Temperature Excursion Management: A Tier-Based Approach for Commercial Oral Solid Dosage Forms.

Temperature excursions during product storage, transportation, and handling can deteriorate product quality. Following a temperature excursion event, the impact of the event on the product quality should be evaluated to determine if the product can be used or if it needs to be discarded. Pharmaceutical companies are required to have defined procedures for managing temperature excursions and performing impact assessment after an excursion occurs. In an increasingly complex supply chain, it is vital to develop processes that can expedite the review of these events. A tier-based approach is presented for analyzing the impact of temperature excursion on commercial small molecule drug products intended to be stored at room temperature. Utilization of each of the three tiers is based on whether the excursion temperature and/or excursion duration are within a predetermined, product-specific, allowable range. The stress study temperature defines the allowable temperature range, while the allowable duration is determined using a mathematical approach outlined in this article. Tier 1, specific to the product, allows products to be dispositioned for use without further assessment when temperature excursion events fall within both the product-specific allowable excursion temperature and duration ranges. Tier 2 applies when the excursion temperature is within the allowable range, but the duration exceeds it. Lot-specific release data is used for impact assessment in this tier. Finally, Tier 3 utilizes Arrhenius extrapolation to predict the final degradation and perform the impact assessment when the excursion temperature surpasses the allowable temperature range.

Nitrogen and Sulfur Co-Doped Carbon Quantum Dots as Fluorescent Nanosensors for Determination of Two Tetracycline Antibiotics in Dosage Forms and Human Plasma: Compliance With Greenness Metrics.

In this study, a novel, sensitive, and cost-effective spectrofluorimetric approach was established for the estimation of two important tetracycline antibiotics, tetracycline and doxycycline, without any pre-treatment procedures or harsh reaction conditions, for the first time. The proposed methodology is based on the quantitative quenching effect of each tetracycline and doxycycline on the native fluorescence of nitrogen and sulfur co-doped carbon quantum dots (NS-CQDs). A simple and ultrafast approach was applied to synthesize NS-CQDs using thiosemicarbazide and citric acid as starting materials after incubation in a microwave for only 1 min. Utilizing an excitation wavelength of 360 nm, NS-CQDs showed maximum emission peak at 430 nm. Calibration curves revealed excellent linearity within the ranges of 1.0-10.0 and 0.8-12.0 µg/mL with detection limits of 0.20 and 0.09 µg/mL for tetracycline and doxycycline, respectively. Due to the method's high sensitivity and selectivity, the proposed approach was applied for the determination of the studied drugs in their capsules and human plasma samples with high %recoveries. The developed approach was validated according to ICHQ2(R2) guidelines. GAPI and AGREE metric tools were used to verify the method's greenness and eco-friendliness, suggesting its use as a green substitute for the analysis of the studied drugs.

One-Pot Synthesis of Sustainable Fluorescent Nanomaterials via Microwave Irradiation as a Probe for the Determination of Metformin in Pure and Pharmaceutical Dosage Forms: Greenness and Whiteness Metrics.

A rapid, green and sensitive technique for the determination of metformin determination was developed based on the direct fluorescence enhancement of carbon dots (CDs) induced by the cited drug. The water-soluble CDs were prepared via a one-pot synthesis from avocado peels using domestic microwave. The prepared CDs exhibited strong fluorescence at 405 nm after excitation at 320 nm with a quantum yield of 51%. The fluorescence of CDs was enhanced linearly by increasing the concentration of metformin within the range 0.5-25 µg/mL with limit of detection 0.087 µg/mL and limit of quantification 0.263 µg/mL. The designed probe was proved to be selective toward metformin in the presence of other drugs such as vildagliptin and alogliptin and also in the presence of excipients in the pharmaceutical dosage form. The suggested and reported methods were compared with the help of the whiteness and greenness tools, specifically the white analytical chemistry and analytical greenness metric tools, for assessing hazardous solvents and reagents used.

P-doped carbon dot nano-probe for inner filter effect-based determination of sarecycline in pharmaceutical dosage form and human plasma.

