Gas-saturated solution process to obtain microcomposite particles of alpha lipoic acid/hydrogenated colza oil in supercritical carbon dioxide.

Alpha lipoic acid (ALA), an active substance in anti-aging products and dietary supplements, need to be masked with an edible polymer to obscure its unpleasant taste. However, the high viscosity of the ALA molecules prevents them from forming microcomposites with masking materials even in supercritical carbon dioxide (scCO2). Therefore, the purpose of this study was to investigate and develop a novel production method for microcomposite particles for ALA in hydrogenated colza oil (HCO). Microcomposite particles of ALA/HCO were prepared by using a novel gas-saturated solution (PGSS) process in which the solid-dispersion method is used along with stepwise temperature control (PGSS-STC). Its high viscosity prevents the formation of microcomposites in the conventional PGSS process even under strong agitation. Here, we disperse the solid particles of ALA and HCO in scCO2 at low temperatures and change the temperature stepwise in order to mix the melted ALA and HCO in scCO2. As a result, a homogeneous dispersion of the droplets of ALA in melted HCO saturated with CO2 is obtained at high temperatures. After the rapid expansion of the saturated solution through a nozzle, microcomposite particles of ALA/HCO several micrometers in diameter are obtained.

Comparative evaluation of cariogenic and erosive potential of commonly prescribed pediatric liquid medicaments: an in vitro study.

INTRODUCTION: Liquid oral medicines being the most accepted form of medication in children are frequently prescribed. The harmful effects of these liquid medicaments on a child's dental health are not known to many. The present study aimed to evaluate and compare the cariogenic and erosive potential of 5 most commonly prescribed pediatric liquid medicaments (PLM) in Pimpri Chinchwad and Pune city, Pune district. MATERIALS AND METHODS: Most commonly prescribed PLM in Pune district were selected as opined by 50 pediatricians. The selected medicaments were Syr. Augmentin® Duo, Syr. Valparin®, Syr. Combiflam®, Syr. Visyneral and Syr. Orofer®. An estimation of pH, percentage of sucrose concentration and calcium dissolving capacity of these preparations was carried out. The results as obtained were subjected to statistical analysis using SPSS v 17.0 for windows. The statistical test as undertaken was Pearson's correlation coeffcient(r). RESULTS: Sucrose was seen to be present in Syr. Combiflam® (35.75% ± 0.25%) and Syr. Visyneral (18.48% ± 0.43%). Acidic pH was observed for Syr. Visyneral (mean pH 3.63 ± 0.04), Syr. Combiflam®(mean pH 5.03 ± 0.02) and Syr. Augmentin® (mean pH 6.22 ± 0.02). Highest calcium dissolution was seen with Syr. Combiflam®(295.86 mg/ml) and the least with Syr. Orofer® (25.51 mg/ml). No statistical significant correlation was observed with calcium dissolution potential of PLM in comparison with their respective pH. CONCLUSION: Syr. Combiflam® can be regarded as the highest cariogenic and erosive potential medicament among the compared and tested PLM. CLINICAL SIGNIFICANCE: Considering syrups with high cariogenic and erosive potential should always follow with proper oral hygiene practices or search for an alternative drugs void of such detrimental effects.

Application of high-performance liquid chromatography with charged aerosol detection for universal quantitation of undeclared phosphodiesterase-5 inhibitors in herbal dietary supplements.

Incidents of detecting novel analogues of phosphodiesterase 5 (PDE-5) inhibitors in illicit dietary supplements for erectile dysfunction are constantly reported. However, little is known about their content in a single dose, mainly due to the poor availability or inaccessibility of pure reference standards. This study presents a new strategy of quantitative analysis of unknown and recently identified compounds. Charged aerosol detector (CAD), described as "universal detector", combined with high-performance liquid chromatography (HPLC) system proved to be a useful tool for fast and simple quantitation of PDE-5 inhibitors' analogues in a complex herbal matrix without individual reference standards available. Universal calibration was employed for calculations. Two easily obtainable reference materials - sildenafil and tadalafil - were selected as universal standards and the content of analogues was estimated with respect to their response. The error of proposed indirect determination was found to be ± 3%, which is less than enough to obtain a reliable result of the content. The elaborated method was applied for quantitative analyses of PDE-5 inhibitors and 10 analogues detected in 22 illicit dietary supplements and two bulk powdered herbal materials. All target analogues were identified using time-of-flight mass spectrometry with electrospray ionization. Obtained results indicate that the quantity of PDE-5 inhibitors in all tested samples is considered to be pharmacologically relevant.

