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Background: The dissolution test is a critical quality control method in the pharmaceutical industry, primarily used to assess drug bioavailability and ensure the consistency of manufactured batches. This test simulates the release of the active ingredient in the body and verifies compliance with specifications through multiple stages (e.g., S1, S2, S3). However, measurement uncertainty can undermine the reliability of test results, potentially leading to erroneous conformity decisions. This study aims to quantify the uncertainties arising from the dissolution, sampling, and quantification steps, as well as to estimate the risk of false conformity decisions in the dissolution test results for tablets., Results: A comprehensive uncertainty evaluation was conducted for the dissolution, sampling, and quantification stages. The Monte Carlo method (MCM) was applied to assess the overall measurement uncertainty, which was determined to be approximately 5.2 %. The study revealed that sampling was the predominant contributor, accounting for 92 % of the total uncertainty, compared to 7 % from quantification and 1 % from dissolution steps. An MS Excel spreadsheet was developed to calculate the total risk value and classify it as either producer or consumer risk. This tool enables the evaluation of uncertainty in both individual tested units and mean values, depending on the stage criteria (e.g., S1, S2, S3). The proposed improved criteria were tested across various scenarios where the risk of false decisions due to measurement uncertainty was considered. These tests demonstrated the effectiveness of the criteria in managing consumer risk, highlighting the critical impact of sampling uncertainty on the decision-making process., Significance and Novelty: This study introduces novel, improved criteria for the dissolution test that account for the risk of false decisions due to measurement uncertainty. The proposed criteria significantly enhance the reliability of drug quality assessments. The study provides a robust framework for minimizing false conformity decisions. The development of a practical MS Excel tool further supports the reliable assessment of dissolution test results, ensuring higher standards of drug safety and efficacy in pharmaceutical quality control., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Felipe Rebello Lourenco reports financial support was provided by State of Sao Paulo Research Foundation. Felipe Rebello Lourenco reports a relationship with State of Sao Paulo Research Foundation that includes: funding grants. None. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Drying time, velocity, and temperature are important aspects of the drying process for pharmaceutical granules observed during tablet manufacturing. However, the drying mechanism of single granules is often limited to modelling and simulation, with the internal and physical changes difficult to quantify at an experimental level. In this study, in-situ synchrotron-based X-ray imaging techniques were used for the first time to investigate the dynamic drying of single pharmaceutical granules, quantifying internal changes occurring over the drying time. Two commonly used excipients (lactose monohydrate (LMH) and microcrystalline cellulose (MCC)) were used as pure components and binary mixtures with one of either two active pharmaceutical ingredients of differing hydrophilicity/hydrophobicity (acetaminophen (APAP) and carbamazepine (CBZ)). Water was used as a liquid binder to generate single granules of 25 % to 30 % moisture content. Results showed that for most samples, the drying time and composition significantly influences the pore volume evolution and the moisture ratio, with the velocity and temperature of the drying air possessing mixed significance on increasing the rate of pore connectivity and moisture removal depending on the sample composition. Effects of active ingredient loading resulted in minimal influence on the drying of CBZ and generated binary mixtures, with APAP and its respective mixtures' drying behaviour dominated by the material's hydrophilic nature., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Magnesium stearate (MgSt) is a common tablet lubricant. As variations in MgSt properties are known to influence tablet attributes, the impact of MgSt fatty acid composition, particularly the significance of the stearate and palmitate contents, and its effects on tablet properties warrant further investigation. This study investigated the effect of MgSt with different stearate and palmitate contents but comparable physical properties (e.g. particle size, crystallinity, specific surface area and morphology) on lubrication performance and resulting tablet quality attributes, including mechanical strength, disintegratability and drug release. The influence of MgSt concentration and blending duration on the resulting tablet properties was also examined. Tablets produced using the lower stearate content MgSt had slightly higher tensile strength. The effect of MgSt stearate content was more apparent in the disintegration time and drug release, whereby MgSt of lower stearate content resulted in tablets with longer disintegration time and slower drug release. The lower stearate content also resulted in a lower lubrication performance, leading to a lesser reduction in tablet ejection force. As expected, a longer blending time of the tablet formulation blend with MgSt yielded tablets with reduced tensile strength, shorter disintegration time and slower drug release. Tablets with higher MgSt concentration showed a greater reduction in tensile strength, longer disintegration time and faster drug release. The study findings reinforced observations by other researchers and provided a better understanding of the fatty acid composition effects of MgSt on lubrication performance and the resulting tablet properties., (© 2024. The Author(s).)

Hot-melt extrusion (HME) is a widely used method for creating amorphous solid dispersions (ASDs) of poorly soluble drug substances, where the drug is molecularly dispersed in a solid polymer matrix. This study examines the impact of three different copovidone excipients, their reactive impurity levels, HME barrel temperature, and the distribution of colloidal silicon dioxide (SiO 2 ) on impurity levels, stability, and drug release of ASDs and their tablets. Initial peroxide levels were higher in Kollidon VA 64 (KVA64) and Plasdone S630 (PS630) compared to Plasdone S630 Ultra (PS630U), leading to greater oxidative degradation of the drug in fresh ASD tablets. However, stability testing (50 °C, closed container, 50 °C/30% RH, open conditions) showed lower oxidative degradation impurities in ASD tablets prepared at higher barrel temperatures, likely due to greater peroxide degradation. Plasdone S630 is suitable for ASDs with drugs prone to oxidative degradation, while standard purity grades may benefit drugs susceptible to free radical degradation, as they generate fewer free radicals post-HME. ASD tablets exhibited greater physical stability than milled extrudate samples, likely due to reduced exposure to stability conditions within the tablet matrix. Including SiO 2 in the extrudate composition resulted in greater physical stability of the ASD system in the tablet; however, it negatively affected chemical stability, promoting greater oxidative degradation and hydroxylation of the drug substance. No impact of the distribution of SiO 2 on drug release was observed. The study also confirmed the congruent release of copovidone, the drug substance, and Tween 80 using flow NMR coupled with in-line UV/vis. This research highlights the critical roles of peroxide levels and SiO 2 in influencing the dissolution and physical and chemical stability of ASDs. The findings provide valuable insights for developing stable and effective pharmaceutical formulations, emphasizing the importance of controlling reactive impurities and excipient characteristics in ASD products prepared by using HME.

A simple, specific, sensitive, rapid, and cost-effective spectrofluorometric method for quantifying folic acid has been developed using basic fuchsin as a fluorescence quenching agent. This method relies on the quenching effect of folic acid on the inherent fluorescence of basic fuchsin, facilitated by their interaction in Britton-Robinson buffer solution at pH 9, leading to the formation of an ion-associated complex. The decrease in fluorescence intensity of basic fuchsin was measured at 730 nm, with excitation at 365 nm. The method demonstrated a linear relationship (R 2  = 0.9977) between the quenching fluorescence intensity (ΔF) and folic acid concentration over the range of 4-20 μg/mL, with a detection limit of 0.17 μg/mL. The method showed no significant interference from common excipients found in pharmaceutical tablets. The results obtained were in good agreement with those from high-performance liquid chromatography, with no significant differences in precision or accuracy. This spectrofluorimetric method was successfully applied to determine the folic acid content in various commercial pharmaceutical tablets., (© 2024 John Wiley & Sons, Ltd.)

