•The aim of this assay is to develop a tool to quantify tyrosine kinase inhibitors.•The tool must be fast with high throughput.•Solid phase extraction, high-pressure liquid chromatography, and mass ...spectrometry were used.•Assay validation procedure was performed according to international recommendations (EMA, FDA).•Targeted plasma concentrations of TKI are proposed according to literature.
Several studies have shown that therapeutic drug monitoring of tyrosine kinase inhibitors (TKI) can improve their benefit in cancer. An analytical tool has been developed in order to quantify 17 tyrosine kinase inhibitors and 2 metabolites in human plasma (afatinib, axitinib, bosutinib, crizotinib, dabrafenib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, ponatinib, regorafenib, regorafenib M2, regorafenib M5, ruxolitinib, sorafenib, sunitinib, vandetanib). Drugs were arranged in four groups, according to their plasma concentration range: 0.1–200ng/ml, 1–200ng/ml, 4–800ng/ml and 25–5000ng/ml. Solid phase extraction was used and separation was performed with HPLC using a gradient system on a solid core particle C18 column (5×2.1mm, 1.6μm). Ions were detected with a triple quadrupole mass spectrometry system. This assay allows rapid determination of 19 TKI in less than 5min per run. This high throughput routine method will be useful to adjust doses of oral anticancer drugs in order to improve treatments efficacy.
Training and certification of personnel in capsule preparation are essential procedures, overseen by the pharmacist who delegates these tasks. These procedures aim not only to ensure the efficacy and ...safety of operations but also to establish a clear chain of responsibility. They align with established best practices. Certification grants formal authorization to qualified individuals to perform specific tasks. For new hires, a comprehensive training program is designed to facilitate their integration and empower them from the onset. We propose training objectives structured around a competency-based approach, highlighting objective evaluation criteria applicable in real-world practical settings. These training objectives address critical aspects such as the handling of hazardous substances, weighing and mixing of powders, and capsule filling. They also emphasize the importance of documentation and traceability. Specialized preparations and tools are offered to facilitate the assessment of learning outcomes.
Abstract
Background
Stability of low amoxicillin oral dosage form (5 mg) used in reintroduction drug test was not fully documented. Furthermore, the impact of (1) salt moiety of amoxicillin and (2) ...amoxicillin – excipient interactions upon the antibiotic formulation stability during the storage was not characterized so that the estimation of the pharmaceutical expiration date from shelf-life was uncertain. Thus, the main goal of this study was to estimate the shelf-life of two formulations of amoxicillin, using a semi-predictive methodology.
Methods
Amoxicillin sodium (AS) and amoxicillin trihydrate (ATH), corresponding to 5-mg amoxicillin, were compounded with microcrystalline cellulose (MCC) in oral hard capsules which were, then, submitted to four environmental conditions (25 °C / 60% or 80% relative humidity (RH); 40 °C / 75% RH; 60 °C / 5% RH) in climatic chambers for 45 and 84 days. Therefore, the characterization of amoxicillin-MCC mixture was assessed by attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR) The profiles of amoxicillin content (determined by stability indicating chromatographic method) as a function of storage time, temperature and RH were fitted to pre-defined kinetic models performed by accelerated predictive stability (APS).
Results
ATR-FTIR analysis of AS, ATH, MCC and bulk specimens stored in heated and humid atmosphere confirmed water sorption to cellulose described by a broad and unresolved 3600 to 3000 cm
−1
band associated with (1) general intramolecular and intermolecular hydrogen bonding between water and hydroxyl groups of the cellulose, and with (2) free hydroxyl in cellulose. Moreover, a dramatic decrease of absorption at 1776 and 1687 cm
−1
respectively characteristic of the β-lactam ring (
ν
C=O
) and amide group (
ν
C=O
), was revealed as a consequence of AS and ATH degradation caused by moisturization of bulk. Amoxicillin degradation was established by chromatographic analysis showing faster AS degradation than ATH throughout time exposure. The combined effects of temperature – RH were successfully modeled by APS, where AS and ATH showed accelerated (auto-catalysis degradation mechanism) and linear degradation, respectively. The faster AS degradation was assumed to be linked to lower hydrogen donor to hydrogen acceptor count ratio and polar surface than ATH, increasing the probability of AS hydrolysis by water adsorption to AS-MCC solid dispersion (e.g., by reduction of protective intramolecular hydrogen bonds between AS molecules). Furthermore, the compounding which involved a drastic homogenization of solids may have affected the crystalline degree of MCC with an increase of amorphous phase more sensitive to water adsorption.
Conclusions
The improvement of amoxicillin compounding for oral dose forms might be rationalized by taking into account the molecular descriptors of salt moiety and excipients, improved by the choice of an appropriate process of production, characterized from infrared vibrational spectroscopy and chromatographic analysis and finally predicted from accelerated stability assays.
