Highly Soluble Dacarbazine Multicomponent Crystals Less Prone to Photodegradation.

Dacarbazine (DTIC) is a widely prescribed oncolytic agent to treat advanced malignant melanomas. Nevertheless, the drug is known for exhibiting low and pH-dependent solubility, in addition to being photosensitive. These features imply the formation of the inactive photodegradation product 2-azahypoxanthine (2-AZA) during pharmaceutical manufacturing and even drug administration. We have focused on developing novel DTIC salt/cocrystal forms with enhanced solubility and dissolution behaviors to overcome or minimize this undesirable biopharmaceutical profile. By cocrystallization techniques, two salts, two cocrystals, and one salt-cocrystal have been successfully prepared through reactions with aliphatic carboxylic acids. A detailed structural study of these new multicomponent crystals was conducted using X-ray diffraction (SCXRD, PXRD), spectroscopic (FT-IR and 1H NMR), and thermal (TG and DSC) analyses. Most DTIC crystal forms reported display substantial enhancements in solubility (up to 19-fold), with faster intrinsic dissolution rates (from 1.3 to 22-fold), contributing positively to reducing the photodegradation of DTIC in solution. These findings reinforce the potential of these new solid forms to enhance the limited DTIC biopharmaceutical profile.

Intravitreal acetazolamide implant for pseudophakic cystoid macular edema.

BACKGROUND: Pseudophakic cystoid macular edema (PCME) is the most common cause of visual acuity deterioration after uncomplicated cataract surgery. There is no consensus regarding how to manage recurrent or refractory cases. REPORT: A 54-year-old woman complained of decreased vision and central metamorphopsia in the right eye (OD) 3 months after uneventful cataract surgery. Visual acuity was 0.3 logMAR (20/40) OD and 0.1 logMAR (20/25) OS. Reduced macular brightness was seen OD on funduscopy associated with increased macular thickness on optical coherence tomography (OCT). Pseudophakic cystoid macular edema (PCME) was diagnosed, and treatment with oral acetazolamide was tried without success. The patient underwent a single intravitreal injection of an acetazolamide implant (260 µg) OD as off-label treatment. Four weeks following the injection, she reported complete resolution of her metamorphopsia and visual loss OD. Four months later, her visual acuity was 0.0 logMAR (20/20) in OD and 0.1 logMAR (20/25) in OS. The patient reported no discomfort after the injection procedure. Laboratory and ophthalmologic tests did not identify any adverse effects of the medication. CONCLUSION: We show that PCME refractory to conventional treatment improved after intravitreal acetazolamide implant injection. Further investigation is warranted to confirm these preliminary findings.

Thermal energy and tableting effects in benznidazole product: the impacts of industrial processing.

OBJECTIVE: The investigation of benznidazole (BZN), excipients, and tablets aims to evaluate their thermal energy and tableting effects. They aim to understand better the molecular and pharmaceutical processing techniques of the formulation. SIGNIFICANCE: The Product Quality Review, part of Good Manufacturing Practices, is essential to highlight trends and identify product and process improvements. METHODS: A set of technique approaches, infrared spectroscopy, X-ray diffraction, and thermal analysis with isoconversional kinetic study, were applied in the protocol. RESULTS: X-ray experiments suggest talc and α-lactose monohydrate dehydration and conversion of ß-lactose to stable α-lactose upon tableting. The signal crystallization at 167 °C in the DSC curve confirmed this observation. A calorimetric study showed a decrease in the thermal stability of BZN tablets. Therefore, the temperature is a critical process parameter. The specific heat capacity (Cp) of BZN, measured by DSC, was 10.04 J/g at 25 °C and 9.06 J/g at 160 °C. Thermal decomposition required 78 kJ mol-1. Compared with the tablet (about 200 kJ mol-1), the necessary energy is two-fold lower, as observed in the kinetic study by non-isothermal TG experiment at 5; 7.5; 10; and 15 °C min-1. CONCLUSIONS: These results indicate the necessity of considering the thermal energy and tableting effects of BZN manufacturing, which contributes significantly to the molecular mechanistic understanding of this drug delivery system.

