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Aims: The gold standard for percutaneous Achilles tendon tenotomy during the Ponseti treatment for idiopathic clubfoot is a tenotomy with a No. 15 blade. This trial aims to establish the technique where the tenotomy is performed with a large-bore needle as noninferior to the gold standard., Methods: We randomized feet from children aged below 36 months with idiopathic clubfoot on a 1:1 basis in either the blade or needle group. Follow-up was conducted at three weeks and three months postoperatively, where dorsiflexion range, Pirani scores, and complications were recorded. The noninferiority margin was set at 4° difference in dorsiflexion range at three months postoperatively., Results: The blade group had more dorsiflexion at both follow-up consultations: 18.36° versus 18.03° (p = 0.115) at three weeks and 18.96° versus 18.26° (p = 0.001) at three months. The difference of the mean at three months 0.7° is well below the noninferiority margin of 4°. There was no significant difference in Pirani scores. The blade group had more extensive scar marks at three months than the needle group (8 vs 2). No major complications were recorded., Conclusion: The needle tenotomy is noninferior to the blade tenotomy for usage in Ponseti treatment for idiopathic clubfoot in children aged below 36 months., Competing Interests: This work was conducted with support from Harvard Catalyst and The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR002541) and its affiliated academic healthcare centers for the statistical analysis section of this trial. M. Pigeolet is supported by a GRANT of the Belgian Kids’ Fund (BKF) for Pediatric Research., (© 2024 The British Editorial Society of Bone & Joint Surgery.)

A brompheniramine taste-masked pediatric formulation was developed as part of the National Institutes of Health Pediatric Formulation Initiative to help address low patient compliance caused by the bitter taste of many adult formulations. To confirm that the taste-masked formulation can provide a similar pharmacological effect to the previous marketed adult formulations, a juvenile porcine model was used to screen the model pediatric formulation to compare the bioavailability between the marketed brompheniramine maleate and the taste-masked maleate/tannate formulation. Pigs were dosed orally with both formulations and blood samples were obtained from 0 to 48 h. Plasma samples were prepared and extracted using solid-phase extraction. The mass spectrometer was operated under selected ion monitoring mode. The selected ion monitoring channels were set to m/z 319.1 for brompheniramine and m/z 275.2 for the internal standard chlorpheniramine. Calibration curves were linear over the analytical range 0.2-20 ng/ml (r 2  > 0.995) for brompheniramine in plasma. The intra- and inter-day accuracies were between 98.0 and 105% with 5.73% RSD precision. The bioanalytical method was successfully applied to a preclinical bioavailability study. The bioavailability profiles were not significantly different between the two formulations, which demonstrates that taste-masking with tannic acid is a promising approach for formulation modification for pediatric patients., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

Purpose: Products formulated for intramammary (IMM) infusion are intended for the delivery of therapeutic moieties directly into the udder through the teat canal to maximize drug exposure at the targeted clinical site, the mammary gland, with little to no systemic drug exposure. Currently, to our knowledge, there has been no in-vitro matrix system available to differentiate between IMM formulations. Our goal is to develop A custom tailored in-vitro "Matrix of Chemistry, Manufacturing and Control" (MoCMC) System to be a promising future tool for identifying inequivalent IMM formulations. MoCMC can detect inter and intra batch variabilities, thereby identifying potential generics versus brand product similarities or differences with a single numeric value and a specific & distinctive fingerprint., Methods: The FDA-approved IMM formulation, SPECTRAMAST Ⓡ LC, was selected as the reference product for the MoCMC. Twelve in-house test formulations containing ceftiofur hydrochloride were formulated and characterized. The MoCMC was developed to include six input parameters and three output parameters. The MoCMC system was used to evaluate and compare SPECTRAMAST Ⓡ LC with its in-house formulations., Results: Based on the MoCMC generated parameters, the distinctive fingerprints of MoCMC for each IMM formulations, and the statistical analyses of MCI and PPI values, in-house formulations, F-01 and F-02 showed consistency while the rest of in-house formulations (F-03-F-12) were significantly different as compared to SPECTRAMAST Ⓡ LC., Conclusion: This research showed that the MoCMC approach can be used as a tool for intra batch variabilities, generics versus brand products comparisons, post-approval formulations changes, manufacturing changes, and formulation variabilities., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Between February 2020 and January 2022, the Food and Drug Administration (FDA) recalled 281 metformin extended-release products due to the presence of N-nitrosodimethylamine (NDMA) above the acceptable daily intake (ADI, 96 ng/day). Our previous studies indicated presence of NDMA levels above ADI in both metformin immediate and extended-release products. When metformin products have NDMA impurities, it is indispensable to check for the same impurities in metformin combination products. Therefore, the objective of the present study was to evaluate in-use stability of commercial metformin combination products for NDMA. For this purpose, metformin products in combination with glyburide (GB1-GB12), glipizide (GP1-GP8), pioglitazone (P1-P3), alogliptin (A1, A2), and linagliptin (L1, L2) were repacked in pharmacy vials, stored at 30°C/75% RH for 3 months, and monitored for NDMA impurity. The NDMA level varied from 0 to 156.8 ± 32.8 ng/tablet initially and increased to 25.4 ± 5.1 to 455.0 ± 28.4 ng/tablet after 3 months of exposure to in-use condition. Initially, 18 products have NDMA level below ADI limit before exposure which decreased to 7 products (GB5, GP3, GP5, A1, A2, L1, and L2) meeting specification. In conclusion, in-use stability study provides quality and safety risk assessment of drug products where nitroso impurities are detected in the probable condition of use., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The aim of this paper was to investigate the effects of formulation parameters on the physicochemical and pharmacokinetic (PK) behavior of amorphous printlets of lopinavir (LPV) manufactured by selective laser sintering 3D printing method (SLS). The formulation variables investigated were disintegrants (magnesium aluminum silicate at 5-10%, microcrystalline cellulose at 10-20%) and the polymer (Kollicoat® IR at 42-57%), while keeping printing parameters constant. Differential scanning calorimetry, X-ray powder diffraction, and Fourier-transform infrared analysis confirmed the transformation of the crystalline drug into an amorphous form. A direct correlation was found between the disintegrant concentration and dissolution. The dissolved drug ranged from 71.1 ± 5.7% to 99.3 ± 2.7% within 120 min. A comparative PK study in rabbits showed significant differences in the rate and extent of absorption between printlets and compressed tablets. The values for T max , C max , and AUC were 4 times faster, and 2.5 and 1.7 times higher in the printlets compared to the compressed tablets, respectively. In conclusion, the SLS printing method can be used to create an amorphous delivery system through a single continuous process., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Purpose: Intramammary (IMM) formulations are locally acting and delivered intracisternally into the udder. No pharmacopeial in-vitro release method is available to differentiate between the IMM formulations. Our research aim is to develop in-vitro release methods that discriminate different IMM formulations (SPECTRAMAST® LC and in-house formulations)., Methodology: Different in-house formulations were developed to simulate SPECTRAMAST® LC generics. SPECTRAMAST® LC and the in-house formulations were characterized for physicochemical attributes, such as particle size, rheology, drug content, sedimentation rate, and flocculation rate. The in-vitro release method was optimized by evaluating drug release using USP apparatuses 1, 2 (with and without enhancer/customized cells), and 4. Various test parameters, including medium effect (whole homogenized bovine milk versus aqueous buffer), medium volume (200-900 mL), and rotational speed (50-200 rpm) were investigated., Results: Two potential in-vitro systems can be used as discriminatory methods for IMM formulations: USP apparatus 2 with the IMM formulation loaded into two containers a) customized formulation container (83.1 cm in height and 56.4 cm in width) or b) enhancer cells with their top adapted with mesh #40 (rotation speed:125 rpm and 900 mL of whole homogenized bovine milk). The release profile of SPECTRAMAST® LC at 1 h (99.8%) was not significantly different from formulations with similar physicochemical characteristics F-01 (99.1%) and F-02 (100.5%). Formulation with different physicochemical characteristics F-03 (44.3%) and F-04 (57.2%) showed slower release (1 h) than SPECTRAMAST® LC (98.8%)., Conclusion: The developed in-vitro release methods can be used as a potential tool for in-vitro comparability evaluations for IMM formulations., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The aim of this work was to design pediatric-friendly, dose-flexible orally disintegrating drug delivery systems (printlets) of the antiviral drug tenofovir disoproxil fumarate (TDF) by selective laser sintering (SLS) for potential use in hospitals along with other antiviral drugs. In order to obtain a consistent quality of printlets with desired properties, it is important to understand certain critical quality attributes for their main and interactions effect. The printlets were optimized by Box-Behnken's design of the experiment by varying process variables while keeping the composition constant. The composition contained 16.3% TDF, 72.7% polyvinyl pyrrolidone K16-18, 8% magnesium aluminum silicate, 3% Candurin ® NXT Ruby Red, and 0.3% colloidal silicon dioxide. The process variables studied were surface (X 1 ), chamber temperatures (X 2 ), and laser scanning speed (X 3 ). The range of variable levels was 75-85°C for X 1 , 50-70°C for X 2 , and 200-240 mm/s for X 3 , respectively. The responses studied were hardness, disintegration time, dissolution, physiochemical, and pharmacokinetic characterization. X-ray powder diffraction indicated partial or complete conversion of the crystalline drug into amorphous form in the printlets. Comparative pharmacokinetics between Viread ® (generic) and printlets in rats were superimposable. Pharmacokinetic parameters showed statistically insignificant differences between the two formulations in terms of T max , C max , and AUC of (p > 0.05). Printlets were bioequivalent to Viread ® as per FDA bioequivalence criteria. Thus, the SLS printing method showed the fabrication of dose-flexible printlets with quality, and in vivo performance equivalent to commercial tablets., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The focus of the present work was to develop co-amorphous dispersion (CAD) formulations of tacrolimus (TAC) using sucrose acetate isobutyrate as a carrier, evaluate by in vitro and in vivo methods and compare its performance with hydroxypropyl methylcellulose (HPMC) based amorphous solid dispersion (ASD) formulation. CAD and ASD formulations were prepared by solvent evaporation method followed by characterization by Fourier transformed infrared spectroscopy, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), dissolution, stability, and pharmacokinetics. XRPD and DSC indicated amorphous phase transformation of the drug in the CAD and ASD formulations, and dissolved more than 85% of the drug in 90 min. No drug crystallization was observed in the thermogram and diffractogram of the formulations after storage at 25 °C/60% RH and 40 °C/75% RH. No significant change in the dissolution profile was observed after and before storage. SAIB-based CAD and HPMC-based ASD formulations were bioequivalent as they met 90% confidence of 90-11.1% for C max and AUC. The CAD and ASD formulations exhibited C max and AUC 1.7-1.8 and 1.5-1.8 folds of tablet formulations containing the drug's crystalline phase. In conclusion, the stability, dissolution, and pharmacokinetic performance of SAIB-based CAD and HPMC-based ASD formulations were similar, and thus clinical performance would be similar.

