Pharmaceutical Drug Products Research Articles

Computer-Aided formulation design for pharmaceutical drug product development, part 01: Materials exploration through a visualization tool

An interactive tool has been developed to help design oral solid dosage form formulations. The tool enables quantitative explorations and comparisons of physical, bulk, and mechanical properties, and takes into account functional characteristics as well. In this manner, comparisons and clustering of both excipients and APIs can be carried out. These comparisons enable the generation of alternatives as well as surrogate identification, so as to spare resources and material.Multiple data sources were merged to create a “joint” data table with all relevant properties. Four main workflow activities are supported: Explore Materials, Search Similar APIs, Search Similar Excipients and Search Material Clusters.Multi-dimensional filtering can be superimposed to each functionality. Suggested visualizations are made particularly accessible by providing them as “standard plots”.The underlying philosophy is to empower formulation scientists to explore options, rather than prescribe decisions on exclusively mathematical grounds. The tool described here is the first step towards a holistic optimization incorporating predictions of mixture properties. Methodology of use is illustrated through three material selection application examples.

Stability-indicating RP-HPLC method development and validation for the quantification of amlodipine besylate and valsartan tablets in solid oral dosage form.

The present study discusses the development of simple, rapid, specific, precision, accuracy, stability indicating the HPLC method for the analysis of amlodipine besylate and valsartan tablet dosage form. The chromatographic separation was achieved using phosphate buffer with 1% triethyl amine (pH3.0) as mobile phase-A and mixed Methanol and buffer in the ratio of (65:35)(v/v) as mobile phase-B. The detection of components was made at 237 nm for amlodipine besylate and valsartan. Analytical techniques should enrich sensitivity and specificity for the estimation of pharmaceutical drug products. Evaluated stress studies under different types of ICH conditions. The optimized HPLC method was validated as per the current ICH guidelines. The validated HPLC method was obtained highly specific with linearity ranging between 25 and 200 μgmL-1 of amlodipine besylate and 40-320 μgmL-1 of valsartan and both components correlation coefficient was > 0.999. The method showed high accuracy more than 97%. In stress studies, amlodipine besylate and valsartan were found to be sensitive to acid stress conditions and oxidation stress conditions. The method was found to be suitable for the quality control of amlodipine besylate and valsartan in the tablet as well as in stability-indicating studies. The method was applied to the analysis of stability samples.

Mass Balance in Pharmaceutical Stress Testing: A Review of Principles and Practical Applications.

Stress testing (also known as forced degradation) of pharmaceutical drug substances and products is a critical part of the drug development process, providing insight into the degradation pathways of drug substances and drug products. This information is used to support the development of stability-indicating methods (SIMs) capable of detecting pharmaceutically relevant degradation products that might potentially be observed during manufacturing, long-term storage, distribution, and use. Assessing mass balance of stressed samples is a key aspect of developing SIMs and is a regulatory expectation. However, the approaches to measure, calculate, and interpret mass balance can vary among different pharmaceutical companies. Such disparities also pose difficulties for health authorities when reviewing mass balance assessments, which may result in the potential delay of drug application approvals. The authors have gathered input from 10 pharma companies to map out apractical review of science-based approaches and technical details to assess and interpret mass balance results. Key concepts of mass balance are introduced, various mass balance calculations are demonstrated, and recommendations on how to investigate poor mass balance results are presented using real-world case studies. Herein we provide a single source reference on the topic of mass balance in pharmaceutical forced degradation for small molecule drug substances and drug products in support of regulatory submissions with the goal of facilitating a shared understanding among pharmaceutical scientists and health authorities.

Analytical Methodologies to Detect N-Nitrosamine Impurities in Active Pharmaceutical Ingredients, Drug Products and Other Matrices.