Tocotrienols-enriched Self-nanoemulsifying Drug Delivery System Enhances the Antileukemic Activity of All-trans Retinoic Acid but not Electrocardiogram Alterations Evoked by Its Combination with Arsenic Trioxide.

All-trans retinoic acid and arsenic trioxide are the leading choices for the treatment of acute promyelocytic leukemia. Notwithstanding the impressive differentiative properties of all-trans retinoic acid and the apoptotic properties of arsenic trioxide, some problems still occur in acute promyelocytic leukemia treatment. These problems are due to patients' relapses, mainly related to changes in the ligand-binding domain of RARα (retinoic acid receptor α) and the cardiotoxic effects caused by arsenic trioxide. We previously developed a self-nanoemulsifying drug delivery system enriched with tocotrienols to deliver all-trans retinoic acid (SNEDDS-TRF-ATRA). Herein, we have evaluated if tocotrienols can help revert ATRA resistance in an APL cell line (NB4-R2 compared to sensitive NB4 cells) and mitigate the cardiotoxic effects of arsenic trioxide in a murine model. SNEDDS-TRF-ATRA enhanced all-trans retinoic acid cytotoxicity in NB4-R2 (resistant) cells but not in NB4 (sensitive) cells. Moreover, SNEDDS-TRF-ATRA did not significantly change the differentiative properties of all-trans retinoic acid in both NB4 and NB4-R2 cells. Combined administration of SNEDDS-TRF-ATRA and arsenic trioxide could revert QTc interval prolongation caused by ATO but evoked other electrocardiogram alterations in mice, such as T wave flattening. Therefore, SNEDDS-TRF-ATRA may enhance the antileukemic properties of all-trans retinoic acid but may influence ECG changes caused by arsenic trioxide administration. SNEDDS-TRF-ATRA presents cytotoxicity in resistant APL cells (NB4-R2). Combined administration of ATO and SNEDDS-TRF-ATRA in mice prevented the prolongation of the QTc interval caused by ATO but evoked ECG abnormalities such as T wave flattening.

Microextraction by packed sorbent and high-performance liquid chromatography for determination of benznidazole in human plasma.

Benznidazole is the main drug used in Chagas disease and its determination in plasma samples is useful in several situations. Hence, robust and accurate bioanalytical methods are needed. In this context, sample preparation deserves special attention, as it is the most error-prone, labor-intensive and time-consuming step. Microextraction by packed sorbent (MEPS) is a miniaturized technique, developed to minimize the use of hazardous solvents and sample amount. In this context, this study aimed to develop and validate a MEPS coupled to high performance liquid chromatography method for the analysis of benznidazole in human plasma. MEPS optimization was performed by a 24 full factorial experimental design, which resulted in about 25 % of recovery. The best condition was achieved when 500 µL of plasma,10 draw-eject cycles, sample volume drawn of 100 µL, and desorption with three times of 50 µL of acetonitrile were used. The chromatographic separation was performed with a C18 (150 × 4.5 mm, 5 µm) column. The mobile phase was composed of water:acetonitrile (60:40) at a flow rate of 1.0 mL min-1. The developed method was validated and proved to be selective, precise, accurate, robust and linear in the range from 0.5 to 6.0 µg mL-1. The method was applied to three healthy volunteers that made use of benznidazole tablets and showed to be adequate to assess this drug in plasma samples.

Thermoresponsive in-situ gel containing hyaluronic acid and indomethacin for the treatment of corneal chemical burn.

Ocular chemical burns are prevalent injuries that must have immediate and effective treatment to avoid complications. Aiming to improve bioavailability and efficacy, a poloxamer-based thermoresponsive in-situ gelling system containing hyaluronic acid and indomethacin was developed. Formulations with different polymeric proportions were screened through rheological measurements resulting in an optimized system (F2) with gelling temperature of 34.2 ± 0.11 °C. Its maximum viscosity varied from 77.33 mPa (25 °C) to 82.95 mPa (34 °C) following a non-Newtonian profile and a pH of 6.86 ± 0.01. No incompatibilities were found after infrared analysis. Polarized light microscopy and cryo-transmission electron microscopy have demonstrated micelles of nano-sized dimensions (21.86 nm) with indomethacin entrapped in the core, forming a polymeric network under heating. In vitro tests revealed a cumulative release of 59.75 ± 3.17 % up to 24 h under a sustained release profile. Results from HET-CAM assay indicated that F2 was well tolerated. Corneal wound healing was significantly faster in animals treated with F2 compared to a commercial formulation and an untreated group. These findings suggests that F2 could be an efficient system to delivery drugs into the ocular surface improving wound healing.