Correlation of screening and confirmatory results in tiered immunogenicity testing by solution-phase bridging assays.

Biotherapeutic proteins induce undesired immune responses that can affect drug efficacy and safety. For this reason, immunogenicity assessment is an integral part of drug development and is mandated by the regulatory authorities. Immunogenicity is typically evaluated by a tiered approach consisting of a screening assay followed by a competitive inhibition with unlabeled drug serving as confirmatory assay and additional characterization of the immune response. The confirmatory assay is intended to reduce the number of false positive responses generated in the screening tier and ensure that all samples are correctly classified as positive or negative. The positive-negative sample decisions are based on screening and confirmatory assay cut points that are statistically derived through evaluation of drug-naive samples. In this paper, we describe the analysis of cut point data for the presence of statistical correlation between the screening and confirmatory results. Data were obtained from validations of solution-phase bridging assays for detection of anti-drug antibodies against monoclonal antibody therapeutics. All data sets showed moderate to strong positive correlation, indicating that the screening and confirmatory assays were not independent and were likely to generate similar information. We present theoretical evidence that correlated results may be a general feature of the tiered approach when the same test platform is used for both screening and confirmatory assays. The competitive inhibition test, therefore, may be of limited value beyond reduction of the overall false positive rate. Our results indicate that similar sample results could be obtained by using just the screening assay with the false positive rate set to 1%.

[Simultaneous quantification of five impurities in puerarin and its injections by HPLC method with correction factor].

OBJECTIVE: To establish a HPLC method with the relative correction factors (RCFs) for quantification of five critical related substances (A, B, C, D and E) in puerarin and its injection. METHOD: Taking puerarin as the internal standard, corresponding RCFs of the critical related substances were determined respectively. According to their RCFs, simultaneous determination of five related substances in puerarin and its injection was performed. The method was evaluated by comparison the quantitative results of external standard method and the method with RCFs correction. RESULT: There were no significant differences in the results of five critical related substances in 38 batches of puerarin and its injection by external standard method and the method with RCFs correction. CONCLUSION: The HPLC method with RCFs was validated to be accurate and can be successfully applied to determine the critical related substances in puerarin and its injection.

In-line monitoring of alcohol precipitation by near-infrared spectroscopy in conjunction with multivariate batch modeling.

Alcohol precipitation is a critical unit operation during the manufacture of Chinese herbal injections. To facilitate enhanced process understanding and develop control strategy, the use of near-infrared spectroscopy (NIRS) combined with multivariate statistical process control (MSPC) methodology was investigated for in-line monitoring of alcohol precipitation. The effectiveness of the proposed approach was evaluated through an experimental campaign. Six batches were run under normal operating conditions to study batch-to-batch variation or batch reproducibility and establish MSPC control limits, while artificial process variations were purposefully introduced into the four test batches to assess the capability of the model for real-time fault detection. Several MSPC tools were compared and assessed. NIRS, in conjunction with MSPC, has proven to be a feasible process analytical technology (PAT) tool for monitoring batch evolution and potentially facilitating model-based advanced process control of the alcohol precipitation during the manufacture of Chinese herbal injections.

[Analysis of the content of mineral elements in Scutellaria baicalensis, skullcap tea and its solution].

The content of nine mineral elements in the root, stem and leaf of 1-3 years old Scutellaria baicalensis, skullcap tea, and its solution was determined by the inductively coupled plasma atomic emission spectrometry (ICP-AES). The results show that the main mineral elements in the root, stem and leaf are similar. The main mineral elements include K, Ca, Mg, P, Al and Fe. The content ratio of Zn, Mn, Cu, Fe, Al, P, Mg, Ca and K in the leaf of Scutellaria haicalensis is 1 : 3 : 6 : 15 : 18 19 : 41 : 333 : 423. The contents of Fe, Mn, P, Mg and Ca in the stems and leaves of Scutellaria baicalensis increase with the increase of cultivation period. There were K, Ca, Mg and other mineral elements in the skullcap tea, and Fe, Zn and Mg were easy to be dissolved, the dissolution rates were 61.8%, 55.4% and 61.4% respectively. This study can provide scientific basis for rational utilization of the above ground resources of Scutellaria baicalensis.

