Triboelectrification of Active Pharmaceutical Ingredients: Amines and Their Hydrochloride Salts.

The triboelectric properties of active pharmaceutical ingredients (APIs) contribute to problems during the manufacturing of pharmaceuticals. However, the triboelectric properties of APIs have not been comprehensively characterized. In this study, the effect of salt formulation on the triboelectric properties of APIs was investigated. The triboelectric properties of three groups of amines, namely tertiary amines, purine bases, and amino acids, and their hydrochlorides were evaluated using a suction-type Faraday cage meter. Most of the hydrochloride salts exhibited more negative charges than the corresponding free bases, and the degree by which the triboelectric property changed upon hydrochlorination depended on the structural groups of the compounds. In the case of tertiary amines, the change in the zero-charge margin upon hydrochlorination was negatively correlated with the zero-charge margin of the free base. In contrast, hydrochlorination of the amino acids led to a significant change in the zero-charge margin. In most cases, salt formation also affected the triboelectric properties of API powders. Controlling the triboelectric properties of APIs solves various problems caused by the electrification of raw material powders and granules during the production of pharmaceuticals, thereby increasing the quality of produced pharmaceuticals.

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.

Application of marine sponges for biomonitoring active pharmaceutical ingredients (APIs) in coral reefs. Optimization of an SPME and ESI-LC-MS/MS method.

Chemical pollution is a threat to coral reefs. To preserve them, it is crucial to monitor novel contaminants and assess the related risks. The occurrence of active pharmaceutical ingredients (APIs) in coral reefs has been poorly investigated until now. Under this light, we tested the use of the marine sponge Cf. Hyrtios as bio-monitors and conducted a pilot study in the Faafu Atoll (Maldives). Analyses were carried out by in vivo solid-phase microextraction (SPME) and liquid chromatography (LC) electrospray ionization (ESI) tandem mass spectrometry (MS/MS). Twelve APIs were selected for method optimization. Limits of quantitation (LOQs) were in the 0.6 and 2.5 ng/g range, accuracy between 86.5 % and 104.7 %, and precision between 3.0 % and 14.9 %. All the sponges located in the inner reefs resulted contaminated with at least one API. Gabapentin and Carbamazepine displayed the highest detection rates, while Ketoprofen had the highest concentration (up to 15.7 ng/g).

Estimating The Effects Of COVID-19 On Globalized Markets For Active Pharmaceutical Ingredients.

Global supply chains for active pharmaceutical ingredients (APIs) are highly centralized in certain countries and are susceptible to supply-chain shocks. However, there is no systematic monitoring or global coordination to manage risk and ensure equitable supply continuity during public health emergencies. In this study, we applied quasi-experimental methods on shipment-level customs data to determine how prices and export volume for APIs exported from India were affected by the COVID-19 pandemic. We found that API prices for key essential medicines not used for COVID-19 did not change significantly in the year after the World Health Organization pandemic declaration, but volume decreased by 80 percent. Prices for medicines speculatively repurposed for COVID-19, such as hydroxychloroquine and ivermectin, increased by as much as 250 percent compared with prices for nonrepurposed medicines, but only ivermectin saw a decrease in volume. Systematic monitoring of API markets, investments to promote supply diversification, and legal and political reforms to disincentivize price speculation could support supply-chain resilience and safeguard access to medicines.

Application of deep UV resonance Raman spectroscopy to column liquid chromatography: Development of a low-flow method for the identification of active pharmaceutical ingredients.

In this study, deep UV resonance Raman spectroscopy (DUV-RRS) was coupled with high performance liquid chromatography (HPLC) to be applied in the field of pharmaceutical analysis. Naproxen, Metformin and Epirubicin were employed as active pharmaceutical ingredients (APIs) covering different areas of the pharmacological spectrum. Raman signals were successfully generated and attributed to the test substances, even in the presence of the dominant solvent bands of the mobile phase. To increase sensitivity, a low-flow method was developed to extend the exposure time of the sample. This approach enabled the use of a deep UV pulse laser with a low average power of 0.5 mW. Compared to previous studies, where energy-intensive argon ion lasers were commonly used, we were able to achieve similar detection limits with our setup. Using affordable lasers with low operating costs may facilitate the transfer of the results of this study into practical applications.

