Mg Of Active Pharmaceutical Ingredient Research Articles

Microwell Plate-Based Dynamic Light Scattering as a High-Throughput Characterization Tool in Biopharmaceutical Development.

High-throughput light scattering instruments are widely used in screening of biopharmaceutical formulations and can be easily incorporated into processes by utilizing multi-well plate formats. High-throughput plate readers are helpful tools to assess the aggregation tendency and colloidal stability of biological drug candidates based on the diffusion self-interaction parameter (kD). However, plate readers evoke issues about the precision and variability of determined data. In this article, we report about the statistical evaluation of intra- and inter-plate variability (384-well plates) for the kD analysis of protein and peptide solutions. ANOVA revealed no significant differences between the runs. In conclusion, the reliability and precision of kD was dependent on the plate position of the sample replicates and kD value. Positive kD values (57.0 mL/g, coefficients of variation (CV) 8.9%) showed a lower variability compared to negative kD values (−14.8 mL/g, CV 13.4%). The variability of kD was not reduced using more data points (120 vs. 30). A kD analysis exclusively based on center wells showed a lower CV (<2%) compared to edge wells (5–12%) or a combination of edge and center wells (2–5%). We present plate designs for kD analysis within the early formulation development, screening up to 20 formulations consuming less than 50 mg of active pharmaceutical ingredient (API).

Improved Achiral and Chiral HPLC-UV Analysis of Ruxolitinib in Two Different Drug Formulations

In this paper, two new reversed-phase (RP) HPLC-UV methods enabling the quantitative achiral and chiral analysis of ruxolitinib in commercial tablets (containing 20 mg of active pharmaceutical ingredient, API) and not commercially available galenic capsules (with 5 mg of API) are described. For the achiral method based on the use of a water/acetonitrile [70:30, v/v; with 0.1% (v) formic acid] eluent, a “research validation” study was performed mostly following the “International Council for Harmonization” guidelines. All the system suitability parameters were within the acceptance criteria: tailing factor, between 1.7 and 2.0; retention factor, 2.2; number of theoretical plates, &gt;9000. The linearity curve showed R2 = 0.99 (Rxv2 = 0.99), while trueness (expressed as recovery) was between 96.3 and 106.3%. Coefficient of variations (CVs) (repeatability: CVw and intermediate precision: CVIP) did not exceed 1.3% and 2.9%, respectively. Moreover, the use of the enantiomeric Whelk-O1 chiral stationary phases operated under similar RP eluent conditions as for the achiral analyses, and the “inverted chirality columns approach (ICCA)” allowed us to establish that the enantiomeric purity of ruxolitinib is retained upon reformulation from tablets to capsules. The two developed methods can allow accurate determinations of ruxolitinib in drug formulations for medical use.

Environmental sustainability assessment of the manufacturing process of a biological active pharmaceutical ingredient

AbstractBACKGROUNDAlthough the biopharmaceutical market grows rapidly, the environmental impacts of biopharmaceutical manufacturing have been hardly evaluated. The aim of the study is to comprehensively assess the environmental sustainability of a biologically‐produced active pharmaceutical ingredient (API) manufacturing process. For this purpose, an exergy analysis and an (exergetic) life cycle assessment were performed using primary (foreground system) and modeled data (background system). Infliximab, a monoclonal antibody, was considered.RESULTSThe fermentation and its raw materials' supply chain was determined to have the highest environmental impact, since the culture media requires chemicals and complex compounds such as animal‐derived materials (ADMs). The total impact per 100 mg of API produced ranged between 18.6 and 101.8 MJex and 2.0–3.1 kg CO2‐eq, mainly as a function of the ADMs' source. A comparison of infliximab and ustekinumab, a biopharmaceutical produced without ADMs, showed that eliminating these materials can reduce the cumulative resource consumption of monoclonal antibody manufacturing by up to 7.5 times. The fermentation is the process taking the longest and the heating, ventilation and air conditioning system which support fermentation areas consumes approximately 75% of all plant electricity use.CONCLUSIONSCulture media nutrients and cleanroom requirements are driving factors in the environmental impact of biological API manufacturing. Obtaining more precise data of the bioprocesses behind these nutrients' supply chain is crucial to corroborating this study's results. © 2019 Society of Chemical Industry

