The development of non-toxic ionic liquid-based active pharmaceutical ingredients (IL-APIs) for effective topical drug delivery is still challenging. The properties of IL-APIs can be boosted up by ...selecting potential biocompatible cations. Here, we introduced N-methyl-2-pyrrolidone (NMP) as a potent biocompatible counter ion to prepare ionic liquefied drugs for topical drug delivery. The cytotoxicity of NMP cation was investigated using mammalian cell lines (HepG2, NIH3T3 and L929 cells) and compared with conventional IL-forming cations. The synthesized NMP cation has lower toxicity than that of conventional IL-forming cations. The NMP cation showed at least 3.6, 15.2 and 58.9 times lower toxicity than that of conventional imidazolium, ammonium and phosphonium cations, respectively. The synthesized NMP-based ionic liquid (NMP-IL) was characterized using 1H &13C NMR, FT-IR, DSC and TGA. NMP-IL showed better physico-thermal stability, enhanced skin penetration, and enriched drug accumulation 2.6 times higher than that of IL ChoIbu in the target tissue. These results suggested that NMP cation based API-IL can be an effective biocompatible formulation for topical drug delivery by accumulating active drugs in the skin.
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•Biocompatible N-methyl-2-pyrrolidone (NMP) cation was designed from NMP solvent.•NMP cation showed lower toxicity as compared with conventional IL-forming cations.•IL with NMP cation exhibited better physico-thermal stability and enhanced skin penetration.•NMP-IL has enriched higher drug accumulation than that of Cho-IL in the target tissue.
Access to cyclopropanol is improved by developing a route from highly available cyclopropyl methyl ketone. The Baeyer–Villiger oxidation inserts oxygen between the cyclopropyl and ketone ...functionalities, and the alcohol is subsequently unmasked by cleaving the ester with an amine. Optimization resulted in high yield (>90% for each step), isolation of volatile and water-soluble cyclopropanol, selection of a peroxide with improved safety profile (urea hydrogen peroxide, UHP), and implementation of continuous flow to handle an exotherm. The urea present in the peroxide unexpectedly enhanced conversion of the ketone to the ester, and the addition of a rheology modifier to a 20 wt % suspension of UHP in DCM facilitated continuous delivery of an otherwise difficult-to-pump slurry.
Trityl olmesartan ethyl ester (TOEE), a key intermediate of the launched angiotensin II receptor blocker olmesartan medoxomil, was built using two blocks via an N-alkylation reaction, wherein the ...imidazole N-1 isomer of this intermediate was the only isomeric product reported previously. Unexpectedly, from a sample of laboratory trials, an undesired impurity (a level of 0.2–0.3%) sharing the same molecular mass with TOEE was detected and assumed to be an N-3 regioisomeric impurity of TOEE. Accordingly, a five-step lactone ring-opening synthetic route was designed and successfully used to obtain this impurity, whose structure perfectly matched the NMR and mass spectra. Subsequent characterization by SCXRD directly confirmed the initial speculation of it being an N-3 regioisomer, which was reported for the first time. Next, two downstream impurities toward the active pharmaceutical ingredient (API) were synthesized, in which the N-3 impurity of API proved to be inseparable with the API molecule under the European Pharmacopoeia chromatography method, introducing a risk of impurity identification. Sequential investigations focusing on impurity tracing and control strategies of the downstream impurities were conducted to meet the quality control requirements.
The technological utility of active pharmaceutical ingredients (APIs) is enormously improved when they are converted into ionic liquids (ILs). API-ILs possess better aqueous solubility and thermal ...stability than that of solid-state salt or crystalline drugs. However, many such API-ILs are not biocompatible or biodegradable. In the current study, we synthesized a series of IL-APIs using methotrexate (MTX), a potential anticancer prodrug, and biocompatible IL-forming cations (choline and amino acid esters). The MTX-IL moieties were characterized through 1H NMR, FTIR, p-XRD, DSC and thermogravimetric analysis. The solubility of the MTX-ILs was evaluated in simulated body fluids (phosphate-buffered saline, simulated gastric, and simulated intestinal fluids). An assessment of the in vitro antitumor activity of the MTX-ILs in a mammalian cell line (HeLa cells) was used to evaluate their cytotoxicity. The MTX-ILs showed aqueous solubility at least 5000 times higher than that of free MTX and two orders of magnitude higher compared with that of a sodium salt of MTX in both water and simulated body fluids. Importantly, a proline ethyl ester MTX prodrug showed similar solubility as the MTX sodium salt but it provided improved in vitro antitumor activity. These results clearly suggest that the newly synthesized API-ILs represent promising potential drug formulations.
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•A series of methotrexate ionic liquids (MTX-ILs) was synthesized as a potential anticancer prodrug.•The MTX-ILs showed aqueous solubility at least 5000 times higher than that of free MTX.•A proline ethyl ester MTX prodrug showed improved in vitro antitumor activity as compared with MTX sodium salt.•The newly synthesized API-ILs represent promising potential drug formulations.