Potential of Powder Rheology for Detecting Unforeseen Cross-Contamination of Foreign Active Pharmaceutical Ingredients.

Unexpected cross-contamination by foreign components during the manufacturing and quality control of pharmaceutical products poses a serious threat to the stable supply of drugs and the safety of customers. In Japan, in 2020, a mix-up containing a sleeping drug went undetected by liquid chromatography during the final quality test because the test focused only on the main active pharmaceutical ingredient (API) and known impurities. In this study, we assessed the ability of a powder rheometer to analyze powder characteristics in detail to determine whether it can detect the influence of foreign APIs on powder flow. Aspirin, which was used as the host API, was combined with the guest APIs (acetaminophen from two manufacturers and albumin tannate) and subsequently subjected to shear and stability tests. The influence of known lubricants (magnesium stearate and leucine) on powder flow was also evaluated for standardized comparison. Using microscopic morphological analysis, the surface of the powder was observed to confirm physical interactions between the host and guest APIs. In most cases, the guest APIs were statistically detected due to characteristics such as their powder diameter, pre-milling, and cohesion properties. Furthermore, we evaluated the flowability of a formulation incorporating guest APIs for direct compression method along with additives such as microcrystalline cellulose, potato starch, and lactose. Even in the presence of several additives, the influence of the added guest APIs was successfully detected. In conclusion, powder rheometry is a promising method for ensuring stable product quality and reducing the risk of unforeseen cross-contamination by foreign APIs.

Comparison of permitted daily exposure (PDE) values for active pharmaceutical ingredients (APIs) - Evidence of a robust approach.

Permitted Daily Exposure Limits (PDEs) are set for Active Pharmaceutical Ingredients (APIs) to control cross-contamination when manufacturing medicinal products in shared facilities. With the lack of official PDE lists for pharmaceuticals, PDEs have to be set by each company separately. Although general rules and guidelines for the setting of PDEs exist, inter-company variations in the setting of PDEs occur and are considered acceptable within a certain range. To evaluate the robustness of the PDE approach between different pharmaceutical companies, data on PDE setting of five marketed APIs (amlodipine, hydrochlorothiazide, metformin, morphine, and omeprazole) were collected and compared. Findings show that the variability between PDE values is within acceptable ranges (below 10-fold) for all compounds, with the highest difference for morphine due to different Point of Departures (PODs) and Adjustment Factors (AFs). Factors of PDE variability identified and further discussed are: (1) availability of data, (2) selection of POD, (3) assignment of AFs, (4) route-to-route extrapolation, and (5) expert judgement and differences in company policies. We conclude that the investigated PDE methods and calculations are robust and scientifically defensible. Additionally, we provide further recommendations to harmonize PDE calculation approaches across the pharmaceutical industry.

Analysis of unknown (unlabeled/mislabeled) drug products for active pharmaceutical ingredients and related substances by an international mail facility satellite laboratory equipped with rapid screening devices.

Two chemists employed a three-device rapid screening "toolkit" consisting of a handheld Raman spectrometer, transportable mass spectrometer, and portable Fourier transform infrared (FT-IR) spectrometer at an international mail facility (IMF) satellite laboratory to examine unknown (unlabeled/mislabeled) products for the presence of active pharmaceutical ingredients (APIs). Phase I of this project previously demonstrated that this toolkit was the most effective collection of instruments for identifying APIs in product types collected at IMFs during a nationwide mail blitz and Phase II of this project previously demonstrated that results generated using the toolkit during a satellite laboratory pilot program were as reliable as those generated by a full-service library when two or more of these instruments identify an API. This study (Phase III) described the results of the satellite laboratory toolkit during production mode and encompassed the period ranging from June 2021 through December 2022. During this study, a total of 858 products were examined on-site at the IMF. The satellite laboratory yielded conclusive results for 726 (84.6%) products, which were used to support regulatory action, and identified 132 (15.4%) products that required additional full-service laboratory analyses due to inconclusive results. The satellite and full-service laboratory verified/confirmed at least one API/related substance in 617 (71.9%) products. A total of 709 APIs/related substances were found in the 617 products, and 202 of these 709 compounds were unique/different. Overall, during Phases I through III of this program, 350 different substances have been identified in products collected at IMFs.

