Search

Multifunctional materials, such as restricted access molecularly imprinted polymers covered with bovine serum albumin (RAMIP-BSA), are effective alternatives for sample preparation techniques. This material selectively adsorbs analytes while excluding macromolecules, enhancing the analysis's efficiency. Among analytical techniques, ESI-MS/MS (Electrospray Ionization-Tandem Mass Spectrometry) has successfully identified and quantified various molecules, including trace-level drugs. Therefore, we proposed, for the first time, an integrated online extraction/analysis system that combines the benefits of RAMIP-BSA and ESI-MS/MS for analyzing mebendazole (MBZ) and albendazole (ABZ) in milk samples without the need for chromatographic separation. Initially, a RAMIP selective for MBZ was synthesized using the bulk method with methacrylic acid and glycidyl methacrylate. Then, the polymer was covered with bovine serum albumin. Subsequently, this adsorbent was packed in a small column and coupled with an ESI-MS/MS instrument in an online configuration. Milli-Q water was used as the loading and reconditioning mobile phases, and a solution of formic acid in methanol (1:100 v/v) was employed as the elution phase. The system enabled simultaneous extraction and determination of MBZ and ABZ in milk samples. The method exhibited linearity between 15.0 and 125.0 μg L -1 for MBZ and 10.0 and 125.0 μg L -1 for ABZ (with a correlation coefficient exceeding 0.99). The limits of quantification were 15.0 and 10.0 μg L -1 for MBZ and ABZ, respectively. Good precision and accuracy were achieved. The developed method was used to analyze MBZ and ABZ in real milk samples and proved to be a viable alternative to conventional sample preparation and chromatographic techniques., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Amanda Aparecida Marques Louredo reports financial support was provided by Coordination of Higher Education Personnel Improvement. Mariane Goncalves Santos reports financial support was provided by Minas Gerais State Foundation of Support to the Research. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ciprofibrate (CIP) is an active pharmaceutical ingredient (API) classified as class II on the basis of biopharmaceutical classification system (BCS), what indicates that it has low solubility in aqueous solvents. The use of API salts has attracted attention due to their improvements in solubility, tolerability, higher rate and extent of absorption, and faster onset of the therapeutic effect. In this work, a new crystalline CIP monohydrated calcium salt (Ca(CIP) 2 .H 2 O) was successfully obtained and its crystal structure determined by single crystal X-ray diffraction analysis (SCXRD). Additionally, Ca(CIP) 2 .H 2 O was widely characterized by powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and submitted to solubility, intrinsic dissolution and accelerated stability studies. Ca(CIP) 2 .H 2 O exhibited higher solubility and dissolution rate than CIP-free form and was stable up to 6 months at 40 °C (75 %RH). Therefore, Ca(CIP) 2 .H 2 O may be a viable alternative for use in solid dosage forms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

The presence of impurities in active pharmaceutical ingredients (APIs) and drug products represents a risk to patients' health. Such substances are related to diverse side effects and may have mutagenic potential. That's why it is necessary to establish acceptable limits for these by-products, to minimize the risk associated with medicinal therapy. This work focused on presenting a critical review of relevant points related to the presence of impurities in pharmaceuticals. The main legislation and guidelines from the FDA, EMA, ICH, and Pharmacopeias about the subject were evaluated, and recent articles related to the topic were searched in Scopus, ScienceDirect, PubMed, and Web of Science from 2013 to 2023. Additionally, the analytical techniques used for quantifying impurities were discussed, along with relevant tests for assessing the toxicological and mutagenic risks of these by-products. Recent legislation, including ICH Q3A (R2), ICH Q3B (R2), ICH M7 (R2), ICH Q3D (R2), ICH Q3C (R9), ICH Q3E, ICH Q6A, ICH M3 (R2), as well as FDA and EMA guidelines, highlights a comprehensive and effective framework for controlling impurities in pharmaceuticals. Despite this, there remains a lack of harmonization and standardized procedures across different regions. From the review of scientific literature, we observed that advancements in analytical techniques have significantly improved the sensitivity and selectivity in detecting impurities and degradation products. This underscores the ongoing commitment of health agencies and the pharmaceutical industry to ensure the safety and efficacy of medicinal products.