Since 2018, N-nitrosamine impurities have become a widespread concern in the global regulatory landscape of pharmaceutical products. This concern arises due to their potential for contamination, toxicity, carcinogenicity, and mutagenicity and their presence in many active pharmaceutical ingredients, drug products, and other matrices. N-Nitrosamine impurities in humans can lead to severe chemical toxicity effects. These include carcinogenic effects, metabolic disruptions, reproductive harm, liver diseases, obesity, DNA damage, cell death, chromosomal alterations, birth defects, and pregnancy loss. They are particularly known to cause cancer (tumors) in various organs and tissues such as the liver, lungs, nasal cavity, esophagus, pancreas, stomach, urinary bladder, colon, kidneys, and central nervous system. Additionally, N-nitrosamine impurities may contribute to the development of Alzheimer's and Parkinson's diseases and type-2 diabetes. Therefore, it is very important to control or avoid them by enhancing effective analytical methodologies using cutting-edge analytical techniques such as LC-MS, GC-MS, CE-MS, SFC, etc. Moreover, these analytical methods need to be sensitive and selective with suitable precision and accuracy, so that the actual amounts of N-nitrosamine impurities can be detected and quantified appropriately in drugs. Regulatory agencies such as the US FDA, EMA, ICH, WHO, etc. need to focus more on the hazards of N-nitrosamine impurities by providing guidance and regular updates to drug manufacturers and applicants. Similarly, drug manufacturers should be more vigilant to avoid nitrosating agents and secondary amines during the manufacturing processes. Numerous review articles have been published recently by various researchers, focusing on N-nitrosamine impurities found in previously notified products, including sartans, metformin, and ranitidine. These impurities have also been detected in a wide range of other products. Consequently, this review aims to concentrate on products recently reported to contain N-nitrosamine impurities. These products include rifampicin, champix, famotidine, nizatidine, atorvastatin, bumetanide, itraconazole, diovan, enalapril, propranolol, lisinopril, duloxetine, rivaroxaban, pioglitazones, glifizones, cilostazol, and sunitinib.

How Important is the Metal-free Catalytic Knoevenagel Reaction in Medicinal Chemistry? An Updated Review.

The Knoevenagel condensation is a powerful and primary step for the development of carbon-carbon bond transformations. These condensations offer versatile products/ intermediates for diverse uses in polymers, cosmetics, chemical industries, and medicinal chemistry. Various homogenous and heterogenous catalysts have been found to promote the Knoevenagel condensation reaction, both environmentally and economically. Due to their attractive use in the production of pharmaceutical drugs, they are proven to be the main force that drives the synthesis involving numerous multi-component and multistep reactions. The present study, therefore, aims to summarise reported Knoevenagel condensation reactions using metal-free catalysts resulting in pharmaceutically useful compounds with anti-cancer, anti-tumor, anti-oxidant, anti-malarial, anti-diabetic, and anti- bacterial activities. By considering factors like their structure-activity relationships (SARs), the reaction conditions, and the steps involved, as well as the advantages and limitations of the particular approach, we also provide a general framework and direction in order to achieve superior characteristics of the catalyst.

Pharmaceutical Market Access in Latin America: Analyzing Approval Requirements in Three Key Nations: Ecuador, Dominican Republic and Nicaragua

: This article presents a comprehensive and comparative analysis of the regulatory frameworks governing the approval of pharmaceuticals in the Dominican Republic, Ecuador, and Nicaragua. It delves into the intricate scientific terminology and complex procedures inher-ent in these regulatory systems, shedding light on the demanding requirements that pharmaceu-tical companies must fulfil to secure market access in these countries. Employing a comparative approach, the article explores both the analogy and differences in the approval processes, focus-ing on factors such as safety standards, efficacy assessments, clinical trial prerequisites, post-marketing surveillance, and overall transparency. The findings contribute to a deeper under-standing of the scientific accuracy and ongoing efforts towards regulatory harmonisation within the pharmaceutical industry across these countries. Furthermore, this study aims to define the regulatory requirements for drug approval in the LATAM region, explicitly emphasising the Dominican Republic, Ecuador, and Nicaragua. It provides insights into the current pharmaceuti-cal market landscape in Latin America, compares the regulatory requirements for drug approval in these three countries, and offers guidance on preparing dossiers for obtaining authorisation of pharmaceutical drug products. By examining the similarities and differences in regulatory stand-ards, this article facilitates a comprehensive understanding of the stringency ratios between these countries and assists companies in navigating the specific regulatory landscapes to achieve suc-cessful drug approvals

Optimization and Evaluation of Column Efficiency in RP-HPLC Method for Pharmaceutical and Forensic Drug Analysis

