Development and Validation of Matrix of Chemistry, Manufacturing, and Control (MoCMC) System for Intramammary Drug Products (IMM).

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.

Development and Validation of Discriminatory In-vitro Release Method for Intramammary Drug Product.

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.

Local Identifiability Analysis, Parameter Subset Selection and Verification for a Minimal Brain PBPK Model.

Physiologically-based pharmacokinetic (PBPK) modeling is important for studying drug delivery in the central nervous system, including determining antibody exposure, predicting chemical concentrations at target locations, and ensuring accurate dosages. The complexity of PBPK models, involving many variables and parameters, requires a consideration of parameter identifiability; i.e., which parameters can be uniquely determined from data for a specified set of concentrations. We introduce the use of a local sensitivity-based parameter subset selection algorithm in the context of a minimal PBPK (mPBPK) model of the brain for antibody therapeutics. This algorithm is augmented by verification techniques, based on response distributions and energy statistics, to provide a systematic and robust technique to determine identifiable parameter subsets in a PBPK model across a specified time domain of interest. The accuracy of our approach is evaluated for three key concentrations in the mPBPK model for plasma, brain interstitial fluid and brain cerebrospinal fluid. The determination of accurate identifiable parameter subsets is important for model reduction and uncertainty quantification for PBPK models.

Bioavailability assessment of a brompheniramine taste-masked pediatric formulation in a juvenile porcine model.

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 (r2 > 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.

Patient In-Use Stability Testing of FDA-Approved Metformin Combination Products for N-Nitrosamine Impurity.

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.

In Vitro and In Vivo testing of 3D-Printed Amorphous Lopinavir Printlets by Selective Laser Sinitering: Improved Bioavailability of a Poorly Soluble Drug.

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 Tmax, Cmax, 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.

A robust fluorescence-based assay for human erythrocyte Ca++ efflux suitable for high-throughput inhibitor screens.

Intracellular calcium is maintained at very low concentrations through the action of PMCA Ca++ extrusion pumps. Although much of our knowledge about these Ca++ extrusion pumps derives from studies with human erythrocytes, kinetic studies of Ca++ transport for these cells are limited to radioisotope flux measurements. Here, we developed a robust, microplate-based assay for erythrocyte Ca++ efflux using extracellular fluorescent Ca++ indicators. We optimized Ca++ loading with the A23187 ionophore, established conditions for removal of the ionophore, and adjusted fluorescent dye sensitivity by addition of extracellular EGTA to allow continuous tracking of Ca++ efflux. Efflux kinetics were accelerated by glucose and inhibited in a dose-dependent manner by the nonspecific inhibitor vanadate, revealing that Ca++ pump activity can be tracked in a 384-well microplate format. These studies enable radioisotope-free kinetic measurements of the Ca++ pump and should facilitate screens for specific inhibitors of this essential transport activity.

Nitroso Impurities in Drug Products: An Overview of Risk Assessment, Regulatory Milieu, and Control Strategy.

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.

Preparation and Characterization of 3D-Printed Dose-Flexible Printlets of Tenofovir Disoproxil Fumarate.

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 (X1), chamber temperatures (X2), and laser scanning speed (X3). The range of variable levels was 75-85°C for X1, 50-70°C for X2, and 200-240 mm/s for X3, 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 Tmax, Cmax, 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.

Experimental and theoretical investigation of waveguided plasmonic surface lattice resonances.

Plasmonic nanostructures are good candidates for refractive index sensing applications through the surface plasmon resonance due to their strong dependence on the surrounding dielectric media. However, typically low quality-factor limits their application in sensing devices. To improve the quality-factor, we have experimentally and theoretically investigated two-dimensional gold nanoparticle gratings situated on top of a waveguide. The coupling between the localized surface plasmon and waveguide modes results in Fano-type resonances, with high quality-factors, very similar to plasmonic surface lattice resonances. By combining plasmonic surface lattice resonance and waveguide theory, we present a theoretical framework describing the structures. By immersing the fabricated samples in three different media we find a sensitivity of ∼50 nm/RIU and figure of merit of 8.9, and demonstrate good agreement with the theory presented. Further analysis show that the sensitivity is very dependent on the waveguide parameters, grating constant and the dielectric environment, and by tuning these parameters we obtain a theoretical sensitivity of 887 nm/RIU.