Based on novel phosphorus-doped carbon dots (PCDs), a simple, quick, and accurate fluorescence probe for sarecycline (SAR) determination has been created. The PCDs were prepared in just five minutes using green, straightforward one-step microwave pyrolysis. To create the PCD probe, sodium phosphate monobasic was utilized as a phosphorus dopant and citric acid as a carbon supply. The proposed synthesis method was energy efficient and yielded CDs with a narrow particle size distribution. Based on inner-filter effect mechanism, the generated PCDs were used as nano-probe for SAR determination. The fluorescence quenching intensity showed a strong linear relationship with SAR concentration in the 3-90-µM range with a detection limit of 0.88 µM. Because there is no surface alteration of the CDs or creation of a covalent bond between SAR and PCDs, the developed approach is quick, easy, inexpensive, and requires less time. The new probe's enhanced sensitivity, broad linear range, and acceptable selectivity made it suitable for SAR measurement in pharmaceutical formulations and spiked human plasma. Most importantly, the Green Analytical Procedure Index (GAPI) and Analytical GREEnness (AGREE) assessments showed that the suggested method was environmentally friendly.

Quality evaluation of Qiangli Tianma Duzhong (QLTMDZ) employing UHPLC-MS: A multivariate statistical analysis across multiple dosage forms and manufacturers.

Traditional Chinese medicine (TCM) and its preparations have become increasingly popular in recent years. Nonetheless, due to the high complexity of the compounds in Traditional Chinese Patent Medicine (TCPM), the quality differences between different dosage forms and products from various manufacturers pose numerous challenges and difficulties in quality evaluation. The Qiangli Tianma Duzhong (QLTMDZ) prescription, comprising twelve TCM, is widely used in China. Despite its prevalence, current research on QLTMDZ is limited and lacks in-depth and systematic analysis of the chemical composition of the prescription. In this study, a comprehensive strategy was proposed for characterizing the chemical profile of QLTMDZ based on UHPLC-Q-TOF-MS. A total of 122 compounds were identified in QLTMDZ under both positive and negative ion modes. Subsequently, multivariate statistical methods such as principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were conducted in the MS-DIAL software to further elucidate quality differences among 55 batches of QLTMDZ samples from seven manufacturers. Lastly, multiple reaction monitoring (MRM) mode was utilized in conjunction with UHPLC-QQQ-MS, for the precise quantification of the identified 24 compounds within the QLTMDZ preparation and providing supplementary information in quality evaluation. The established analytical method in this study is sensitive and efficient, enabling qualitative and quantitative analysis of the chemical constituents within QLTMDZ. The application of multivariate statistical analyses effectively discriminates samples based on different dosage forms and manufacturers, thereby providing new research directions and scientific support for further studies on the quality control of the prescription.

Rational prescribing and dispensing of oral dosage forms of medicines to children: an observational study.

INTRODUCTION: Irrational prescribing and dispensing of oral dosage forms of medicines to paediatric patients are major public health issues, especially in low-income and middle-income countries. Many challenges affect the rational use of oral dosage forms of medicines in children; these include a lack of dosage forms appropriate for the age and a lack of dose flexibility in dosage forms. OBJECTIVES: To assess the rational prescribing and dispensing practices of oral dosage forms to children at dispensaries of the University of Gondar Comprehensive and Specialised Hospital (UoGCSH). METHOD: A retrospective design for prescribing indicators and a cross-sectional study design to assess rational dispensing were used at the outpatient dispensary units of UoGCSH. A total of 931 oral dosage forms to assess prescribing indicators and 400 for dispensing indicators were used. The data were analysed using the Statistical Package for Social Sciences (SPSS V.26.0, IBM Corporation). Descriptive statistics were used to analyse indicators, and the χ2 test was used to compare indicators between dispensaries. RESULT: Out of a total of 931 oral dosage forms for 700 prescriptions, 56.3% were solid oral dosage forms. An average number of oral dosage forms per child was 1.33±0.62. Only 150 (16.13%) (95% CI: 14% to 18.4%) were adequate for the weight of the child. The percentage of oral dosage forms not suitable for the age was 7.1% (66), (95% CI: 5.6% to 8.8%), and about 0.8% (95% CI: 0% to 1.8%) were adequately labelled. Drugs that needed manipulation before administering a single unit were 81 (39.7%), 95% CI: 33.7% to 47.1%. CONCLUSION: The proportion of the prescribed medications that were adequate for the weight of the child was low, although the majority of prescriptions' weights were not recorded. Oral dosage forms not suitable for children were prescribed. The proportion of medications that needed manipulation before being administered as a single unit was high.