Reverse Phase High Performance Liquid Chromatography (RP-HPLC) is an efficient and reliable technique employed in pharmaceutical and forensic analysis. The assay determination in pharmaceutical and certain molecular detection is performed using this technique. Performance of chromatographic columns play a central role in development of more efficient separation methods. It is one of the main component of system suitability testing in a chromatographic system. The column efficiency can be assessed by using various traditional methods and reproducible results can be evaluated using liquid chromatography We studied the column efficiency using RP-HPLC technique for pharmaceutical drug product Aceclofenac in a validated method. Two mobile phases combinations Acetonitrile: Methanol (80:20 v/v) and Acetonitrile: Methanol: Ammonia (225:50:1 v/v) were compared on C-8 Lichrospher RP-HPLC column for Aceclofenac and three tablet samples (30 ppm). The height equivalent to theoretical plate (HETP) referred as direct measure of column efficiency produced efficient results (530-545 and 190-230) for respective mobile phases. The lower HEPT is an indication of efficient elution in second mobile phase. The change in polarity as per pKa of the analyte may enhance elution and resolution. helpful in method development for pharmaceutical and forensic drug analysis using liquid chromatography.

Gold nanoparticles assisted colorimetric sensing of paroxetine, duloxetine, and olanzapine in aqueous and micellar systems with improved sensitivity

The present study explored a rapid and facile colorimetric identification of two antidepressants (paroxetine and duloxetine) and one antipsychotic drug (olanzapine) in aqueous and micellar systems using citrate-stabilized gold nanoparticles (Cit-AuNPs). The sensing approach involved hydrogen bonding and electrostatic interactions on the surface of Cit-AuNPs. The attributes of Cit-AuNPs and their interactions with the drugs were probed using characterization techniques like UV–Vis spectroscopy, scanning electron microscopy (SEM), dynamic light scattering (DLS), zeta potential measurement, and Fourier-transform infrared spectroscopy (FT-IR). Various factors including the volume of Cit-AuNPs, pH, reaction time, surfactant concentration, and the sequence of addition of reagents were optimized to inspect their impacts on sensing results. Under optimized conditions, the probe showed good linearity for the three drugs at the nanomolar (nM) range. Consequently, the color of the Cit-AuNP solution transformed from red to royal purple and blue, which was visible to the naked eye and monitored by visible absorption spectra. This label-free optical detection approach could recognize paroxetine (Prx), duloxetine (Dlx), and olanzapine (Olz) in aqueous system at concentrations ranging from 1 to 17 nM with a limit of detection (LOD) of 0.312, 0.258, and 0.418 nM (S/N = 3), respectively. Meanwhile, the sensitivity was improved in the Triton X-100 (TX-100) micellar system with LOD of 0.029, 0.030, and 0.029 nM for Prx, Dlx, and Olz, respectively accompanied by a shift in the absorption bands. The micellar system contributes stability to the Cit-AuNP-drug complex. The devised colorimetric approach was convenient and did not require any complex equipment. It was efficaciously used to detect three drugs in pharmaceutical products, spiked human urine, and blood serum samples with satisfactory recoveries of 99.83–103.45% and RSD < 3.5%. Notably, the sensing assay demonstrated good selectivity for three drugs in the existence of commonly encountered foreign species and certain common drugs with a relative error below 3%. The results of the present study were statistically compared with reference methodology. The results were validated with no significant difference between the devised and reported approaches considering precision and accuracy, respectively.

Review on method development and validation for different pharmaceutical dosage form

Pharmaceutical analysis is crucial for bulk and formulation quality control. Due to global medication manufacturing and pharmaceutical sector expansion, innovative analytical methods are in demand. Developing analytical procedures is now the most significant part of analysis. Improvements in analytical instruments have led to new analytical methods. The improvement of analytical methodologies and technologies has reduced analysis time, increased precision and accuracy, and decreased analysis costs. As a consequence, the majority of pharmaceutical businesses are investing heavily in specialist analysis labs. Analytical techniques for active pharmaceutical ingredients (API), excipients, drug products, degradation products and related substances, residual solvents, and other chemicals are created and verified. As a consequence, it has become an essential component of the regulating organization's standards. Development of analytical methodologies leads to official test methods. Quality control labs utilize these methods to verify drug identity, purity, safety, effectiveness, and performance. Production analytical methods are becoming relevant to regulators. Regulatory agencies expect applicants to demonstrate control of the drug development process using established analytical methodologies.