Screening method for ethylene glycol and diethylene glycol in glycerin-containing products.

This paper describes a capillary gas chromatographic method with flame ionization detection for the identification/quantification of ethylene glycol (EG) and diethylene glycol (DEG) in glycerin. The validation study shows that the proposed method is specific, sensitive, precise, and accurate. The linear range of the method was 0.013-0.031mg/mL for EG and 0.012-0.030mg/mL for DEG. Wider ranges may be achievable but were not investigated. The limit of detection of EG and DEG were determined as 0.0018% and 0.0036% (w/w) respectively, and at this concentration the signal-to-noise ratios for EG and DEG were approximately 3:1. The method was also used to determine EG and DEG in toothpaste. The results were compared to those obtained by thin-layer chromatography (TLC) and showed greater sensitivity and specificity.

Development of an alternative method for determination of terpene lactones in ginkgo dry extract.

A new liquid chromatographic mass spectrometric (LC-MS) method for determination of terpene lactones in ginkgo dry extract has been developed. The new method has several advantages over the existing European Pharmacopoeia (Ph. Eur.) method for analysis of terpene lactones in ginkgo dry extract, the major ones being a very simple sample pre-treatment and an excellent selectivity. 5 terpene lactones were analysed with a precision expressed as relative standard deviation (RSD) of 0.4-3.1% and a mean relative error (RE) within +/-4.6%. The method was used to analyse 9 samples of ginkgo dry extracts from 3 different extract producers. The content of bilobalide was found to be in the range of 2.6-3.4% in all samples, whereas the sum of ginkgolides A, B and C was found to be in the range of 3.0-3.6%. Ginkgolide J was found in the range of 0.3-0.6%.

Determination of aluminum in large volume parenteral drug products used in total parenteral nutrition therapy by ICP-MS with a dynamic reaction cell.

The proposed method was developed for the determination of aluminum (Al) in large volume parenteral (LVP) drug products used in total parenteral nutrition (TPN) therapy. The determination of Al in LVP drug products was performed by an inductively coupled plasma mass spectrometer equipped with a dynamic reaction cell (DRC-ICP-MS). DRC-ICP-MS conditions for the analysis of Al were studied to obtain the best signal to background (S/N) ratios. The interfering polyatomic ions at mass 27 (Al) were reduced by using NH(3) as a reaction gas. The detection limit of Al in a 1% (v/v) HNO(3) aqueous solution was 2 ng/l. The Al contents in LVP drug products obtained by this method were in the range of 1.16-4.33 microg/l and were less than 25 microg/l, that is, the regulation value of Food and Drug Administration (FDA). In order to trace the origin of Al in LVP drug products, each part of the LVP drug product, which is composed of three chambers, was investigated. However, a clear difference of the Al contents in each chamber was not observed. Furthermore, the Al contents in injection bags were quantified. Although the Al contents in injection bags were relatively high (in the range of 27.5-33.6 microg/g), dissolution of Al from the injection bags was not observed in the stability testing. From all of these results, it was concluded that the Al contents in the LVP drug products investigated originated in the amount of the Al in each raw material.

[Study on the TLC-fingerprint of Xiatianwu].

OBJECTIVE: To develop a method that can well evaluate the quality of Xiatianwu. METHODS: Methods are researched and discussed to construct the TLC-FP (thin-layer chromatography finger-print) of Xiatianwu to evaluate its quality. RESULTS: The areas of six evident peaks in the thin-layer chromatography of Xiatianwu are compared with the area of dl-tetrahydropalmatine peak companied with them in the same chromatography. The Rr of every peak and its relative area were acquired to evaluate the quality of Xiatianwu and identify it. CONCLUSION: The TLC-fingerprint of Xiatianwu can well evaluate the quality of Xiatianwu.

[Study on the method of rapid quality control of aqueous solution of flos lonicerae japonicae extraction in the preparation of qingkailing injection].