Manipulation of solid dosage forms for oral administration to paediatric patients for drug-resistant tuberculosis in South Africa: an observation study.

BACKGROUND: Children represent a particularly vulnerable demographic in the context of drug-resistant (DR) tuberculosis (TB) due to their increased likelihood of close contact with adults diagnosed with the disease. Approximately 25 000-30 000 children develop DR-TB annually. While treatment success rates for DR-TB in children surpass those in adults, children and adolescents encounter distinct challenges throughout the diagnosis and treatment of DR-TB (including MDR-TB, Pre-XDR TB, and XDR-TB). AIM: To identify current practices in drug administration to children diagnosed with DR-TB where appropriate dosage forms are not available in South Africa. METHOD: An observational study was carried out at the study site to determine how medication prescribed was manipulated and administered by nursing staff to paediatric patients in the wards. RESULTS: The observational study identified 8 drugs used in DR-TB at the study site, where some manipulation to the formulation was necessary to enable administration to paediatric patients. Linezolid and para-aminosalicylic acid are the only drugs available and registered in the South Africa in a formulation that is suitable for administration to paediatric patients. Activities carried out by nursing staff to enable the administration of DR-TB medication included cutting capsules and tablets and dissolving the tablet or capsule contents in distilled water to obtain the required suitable dose. DISCUSSION: Lack of availability of suitable dosage forms for paediatrics patients results in several challenges, such as additional time required for drug preparation, increased time duration of medication administration, and unpalatability of drugs. These challenges may subsequently affect compliance and therapeutic outcomes of the treatment of paediatric patients, especially as outpatients. CONCLUSION: Research needs to focus on the development of appropriate dosage forms for the paediatric population and focus on identifying cases of DR-TB in children. This will assist in building evidence to advocate for registration of child-friendly dosage forms thereby ensuring a sustainable supply of medication.

Indicator-based assessment of potential supply risks for pharmaceutical excipients: Method and application.

This work presents an indicator-based assessment of potential supply risks for pharmaceutical excipients. The assessment was conducted systematically through the steps of survey, data collection, and indicator value calculation. Japan was specified as the target, and all marketed products were analyzed. As the basis of the indicator, the Herfindahl-Hirschman index (HHI), a well-established method for measuring market concentration in economics, was adopted. Modifications were made to enable comparison of the risk levels of compounds, dosage forms, and diseases. Case studies were performed on each of these levels, and recommendations were obtained for risk mitigation. On the compound level, magnesium stearate, a commonly used lubricant, showed the highest risk, and a switch to alternative compounds was recommended. The dosage-form level evaluation showed that tablets and capsules could have higher risk levels than granules, indicating the importance of diversification. Finally, the disease-level evaluation showed that the supply of adult disease drugs might be risky because of the frequent use of tablets; less reliance on tablet forms was advised for adult diseases.

Paediatric excipient risk assessment (PERA) tool and application for selecting appropriate excipients for paediatric dosage forms - Part 2.

It is necessary to use a scientifically sound process for excipient risk evaluation, selection, and management in order to develop paediatric medicinal products that are both safe and effective. The "Paediatric Excipient Risk Assessment (PERA)" framework, which proposes a comprehensive approach by considering all relevant factors related to patient, dosage form, and excipient attributes, was developed and published as part 1 of this paper series, to enable the rational selection of excipients for paediatric medicinal products. This article is Part 2 of the series and presents the PERA tool that allows easy adoption of the PERA framework. Using a straightforward heat map scoring approach (Red, Yellow, and Green category) for risk evaluation, the PERA tool can be used to compare and choose excipients. The PERA tool will help users identify potential gaps in excipients information that will help with risk-based mitigation planning. Several case studies covering frequently used and novel excipients for oral, as well as the choice of excipient for parenteral products for neonatal administration, serve to illustrate the PERA tool's usefulness.