Boron nitride nanotubes for extraction of angiotensin receptor blockers from human plasma.

The limitations of silica-based sorbents boosted the development of new extraction phases. In this study, boron nitride nanotubes functionalized with octadecyl groups were used for the first time as sorbent for extraction of losartan and valsartan, the most used angiotensin receptor blockers in the clinical practice, from human plasma. The nanotubes were synthesized using the chemical vapor deposition technique, purified by acid treatment, functionalized with octadecylamine in a microwave reactor, and characterized by different techniques. The functionalized nanotubes were packed in solid phase extraction cartridges. Extraction conditions were optimized by means of a 23 factorial design with center points. The separation was performed on a biphenyl core-shell (100 × 4.6 mm; 2.6 µm) column, using 0.1 % (v/v) triethylamine solution and methanol (pH 3.2) as mobile phase, at 0.7 mL/min, in gradient elution. The injection volume was 10 µL and fluorescence detection was performed at excitation and emission wavelengths of 250 and 375 nm, respectively. The developed method was validated according to Brazilian Health Regulatory Agency (ANVISA), United States Food and Drug Administration (US FDA) and European Medicines Agency (EMA) guidelines and presented selectivity, precision, accuracy, and linearity in the concentration ranges of 50-1200 ng/mL for losartan and 20-1700 ng/mL for valsartan. Recoveries higher than 80 % were obtained. The method was fit for the quantification of losartan in plasma samples from patients under antihypertensive therapy, being useful in therapeutic drug monitoring, pharmacokinetics and bioequivalence studies.

Vortex-assisted liquid-liquid microextraction combined with liquid chromatography tandem mass spectrometry for simultaneous determination of cardiovascular drugs in human plasma.

Hypertension and dyslipidemias are among the main risk factors for the development of cardiovascular diseases, which are responsible for the death of approximately 17 million people each year. There are several drugs available for the treatment of these diseases. Therefore, methods for the simultaneous analysis of several of these drugs are useful in a wide range of situations. In this context, this study aimed to develop a modern method for the simultaneous determination of eight cardiovascular drugs in human plasma. A vortex-assisted liquid-liquid microextraction (VALLME) procedure, combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. Mass spectrometry conditions, chromatographic separation, and sample preparation were optimized. For VALLME optimization, pH, sodium chloride concentration, volume of buffer solution, extraction solvent (type and volume), and vortex stirring time were evaluated. The method proved to be simple, fast, and environmentally friendly since low volumes of organic solvent were employed. Furthermore, the VALLME procedure required small sample volume, which is desirable when large volumes are scarce. Suitable recoveries and lower limits of quantification were achieved with a chromatographic run of only 8 min. The method was validated, showing to be selective, precise, and accurate. Furthermore, the analytical curves were well fitted to the selected models and the matrix effect did not affect method reliability. The developed method was successfully applied for the analysis of plasma samples obtained from volunteers attending a hospital service.

Cholesterol improves stability of amphotericin B nanoemulsion: promising use in the treatment of cutaneous leishmaniasis.

Aim: Amphotericin B (AmB) is an antileishmanial drug with high toxicity; however, this drawback might overcome by decreasing the AmB self-aggregation state. This work aimed at evaluating the influence of cholesterol on the aggregation state of AmB loaded in a nanoemulsion (NE-AmB) for the treatment of cutaneous leishmaniasis. NE-AmB (1, 4 and 8 mg/kg/day) was administered intravenously to animals infected by Leishmania major every 2 days for a total of five injections. Results: Ultraviolet-visible spectroscopy and circular dichroism studies demonstrated that cholesterol reduced AmB aggregation state in NE. NE-AmB was stable after 180 days, and its hemolytic toxicity was lower than that observed for the conventional AmB. NE-AmB administered intravenously into animals infected by Leishmania major at 8 mg/kg was capable of stabilizing the lesion size and reducing the parasitic load. Conclusion: These findings support the NE potential as a stable nanocarrier for AmB in the treatment of cutaneous leishmaniasis.

