Mechanical, optical, and physicochemical properties of HPMC-based doxazosin mesylate orodispersible films

Abstract In this study, orodispersible films formed from hydroxypropyl methylcellulose (HPMC) E6 (2, 2.5, and 3%) and plasticizers ((glycerin (Gly), propylene glycol (PP), or polyethylene glycol (PEG)), containing doxazosin mesylate, were prepared by the solvent casting method and characterized. Design of experiments (DoE) was used as a statistical tool to facilitate the interpretation of the experimental data and allow the identification of optimal levels of factors for maximum formulation performance. Differential scanning calorimetry (DSC) curves and X-ray powder diffraction (XRPD) diffractograms showed doxazosin mesylate amorphization, probably due to complexation with the polymer (HPMC E6), and the glass transition temperature of the polymer was reduced by adding a plasticizer. Fourier transformed infrared (FTIR) spectroscopy results showed that the chemical structure of doxazosin mesylate was preserved when introduced into the polymer matrix, and the plasticizers, glycerin and PEG, affected the polymer matrix with high intensity. The addition of plasticizers increased the elongation at break and adhesiveness (Gly > PEG > PP), confirming the greater plasticizer effect of Gly observed in DSC and FTIR studies. Greater transparency was observed for the orodispersible films prepared using PP. The addition of citric acid as a pH modifier was fundamental for the release of doxazosin mesylate, and the desirability formulation had a release profile similar to that of the reference product

Desirability Function in analytical method development for determination of glitazones and metabolites employing HF-LPME

Abstract Thiazolidinedione, often shortened to TZD or glitazone, helps lower insulin resistance, which is the underlying problem for many people with type 2 diabetes. The two most known glitazones are pioglitazone (PGZ), with the brand name medicine Actos®, and rosiglitazone (RSG), which is Avandia®. This study presented a multivariate optimization in the microextraction procedure employing Fractional Factorial Design (FFD) combined with Desirability Function (DF) to determine TZD and metabolites in biological samples. Microextraction requires several parameters to be optimized; however, most of them still use univariate optimization. Finding optimum conditions by simple response is relatively simple, but the problems, in case of microextractions, are often more complex when it has more responses. For example, changing one factor that promotes one response may suppress the effect of the others. Thus, this multivariate optimization was applied for two bioanalytical methods for determination of TZD and metabolites, one by HPLC and other by CE, both using Hollow Fiber Liquid-Phase Microextraction (HF-LPME). The results establish the optimal values and elucidate how the factors that affect HF-LPME procedure perform in extraction efficiency for TZDs. Additionally, this study demonstrates that DF can be an important tool to optimize microextraction procedures.

Chemometric-assisted RP-HPLC method for the simultaneous determination of ambroxol hydrochloride, terbutaline sulfate, and guaiphenesin in combined dosage form

An isocratic reverse-phase High performance liquid chromatography (HPLC) method using a chemometric modelwas developed and validated for the simultaneous determination of ambroxol hydrochloride, terbutaline sulfate,and guaiphenesin in their combined dosage form. Central composite design which is a subset of response surfacemethodology was used as the chemometric model. The separation of three drugs was carried out by using a PhenomenexC18 column and detection at 220 nm using a UV detector. Based on initial trials, the three factors selected for thedesign were methanol (MN) concentration, mobile phase pH, and flow rate in the range of 55%–65% (v/v), 4–5 units,and 0.6–1 ml/min, respectively. The impact of the selected factors on the responses like retention time of first peak(tR1), resolution of 2nd and 3rd peak (Rs2,3), and theoretical plates of the first peak (TP1) were evaluated. Derringers’desirability function was used to optimize the responses. The conditions which were optimized for the assay of drugswere MN, ACN, and 50 mM KH2PO4 (pH 5) in the ratio of 55:10:35 at a flow rate of 0.8 ml/minute. The developedand optimized method was validated as per the International conference on harmonization (ICH) guidelines and canbe used for routine analysis in quality control laboratories.

Formulation optimization, in situ intestinal absorption and permeability of psoralen and isopsoralen / 中草药·英文版

Objective: To optimize a self-emulsifying drug delivery system (SEDDS) formulation for psoralen and isopsoralen (PSO and IPSO) isolated from Psoraleae Fructus. Methods: A D-optimal design was used to investigate the influence of oil percentage, surfactant percentage and cosurfactant percentage on several properties of SEDDS including particle size, polydispersity, equilibrium solubility, in situ intestine absorption rate and intestinal permeability. Furthermore, the desirability function approach was applied to obtain the optimal formulation for the system. Results: The oil percentage, surfactant percentage and cosurfactant percentage were optimized to be 53.6%, 35.7% and 10.7%, respectively, which means the model is available. Conclusions: The D-optimal design is valuable to optimize the SEDDS formulation and understand formulation compositions’ functions on SEDDS properties.

Formulation and in vitro evaluation of berberine containing liposome optimized by 32 full factorial designs.

