Silent Side Effects: Pharmaceuticals as Contaminants of Emerging Concern

This article is the second of a series of articles detailing the development of near-infrared (NIR) methods for solid dosage-form analysis. Experiments were conducted at the Duquesne University Center for Pharmaceutical Technology to demonstrate a method for developing and validating NIR models for the analysis of active pharmaceutical ingredient (API) content and hardness of a solid dosage form. Robustness and cross-validation testing were used to optimize the API content and hardness models. For the API content calibration, the optimal model was determined as multiplicative scatter correction with Savitsky-Golay first-derivative preprocessing followed by partial least-squares (PLS) regression including 4 latent variables. API content calibration achieved root mean squared error (RMSE) and root mean square error of cross validation (RMSECV) of 1.48 and 1.80 mg, respectively. PLS regression and baseline-fit calibration models were compared for the prediction of tablet hardness. Based on robustness testing, PLS regression was selected for the final hardness model, with RMSE and RMSECV of 8.1 and 8.8 N, respectively. Validation testing indicated that API content and hardness of production-scale tablets is predicted with root mean square error of prediction of 1.04 mg and 8.5 N, respectively. Explicit robustness testing for high-flux noise and wavelength uncertainty demonstrated the robustness of the API concentration calibration model with respect to normal instrument operating conditions.

Transmission Raman Spectroscopy (TRS) has become an increasingly applied technology in the analysis of pharmaceutical tablets for quality control purposes and developing formulation and process understanding. One area that has received only cursory attention to date is that of bilayered tablets that represents an unusually challenging situation. This study aims to provide an understanding of the relationship of the active pharmaceutical ingredient (API) content and the transmission Raman spectral response in bilayered pharmaceutical tablets to facilitate development of quantitative models for the prediction of API content in multilayer tablets. The Raman intensity was considered as a function of the Raman photon generation and decay in a layer of interest (the API layer) and Raman photon decay from a second layer (the non-API layer). To separate and understand the various contributions, a variety of tablet configurations were studied and it was found that (1) with increasing the thickness of the non-API layer, the API Raman signal displayed an exponential decay as a function of the non-API layer thickness as well as the total tablet thickness; (2) when only changing API concentration, the Raman signal linearly responds to the API content; and (3) when increasing the weight/thickness of the API layer and keeping the non-API layer constant, the Raman signal reaches a maximum at a particular thickness and then decays as tablets become thicker. The complex spectral response was effectively modeled according to a modified Schrader, Kubelka-Munk model where both the Raman photon generation factor and photon losses were accounted for. Coupling the results of these studies together yields a comprehensive approach for modeling multi-component bilayer tablets. The addition of a beam enhancer on the bottom surface allowed for a selective over-enhancement of the bottom layer, which helps in the analysis of thin layers or coatings.

The combination of different active substances in drug products is responsible for optimizing therapies and improving patient adherence. However, the development process of these formulations is highly challenging due to differences in the physicochemical properties of the active ingredients, which can impact formulation stability. Thus, the present study evaluated the incompatibility profile in five different combinations/formulations containing phenylephrine hydrochloride and the maleate compound as a counter-ion by measuring the active pharmaceutical ingredient (API) content and the degradation products (succinyl phenylephrine adducts). This incompatibility occurs due to reactions via Michael addition. The quantification of the API and degradation products was performed using an HPLC-DAD system. The analyses revealed that in all formulations where there is no physical separation between phenylephrine and the maleate counter-ion, a decrease in phenylephrine content and appearance of impurities were observed. Furthermore, the physical separation between the active ingredients was effective, and no markers of the respective reaction were identified. Based on these findings, it is evident that the pharmaceutical form impacts formulation stability, and the reduction in API content along with the increase in impurities may negatively affect product efficacy, quality and safety parameters. This reinforces the need for additional information regarding regulatory registration aspects.

Real-time determination and visualization of two independent quantities during a manufacturing process of pharmaceutical tablets by near-infrared hyperspectral imaging combined with multivariate analysis.

