Synthesis and characterization of dual-responsive poly(N-vinylcaprolactam-co-N-methylolacrylamide) nanogels.

This article reports the synthesis of poly(N-vinylcaprolactam-co-N-methylolacrylamide) (P(NVCL-co-NMA)) nanogels and investigates their thermo-/pH-responsive behavior. The formation of nanogels was synthesized using free radical emulsion polymerization by varying the monomer composition of NVCL:NMA, and their molecular structure was characterized by 1H-NMR and FTIR. It was found that the nanogels were successfully prepared, and the nanogels exhibited LCST-type phase transition behavior. Cloud point transition temperature (Tc) was studied as a function of copolymer composition, MBA concentration, and pH of the solution by exploring their changes in turbidity using UV-vis spectrophotometer. Our studies reveal that Tc nanogels increased with increasing concentration of NMA, which is due to the hydrophilicity of NMA. Our research also demonstrated that the increase in MBA percentage could decrease the Tc of the synthesized nanogels. Interestingly, P(NVCL-co-NMA) nanogels showed not only a thermoresponsive behavior but also a pH response with increasing Tc in a strong acidic environment owing to the H-bonds within the polymer chains. The results show that nanogels with initial monomer composition of NVCL and NMA of 75% and 25%, respectively, and using 4% of MBA showed Tc around 35°C at pH 7.4. In addition, DLS studies also confirmed this result since the particle sizes became much larger after surpassing the temperature of 35°C. Due to this founding, such nanogels might have potential application in controlled release. Nevertheless, further studies regarding the adjustment of Tc are still needed.

The Scalability of Wet Ball Milling for The Production of Nanosuspensions.

BACKGROUND: Miniaturization of nanosuspensions preparation is a necessity in order to enable proper formulation screening before nanosizing can be performed on a large scale. Ideally, the information generated at small scale is predictive for large scale production. OBJECTIVE: This study was aimed to investigate the scalability when producing nanosuspensions starting from a 10 g scale of nanosuspension using low energy wet ball milling up to production scales of 120 g nanosuspension and 2 kg nanosuspension by using a standard high energy wet ball milling operated in batch mode or recirculation mode, respectively. METHODS: Two different active pharmaceutical ingredients, i.e. curcumin and hesperetin, have been used in this study. The investigated factors include the milling time, milling speed, and the type of mill. RESULTS: Comparable particle sizes of about 151 nm to 190 nm were obtained for both active pharmaceutical ingredients at the same milling time and milling speed when the drugs were processed at 10 g using low energy wet ball milling or 120 g using high energy wet ball milling in batch mode, respectively. However, an adjustment of the milling speed was needed for the 2 kg scale produced using high energy wet ball milling in recirculation mode to obtain particle sizes comparable to the small scale process. CONCLUSION: These results confirm in general, the scalability of wet ball milling as well as the suitability of small scale processing in order to correctly identify the most suitable formulations for large scale production using high energy milling.

Systematic screening of different surface modifiers for the production of physically stable nanosuspensions.

The role of a surface modifier is important in the formation of stable nanosuspensions. In this study, a simple and systematic screening method for selecting optimum surface modifiers was performed by utilizing a low-energy wet ball milling method. Nine surface modifiers from different classes with different stabilization mechanisms were applied on six different models of active pharmaceutical ingredients (API). Particle size analysis showed that at concentration five times higher than the critical micelle concentration, SDS and sodium cholate (anionic surfactant) showed the highest percent success to produce stable nanosuspensions with particle size smaller than 250 nm. Similar findings were also shown by poloxamer 188 (nonionic surfactant) and hydroxypropylmethylcellulose E5 (polymeric stabilizer) at concentration 1% (w/v) and 0.8% (w/v), respectively. In addition, combinations of anionic surfactant and nonionic surfactant as well as combinations of anionic surfactant and polymeric stabilizer showed high percent success in the formation of stable nanosuspensions. In general, no correlation can be found between the physicochemical characteristics of the model API (molecular weight, melting point, log P, pKa, and crystallinity) with its feasibility to be nanosized. The concentration and the principle of stabilization of surface modifier determine the formation of stable nanosuspensions.

Systematic Screening of Different Surface Modifiers for the Production of Physically Stable Nanosuspensions.