Formulation of Amphotericin B in PEGylated Liposomes for Improved Treatment of Cutaneous Leishmaniasis by Parenteral and Oral Routes.

Liposomal amphotericin B (AmB) or AmBisome® is the most effective and safe therapeutic agent for visceral leishmaniasis (VL), but its clinical efficacy is limited in cutaneous leishmaniasis (CL) and HIV/VL co-infection. The aim of this work was to develop a formulation of AmB in PEGylated liposomes and compare its efficacy to AmBisome® in a murine model of CL. Formulations of AmB in conventional and PEGylated liposomes were characterized for particle size and morphology, drug encapsulation efficiency and aggregation state. Those were compared to AmBisome® in Leishmania amazonensis-infected BALB/c mice for their effects on the lesion size growth and parasite load. The conventional and PEGylated formulations showed vesicles with 100-130 nm diameter and low polydispersity, incorporating more than 95% of AmB under the non-aggregated form. Following parenteral administration in the murine model of CL, the PEGylated formulation of AmB significantly reduced the lesion size growth and parasite load, in comparison to control groups, in contrast to conventional liposomal AmB. The PEGylated formulation of AmB was also effective when given by oral route on a 2-day regimen. This work reports for the first time that PEGylated liposomal AmB can improve the treatment of experimental cutaneous leishmaniasis by both parenteral and oral routes.

Simultaneous quantification of ethylene glycol and diethylene glycol in beer by gas chromatography coupled to mass spectrometry.

An analytical method for the simultaneous determination of ethylene glycol and diethylene glycol in beer was developed and validated according to current legislation. This method includes the application of sample dilution with ethanol followed by quantification using gas chromatography coupled to mass spectrometry. All figures of merit were within the limits established by regulation. The recoveries of the analytes, expressed as mean recovery, were between 91.9% and 108.9%. Precision, in terms of repeatability and intermediate precision, was established (relative standard deviations were lower than or equal to 10%). The limits of detection (10.0 and 5.0 mg.L-1 for ethylene glycol and diethylene glycol, respectively) and quantification (15.0 mg.L-1 for ethylene glycol and diethylene glycol) obtained were appropriate. Finally, the present method was applied for determination of ethylene glycol and diethylene glycol in 701 beer samples (from 67 different brands and 128 different labels), proving to be reliable.

Chromatographic bioanalysis of antiglaucoma drugs in ocular tissues.

Glaucoma is a heterogeneous group of multifactorial optic neuropathies and the leading cause of irreversible blindness and visual impairment. Epidemiological data has estimated that in 2020 there will be more than 80 million individuals affected by the disease worldwide. Nowadays, intraocular pressure (IOP) lowering is carried out mainly by pharmacotherapy, with different drugs. The study of ocular pharmacokinetics of antiglaucoma drugs, crucial for better understanding of ocular distribution, bioavailability, and pharmacodynamic parameters, can benefit the development of antiglaucoma drugs or formulations. Bioanalysis of drugs in ocular matrices is still underestimated, since it is challenging and rarely performed. Therefore, this review summarized the chromatographic methods employed for the quantification of several antiglaucoma drugs in different ocular matrices, discussing bioanalytical steps, such as sample preparation, separation, and detection. Animals and matrices as well as the challenges faced in ocular bioanalysis were also discussed. Ocular bioanalysis has been performed mainly in rabbits, the most adequate animal model for ocular studies. The matrix most used is aqueous humor, because it is cleaner and easier to sample. Sample preparation was carried out primarily employing classic techniques, such as liquid-liquid extraction, protein precipitation, and solid-phase extraction, with conventional solvents and sorbents. Chromatographic separation was achieved predominantly by reversed-phase liquid chromatography. Ultraviolet spectrophotometry and tandem mass spectrometry prevailed for detection, although other techniques, such as fluorimetry, have also been used. It was evidenced that more efforts must be directed towards miniaturized, eco-friendly, and non-terminal sampling for sample preparation. In its turn, ultra high-performance liquid chromatography and mass spectrometry should gain prominence in ocular bioanalysis for separation and detection, respectively, since it combines high separation capacity with selectivity and sensitivity, in addition to being an environmental friendly approach.