The present study demonstrates the application of 32 full factorial design for optimization of berberine loaded liposome for oral administration. Thin film hydration method was used to prepare liposome and optimization was done by 32 full factorial designs combined with desirability function. Nine formulations were prepared by using different drug : lipid and soyphosphatidylcholine : cholesterol (SPC:CHOL) ratios and evaluated for entrapment efficiency and vesicle size. The statistical validity of model was done by analysis of variance (ANOVA). Response surface graph and contour plots were used to understand the effect of variables on responses. The optimized formulation with 0.782 desirability value was prepared and evaluated for responses. The results of entrapment efficiency and vesicle size were found to be very close with the predicted values. In addition, an optimized formulation was also characterized for zeta potential, in vitro drug release and morphology. The formulation was found to be spherical shape with an average diameter of 0.823 nm and -1.93 mV zeta potential and also shows sustained release pattern. These results support the fact that 32 full factorial designs with desirability function could be effectively used in optimization of berberine loaded liposome.

Multiple responses optimization in the development of a headspace gas chromatography method for the determination of residual solvents in pharmaceuticals / 药物分析学报

An efficient generic static headspace gas chromatography (HSGC) method was developed, optimized and validated for the routine determination of several residual solvents (RS) in drug substance, using a strategy with two sets of calibration. Dimethylsulfoxide (DMSO) was selected as the sample diluent and internal standards were used to minimize signal variations due to the preparative step. A gas chroma-tograph from Agilent Model 6890 equipped with flame ionization detector (FID) and a DB-624 (30 m × 0.53 mm i.d., 3.00μm film thickness) column was used. The inlet split ratio was 5:1. The influ-encing factors in the chromatographic separation of the analytes were determined through a fractional factorial experimental design. Significant variables: the initial temperature (IT), the final temperature (FT) of the oven and the carrier gas flow rate (F) were optimized using a central composite design. Response transformation and desirability function were applied to find out the optimal combination of the chromatographic variables to achieve an adequate resolution of the analytes and short analysis time. These conditions were 30 °C for IT, 158 °C for FT and 1.90 mL/min for F. The method was proven to be accurate, linear in a wide range and very sensitive for the analyzed solvents through a comprehensive validation according to the ICH guidelines.

Derringer desirability and kinetic plot LC-column comparison approach for MS-compatible lipopeptide analysis / 药物分析学报

Lipopeptides are currently re-emerging as an interesting subgroup in the peptide research field, having historical applications as antibacterial and antifungal agents and new potential applications as antiviral, antitumor, immune-modulating and cell-penetrating compounds. However, due to their specific structure, chromatographic analysis often requires special buffer systems or the use of trifluoroacetic acid, limiting mass spectrometry detection. Therefore, we used a traditional aqueous/acetonitrile based gradient system, containing 0.1% (m/v) formic acid, to separate four pharmaceutically relevant lipopeptides (polymyxin B1, caspofungin, daptomycin and gramicidin A1), which were selected based upon hierarchical cluster analysis (HCA) and principal component analysis (PCA). In total, the performance of four different C18 columns, including one UPLC column, were evaluated using two parallel approaches. First, a Derringer desirability function was used, whereby six single and multiple chromatographic response values were rescaled into one overall D-value per column. Using this approach, the YMC Pack Pro C18 column was ranked as the best column for general MS-compatible lipopeptide separation. Secondly, the kinetic plot approach was used to compare the different columns at different flow rate ranges. As the optimal kinetic column performance is obtained at its maximal pressure, the length elongation factorλ(Pmax/Pexp) was used to transform the obtained experimental data (retention times and peak capacities) and construct kinetic performance limit (KPL) curves, allowing a direct visual and unbiased comparison of the selected columns, whereby the YMC Triart C18 UPLC and ACE C18 columns performed as best. Finally, differences in column performance and the (dis)advantages of both approaches are discussed.

Effect of vermicompost, worm-bed leachate and arbuscular mycorrizal fungi on lemongrass (Cymbopogon citratus (DC) Stapf. ) growth and composition of its essential oil

The objective of this study was to investigate the effect of vermicompost, worm-bed leachate (WBL) and Glomus mosseae, an arbuscular mycorrhizal fungi (AMF), on growth of lemongrass (Cymbopogon citratus (DC.) Stapf). A response surface methodology, i.e. a three-level Box Benhen design with three repetitions and three blocks, was applied to optimize biomass production, essential oil yield and its composition. Application rates of Glomus mosseae were 0, 1 or 2 g plant-1, vermicompost 0, 5 or 10 g plant-1 and WBL 0, 10 and 20 percent. The AMF had no significant effect on the variables tested, but vermicompost had a significant effect on essential oil yield and WBL on essential oil yield, myercene concentration and shoot dry weigh (p < 0.05). It was found that lemongrass fertilized with 2.0 g G. mosseae, 5.0 g vermicompost and 20 percent worm-bed leachate would yield 0.797 percent essential oil of which 62.6 percent was citral.