NMR Longitudinal Rotating Frame Relaxation Time (T1ρ) with a Weak Spin Locking Field as an Approach to Characterize Solid-State Active Pharmaceutical Ingredients: Proof of Concept.

Nuclear magnetic resonance (NMR) longitudinal rotating frame relaxation time (T1ρ), rarely used in low-field NMR, can be more effective than conventional T1 and T2 relaxation times to differentiate polymorphic forms of solid pharmaceuticals. This could be attributed to T1ρ sensibility to structural and molecular dynamics that can be enhanced by changing the strength of the oscillating magnetic field (B1) of spinlock pulses. Here, we compared the capacity of T1, T2, and T1ρ to differentiate inactive (A) and active (C) crystalline forms of the World Health Organization essential drug Mebendazole. The results showed that T1 and T2 values of both forms were statistically identical at 0.47 T. Conversely, T1ρ of both forms measured with weak spinlock B1 fields, ranging from 0.08 to 0.80 mT were statistically different in the same spectrometer. The T1ρ also has the limit of detection to detect the presence of at least 10% of inactive A form in the active C form. Therefore, T1ρ, measured with weak spinlock B1 fields can be an effective, streamlined, and complementary approach for characterizing not only solid active pharmaceutical ingredients but other solid-state materials as well.

Global Production of Active Pharmaceutical Ingredients for US Generic Drugs Experiencing Shortages.

This study evaluates the characteristics of generic active pharmaceutical ingredients (APIs) used to manufacture drugs with shortages in the US and facilities producing APIs worldwide.

Potential and performance of anisotropic 19F NMR for the enantiomeric analysis of fluorinated chiral active pharmaceutical ingredients.

Controlling the enantiomeric purity of chiral drugs is of paramount importance in pharmaceutical chemistry. Isotropic 1H NMR spectroscopy involving chiral agents is a widely used method for discriminating enantiomers and quantifying their relative proportions. However, the relatively weak spectral separation of enantiomers (1H Δδiso(R, S)) in frequency units at low and moderate magnetic fields, as well as the lack of versatility of a majority of those agents with respect to different chemical functions, may limit the general use of this approach. In this article, we investigate the analytical potential of 19F NMR in anisotropic chiral media for the enantiomeric analysis of fluorinated active pharmaceutical ingredients (API) via two residual anisotropic NMR interactions: the chemical shift anisotropy (19F-RCSA) and dipolar coupling ((19F-19F)-RDC). Lyotropic chiral liquid crystals (CLC) based on poly-γ-benzyl-L-glutamate (PBLG) show an interesting versatility and adaptability to enantiodiscrimination as illustrated for two chiral drugs, Flurbiprofen® (FLU) and Efavirenz® (EFA), which have very different chemical functions. The approach has been tested on a routine 300 MHz NMR spectrometer equipped with a standard probe (5 mm BBFO probe) in a high-throughput context (i.e., ≈10 s of NMR experiments) while the performance for enantiomeric excess (ee) measurement is evaluated in terms of trueness and precision. The limits of detection (LOD) determined were 0.17 and 0.16 µmol ml-1 for FLU and EFA, respectively, allow working in dilute conditions even with such a short experimental duration. The enantiodiscrimination capabilities are also discussed with respect to experimental features such as CLC composition and temperature.

Non-destructive Raman Method Development for Quantifying Active Pharmaceutical Ingredient in an Oral Suspension Through Plastic Dosing Syringes.

