Ionic Liquid Forms of Carvedilol: Preparation, Characterization, and Solubility Studies Abstract Purpose Pharmaceutically active compounds (API) in solid form have several disadvantages which may include polymorphism, poor solubility, and low bioavailability. To overcome these issues, API-based ionic liquids have been proposed to solve this problem. Methods Solvent evaporation method was selected to prepare ionic liquid forms of CVD. A binary mixture of CVD with citric acid, tartaric acid, and saccharin in 1:1 M ratio was dissolved in 5 ml of methanol then they left 4 days for solvent evaporation. The solubility of CVD and prepared ionic liquids were measured in different media. Results A viscous yellow liquid in all cases was obtained. More than three-unit differences between pKa of CVD and studied compounds and characterization by different instrumental analysis methods confirmed the formation of an ionic liquid form of CVD and the prepared ionic liquids could significantly change the solubility of CVD. Conclusion Overall, ionic liquids of CVD could be used for overcoming the disadvantages of its solid form and increasing CVD solubility. However, pH, type, and concentration of dissolution medium and the solubility of counter-ions are critical issues which they should be considered in evaluating solubility of CVD and its ionic liquid forms.

A System for Real-Time Syringe Classification and Volume Measurement Using a Combination of Image Processing and Artificial Neural Networks Abstract Purpose The purpose of this research was to develop a system that can read and report the volume of liquid medication present in syringes. Methods The system is comprised of a digital webcam which is designed to communicate with a computer program developed using MATLAB. The system includes two functional modules, one supporting syringe classification, and another supporting volume measurement. Adaptive template matching was used to determine the best match point between target and template images. The connected component labeling method was used during volume measurement. An artificial neural network (ANN) model was developed using MATLAB to support the intended volume measurement functionality. The developed ANN was designed as a classifier which determines the plunger depth of the syringe and then leverages this result to calculate and derive the volume of medication inside the syringe as the final system output. Commercial Luer-lock syringes of sizes from 1 to 30 ml were used in conjunction with syringe tip caps of blue and yellow color. Tap water or aqueous dye solutions of yellow, red, and blue color simulated liquid medication in the syringe. Results The developed syringe classification system successfully detected and categorized all tested syringes according to their size. The best accuracy of the system was found to be 99.95% with a 3-ml syringe, while the worst accuracy was 95.82% with a 5-ml syringe. It took approximately 6 s to perform the entire task demonstrating the utility of this system to report volumes in real time. Conclusion The developed system can be used across a variety of settings that routinely support measuring and handling liquids in syringes including hospitals, pharmacies, and the pharmaceutical industry.

Response Surface Methodology for Optimization of Ultrasound-Assisted Transdermal Delivery and Skin Retention of Asenapine Maleate Abstract Purpose Asenapine maleate (ASP) is an antipsychotic agent used in the treatment of schizophrenia and bipolar disorder. It has extremely low oral bioavailability of < 2%, necessitating the utilization of alternate route of administration. The objective of this work is to study and optimize the sonophoretic transdermal delivery and skin retention of ASP statistically, in Sprague-Dawley rat skin, using response surface methodology in Design of Experiments (DoE). Method I-optimal design was employed, using the ultrasound (US) parameters viz., duration of US application, amplitude of US, and mode of US application (simultaneous application or pretreatment) as the input variables. Steady-state flux (Jss) of ASP and amount of drug retained in skin after 24 h was taken as the output responses. Results The model and dependent variables were found to be significant and representative of the data and response surface. While passive diffusion yielded Jss of 2.575 μg/cm2/h, the same values with US application ranged from 8.18 to 127.68 μg/cm2/h. Passive diffusion of drug showed 46.22 ± 5.2 μg/cm2 of ASP retained in 24 h, while US application resulted in 99.07 to 1495.6 μg/cm2 of drug retained in skin in 24 h. Based on the findings from optimization studies, 30 min of US application, with amplitude of 27–28, and simultaneous application mode was found to achieve the optimal transdermal drug flux, with slightly lower retention values in skin. Conclusion The study found that the sonophoretic transdermal permeation and retention of ASP in vitro could be optimized using response surface methodology.