Background: Magnetic ionic liquids (MILs) have been explored in dispersive liquid-liquid microextraction (DLLME). Their usage allows to substitute centrifugation and/or filtration steps by a quick magnetic separation. Besides, effervescence-assisted DLLME is one of the most known options to improve the dispersion of the extractant in the sample, while allowing to avoid the consumption of external energy during dispersion. Despite these interesting features, only one study incorporates MILs containing the tetrachloroferrate anion in effervescence tablets. These MILs are highly viscous and liquid at room temperature, thus compromising the stability of the tablets when used as extraction microdevices in effervescence-assisted DLLME, and only allowing their use in the conventional MIL-DLLME mode., Results: A new class of effervescence tablets containing a Ni(II)-based MIL, that is solid at room temperature, is here proposed. This type of tablets permits their use, for first time, in the in situ DLLME mode, occurring through the transformation of a water-soluble MIL into a water-insoluble MIL microdroplet. This way, the tablet formulation included: the MIL, the metathesis reagent lithium bis[(trifluoromethyl)sulfonyl]imide, NaH 2 PO 4 and K 2 CO 3 as effervescence precursors salts, and Na 2 SO 4 as salting-out and desiccating agent. The method is combined with high-performance liquid-chromatography and both fluorescence and ultraviolet detection, for the determination of monohydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) and benzophenones (BPs), as biomarkers in urine. The method simply involved the addition of the effervescence tablet to the sample, thus taken place simultaneously the effervescence process and the metathesis reaction, without requiring any external energy consumption. The method presented limits of detection down to 10 ng L -1 for OH-PAHs and to 0.60 μg L -1 for BPs, inter-day relative standard deviations lower than 17 %, and average relative recoveries of 94 % in urine. The determined OH-PAHs contents in urine were between 0.40 and 16 μg L -1 , and between 17.8 and 334 μg L -1 for BPs., Significance: We have developed the first MIL-based effervescence tablets that are completely solid, thus improving the stability and robustness of these microdevices with respect to previously reported tablets involving MILs, while permitting to perform into the in situ DLLME mode (thus gaining in extraction efficiency). This approach including the MIL-based effervescence tablets constitutes an alternative on-site platform for the analysis of urine, as satisfactory precision, accuracy, and sensitivity are achieved despite not involving any external energy input within the analytical sample preparation setup. This method also constitutes the first application of MIL-based effervescence tablets for bioanalysis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The present study utilized Analytical Quality by Design (AQbD) approach to develop a stability-indicating high-performance liquid chromatography (HPLC) method for estimating evogliptin tartrate using design expert software. The key parameters were methodically optimized, contours were plotted, and stability was evaluated using various forced degradation conditions. Using an Agilent HPLC system with a photo diode array (PDA) detector along with Fortis C18 column (250 × 4.6 mm, 5 μm) effectively separated the drug from its degradants. The mobile phase used was methanol: water (pH adjusted to 3.0, 76:24; v/v) at 0.8 mL/min flow rate. Evogliptin was eluted at 2.98 min, at a detection wavelength of 267 nm. The proposed method was found to be specific, precise, linear and robust. The drug was sensitive to acidic, basic, oxidative, thermal, and photodegradation resolving six degradation products. Thus, the developed AQbD-based stability-indicating HPLC method is applicable in analyzing evogliptin in bulk, tablet dosage form and stability samples., (© 2024 John Wiley & Sons Ltd.)

Neratinib (an active pharmaceutical ingredient [API]) is an irreversible pan-human epidermal growth factor receptor (HER) inhibitor used to treat HER2-positive breast cancer. The dosage form (marketed in the United States, China, Europe, and other regions) is a tablet for oral administration, and the brand product (NERLYNX) has patent protection for the crystalline neratinib maleate monohydrate form. This paper describes the product development using stable crystalline neratinib maleate anhydrous form, stability study, bioequivalence (BE) study of the products, and discussion of the adverse effects observed in the clinical study., (© 2024 John Wiley & Sons Ltd.)

In this study, SeDeM-ODT parametric tests were performed to determine the use of ludipress as a directly compressible tableting excipient for the development of a flurbiprofen orally disintegrating tablet. The preformulation features of different formulations (F1 -F9) were analyzed by the SeDeM-ODT tool which showed that all the powder blends were appropriate for direct compression since all the blends had index of good compressibility and bucodispersibility (IGCB) values above 5, signifying direct compression is the most appropriate method. The powder blend of the optimized formulation was assessed by the DSC-TGA technique. The optimization of nine different formulations blends of orally disintegrating tablets (ODTs) was prepared in various ratios by the implementation of design of experiments (DoE), using the central composite design by selecting ludipress (X1) (49-55%) and croscarmellose sodium (X2) (1-5%) while hardness, friability, and disintegration tests were selected as responses. The optimized formulations were evaluated by various tests and the results indicated that all the formulations were found to be in adequate range. Formulations were subjected to stability studies at accelerated states following ICH guidelines. Shelf life was found to be 51.144-56.186 months. Results of multiple-point dissolution studies revealed that formulations followed the Higuchi kinetic model. This study revealed that the SeDeM-ODT tool has been successfully used to determine the compression behavior of active compounds and their powder blends for the direct compression (DC) method in formulating flurbiprofen-ODT tablets., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Fatima et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

We propose a two-stage reduced-order model (ROM) of pharmaceutical tablet dissolution that is comprised of (i) a mechanistic dissolution function of the active pharmaceutical ingredient (API) and (ii) a tablet wetting function. The former is derived from a population balance model, using a high-resolution finite volume algorithm for a given API crystal size distribution and dissolution rate coefficient. The latter is obtained from the mechanistic understanding of water penetration inside a porous tablet, and it estimates the rate at which the API is exposed to the buffer solution for a given formulation and the dimensions of the tablet, contact angle, and surface tension between the solid and liquid phases, liquid viscosity, and mean effective capillary radius of the pore solid structure. In turn, the two-stage model is mechanistic in nature and one-way coupled by means of convolution in time to capture the start time of the API dissolution process as water uptake, swelling, and disintegration take place. The two-stage model correlates dissolution profiles with critical process parameters (CPPs), critical material attributes (CMAs), and other crucial critical quality attributes (CQAs). We demonstrate the model's versatility and effectiveness in predicting the dissolution profiles of diverse pharmaceutical formulations. Specifically, we formulate and fabricate acetaminophen and lomustine solid tablets using different API content and size distributions, characterize their dissolution behavior, and estimate capillary radius as a function of tablet porosity. The estimations generated by the proposed models consistently match the experimental data across all cases investigated in this study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The effects of glass bead size in the conical space of flow-through cells on the dissolution profiles were investigated in a USP apparatus 4. Dissolution tests of disintegrating and non-disintegrating tablets in flow-through dissolution systems were performed using semi-high precision glass beads with diameters ranging from 0.5 mm to 1.5 mm. Computational fluid dynamics (CFD) was used to evaluate the effect of shear stress from the dissolution media flow. The use of smaller glass beads in a larger cell resulted in a faster dissolution of the model formulations under certain test conditions. The effect on the dissolution was highly dependent on the size of the beads in the top layer, including those in contact with the tablets. The absence of a bead-size effect on the dissolution of an orodispersible tablet in a small cell can be explained by the floating fragments during the test. CFD analysis showed that smaller bead diameters led to greater shear stress on the tablet, which was correlated with the dissolution rate. Hence, fluid flow through the narrow gaps between the small beads generated strong local flows, causing shear stress. The size of the glass beads used in flow-through cells affects the dissolution rate of tablets by altering the shear stress on the tablets in certain cases (e.g., direct deposition of the formulation on glass beads, large cells, and very low flow rates). Thus, glass bead size must be considered for a robust dissolution test in a flow-through cell system., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Mesoporous silica offers an easy way to transform liquids into solids, due to their high loading capacity for liquid or dissolved active ingredients and the resulting enhanced dissolution properties. However, the compression of both unloaded and loaded mesoporous silica bulk material into tablets is challenging, due to poor/non-existing binding capacity. This becomes critical when high drug loads are to be achieved and the fraction of additional excipients in the final tablet formulation needs to be kept at a minimum. Our study aimed to investigate the mechanism of compression and tabletability dependent on the Liquid Load Level of the silica and type of filler/binder in binary tabletting mixtures. To this end, Vivapur® 101, FlowLac® 90, Pearlitol® 200 SD and tricalcium citrate tetrahydrate were selected and mixed with Syloid® XDP 3050 at various Liquid Load Levels. Compaction characteristics were analysed using the StylOne® Classic 105 ML compaction simulator. Additionally, the Overall Liquid Load (OLL) was defined as a new critical quality attribute for liquisolid tablets. The Overall Liquid Load allows straightforward, formulation-relevant comparisons between various fillers/binders, liquid components, and silica types. Results indicate strong binding capacity and high plasticity of the fillers/binders as key components for successful high liquid load silica tablet formulation. A volumetric combination of 30% Vivapur® 101 and 70% 0.75 mL/g loaded Syloid® XDP 3050 proved to be the most effective mixture, achieving an Overall Liquid Load of 36-41% [v/v] and maintaining a tensile strength of 1.5 N/mm 2 with various liquid vehicles., (© 2024. The Author(s).)