Historically, the piperazine moiety has been demonstrated to possess pharmacophoric properties, and has subsequently been incorporated in many drugs that have antitumor, antimalarial, antiviral, antibacterial and antifungal properties. Derivatives of eugenol and dihydroeugenol have also been reported as being bioactive compounds. This study reports the synthesis of a range of eugenol/dihydroeugenol - piperazine derivatives which have been tested as antimicrobial compounds against Gram positive, Gram negative and rapid-growing mycobacteria (RGM). The rationale employed in the design of the structural pattern of these new derivatives, provides useful insights into the structure-activity relationships (SAR) of the series. Antimicrobial activity tests were extremely encouraging, with the majority of the synthesised compounds being more active than eugenol and dihydroeugenol starting materials. The antimicrobial potential was most notable against the Gram-negative species K. pneumoniae and P. aeruginosa, but there was also significant performance against the Gram-positive strains S. epidermidis and S. aureus and the Rapidly Growing Mycobacteria (RGM) strains tested. Tests using the synthesised compounds against multidrug-resistance clinical (MDR) isolates also showed high activity. The biofilm inhibition tests using M. fortuitum showed that all evaluated derivatives were able to inhibit biofilm formation even at low concentrations. In terms of structural-activity relationships; the results generated by this study demonstrate that the compounds with bulky substituents on the piperazine subunit were much more active than those with less bulky groups, or no groups. Importantly, the derivatives with a sulfonamide side chain were the most potent compounds. A further observation was that those compounds with a para-substituted benzenesulfonamide ring stand out, regardless of whether this substituent is a donor or an electron-withdrawing group., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Ketoprofen (KTP) is an Active Pharmaceutical Ingredient (API) that has low solubility in aqueous solvents. The use of KTP salts has attracted attention due to its improvements in terms of solubility, tolerability, higher rate and extent of absorption, and faster onset of the therapeutic effect. In this work, a crystalline KTP sodium salt (coded as KTP-Na) was successfully obtained and widely characterized by X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), solubility and accelerated stability studies. XRD results showed that KTP-Na is not yet reported in the literature. Moreover, FTIR, DSC and TGA were useful for differentiation of KTP-Na from the KTP commercialized form (coded as KTP-R1). The solubility of KTP-Na in water was about 80 times greater than the KTP-R1. However, KTP-Na showed lower physical stability in storage conditions at 40 ± 2°C/ 75% ± 5% RH when compared to KTP-R1, which was shown to be related to a high hygroscopicity of KTP-Na. Therefore, due to its higher solubility, KTP-Na may be a viable alternative for use in solid dosage forms. However, the presence of moisture must be strictly controlled to avoid water absorption and consequent amorphization., Competing Interests: Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Since each solid form of an active pharmaceutical ingredient (API) can exhibit particular physicochemical properties, the objectives of this work were to characterize and study the solubility/stability properties of allopurinol hydrochloride salt (ALO-HCl) for the first time. ALO-HCl was obtained through an unreported recrystallization process and studied by X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). All characterization techniques were effective for the differentiation of ALO-HCl from the preferred pharmaceutical form (ALO). DSC and TGA studies showed a solid-state conversion from ALO-HCl to ALO upon HCl loss. Solubility and dissolution tests showed that ALO-HCl converts to ALO in aqueous media. Moreover, the effect of the common ion decreased the amount of drug released from ALO-HCl during the intrinsic dissolution assay in HCl medium. The stability studies showed a partial conversion from ALO-HCl to ALO after 6 months of storage. The results indicate that comparative studies between crystalline forms of APIs are of great importance, as they contribute to the understanding of aspects related to the quality of medicines.

