In this study a sensitive and selective gradient reverse phase UPLC-MS/MS method was developed for the simultaneous determination of six process related impurities viz., Imp-I, Imp-II, Imp-III, Imp-IV, Imp-V and Imp-VI in darunavir. The chromatographic separation was performed on Acquity UPLC BEH C18 (50 mm×2.1mm, 1.7μm) column using gradient elution of acetonitrile-methanol (80:20, v/v) and 5.0mM ammonium acetate containing 0.01% formic acid at a flow rate of 0.4mL/min. Both negative and positive electrospray ionization (ESI) modes were operated simultaneously using multiple reaction monitoring (MRM) for the quantification of all six impurities in darunavir. The developed method was fully validated following ICH guidelines with respect to specificity, linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy, precision, robustness and sample solution stability. The method was able to quantitate Imp-I, Imp-IV, Imp-V at 0.3ppm and Imp-II, Imp-III, and Imp-VI at 0.2ppm with respect to 5.0mg/mL of darunavir. The calibration curves showed good linearity over the concentration range of LOQ to 250% for all six impurities. The correlation coefficient obtained was >0.9989 in all the cases. The accuracy of the method lies between 89.90% and 104.60% for all six impurities. Finally, the method has been successfully applied for three formulation batches of darunavir to determine the above mentioned impurities, however no impurity was found beyond the LOQ. This method is a good quality control tool for the trace level quantification of six process related impurities in darunavir during its synthesis.
Ethosomal systems are novel lipid vesicular carriers containing a relatively high percentage of ethanol. These nanocarriers are especially designed for the efficient delivery of therapeutic agents with different physicochemical properties into deep skin layers and across the skin. Ethosomes have undergone extensive research since they were invented in 1996; new compounds were added to their initial formula, which led to the production of new types of ethosomal systems. Different preparation techniques are used in the preparation of these novel carriers. For ease of application and stability, ethosomal dispersions are incorporated into gels, patches, and creams. Highly diverse in vivo models are used to evaluate their efficacy in dermal/transdermal delivery, in addition to clinical trials. This article provides a detailed review of the ethosomal systems and categorizes them on the basis of their constituents to classical ethosomes, binary ethosomes, and transethosomes. The differences among these systems are discussed from several perspectives, including the formulation, size, ζ-potential (zeta potential), entrapment efficiency, skin-permeation properties, and stability. This paper gives a detailed review on the effects of ethosomal system constituents, preparation methods, and their significant roles in determining the final properties of these nanocarriers. Furthermore, the novel pharmaceutical dosage forms of ethosomal gels, patches, and creams are highlighted. The article also provides detailed information regarding the in vivo studies and clinical trials conducted for the evaluation of these vesicular systems.
The field of pharmaceutical technology is expanding rapidly because of the increasing number of drug delivery options. Successful drug delivery is influenced by multiple factors, one of which is the appropriate identification of materials for research and engineering of new drug delivery systems. Bacterial cellulose (BC) is one such biopolymer that fulfils the criteria for consideration as a drug delivery material.
Diabetes mellitus is a chronic disease accompanied by a multitude of problems worldwide with subcutaneously administered insulin being the most common therapy currently. Controlledrelease insulin is assumed to be of high importance for long-term glycaemic control by reducing the number of daily injections. Long-acting insulin also mimics the basal insulin levels in normal individuals that may be lacking in diabetic patients. Nanoparticles of carbonate apatite as established for efficient intracellular transport of DNA and siRNA have the potential to be used for sustained release of insulin as responsive nano-carriers. The flexibility in the synthesis of the particles over a wide range of pHs with eventual adjustment of pH-dependent particle dissolution and the manageable variability of particle-integrity by incorporating selective ions into the apatite structure are the promising features that could help in the development of sustained release formulations for insulin. In particular strontium-incorporated carbonate apatite particles were formulated and compared with those of unsubstituted apatite in the context of insulin binding and subsequent release kinetics in DMEM, simulated buffer and finally human blood over a period of 20 hours. Clearly, the former demonstated to have a stronger electrostatic affinity towards the acidic insulin molecules and facilitate to some extent sustained release of insulin by preventing the initial burst effect at physiological pH in comparison with the latter. Thus, our findings suggest that optimization of the carbonate apatite particle composition and structure would serve to design an ideal insulin nano-carrier with a controlled release profile.