Nitrosamine compounds pose a significant concern as potential carcinogens, prompting heightened scrutiny from regulatory bodies, particularly regarding their presence in pharmaceuticals. The detection of unacceptable levels of N-nitrosodiethylamine (NDMA) in ranitidine has led to widespread recalls, driving interest in alternative medications such as nizatidine, which shares a similar pharmacological class and is used to treat various gastrointestinal conditions. Despite fewer reports on NDMA levels in nizatidine, its structural similarity to ranitidine, characterized by a tertiary amine, underscores the potential for NDMA formation. Addressing the analytical challenges associated with nitrosamine detection, this study focuses on developing and validating an ultra-high pressure liquid chromatography triple quadrupole mass spectrometry (UHPLC-MS/MS) method for quantifying NDMA in both nizatidine active pharmaceutical ingredients and tablet formulations. Method validation adheres to International Council for Harmonisation recommendations, with a demonstrated linear range of 0.25-100 ng/mL for NDMA, exhibiting excellent linearity (regression coefficient >0.999) and efficient recovery rates ranging from 95.98% to 109.57%. The method shows high sensitivity, with limits of detection and quantification of 0.25 and 0.5 ng/mL, respectively. The developed UHPLC-MS/MS method offers a simple, precise, accurate, and selective approach for monitoring NDMA levels in nizatidine formulations available in Australia, promising enhanced sensitivity and specificity with limits of quantification in the ppb and sub-ppb ranges., (© 2024 John Wiley & Sons Ltd.)

We explored the feasibility of high-speed and high-accuracy quantification of active pharmaceutical ingredient (API) content in tablet products by near-infrared (NIR) spectroscopy to improve the reliability of pharmaceuticals. For this purpose, we employed a high-power NIR time-stretch transmission spectrometer recently developed by us. By using this transmission spectrometer with a multivariate calibration model, we demonstrated the ability to quantify API content with a short measurement time of 3.9 ms per tablet for model pharmaceuticals. For the model tablet, the quantification ability of our spectrometer was comparable to that achieved by a commonly used Fourier-transform NIR (FT-NIR) spectrometer with a measurement time of several seconds. We also confirmed that the effect of irradiating tablets with the NIR pulses used in our spectrometer was negligible., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Koji Nakayama reports writing assistance was provided by Japan Agency for Medical Research and Development. Koji Nakayama has patent #JPA2020159971, JPA2023036975 issued to Ushio Inc., TOWA PHARMACEUTICAL CO., LTD. Koji Nakayama has patent #EPA3951366, USA2022/0178848, CNA113614518, INA202117044615 pending to Ushio Inc., TOWA PHARMACEUTICAL CO., LTD. Aya Ikarashi (Ota) has patent #JPA2020159971, JPA2023036975 issued to Ushio Inc., TOWA PHARMACEUTICAL CO., LTD. Aya Ota has patent #EPA3951366, USA2022/0178848, CNA113614518, INA202117044615 pending to Ushio Inc., TOWA PHARMACEUTICAL CO., LTD. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Present study evaluates the usability of compaction simulation-based mechanical models as a material-sparing approach to predict tablet capping under processing compression conditions using Acetaminophen (APAP) and Ibuprofen (IBU). Measured mechanical properties were evaluated using principal component analysis (PCA) and principal component regression (PCR) models. PCR models were then utilized to predict the capping score (CS) from compression pressure (CP). APAP formulations displayed a quadratic correlation between CS and CP, with CS rank order following CP of 200MPa < 300MPa < 100MPa, indicating threshold compression pressure (TCP) limit between 200 and 300 MPa, resulting in higher CS at 300 than 200 MPa regardless of increased CP. IBU formulations displayed a linear correlation between CS and CP, with CS rank order following CP of 100MPa < 200MPa < 300MPa, indicating TCP limit between 100 and 200 MPa, resulting in higher CS at 200 and 300 than 100 MPa regardless of increased CP. Molecular models were developed as validation methods to predict capping from CP. Measured XRPD patterns of compressed tablets were linked with calculated Eatt and d-spacing of slip planes and analyzed using variable component least square methods to predict TCP triggering cleavage in slip planes and leading to capping. In APAP and IBU, TCP values were predicted at 245 and 175 MPa, meaning capped tablets above these TCP limits regardless of increased CP. A similar trend was observed in CS predictions from mechanical assessment, confirming that compaction simulation-based mechanical models can predict capping risk under desired compression conditions rapidly and accurately., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The objective of this study was to examine the impact of the physicochemical properties of the loaded drug or excipient, the concentration of Kollidon®SR (KSR), and the mechanical characteristics of KSR compacts on their disintegration times. Using disintegration apparatus, a two-hour constraint was chosen as the process's end point. Lactose-KSR compacts subjected to the highest compression pressure and Microcrystalline cellulose-KSR compacts with KSR concentrations exceeding 30% exhibited disintegration times of less than ten minutes. Likewise, compacts containing Diltiazem HCl-KSR demonstrated brief disintegration times across all tested KSR concentrations and compression pressures. Compacts of Modafinil, Metformin HCl, and Ascorbic acid-KSR displayed disintegration times ranging from fast to moderate, contingent upon the levels of KSR and compression pressure applied. Compacts containing KSR with Aspirin, Salicylic acid, or Ibuprofen did not exhibit significant disintegration even at minimal amounts of KSR (0.5%). Theophylline-KSR tablets also showed prolonged dissolution times, even at very low concentrations of KSR. The disintegration times of Dic-KSR tablets were roughly close to an hour and were predominantly unaffected by varying KSR levels and only marginally influenced by compression pressures. It is possible to draw the conclusion that different drugs or excipients have different minimum KSR requirements to resist compacts' disintegration process. Compounds that demonstrate low solubility in water can result in extended disintegration times for KSR compacts. The melting points of these compounds, in conjunction with the Py values of the compacts and their compaction properties, could affect the disintegration process, although a precise evaluation is necessary., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Biorelevant dissolution and its concept have been widely accepted and further developed to meaningfully predict the bioperformance of oral drug products. Biorelevant methodologies have been applied to design and optimize oral formulations, to facilitate formulation bridging, and to predict the outcome of bioperformance by coupling the results with modeling. Yet, those methodologies have often been independently customized to align with specific aspects of the oral drug products being developed. Therefore, the evolution of biorelevant dissolution methodologies has taken slightly diverse pathways rather than being standardized like compendial quality control (QC) methodologies. This manuscript presents an effort through the Product Quality Research Institute (PQRI, https://pqri.org) consortium entitled: the standardization of " in vivo predictive dissolution methodologies and in silico bioequivalent study working group" to find the key parameters for biorelevant dissolution, to identify the best practices, and to move toward standardization of biorelevant dissolution methodologies. This working group is composed of members from 10 pharmaceutical companies and academic institutes. The consortium project will be accomplished in five phases, whereby the first two phases have already been completed and published. In this paper, the next two phases are addressed by reporting the biorelevant dissolution profiles of dipyridamole, a weak base model drug, then incorporating the dissolution results into physiologically based biopharmaceutics modeling (PBBM) to determine whether they would lead to bioequivalence (BE) or non-BE.

Praziquantel (PZQ) is the treatment of choice for schistosomiasis, which affects more than 250 million people globally. Commercial tablets contain the crystalline racemic compound ( RS -PZQ) which limits drug dissolution and oral bioavailability and can lead to unwanted side effects and poor patient compliance due to the presence of the S -enantiomer. While many approaches have been explored for improving PZQ's dissolution and oral bioavailability, studies focusing on investigating its release from amorphous solid dispersions (ASDs) have been limited. In this work, nucleation induction time experiments were performed to identify suitable polymers for preparing ASDs using RS -PZQ and R -PZQ, the therapeutically active enantiomer. Cellulose-based polymers, hydroxypropyl methylcellulose acetate succinate (HPMCAS, MF grade) and hydroxypropyl methylcellulose (HPMC, E5 LV grade), were the best crystallization inhibitors for RS -PZQ in aqueous media and were selected for ASD preparation using solvent evaporation (SE) and hot-melt extrusion (HME). ASDs prepared experimentally were subjected to X-ray powder diffraction to verify their amorphous nature and a selected number of ASDs were monitored and found to remain physically stable following several months of storage under accelerated-stability testing conditions. SE HPMCAS-MF ASDs of RS -PZQ and R -PZQ showed faster release than HPMC E5 LV ASDs and maintained good performance with an increase in drug loading (DL). HME ASDs of RS -PZQ formulated using HPMCAS-MF exhibited slightly enhanced release compared to that of SE ASDs. SE HPMCAS-MF ASDs showed a maximum release increase of the order of 6 times compared to generic and branded (Biltricide) PZQ tablets. More importantly, SE R -PZQ ASDs with HPMCAS-MF released the drug as effectively as RS -PZQ or better, depending on the DL used. These findings have significant implications for the development of commercial PZQ formulations comprised solely of the R -enantiomer, which can result in mitigation of the biopharmaceutical and compliance issues associated with current commercial tablets.