Chronic use of antihistamines can induce abnormalities in lipid absorption with potential excessive accumulation of lipids in the mesentery that can lead to the development of obesity and a metabolic syndrome. The focus of the present work was to develop a transdermal gel formulation of desloratadine (DES) to prevent/reduce obesity and metabolic syndromes. Nine formulations were prepared to contain hydroxypropyl methylcellulose (2-3%), DES (2.5-5.0%), and Transcutol ® (15-20%). The formulations were evaluated for cohesive and adhesive properties, viscosity, drug diffusion through synthetic and pig ear skin, and pharmacokinetics in New Zealand white rabbits. Drug permeation was faster through the skin compared to synthetic membranes. The drug had good permeation, as indicated by very short lag time (0.08-0.47 h) and high flux (59.3-230.7 μg/cm 2 .h). The maximum plasma concentration (C max ) and area under the curve (AUC) of transdermal gel formulations were 2.4 and 3.2 fold that of the Clarinex tablet formulation. In conclusion, as indicated by the higher bioavailability, transdermal gel formulation of DES may decrease the dose of the drug, compared to commercial formulation. It has the potential to reduce or eliminate metabolic syndromes associated with oral antihistamine therapy.

Many nitrosamines have been recognized to be carcinogenic for many decades. Despite the fact that several nitrosamine precursors are frequently used in the manufacturing of pharmaceutical products, their potential presence in pharmaceutical products has previously been overlooked due to a lack of understanding on how they form during the manufacturing process. From the risk assessment, it is clear that nitrosamines or their precursors may be present in any component of the finished dosage form. As a risk mitigation strategy, components with a high potential to form nitrosamine should be avoided. In the absence of suitable alternatives, sufficient measures to maintain nitrosamines below acceptable intake levels must be applied. Excipient manufacturing pathways must be extensively studied in order to identify probable excipient components that may contribute to nitrosamine formation. The manufacturers must not solely rely on pharmacopeial specifications for APIs and excipients, rather, they should also develop and implement additional strategies to control nitrosamine impurities. The formulation can be supplemented with nitrosating inhibitors, such as vitamin C, to stop the generation of nitrosamine. The purpose of this review is to identify key risk factors with regard to nitrosamine formation in pharmaceutical dosage forms and provide an effective control strategy to contain them below acceptable daily intake limits., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Objectives: The focus of the present research is to develop printlet formulations of pyrimethamine (PMT)., Methods: Printlets formulation of PMT were developed by screening design by varying laser scanning speed, Kollidon® VA 64, polyvinylpyrrolidone, and disintegrant., Results: Laser scanning speed, Kollidon® VA, and disintegrant had statistically significant effect on hardness, disintegration time, and/or dissolution (p < 0.05). Dissolution was almost 100% in 30 min. X-ray powder diffraction indicated partial amorphous transformation of the crystalline drug. Pharmacokinetic and anti-toxoplasma activity profiles of the printlets and compressed tablets were superimposable with no statistical difference (p > 0.05)., Conclusion: Clinical performance of the printlets would be similar to the compressed tablets.

Data integrity (DI) reaffirms the pharmaceutical industry's commitment to manufacture drugs that are safe, effective and fulfil quality standards. At the same time, DI is a crucial tool for regulatory authorities to use in protecting public health. Recent FDA Form-483 observations and warning letters indicate that DI is the main issue the pharmaceutical industry is currently dealing with. Failure to comply with DI requirements may result in a high number of un-validated results, which may cause post-marketing issues and frequent product recalls. To address the underlying causes of DI problems, a comprehensive approach is necessary. The majority of DI issues are caused by poor quality culture, organizational or individual behaviour, leadership, processes, or technology. DI should be effectively integrated into the quality management system, and it should apply to both paper and electronic records. Employees should be trained on 21 CFR Part 11. Consistent review and audit are required to ensure that procedures are followed and audit trails are generated. Electronic systems, in addition to being an efficient solution (system integration, data verification at both input and output, security), offer advantages over traditional paper-based systems in terms of improved compliance with DI regulatory requirements. For example, many electronic system platforms provide enhanced security features and audit trail capabilities. Finally, management support for data governance is essential for successful implementation of DI. This article reviews commonly observed deviations by FDA pertaining to DI and discusses measures to be undertaken to avoid them., 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 © 2022 Elsevier B.V. All rights reserved.)

The aim of this study was to improve the physicochemical properties and oral bioavailability of dasatinib (DST) by the amorphous solid dispersion (ASD) approach using cellulose acetate butyrate (CAB) as a carrier. Various formulations of ASD (DST:CAB 1:1 to 1:5) were prepared by the solvent evaporation method. ASDs were characterized for physicochemical attributes, stability and pharmacokinetics. Scanning electron microscopy, Fourier transformed infrared, X-ray powder diffraction, and differential scanning calorimetry confirmed the transformation of the crystalline drug into amorphous phase. ASD formation resulted in a 3.7−4.9 fold increase in dissolution compared to DST or physical mixture. The ASDs formulation exhibited relative stability against transformation from the unstable amorphous phase to a stable crystalline phase that was indicated by spectral and X-ray powder diffraction data, and insignificant (p > 0.05) decrease in dissolution. Tmax, Cmax and AUC0-∞ of ASD were 4.3-fold faster and 2.0 and 1.5 fold higher than the corresponding physical mixture. In conclusion, the ASD of DST significantly improved dissolution and oral bioavailability which may be translated into a reduction in dose and adverse events.