In Indonesia, antibiotics are often purchased without a prescription at community pharmacies, contrary to current regulations. This practice may increase the risk of out-of-specification (OOS) medicines being dispensed, potentially contributing to treatment failure and antibiotic resistance. To address this concern, we assessed the quality of antibiotics purchased without a prescription at private drug retail outlets (PDROs) in Indonesia. We conducted a cross-sectional study in Tabalong and Bekasi, Indonesia, using standardised patients (SPs) who purchased antibiotics without a prescription for three clinical scenarios: upper respiratory tract infection (URTI), tuberculosis (TB) and child diarrhoea. The pharmacies and drug stores were randomly selected from each subdistrict based on the probability proportional method. We measured the active pharmaceutical ingredient (API) content of the antibiotic samples using high-performance liquid chromatography (HPLC). The quality of 183 antibiotics including amoxicillin tablets (148/183, 80.9%, 95% CI 74.7% to 86.1%), amoxicillin dry syrup (12/183, 6.6%, 95% CI 3.6% to 10.8%), ampicillin tablets (5/183, 2.7%, 95% CI 1.1% to 5.9%) and ciprofloxacin tablets (18/183, 9.8%, 95% CI 6.2% to 14.8%) obtained from 117/166 (70.5%, 95% CI 62.8 to 77.2) PDROs were tested. Descriptive statistics were used to describe the characteristics of the purchased antibiotics, and the API content of each antibiotic was compared against the United States Pharmacopeia 43-National Formulary 38 (USP 43-NF 38) standards in absolute values and percentages. Almost all samples produced in Indonesia (182/183, 99.5%, 95% CI 97.5% to 99.9%) were unbranded (123/183, 67.2%, 95% CI 60.2% to 73.7%) or branded generic (60/183, 32.8%, 95% CI 26.3% to 39.8%) and packaged in strips (165/183, 90.2%, 95% CI 85.2% to 93.8%). Around 12/183 (6.6%, 95% CI 3.6% to 10.8%) antibiotics were found to be OOS; these were mostly amoxicillin 125 mg dry syrup (6/12, 50%, 95% CI 24.3% to 75.7%) and ciprofloxacin 500 mg tablet (5/18, 27.8%, 95% CI 11.5% to 50.6%). Around 33% (4/12, 95% CI 12.5% to 61.2%) of amoxicillin 125 mg dry syrup samples had an API content above the label claim, the highest being 187%, whereas 16.7% (2/12, 95% CI 3.6% to 43.6%) were below the label claim, the lowest being 64%. About 27.8% (5/18, 95% CI 11.5% to 50.6%) of ciprofloxacin samples tested had an API content above the label claim; the highest was 120%. While the proportion of OOS antibiotics identified was relatively small, at a population level, it represents a significant proportion of sub-optimally treated infections.

This study determined the content of solid active pharmaceutical ingredient (API) powders dispersed in suspension-type pharmaceutical oral jellies using a low-field time-domain NMR (TD-NMR). The suspended jellies containing a designated API content were prepared and tested. Acetaminophen (APAP), indomethacin (IMC) and L-valine were used as test APIs. First, this study measured the T2 relaxation rate (the reciprocal of T2 relaxation time) by the Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence, and then evaluated whether the API content could be determined by the acquired T2 relaxation rate. The T2 relaxation rate negatively correlated with API content to a certain extent, but their correlation was not sufficient for achieving a precise determination. Subsequently, the solid-echo pulse sequence measurement was adopted for this study. We found that NMR signals corresponding to solid components strongly correlated with API content. Thus, this method achieved a precise determination of API contents in suspended jellies. In addition, this study confirmed the effect of API particle size on the T2 relaxation rate by using an L-valine-containing jelly: the T2 relaxation rate became faster when a smaller API size was incorporated into the suspended jelly, while there was no difference in terms of the NMR signals measured by solid-echo pulse sequence. From these findings, TD-NMR could be a powerful tool for evaluating the API dispersion state in suspended oral jellies.