An efficient gram-scale synthesis of the antituberculosis agent pretomanid using straightforward chemistry, mild reaction conditions, and readily available starting materials is reported. Four ...different protecting groups on the glycidol moiety were investigated for their technical feasibility and ability to suppress side reactions. Starting from readily available protected (R)-glycidols and 2-bromo-4-nitro-1H-imidazole, pretomanid could be prepared in a linear three-step synthesis in up to 40% isolated yield. In contrast to most syntheses reported so far, deprotection and cyclization were performed in a one-pot fashion without any hazardous steps or starting materials.
Solvents play key roles in designing drug delivery systems (DDSs). They are used as the reaction media in the preparation of DDSs and as vehicles for delivery of problematic drugs. The number of ...pharmaceutically acceptable solvents is limited and developing new green ones is of a great of interest. A deep eutectic solvent (DES) is a room temperature liquid composed of a mixture of hydrogen bond acceptor and hydrogen bond donor. DESs exhibit interesting physical and chemical characteristics such as low vapor pressure, non-inflammability, chemically tailorable, solvency power for a wide range of solutes, and water non-reactivity. Furthermore, they can be easily prepared from low toxicity, readily available, and inexpensive constituents. Due to these properties, DESs have attracted growing attention as green solvents in different areas of science from chemistry to material engineering and biology. In this review, after a brief introduction about DESs, we provide an overview about current advances made over the last decade in utilizing of DESs for solubilization of water insoluble drugs, transdermal drug delivery, inorganic nanoparticle synthesis, and designing polymeric and self-assembled drug carriers. This paper also discusses main challenges and limitations of DESs that should be considered before using of them.
Due to their unique properties, such as controlled drug release and improved bioavailability, polymeric microparticles and nanoparticles (MPs and NPs) have gained considerable interest in the ...pharmaceutical industry. Nevertheless, the high costs associated with biodegradable polymers and the active pharmaceutical ingredients (APIs) used for treating serious diseases, coupled with the vast number of API-polymer combinations, make the search for effective API-polymer MPs and NPs a costly and time-consuming process. In this work, the correlation between the compatibility of selected model APIs (i.e., ibuprofen, naproxen, paracetamol, and indomethacin) with poly(lactide-co-glycolide) (PLGA) derived from respective binary phase diagrams and characteristics of prepared MPs and NPs, such as the drug loading and solid-state properties, was investigated to probe the possibility of implementing the modeling of API-polymer thermodynamic and kinetic phase behavior as part of rational design of drug delivery systems based on MPs and NPs. API-PLGA-based MPs and NPs were formulated using an emulsion-solvent evaporation technique and were characterized for morphology, mean size, zeta potential, drug loading, and encapsulation efficiency. The solid-state properties of the encapsulated APIs were assessed using differential scanning calorimetry and X-ray powder diffraction. The evaluated compatibility was poor for all considered API-PLGA pairs, which is in alignment with the experimental results showing low drug loading in terms of amorphous API content. At the same time, drug loading of the studied APIs in terms of amorphous content was found to follow the same trend as their solubility in PLGA, indicating a clear correlation between API solubility in PLGA and achievable drug loading. These findings suggest that API-polymer phase behavior modeling and compatibility screening can be employed as an effective preformulation tool to estimate optimum initial API concentration for MP and NP preparation or, from a broader perspective, to tune or select polymeric carriers offering desired drug loading.
This manuscript provides the results of an in-depth survey assessment of the capabilities, experience, and perspectives on continuous processing in the pharmaceutical sector, with respondents from ...both pharmaceutical companies and Contract Manufacturing Organizations (CMOs). The survey includes staffing (personnel), chemistry, reaction platforms, postreaction processing, analytical, regulatory, and factors that influence the adoption of continuous manufacturing. The results of the survey demonstrate that the industry has been increasing, and will continue to increase, the portion of total manufacturing executed as continuous processes with a decrease in batch processing. In general, most of the experience with continuous processing on scale have been enabling reaction chemistry, while postprocessing and analytical remain in the very early stages of development and implementation.
Crystallization as one of the final steps in the industrial production of active pharmaceutical ingredients (APIs) significantly influences their physicochemical and rheological properties. Different ...crystallization procedures including antisolvent crystallization, seeding crystallization, crystallization with templates and sonocrystallization were utilized for the production of corticosteroid APIs—fluticasone propionate. The final crystalline APIs obtained by individual crystallization procedures were characterized by a wide range of characterization techniques. We show that nucleation is a critical step that significantly affects APIs' properties. Controlled nucleation thus represents an easy method for managing these properties. Well-designed nucleation yields to crystalline products, which does not necessitate any post-processing including, e.g., micronization. These findings can be widely applied to the production of API with targeted properties.
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•Different crystallization processes of fluticasone propionate were investigated.•Antisolvent, seeding, template and sono-crystallization were employed.•Physicochemical properties of the produced powders were analyzed.•Controlled nucleation represents an easy method for targeted influence of APIs' properties.