The selection of appropriate materials and compatibility of selected materials with drugs and formulations are limiting steps in three-dimensional printing technology. In this study, SmartEx QD 100 (SM QD 100) was introduced as a novel, coprocessed, unexplored excipient that can be used in SLS-mediated 3D printing. The current study aimed to evaluate the feasibility of fabricating SM QD 100 containing INH-embedded SLS-mediated immediate gastric release tablets. The prepared physical mixtures were subjected to the fabrication of 3D printlets by using SLS-mediated 3D printing. The fabricated 3D printlets were subjected to physicochemical characterization by using various analytical techniques. After oral administration of sintered 3D printlets to rabbits, samples were collected and pharmacokinetic parameters were analyzed using the developed LC-APCI-MS/MS method. The optimized batch was able to release 100% INH within 15 min, which confirmed the immediate gastric release. Similarly, sintered 3D printlets were stable under accelerated stability conditions for three months. Finally, the pharmacokinetic parameters revealed the rate and extent of absorption of INH from sintered 3D printlets. As evidenced by in vitro and in vivo analyses, SM QD 100 was able to sinter SLS-mediated INH-embedded stable immediate gastric release tablets. SM QD 100 is a novel material for SLS-mediated 3D printing in pharmaceutical applications.

Our previous work (Mol Pharm, 20 (2023) 3427) showed that crystalline excipients, specifically anhydrous dibasic calcium phosphate (DCPA), facilitated the dehydration of carbamazepine dihydrate (CBZDH) and the formation of an amorphous product phase during the mixing stage of continuous tablet manufacturing. Understanding the mechanism of this excipient-induced effect was the object of this study. Blending with DCPA for 15 min caused pronounced lattice disorder in CBZDH. This was evident from the 190% increase in the apparent lattice strain determined by the Williamson-Hall plot. The rapid dehydration was attributed to the increased reactivity of CBZDH caused by this lattice disorder. Lattice disorder in CBZDH was induced by a second method, cryomilling it with DCPA. The dehydration was accelerated in the milled sample. Annealing the cryomilled sample reversed the effect, thus confirming the effect of lattice disorder on the dehydration kinetics. The hardness of DCPA appeared to be responsible for the disordering effect. DCPA exhibited a similar effect in other hydrates, thereby revealing that the effect was not unique to CBZDH. However, its magnitude varied on a case-by-case basis. The high shear powder mixing was necessary for rapid and efficient powder mixing during continuous drug product manufacturing. The mechanical stress imposed on the CBZDH, and exacerbated by DCPA, caused this unexpected destabilization.

Stimuli-responsive ultralong organic phosphorescence (UOP) materials that in response to external factors such as light, heat, and atmosphere have raised a tremendous research interest in fields of optoelectronics, anticounterfeiting labeling, biosensing, and bioimaging. However, for practical applications in life and health fields, some fundamental requirements such as biocompatibility and biodegradability are still challenging for conventional inorganic and aromatic-based stimuli-responsive UOP systems. Herein, an edible excipient, sodium carboxymethyl cellulose (SCC), of which UOP properties exhibit intrinsically multistimuli responses to excited wavelength, pressure, and moisture, is reported. Impressively, as a UOP probe, SCC enables nondestructive detection of hardness with superb contrast (signal-to-background ratio up to 120), while exhibiting a response sensitivity to moisture that is more than 5.0 times higher than that observed in conventional fluorescence. Additionally, its applicability for hardness monitoring and high-moisture warning for tablets containing a moisture-sensitive drug, with the quality of the drug being determinable through the naked-eye visible UOP, is demonstrated. This work not only elucidates the reason for stimulative corresponding properties in SCC but also makes a major step forward in extending the potential applications of stimuli-responsive UOP materials in manufacturing high-quality and safe medicine., (© 2024 Wiley‐VCH GmbH.)

Background: The SeDeM-ODT expert system is designed to assess the suitability of the pharmaceutical ingredients for their conversion into an orodispersible formulation by direct compression. The tool can be utilized to select the most appropriate excipients that improve the compressibility and buccodispersibility of the formulation., Objective: This study aimed to utilize the SeDeM-ODT expert system to evaluate the performance of superdisintegrants and select an appropriate superdisntegrant for Doxylamine Succinate orodispersible formulation., Method: The SeDeM-ODT expert system scrutinized the excipients to develop an orodispersible Doxylamine Succinate formulation. Among the 15 parameters of the tool, some of them were determined through experimental work, while the remaining were calculated through the experimental values of other parameters. The central composite design approach was used for formulation development. The prepared powder blends were compressed using the direct compression method and evaluated for different parameters (hardness, thickness, diameter, friability, weight variation, water absorption ratio, wetting time, and disintegration time)., Results: The results of the SeDeM-ODT expert system were correlated with the values obtained by the post-compression tests. The Crospovidone formulation (F7) was found to be an optimized formulation as it disintegrated quickly compared with the other formulations containing other superdisintegtrants. The results perfectly endorsed the SeDeM-ODT expert system evaluation, as Crospovidone showed the highest IGCB value of 6.396., Conclusion: The study observed the effectiveness of the expert system in accurately examining the performance of disintegrating agents. The study observed the effectiveness of the expert system in accurately examining the performance of disintegrating agents. The assessment proved Crospovidone to produce quicker disintegration in Doxylamine Succinate orodispersible formulation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ahmad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Paracetamol, also known as acetaminophen, is categorized as an analgesic and antipyretic medication and is available as over the counter (OTC) medication. It is commonly used in conditions associated with pain and fever. There is a tendency for community to prefer using imported paracetamol tablets from Europe and United States than from Asia and Africa worrying of the quality of the products. Safety, effectiveness, and efficacy of a medicine can be guaranteed when its quality is reliable; however, there is limited data on the quality of locally manufactured paracetamol tablets, thus necessitating this study. Aim: This study is aimed at assessing the quality of paracetamol tablets 500 mg manufactured by local companies by evaluating their physical parameters, assay results, and dissolution profiles. The compliance of these tablets with the specifications outlined in the British Pharmacopoeia (BP) was analyzed. Additionally, a comparative dissolution test was conducted to assess dissolution profile for innovator product and generics. Method: Five different brands from East African countries with 76 tablets from each brand were compared with the innovator product regarding weight variation, hardness, friability, assay, and dissolution test based on the BP specifications. Results and discussion: All samples of paracetamol tablets 500 mg from the local manufacturers in this study met the specifications set by the BP for physical parameters, including weight variation, friability, hardness, and disintegration tests. The weight variation test, directly related to drug content variation, demonstrated compliance within the acceptable deviation of 5%. Similarly, the assay test, which determines the concentration of the active pharmaceutical ingredient (API), confirmed that all samples complied with the acceptable concentration range of 90%-110% for paracetamol. The dissolution test, assessing the percentage release of the API within a specified time, demonstrated that at 15 min, two samples (diodol and enamol) exhibited lower concentration releases than the required 80%, indicating potential delays in their bioavailability and onset of action. Conclusion: To conclude, all samples had good quality and they can be used for their therapeutic purposes., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Gerald Marisa et al.)