For liquid drug products, e.g., solutions or suspensions for oral or parenteral dosing, stability needs to be demonstrated in primary packaging during storage and in dosing devices during in-use periods per quality guidelines from the International Conference on Harmonisation (ICH) and the European Agency for the Evaluation of Medicinal Products (EMEA). One aspect of stability testing for liquid drug products is in-use stability, which typically includes transferring the liquid samples into another container for further sample preparation with extraction diluent and necessary agitation. Samples are then analyzed with traditional chromatography methods, which are laborious, prone to human errors, and time-consuming, especially when this process needs to be repeated multiple times during storage and in-use periods. Being able to analyze the liquid samples non-destructively would significantly improve testing efficiency. We investigated different Raman techniques, including transmission Raman (TRS) and back scatter Raman with a non-contact optic (NCO) probe, as alternative non-destructive tools to the UHPLC method for API quantitation in in-use liquid samples pulled into plastic dosing syringes. The linearity of the chemometric methods for these two techniques was demonstrated by cross-validation sample sets at three levels over an API concentration range of 60 to 80 mg/mL. The accuracy of the chemometric models was demonstrated by the accurate prediction of the API concentrations in independent samples from four different pilot plant batches manufactured at different sites. Both techniques were successful in measuring a signal through a plastic oral dosing syringe, and predicting the suspension API concentration to within 4% of the UHPLC-measured value. For future work, there are opportunities to improve the methodology by exploring additional probes or to expand the range of applications by using different sample presentations (such as prefilled syringes) or formulation matrices for solutions and suspensions.

Quantitation of Active Pharmaceutical Ingredients in Polymeric Drug Products Using Elemental Analysis.

Polymeric prodrugs have gained significant popularity as a strategy to enhance the bioavailability and improve the pharmacokinetic properties of active pharmaceutical ingredients (API). Since the amount of the API in a polymeric prodrug product directly impacts both safety and efficacy, there is a pressing need for robust and accurate analytical methods to quantify the API in these formulations. Presently, drug quantification methods include reversed-phase high-performance liquid chromatography (RP-HPLC) and size exclusion chromatography (SEC)-based molecular weight determination. Even though these methods are highly precise and reproducible, a deep understanding of chromatography is required for complex method development, including optimization of the elution profile and selecting the appropriate column and mobile phase. In this chapter, we introduce the automated elemental analyzer for drug quantification, which is simple to use and does not require special method development.

Continuous flow reactions in the preparation of active pharmaceutical ingredients and fine chemicals.

Herein, we present an overview of continuous flow chemistry, including photoflow and electroflow technologies in the preparation of active pharmaceutical ingredients (APIs) and fine chemical intermediates. Examples highlighting the benefits and challenges associated with continuous flow processes, mainly involving continuous thermal, photo- and electrochemical transformations, are drawn from the relevant literature, especially our experience and collaborations in this area, with emphasis on the synthesis and prospective scale-up.

Microencapsulation for Pharmaceutical Applications: A Review.

In order to improve bioavailability, stability, control release, and target delivery of active pharmaceutical ingredients (APIs), as well as to mask their bitter taste, to increase their efficacy, and to minimize their side effects, a variety of microencapsulation (including nanoencapsulation, particle size <100 nm) technologies have been widely used in the pharmaceutical industry. Commonly used microencapsulation technologies are emulsion, coacervation, extrusion, spray drying, freeze-drying, molecular inclusion, microbubbles and microsponge, fluidized bed coating, supercritical fluid encapsulation, electro spinning/spray, and polymerization. In this review, APIs are categorized by their molecular complexity: small APIs (compounds with low molecular weight, like Aspirin, Ibuprofen, and Cannabidiol), medium APIs (compounds with medium molecular weight like insulin, peptides, and nucleic acids), and living microorganisms (such as probiotics, bacteria, and bacteriophages). This article provides an overview of these microencapsulation technologies including their processes, matrix, and their recent applications in microencapsulation of APIs. Furthermore, the advantages and disadvantages of these common microencapsulation technologies in terms of improving the efficacy of APIs for pharmaceutical treatments are comprehensively analyzed. The objective is to summarize the most recent progresses on microencapsulation of APIs for enhancing their bioavailability, control release, target delivery, masking their bitter taste and stability, and thus increasing their efficacy and minimizing their side effects. At the end, future perspectives on microencapsulation for pharmaceutical applications are highlighted.

Extemporaneous Topical Minoxidil Solutions for the Treatment of Androgenetic Alopecia- Stability Studies and Incorporation Tests of Active Pharmaceutical Ingredients in Aloplus Total Base.