Multicomponent ionic crystals of diltiazem with dicarboxylic acids toward understanding the structural aspects driving the drug-release.

Diltiazem (DIL) is a calcium channel blocker antihypertensive drug commonly used in the treatment of cardiovascular disorders. Due to the high solubility and prompt dissolution of the commercial form hydrochloride (DIL-HCl) that is closely related to short elimination drug half-life, this API is known for exhibiting an unfitted pharmacokinetic profile. In an attempt to understand how engineered multicomponent ionic crystals of DIL with dicarboxylic acids can minimize these undesirable biopharmaceutical attributes, herein, we have focused on the development of less soluble and slower dissolving salt/cocrystal forms. By the traditional solvent evaporation method, two hydrated salts of DIL with succinic and oxalic acids (DIL-SUC-H2O and DIL-OXA-H2O), and one salt-cocrystal with fumaric acid (DIL-FUM-H2FUM) were successfully prepared. An in-depth crystallographic description of these new solid forms was conducted through single and powder X-ray diffraction (SCXRD, PXRD), Hirshfeld surface (HS) analysis, energy framework (EF) calculations, Fourier Transform Infrared (FT-IR) spectroscopy, and thermal analysis (TG, DSC, and HSM). Structurally, the inclusion of dicarboxylic acids in the crystal structures provided the formation of 2D-sheet assemblies, where ionic pairs (DIL+/anion-) are associated with each other via H-bonding. Consequently, a substantial lowering in both solubility (16.5-fold) and intrinsic dissolution rate (13.7-fold) of the API has been achieved compared to that of the hydrochloride salt. These findings demonstrate the enormous potential of these solid forms in preparing of novel modified-release pharmaceutical formulations of DIL.

pH-sensitive doxorubicin-tocopherol succinate prodrug encapsulated in docosahexaenoic acid-based nanostructured lipid carriers: An effective strategy to improve pharmacokinetics and reduce toxic effects.

Side effects often limit the use of doxorubicin (DOX) in cancer treatment. We have recently developed a nanostructured lipid carrier (NLC) formulation for synergistic chemotherapy, encapsulating DOX and the anticancer adjuvants docosahexaenoic acid (DHA) and α-tocopherol succinate (TS). Hydrophobic ion-pairing with TS allowed a high DOX entrapment in the nanocarrier. In this work, we investigated the pharmacokinetics of this formulation after intravenous administration in mice. The first data obtained led us to propose synthesizing covalent DOX-TS conjugates to increase DOX retention in the NLC. We successfully conjugated DOX to TS via an amide or hydrazone bond. In vitro studies in 4T1 tumor cells indicated low cytotoxicity of the amide derivative, while the hydrazone conjugate was effective in killing cancer cells. We encapsulated the hydrazone derivative in a DHA-based nanocarrier (DOX-hyd-TS/NLC), which had reduced particle size and high drug encapsulation efficiency. The pH-sensitive hydrazone bond allowed controlled DOX release from the NLC, with increased drug release at acidic conditions. In vivo studies revealed that DOX-hyd-TS/NLC had a better pharmacokinetic profile than free DOX and attenuated the short-term cardiotoxic effects caused by DOX, such as QT prolongation and impaired left ventricular systolic function. Moreover, this formulation showed excellent therapeutic performance by reducing tumor growth in 4T1 tumor-bearing mice and decreasing DOX-induced toxicity to the heart and liver, demonstrated by hematologic, biochemical, and histologic analyses. These results indicate that DOX-hyd-TS/NLC may be a promising nanocarrier for breast cancer treatment.

UHPLC for quality evaluation of genuine and illegal medicines containing sildenafil citrate and tadalafil.