New coumarin derivatives, namely 7-[(5-amino-1,3,4-thiadiazol-2-yl)methoxy]-2H-chromen-2-one, 5-[(2-oxo-2H-chromen-7-yloxy)methyl]-1,3,4-thiadiazol-2(3H)-one, 2-[2-(2-oxo-2H-chromen-7-yloxy)acetyl]-N-phenylhydrazinecarbothioamide, 7-[(5-(phenylamino)-1,3,4-thiadiazol-2-yl)methoxy]-2H-chromen-2-one and 7-[(5-mercapto-4-phenyl-4H-1,2,4-triazol-3-yl)methoxy]-2H-chromen-2-one were prepared starting from the natural compound umbelliferone. The newly synthesized compounds were characterized by elemental analysis and spectral studies (IR, ¹H-NMR and ¹³C-NMR).
Virgin coconut oil (VCO)-in-water, nano-emulsion in the form of cream stabilized by Emulium Kappa as an emulsifier, was prepared by using the Emulsion Inversion Point method. A nano-emulsion with droplet size <300 nm was then obtained. VCO has recently become a more popular new material in the cosmetic industries. Emulium Kappa is an ionic emulsifier that contains sodium stearoyl lactylate, the active whitening ingredient was Kojic Dipalmitate. Ostwald ripening is the main destabilizing factor for the nano-emulsion. This decline can be reduced by adding non-soluble oil, namely squalene, to the virgin coconut oil. We tested VCO:squalene in the ratios of 10:0, 9.8:0.2, 9.6:0.4, 9.4:0.6, 9.2:0.8, 9:1 and 8:2 and discovered that squalene's higher molecular weight (above critical molecular weight) resulted in low polarity and insolubility in the continuous phase. The continuous partitioning between the droplets results in the decline of Ostwald ripening. Furthermore, flocculation may occur due to the instability of nano-emulsion, especially for the preparations with little or no squalene at all. The stability of the nano-emulsion was evaluated by the electrophoretic properties of the emulsion droplets. The zeta potential values for the emulsion increased as the percentage of squalene oil increased.
The predilection of a bi-layered tablet to fail in the interface region after its initial formation in the compaction process reduces its practicality as a choice for controlled release solid drug delivery system. Hence, a fundamental appreciation of the governing mechanism that causes the weakening of the interfacial bonds within the bi-layered tablet is crucial in order to improve the overall bi-layered tablet mechanical integrity. This work has shown that the occurrence of the elastic relaxation in the interface region during the ejection stage of the compaction process decreases with the increase in the bi-layered tablet interface strength. This is believed to be due to the increase in the plastic bonding in the interface region. The tablet diametrical elastic relaxation affects the tablet height elastic relaxation, where the impediment of the tablet height expansion is observed when the interface region experiences a diametrical expansion.
Pyrrolothiazolyloxindole analogues share vital pharmacological properties, considered useful in Alzheimer's disease (AD). The aim of this study was synthesis and evaluate pyralothiazolyloxindole analogues if possess acetyl cholinesterase (AChE) inhibitory activity. The easily accessible one-pot synthesis of these compounds resulted to be significantly less difficult and expensive than that of donepezil. Several compounds possess anti-cholinesterase activity in the order of micro and sub-micromolar. Particularly, compound was the most potent inhibitors of the series against acetyl cholinesterase enzyme with IC(50) 0.11μmol/L.
The pediatric population is an enormously diverse segment of population varying both in size and age. The diversity caused pharmacists face various challenges primarily related to procuring, provision as well as use of drugs in this group of patients. Pediatric dose calculation is particularly a concern for pharmacists. Another challenge faced by pharmacists is unavailability of suitable formulations for pediatric use. This has also led many pharmacists to prepare extemporaneous liquid preparations, even though stability data on such preparations are scarce. Some extemporaneous preparations contain excipients which are potentially harmful in children. Besides that, inadequate labeling and drug information for pediatric drug use had not only challenged pharmacists in recommending and optimizing drug use in children, but also inadvertently caused many drugs used outside the approved terms of the product license (off-label use). Pharmacists are striving to stay connected to overcome the common and comparable challenges faced in their day to day duties and strive to maximize the safe and effective use of medicines for children.