Spherical agglomeration (SA) is a processing technique that enhances the physical properties of particles, reduces the number of unit operations in pharmaceutical manufacturing, and improves process efficiency. However, one of the limitations of SA is its high nonlinearity, which makes scalability a challenge. This prospective study was designed to realize the optimization of SA process parameters of aspirin, the world's first and most widely used nonsteroidal anti-inflammatory drug, by developing a green SA model through response surface methodology. First, Plackett-Burman experiments were conducted to identify the key operating variables affecting SA, and Sustainability Index (STI) was defined to evaluate the effects of these operating variables on the SA and the energy input to the environment during the post-processing process. Furthermore, the effects of three independent variables on mean size, yield, and STI were investigated based on Box-Behnken design. A second-order regression equation with response values was developed to optimize the above three objectives. As a result, the spherical products were obtained with excellent powder properties, including anti-caking property, filtration property, and tableting performance compared to the raw materials. This work provides an experimental and modelling basis for the further application of this environmentally-friendly SA technology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Vanillin finds widespread applications in various industries, such as food, pharmaceuticals, and cosmetics. However, excessive intake of vanillin could pose risks to human health. This study detailed the successful creation of a heterojunction of branched benzopyrazine-based polymers coating on graphene (CMP-rGO) through the Sonogashira-Hagihara coupling reaction. Utilizing the CMP-rGO, a novel electrochemical sensor for vanillin detection was developed. Besides, the synthesized materials were validated using standard characterization techniques. Both cyclic voltammetry and differential pulse voltammetry techniques were employed to investigate vanillin's electrochemical characteristics on this sensor. The findings indicated a significant enhancement in vanillin's electrochemical signal responsiveness with the application of CMP-rGO. Under optimal conditions, the sensor demonstrated a linear response to vanillin concentrations ranging from 0.08 to 33 μM and achieved a detection limit as low as 0.014 μM. Also, the constructed electrochemical sensor exhibited excellent selectivity, stability, and reproducibility. It has been effectively employed to detect vanillin in real samples such as human serum, human urine, and vanillin tablets, with a recovery rate of 99.13-103.6 % and an RSD of 3.46-1.26 %. Overall, this innovative sensor offers a novel approach to the efficient and convenient detection of vanillin., Competing Interests: Declaration of competing interest This manuscript entitled “Heterojunction of branched benzopyrazine-based polymers coating on graphene for electrochemical sensing of vanillin” has not been published or presented elsewhere in part or in entirety, and it is not under consideration by another journal. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We have read and understood your journal's policies, and we believe that neither the manuscript nor the study violates any of these policies., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Manidipine (MP) is a dihydropyridine drug, which is treated for the reduction of high blood pressure. The aim of this study is to clarify the photochemical behavior of MP in the case of ultraviolet light (UV) irradiation for MP tablets (Calslot ® tablets). The tablets and its altered forms (powders and suspensions) were UV-irradiated using a black light, and residual amounts of active pharmaceutical ingredients (APIs) were monitored by high-performance liquid chromatography (HPLC). Due to the photoproducts of MP were detected in HPLC chromatograms, the elucidation of their chemical structures was carried out utilizing electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). As a result, APIs in Calslot ® tablets were almost completely photodegraded in the case that Calslot ® tablets were suspended in an aqueous media along with the generation of some MP photoproducts. LC-ESI-MS/MS analysis clarified the chemical structures of three MP photoproducts, indicating that they were a pyridine analogue, benzophenone and a hydrolysate. Benzophenone was a main MP photoproduct. It was possible that MP might be firstly oxidized to form its pyridine analogue, followed by the oxidation of a dimethyl methylene moiety. This moiety seemed to be eliminated as a benzophenone, and the cleavage of an ester bond of the residual moiety resulted in the generation of a hydrolysate. Finally, toxicological potencies of MP and its photoproducts were predicted in silico toxicity evaluation, suggesting some of biological effects of the photoproducts might be altered compared with MP., (© 2024. The Author(s), under exclusive licence to The Japan Society for Analytical Chemistry.)

Dwell time is an important parameter responsible for the material deformation and the mechanical and biopharmaceutical properties of the tablet. Thus, it is widely used for scale-up purposes. The geometric dwell time (GDT) can be assumed based on the shape of the punch head and the diameter and speed of the turret. This research is aimed to compare compaction simulator-recorded dwell time according to force (DTF) and the GDT calculated for the simulated rotary tablet press using the microcrystalline cellulose and calcium phosphate mixtures (CEOLUS™ UF-711 and DI-CAFOS ® A60) in different proportions. Tablets were prepared, and DTF was analyzed with a compaction simulator (STYL'One Nano and Alix software) upon simulating a small rotary press at 70 rpm and a compression pressure of 10-50 kN (100-500 MPa). While GDT comprised of 14.4 ms, DTF was compression force and formulation dependent. The differences between the DTF values of the formulations decreased as the compression force increased, which was most pronounced at compression forces of 10 and 15 kN.

Lamivudine (LMD), an enantiomer of 2'-deoxy-3'-thiacytidine, plays a crucial role in combatting HIV-1 and managing hepatitis B virus infections. Despite its effectiveness, challenges arise from its difficult flowability and tendency to agglomerate during storage, necessitating a granulation step before tablet compression, as direct compression has proven ineffective. This study aimed to optimize Lamivudine spherical agglomerates using response surface methodology, delving into the intricate relationship between design factors (concentration of tween, span, and acetone) and experimental outcomes (yield and particle size) through central composite design. Analysis of variance (ANOVA) was employed for optimization, with the Quasi-emulsion solvent-diffusion (QESD) crystallization technique utilized for the checkpoint batch. This technique, involving a single solvent and antisolvent with surfactants, showcased remarkable enhancements in flowability and reduced storage agglomeration. The impact of various surfactants [Hydroxy Propyl Methyl Cellulose (HPMC), polysorbate 80, and sorbitane monooleate] on particle morphology, flowability, and storage agglomeration during crystallization was thoroughly assessed. While achieving direct compression into tablets, the porous structure of LMD agglomerates presented challenges in tablet press production speeds, prompting adjustments such as reducing punch speed or implementing a precompression step. Positive outcomes were realized for disintegration and in vitro drug release in comparison to direct compression and wet granulation methods. In conclusion, the QESD crystallization technique successfully yielded hollow, spherical LMD agglomerates with enhanced properties, representing a significant milestone in pharmaceutical formulation., (Copyright © 2024. Published by Elsevier B.V.)

Principal component analysis (PCA) and partial least squares regression (PLS) were combined in this study to identify key material descriptors determining tabletability in direct compression and roller compaction. An extensive material library including 119 material descriptors and tablet tensile strengths of 44 powders and roller compacted materials with varying drug loads was generated to systematically elucidate the impact of different material descriptors, raw API and filler properties as well as process route on tabletability. A PCA model was created which highlighted correlations between different powder descriptors and respective characterization methods and, thus, can enable reduction of analyses to save resources to a certain extent. Subsequently, PLS models were established to identify key material attributes for tabletability such as density and particle size but also surface energy, work of cohesion and wall friction, which were for the first time demonstrated by PLS as highly relevant for tabletability in roller compaction and direct compression. Further, PLS based on extensive material characterization enabled the prediction of tabletability of materials unknown to the model. Thus, this study highlighted how PCA and PLS are useful tools to elucidate the correlations between powder and tabletability, which will enable more robust prediction of manufacturability in formulation development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

High shear wet granulation (HSWG) is widely used in tablet manufacturing mainly because of its advantages in improving flowability, powder handling, process run time, size distribution, and preventing segregation. In line process analytical technology measurements are essential in capturing detailed particle dynamics and presenting real-time data to uncover the complexity of the HSWG process and ultimately for process control. This study presents an opportunity to predict the properties of the granules and tablets through torque measurement of the granulation bowl and the force exerted on a novel force probe within the powder bed. Inline force measurements are found to be more sensitive than torque measurements to the granulation process. The characteristic force profiles present the overall fingerprint of the high shear wet granulation, in which the evolution of the granule formation can improve our understanding of the granulation process. This provides rich information relating to the properties of the granules, identification of the even distribution of the binder liquid, and potential granulation end point. Data were obtained from an experimental high shear mixer across a range of key process parameters using a face-centred surface response design of experiment (DoE). A closed-form analytical model was developed from the DOE matrix using the discovery of evolutionary equations. The model is able to provide a strong predictive indication of the expected tablet tensile strength based only on the data in-line. The use of a closed form mathematical equation carries notable advantages over other AI methodologies such as artificial neural networks, notably improved interpretability/interrogability, and minimal inference costs, thus allowing the model to be used for real-time decision making and process control. The capability of accurately predicting, in real time, the required compaction force required to achieve the desired tablet tensile strength from upstream data carries the potential to ensure compression machine settings rapidly reach and are maintained at optimal values, thus maximising efficiency and minimising waste., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The Qiye Shen'an tablet is formulated using total saponins extracted from Notoginseng stems and leaves. At present, the study on its chemical composition remains scarce and the quality control indicators are limited, which seriously hindering the effective quality control and clinical research. Hence, this study aims to comprehensively identify and characterize the Qiye Shen'an tablet while controlling its main component contents. To achieve a comprehensive understanding of this tablet, an ultra-high performance liquid coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) method was employed for its separation and characterization. Through the analysis of 99 batches of Qiye Shen'an tablet produced by 9 enterprises, the characteristic quantitative components were further obtained. A total of 113 compounds were characterized and identified, among which 17 representative compounds were selected, and the ultra-high performance liquid-triple quadrupole tandem mass spectrometry (UPLC-TQS-MS/MS) method was established for further quantitative determination. It has been successfully applied to the content determination of 99 batches of Qiye Shen'an tablet, and a new quality control method is being formed. This study provides a new method for chemical spectrum analysis and determination of labeled compounds of Qiye Shen'an tablet, and lays a solid foundation for further study of potential active ingredients and comprehensive quality evaluation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this work, κ-carrageenan and olive oil at different oil to κ-carrageenan ratios (OCR) are homogenized to create emulsion gels. Interestingly, confocal imaging shows that the oil droplets are stabilized in the κ-carrageenan-structured gel matrix without using any surfactants. Rheological studies show that the oil droplets enhanced the oscillatory yield stress and the maximum printable height of the emulsion gels. The creation of the emulsion gels with an OCR of 1:9-3:7 led to an improvement in the structural integrity of extrusion printed structures. The emulsion gel with an OCR of 3:7 efficiently encapsulates vitamin C in the aqueous phase and curcumin in the hydrophobic oil phase, enabling the extrusion 3D printing of tablets with varying surface area to volume (SA/V) ratios. The release of vitamin C and curcumin is influenced by the preparation method of printing versus casting and the SA/V ratio of the tablets. The hollow cylinder with the highest SA/V ratio was observed to have the highest vitamin C release, whereas for curcumin, the printed tablets had a higher release compared to the cast tablet. Additionally, through rheo-dissolution experiments, we observe a lower modulus and higher vitamin C release from the 3D-printed disc versus the higher modulus and lower vitamin C release from the cast disc tablet.