Residence Time Distribution (RTD)-Based Control System for Continuous Pharmaceutical Manufacturing Process Abstract Purpose During continuous manufacturing, there may be some out of specification tablets that need to be diverted in real time, in order to ensure the quality of the final product. Specifically, the content uniformity of each tablet must be guaranteed before it can be released to market. However, currently, no methods or tools are available that can assure the content uniformity and divert the non-confirming products in real time. The aim of this work is to develop and evaluate a strategy to divert the non-confirming tablets in real time and thereby assure drug concentration of final tablets. Methods This work has been conducted in silico using a combination of MATLAB and Simulink. A methodology to implement a residence time distribution (RTD)-based control system for drug concentration-based tablet diversion which uses the convolution integral was developed and implemented in MATLAB. Comparisons between the performance of “fixed window” and “RTD-based” approaches for diversion have also been presented and used to assess optimal usability. Results In this work, two novel strategies namely, “fixed window approach” and “RTD-based approach” have been developed and evaluated for real-time diversion of non-confirming tablets. The RTD-based control system was designed, developed, and implemented in silico. A framework for its implementation in a real-time system has also been elaborated on. This methodology was compared to an alternative fixed window approach. The proposed control system is analyzed for various manufacturing scenarios, systems, and disturbances. Conclusions A comparison of the two proposed strategies suggests that the “RTD-based control system” is more efficient in every simulated scenario. The relative performance is best when the disturbances in the system are characterized by short pulse-like changes.

Quality Deviation Handling on the Polymeric Coating of Pharmaceutical Tablets Abstract Purpose This work aimed to map and discuss tablet-coating choice, quality deviations of this process, and corrective actions taken by Research and Development (R&D) teams from pharmaceutical industries. Methods A cross-sectional study of polymeric film coating was conducted in Brazil: a questionnaire based on literature information was sent to R&D divisions from several different companies that produce coated tablets in the country, which focused on the main type of coating systems used, most common quality issues, corrective action to each nonconformity, and the main influences in the choice of the coating system. Results The most used film coating systems are hydroxypropylmethylcellulose + Polyethylene glycol (HPMC/PEG) and polyvinyl alcohol + PEG (PVA/PEG), and the most common non-conformities are orange peel, picking sticking, chipping, and peeling. The main suggestive corrective actions include temperature control, pan speed, spray, and pressure rate. All results were analyzed by us according to literature and authors’ expertise. Finally, stability was the main factor that influences the selection of a coating system. Conclusion These data brought knowledge on routine industrial practices, when real deviations happen and matter, with no reports found in the literature.

Mechanochemical Synthesis of Carvedilol Cocrystals Utilizing Hot Melt Extrusion Technology Abstract Purpose To improve the solubility of carvedilol by preparing cocrystals utilizing solvent-free, continuous technology hot melt extrusion. Methods Cocrystals of carvedilol and nicotinamide were formed in 1:2 ratio using hot melt extrusion (HME) by altering the parameters associated with the temperature of barrels and screw speed of the shaft. The product was characterized by DSC, PXRD, and FTIR, while the morphology was determined by SEM. Saturation solubility studies and dissolution rate were compared with carvedilol. Results The processing parameters in HME significantly affected the cocrystallization which improved on changing the temperature and screw speed (cocrystals were formed when the temperature was set above the eutectic melting point). The obtained carvedilol cocrystals showed a distinct difference in morphological characteristics as compared to pure drug. The cocrystals showed the presence of additional peaks in DSC thermograph as well as band shifts in infrared spectrum. The powder XRD of cocrystals showed the difference in the 2θ values as compared with carvedilol indicating an interaction between carvedilol and nicotinamide. The saturation solubility studies and in vitro dissolution studies showed of cocrystals showed an increase in solubility and drug release, respectively, in 0.1N HCl. Conclusion Hence, cocrystallization utilizing HME marks an important advantage over other conventional techniques. A single step, continuous process, scalable, and solvent-free HME process proved to be the best method to produce cocrystals on a larger scale with maximum yield. However, to further decrease the number of manufacturing steps, efforts are being made to combine crystallization and formulation in a single step.

The Assessment of pH-Induced Supersaturation and Impact of an Additional Drug on the Solution Phase Behavior of Saquinavir Abstract Purpose The goal of this study was to investigate the ability of saquinavir to generate the in vivo supersaturation and the impact of the presence of another solute, i.e., ritonavir, on the phase behavior of the former. Method The phase behavior of saquinavir alone and in the presence of ritonavir was studied by pH shift supersaturation assay. The generation of drug-rich phase was confirmed by dynamic light scattering (DLS) and UV extinction method. The nature of precipitate generated after pH shift was investigated by employing DSC and XRPD. Further, the flux studies were performed by employing dialysis membrane using Franz diffusion cell. Results Saquinavir precipitated in the amorphous form exhibiting type-II precipitation behavior generating the drug-rich phase and undergoing glass-liquid phase separation (GLPS) after the shift in pH towards higher side. The supersaturation advantage of saquinavir was marginally lowered in the presence of amorphous ritonavir. However, the free drug concentration of ritonavir was significantly reduced below the saturation solubility generating a subsaturated state. Both the drugs exhibited lowering in the chemical potential in the presence of each other, thereby reducing their flux/diffusion. The decrease in the free drug concentration and chemical potential were found dependent on the mole fraction of the solute present in the binary supersaturated solution. Conclusion The findings of the phase behavior of weak bases in the presence of other solutes are of great value not only in fixed-dose combination and concomitantly administered drugs but also in formulating supersaturated systems like amorphous solid dispersions and co-amorphous systems.