Selecting appropriate excipients for paediatric dosage form - Paediatric excipients risk assessment (PERA) framework - Part 1.

Excipients are often the major component of the formulation that critically affect the dosage form, manufacturing process, product performance, stability and safety. They exert different roles and functions in a dosage form. Selecting excipients with appropriate safety and tolerability is a major hurdle in paediatric formulation development. The suitability of a particular excipient will be dependent on the context of its use with regard to the paediatric age range, acute versus chronic use, and clinical risk-benefit of the disease, active and excipient. Scientists are encouraged to apply the principle of risk-benefit to assess the suitability of excipients to the specific paediatric population. Indicative list of parameters that should be taken into consideration and hierarchy of information sources when assessing the excipients risks is provided by regulatory agencies. However, the approach to be taken and details of how the risk evaluation should be undertaken are lacking. There is a need for a systematic approach to selection of excipients and assessment of the risk of excipient exposure. The Paediatric Excipients Risk Assessment (PERA) framework developed and proposed in this paper provides a structured, systematic decision-making framework via customizable tools and processes that can help to improve the transparency and communications on the selection and justification of use of excipients in a paediatric formulation.

A Model of Linear Response with Progressive Decay Equally Suited for RiboGreen® Quantitation of RNA and Dissolution of Solid Oral Dosage forms.

A new regression model is presented which offers flexibility, freedom from subjective determinations of linear range, and very wide applicability to measurement systems of industrial importance. This "progressive decay" model starts as a deceptively simple ordinary differential equation. We show here that its solution faithfully describes real but seemingly unconnected data from a plate-based assay for quantitation of RNA with RiboGreen® and dissolution data for a triple fixed-dose combination solid oral dosage form.

Quantitative analysis of solid dosage forms of Atenolol by Raman spectroscopy.

OBJECTIVE: To develop a Raman spectroscopy-based analytical model for quantification of solid dosage forms of active pharmaceutical ingredient (API) of Atenolol.Significance: For the quantitative analysis of pharmaceutical drugs, Raman Spectroscopy is a reliable and fast detection method. As part of this study, Raman Spectroscopy is explored for the quantitative analysis of different concentrations of Atenolol. METHODS: Various solid-dosage forms of Atenolol were prepared by mixing API with excipients to form different solid-dosage formulations of Atenolol. Multivariate data analysis techniques, such as Principal Component Analysis (PCA) and Partial least square regression (PLSR) were used for the qualitative and quantitative analysis, respectively. RESULTS: As the concentration of the drug increased in formulation, the peak intensities of the distinctive Raman spectral characteristics associated with the API (Atenolol) gradually increased. Raman spectral data sets were classified using PCA due to their distinctive spectral characteristics. Additionally, a prediction model was built using PLSR analysis to assess the quantitative relationship between various API (Atenolol) concentrations and spectral features. With a goodness of fit value of 0.99, the root mean square errors of calibration (RMSEC) and prediction (RMSEP) were determined to be 1.0036 and 2.83 mg, respectively. The API content in the blind/unknown Atenolol formulation was determined as well using the PLSR model. CONCLUSIONS: Based on these results, Raman spectroscopy may be used to quickly and accurately analyze pharmaceutical samples and for their quantitative determination.

Application of 3D printing on the design and development of pharmaceutical oral dosage forms.

3D printing technologies confer an unparalleled degree of control over the material distribution on the structures they produce, which has led them to become an extremely attractive research topic in pharmaceutical dosage form development, especially for the design of personalized treatments. With fine tuning in material selection and careful design, these technologies allow to tailor not only the amount of drug administered but the biopharmaceutical behaviour of the dosage forms as well. While fused deposition modelling (FDM) is still the most studied 3D printing technology in this area, others are gaining more relevance, which has led to many new and exciting dosage forms developed during 2022 and 2023. Considering that these technologies, in time, will join the current manufacturing methods and with the ever-increasing knowledge on this topic, our review aims to explore the advantages and limitations of 3D printing technologies employed in the design and development of pharmaceutical oral dosage forms, giving special focus to the most important aspects governing the resulting drug release profiles.