An inspection in tablet appearance integrity before bottling is regarded as a routine task in a pharmaceutical factory. Although some methods such as automated optical instrument, video or artificial intelligence (AI) are currently available in industry, it usually pays for a complex computational process as well as high cost. Based on the symmetry of tablet appearance in reality, this study develops a biaxial scanning slope symmetry algorithm to realize a dynamic real-time tablet defect detection with a simple arithmetic operation. First, the tablet is discretely scanned using image sensor in two axes, i.e. X and Y directions, simultaneously. Second, the analogy output signals generated from the sensor during the scanning process is discretely digitized and stored in an array. Third, the coordinate of center point in the series data array is identified from every line scanning. Fourth, every section slope between two nearby center points from the first to last lines is formulated and calculated sequentially. Finally, the square mean error (SME) is used to evaluate the shape defect situation according to all accumulated errors from every slope variation. The experimental results verify that the proposed algorithm can achieve both fast and accurate detection performance., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2024. Published by Elsevier Inc.)

Roll compaction (RC) is a cost-effective dry granulation method, widely implemented in the pharmaceutical industry. In early formulation development however, when the material availability is limited, being able to predict the most important parameters in RC, like gap width and specific compaction force (SCF), to obtain a target ribbon solid fraction (SF) would significantly improve the formulation development efficiency as it would avoid the need of performing experiments on the roller compactor itself. However, at the present state of things, experiments on RC mechanical simulators present an overestimation of the target SF, when compared to roller compactor SF values. Although numerous correction approaches have been developed to improve the predictive performance of different mathematical models applied to the simulation experimental results, no study has collected a database wide enough to demonstrate the validity of a correction factor that allows to accurately simulate the compaction behavior of multicomponent mixtures. Here, 25 different formulations at 40 % drug load are compacted at different SCFs, both on a RC mimicking device (Styl'One Evolution) and on an actual roller compactor (Gerteis Mini-Pactor): following a similar approach as Reimer et al. and implementing a simplified version of the Johanson's mathematical model, 4 different correction factors are calculated, depending on how their material properties and pressure dependencies are considered. In conclusion, one correction factor is identified as the optimal trade-off between the SF prediction accuracy on the Gerteis Mini-Pactor and its applicability to a wide range of formulations, as it is independent of the material properties. This finding is particularly relevant when applied to scale-up to this specific roller compactor or early development processes of new formulations that have not been mechanically characterized yet., Competing Interests: Declaration of competing interest The authors declare there is no conflict of interests., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Rationale: Huahong tablet, a commonly used clinical Chinese patent medicine, shows good efficacy in treating pelvic inflammation and other gynaecological infectious diseases. However, the specific composition of Huahong tablets, which are complex herbal formulations, remains unclear. Therefore, this study aims to identify the active compounds and targets of Huahong tablets and investigate their mechanism of action in pelvic inflammatory diseases., Methods: We utilised ultrahigh-performance liquid chromatography Q-Exactive-Orbitrap mass spectrometry and the relevant literature to identify the chemical components of Huahong tablets. The GNPS database was employed to further analyse and speculate on the components. Potential molecular targets of the active ingredients were predicted using the SwissTargetPrediction website. Protein-protein interaction analysis was conducted using the STRING database, with visualisation in Cytoscape 3.9.1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the DAVID database. Additionally, a traditional Chinese medicine-ingredient-target-pathway network was constructed using Cytoscape 3.10.1. Molecular docking validation was carried out to investigate the interaction between core target and specific active ingredient., Results: A total of 66 chemical components were identified, and 41 compounds were selected as potential active components based on the literature and the TCMSP database. Moreover, 38 core targets were identified as key targets in the treatment of pelvic inflammatory diseases with Huahong tablets. GO and KEGG enrichment analysis revealed 986 different biological functions and 167 signalling pathways., Conclusion: The active ingredients in Huahong tablets exert therapeutic effects on pelvic inflammatory diseases by acting on multiple targets and utilising different pathways. Molecular docking confirmed the high affinity between the specific active ingredients and disease targets., (© 2024 John Wiley & Sons Ltd.)

The development of new methods of identification of active pharmaceutical ingredients (API) is a subject of paramount importance for research centers, the pharmaceutical industry, and law enforcement agencies. Here, a system for identifying and classifying pharmaceutical tablets containing acetaminophen (AAP) by brand has been developed. In total, 15 tablets of 11 brands for a total of 165 samples were analyzed. Mid-infrared vibrational spectroscopy with multivariate analysis was employed. Quantum cascade lasers (QCLs) were used as mid-infrared sources. IR spectra in the spectral range 980-1600 cm -1 were recorded. Five different classification methods were used. First, a spectral search through correlation indices. Second, machine learning algorithms such as principal component analysis (PCA), support vector classification (SVC), decision tree classifier (DTC), and artificial neural network (ANN) were employed to classify tablets by brands. SNV and first derivative were used as preprocessing to improve the spectral information. Precision, recall, specificity, F1-score, and accuracy were used as criteria to evaluate the best SVC, DEE, and ANN classification models obtained. The IR spectra of the tablets show characteristic vibrational signals of AAP and other APIs present. Spectral classification by spectral search and PCA showed limitations in differentiating between brands, particularly for tablets containing AAP as the only API. Machine learning models, specifically SVC, achieved high accuracy in classifying AAP tablets according to their brand, even for brands containing only AAP.

This study aims to optimize and evaluate drug release kinetics of Modified-Release (MR) solid dosage form of Quetiapine Fumarate MR tablets by using the Artificial Neural Networks (ANNs). In training the neural network, the drug contents of Quetiapine Fumarate MR tablet such as Sodium Citrate, Eudragit® L100 55, Eudragit® L30 D55, Lactose Monohydrate, Dicalcium Phosphate (DCP), and Glyceryl Behenate were used as variable input data and Drug Substance Quetiapine Fumarate, Triethyl Citrate, and Magnesium Stearate were used as constant input data for the formulation of the tablet. The in-vitro dissolution profiles of Quetiapine Fumarate MR tablets at ten different time points were used as a target data. Several layers together build the neural network by connecting the input data with the output data via weights, these weights show importance of input nodes. The training process optimises the weights of the drug product excipients to achieve the desired drug release through the simulation process in MATLAB software. The percentage drug release of predicted formulation matched with the manufactured formulation using the similarity factor (f 2 ), which evaluates network efficiency. The ANNs have enormous potential for rapidly optimizing pharmaceutical formulations with desirable performance characteristics., (© 2024. The Author(s).)