One of the highest incidences of illegal drug products is related to phosphodiesterase-5 inhibitors, used in treatment of erectile dysfunction, including those containing sildenafil citrate and tadalafil. In this context, comprehensive evaluation of the quality of genuine and illegal medicines was performed. A simple and rapid ultra-high performance liquid chromatography (UHPLC-UV) method to quantify sildenafil and tadalafil in the presence of six degradation products was developed and validated. Sildenafil and tadalafil were submitted to forced degradation. The separation was carried out on a Kinetex C18 (50 × 2.1 mm; 1.7 µm) column with mobile phase composed of acetonitrile and aqueous triethylamine solution. The calibration curves were linear in the range of 14-126 µg mL-1 for sildenafil citrate and 4-36 µg mL-1 for tadalafil and the method proved to be selective, precise, accurate and robust. Sildenafil degraded in oxidative media, whereas tadalafil degraded in acidic, alkaline and oxidative environment. The chemical structures and the mechanisms for the formation of the main degradation products were proposed by UHPLC coupled to tandem mass spectrometry. The UHPLC-UV method was applied in the pharmaceutical analysis of genuine and seized medicines. Some of them did not meet quality standards, mainly due to contents below specifications and the large variation on contents between units within a batch.

Microextraction by packed sorbent and high performance liquid chromatography for simultaneous determination of lumefantrine and desbutyl-lumefantrine in plasma samples.

A bioanalytical method for the determination of lumefantrine and its metabolite desbutyl-lumefantrine in plasma samples using microextraction by packed sorbent (MEPS) and high-performance liquid chromatography was developed and validated. A complete factorial planning and surface response approach were employed to optimize the extraction parameters sample volume, dilution, aspirated sample volume and extraction cycles. The method employed C18 MEPS sorbent and diazepam as internal standard (IS). Separation was performed on a Luna C18 column (250 mm × 4.6 mm, 5 µm) at 35 °C, with mobile phase composed of acetonitrile and 0.05 % trifluoroacetic acid (68:32, v/v), detection at 305 nm and injection volume of 25 µL. The developed method showed to be selective, precise, accurate and linear in the range of 50-5000 ng/mL for lumefantrine and desbutyl-lumefantrine. Using the optimized MEPS procedure, high recovery rates were obtained for both analytes and IS (92.2 %-99.0 %). The method was successfully applied for the determination of lumefantrine and its metabolite in human plasma samples after oral administration of lumefantrine tablets in healthy volunteers.

A simple and sensitive HPLC-FL method for simultaneous determination of angiotensin II receptor antagonists in human plasma.

Angiotensin II receptor antagonists are one of the most widely used classes of antihypertensive drugs. In this study, an HPLC fluorescence method after protein precipitation (PPT) extraction was developed and validated for determination of olmesartan, losartan, irbesartan, and valsartan in human plasma. The separation was carried out on a Luna cyano (250 × 4.6 mm i.d.; 5 µm particle size) column and the mobile phase was composed of acetonitrile and 0.1 % phosphoric acid in gradient elution, at a flow rate of 1.2 mL min-1. A PPT method was optimized by a two-level factorial design with triplicate at the central point. The parameters that could affect the extraction (sample volume and acetonitrile/plasma volume ratio) were evaluated and the method was compared to microextraction by packed sorbent (MEPS) and liquid-liquid extraction (LLE). The developed method allowed the simultaneous quantification of the analytes employing a simple and cheap sample preparation method and a short chromatographic run (13 min). This method was fully validated showing selectivity, precision, accuracy, and linearity over the range of 25.0-1500.0 ng mL-1 for olmesartan and valsartan, 25.0-2500.0 ng mL-1 for irbesartan, and 35.0-2500.0 ng mL-1 for losartan. Finally, the method was successfully applied in the analysis of human plasma from volunteers.

Synthesis and characterization of a molecularly imprinted polymer (MIP) for solid-phase extraction of the antidiabetic gliclazide from human plasma.