Minoxidil is one of the most employed active pharmaceutical ingredients for the  treatment of androgenetic alopecia. The authors propose a new method for production of minoxidil lotions using Aloplus Total. The latter is a propylene glycol-free liquid base in which the presence of hydroxypropyl-ß-cyclodextrin and ethanol allows the solubilization of high drug amounts. Minoxidil intrinsic solubility in the base was determined, and a comprehensive chemical and physical stability study was conducted on 8% w/w minoxidil lotions. Incorporation tests of different active pharmaceutical ingredients that can be combined to 5% w/w minoxidil were also carried out. The analyses showed that minoxidil intrinsic solubility in the new base was 85.93 mg/mL ± 4.17 mg/mL (8.64% w/w ± 0.42% w/w) at 25°C, and the topical lotions were found to be physically and chemically stable for more than 180 days when stored at 25°C or 40°C. Incorporation tests of several active pharmaceutical ingredients also were successful, indicating that Aloplus Total is a liquid vehicle also useful for the preparation of minoxidil-based topical lotions for a synergistic treatment of androgenetic alopecia.

Nanoneuroscience: Cutting-edge Approach for Disease Management.

Neurological disorders (ND) have affected a major part of our society and have been a challenge for medical and biosciences for decades. However, many of these disorders haven't responded well to currently established treatment approaches. The fact that many active pharmaceutical ingredients can't get to their specified action site inside the body is one of the main reasons for this failure. Extracellular and intracellular central nervous system (CNS) barriers prevent the transfer of drugs from the blood circulation to the intended location of the action. Utilizing nanosized drug delivery technologies is one possible way to overcome these obstacles. These nano-drug carriers outperform conventional dosage forms in many areas, including good drug encapsulation capacity, targeted drug delivery, less toxicity, and enhanced therapeutic impact. As a result, nano-neuroscience is growing to be an intriguing area of research and a bright alternative approach for delivering medicines to their intended action site for treating different neurological and psychiatric problems. In this review, we have included a short overview of the pathophysiology of neurological diseases, a detailed discussion about the significance of nanocarriers in NDs, and a focus on its recent advances. Finally, we highlighted the patented technologies and market trends, including the predictive analysis for the years 2021-2028.

Pharmaceutical cocrystals: a rising star in drug delivery applications.

Pharmaceutical cocrystals, owing to their manifold applications, are acting as bridge between drug discovery and pharmaceutical product development. The ability to scale up pharmaceutical cocrystals through continuous manufacturing approaches offers superior and economic pharmaceutical products. Moreover, cocrystals can be an aid for the nanoparticulate systems to solve the issues related to scale-up and cost. Cocrystals grabbed attention of academic researchers and pharmaceutical scientist due to their potential to target various diseases like cancer. The present review is mainly focussed on the diverse and comprehensive applications of pharmaceutical cocrystals in drug delivery including solubility and dissolution enhancement, improvement of bioavailability of drug, mechanical and flow properties of active pharmaceutical ingredients, controlled/sustained release and colour tuning of API. Besides, phytochemical based cocrystals, multi-drug cocrystals and cocrystals for tumour therapy have been discussed in this review. Additionally, recent progress pertinent to pharmaceutical cocrystals is also included, which may provide future directions to manufacturing and scale-up of cocrystals.

Occurrence of phthalic acid esters (PAEs) and active pharmaceutical ingredients (APIs) in key species of anthozoans in Mediterranean Sea.

The Mediterranean Sea's biodiversity is declining due to climate change and human activities, with plastics and emerging contaminants (ECs) posing significant threats. This study assessed phthalic acid esters (PAEs) and active pharmaceutical ingredients (APIs) occurrence in four anthozoan species (Cladocora caespitosa, Eunicella cavolini, Madracis pharensis, Parazoanthus axinellae) using solid phase microextraction (SPME) and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). All specimens were contaminated with at least one contaminant, reaching maximum values of 57.3 ng/g for the ∑PAEs and 64.2 ng/g (wet weight) for ∑APIs, with dibutyl phthalate and Ketoprofen being the most abundant. P. axinellae was the most contaminated species, indicating higher susceptibility to bioaccumulation, while the other three species showed two-fold lower concentrations. Moreover, the potential adverse effects of these contaminants on anthozoans have been discussed. Investigating the impact of PAEs and APIs on these species is crucial, given their key role in the Mediterranean benthic communities.