Shen-Wu-Yi-Shen tablets (SWYST) is a traditional Chinese medicine prescription used for treating chronic kidney disease (CKD). This study aims to characterize the constituents in SWYST and evaluate the quality based on the quantification of multiple bioactive components. SWYST samples were analyzed with ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and a data-processing strategy. As a result, 215 compounds in SWYST were unambiguously identified or tentatively characterized, including 14 potential new compounds. Meanwhile, strategies based on characteristic fragments for rapid identification were summarized, indicating that the qualitative method is accurate and feasible. Notably, the glucose esters of laccaic acid D-type anthraquinone were first found and their fragmentation patterns were described by comparing that of O-glycoside isomers. Besides, based on comparisons of the cleavage ways of mono-acyl glucose with different acyl groups or acylation sites, differences in fragmentation pathways between 1,2-di-O-acyl glucose and 1,6-di-O-acyl glucose were proposed for the first time and verified by reference substances. In addition, a validated UPLC-DAD was established for the determination of 11 major bioactive components related to treatment of CKD (albiflorin, paeoniflorin, 2,3,5,4'-tetrahydroxy-stilbene-2-O-β-d-glucoside (TSG), 1-O-galloyl-2-O-cinnamoyl-β-d-glucose, emodin-8-O-β-d-glucoside, chrysophanol-O-β-d-glucoside, aloe-emodin, rhein, emodin, chrysophanol and physcion). Moreover, TSG and 1-O-galloyl-2-O-cinnamoyl-β-d-glucose were found as the quality markers related to the origins of SWYST based on multivariate statistical analysis. Conclusively, the findings in this work provide a feasible reference for further studies on quality research and mechanisms of action in treating CKD., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Central composite design based RP-HPLC method optimization for the synchronized analysis of Efonidipine Hydrochloride Ethanolate (EFE) and Chlorthalidone (CHL) in tablet. The effective separation was performed using Inertsil ODS C18 column (250 × 4.6 mm, 5 μm), PDA detector with 0.05 M KH2PO4 Buffer (pH 4.5): Acetonitrile (40:60%v/v) mobile phase. Independent variables were investigated include the concentration of KH2PO4 (X1) and flow rate of mobile phase (X2). Based on responses obtained (retention time, resolution and tailing factor), the optimum condition selected was X1 = 40% and X2 = 1 ml/min. Optimized HPLC condition was validated by assessing validation parameters and it meets the acceptance criteria set by ICH. The linear calibration curve was found to be in the quantity range 6.25-18.75 and 20-60 μg/ml Assay of drugs was 100.94 and 100.06% for CHL and EFE. The validated RP-HPLC-PDA method can be used for routine analysis of EFE and CHL in tablet., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Gummy formulations are considered suitable alternatives to traditional oral dosage forms like tablets and capsules due to their merits that include chewability, softness/flexibility, improved drug release, administration without water, appealing organoleptic properties, better patient compliance, easy preparation and usefulness for persons of different ages (e.g. children). Though there is increasing interest in gummy formulations containing drugs, measurable parameters, and specification limits for evaluating their quality are scarce. Quality check forms an essential part of the pharmaceutical development process because drug products must be distributed as consistently stable, safe, and therapeutically effective entities. Consequently, some quality parameters that could contribute to the overall performance of typical gummy formulations were investigated employing six brands of non-medicinal gummies as specimens. Accordingly, key physicochemical and micromechanical characteristics namely adhesiveness (0.009 - 0.028 mJ), adhesive force (0.009 - 0.055 N), chewiness (2.780 - 6.753 N), cohesiveness (0.910 - 0.990), hardness (2.984 - 7.453 N), springiness (0.960 - 1.000), and resilience (0.388 - 0.572), matrix firmness - compression load (2.653 - 6.753 N) and work done (3.288 - 6.829 mJ), rupture (5.315 - 29.016 N), moisture content (< 5%), weight uniformity (< 2.5 g; < 7.5% deviation), and intraoral dissolution pH (≥ 3.5 ≤ 6.8) were quantified to identify measures that may potentially function as specification limits and serve as prospective reference points for evaluating the quality of gummy formulations. Findings from this work contribute to ongoing efforts to standardize the quality control strategies for gummy formulations, particularly those intended for oral drug delivery., (© 2024. Crown.)

This study investigated the added value of combining both near-infrared (NIR) and Raman spectroscopy into a single NIRaman Combi Fiber Probe for in-line blend potency determination in the feed frame of a rotary tablet press. A five-component platform formulation was used, containing acetylsalicylic acid as the Active Pharmaceutical Ingredient (API). Calibration models for the determination of 1 and 5% w/w label claim tablets were developed using NIR and Raman spectra of powder blends ranging from 0.75 to 1.25% w/w and 3.75 to 6.25% w/w API, respectively. Step-change experiments with deliberate 10% deviation steps from the label claims were performed, from which the collected spectra were used for model validation. For model development and validation, low-level data fusion was explored through concatenation of preprocessed NIR and Raman spectra. Mid-level data fusion was also evaluated, based on extracted features of the preprocessed data. Herewith, score vectors were extracted by transforming preprocessed spectra through Principal Component Analysis, followed by critical feature selection through Elastic Net Regression. Partial Least Squares regression was applied to regress singular, low-level or mid-level fused data versus blend potency. It could be concluded that irrespective of the data fusion technique, an increase in Step-Change Sensitivity (SCS) and decrease in Root Mean Squared Error (RMSE) was observed when predicting the 5% w/w step-change experiment. For the prediction of the 1% w/w step-change experiment, no added benefit with regard to SCS and RMSE was observed due to the addition of the noisy NIR spectra.

Introduction: Yangxinshi tablet (YXST) is a traditional Chinese medicine preparation characterized by its high efficacy and safety for the treatment of cardiovascular diseases. Anionic compounds have been revealed as potential active components. However, there is currently limited research regarding its quality control., Objective: We aimed to establish a strategy for the simultaneous separation and determination of five key anionic compounds in YXST., Method: A sensitive and efficient analytical method was developed and applied for the simultaneous separation and determination of five key compounds in YXST using large-volume sample stacking with polarity switching and micelle electrokinetic chromatography (LVSS-PS-MEKC) coupled with diode array detection. Crucial parameters, including sample volume, applied voltage, composition and pH of the running buffer, concentration of organic modifier, and switching time of the polarity, were systematically evaluated and optimized using a single variable method to enhance separation performance. Furthermore, the impact of cyclodextrin and sodium dodecyl sulfate as electrolyte modifiers was also investigated., Results: Under the optimal conditions, baseline separation of the five compounds (daidzein, puerarin, glycyrrhiztinic acid, chlorogenic acid, and salvianolic acid B) was achieved within 20 min. In comparison to the conventional MEKC mode, the constructed LVSS-PS-MEKC method exhibited a more than sixfold increase in the enrichment factor. The method was validated in terms of linearity, precision, accuracy, 24 h stability, and recovery and successfully applied to analyze YXST samples., Conclusion: A sensitive strategy was developed for the simultaneous separation and determination of five key anionic components in YXST, offering a robust and efficient strategy for pharmaceutical analysis., (© 2024 John Wiley & Sons Ltd.)

Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopic imaging is a powerful tool to visualize the distribution of components, and it has been used to analyze drug release from tablets. In this work, ATR-FTIR spectroscopic imaging was applied for observing the dissolution of molecular crystals from tablet compacts. The IR spectra provided chemically specific information about the transformation of crystal structures during the dissolution experiments. Theophylline (TPL) anhydrate and its cocrystals were used as model systems of molecular crystals. The IR spectra during the dissolution of TPL revealed information about the crystal structure of TPL, which transformed from anhydrate to monohydrate in water. During a dissolution test of a model cocrystal system, it was suggested that an active pharmaceutical ingredient (API) and a coformer were dissolved in water simultaneously. The IR spectra that were acquired during the dissolution of a cocrystal tablet showed new spectral bands attributed to the API after 5 min. This suggested that the precipitation of API was observed during the dissolution experiment. Measurements from ATR-FTIR spectroscopic imaging can visualize the drug release from the tablet and determine the transformation of molecular crystals during their dissolution. These results will have an impact on clarifying the dissolution mechanism of molecular crystals.