Introduction: Vancomycin administration in individuals with hematological malignancy or neutropenia is associated with a suboptimal trough concentration. Nonetheless, most studies did not distinguish whether low vancomycin trough concentrations were due to hematological malignancies or neutropenia. This study aimed to determine the association between types of hematological malignancy and febrile neutropenia with low vancomycin concentrations., Methods: The present retrospective chart review study was conducted by using clinical data adopted from computerized physician order entries (BestCare®) for all of the patients who received intravenous vancomycin treatment between January 2017 and December 2020 at King Abdulaziz Medical City in Jeddah., Results: Out of the 296 patients, 217 were included. There was no significant association between the type of hematological malignancy and the incidence of a low trough concentration (p > 0.05), while a significant association between febrile neutropenia and the incidence of a low trough concentration was observed (p < 0.05). Furthermore, the predictors for a low trough among febrile neutropenic patients were creatinine clearance (CrCI) and a low albumin concentration. In addition, there was a significant association between febrile neutropenia and augmented renal clearance (p < 0.05)., Conclusions: The findings of this study conclude that febrile neutropenia is associated with low vancomycin concentrations. Interestingly, augmented renal clearance was observed in most of the febrile neutropenia patients with a significant association, which is considered the main driver for a low trough in neutropenic patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Alzahrani et al.)

The focus of present work was to synthesize prodrugs of dolutegravir (DTG) for ultra-long delivery purpose. The prodrug was synthesized by esterification of hydroxyl group with carboxyl group of fatty acid (lauric or myristic acid). The prodrugs were characterized by differential scanning calorimetry, X-ray powder diffraction, nuclear magnetic resonance, Fourier transformed infrared, near infrared-chemical imaging, pH-solubility, partition coefficient, and stability (solid and liquid). Stability studies were performed by exposing the powder drugs to 40°C/75% RH for three months and buffer solutions at room temperature for 72 h. The prodrugs and drug were formulated into in-situ implant using biodegradable polymer. Thermal, spectral, and diffractometric data indicated formation of new chemical and solid forms. Formation of prodrugs resulted in lowering of melting point of DTG from 191.1°C to 163.7 and 140.7°C for DTG-Laurate and DTG-Myristate prodrugs, respectively. A decrease in solubility of 18.2-115.9 and 124.5-1594.9 folds was observed for DTG-Laurate and DTG-Myristate, respectively compared to DTG. Similarly, the prodrugs were highly lipophilic compared to DTG. Solid-state and pH-stability profiles of DTG and prodrugs were comparable. Implant formulation released 60.1% in 77 days compared to 95.6% in 35 days in the case of DTG-Myristate and DTG, respectively. In summary, combining prodrug and drug delivery approaches can be utilized for delivering drug for ultra-long period., Competing Interests: Declaration of Interests 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 © 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

The focus of this research was to understand the effects of formulation and processing variables on the very-rapidly dissolving printlets of isoniazid (INH) manufactured by the selective laser sintering (SLS) three-dimensional (3D) printing method, and to characterize their physicochemical properties, stability, and pharmacokinetics. Fifteen printlet formulations were manufactured by varying the laser scanning speed (400-500 mm/s, X 1 ), surface temperature (100-110 °C, X 2 ), and croscarmellose sodium (CCS, %, X 3 ), and the responses measured were weight ( Y 1 ), hardness ( Y 2 ), disintegration time (DT, Y 3 ), and dissolution ( Y 4 ). Laser scanning was the most important processing factor affecting the responses. DT was very rapid (≥3 s), and dissolution (>99%) was completed within 3 min. The root-mean-square error in the studied responses was low and analysis of variance (ANOVA) was statistically significant ( p < 0.05). X-ray micro-computed tomography (micro-CT) images showed very porous structures with 24.6-34.4% porosity. X-ray powder diffraction and differential scanning calorimetry data indicated partial conversion of the crystalline drug into an amorphous form. The printlets were stable at 40 °C/75% RH with no significant changes in assay and dissolution. Pharmacokinetic profiles of the printlets and compressed tablets were superimposable. In conclusion, the rapidly dissolving printlets of the INH were stable, and oral bioavailability was similar to that of compositionally identical compressed tablets.

Metformin is a widely used first-line oral antidiabetic agent. TheFood and Drug Administration (FDA) confirmed the presence of the ofN-nitrosodimethylamine (NDMA) impurity, a carcinogenic, above the acceptable daily intake (ADI, 96 ng/day) in certain metformin products. The objective of the present study was to assess in-use stability of commercial metformin products for NDMA and dissolution quality attributes. Four immediate-release (M1-M4) and six extended-rerelease (M5-M10) metformin products were evaluated in the stability testing. All products were repacked in pharmacy vials and stored at 30 °C/75% RH for 12 weeks. Five products (M2, M3, M5, M7 and M10) had NDMA level above ADI limit (96 ng/day) before in-use stability exposure. NDMA in M2 (1164 ± 52.9 ng/tablet) and M3 (3776 ± 351.9 ng/tablet) products were 12 and 39 folds of ADI, respectively. Similarly, ER products, M5 (191 ± 94.1 ng/tablet), M7 (1473 ± 47.3 ng/tablet) and M10 (423 ± 55.8 ng/tablet) exhibited NDMA of 1.9, 15.3 and 4.4 folds of ADI, respectively. The impurity level significantly (p < 0.05) increased after 12-week stability exposure to 2.72, 2.47, 2.23 and 2.78 folds of initial values in M2, M3, M7 and M10. In summary, these findings suggested that carcinogenic impurity generation was affected by in-use stability condition exposure and it is expected that several more products currently in the market may also be recalled soon., (Copyright © 2022. Published by Elsevier B.V.)

Clinical research has proven that HIV-positive (HIV + ) individuals with cocaine abuse show behavioral and neurocognitive disorders. Noncoding RNAs (ncRNAs), such as long ncRNAs (lncRNAs) and microRNAs (miRNAs), are known to regulate gene expression in the contexts of HIV infection and drug abuse. However, there are no specific lncRNA or miRNA biomarkers associated with HIV-1 Transactivator of transcription protein (Tat) and cocaine coexposure. In the central nervous system (CNS), astrocytes are the primary regulators of energy metabolism, and impairment of the astrocytic energy supply can trigger neurodegeneration. The aim of this study was to uncover the roles of lncRNAs and miRNAs in the regulation of messenger RNA (mRNA) targets affected by HIV infection and cocaine abuse. Integrative bioinformatics analysis revealed altered expression of 10 lncRNAs, 10 miRNAs, and 4 mRNA/gene targets in human primary astrocytes treated with cocaine and HIV-1 Tat. We assessed the alterations in the expression of two miRNAs, hsa-miR-2355 and hsa-miR-4726-5p; four lncRNAs, LINC01133, H19, HHIP-AS1, and NOP14-AS1; and four genes, NDUFA9, KYNU, HKDC1, and LIPG. The results revealed interactions in the LINC01133-hsa-miR-4726-5p-NDUFA9 axis that may eventually help us understand cocaine- and HIV-1 Tat-induced astrocyte dysfunction that may ultimately result in neurodegeneration., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Portioned moist snuff and snus, two subcategories of smokeless tobacco products (STP) were dissolution tested as a quality control test. A USP Apparatus 4 was employed to develop and validate the method. The method was assessed based on time to reach nicotine dissolution plateau, percentage difference between two profiles at each time point, relative standard deviation (RSD), and f1 (similarity) and f2 (dissimilarity) values. Based on these criteria, 200 ml volume and 8 ml/min flow were found be discriminatory. The amount of nicotine dissolved from the nine products varied widely (2.0-3.4, 2.1-4.1, 3.3-4.6, 5.5-6.6, 6.9-9.1, 11.5-14.2, 12.5-14.6, 14.0-15.5, and 15.5-19.6 mg/pouch at 60 min). RSDs of the dissolution ranges were more than 20% at earlier time points and less than 20% at later timepoints. The developed method produced distinct profiles for all the tested products, which was further confirmed by f1>15 and f2<50 values. In conclusion, the developed method was discriminatory and can be employed as a quality control test and to differentiate among moist snuff and snus products., (Copyright © 2021. Published by Elsevier Inc.)