To establish a rapid and accurate on-line quality control method for aqueous solution of Flos Lonicerae Japonicae extraction (ASFLJE) in the preparation of Qingkailing injection, the wavelength of UV original spectrum and its first derivative spectrum of ASFLJE were scanned. The most suitable spectrum type and wavelength correlated with the chlorogenic acid content in ASFLJE determined by RP-HPLC were chosen to build a regress model. The UV equation for predicting chlorogenic acid content in ASFLJE was established. Other 10 batches of ASFLJE were used for testing the on-line prediction results by comparison of the values of chlorogenic acid content determined by HPLC and predicting equation respectively. The most suitable wavelengths correlated with chlorogenic acid content were 294 nm (r = 0.991 9, n = 28) in the original UV spectrum and 316 nm (r = 0.995 9, n = 28) in the first derivative spectrum respectively. The predicting equation of chlorogenic acid content was: c(mg x mL(-1)) = 506. 254 3 x A316 nm + 0.177 1 (r = 0.995 9, n = 28). This predicting equation is credible and accurate, as tested by HPLC method (r = 0.991 5, n = 10). The prediction results of chlorogenic acid content were: the chlorogenic acid content in probable 90 percent ASFLJE was: 0.4-4.0(mg x mL(-1)). This method is rapid, simple and accurate, and can be used for the on-line quality control of ASFLJE in Qingkailing injection preparation.

LC/MS fingerprinting of Shenmai injection: a novel approach to quality control of herbal medicines.

Chromatographic fingerprinting has been recommended as a potential and reliable strategy for the quality control of herbal medicines. Although varieties of chromatographic techniques, particularly HPLC, have been widely employed, hyphenated chromatographic approach has not been sufficiently exploited in chromatographic fingerprinting. In this work, LC/MS fingerprinting of Shenmai injection was developed. Thirty ginsenosides as well as seven ophioponins were selected to construct the LC/MS fingerprint using selective ion monitoring (SIM) mode, while previous HPLC fingerprint [H.J. Zhang, Y.J. Wu, Y.Y. Cheng, J. Pharm. Biomed. Anal. 31 (2003) 175-183] only represents the ginsenosides. Subsequently, the proposed LC/MS fingerprints were applied to identifying the product manufacturers. All the samples were accurately classified based on their LC/MS fingerprints in conjunction with principal components analysis (PCA). This study would be potentially helpful to improve the quality control ability of fingerprinting-based strategy for complex herbal medicines.

A rapid HPLC-ESI-MS/MS for qualitative and quantitative analysis of saponins in "XUESETONG" injection.

'XUESETONG' injection, one of the most widely used proprietary medicines in traditional Chinese medicine, consists of total saponins made from Panax notoginseng, which is a highly valued and important Chinese medicinal herb. It is used to treat cardiovascular diseases. In order to control the quality of XUESETONG injection, a rapid HPLC-ESI-MS/MS method was developed for qualitative and quantitative determination of the saponins. The analyses were performed on SB-C18 column using gradient elution in 25 min. Full scan and time programmed selected reaction monitoring (SRM) were used for qualitative and quantitative analysis of saponins, respectively. Twenty-seven saponins were identified and nine of them including notoginsenoside R1, ginsenoside Rb1, Rb2, Rb3, Rc, Rd, Re, Rf and Rg1 were quantified. Ten XUESETONG injections were analyzed and compared. The results showed that there is a great variation among different samples. In conclusion, the developed method is rapid, accurate and sensitive for qualitative and quantitative analysis of saponins in XUESETONG injection. Moreover, it also can be used for the quality control of P. notoginseng raw material and its preparations.

Effect of various halide salts on the incompatibility of cyanocobalamin and ascorbic acid in aqueous solution.

Combination of cyanocobalamin (VB12) and ascorbic acid (VC) has been widely seen in pharmaceutical products and dietary supplements. However, VB12 has been reported that its behavior in stability in aqueous solution is quite different when VC is mixed. In the present study, we examined the stabilities of these vitamins in acetate buffer (pH 4.8) using high performance liquid chromatography. Degradation of VB12 was not observed in the absence of VC in the buffer. However, when VC was mixed in the VB12 solution, VB12 concentrations decreased in accordance with VC degradation. VB12 and VC degradations were inhibited by adding sodium halides to acetate buffer at pH 4.8. These stabilization effects were also observed in the range from pH 3.5 to 5.3 and by adding potassium, magnesium, and calcium halides. Furthermore, our data demonstrated that increases in the halide anion concentrations and atomic number (Cl-