An abrupt cessation of antidepressant medication can be challenging due to the appearance of withdrawal symptoms. A slow hyperbolic tapering of an antidepressant, such as citalopram hydrobromide (CHB), can mitigate the withdrawal syndrome. However, there are no viable dosage forms on the market to implement the tapering scheme. A solution using a tunable modular design (TMD) approach to produce flexible and accurate doses of CHB is proposed. This design consists of two parts: 1) a module with a fixed amount of preloaded CHB in a freeze-dried polymer matrix, and 2) fine-tuning the CHB dose by inkjet printing. A noncontact food-grade printer, used for the first time for printing pharmaceuticals, is modified to allow for accurate printing of the highly concentrated CHB ink on the porous CHB-free or CHB-preloaded modules. The produced modules with submilligram precision are bench-marked with commercially available CHB tablets that are manually divided. The TMD covers the entire range of doses needed for the tapering (0.5-23.8 mg). The greatest variance is 13% and 88% when comparing the TMD and self-tapering, respectively. Self-tapering is proven inaccurate and showcases the need for the TMD to make available accurate and personalized doses to wean off treatment with CHB., (© 2024 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

Orodispersible tablets (ODTs) represent a growing category of dosage forms intended to increase the treatment acceptability for special groups of patients. ODTs are designed to rapidly disintegrate in the oral cavity and to be administered without water. In addition, ODTs are easy to manufacture using standard excipients and pharmaceutical equipment. This study adds to previously published research that developed an instrumental tool to predict oral disintegration and texture-related palatability of ODTs with different formulations. The current study aimed to challenge the predictive capacity of the models under variable process conditions. The studied process parameters with potential impact on the pharmaceutical properties, texture profiles, and palatability were the compression pressure, punch shape and diameter. Subsequently, for all the placebo and drug-loaded ODTs, the in vivo disintegration time and texture-related palatability were determined with healthy volunteers. Previously developed regression models were applied to predict the formulation's disintegration time and texture-related palatability characteristics of ODTs obtained under different experimental conditions. The influence of process variables on the predictive performance of the models was estimated by calculating the residuals as the difference between the predicted and observed values for the investigated response. Increasing the speed of the analyser`s probe from 0.01 mm/s to 0.02 mm/s led to an improved differentiation of the texture profiles. The in vivo disintegration time and texture-related palatability scores were only influenced by the mechanical resistance and the tablet shape. Lower score was observed for the larger diameter tablets (10 mm). Overall, the prediction of the disintegration time at 0.02 mm/s was more accurate, except for stronger tablets. The best prediction of texture-related palatability was achieved for the 10 mm tablets, tested at 0.01 mm/s speed. The same model achieved good predictions of the oral disintegration time for all API-loaded formulations, which confirmed the ability of the texture analysis to capture process-related variability. Drug loading decreased the predictive capacity of the texture-related palatability because of the taste effect., (Copyright © 2024. Published by Elsevier B.V.)

The two-step preconcentration technique consisting of large-volume sample stacking (LVSS) and micelle to solvent stacking (MSS) in cyclodextrin-modified electrokinetic chromatography (CDEKC) was developed for the analysis of five cationic alkaloids in complex Chinese herbal prescriptions. Relevant parameters affecting separation and stacking performance were optimized separately. Under the optimal LVSS-MSS-CDEKC conditions, less analysis time and organic solvent were required, and the enhancement factors of analytes ranged from 12 to 15 compared with the normal CDEKC separation mode. Further, all validation results demonstrated good applicability and multiple alkaloids (epiberberine, dehydrocorydaline, jatrorrhizine, coptisine and berberine) in Yangxinshi tablet (YXST) have been simultaneously determined. This approach presents powerful potential for the determination of multiple components in complex preparations of Chinese medicine., (© 2024 John Wiley & Sons Ltd.)

Bonding area (BA) and bonding strength (BS) interplay dictates tensile strength of a tablet and, hence, tabletability. Using a series of alkali halides with mechanical properties spanning more than one order of magnitude, the role of compaction pressure and mechanical properties on tabletability is systematically investigated and explained using the BA-BS interplay. Results reveal that BA dominates the BA-BS interplay at low pressures, where more plastic powders attain higher tensile strength due to larger BA. In contrast, BS dominates the interplay at high pressures, when difference in BA between powders is minimized. Under the typical compaction pressures of 100-300 MPa, tablet tensile strength is the highest for materials with intermediate hardness, or plasticity, due to an optimal BA-BS interplay., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, a chemiluminescence (CL) method was developed to determine diphenoxylate in tablets and human plasma. This is the first CL method proposed to determine diphenoxylate. Creating three-dimensional data caused the parallel factor analysis algorithm (PARAFAC) to be used for the first time in CL methods. The method is based on the fact that diphenoxylate enhances the weak CL produced in the reaction of Ru(phen) 3 2+ and acidic Ce(IV), and the concentration of Ce(IV) solution has a different effect on the CL response of diphenoxylate and the blank plasma. The calibration curve was linear from 4.0 × 10 -8 to 1.6 × 10 -6  mol L -1 (R 2  = 0.9954), and the detection limit was 1.3 × 10 -8  mol L -1 (S/N = 3). The sampling rate was about 30 samples per hour, and the % RSD for 10 repeated measurements of 4 × 10 -7  mol L -1 diphenoxylate was 5.4%. The interference effects of some ions, amino acids, and common additives were also investigated. The CL method was successfully used to determine diphenoxylate in tablets, and the results were statistically confirmed by the reference method. The proposed CL method and the PARAFAC algorithm were successfully used to determine the concentration of diphenoxylate in human blood plasma samples., (© 2024 John Wiley & Sons Ltd.)

In this paper, the development and application of a multiple heart-cutting achiral-chiral LC-LC method (mLC-LC) for the analysis of dansylated (Dns) branched-chain amino acids in commercial tablets are described. In the first dimension, a Waters Xbridge RP C18 achiral column was used under gradient conditions with buffered aqueous solution and acetonitrile. The elution order Dns-valine (Dns-Val) < Dns-isoleucine (Dns-Ile) < Dns-leucine (Dns-Leu) turned out with full resolution between adjacent peaks: 7.25 and 1.50 for the Val/Ile and the Ile/Leu pairs, respectively. A "research" validation study was performed, revealing high accuracy (Recovery%) and precision (RSD%) using two external set solutions, respectively, in the range 93.7%-104.1% and 0.4%-3.2%. The C18 column was connected via a two-position six-port switching valve to the quinidine-based Chiralpak quinidine-anion-exchange chiral column. A water/acetonitrile, 30/70 (v/v) with 50 mM ammonium acetate (apparent pH of 5.5) eluent allowed getting the three enantiomers' pairs resolved: R S equal to 4.3 for Dns-Val and Dns-Ile, and 1.7 for Dns-Leu. The application of the mLC-LC method confirmed that the content of Val, Ile, and Leu in the tablets was compliant with that labeled by the producer. Only l-enantiomers were found in the food supplement, as confirmed by LC-MS/MS analysis., (© 2024 Wiley‐VCH GmbH.)

The main goal of the study was to improve the compliance and convenience of patients by designing and development of an immediate release (IR) fixed-dose combination (Clopidogrel bisulphate and Aspirin) tablets. The proposed combination product utilizes Clopidogrel to protect the moisture-sensitive aspirin component, enhancing its stability against atmospheric conditions. Response-surface approach (Design Expert vs. 13) was used to generate this IR tablet by calculating the right composition of independent variables such as Microcrystalline cellulose 102, pregelatinized starch and Hydroxypropyl cellulose. 32 factorial design was used to estimate the effects of these independent variables on the responses of dependent variables (disintegration & friability) and constructed a total of nine (9) formulations. Pre and Post formulation, quality control parameters were investigated as per pharmacopeia. A systematic approach was used for the optimization process and a prototype checkpoint batch (CPB) based on the better contrast of independent variables was prepared. In vitro analysis of formulations was carried out to estimate the responses. Friability was found in the range of 0.088-1.076%w/w, except F1 = 1.076 all are within limits (NMT 1.0%). Disintegration time was recorded 7.3 ± 1.20 as lower and 24.5 ± 1.63 min was the highest. The release of drugs from their dosage form was fast and rapid, for clopidogrel after 15min was 70.42-96.82% with SD ± 8.71 and aspirin was 69.88-91.49% in 15 min with SD ± 6.41, all the tablets were released more than 80% in 20 min. The stability outcomes of CPB tablets after 15 days of stress study (60 ± 2°C and 75 ± 5%) indicated good compatibility and stability of APIs with excipients. It was concluded that the direct compression method can be preferred to prepare a combination product with cost-effectiveness. It was also concluded that the proposed methodology could increase Aspirin's stability and allow for an aqueous coating system to finish the product with a film coating. By using Design Expert software, the best composition of the formulation can be selected and optimized in a short period of time with minimum trial and errors. The results also demonstrated that the use of a fixed-dose combination tablet instead of the individual is expected to be more convenient to patients and thus improves patient compliance and decreases the occurrence of adverse effects and side effects., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Usman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)