Aim: To understand the effect of HIV infection and cocaine exposure on piRNA expression in human primary astrocytes. Materials & methods: We used small RNA sequencing analysis to investigate the impacts of HIV-1 Tat and cocaine coexposure on the expression of piRNAs in human primary astrocytes. Results: We identified 27,700 piRNAs and analyzed them by small RNA next-generation sequencing. A total of 239 piRNAs were significantly altered by HIV-1 Tat and cocaine coexposure. We also identified PIWIL1, PIWIL2, PIWIL3 and PIWIL4 as interacting partners of piRNAs that were affected by cocaine and HIV-1 Tat coexposure. Epigenetic changes in the expression levels of these piRNA targets were associated with Kyoto Encyclopedia of Genes and Genomes pathways of energy metabolism and neurodegeneration. Conclusion: These findings provide evidence that cocaine exposure and HIV infection affect the expression levels of piRNA, PIWIL1, PIWIL2, PIWIL3 and PIWIL4.

The focus of the present investigation was to develop amorphous glassy solutions (AGSs) of BCS Class II and IV drugs using sucrose acetate isobutyrate (SAIB). The drugs studied were rifaximin (RFX), dasatinib (DST), aripiprazole (APZ), dolutegravir (DLT), cyclosporine (CYS), itraconazole (ITZ), tacrolimus (TAC), sirolimus (SRL), aprepitant (APT), and carbamazepine (CBZ). AGSs were prepared by dissolving known quantity of the drug in the SAIB at 120 (TAC and APZ), 140 (CYS) or 150 o C (RFX, DST, DLT, ITZ, SRL, APT, and CBZ). They were characterized visually and by NIR, NIR hyperspectroscopy (NIR-H), and XRPD. Stability were determined by exposing open vials to 40 o C/75% RH for a week. AGSs behave like a glassy solid at room temperature and liquified above 60 o C. The solubility of APT, DLT, SRL, APZ, RFX, CBZ, TAC and CYS in SAIB was 0.4±0.0, 1.7±0.4, 1.9±0.0, 21.6±2.6, 36.4±0.9, 76.5±4.0, 115.1±2.3, and 239.0±12.6 mg/g, respectively. NIR, NIR-H, and XRPD data indicated the amorphous nature of the AGSs. Furthermore, AGSs were stable against devitrification on exposure to high temperature and humidity. In summary, SAIB can be employed to develop stable AGSs of poorly soluble drugs to increase dissolution, and oral bioavailability with the addition of hydrophilic excipients., (© 2021. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Astrocytes are the primary regulator of energy metabolism in the central nervous system (CNS), and impairment of astrocyte's energy resource may trigger neurodegeneration. HIV infections and cocaine use are known to alter epigenetic modification, including miRNAs, which can target gene expression post-transcriptionally. However, miRNA-mediated astrocyte energy metabolism has not been delineated in HIV infection and cocaine abuse. Using next-generation sequencing (NGS), we identified a total of 1900 miRNAs, 64 were upregulated and 68 miRNAs were downregulated in the astrocytes by HIV-1 Tat with cocaine exposure. Moreover, miR-4727-3p, miR-5189-5p, miR-5090, and miR-6810-5p expressions were significantly impacted, and their gene targets were identified as VAMP2, NFIB, PPM1H, MEIS1, and PSD93 through the bioinformatic approach. In addition, the astrocytes treated with the nootropic drug piracetam protects these miRNAs. These findings provide evidence that the miRNAs in the astrocytes may be a potential biomarker and therapeutic target for HIV and cocaine abuse-induced neurodegeneration., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Substance abuse affects the central nervous system (CNS) and remains a global health problem. Psychostimulants, such as cocaine and methamphetamine (METH), and opioids affect neuronal function and lead to behavioral impairments via epigenetic modification. Epigenetic changes occur via classical pathways, especially the class III histone deacetylase (HDAC)-sirtuin (SIRT) family, that act as cellular sensors to regulate energy homeostasis and coordinate cellular responses to maintain genome integrity. However, SIRT family (1-7)-associated neurodegeneration has not been elucidated in the context of energy metabolism. The present study examined the effects of psychostimulants, such as cocaine and METH, and opioids, such as morphine, on SIRT family (1-7) [class I, II, III and IV] expression and cellular translocation-mediated dysfunction in astrocytes and microglial cells. The "nootropic" drug piracetam played a preventative role against psychostimulant- and opioid-induced SIRT (1-7) expression in astrocytes. These results indicate that cocaine, METH, and morphine affected deacetylation and cellular function, and these changes were prevented by piracetam in astrocytes., (© 2021. The Author(s).)

Introduction: Warfarin is the core component in the management of various thromboembolic disorders, which requires specialized expertise to optimize outcomes. There is limited data comparing a pharmacist vs. a haematologist-managed anticoagulation clinic in our setting, and in the Middle East. We aimed to evaluate the effectiveness and safety of a pharmacist vs. a haematologist-managed anticoagulation clinic in the Ambulatory Care Center at King Abdulaziz Medical City, Jeddah, Saudi Arabia., Methods: A retrospective cohort study was conducted from 2016 to 2018, which included adult patients who have been followed-up for at least six months and who received warfarin for an extended period. The primary outcome was the proportion of time the patients in the two arms were in the therapeutic range. The secondary outcomes were the differences in expanded time in the therapeutic range, as well as the frequency of bleeding and thromboembolic events between the two arms., Results: We enrolled 104 and 124 patients in the pharmacist and haematologist arms respectively. The median time in the therapeutic range for the pharmacist arm was 71.4%, IQR (60.8-83.8) vs. 65%, IQR (43.5-79.1), in the haematologist arm (p = 0.0049). The median expanded time in the therapeutic range was 86.4%, IQR (77.5-95.3) vs. 81.21%, IQR (67.1-93.3) in the pharmacist vs. haematologist arm (p = 0.015) respectively. Major bleeding events occurred in 5.7 % vs. 3.2 %, and thromboembolic events in 5.7% vs. 4%, in the pharmacist vs. haematologist arm respectively., Conclusions: Our results demonstrated that the time in the therapeutic range was significantly higher in the pharmacist arm, with no significant difference in bleeding and thromboembolic events compared to the haematologist arm., Competing Interests: 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., (© 2021 The Author(s).)