Advances in Continuous Active Pharmaceutical Ingredient (API) Manufacturing: Real- t ime Monitoring Using Multivariate Tools Abstract Purpose The implementation of continuous processing technologies for pharmaceutical manufacturing has increased due to its potential to enhance supply chain flexibility, reduce the footprint of the manufacturing facility, and deliver more consistent quality. Additionally, it facilitates extensive, real-time monitoring by sensors and process analytical technology (PAT) tools without perturbing the process. In the presented case study, the use of multivariate tools for the real-time monitoring and retrospective review of a continuous active pharmaceutical ingredient (API) synthesis was evaluated from process development through to commercialization. Method A multivariate statistical process monitoring (MSPM) approach summarizing variability in both quality critical (controlled flow rates, temperatures) and non-quality critical parameters (pressures, pump speeds, conductivity) was used to monitor three telescoped chemistry stages of a continuous API synthesis. Four different modeling strategies were presented addressing specific monitoring and analysis requirements during the pharmaceutical development lifecycle. Results During development (R&D and commercial facility), the implemented multivariate monitoring resulted in the identification of potential failure modes, a deeper understanding of the natural process variability and accelerated root cause analysis for a recurrent reagent blockage. During manufacturing (commercial facility), the multivariate tool confirmed potential for predictive maintenance and early fault detection. Conclusions While the implemented control strategy based on parametric control and offline analytical testing provided the required quality assurance, the multivariate trends provided additional information on process performance. More specifically, they enabled more detailed process understanding during the development of the continuous API synthesis following quality by design (QbD) principles and demonstrated the potential for enhanced process performance during commercial manufacturing.

Current In Vitro Assays for Prediction of T Cell Mediated Immunogenicity of Biotherapeutics and Manufacturing Impurities Abstract Purpose Biotherapeutics are a large and rapidly growing class of drugs being produced by pharmaceutical companies to treat a diverse range of clinical indications. The overall efficacy and safety of these products can be greatly impacted by their capacity to induce undesired immune responses. This review discusses in vitro cell-based methods used to assess the T cell mediated immunogenicity risk of proteinaceous therapeutic modalities and manufacturing impurities. Methods Here, we outline the potential sources and factors that influence immunogenicity. We present patient and product considerations that should be made in designing appropriate in vitro experiments that evaluate T cell epitopes capable of triggering treatment and outcome impacting anti-drug antibody responses and other adverse events. Results We present the current in vitro assays used to assess T cell activation towards biotherapeutics and the product impurities. Lastly, we outline the caveats, concerns, and challenges that remain with these cell-based assays. Conclusions Data generated from these in vitro antigenicity/immunogenicity assays may be used to derive immunogenicity risk assessments for programs and production processes and provides an opportunity for early selection of candidates or manufacturing impurities with lower likelihood of generating or exacerbating clinical immunogenicity.

Validation of Alternative Microbiological Method in Non-sterile Pharmaceutical Product Through the Reference Strains and Productive Environment Bioburden Abstract Purpose The traditional methods described in pharmacopeias most commonly used by the pharmaceutical industry are easy to perform and the costs are affordable, but they require long periods of time to obtain the results and often do not present sensitivity for recovering microorganisms in vulnerable physiological states known as viable but nonculturable. Thus, the objectives of this study were to evaluate the potential applicability of flow cytometry in non-sterile pharmaceutical products. Methods This paper implemented the analytical validation steps, through the reference strains and productive environment bioburden, by analyzing the traditional method in parallel to the alternative method with flow cytometry. Results The results indicated, with a 95% probability of detection, that there were no significant differences between the methods in relation to the ability to detect microbial contamination; however, the detection was faster with the flow cytometry method than the traditional method, which indicates that this technology is a viable alternative to be implemented. Conclusions The study demonstrated that the alternative microbiological method presents greater sensitivity in the analyses carried out, guaranteeing greater patient safety, besides allowing results to be obtained in a short period of time, thus enabling anticipation of investigations on possible failures that may occur during the process. Additionally, the study contributes to the environment by reducing waste generation and saving energy.