendIt. This base is a sugar-free, paraben-free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. The study design included two clonidine hydrochloride concentrations to provide stability documentation over a bracketed concentration range for eventual use by compounding pharmacists. A robust stability-indicating high-performance liquid chromatographic assay for the determination of the chemical stability of clonidine hydrochloride in PCCA SuspendIt was developed and validated. Suspensions of clonidine hydrochloride were prepared in PCCA SuspendIt at 20-mcg/mL and 100-mcg/mL concentrations, selected to represent a range within which the drug is commonly dosed. Given the potent nature of the drug, a 2% triturate of clonidine hydrochloride in microcrystalline cellulose was used to prepare the samples. Samples were stored in amber plastic prescription bottles at two temperature conditions (5°C and 25°C). Samples were assayed initially, and on the following time points (days): 7, 14, 28, 42, 63, 91, 119 and 182. Physical data such as pH, viscosity and appearance were also noted. Microbiological stability was tested. All measurements were obtained in triplicate. A stable extemporaneous product is defined as one that retains at least 90% of the initial drug concentration throughout the sampling period and is protected against microbial growth. Using this criterion, no significant degradation of the clonidine hydrochloride was observed over the 182-day test period for either concentration under refrigerated conditions. Drug concentrations were at, or above 94.6% of initial values. However, at room temperature the concentration of the 20-mcg/mL samples dropped below 90% after 119 days. No microbial growth was observed. pH values remained fairly constant. The viscosity of the suspensions allowed easy re-dispersal of the drug particles upon shaking. This study demonstrates that clonidine hydrochloride is physically, chemically, and microbiologically stable in PCCA SuspendIt for 182 days in the refrigerator and for 119 days at room temperature at both concentrations studied, thus providing a viable, compounded alternative for clonidine hydrochloride in a liquid dosage form, with an extended BUD to meet patient needs.

Bethanechol chloride is a cholinergic agent used to treat acute postoperative and postpartum nonobstructive (functional) urinary retention and for neurogenic atony of the urinary bladder with retention. It is available in the United States as tablets for oral administration in four dosage strengths: 5 mg, 10 mg, 25 mg, and 50 mg. A review of the therapeutic uses of bethanechol chloride reveals the need for flexibility in dosing. This flexibility is readily achieved using an oral liquid dosage form. However, no commercial liquid dosage form of bethanechol chloride currently exists. An extemporaneously compounded suspension from pure drug powder or commercial tablets would provide a flexible, customizable option to meet unique patient needs with convenient and accurate dosing options. The purpose of this study was to determine the physicochemical and microbiological stability of extemporaneously compounded bethanechol chloride suspensions using two brands of commercially available tablets (Amneal and Upsher-Smith) in the PCCA Base, SuspendIt. This base is a sugar-free, paraben-free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. The study design included two bethanechol chloride concentrations to provide stability documentation over a bracketed concentration range for eventual use by compounding pharmacists. A robust stability-indicating ultra-high-performance liquid chromatographic assay for the determination of the chemical stability of bethanechol chloride in PCCA SuspendIt was validated. Suspensions of bethanechol chloride were prepared from the tablets in PCCA SuspendIt at 1-mg/mL and 5-mg/mL concentrations, selected to represent a range within which the drug is commonly dosed. Samples were stored in amber plastic prescription bottles at room temperature (25°C). Samples were assayed initially, and on the following time points (days): 14, 30, 60, 90, and 180. Physical data such as pH and appearance were also noted. Microbiological stability was tested. A stable extemporaneous product is defined as one that retains at least 90% of the initial drug concentration throughout the sampling period and is protected against microbial growth. Using this criterion, no significant degradation of the bethanechol chloride was observed over the 180-day test period for either concentration at room temperature. Drug concentrations were at, or above 93% of initial values for both brands of commercially available tablets. No microbial growth was observed. pH values remained fairly constant. This study demonstrates that bethanechol chloride tablets are physically, chemically, and microbiologically stable in PCCA SuspendIt for 180 days at room temperature at both concentrations studied, thus providing a viable, compounded alternative for bethanechol chloride in a liquid dosage form, with an extended BUD to meet patient needs.