Statistical approaches to evaluate in vitro dissolution data against proposed dissolution specifications.

In vitro dissolution testing is a regulatory required critical quality measure for solid dose pharmaceutical drug products. Setting the acceptance criteria to meet compendial criteria is required for a product to be filed and approved for marketing. Statistical approaches for analyzing dissolution data, setting specifications and visualizing results could vary according to product requirements, company's practices, and scientific judgements. This paper provides a general description of the steps taken in the evaluation and setting of in vitro dissolution specifications at release and on stability.

Quality by Design (QbD) Paradigm: An Integrated Multivariate Approach to Transdermal Patch System Development

: The International Council on Harmonization issued quality by design (QbD) guidelines, including Q8 (R2) pharmaceutical development, Q9 quality risk management, and Q10 pharmaceutical quality system, to ensure the quality of pharmaceutical products. For continual and consistent improvement of the quality of pharmaceutical drug products, QbD tools, such as risk assessment, design of experiment, and control strategy, are used, which can solve the narrow areas in product development. Transdermal patch systems (TPS) are gaining attention among scientists and are one of the strong-growing drug delivery systems in the market as a result of numerous benefits, including lowering the dosing frequency, adverse effects and invasiveness, avoiding pre-systemic metabolism, and better patient efficiency and compatibility. Transdermal patch systems are a likable dosage form when compared to other dosage forms. However, several challenges are faced in TPS product development which has hindered enormous products concerning the market status of TPS in comparison to the oral dosage forms. The implementation of the QbD concept was much focused on oral dosage forms. Additionally, the lack of understanding of the development of TPS leads to failure and withdrawal from markets. Therefore, to understand the QbD concepts of TPS, an attempt has been made to review the QbD approach for the development of TPS from the identification of the Quality Target Product Profile to the arrival of design space, which might help the formulator to navigate the sticky areas, in the TPS development.

Development of a New Bioequivalent Omeprazole Product.

Background and Objectives: The enteric form of omeprazole is one of the most commonly prescribed medications. Similarly to Europe, Kazakhstan relies on the localization of pharmaceutical drug production as one of its primary strategies to ensure that its population has access to affordable and good-quality medicines. This study comprehensively describes the technologically available development of bioequivalent delayed-release omeprazole. Materials and Methods: Various regimes and technological parameters were tested on laboratory- and production-scale equipment to establish a technical process where a functional and gastro-protective layer is essential. According to the ICH guidance on stability testing and Kazakhstan local rules, stability studies were conducted under conditions appropriate for climate zone II. The comparison of the rate and extent of absorption with subsequent assessment of the bioequivalence of the generic and reference drugs after a single dose of each drug at a dose of 40 mg was performed. Results: The quantitative and qualitative composition and technology of producing a new generic enteric form of omeprazole in capsules were developed and implemented at the manufacturing site of solid forms. Dissolution profiles in media with pH 1.2 and 6.8 were proven. During the accelerated six-month and long-term twelve-month studies, the developed formulation in both packaging materials at each control point passed the average weight and mass uniformity test, dissolution test, acid-resistance stage test, buffer stage test, impurity assay, and microbiological purity test and met all the specification criteria. A bioequivalence study in 24 healthy volunteers compared against the innovative drug showed the bioequivalency of the new generic system. The obtained values from the test and reference products were 1321 ± 249.0 ng/mL and 1274 ± 233 ng/mL for Cmax, 4521 ± 841 ng·h /mL and 4371 ± 695 ng·h /mL for AUC0-t, and 4636 ± 814 ng·h /mL and 4502 ± 640 ng·h /mL for AUC0-∞. Conclusions: Using affordable technologies, a bioequivalent generic delayed-release formulation of 20 and 40 mg omeprazole has been developed.

Modernizing non-classical protein crystallization through industry 4.0: Advanced monitoring and modelling utilizing process analytical technology

Modernizing manufacturing processes of pharmaceutical drug products with advanced monitoring and modelling can aid in the transition towards Industry 4.0 with the benefit of increased productivity. This study investigated the use of process analytical technology in combination with partial least squares (PLS) regressions to create two soft sensors to predict the mass fraction of crystallised active pharmaceutical ingredient (API) and mass fraction of dissolved API during a non-classical protein crystallization with amorphous precursors. The PLS model for predicting the amount of crystalline API was based on Raman spectra, chord length distributions and turbidity data using small-angle X-ray scattering as a reference method. The model had a root mean square error on cross-validation (RMSECV) of 5 %. The model predicting mass fraction of dissolved API was based only on the Raman spectra and used high performance liquid chromatography as reference method. This model had a RMSECV of 3 % A two-step nucleation model was fitted to the predictions from the sensors and showed good agreement between data and model with a root mean square error of 2 %.