Corticosteroids are a class of hormones released by the adrenal cortex, which includes glucocorticoids and mineralocorticoids. Glucocorticoids have an important role in the metabolism of carbohydrates, proteins and calcium and effective anti-inflammatory and immunosuppressive activity. Due to their intense immunomodulatory and anti-inflammatory activity, glucocorticoids are used in the treatment of various inflammatory, malignant, allergic conditions such as rhinitis, asthma, dermatological, rheumatic, ophthalmic and neurological diseases, as well as after organ transplants. They are the most widely prescribed drugs in the world. The objective of this review is to provide an overview of the analytical methods in pharmaceutical matrices for determination of corticosteroids. In this study, the predominance of liquid chromatography methods for the analysis of corticosteroids from pharmaceutical products is evident for both liquid and semisolid dosage forms as well as for solids. The same can be said for topical, oral and parenteral formulations. Methods such as spectrophotometry are also used, but given the advantages of chromatographic methods such as better selectivity and sensitivity, they have become the choice for analysis of these drugs, however, most methods still do not meet the credentials of "green chemistry."

Spironolactone (SPR) is a poorly water-soluble drug widely used for the treatment of various diseases. The objective of this study was to carry out the preparation and solid-state characterization of SPR 1/3 hydrate. The solid form was generated by an unreported recrystallization process in acetone and characterized for the first time by a combination of X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FTIR), equilibrium solubility, and an accelerated stability study. XRD, DSC, and TGA studies revealed that SPR 1/3 hydrated converts completely to form II after heating to 180°C. Solubility studies at 37°C showed that SPR 1/3 hydrate was statistically less soluble than SPR form II in all tested media and that SPR form II partially converts to SPR 1/3 hydrate in aqueous media. Accelerated stability studies demonstrated that both forms were physically and chemically stable up to 6 months (40°C/75% RH). We concluded that contamination of SPR 1/3 hydrate in SPR raw materials is undesirable. Taking this into account we recommend its polymorphic monitoring either in active pharmaceutical ingredients or commercial tablets by solid-state identification/quantification methods (XRD, DSC, TGA, and FTIR). Of these, XRD proved to be the most conclusive and accurate., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