The focus of present work was to characterize ultra-long acting prodrug of dolutegravir (DTG) and develop biodegradable microparticle formulation. Palmitic acid (PA) conjugated prodrug of DTG was prepared by esterification of hydroxyl group of DTG with the carboxyl group of PA. Physicochemical properties of the prodrug was characterize by MS, NMR, FTIR, SEM, DSC, NIR-CI, pH-solubility, and solid and liquid pH-stability. Comparative solid and liquid stability was performed by storing powder DTG and DTG-Palmitate at 40 °C/75% RH for three months and liquid solution pH 2-8 at room temperature for 24 h, respectively. Pharmacokinetic evaluation was performed in white albino New Zealand rabbits by subcutaneous injection (30 mg/Kg). Poly(lactide-co-glycolide) microparticle formulation was prepared by emulsification-evaporation method and characterized for particle size distribution, shape, drug loading and in-vitro release. MS, NMR, FTIR, SEM, DSC, NIR-CI indicated formation of prodrug. Melting point of the prodrug was lower than DTG but higher than PA. Shape of DTG crystals was irregular while DTG-Palmitate crystals was fine-needle. Solid and liquid stability profiles of the prodrug were similar to DTG. Plasma half-life, area under the curve, and mean-residence time of DTG-Palmitate were 8.8, 2.3 and 14.7 folds of DTG. D 90 of DTG and DTG-Palmitate microparticles was 107.1 ± 2.7 and 94.3 ± 3.4 µm, respectively. The in-vitro drug release was almost complete in three weeks from DTG microparticles while it was <85% in six months from DTG-Palmitate microparticles. In conclusion, physicochemical and pharmacokinetic properties and biodegradable microparticles of the prodrug suggested that the prodrug has potential of sustaining DTG release for ultra-long period compared to DTG., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This study aimed to improve the dissolution of the poorly soluble drug lopinavir (LPV) by preparing amorphous solid dispersions (ASDs) using solvent evaporation method. The ASD formulations were prepared with ternary mixtures of LPV, Eudragit® E100, and microcrystalline cellulose (MCC) at various weight ratios. The ASDs were subjected to solid-state characterization and in vitro drug dissolution testing. Chemometric models based on near infrared spectroscopy (NIR) and NIR-hyperspectroscopy (NIR-H) data were developed using the partial least squares (PLS) regression and externally validated to estimate the percent of the crystalline LPV in the ASD. Initially, the solid-state characterization data of ASDs showed transformation of the drug from crystalline to amorphous. Negligible fraction of crystalline LPV was present in the ASD (3%). Compared to pure LPV, ASDs showed faster and higher drug dissolution (<2% vs. 60.3-73.5%) in the first 15 min of testing. The ASD was stable against crystallization during stability testing at 40 °C/75% for a month. In conclusion, the prepared ASD was stable against devitrification and enhance the dissolution of LPV., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The objective of current research was to develop the models of dissolution prediction of tablets coated with cellulose acetate (CA 320S or CA 398-10) and cellulose acetate phthalate (C-A-P) blends. Independent variables selected were coating percent (X 1 ) and percent of CA 320S or CA 398-10 (X 2 ) in the blend. Dependent variables selected were dissolution in 1 (Y 1 ), 8 (Y 2 ), and 24 h (Y 3 ). Diclofenac sodium core tablets were coated with blend of either CA 320S and C-A-P or CA 398-10 and C-A-P at approximately 5, 7.5, and 10% weight gain. CA 320S and CA 398-10 content in the corresponding blends varied from 33.3-66.7% and 25.0-50.0% relative to C-A-P, respectively. Dissolution was performed in phosphate buffer 6.8 using USP apparatus 2. Coated tablets were also characterized for surface morphology and coating uniformity by near infrared hyperspectroscopy. Y 1 , Y 2 , and Y 3 were statistically (p < 0.05) affected by X 2 in CA 320S/C-A-P and CA 398-10/C-A-P blends coated tablets. On the other hand, X 1 had statistically significant (p < 0.05) effect only on the Y 3 in CA 320S/C-A-P while Y 1 was statistically (p < 0.05) affected by X 2 in CA 398-10/C-A-P. Analysis of variance also indicated statistically significant (p < 0.05) effect of the studied variables on the dependent variables for both the blends. The models were verified by independent experiment. Model predicted and empirical values of Y 1 , Y 2 , and Y 3 were close with maximum residual of 7.0%. In conclusion, dissolution can be modulated by varying composition of blend, polymer type, and coating weight.

The focus of present work was to prepare salt of aripiprazole (APZ) with dicarboxylic acids to improve physicochemical properties the drug. Dicarboxylic acids used in the study were malonic acid, maleic acid and succinic acid. The salts were prepared with solubilization-crystallization method. The salts were characterized for pH-solubility, dissolution, and stabilities. The Fourier infrared spectroscopy, X-ray powder diffraction, differential scanning calorimetry and near infrared chemical imaging indicated formation of new solid phase. pH-solubility profiles of the salts were similar to the drug except higher solubility were observed in the salts at all tested pH. The highest solubility was observed for APZ-Malonate salt among all the prepared salts. The solubility curve was inverted 'V' shape for APZ-maleate and APZ-succinate while it was inverted 'U' shape for APZ-malonate. The water solubility of APZ, APZ-malonate, APZ-maleate and APZ-succinate were 0.07 ± 0.02, 3503.9 ± 37.4, 269.3 ± 6.9 and 729.4 ± 9.4 µg/mL, respectively. The dissolution was 2.9 ± 0.4, 18.4 ± 3.9, 19.5 ± 1.4 and 36.6 ± 4.0% in 45 min for APZ, APZ-maleate, APZ-malonate, and APZ-succinate. The stabilities of the salts were similar to the drug. Thus, salts improved the physicochemical properties of the drug, and have similar stability profiles as that of APZ.

The similarity between originator and biosimilar monoclonal antibody candidates are rigorously assessed based on primary, secondary, tertiary, quaternary structures, and biological functions. Minor differences in such parameters may alter target-binding, potency, efficacy, or half-life of the molecule. The charge heterogeneity analysis is a prerequisite for all biotherapeutics. Monoclonal antibodies are prone to enzymatic or non-enzymatic structural modifications during or after the production processes, leading to the formation of fragments or aggregates, various glycoforms, oxidized, deamidated, and other degraded residues, reduced Fab region binding activity or altered FcR binding activity. Therefore, the charge variant profiles of the monoclonal antibodies must be regularly and thoroughly evaluated. Comparative structural and functional analysis of physically separated or fractioned charged variants of monoclonal antibodies has gained significant attention in the last few years. The fraction-based charge variant analysis has proved very useful for the biosimilar candidates comprising of unexpected charge isoforms. In this report, the key methods for the physical separation of monoclonal antibody charge variants, structural and functional analyses by liquid chromatography-mass spectrometry, and surface plasmon resonance techniques were reviewed., 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 © 2021 Elsevier B.V. All rights reserved.)

Background: The aim of this study is to evaluate the feasibility of en-route resuscitative endovascular balloon occlusion of the aorta (REBOA) on board of a helicopter., Methods: Six sedated male sheep (weighing 42-54 kg) underwent a controlled hemorrhage until the systolic blood pressure (BP) dropped to <90 mmHg, and were placed into a low capacity Eurocopter AS-350 (France). During the 30-minutes normal flight, every animal underwent blind (left side) and ultrasound-guided (US) (right side) vascular access (VA) to the femoral artery followed by REBOA: the first catheter (Rescue balloon, Japan) - into Zone I, the second one (MIT, Russia) - Zone III. In case of blind VA failure, an alternate US-puncture was attempted. Six experienced flight anesthetists were enrolled into the study. Vascular access and REBOA catheter placement (confirmed by X-Ray later) success rate and timing were recorded., Results: Among six blind punctures one was successful, 2/6 - were into the vein, 3/6 - completely failed and switched to US-punctures (making total number of US-punctures nine). Eight out of nine US-punctures were successful. However, correct wire insertion and sheath placement was performed in 1/6 animal in the 'blind' group and only in 6/9 animals in the 'US' group. It took a median of 65 seconds (range 5-260) for US-puncture and a median of 4 minutes to get the sheath in. Among the 9 VAs, there were 2 REBOA failures (1 ruptured balloon [MIT] and 1 mistaken vena cava placement primarily recognized by a sudden drop of BP and later confirmed by X-Ray). Five out of seven balloons were placed in a desired intra-aortic position: 4/5 in Zone I and 1/2 - in Zone III. A median time for a successful REBOA procedure was 5.0 (range 2.5-10.0) minutes (1 min after sheath placement)., Conclusion: Our study demonstrates the potential feasibility of the en-route REBOA which can be performed within 5 minutes. Ultrasound-guidance is critically important to achieve en-route VA., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest. No specific funding was provided., (Copyright © 2020. Published by Elsevier Ltd.)