Regulatory Procedures and Integrated Requirements for Early Phase Development of a Pharmaceutical Drug Product.

Regulatory Procedures and Integrated Requirements for Early Phase Development of a Pharmaceutical Drug Product.

A Multi-Objective Approach Optimizing Pharmacy Industry Decisions through MOORA Method

The pharmacy industry, a crucial pillar of the healthcare sector, encompasses the discovery, development, production, distribution, and sale of pharmaceutical drugs and medications. With an intricate interplay of scientific innovation, medical expertise, and commercial activities, this industry plays an indispensable role in safeguarding and improving human health. From the inception of groundbreaking drugs to their widespread distribution, the pharmacy industry integrates various stakeholders, including pharmaceutical companies, researchers, healthcare professionals, regulators, and consumers. It strives to address a wide spectrum of health conditions, from acute ailments to chronic diseases, by developing innovative treatments, generic medicines, and over-the-counter drugs. The pharmacy industry's evolution has been marked by technological advancements, research breakthroughs, and regulatory frameworks to ensure drug safety and efficacy. As the global population continues to grow and age, the industry faces the challenges of maintaining affordability, accessibility, and quality of medications. Furthermore, the pharmacy industry is a catalyst for economic growth, creating jobs, fostering research collaborations, and contributing to national and international healthcare systems. Its multifaceted nature, ranging from drug research to patient care, underscores its significance in the broader landscape of healthcare and public well-being. Research within the pharmacy industry holds immense significance due to its pivotal role in advancing medical knowledge and improving patient outcomes. Pharmaceutical research drives the development of new medications, innovative therapies, and treatment protocols, enhancing the efficacy and safety of drugs. It also uncovers insights into disease mechanisms, fostering a deeper understanding of health conditions. Furthermore, research guides regulatory decisions, ensuring drugs' quality, and promotes evidence-based medical practices. Through ongoing investigation, the pharmacy industry continually evolves, addressing emerging health challenges, optimizing drug utilization, and ultimately contributing to the overall enhancement of global healthcare standards. MOORA (Multi-Objective Optimization by Ratio Analysis) is a decision-making method used to evaluate and prioritize alternatives based on multiple conflicting criteria. It involves comparing alternatives' performance ratios against reference alternatives, considering both benefits and drawbacks. By assigning weights to criteria, MOORA quantifies their importance and ranks alternatives accordingly. This technique assists in complex decision scenarios where various factors must be balanced. MOORA's systematic approach aids in reaching well-informed decisions by quantifying trade-offs and providing a structured framework for considering multiple objectives simultaneously. Product Innovation, Market Share (%), Research Investment ($ billion), Patient Satisfaction, Drug Efficacy (%), Global Reach (countries). Pfizer, Johnson &amp; Johnson, Roche, Novartis, GlaxoSmithKline, CVS Health, Walgreens Boots Alliance, Rite Aid.From the result it is seen that Novartisis got the first rank where as is the Rite Aidis having the lowest rank.

Quantitative analysis of the effects of multi-component formulation parameters on granule and tablet properties via a combined population balance and statistical predictive model

In pharmaceutical drug product manufacturing, the use of multi-component mixtures in the formulation is a common practice. However, the introduction of each material alters the powder blend properties and affects the granule growth mechanisms in a wet granulation process. In this study, we quantified the effects of varying formulation parameters on granule growth rate, expressed by the liquid amount required for granulation to reach completion, and on granule and tablet quality attributes. Process models, including population balance and statistical models, were developed to represent the granulation, milling, and tableting process, and predict relevant granule and tablet properties. Overall, prediction of granule properties had an accuracy of above 80% and the prediction of different tablet properties ranged from an R2 of 0.68 to 0.9. These models are computationally efficient and can be simulated serially to predict the performance of different multi-component formulations by using the pre-blend properties as model inputs.