There has been significant progress in the last few decades in addressing the biomedical applications of polymer hydrogels. Particularly, stimuli responsive hydrogels have been inspected as elegant drug delivery systems capable to deliver at the appropriate site of action within the specific time. The present work describes the synthesis of pH responsive semi-interpenetrating network (semi-IPN) hydrogels of N-succinyl-chitosan (NSC) via Schiff base mechanism using glutaraldehyde as a crosslinking agent and Poly (acrylamide-co-acrylic acid)(Poly (AAm-co-AA)) was embedded within the N-succinyl chitosan network. The physico-chemical interactions were characterized by Fourier transform infrared (FTIR), X-ray diffraction (XRD), thermogravimetric analysis (TGA), and field emission scanning electron microscope (FESEM). The synthesized hydrogels constitute porous structure. The swelling ability was analyzed in physiological mediums of pH 7.4 and pH 1.2 at 37°C. Swelling properties of formulations with various amounts of NSC/ Poly (AAm-co-AA) and crosslinking agent at pH 7.4 and pH 1.2 were investigated. Hydrogels showed higher swelling ratios at pH 7.4 while lower at pH 1.2. Swelling kinetics and diffusion parameters were also determined. Drug loading, encapsulation efficiency, and in vitro release of 5-fluorouracil (5-FU) from the synthesized hydrogels were observed. In vitro release profile revealed the significant influence of pH, amount of NSC, Poly (AAm-co-AA), and crosslinking agent on the release of 5-FU. Accordingly, rapid and large release of drug was observed at pH 7.4 than at pH 1.2. The maximum encapsulation efficiency and release of 5-FU from SP2 were found to be 72.45% and 85.99%, respectively. Kinetics of drug release suggested controlled release mechanism of 5-FU is according to trend of non-Fickian. From the above results, it can be concluded that the synthesized hydrogels have capability to adapt their potential exploitation as targeted oral drug delivery carriers.
The purpose of this research was to study processing variables at the laboratory and pilot scales that can affect hydration rates of xanthan gum matrices containing diclofenac sodium and the rate of drug release. Tablets from the laboratory scale and pilot scale proceedings were made by wet granulation. Swelling indices of xanthan gum formulations prepared with different amounts of water were measured in water under a magnifying lens. Granules were thermally treated in an oven at 60 degrees C, 70 degrees C, and 80 degrees C to study the effects of elevated temperatures on drug release from xanthan gum matrices. Granules from the pilot scale formulations were bulkier compared to their laboratory scale counterparts, resulting in more porous, softer tablets. Drug release was linear from xanthan gum matrices prepared at the laboratory scale and pilot scales; however, release was faster from the pilot scales. Thermal treatment of the granules did not affect the swelling index and rate of drug release from tablets in both the pilot and laboratory scale proceedings. On the other hand, the release from both proceedings was affected by the amount of water used for granulation and the speed of the impeller during granulation. The data suggest that processing variables that affect the degree of wetness during granulation, such as increase in impeller speed and increase in amount of water used for granulation, also may affect the swelling index of xanthan gum matrices and therefore the rate of drug release.
Orally disintegrating tablet (ODT) is a friendly dosage form that requires no access to water and serves as a solution to non-compliance. There are many co-processed adjuvants available in the market. However, there is no single product possesses all the ideal characteristics such as good compressibility, fast disintegration and good palatability for ODT application. The aim of this research was to produce a xylitol-starch base co-processed adjuvant which is suitable for ODT application. Two processing methods namely wet granulation and freeze drying were used to compare the characteristics of co-processed adjuvant comprising of xylitol, starch and crospovidone XL-10 mixed at various ratios. The co-processed excipients were compressed into ODT and physically characterized for powder flow, particle size, hardness, thickness, weight, friability, in-vitro disintegration time and in-situ disintegration time, lubricant sensitivity, dilution potential, Fourier transform infrared spectroscopy, scanning electronic microscopy and x-ray diffraction analysis. Formulation F6 was selected as the optimum formulation due to the fastest in-vitro (135.33±11.52 s) and in-situ disintegration time (88.67±13.56s) among all the formulations (p<0.05). Increase in starch component decreases disintegration time of ODT. The powder flow fell under the category of fair flow. Generally, it was observed that freeze drying method produced smaller particle size granules compared to wet granulation method. ODT produced from freeze drying method had shorter disintegration time compared to ODT from wet granulation batch. In conclusion, a novel co-processed excipient comprised of xylitol, starch and crospovidone XL-10, produced using freeze drying method with fast disintegration time, good compressibility and palatability was developed and characterized. The co-processed excipient is suitable for ODT application.