The focus of the study was to develop discriminatory dissolution methods for portioned snus and moist snuff sub-categories of smokeless tobacco products (STPs) using USP basket and paddle apparatuses. Skoal Classic Wintergreen (SCW) and CORESTA CRP1.1 pouches were used as test products. The dissolution was performed at 10, 20, 30, 40, and 50 rpm basket or paddle speed in 500 ml artificial saliva pH 6.8. The products were also characterized for assay, pH, particle size, and loss on drying. The dissolution profiles were evaluated for amount/% of nicotine dissolved, time to reach plateau, and profiles comparison by f2 and f1 factors. The nicotine assay was 13.3 ± 0.2 and 7.6 ± 0.1 mg/pouch for SCW and CRP1.1, respectively. The nicotine dissolved in 30 min from SCW and CRP1.1 were 38.4-81.8 and 37.6-88.1, and 50.5-64.9 and 72.3-92.1% by paddle and basket methods, respectively. The f2 and f1 values were ≤ 39.2 and ≥ 42.1 and ≤ 43.2 and ≥ 34.1 for basket methods and paddle methods. RSD were less than 20% at all points of dissolution profiles, and dissolution plateau were achieved in 30 min at some of the tested conditions. In summary, dissolution methods based on basket and paddle can be used as a performance test for STPs.

Aripiprazole (APZ) has poor physicochemical properties and bitter taste. The current study aimed to prepare salts of APZ with polycarboxylic acids (citric, malic, and tartaric acids) to improve physicochemical properties and impart sour taste to the drug. The salts were prepared by solubilization-crystallization method, and characterized by electron microscopic, spectroscopic, diffractometry, and thermal methods. The salts were assessed for pH solubility, pH-stability, dissolution, and solid-state stability. Fourier transformed infrared, X-ray powder diffraction, and differential scanning calorimetry data indicated formation of new solid phases. APZ and the salts exhibited pH-dependent solubility. The pH solubility curve shape was inverted "V," inverted "W," and inverted "U" for APZ, APZ-Citrate, and APZ-Malate and APZ-Tartrate, respectively. Compared to APZ, the solubility of salts at pH 4, 5, and 6 was 3.6-7.1, 23.9-31.5, and 143.4-373.3 folds of APZ. Increase in solubility in water by citrate, malate, and tartrate salts was 5562.8, 21,284.7, and 22,846.7 folds of APZ. The salt formation also leads to an increase in rate and extent of dissolution. The dissolution extent was 3.5 ± 0.5, 71.3 ± 1.2, 80.1 ± 6.2, and 86.1 ± 1.1% for APZ, APZ-Citrate, APZ-Malate, and APZ-Tartrate, respectively. Liquid and solid-state stabilities of the salts were comparable to APZ. In conclusion, salts of APZ with polycarboxylic acids improved solubility, and dissolution, and impart sour taste, which may improve palatability of the drug.

The objectives of this study were to develop and characterize amorphous lopinavir (LPV) printlets and to the quantify crystalline fraction of LPV in the printlets by X-ray powder diffraction (XRPD)-chemometric models. Amorphous printlets (4.5 mm diameter × 3 mm height) of various LPV concentrations were fabricated by selective laser sintering (SLS) 3D technique. The printlets were characterized for physicochemical properties. The XRPD data in conjunction with chemometric method were used to quantify the crystalline fraction of the drug. The LPV content in the printlets was 95.2-100.9%, disintegration time was < 2 min, and dissolution was fast (>90% of LPV was dissolved in < 30 min). The porosity of the printlets increased with an increase in the LPV percentage. The differential scanning calorimetry (DSC) and XRPD data of the printlets demonstrated that the majority of LPV was present in amorphous form. The XRPD-chemometric models showed good linearity and low root mean squared error, standard error, and bias. Models validation showed that the actual values of crystalline and amorphous fractions of the drug were close to the predicted values. These results demonstrated the feasibility of fabricating amorphous printlets by SLS method, and the application of the XRPD-chemometric models to quantify low fractions of crystalline drug in the 3D formulations if they are formed due to process or environment related variables., (Copyright © 2020. Published by Elsevier B.V.)

Backgroud: Oral medications are commonly prescribed for many cancer patients. Unfortunately, most of them are dispensed without proper counseling about handling practices. We aimed to evaluate the handling, storage, and disposal practices of oral anticancer medications among cancer patients and their caregivers at home., Methods: A cross-sectional questionnaire was filled in by adult cancer patients or caregivers who received oral anticancers and/or visited an outpatient pharmacy over two months., Results: A total of 201 participants were interviewed, 67% were female, and nearly 44% were between 40 and 60 years of age. The majority of participants were educated (78%). The top five medications involved were: tamoxifen, capecitabine, letrozole, dasatinib, and imatinib. More than 95% of participants reported that medications were kept away from children and pets in the original container and stored away from extreme heat, cold, and humidity. Hand washing and wearing gloves were not consistently practiced. Only 5% reported "Always" wearing gloves, while 24% reported "Always" washing hands after handling anticancer medications. The participants reported that they had been informed about safe handling and storage by their physician (39%) and pharmacist (25%), while 34% had not been informed. In terms of disposal practices, 66% of patients have not had any unused or expired medications, 29% disposed them in the trash, and 27% returned them., Conclusions: Our findings suggest that patients and caregivers' handling practices of oral anticancer medications are inconsistent with the published recommendations. Hence, appropriate and comprehensive education is needed to mitigate the risk of exposure to these agents in the home setting.

Rifaximin (RFX) exhibit polymorphism and commercial formulation contains the α form. The polymorphic transformation of the RFX in the drug product have significant effect on the clinical outcome. The focus of present work was to understand effect of formulation component and manufacturing method, and exposure to stability condition on polymorphic stability and dissolution of RFX tablets. The RFX tablets containing 2.5, 5 and 10% glyceryl palmitostearate (GPS) were manufactured by direct-compression and wet-granulation followed by compression. Ethanol was used as a granulating solvent. The tablets were packed in pharmacy vials and exposed to 40 °C/75% RH for four weeks. The tablets were characterized for polymorphic form by X-ray powder diffraction (XRPD) and Fourier infrared spectroscopy (FTIR), assay and dissolution. Before exposure to stability condition, dissolution ranged from 78.0 ± 2.3 to 81.9 ± 3.5%, and 72.7 ± 2.0 and 75.9 ± 5.8% in directly compressed and ethanol-granulated formulations, respectively. GPS amount of 10% caused a decrease in dissolution albeit insignificant (p > 0.05). The polymorphic forms of RFX were α and γ in directly compressed and ethanol-granulated formulations, respectively. There was a decrease in dissolution rate and extent after exposure to 40 °C/75% RH in directly compressed formulations. On the other hand, only dissolution rate was affected in ethanol-granulated formulations. The dissolution ranged from 52.8 ± 2.0 to 70.0 ± 3.0% in directly compressed formulations after four weeks exposure to 40 °C/75% RH exposure. A decrease in dissolution was linked to polymorphic transformation of the drug and GPS in the formulations after exposure to stability condition. XRPD and FTIR data indicated α to β transformation in directly compressed formulations while no polymorphic change was observed in ethanol-granulated formulations. In conclusion, this study clearly showed effect of formulation and manufacturing variables, and stability exposure on the polymorphic stability and dissolution of RFX, which may have clinical ramification., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The focus of the present investigation was to develop a predictive dissolution model for tablets coated with blends of cellulose acetate butyrate (CAB) 171-15 and cellulose acetate phthalate (C-A-P) using the design of experiment and chemometric approaches. Diclofenac sodium was used as a model drug. Coating weight gain (X 1 , 5, 7.5 and 10%) and CAB 171-15 percentage (X 2 , 33.3, 50 and 66.7%) in the coating composition relative to C-A-P and were selected as independent variables by full factorial experimental design. The responses monitored were dissolution at 1 (Y 1 ), 8 (Y 2 ), and 24 (Y 3 ) h. Statistically significant ( p < 0.05) effects of X 1 on Y 1 and X 2 on Y 1 , Y 2, and Y 3 were observed. The models showed a good correlation between actual and predicted values as indicated by the correlation coefficients of 0.964, 0.914, and 0.932 for Y 1 , Y 2, and Y 3 , respectively. For the chemometric model development, the near infrared spectra of the coated tablets were collected, and partial least square regression (PLSR) was performed. PLSR also showed a good correlation between actual and model predicted values as indicated by correlation coefficients of 0.916, 0.964, and 0.974 for Y 1 , Y 2 , and Y 3 , respectively. Y 1 , Y 2, and Y 3 predicted values of the independent sample by both approaches were close to the actual values. In conclusion, it is possible to predict the dissolution of tablets coated with blends of cellulose esters by both approaches.