Application of Artificial Intelligence in the Pharmaceutical Industry

Background: The potentials of artificial intelligence (AI) have permeated all industries and fields, and the advantages of AI are extensively employed. This technology offers a wide range of benefits in the pharmaceutical industry, including reducing human interventions and increasing the speed and accuracy of tasks. This can expedite time-consuming activities, such as drug discovery, production, clinical trials, research and development, and ultimately, determining a drug’s position in target markets.&#x0D; Methods: A comprehensive scope review was performed in this descriptive, applied study on the applications of AI in the pharmaceutical industry in Iran. Relevant data were meticulously gathered and extracted from diverse sources, including various search engines, key databases, such as Medline, PubMed, Elsevier, and the Iranian Center for Scientific Information and Documentation, and information databases, reference books, and reports from the World Health Organization. These results represent our research on key themes, including AI, the pharmaceutical industry, drug production, innovation, and evolution. Our main focus lies on the application of AI in the manufacturing part of the pharmaceutical industry, with a deliberate decision not to delve into the technical aspects. This approach allowed us to prioritize a comprehensive understanding of the practical implications and advancements in the manufacturing processes facilitated by artificial intelligence.&#x0D; Results: The retrieved studies showed that AI has the potential to enhance crucial processes in pharmaceutical companies across various dimensions. These potential capabilities are observed in areas such as quality control, human resource management, research and development, finance, supply chain management, logistics, data management, operations management, customer relationship management, and commerce, which are further discussed.&#x0D; Conclusions: Pharmaceutical companies can utilize the tools provided by AI in various value-creating processes to enhance their efficiency and effectiveness. This requires the adoption and integration of this innovative technology at various levels of organizational planning so that these companies can harness the greater potential it offers with appropriate investments.

Review: Instrumental analytical techniques for evaluating some anti-infective drugs in pharmaceutical products and biological fluids

Quality and safety of drugs are essential for effective therapeutic performance. Impurities can compromise the quality and safety of drugs, and they can arise during various stages of the development, production, storage and even transportation process. Therefore, detecting and measuring the number of impurities with high accuracy in drugs is necessary to ensure the quality and safety of drugs and to reduce the risks associated with taking them. Detecting and measuring impurities in drugs require advanced analytical techniques. The review highpoints a variety of analytical chemistry techniques include spectrophotometric and chromatographic methods in addition to some electrochemistry methods that have been applied for determination of certain drugs such as Ciprofloxacin, Metronidazole, Hydroxychloroquine and Cefotaxime in their pure form, combined form with other drugs, combined form with degradation products, and in biological fluids.

A Compounding Problem: Pharmaceutical Importation and Drug Production in the United States

Abstract Drug shortages are not a new phenomenon in the United States. Current policies and regulations can be improved to better utilize drug compounding facilities to ensure patient safety, provide practical standards for the interstate market, and focus on patient needs in the marketplace. Adjustments in regulation and incentives such as performance-based bonuses are necessary to encourage registration for 503B outsourcing facilities and address shortages for less profitable drugs. Diversity of drug supply sources is also of the utmost importance to secure the trade of essential medicines in times of drug shortages through a globally diverse supply chain along with a strong system for domestic drug manufacturing and compounding facilities.

Product Patrolling: Learning Recall execution Strategies through Case studies

There has been an increasing trend in the number of prescribed and over-the-counter drug recall over the last few years. The recall is usually due to company’s discovery, customer’s complaint or Food and Drug Administration (FDA) observation. The process of recall involves a planned specific course of action, which addresses the depth of recall, need for public warning, and the extent of effectiveness checks for the recall.This abstract explores the critical aspects of pharmaceutical drug product recalls, focusing on their classification, recall levels, and effective recall strategies. The pharmaceutical industry faces challenges in ensuring the safety and efficacy of drug products, necessitating a robust recall framework. We delve into the classification of recalls, ranging from voluntary actions to mandated recalls, emphasizing the importance of prompt and transparent communication. Recall levels, categorized based on the severity of potential health risks, are examined to provide a comprehensive understanding of the regulatory landscape. Furthermore, this abstract highlights innovative recall strategies, encompassing technology-driven traceability, stakeholder collaboration, and crisis communication. By addressing these key elements, this research contributes to enhancing the efficiency and reliability of drug product recall processes, ultimately safeguarding public health and bolstering industry resilience.