Very-Rapidly Dissolving Printlets of Isoniazid Manufactured by SLS 3D Printing: In Vitro and In Vivo Characterization.

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, X1), surface temperature (100-110 °C, X2), and croscarmellose sodium (CCS, %, X3), and the responses measured were weight (Y1), hardness (Y2), disintegration time (DT, Y3), and dissolution (Y4). 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.

Unsupervised learning methods for efficient geographic clustering and identification of disease disparities with applications to county-level colorectal cancer incidence in California.

Many public health policymaking questions involve data subsets representing application-specific attributes and geographic location. We develop and evaluate standard and tailored techniques for clustering via unsupervised learning (UL) algorithms on such amalgamated (dual-domain) data sets. The aim of the associated algorithms is to identify geographically efficient clusters that also maximize the number of statistically significant differences in disease incidence and demographic variables across top clusters. Two standard UL approaches, k means with k++ initialization (k++) and the standard self-organizing map (SSOM), are considered along with a new, tailored version of the SOM (TSOM). The TSOM algorithm involves optimization of a customized objective function with terms promoting individual geographic cluster cohesion while also maximizing the number of differences across clusters, and two hyper-parameters controlling the relative weighting of geographic and attribute subspaces in a non-Euclidean distance measure within the clustering problem. The performance of these three techniques (k++, SSOM, TSOM) is compared and evaluated in the context of a data set for colorectal cancer incidence in the state of California, at the level of individual counties. Clusters are visualized via chloropleth maps and ordered graphs are also used to illustrate disparities in disease incidence among four identity groups. While all three approaches performed well, the TSOM identified the largest number of disease and demographic disparities while also yielding more geographically efficient top clusters. Techniques presented in this study are relevant to applications including the delivery of health care resources and identifying disparities among identity groups, and to questions involving coordination between county- and state-level policymakers.

HIV-1 Tat and cocaine impact astrocytic energy reservoir influence on miRNA epigenetic regulation.

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.

Biological Synthesis of Silver Nanoparticles and Prospects in Plant Disease Management.

Exploration of nanoparticles (NPs) for various biological and environmental applications has become one of the most important attributes of nanotechnology. Due to remarkable physicochemical properties, silver nanoparticles (AgNPs) are the most explored and used NPs in wide-ranging applications. Also, they have proven to be of high commercial use since they possess great chemical stability, conductivity, catalytic activity, and antimicrobial potential. Though several methods including chemical and physical methods have been devised, biological approaches using organisms such as bacteria, fungi, and plants have emerged as economical, safe, and effective alternatives for the biosynthesis of AgNPs. Recent studies highlight the potential of AgNPs in modern agricultural practices to control the growth and spread of infectious pathogenic microorganisms since the introduction of AgNPs effectively reduces plant diseases caused by a spectrum of bacteria and fungi. In this review, we highlight the biosynthesis of AgNPs and discuss their applications in plant disease management with recent examples. It is proposed that AgNPs are prospective NPs for the successful inhibition of pathogen growth and plant disease management. This review gives a better understanding of new biological approaches for AgNP synthesis and modes of their optimized applications that could contribute to sustainable agriculture.

Rotationally tunable varifocal 3D metalens.

Varifocal optics have a variety of applications in imaging systems. Metasurfaces offer control of the phase, transmission, and polarization of light using subwavelength engineered structures. However, conventional metasurface designs lack dynamic wavefront shaping which limits their application. In this work, we design and fabricate 3D doublet metalenses with a tunable focal length. The phase control of light is obtained through the mutual rotation of the singlet structures. Inspired by Moiré lenses, the proposed structure consists of two all-dielectric metasurfaces. The singlets have reverse-phase profiles resulting in the cancellation of the phase shift in the nominal position. In this design, we show that the mutual rotation of the elements produces different wavefronts with quadratic radial dependence. Thus, an input plane wave is converted to spherical wavefronts whose focal length depends on the rotation. We use a combination of a nanopillar and a phase plate as the unit cell structure working at a wavelength of 1500 nm. Our design holds promise for a range of applications such as zoom lenses, microscopy, and augmented reality.