The aims of the current study were to develop and evaluate clindamycin palmitate hydrochloride (CPH) 3D-printed tablets (printlets) manufactured by selective laser sintering (SLS). Optimization of the formulation was performed by studying the effect of formulation and process factors on critical quality attributes of the printlets. The independent factors studied were laser scanning speed, microcrystalline cellulose (MCC), and lactose monohydrate (LMH) concentration. The responses measured were printlets weight, hardness, disintegration time (DT), and dissolution in 30 min. The printlets were characterized for content uniformity, chemical interactions, crystallinity, drug distribution, morphology, and porosity. The laser scanning speed showed statistically significant effects on all the studied dependent responses (p < 0.05). MCC showed statistically significant effects on hardness, DT, and dissolution (p < 0.05), while LMH showed statistically significant effect on hardness and dissolution (p < 0.05). The model was validated by an independent formulation, and empirical values were in close agreement with model-predicted values. X-ray powder diffraction and differential scanning calorimetry data suggested a decrease in crystallinity of the LMH in the printlets. X-ray micro-CT scanning showed porous microstructure of the printlets with a porosity 24.4% and 31.1% for the printlets printed at 200 and 300 mm/s laser speed, respectively. In summary, the SLS method provides an opportunity to fabricate customized dosage forms as per patients' need.

Food and Drug Administration (FDA) has approved a drug product (Spritam®) and many medical devices manufactured by three-dimensional printing (3DP) processes for human use. There is immense potential to print personalized medicines using 3DP. Many 3DP methods have been reported in the literature for pharmaceutical applications. However, selective laser sintering (SLS) printing has remained least explored for pharmaceutical applications. There are many advantages and challenges in adopting a SLS method for fabrication of personalized medicines. Solvent-free nature, availability of FDA approved thermoplastic polymer/excipients (currently used in hot melt-extrusion process), minimal/no post-processing step, etc. are some of the advantages of the SLS printing process. Major challenges of the technology are requirement of at least one thermoplastic component in the formulation and thermal stability of drug and excipients. This review provides an overview of the SLS printing method, excipient requirements, process monitoring, quality defects, regulatory aspects, and potential pharmaceutical applications.

The focus of the present work was to investigate compatibility between commonly used diluents and the drug (salt and acid form of the phenytoin). Lactose monohydrate (LMH), lactitol hydrate (LCT), and mannitol (MNT) were selected based on commercial products information of phenytoin sodium (PS) and phenytoin acid (PHT). Binary mixtures of the drug-diluent were stored at 60°C and 40°C/75% RH. Similarly, two commercial products, namely Product-A and Product-B, were also investigated in in-use stability. Color of PS-LMH changed from white to yellowish-brown and pH dropped by 3.4 units after 4 weeks exposure. FTIR, XRPD, and NIR chemical images indicated disproportionation in PS-LMH and PS-LCT mixtures stored at 40°C/75% RH. Furthermore, PS-LMH also indicated chemical interactions as indicated by distortion of LMH peaks. PHT-diluent mixture did not exhibit any physical and chemical modifications. Product-A changed color, increased weight, dropped pH value, and exhibited disproportionation and chemical reactions. The dissolution of Product-A decreased from 83.3 ± 1.4 to 7.1 ± 4.4% on 8 weeks exposure to 30°C/75% RH. On the other hand, Product-B did not change; however, dissolution decreased by 15%. In conclusion, PS showed disproportionation and chemical reactions with LMH. Therefore, LMH should be avoided in PS formulations.

The objective of the present investigation was to understand the effect of sucrose acetate isobutyrate (SAIB) on abuse-deterrent properties (ADPs) of abuse-deterrent formulations (ADFs) based on Polyox™. SAIB would enhance ADPs of Polyox™-based formulations due to its glassy liquid and hydrophobic properties. Formulations were prepared by granulation followed by compression and heat curing at 90°C. The formulations were evaluated for surface morphology, hardness, manipulation in coffee grinder, particle size distribution, drug (pseudoephedrine hydrochloride) extraction in water, alcohol, 0.1 N HCl, 0.1 N NaOH at room temperature and elevated temperature using microwave and oven, syringeability and injectability, and dissolution. The heat curing of formulations significantly increased the hardness (> 490 N). Addition of SAIB imparted elasticity to formulations and decreased brittleness as indicated by lower values of work done and gradient compared to control formulations. After grinding, about 7.7-25.6% of the powder remained on the sieve (1 mm pore opening), D 90 was 53.1-136.7 μm more, and Q (fraction < 500 μm) was 17.8-40.7% less in SAIB-based formulations compared to control formulations. Drug extraction between control and test intact formulations was similar. However, drug extraction was 23.9-42.5% (water), 20.6-26.1% (0.1 N HCl), and 37.4-50.6% (0.1 N NaOH) less in SAIB-based powder cured and uncured formulations compared to control formulations. Dissolution varied from 65.6 ± 4.2 to 97.6 ± 4.0% in 9 h from the formulations. In conclusion, addition of SAIB to Polyox™-based ADFs has synergistic effect on ADPs. This would further decrease potential of drug abuse/misuse by various routes.

The objective of the present research was to investigate application of sucrose acetate isobutyrate (SAIB) in the development of a meth-deterrent formulation in combination with polyethylene oxide (Polyox TM ) and hydroxypropyl methylcellulose. The formulations were prepared by granulating pseudoephedrine hydrochloride, hydroxypropyl methylcellulose, and Polyox TM with an ethanolic solution of SAIB and compressed into tablets followed by heat curing. The tablets were characterized for surface morphology, crystallinity, drug distribution, hardness, particle size, extraction, and dissolution. Hardness increased insignificantly, surface morphology indicated cracking and crevices, and diffractograms showed an increase and a decrease in drug and PolyoxTM crystallinity, respectively, after heat curing. Pseudoephedrine hydrochloride, Polyox TM , and SAIB distribution was uniform as indicated by near infrared image. The drug extraction varied from 69.5% to 77.8%, 90.3% to 106.5%, 51.3% to 81.2%, and 48.9% to 72.6% in water, ethanol, 0.1 N HCl, and 0.1 N NaOH, respectively. The dissolution was more than 85% in 9 h from all the formulations. Thus, the addition of SAIB to the formulation decreased the drug extraction in various solvents which has the potential to decrease abuse of pseudoephedrine formulation for methamphetamine synthesis., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Biologics are significant drivers of globally escalating healthcare costs. Biosimilars have potential to offer cost savings with comparable efficacy and safety to innovator products and increase the access of treatment to more patients. This study aimed to increase understanding and perception of biosimilars concept. It also described the pharmacoeconomic impact of biosimilar in oncology and formulary consideration of oncology biosimilars substituting with their originators in major oncology centers in the Saudi Arabia. A biosimilar is a biological product that is similar to a reference biopharmaceutical product. As the manufacturing process hinders the ability to identically replicate the structure of the original product, biosimilar cannot be described as an absolute equivalent of the original medication. Different regulatory agencies such as United States Food and Drug Administration, European Medicines Agency, and Saudi Food and Drug Authority have approved several biosimilars of oncology biologics. The experience of biosimilar use in Europe and USA provides valuable insights into the use of biosimilars. The widespread use of biosimilars has the potential to reduce healthcare expenditure, as well as improving access without compromising patient outcomes. There is a need for increasing awareness about biosimilars to improve acceptance rates. The use of biosimilar filgrastim in Ministry of National Guard Health Affairs, Saudi Arabia, has resulted in a significant cost saving annually. It was proposed that further substitution and switching to biosimilars in oncology would lead to major savings in resources., Competing Interests: Conflicts of interest The authors disclosed no conflicts of interest related to this article., (© 2020 Global Journal on Quality and Safety in Healthcare | Published by Wolters Kluwer - Medknow.)