Study and determination of elemental impurities by ICP-MS in active pharmaceutical ingredients using single reaction chamber digestion in compliance with USP requirements

In this work a method for active pharmaceutical ingredients (APIs) digestion using the single reaction chamber (SRC—UltraWaveTM) system was proposed following the new recommendations of United States Pharmacopeia (USP). Levodope (LEVO), primaquine diphosphate (PRIM), propranolol hydrochloride (PROP) and sulfamethoxazole (SULF) were used to evaluate the digestion efficiency of the proposed method. A comparison of digestion efficiency was performed by measuring the carbon content and residual acidity in digests obtained using SRC and in digests obtained using conventional microwave-assisted digestion system (MultiwaveTM). Three digestion solutions (concentrated HNO3, aqua regia or inverse aqua regia) were evaluated for digestion of APIs. The determination of Cd, Ir, Mn, Mo, Ni, Os, Pb, Pd, Pt, Rh, Ru was performed using inductively coupled plasma mass spectrometry (ICP-MS) in standard mode. Dynamic reaction cell (DRC) mode was used for the determination of 51V, 52Cr, 53Cr, 63Cu and 65Cu in order to solve polyatomic ion interferences. Arsenic and Hg were determined using chemical vapor generation coupled to ICP-MS (FI-CVG-ICP-MS). Masses of 500mg of APIs were efficiently digested in a SRC-UltraWaveTM system using only HNO3 and allowing a carbon content lower than 250mgL−1 in final digests. Inverse aqua regia was suitable for digestion of sample masses up to 250mg allowing the determination of Ir, Pd, Pt, Rh and Ru. By using HNO3 or inverse aqua regia, suitable recoveries were obtained (between 91 and 109%) for all analytes (exception for Os). Limits of quantification were in agreement with USP requirements and they ranged from 0.001 to 0.015µgg−1 for all elemental impurities (exception for Os). The proposed method was suitable for elemental impurities determination in APIs and it can be used in routine analysis for quality control in pharmaceutical industries.

Development and Validation of a Dissolution Method for Pioglitazone Tablets

Dissolution testing has emerged in the pharmaceutical field as a very important tool to characterize drug product performance. Pioglitazone hydrochloride, a frequently prescribed antidiabetic, has no dissolution assay in official monographs. The aim of the study was to develop and validate a dissolution test for the quality control of pioglitazone hydrochloride (PH) tablets containing 15 mg of active pharmaceutical ingredient (API). Results from testing sink conditions and stability at 37 ° C show that PH is stable in potassium chloride buffer at pH 1.2, 1.5, 1.8, and in 0.1 N hydrochloric acid. In vitro dissolution tests of PH tablets were performed using different test conditions but always under sink conditions. The effects of filtration and deaeration were evaluated. The most discriminatory test conditions, potassium chloride buffer at pH 1.5 (900 mL at 37 ± 0 .5 ° C) as dissolution medium, paddle method (Apparatus 2), 75 rpm, and 60 min, were satisfactory. The UV spectrophotometric method for determination of released PH was developed and validated. The method presented linearity (r 2 = 0.999) in the concentration range of 10–60 μg/mL. The recoveries were good, ranging from 96.407% to 100.24%. The intraday and interday precision results were 1.704% and 1.3869% RSD, respectively. The developed dissolution test is adequate for its purpose and can be applied for the quality control of 15-mg PH tablets.