OBJECTIVE: In clinical practice, a discrepancy may exist between the prescribed amount of a drug and the commercially available pack sizes in the pharmacy, potentially contributing to drug waste. This study aimed-as an example of this phenomena-to quantify leftover of amoxicillin suspension prescribed to children, due to discrepancies between physician-prescribed and pharmacy-dispensed amounts.
METHODS: We performed a retrospective cohort study including amoxicillin suspension dispensations for patients aged 0-12 years between 2017 and 2019 utilizing the Dutch PHARMO database. Leftover amount of amoxicillin was estimated by assessing the discrepancy between the prescribed and dispensed amounts. Extrapolated amoxicillin weight and economic spillage estimates for the Netherlands were determined. The impact of two theoretical interventions on leftover amount was assessed: (1) introducing vials with half the volume of the current 100 and 30 mL vials and (2) a combination of the first intervention with a maximum of 10% round-down by the dispensing pharmacy of the prescribed dose.
RESULTS: We included 79 512 amoxicillin suspension dispensations for 62 252 patients. The mean leftover amount of amoxicillin suspension per dispensing was 27%. The yearly amount of amoxicillin leftover was 49.8 kg in the study cohort, equivalent to yearly 633 kg and €621 000 when extrapolated to the Netherlands. Employing the first theoretical intervention reduced the mean leftover per dispensing to 20%, reducing the yearly leftover to 31.6 kg amoxicillin in the study cohort, and to 400 kg and €400 000 extrapolated. The second theoretical intervention further reduced leftover to 17%, reducing the yearly leftover to 24.3 kg amoxicillin in the study cohort, and to 300 kg and €300 000 extrapolated.
CONCLUSIONS: Approximately a quarter of amoxicillin suspension remains as leftover per dispensing. Applying different theoretical intervention shows the potential for a significant reduction of amoxicillin leftover.

The pharmaceutical industry faces a significant challenge from the low water solubility of nearly 90% of newly developed Active Pharmaceutical Ingredients (APIs). Despite extensive efforts to improve solubility, approximately 40% of these APIs encounter commercialization hurdles, impacting drug efficacy. In this context, a promising strategy will be introduced in which nanosuspensions, particularly polyvinyl alcohol (PVA) as a stabilizer, are applied to increase drug solubility. In this work using molecular dynamics simulations, the nanosuspension of four poorly water-soluble drugs (flurbiprofen, bezafibrate, miconazole, and phenytoin) stabilized with PVA is investigated. The simulation data showed van der Waals energies between polyvinyl alcohol with flurbiprofen and bezafibrate are - 101.12 and - 58.42 kJ/mol, respectively. The results indicate that PVA is an effective stabilizer for these drugs, and superior interactions are obtained with flurbiprofen and bezafibrate. The study also explores the impact of PVA on water molecule diffusion, providing insights into the stability of nanosuspensions. Obtained results also provide valuable insights into hydrogen bond formation, diffusion coefficients, and nanosuspension stability, contributing to the rational design and optimization of pharmaceutical formulations.

Million tons of tires become waste every year, and the so-called End-of-Life Tires (ELTs) are ground into powder (ELT-dp; size < 0.8 mm) and granules (ELT-dg; 0.8 < size < 2.5 mm) for recycling. The aim of this study was to evaluate the sub-lethal effects of three different concentrations (0.1, 1, and 10 mg/L) of aqueous suspensions from ELT-dp and ELT-dg on Danio rerio (zebrafish) larvae exposed from 0 to 120 h post-fertilization (hpf). Chronic effects were assessed through biomarkers, real-time PCR, and proteomics. We observed a significant increase in swimming behavior and heart rate only in specimens exposed to ELT-dp suspensions at 1 and 10 mg/L, respectively. Conversely, the activities of detoxifying enzymes ethoxyresorufin-O-deethylase (EROD) and glutathione-S-transferase (GST) showed significant modulation only in specimens exposed to ELT-dg groups. Although no effects were observed through real-time PCR, proteomics highlighted alterations induced by the three ELT-dp concentrations in over 100 proteins involved in metabolic pathways of aromatic and nitrogen compounds. The results obtained suggest that the toxic mechanism of action (MoA) of ELT suspensions is mainly associated with the induction of effects by released chemicals in water, with a higher toxicity of ELT-dp compared to ELT-dg.