Palatability of a formulation is one of the primary requirements for therapeutic compliance in children. Clindamycin (CLN) often prescribed to children to treat various infections. However, it has a bitter taste and bad smell. The focus of the present investigation was to develop salt of CLN with a commonly used sweetener such as cyclamic acid (CYA) to improve the palatability. The salt forms were prepared by solubilization crystallization method and characterized by Fourier transformed infrared (FTIR), Near infrared (NIR), Raman, X-ray powder diffraction, scanning electron microscopy, solubility, dissolution, and solid-state physical and chemical stability at 25 °C/60% RH and 40 °C/75% RH for 1 month and 60 °C for 2 weeks. Spectroscopic and diffraction data indicated the formation of a new solid phase, which was different from hydrochloride salt of CLN. Shape of crystal was rectangular prism. Stoichiometric ratio between CLN and CYA in the new salt CLN-CYA was 1:1 and its melting point was 85.6 °C. There was a 2.4-fold reduction in solubility of CLN-CYA at pH 4 compared with CLN-HCl. Moreover, the dissolution rate and extent were similar between the two salts and meeting USP requirement of 85% dissolution in 30 min. Salt was physically and chemically stable at 60 °C, 25 °C/60% RH, and 40 °C/75% RH conditions but hygroscopic at high humidity condition. In conclusion, new salt will provide a new avenue for the development of a palatable formulation of CLN.

Prasugrel hydrochloride (PHCl) undergoes salt disproportionation, and the resulting prasugrel free base (PFB) may lead to the poor in vitro and or in vivo performance of the drug product. The aim of the present work was to develop univariate and multivariate models based on X-ray powder diffraction to quantify the salt and base in the powder and tablet formulations. Compositionally identical formulations of PHCl and PFB were prepared and mixed in various proportions to make 0%-30% PFB sample matrices. The formulations consisted of commonly used excipients, which are generally used in commercially available products. X-ray powder diffraction data were collected and subjected to the least square regression and partial least square regression analysis. The model performance parameters such as root mean squared and standard errors were low for univariate models compared to partial least square regression multivariate models. Model predicted values of the independent sample matrices by both methods matched closely with the actual values of PFB and PHCl. However, residual and standard deviation were low in univariate models predicted values. The models developed in this work have been shown to quantitate the PHCl disproportionation to PFB fraction in the drug product and provide a means to control the disproportionation of PHCl., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

The focus of the study was to understand the effects of formulation and process variables on the printlets quality manufactured by selective laser sintering (SLS) 3D printing. The Box-Behnken response surface methodology was used to evaluate effects of individual variables and combinations thereof. The formulation and process variables studied were printing chamber temperature (°C, X 1 ), laser scanning speed (mm/sec, X 2 ) and lactose monohydrate concentration (%, X 3 ). The responses studied were weight of printlets (mg, Y 1 ), hardness (N, Y 2 ), disintegration time (sec, Y 3 ) and dissolved drug fraction in 15 min (%, Y 4 ). The values of Y 1 , Y 2 , Y 3 and Y 4 varied from 170.2-257.0 mg, 5.5-32.0 N, 20-120 s and 64.4-97.5%, respectively. The studied factors showed statistically significant effects on the dependent variables (p < 0.04). The correlation coefficient between empirical and model predicted values for Y 1 , Y 2 , Y 3 and Y 4 were 0.999, 0.992, 0.998 and 0.983, respectively. The model was validated by an independent experiment and actual values of the responses were in close agreement with model predicted values. Fourier transformed infrared spectroscopy indicated no chemical interactions between the components of the formulation during printing process. X-ray powder diffractograms suggested a decrease in crystallinity of the drug and lactose in the printlets. Chemical images indicated uniform distribution of the drug. Scanning electron microscopy and X-ray micro-CT scanning showed a very porous microstructure of the printlets with a porosity of about 37.89%. In conclusion, the SLS method of manufacturing provides a feasible and flexible avenue for fabricating dosage forms with tailored characteristics., (Copyright © 2019 Elsevier B.V. All rights reserved.)

There has been a long-standing discussion in the scientific literature on the thallium (Tl) binding capacity of ferric hexacyanoferrate (insoluble) and potassium hexacyanoferrate (soluble) forms of Prussian blue (PB). The literature sometime suggests that the soluble form of PB should be used to treat thallium poisoning, instead of the FDA approved insoluble form of PB. The literature debate is further complicated by the lack of fundamental characterization data such as critical quality attributes (CQAs) that clearly define the analog forms. The purpose of this study is to compare, the binding capacity of soluble and insoluble PB analogs with the same CQAs (particle size/distribution and water content). Water content and particle size/particle distribution were determined by TGA, and solid-state laser diffraction particle sizing. Thallium binding studies were conducted at physiological pH to determine the maximal binding capacity (MBC) at equilibrium. Multiple linear regression and principal component analysis was also used for multivariate data analysis. Results indicate that insoluble and soluble analogs, with similar quality attributes, have nearly identical, MBC binding capacities of (441.5 mg/g) for insoluble vs soluble (458.4 mg/g). However, when both analog forms with different CQAs such as water, particle size were compared, results indicated significantly higher or lower thallium binding levels. In conclusion, it is essential that the FDA approved iron form with well-defined CQAs is used to treat thallium poisoning and radioactive thallium metal contamination for consistent therapeutic outcomes., (Published by Elsevier B.V.)

The focus of this work was to explore feasibility of using blends of cellulose esters (CA 320S, CA 3980-10 or CAB 171-15) and enteric polymers (C-A-P, Eudragit® L100 or HPMCP HP-55) for delayed and enteric coating of tablets containing either diclofenac sodium (DFS, high dose) or prednisone (PDS, low dose) drug. The core tablets of DFS or PDS were coated with polymer blends to achieve approximate weight gain of 5% and 10%. The coated tablets were characterized for dissolution (0.1 N HCl and phosphate buffer pH 6.8) and surface morphology. The surface morphology of CA 398-10 or CAB 171-15 based polymer blends was rough and fibrous. Less than 0.5% drug was dissolved in 120 min from 5% w/w coated tablets in acid-phase dissolution testing. The dissolution in phosphate buffer pH 6.8 medium varied from 16.2 ± 0.2 to 98 ± 2.1%, and 30.1 ± 0.5% to 101.7 ± 3.4% in 120 min from DFS and PDS coated tablets, respectively. Dissolution was less in CA 320S based blends compared to CA 398-10 or CAB 171-15 blends in phosphate buffer medium. Furthermore, there were no significant differences observed in dissolution profiles of coated tablets of DFS or PDS. This can be explained by dose of the drugs. Additionally, dissolution was higher in tablets coated with enteric polymer alone compared with the blends. In conclusion, core tablets can be coated with cellulose ester and enteric polymers blend to impart both delayed and enteric release feature to the tablets containing hydrophilic or hydrophobic drug., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The commercial product of rifaximin (RFX) contains α form. The α form can change to β form on exposure to high humidity that can occur during manufacturing, stability, and in-use period. It is critical to maintain α form of the drug in a drug product to avoid variability in clinical response. U.S. Food and Drug Administration dissolution method was found to be nondiscriminatory for RFX formulations containing either 100% α or β form. The objective of this study was to develop a discriminatory dissolution method that can detect low levels of α to β transformation in RFX products. Formulations containing a variable fraction of α and β forms were prepared by using direct compression method. Dissolution parameters investigated were type of dissolution medium (water and phosphate buffer), volume (500, 900, and 1000 mL), and paddle speed (50, 75, and 150 rpm). Dissolution in water with 0.2% sodium lauryl sulfate was less than 80% and nondiscriminatory. However, dissolution tested in a phosphate buffer pH 7.4 with 0.2% sodium lauryl sulfate at 50 rpm was discriminatory with more than 17.5% difference in dissolution profile between formulations containing α and β forms. The developed method can detect polymorphic transformation if there is 25% or more β form conversion., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)