Application of Melt Granulation Technology to Enhance Tabletting Properties of Poorly Compactible High-Dose Drugs

Using metformin HCl as the model drug and hydroxypropylcellulose (HPC) as the polymeric excipient, a melt granulation (MG) process that employs a twin-screw extruder has been developed to enhance compactibility of poorly compactible high-dose drug substances. A high (90%) drug-load tablet formulation, containing 1025 mg of active pharmaceutical ingredients and 109 mg of excipients, was produced. Drug-polymer-powder mixtures were melt granulated at a temperature above glass transition of HPC (130°C) but below melting point of metformin HCl (224°C). MG was compared with modified wet granulation (WG) and solvent granulation (SG) processes. Under identical compression force, the hardness of tablets produced was MG>SG>WG and the friability was MG<SG<WG. The hardness of WG tablets was highly sensitive to moisture content both during compression and subsequent storage, and, although not to the same extent, the hardness of SG tablets was also affected by loss-on-drying levels. MG provided a robust manufacturing process with highest compactibility and lowest friability that were not sensitive to changes in atmospheric moisture level. The process can decrease tablet sizes of high-dose drugs and combination products by decreasing the need for relatively large amounts of excipients generally used to overcome physicochemical limitations of drug substances. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:1553-1565, 2011.

Development and Validation of a Dissolution Test for 6 mg Deflazacort Tablets

The aim of this study was to develop and validate a dissolution test for the quality control of deflazacort (DEF) tablets, a drug mainly used for the prevention of organ transplantation rejection, labeled as containing 6 mg of active pharmaceutical ingredient (API), using an RP-HPLC method. After testing sink conditions and stability at 37°C, DEF was found to be unstable, and decomposed as a function of the dissolution media. However, in water the decomposition was not significant enough to interfere with the determination of dissolution for DEF. The best conditions to carry out the dissolution test were paddle at 50 rpm, with 500 mL of deaerated water at 37°C. Under these conditions, the in vitro release profiles of 6 mg DEF tablets produced by two different laboratories, representing all approved products in the national market, shown to be dissimilar. A correlation between disintegration and in vitro dissolution was found for the two investigated formulations. The developed dissolution test was adequate for its purpose and can be applied for the quality control of 6 mg DEF tablets.

Quantitative determination of captopril and prednisolone in tablets by FT-Raman spectroscopy

A procedure for the quantitative determination of captopril and prednisolone in commercial tablets based on partial least squares (PLS) and principal component regression (PCR) treatment of FT-Raman spectroscopic data is described. In the studied medicines active pharmaceutical ingredients (APIs) constitute 4.2–16.7% of the tablet mass. Results obtained from calibration models built using unnormalised spectra were compared with the values found when an internal standard was added to each sample and the spectra were normalised by its selected band intensity at maximum or integrated. To apprise the quality of the models the relative standard error of predictions (RSEPs) were calculated for calibration and testing data sets. For captopril determination these were 1.8–2.2% (2.1–2.3%) and 2.7–3.1% (2.7–3.6%), respectively for the different PLS (PCR) models. For prednisolone these errors amounted to 1.8–2.1% (2.6–3.5%) and 3.2–3.7% (3.7–5.9%), respectively. Three commercial preparations of captopril containing 12.5 mg and one 25 mg of API per tablet were quantified using developed models. Found captopril contents, calculated versus results of iodometric titration, was equal 99.2–101.2% (99.2–102.0%), for the different PLS (PCR) calibration models and the different preparations. Quantification of prednisolone tablets, declared content 5 mg per tablet, on the basis of PLS (PCR) models gave API amount, calculated versus results of UV–vis method, in the 99.0–101.0% (98.0–102.0%) range.

Development and application of a universal method for quantitation of anionic constituents in active pharmaceutical ingredients during early development using suppressed conductivity ion chromatography

A universal method for quantitation of anionic substances in active pharmaceutical ingredients (API) during early development was developed using ion chromatography (IC). The method was developed to allow rapid characterization of APIs in support of early clinical studies The method parameters were chosen to allow quantitation of monovalent, divalent, and trivalent inorganic ions as well as monvalent and divalent carboxylic acids. These parameters were also chosen to ensure appropriate performance for regulated analyses using less than 10 mg of API per replicate. The method was applied to and validated for a range of anionic analytes in APIs of varying hydrophobicity to demonstrate applicability to various analyses encountered during early development of pharmaceuticals.