Understanding medication recycling practices in Canadian hospitals.

BACKGROUND: Medication recycling within hospitals has proven financial and possible environmental benefits according to local evaluations done in British Columbia. Despite this, the extent of medication recycling in Canadian hospitals remains unclear in the literature. OBJECTIVE(S): To determine if Canadian hospitals recycle medications, provide an estimate of how much medication is recycled by dosage form, and identify medication recycling barriers through the distribution of a cross-sectional survey. METHODS: A nine-question survey was distributed to 171 hospital pharmacy departments across Canada that consented to complete the survey. The survey identified whether sites recycled unused medications, an estimate of how much is recycled based on dosage form, and barriers to recycling. KEY FINDINGS: Of 62 respondents, the majority indicated they do have medication recycling procedures; however, the frequency of recycling is suboptimal (30-50% of medications are not recycled), and not all medication types are always recycled. Individually packaged oral tablets were most often recycled, and oral liquid medications were least often recycled. Many multi-dose medications were not tamper-proofed. Most respondents selected "sanitization/infection control" and "resource constraint" as reasons for not recycling all medications. CONCLUSIONS: Among respondents, the proportion and type of unused medicines that are recycled varied. For sites that did not respond, this might suggest that medication recycling is not a priority. This could represent a missed opportunity to standardize practices and increase medication recycling in hospitals, both of which could represent a meaningful step towards responsible use of medications and reduction of negative impacts on human health and the environment.

Spectrophotometric determination of celecoxib and tramadol in the new approved formulated dosage form using principle component regression assistive model.

Celecoxib and tramadol have been combined in a novel FDA-approved medication to address acute pain disorders requiring opioid treatment when other analgesics proved either intolerable or ineffective. The absorbance spectra of celecoxib and tramadol exhibit significant overlap, posing challenges for their individual quantification. This study introduces a spectrophotometric quantification approach for celecoxib and tramadol using a principle component regression assistive model to assist resolving the overlapped spectra and quantifying both drugs in their binary mixture. The model was constructed by establishing calibration and validation sets for the celecoxib and tramadol mixture, employing a five-level, two-factor experimental design, resulting in 25 samples. Spectral data from these mixtures were measured and preprocessed to eliminate noise in the 200-210 nm range and zero absorbance values in the 290-400 nm range. Consequently, the dataset was streamlined to 81 variables. The predicted concentrations were compared with the known concentrations of celecoxib and tramadol, and the errors in the predictions were evidenced calculating root mean square error of cross-validation and root mean square error of prediction. Validation results demonstrate the efficacy of the models in predicting outcomes; recovery rates approaching 100 % are demonstrated with relative root mean square error of prediction (RRMSEP) values of 0.052 and 0.164 for tramadol and celecoxib, respectively. The selectivity was further evaluated by quantifying celecoxib and tramadol in the presence of potentially interfering drugs. The model demonstrated success in quantifying celecoxib and tramadol in laboratory-prepared tablets, producing metrics consistent with those reported in previously established spectrophotometric methods.

[Improvement of Intestinal and Transmucosal Absorption of Peptide and Protein Drugs].

It is well known that the oral bioavailability of hydrophilic and macromolecular drugs is generally very poor due to their poor membrane permeability characteristics. Among these poorly absorbed drugs, peptide and protein drugs are typical poorly absorbed drugs which have low stability and poor permeability in the gastrointestinal tract. Consequently, the clinical administration of peptide and protein drugs is presently limited to administration by injection. However, such frequent administration subjects the patients to considerable pain, and there is also the possibility of the manifestation of serious side effects. Therefore, various approaches have been examined to overcome the poor absorption characteristics of these drugs. These approaches include (1) to use additives including absorption enhancers and protease inhibitors, (2) to modify the chemical structure of peptide and protein drugs, and (3) to apply dosage forms to these drugs, (4) to develop a novel administration method for these drugs that can serve as an alternative to oral and injection administration. We demonstrated that intestinal and transmucosal absorption of peptide and protein drugs could be improved by using these approaches. These approaches may give us useful basic information to improve the intestinal and transmucosal absorption of peptide and protein drugs.