The main goal of the work was to use rheological methods for assessing the properties of a composition based on polyether ether ketone (PEEK) to determine the concentration limits of the polymer in the composition and select the optimal content of this composition for powder molding. The rheological properties of highly filled suspensions based on PEEK and paraffin, as well as in paraffin-polyethylene mixtures at various component ratios, were studied. These materials are designed for powder injection molding and 3D printing. Suspensions with a PEEK powder content above 50% are not capable of flow and, with increasing pressure, slide along the surface of the channel. For compositions with a higher content (60 and 70 vol.%) PEEK, independence of the storage modulus from frequency is observed, which is typical for solids and confirms the assignment of such suspensions to elastic-plastic media. The introduction of high-density polyethylene into the composition helps improve the technological properties of suspensions, expanding the range of fluidity, although it leads to an increase in viscosity. In suspensions with a mixed composition of the liquid phase, with increasing temperature, a decrease in the storage modulus is observed at 120 °C and, on the contrary, an increase at 180 °C. The latter may be a consequence of the evaporation of paraffin and the softening of PEEK due to the approach to the glass transition temperature of the polymer. Suspensions with 40% PEEK content have an optimal set of rheological properties for powder injection molding. A 3D printing filament was also obtained from a composition with 40% PEEK, which had good technological properties for FDM 3D printing. Products of satisfactory quality from suspensions with 50% PEEK can be produced by powder injection molding, but not by 3D printing. The selected compositions were used to obtain real PEEK products for practical applications.

Infections related to orthopedic/stomatology surgery are widely recognized as a significant health concern. Therefore, the development of new materials with superior biological properties and good stability could represent a valuable alternative to the classical treatments. In this paper, the fluorine-substituted hydroxyapatite (FHAp) suspension, with the chemical formula Ca10(PO4)6(OH)2-2xF2x (where x = 0.05), was prepared using a modified coprecipitation technique. Stability studies were conducted by zeta potential and ultrasound measurements for the first time. The X-ray diffraction (XRD) patterns of FHAp powders displayed a hexagonal structure akin to that of pure hydroxyapatite (HAp). The XPS general spectrum revealed peaks corresponding to the constituent elements of fluorine-substituted hydroxyapatite such as calcium, phosphorus, oxygen, and fluorine. The purity of the obtained FHAp samples was confirmed by energy-dispersive X-ray spectroscopy (EDS) studies. The FHAp morphology was evaluated by scanning electron microscopy (SEM) measurements. Fourier-transform infrared spectroscopy (FTIR) studies were performed in order to study the vibrational properties of the FHAp samples. The FHAp suspensions were tested for antibacterial activity against reference strains such as Staphylococcus aureus 25923 ATCC, Escherichia coli ATCC 25922, and Candida albicans ATCC 10231. Additionally, the biocompatibility of the FHAp suspensions was assessed using human fetal osteoblastic cells (hFOB 1.19 cell line). The results of our biological tests suggest that FHAp suspensions are promising candidates for the future development of new biocompatible and antimicrobial agents for use in the biomedical field.

Cell dielectric property measurement holds significant potential for application in cell detection and diagnosis due to its label-free and noninvasive nature. In this study, we developed a biosensor designed to measure the permittivity of liquid samples, particularly cell suspensions at the nanoliter scale, utilizing microwave and millimeter wave coplanar waveguides in conjunction with a microchannel. This biosensor facilitates the measurement of scattering parameters within a frequency domain ranging from 1 GHz to 110 GHz. The obtained scattering parameters are then converted into dielectric constants using specific algorithms. A cell capture structure within the microchannel ensures that cell suspensions remain stable within the measurement zone. The feasibility of this biosensor was confirmed by comparison with a commercial Keysight probe. We measured the dielectric constants of three different cell suspensions (HepG2, A549, MCF-7) using our biosensor. We also counted the number of cells captured in multiple measurements for each cell type and compared the corresponding changes in permittivity. The results indicated that the real part of the permittivity of HepG2 cells is 0.2-0.8 lower than that of the other two cell types. The difference between A549 and MCF-7 was relatively minor, only 0.2-0.4. The fluctuations in the dielectric spectrum caused by changes in cell numbers during measurements were smaller than the differences observed between different cell types. Thus, the sensor is suitable for measuring cell suspensions and can be utilized for label-free, noninvasive studies in identifying biological cell suspensions.

We develop a microscopic model of antibiotic diffusion in virus suspensions in a liquid crystalline state. We then approximate this with an effective homogenised model that is more amenable to analytical investigation, to understand the effect of charge on the antibiotic tolerance. We show that liquid crystalline virus suspensions slow down antibiotics significantly, and that electric charge strongly contributes to this by influencing the effective diameter and adsorptive capacity of the liquid crystalline viruses so that charged antibiotics diffuse much slower than neutral ones; this can be directly and efficiently derived from the homogenised model and is in good agreement with experiments in microbiology. Charge is also found to affect the relationship between antibiotic diffusion and viral packing density in a nontrivial way. The results elucidate the effect of charge on antibiotic tolerance in liquid crystalline biofilms in a manner that is straightforwardly extendable to other soft matter systems.