The role of a surface modifier is important in the formation of stable nanosuspensions. In this study, a simple and systematic screening method for selecting optimum surface modifiers was performed by utilizing a low-energy wet ball milling method. Nine surface modifiers from different classes with different stabilization mechanisms were applied on six different models of active pharmaceutical ingredients (API). Particle size analysis showed that at concentration five times higher than the critical micelle concentration, SDS and sodium cholate (anionic surfactant) showed the highest percent success to produce stable nanosuspensions with particle size smaller than 250nm. Similar findings were also shown by poloxamer 188 (nonionic surfactant) and hydroxypropylmethylcellulose E5 (polymeric stabilizer) at concentration 1% (w/v) and 0.8% (w/v), respectively. In addition, combinations of anionic surfactant and nonionic surfactant as well as combinations of anionic surfactant and polymeric stabilizer showed high percent success in the formation of stable nanosuspensions. In general, no correlation can be found between the physicochemical characteristics of the model API (molecular weight, melting point, log P, pKa, and crystallinity) with its feasibility to be nanosized. The concentration and the principle of stabilization of surface modifier determine the formation of stable nanosuspensions. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Curcumin.

Curcumin and its two related compounds, that is, demethoxycurcumin and bis-demethoxycurcumin (curcuminoids) are the main secondary metabolites of Curcuma longa and other Curcuma spp. Curcumin is commonly used as coloring agent as well as food additive; curcumin has also shown some therapeutic activities. This review summarizes stability of curcumin in solutions, spectroscopy characteristics of curcumin (UV, IR, Raman, MS, and NMR), polymorphism forms, method of analysis in both of biological and nonbiological samples, and metabolite studies of curcumin. For analysis of curcumin and its related compounds in complex matrices, application of LC-MS/MS is recommended.

Aripiprazole.

Aripiprazole is an atypical antipsychotic drug which belongs to the benzisoxazole derivatives. Aripiprazole is available in many salts and polymorphs forms. X-ray diffraction, IR spectroscopy, and DSC could be used for differentiating the polymorphs of aripiprazole. Some instrumental methods of analysis such as UV spectrophotometer, HPTLC, HPLC, and CE can be applied for analyzing aripiprazole and its impurities. Chromatography methods that have an MS/MS detector is the method of choice for analyzing aripiprazole and its metabolites. Bioavailability studies of the polymorphs of aripiprazole and their pharmaceutical preparations are very important to optimize the formulations of the dosage forms.

Ezetimibe.

Ezetimibe is a drug substance which can be used for lowering low-density lipoprotein cholesterol. Its crystal form and polymorphism have been determined using X-ray diffraction and thermal methods. Quantitative and qualitative analysis of Ezetimibe as well as study of its impurities and degradations were summarized in this chapter.

Glimepiride.

Glimepiride, which belongs to the sulfonylurea group, has been widely analyzed for its physical chemical properties including its crystallinity. Moreover, methods to quantify glimepiride and its impurities, either in pharmaceutical dosage form or in biological sample, have also been extensively developed and reported. This chapter extracts all information needed to give more perspective regarding to this substance.

A novel flow through diffusion cell for assessing drug transport across the buccal mucosa in vitro.

A novel flow through (FT) diffusion cell for assessing the permeability of compounds across the buccal mucosa was designed. Porcine buccal mucosa was mounted between two chambers with flow through capacity in both the donor and receptor chambers. The permeability of caffeine (CAF), triamcinolone acetonide (TAC), and estradiol (E(2)) was determined over 4 h and flux values were compared to those obtained using a modified Ussing chamber (MUC). No significant differences in the flux of each probe compound were observed using either the MUC or the novel FT cell. The design of the FT cell allowed for monitoring appearance of receptor solution within the donor chamber during the initial equilibration period, allowing for visual inspection of tissue integrity. These permeability studies demonstrate that this FT cell is a suitable alternative model for assessing drug permeability across the buccal mucosa, without the limitations associated with the static MUC. This novel model was then utilized to determine whether salmeterol xinafoate (SX) could permeate the buccal mucosa at concentrations expected in the oral cavity following inhalation. Concentration-dependent studies demonstrated that SX permeates the buccal mucosa via passive diffusion and that oral mucosal absorption may contribute significantly to the overall systemic exposure of inhaled SX.