During the early months of the COVID-19 pandemic, the international medical product supply chain was tight, causing breaks in the availability of neuromuscular blocking agents essential for the ...treatment of patients in intensive care units. The present study describes the pharmaceutical development of an injectable 2 mg/mL solution of pancuronium bromide (PC) in a very short lapse of time. The sterile solution was compounded into a good manufacturing practice grade A clean room, filtered (0.2 µm) and filled into 10 mL type I glass, manually sealed with bromobutyl rubber stoppers. A novel HPLC-MS stability indicating method for pancuronium quantification and its degradation product was developed and validated. This fast, sensitive and straightforward method was used to study the stability of the formulation using a semi-predictive method, enabling a very fast attribution of a temporary shelf-life, which was confirmed by a classic prospective stability study. The production line and the analytical tools set-up were performed in six weeks and the semi-predictive stability study was conducted in 90 days, allowing us to predict a shelf life, which was successfully confirmed by prospective study. In conclusion, using innovative methods, we were able to rapidly overcome the shortage of a critical drug.
Display omitted
IntroductionThe COVID-19 pandemic has led to unforeseen and novel manifestations, as illustrated by the management of drug shortages through the development of hospital production of sterile ...pharmaceutical preparations (P2S). Visual inspection of P2S is a release control whose methods are described in monographs of the European Pharmacopoeia (2.9.20) and the United States Pharmacopeia (1790). However, these non-automated visual methods require training and proficiency testing of personnel. The main objective of this work was to compare the reliability and speed of analysis of two visual methods and an automated method for detecting visible particles by image analysis in P2S. Furthermore, these methods were used to evaluate sources of particulate contamination during pre-production processes (washing, disinfection, depyrogenation) and production (filling, capping).Materials and methodsThree pharmacy technicians examined 41 clear glass vials of type I, 10 and/or 50 mL through manual visual inspection (MVI), semi-automated (SAVI), and automated (AVI) inspection. The vials were distributed as follows: (i) 16 vials of water for injection containing either glass particles (224 µm or 600 µm), stopper fragments, or textile fibres; (ii) five sterile injectable specialties; (iii) 20 vials of water for injection prepared under different pre-production conditions.Results and discussionMVI and SAVI detected 100% of visible particles compared with 28% for AVI, which showed a deficiency in detecting textile fibres. All three methods correctly analysed P2S that did not contain visible particles. The three methods detected particles in vials maintained under International Organization for Standardization (ISO) 9 pre-production conditions. However, detections by (i) MVI and SAVI, and by (ii) AVI of particles contained in vials maintained under ISO 8 pre-production conditions were deemed satisfactory and unsatisfactory, respectively.ConclusionThe importance of visual inspection of P2S requires rapid, sensitive, and reliable detection methods. In this context, MVI and SAVI have proven to be more effective than AVI for a more competitive financial, training, and implementation investment.
Several studies have shown that therapeutic drug monitoring of tyrosine kinase inhibitors (TKI) can improve their benefit in cancer. An analytical tool has been developed in order to quantify 17 ...tyrosine kinase inhibitors and 2 metabolites in human plasma (afatinib, axitinib, bosutinib, crizotinib, dabrafenib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, ponatinib, regorafenib, regorafenib M2, regorafenib M5, ruxolitinib, sorafenib, sunitinib, vandetanib). Drugs were arranged in four groups, according to their plasma concentration range: 0.1-200ng/ml, 1-200ng/ml, 4-800ng/ml and 25-5000ng/ml. Solid phase extraction was used and separation was performed with HPLC using a gradient system on a solid core particle C18 column (5x2.1mm, 1.6mum). Ions were detected with a triple quadrupole mass spectrometry system. This assay allows rapid determination of 19 TKI in less than 5min per run. This high throughput routine method will be useful to adjust doses of oral anticancer drugs in order to improve treatments efficacy.
Confusion regarding the identification of medicines by patients, physicians and pharmacists is a major concern. Here, we detail the successful identification of unlabelled medicine from a new tool ...named Medicine Identification New Database (MIND) implemented in our hospital pharmacy. Web tools (drugs.com, WebMD, Google Lens) and MIND were used for identification of an unlabelled unitary (single tablet/capsule) medicine returned from the care unit. MIND combines three modules including organoleptic (form, shape, colour), physical (dimensions, mass) and attenuated total reflectance-Fourier transform infrared spectra of oral medicines. While the web tools failed to identify unlabelled the unitary medicine properly, MIND discriminated the pharmaceutical product and confirmed, from infrared spectroscopy, the real identity of the medication and major excipients. The simplicity of the approach combined with the accuracy of the physical and spectral characterisation confirmed the potential of MIND as suitable tool for quick, simple and accurate identification of unlabelled medication in hospital pharmacies.
PDF