This work aims to evaluate the effect of polymorphism on the physicochemical properties of meloxicam, which is an antipyretic and non-steroidal anti-inflammatory drug. Powder X-ray Diffraction, Infrared Spectroscopy with attenuated total reflectance, Thermogravimetric and Differential Scanning Calorimetry techniques were used for the polymorphic characterization. Comparative tests of solubility, intrinsic dissolution and dissolution profiles were performed on meloxicam active pharmaceutical ingredients (APIs) and formulated tablets. A polymorphic contamination (Forms I and III) was found in a studied meloxicam batch, which showed a higher solubility and greater intrinsic dissolution than those containing only the preconized form (Form I). Consequently, the dissolution profiles of the tablets that contained the polymorphic contamination showed higher drug release. Additionally, a thermal behavior study shows that MLX Form I and III are monotropy polymorphs being MLX Form III a metastable phase, which becomes MLX Form I at approximately 200°C in solid state phase transition governed by kinetic variables. The kinetic of conversion of Form III to Form I in saturated solutions was also studied. These results illustrate the importance of the polymorphic characterization of meloxicam APIs and formulated tablets in order to avoid potential quality and efficacy problems of drug products., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Bufadienolides are the main active compounds in the Bufonidae family of frogs. Recent studies have demonstrated cytotoxic and/or antitumor activity in these molecules. A HPLC-DAD method was developed and validated to quantify three bufadienolides (telocinobufagin, marinobufagin and bufalin) in ethyl acetate extracts of the cane toad poison frogs and smooth-sided toad. The chromatographic analysis was performed on Phenomenex Luna C18 (250.0 × 4.6 mm, 5 μm), using gradient elution with acetonitrile and water, at a flow rate of 1.0 mL min(-1) and detection at 296 nm. The method showed linearity (r > 0.999) and adequate recovery values (86%-111%). The limits of quantification of bufadienolides were 7.4 μg mL(-1) for telocinobufagin, 4.2 μg mL(-1) for marinobufagin and 4.0 μg mL(-1) for bufalin. Intraday and interday values of the method were evaluated and presented standard deviation values lower than 5%. The method was successfully applied to quantify the bufadienolides in the venom extract of the cane toad, which showed a content of 60% of marinobufagin. The same method was not selective for the venom extract of the Rhaebo guttatus, despite being linear, accurate and precise, requiring the development of a technique that presents a greater selectivity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Chlortalidone (CTD) is a diuretic drug largely used as part of antihypertensive therapies. It is marketed as an equimolar mixture of its enantiomers in the racemic crystal phase named Form I, despite of the higher aqueous solubility of another crystal form. The latter, named Form II, was thought to contain both enantiomers as a racemic conglomerate, i.e., in the form of a mixture of crystals, half of which consists solely of the (R)-enantiomer, the other half the (S)-enantiomer. The occurrence of both enantiomers in individual crystals of CTD Form II was demonstrated in this study. Spontaneous resolution does really occur upon crystallization, as presumed previously even without physical evidence of the (S)-enantiomer. Both (R) and (S)-enantiomers were successfully identified as two domains of a twinned by inversion single crystal of CTD Form II. A reliable Flack parameter of 0.14(4) allowed to determine the proportion of the enantiomers in the crystal, which is formed with 86% of the (R)-enantiomer and 14% of the (S)-enantiomer., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Chlorthalidone (CTD) is an antihypertensive drug and exhibits four crystalline forms: I, II, III and IV. In this paper, the incidence of CTD polymorphs in raw materials and in tablets as well as the solubility and dissolution properties of forms I and II have been studied. Raw materials were named as A, B, C, D, and E and tablets as Reference, G1, G2 and S. Using powder X-ray diffraction and infrared spectroscopy analyses we found that A, B, E, Reference and G1 contain CTD form I; C, D and S contain predominantly form II; and G2 contain a mixture of both forms. Solubility experiments showed that form II is up to 49% more soluble than form I and dissolution studies showed a significantly effect of the polymorphism on the dissolution of CTD from tablets. Based on these results, it was concluded that only the CTD form I is acceptable for preparation of tablet form. Moreover, we proposed the polymorphic quality control of CTD raw materials and tablets., (Copyright © 2013 Elsevier B.V. All rights reserved.)

This paper describes the multivariate development of a stability-indicating HPLC method for the quantification of glimepiride in pharmaceutical tablets. Full factorial design, Doehlert design, and response-surface methodology were used in conjunction with the desirability function approach. This procedure allowed the adequate separation of glimepiride from all degradant peaks in a short analysis time (about 9 min). This HPLC method uses potassium phosphate buffer (pH 6.5; 27.5 mmol/L)-methanol (34 + 66, v/v) mobile phase at a flow rate of 1.0 mL/min and UV detection at 228 nm. A Waters Symmetry C18 column (250 x 4.6 mm, 5.0 pm) at controlled room temperature (25 degrees C) was used as the stationary phase. The method was validated according to International Conference on Harmonization guidelines and demonstrated linearity from 2 to 40 mg/L glimepiride, selectivity, precision, accuracy, and robustness. The LOD and LOQ were 0.315 and 1.050 mg/L, respectively. The multivariate strategy adopted in this work can be successfully applied in routine laboratories because of its fast optimization without the additional cost of columns or equipment.