The study aims to characterize the structural relaxation times of quench-cooled co-amorphous systems using Kohlrausch-Williams-Watts (KWW) and to correlate the relaxation data with the onset of crystallization. Comparison was also made between the relaxation times obtained by KWW and the width of glass transition temperature (ΔTg) methods (simple and quick). Differential scanning calorimetry, Fourier-transformed infrared spectroscopy, and polarized light microscopy were used to characterize the systems. Results showed that co-amorphous systems yielded a single Tg and ΔCp, suggesting the binary mixtures exist as a single amorphous phase. A narrow step change at Tg indicates the systems were fragile glasses. In co-amorphous nap-indo and para-indo, experimental Tgs were in good agreement with the predicted Tg. However, the Tg of co-amorphous nap-cim and indo-cim were 20°C higher than the predicted Tg, possibly due to stronger molecular interactions. Structural relaxation times below the experimental Tg were successfully characterized using the KWW and ΔTg methods. The comparison plot showed that KWW data are directly proportional to the ½ power of ΔTg data, after adjusting for a small offset. A moderate positive correlation was observed between the onset of crystallization and the KWW data. Structural relaxation times may be useful predictor of physical stability of co-amorphous systems.
Oral paclitaxel (PTXL) formulations freed from cremophor® EL (CrEL) is always in utmost demand by the cancerous patients due to toxicities associated with the currently marketed formulation. In our previous investigation [Int. J. Pharm. 2014; 460:131], we have developed an oral oil based nanocarrier for the lipophilic drug, PTXL to target bioavailability issue and patient compliance. Here, we report in vivo antitumor activity and 28-day sub-chronic toxicity of the developed PTXL nanoemulsion. It was observed that the apoptotic potential of oral PTXL nanoemulsion significantly inhibited the growth of solid tumor (59.2 ± 7.17%; p
A capillary electrophoretic method for the separation of the aminoglutethimide (AGT) enantiomers using methylated-beta-cyclodextrin (M-beta-CD) as chiral selector is described. Several parameters affecting the separation were studied, including the type and concentration of chiral selector, buffer pH, voltage and temperature. Good chiral separation of the racemic mixture was achieved in less than 9 min with resolution factor Rs=2.1, using a fused-silica capillary and a background electrolyte (BGE) of tris-phosphate buffer solution (50 mmol L(-1), pH 3.0) containing 30 mgm L(-1) of M-beta-CD. The separation was carried out in normal polarity mode at 25 degrees C, 16 kV and using hydrostatic injection. Acceptable validation criteria for selectivity, linearity, precision, and accuracy/recovery were included. The proposed method was successfully applied to the assay of AGT enantiomers in pharmaceutical formulations. The computational calculations for the inclusion complexes of the R- and S-AGT-M-beta-CD rationalized the reasons for the different migration times between the AGT enantiomers.