Utility of green chemistry for feasible spectrofluorometric determination of trifluridine via metal complexation: Application to dosage forms.

The goal of the current research was to establish a quick and practical fluorometric technique for trifluridine analysis. The approach relied on the drug's complex formation with the zinc ion to produce a high-fluorescence product. The fluorescence was further enhanced by adding sodium dodecyl sulfate, and it was observed at 450 nm following excitation at 400 nm. With a determination coefficient of 0.9994, the association between emission intensity and trifluridine concentration was linear between 1 and 125 ng mL-1. The quantitation limit was 0.987 ng mL-1 while 0.333 ng mL-1 was the detection limit. The buffer type, pH and concentration, type of surfactant and concentration, and finally the diluting solvent were among the reaction conditions that were closely examined. With great precision and reliability, the drug in question was quantified using this method in dosage formulations. The proposed method's level of greenness was assessed using two methodologies: the analytical greenness metric (AGREE) and the Green Analytical Procedure Index (GAPI).

Evaluation of the on-off fluorescence method for facile measurement of vilazodone in pharmaceutical dosage form; Application to content uniformity testing and greenness evaluation.

Vilazodone is a recently approved antidepressant medicine used for treating major depressive disorder. A simple, extremely sensitive, accurate and green spectrofluorimetric method was constructed for its determination through formation of ion-pair complex with erythrosine B. The formation of ion-pair complex lowers the dye's native fluorescence emission measured at 552 nm (λ ex = 530 nm). In terms of analysis, the system's parameters for producing the vilazodone-erythrosine B complex have been optimized. The reaction was carried out in Teorell-Stenhagen buffering solution (pH 4.6). The fluorescence emission intensity of the dye decreased linearly in the range of 20 - 600 ng mL-1 and the correlation coefficient was 0.9999. The quantitation and detection limit values were 18.5 and 6.1 ng mL-1, respectively. The proposed strategy has been validated according to the ICH criteria. The proposed technique was thoroughly employed for evaluating vilazodone in raw material and pharmaceutical tablet dosage form. Furthermore, it was also successfully used for content uniformity testing. Lastly, using four advanced tools namely the Eco-Scale, the National Environmental Method Index (NEMI), the Green Analytical Procedure Index (GAPI), and the Analytical Greenness metric approach (AGREE), the greenness of the established technique was evaluated.

Resolution of overlapping spectra using chemometric manipulations of UV-spectrophotometric data for the determination of Atenolol, Losartan, and Hydrochlorothiazide in pharmaceutical dosage form.

Simultaneous determination of atenolol (ATN), losartan potassium (LOS), and hydrochlorothiazide (HCZ) in presence of HCZ impurity B was conducted by chemometric approaches and radial basis function network (RBFN) using UV-spectrophotometry without preliminary separation. Three chemometric models namely, classical least-squares (CLS), principal component regression (PCR), and partial least-squares (PLS) along with RBFN were utilized using the ternary mixtures of the three drugs. The multivariate calibrations were obtained by measuring the zero-order absorbance of the mixtures from 250 to 270 nm at the interval of 0.2 nm. The models were built covering the concentration range of (4.0 to 20.0), (3.8 to 20.2), and (0.9 to 50.1) µg mL-1 for ATN, LOS, and HCZ, respectively. The regression coefficient was calculated between the actual and predicted concentrations of the 3 drugs using CLS, PCR, PLS and RBFN. The accuracy of the developed models was evaluated using the root mean square error of prediction (RMSEP) giving satisfactory results. The proposed methods were simple, accurate, precise and were applied efficiently for the quantitation of the three components in laboratory-prepared mixtures, and in dosage form showing good recovery values. In addition, the obtained results were compared statistically with each other using ANOVA test showing non-significant difference between them.