Content uniformity of pharmaceutical solid dosage forms by near infrared hyperspectral imaging: A feasibility study

Background: Active pharmaceutical ingredient (API) content is a critical quality attribute (CQA) of amorphous solid dispersions (ASDs) prepared by spraying a solution of APIs and polymers onto the excipients in fluid bed granulator. This study presents four methods for quantifying API content during ASD preparation. Methods: Raman and three near-infrared (NIR) process analysers were utilized to develop methods for API quantification. Four partial least squares (PLS) models were developed using measurements from three granulation batches, with an additional batch used to evaluate model predictability. Models performance was assessed using metrics such as root mean square error of prediction (RMSEP), root mean square error of cross-validation (RMSECV), residual prediction deviation (RPD), and others. Results: Off-line and at-line NIR models were identified as suitable for process control applications. Additionally, at-line Raman measurements effectively predicted the endpoint of the spraying phase. Conclusions: To the best of authors’ knowledge, this is the first study focused on monitoring API content during fluidized bed granulation (FBG) used for ASD preparation. The findings provide novel insights into the application of Raman and NIR process analysers with PLS modelling for monitoring and controlling ASD preparation processes.

PAT-based batch statistical process control of a manufacturing process for a pharmaceutical ointment

Spray drying of API nanosuspensions: Importance of drying temperature, type and content of matrix former and particle size for successful formulation and process development

A large fraction of emissions of carbon dioxide (CO 2 )-the greenhouse gas produced by human activities in the greatest quantities-is long lived in the atmosphere, so decisions made today to continue adding CO 2 into the atmosphere may lock future generations into a range of human health and environmental impacts, some of which could become very severe, according to a committee of the National Research Council (NRC).In a report that looks at the short-and long-term effects of the stabilization of Earth's temperature, the NRC committee quantifies, as much as possible, the outcomes of different stabilization targets for the planet, with a focus on the United States. 1The report synthesizes global warming science in myriad fields along with research on the potential impacts for human health and other arenas.Then the committee adds a twist: rather than expressing climate goals in terms of stabilizing atmospheric concentrations of CO 2 , the authors assess such goals using global mean temperature change as the primary metric.The twist allows the authors to link the potential impacts from climate change more directly to temperature change.Research to date suggests many potential impacts can be directly linked to temperature, or to things that can be themselves linked to temperature (e.g., precipitation), although some (e.g., ocean acidification) are linked directly to CO 2 concentration, says Damon Matthews of Concordia University, a report coauthor."But in this report we were . . .noting the additional impacts you would expect for a given degree

Electrospinning is a technology for manufacture of nano- and micro-sized fibers, which can enhance the dissolution properties of poorly water-soluble drugs. Tableting of electrospun fibers have been demonstrated in several studies, however, continuous manufacturing of tablets have not been realized yet. This research presents the first integrated continuous processing of milled drug-loaded electrospun materials to tablet form supplemented by process analytical tools for monitoring the active pharmaceutical ingredient (API) content. Electrospun fibers of an amorphous solid dispersion (ASD) of itraconazole and poly(vinylpyrrolidone-co-vinyl acetate) were produced using high speed electrospinning and afterwards milled. The milled fibers with an average fiber diameter of 1.6 ± 0.9 µm were continuously fed with a vibratory feeder into a twin-screw blender, which was integrated with a tableting machine to prepare tablets with ~ 10 kN compression force. The blend of fibers and excipients leaving the continuous blender was characterized with a bulk density of 0.43 g/cm3 and proved to be suitable for direct tablet compression. The ASD content, and thus the API content was determined in-line before tableting and at-line after tableting using near-infrared and Raman spectroscopy. The prepared tablets fulfilled the USP <905> content uniformity requirement based on the API content of ten randomly selected tablets. This work highlights that combining the advantages of electrospinning (e.g. less solvent, fast and gentle drying, low energy consumption, and amorphous products with high specific surface area) and the continuous technologies opens a new and effective way in the field of manufacturing of the poorly water-soluble APIs.

High throughput in-line content uniformity measurement of tablets based on real-time UV imaging.

Raman spectroscopy for the in-line polymer–drug quantification and solid state characterization during a pharmaceutical hot-melt extrusion process

Development and validation of a new method for predicting spatial and temporal concentration dynamics of active pharmaceutical ingredients in a lake receiving wastewater effluents.