To optimize solubility of drugs, current strategies mainly focus on engineering and screening of smart crystal phases. Two salts of the anti-human immunodeficiency virus (HIV) drug lamivudine--namely, lamivudine hydrochloride and lamivudine hydrochloride monohydrate, were prepared in the course of screening the crystallization conditions of lamivudine duplex, an uncommon DNA-mimic, double-stranded helical structure made up of partially protonated drug pairs. Here, water solubilities of lamivudine hydrochloride, lamivudine hydrochloride monohydrate, and lamivudine duplex are reported. The aqueous solubility of this anti-HIV drug was significantly increased in both salts and also in lamivudine duplex in relation to the water solubility of lamivudine form II. In comparison with the lamivudine form II incorporated into therapeutic formulations, the drug solubility was increased at a temperature of 299 ± 2 K by factors of 1.2, 3.3, and 4.5 in lamivudine hydrochloride, lamivudine hydrochloride monohydrate, and lamivudine duplex, respectively, demonstrating that this solid-state property of lamivudine can be improved by crystal engineering strategies. Solubility profiles were understood on the basis of structural and solvent-solute interaction approaches. At last, correlations between solubility and crystal structures allowed for a rational approach to understand how this physicochemical feature could be enhanced by engineering new salts of the drug., (Copyright © 2012 Wiley Periodicals, Inc.)

Glimepiride, an oral antidiabetic drug, is practically insoluble in water and exists in two polymorphic forms, I and II, of which form II has higher solubility in water. Because the dissolution rate of drugs can depend on the crystal form, there is a need to develop discriminating dissolution methods that are sensitive to changes in polymorphic forms. In this work, a dissolution method for the assessment of 4 mg glimepiride tablets was developed and validated. The optimal dissolution conditions were 1000 mL of phosphate buffer (pH 6.8) containing 0.1% (w/v) of sodium dodecyl sulfate as the dissolution medium and a stirring speed of 50 rpm using a paddle apparatus. The results demonstrated that all the data meet the validation acceptance criteria. Subsequently, tablets containing forms I and II of glimepiride were prepared and subjected to dissolution testing. A significant influence of polymorphism on the dissolution properties of glimepiride tablets was observed. These results suggested that the raw material used to produce glimepiride tablets must be strictly controlled because they may produce undesirable and unpredictable effects., (Copyright © 2011 Wiley Periodicals, Inc.)

Glimepiride is an oral antidiabetic drug in the sulfonylurea class, which is widely used in treatment of Type 2 diabetes and it is currently available in more than 60 countries worldwide. As a result of the importance of this oral hypoglycemic agent in the treatment of noninsulin-dependent diabetes mellitus, this work aims to compile the published analytical methods reported so far in the literature for determination of glimepiride in biologic samples and pharmaceutical formulations. Techniques like high-performance liquid chromatography with ultraviolet, array-diode, mass spectroscopy, evaporative light scattering and charged aerosol detections, liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry, liquid chromatography-electrospray ionization-tandem mass spectrometry, semimicrobore high-performance liquid chromatography with column-switching, micellar electrokinetic chromatography, high-performance thin layer chromatography, polarography, and spectrophotometry have been used for analysis, from which it can be seen that high-performance liquid chromatography methods have been used most extensively.

This paper describes the optimization and validation of an analytical methodology for the determination of losartan potassium in capsules by HPLC using 2(5-1) fractional factorial and Doehlert designs. This multivariate approach allows a considerable improvement in chromatographic performance using fewer experiments, without additional cost for columns or other equipment. The HPLC method utilized potassium phosphate buffer (pH 6.2; 58 mmol L(-1))-acetonitrile (65:35, v/v) as the mobile phase, pumped at a flow rate of 1.0 mL min(-1). An octylsilane column (100 mm x 4.6mm i.d., 5 microm) maintained at 35 degrees C was used as the stationary phase. UV detection was performed at 254 nm. The method was validated according to the ICH guidelines, showing accuracy, precision (intra-day relative standard deviation (R.S.D.) and inter-day R.S.D values <2.0%), selectivity, robustness and linearity (r=0.9998) over a concentration range from 30 to 70 mg L(-1) of losartan potassium. The limits of detection and quantification were 0.114 and 0.420 mg L(-1), respectively. The validated method may be used to quantify losartan potassium in capsules and to determine the stability of this drug.