Hybrid metasurfaces for simultaneous focusing and filtering.

This work presents the design and fabrication of polymeric, structural optical filters that simultaneously focus light. These filters represent a novel, to the best of our knowledge, design at the boundary between diffractive optics and metasurfaces that may provide significant advantages for both digital and hyperspectral imaging. Filters for visible and near-infrared wavelengths were designed using finite-difference time-domain (FDTD) simulations. Prototype filters were fabricated using two-photon lithography, a form of nanoscale 3D printing, and have geometries suitable to replication by molding. The experimentally measured spectral transmission and focused spot size of each filter show excellent agreement with simulation.

Modeling and Parameter Subset Selection for Fibrin Polymerization Kinetics with Applications to Wound Healing.

During the hemostatic phase of wound healing, vascular injury leads to endothelial cell damage, initiation of a coagulation cascade involving platelets, and formation of a fibrin-rich clot. As this cascade culminates, activation of the protease thrombin occurs and soluble fibrinogen is converted into an insoluble polymerized fibrin network. Fibrin polymerization is critical for bleeding cessation and subsequent stages of wound healing. We develop a cooperative enzyme kinetics model for in vitro fibrin matrix polymerization capturing dynamic interactions among fibrinogen, thrombin, fibrin, and intermediate complexes. A tailored parameter subset selection technique is also developed to evaluate parameter identifiability for a representative data curve for fibrin accumulation in a short-duration in vitro polymerization experiment. Our approach is based on systematic analysis of eigenvalues and eigenvectors of the classical information matrix for simulations of accumulating fibrin matrix via optimization based on a least squares objective function. Results demonstrate robustness of our approach in that a significant reduction in objective function cost is achieved relative to a more ad hoc curve-fitting procedure. Capabilities of this approach to integrate non-overlapping subsets of the data to enhance the evaluation of parameter identifiability are also demonstrated. Unidentifiable reaction rate parameters are screened to determine whether individual reactions can be eliminated from the overall system while preserving the low objective cost. These findings demonstrate the high degree of information within a single fibrin accumulation curve, and a tailored model and parameter subset selection approach for improving optimization and reducing model complexity in the context of polymerization experiments.

Evaluation of handling, storage, and disposal practices of oral anticancer medications among cancer patients and their caregivers at home setting in the Princess Noorah Oncology Center.

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.

Effect of silica-core gold-shell nanoparticles on the kinetics of biohydrogen production and pollutant hydrogenation via organic acid photofermentation over enhanced near-infrared illumination.

A biological photoinduced fermentation process provides an alternative to traditional hydrogen productions. In this study, biohydrogen production was investigated at near IR region coupled to a near-field enhancement by silica-core gold-shell nanoparticles (NPs) over a range of acetate concentrations (5-40 mM) and light intensities (11-160 W/m2). The kinetic data were modeled using modified Monod equations containing light intensity effects. The yields of H2 and CO2 produced per acetate were determined as 2.31 mol-H2/mol-Ac and 0.83 mol-CO2/mol-Ac and increased to 4.38 mmol-H2/mmol-Ma and 2.62 mmol-CO2/mmol-Ma when malate was used. Maximum increases in H2 and CO2 productions by 115% and 113% were observed by adding NPs without affecting the bacterial growth rates (6.1-8.2 mg-DCM/L/hour) while the highest hydrogen production rate was determined as 0.81 mmol/L/hour. Model simulations showed that the energy conversion efficiency increased with NPs concentration but decreased with the intensity. Complete hydrogenation application was demonstrated with toxic 2-chlorobiphenyl using Pd catalysts.

Preparation and characterization of dicarboxylic acids salt of aripiprazole with enhanced physicochemical properties.

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.