Gliclazide is a sulfonylurea frequently prescribed for the management of type 2 diabetes mellitus in elderly patients and for patients with chronic renal or hepatic diseases. Even though it is considered a safer alternative, the drug can provoke side effects in some patients, especially hypoglycemia, due to the high interindividual variability. Therefore, the quantification of gliclazide in biological samples is usually recommended in order to assure efficacy and safety of the pharmacotherapy. However, due to the complexity of biological matrices, therapeutic monitoring can be very challenging, especially in the sample preparation step. For that reason, the synthesis and characterization of a novel and selective molecularly imprinted polymer (MIP) was proposed to be employed as sorbent for the extraction of gliclazide from human plasma samples by a molecularly imprinted solid-phase extraction (MISPE) procedure. Synthesis conditions were optimized (monomer, crosslinker and porogen) and the polymer was characterized for its morphological, physicochemical and stability properties. The influence of drug concentration, solvent composition and pH on the coefficient of distribution (Kd) and imprinting factor (IF) were studied, as well as repeatability between batches and selectivity. A bioanalytical method was developed applying the developed MIP as sorbent in solid phase extraction and liquid chromatography using a Poroshell 120 C18 (100 × 4.6 mm, 4 µm) column, acetonitrile and 10 mM potassium phosphate buffer pH 3.0 (50:50) at a flow-rate of 1.2 mL/min as mobile phase, temperature of 30 °C, injection volume of 40 µL and detection at 230 nm. The best reaction yield, extraction capacity, and selectivity was obtained using 2-hydroxyethyl methacrylate (2-HEMA), ethyleneglycol dimethacrylate (EGDMA) and acetonitrile. The optimized MIP showed coefficient of distribution (Kd) of 59.85 µg/g, imprinting factor (IF) of 1.60, and selectivity for gliclazide and other sulfonylureas compared to possible concurrent drugs. The developed method by MISPE-HPLC-UV showed to be appropriate to determine gliclazide in human plasma samples.

Enhancing the solubility and permeability of the diuretic drug furosemide via multicomponent crystal forms.

Furosemide (FSM) is a biopharmaceutical classification system (BCS) class IV drug, being a potent loop diuretic used in the treatment of congestive heart failure and edema. Due to its low solubility and permeability, FSM is known for exhibiting poor oral bioavailability. In order to overcome or even minimize these undesirable biopharmaceutical attributes, in this work we have focused on the development of more soluble and permeable multicomponent solid forms of FSM. Using solvent evaporation as crystallization method, a salt and a cocrystal of FSM with imidazole (IMI) and 5-fluorocytosine (5FC) coformers, named FSM-IMI and FSM-5FC, respectively, were successfully prepared. A detailed structural study of these new solid forms was conducted using single and powder X-ray diffraction (SCXRD, PXRD), Fourier Transform Infrared (FT-IR) and proton Nuclear Magnetic Resonance (1H NMR) spectroscopy and thermal analysis (thermogravimetry, differential scanning calorimetry and hot-stage microscopy). Both FSM-IMI and FSM-5FC showed substantial enhancements in the solubility (up 118-fold), intrinsic dissolution (from 1.3 to 2.6-fold) and permeability (from 2.1 to 2.8-fold), when compared to the pure FSM. These results demonstrate the potential of these new solid forms to increase the limited bioavailability of FSM.

Novel self-nanoemulsifying drug-delivery system enhances antileukemic properties of all-trans retinoic acid.

Aim: All-trans retinoic acid (ATRA) shows erratic oral bioavailability when administered orally against leukemia, which can be solved through its incorporation in self-nanoemulsifying drug-delivery systems (SEDDS). The SEDDS developed contained a hydrophobic ion pair between benzathine (BZT) and ATRA and was enriched with tocotrienols by the input of a palm oil tocotrienol rich fraction (TRF) in its composition. Results: SEDDS-TRF-ATRA-BZT allowed the formation of emulsions with nanometric size that retained ATRA within their core after dispersion. Pharmacokinetic parameters after oral administration of SEDDS-TRF-ATRA-BZT in mice were improved compared with what was seen for an ATRA solution. Moreover, SEDDS-TRF-ATRA-BZT had improved activity against HL-60 cells compared with SEDDS without TRF. Conclusion: SEDDS-TRF-ATRA-BZT is a promising therapeutic choice over ATRA conventional medicine.