Microporous polymeric matrices prepared from poly(ɛ-caprolactone) [PCL] were evaluated for controlled vaginal delivery of the antiprotozoal agent (tinidazole) in the treatment of the sexually transmitted infection, trichomoniasis. The matrices were produced by rapidly cooling co-solutions of PCL and tinidazole in acetone to -80 °C to induce crystallisation and hardening of the polymer. Tinidazole incorporation in the matrices increased from 1.4 to 3.9% (w/w), when the drug concentration in the starting PCL solution was raised from 10 to 20% (w/w), giving rise to drug loading efficiencies up to 20%. Rapid 'burst release' of 30% of the tinidazole content was recorded over 24 h when the PCL matrices were immersed in simulated vaginal fluid. Gradual drug release occurred over the next 6 days resulting in delivery of around 50% of the tinidazole load by day 7 with the released drug retaining antiprotozoal activity at levels almost 50% that of the 'non-formulated' drug in solution form. Basic modelling predicted that the concentration of tinidazole released into vaginal fluid in vivo from a PCL matrix in the form of an intravaginal ring would exceed the minimum inhibitory concentration against Trichomonas vaginalis. These findings recommend further investigation of PCL matrices as intravaginal devices for controlled delivery of antiprotozoal agents in the treatment and prevention of sexually transmitted infections.
Benzathine penicillin G (BPG) is used as first-line treatment for most forms of syphilis and as secondary prophylaxis against rheumatic heart disease (RHD). Perceptions that poor quality of BPG is linked to reported adverse effects and therapeutic failure may impact syphilis and RHD control programs. Clinical networks and web-based advertising were used to obtain vials of BPG from a wide range of countries. The quality of BPG was assessed using a high performance liquid chromatography assay capable of detecting relevant impurities and degradation products. Tests for water content, presence of heavy metals and physical characteristics of BPG, including particle size analysis and optical microscopy, also were conducted. Thirty-five batches of BPG were sourced from 16 countries across 4 WHO regions. All batches passed the US Pharmacopeia requirements for BPG injection (content), with no evidence of breakdown products or other detected contaminants. Water content and heavy metal analysis (n = 11) indicated adherence to regulatory standards and Good Manufacturing Practice. Particle size analysis (n = 20) found two batches with aggregated particles (>400 µm) that were dispersed following sonication. Current batches of BPG were of satisfactory pharmaceutical quality but aggregated particles were found in a modest proportion of samples. Future studies should focus on the physical characteristics of BPG which may contribute to variations in plasma penicillin concentrations an observed needle blockages in clinical practice. Pharmacopeial monographs could be revised to include standards on particle size and crystal morphology of BPG.
Alginate-based bipolymeric-nanobioceramic composite matrices for sustained drug release were developed through incorporation of nano-hydroxyapatite [nHAp] powders within ionotropically-gelled calcium ion-induced alginate-poly (vinyl pyrrolidone) blends polymeric systems. nHAp powders were synthesized by precipitation technique using calcium hydroxide [Ca(OH)2] and orthophosphoric acid [H3PO4] as raw materials. The average particle size of these was synthesized. nHAp powders was found as 19.04 nm and used to prepare nHAp-alginate-PVP beads containing DS. These beads exhibited drug entrapment efficiency (%) of 65.82±1.88 to 94.45±3.72% and average bead sizes of 0.98±0.07 to 1.23±0.15 mm. These beads were characterized by scanning electron microscopy (SEM) and Fourier transform-infra red (FTIR) spectroscopy analyses. Various nHAp-alginate-PVP beads containing DS exhibited prolonged sustained drug release and followed the Koresmeyer-Peppas model of drug release (R2=0.9908-0.9978) with non-Fickian release (anomalous transport) mechanism (n=0.73-0.84) for drug release over 8 h.
Microwave extraction of phytochemicals from medicinal plant materials has generated tremendous research interest and shown great potential. This research highlights the importance of microwave extraction in the analysis of flavonoids, isoflavonoid and phenolics and the antioxidant properties of extracts from three varieties of the Malaysian medicinal herb, Labisia pumila Benth. High and fast extraction performance ability, equal or higher extraction efficiencies than other methods, and the need for small samples and reagent volumes are some of the attractive features of this new promising microwave assisted extraction (MAE) technique. The aims of the present research were to determine the foliar phenolics and flavonoids contents of extracts of three varieties of L. pumila obtained by a microwave extraction method while flavonoid, isoflavonoid and phenolic compounds were analyzed using RP-HPLC. Furthermore, the antioxidant activities were measured by the DPPH and FRAP methods and finally, the chemical composition of the crude methanolic extracts of the leaves of all three varieties were analyzed by GS-MS.