Development and Validation of a Separation and Quantification Method for Residual Solvents in Active Substances by Headspace Gas Chromatography

The main objective was to develop and validate a method to assaying simultaneously nine residual solvents mentioned in the guidelines of the International Conference on Harmonization (ICH) Q3C: toluene, methanol, ethanol, acetone, propan-2-ol, ethyl acetate, tetrahydrofuran, dichloromethane and acetonitrile. Chromatographic separation was achieved on DB-624 column (30 m × 0.53 mm, 1.8 μm), nitrogen carrier gas and flame ionization detector. We have optimized the carrier gas flow, programming oven temperature and the split ratio. We have opted for the dimethyl sulfoxide as dissolution solvent. The developed method was validated for linearity, precision, accuracy and specificity and then applied for the research and quantification of residual solvents levels in two drug substances.  Excellent results were obtained. The developed method proved to be simple, producing symmetric peak shape, good resolution and reasonable retention time for solvents elution before seventeen minutes, specific, precise and linear in the range from the reporting level limit of quantification to 120% of the limit value, with a correlation coefficient greater than 0.999. The use of n-butyl acetate as internal solvent has improved the linearity and precision, compensating for the occurring variability. The quantification of residual solvents levels in two drug substances nefopam and enoxaparin, did not exceed the amount specified by the ICH guidelines.Thus, our method can be applied for the routine quantification of residual solvents levels in different active substances, for pharmaceutical companies and research laboratories

An integrated view of theiInfluence of temperature, pressure, and humidity on the stability of trimorphic cysteamine hydrochloride

Understanding the phase behavior of pharmaceuticals is important for dosage form development and regulatory requirements, in particular after the incident with ritonavir. In the present paper, a comprehensive study of the solid-state phase behavior of cysteamine hydrochloride used in the treatment of nephropathic cystinosis and recently granted orphan designation by the European Commission is presented employing (high-pressure) calorimetry, water vapor sorption, and X-ray diffraction as a function of temperature. A new crystal form (I2/a, form III) has been discovered, and its structure has been solved by X-ray powder diffraction, while two other crystalline forms are already known. The relative thermodynamic stabilities of the commercial form I and of the newly discovered form III have been established; they possess an overall enantiotropic phase relationship, with form I stable at room temperature and form III stable above 37 degrees C. Its melting temperature was found at 67.3 +/- 0.5 degrees C. Cysteamine hydrochloride is hygroscopic and immediately forms a concentrated saturated solution in water with a surprisingly high concentration of 47.5 mol % above a relative humidity of 35%. No hydrate has been observed. A temperature composition phase diagram is presented that has been obtained with the unary pressure temperature phase diagram, measurements, and calculations. For development, form I would be the best form to use in any solid dosage form, which should be thoroughly protected against humidity.Postprint (author's final draft

Development of an Analytical Method for the Plasma Determination of Five Anti-Epileptics and their Metabolites by HPLC: Comparison with Immunoanalytical Methods

International audienc

Use of mouse model in pharmacokinetic studies of poorly water soluble drugs: Application to fenofibrate

International audienceFenofibrate has recently been used as drug model in several studies with the objective of optimizing the development of some drug delivery systems to overcome the problem of poor aqueous solubility of the newly discovered API. The adequacy of the drug delivery systems to improve the oral bioavailability of encapsulated drug is generally evaluated by a pharmacokinetic study. The use of mouse as animal model for pharmacokinetic studies has become more important in the last decade because of many similarities with the human model in terms of the mechanisms of absorption, metabolism and elimination. Nevertheless, the mouse is often hampered by the very small volumes of blood that could be obtained during sampling. The aim of this work was to overcome the problem of lower volumes of plasma withdrawn by developing an appropriate protocol for sample preparation and a suitable HPLC method for drug quantification in mouse plasma. Linear calibration curve was obtained over the concentration range from 0,16 μg/mL to 32 μg/mL (r 2 = 0,9999) with LLOQ of 0,16 μg/mL The RSD in both intra-run and inter-run precision study was less than 11% and the extraction recoveries were above 91.9%. The reproducible method was successfully applied to the pharmacokinetic study of fénofibrate in mouse

Density functional theory and liquid chromatography-multistage mass spectrometry to characterize raltitrexed photo-degradation mechanisms

International audienc

An integrated view of theiInfluence of temperature, pressure, and humidity on the stability of trimorphic cysteamine hydrochloride

Understanding the phase behavior of pharmaceuticals is important for dosage form development and regulatory requirements, in particular after the incident with ritonavir. In the present paper, a comprehensive study of the solid-state phase behavior of cysteamine hydrochloride used in the treatment of nephropathic cystinosis and recently granted orphan designation by the European Commission is presented employing (high-pressure) calorimetry, water vapor sorption, and X-ray diffraction as a function of temperature. A new crystal form (I2/a, form III) has been discovered, and its structure has been solved by X-ray powder diffraction, while two other crystalline forms are already known. The relative thermodynamic stabilities of the commercial form I and of the newly discovered form III have been established; they possess an overall enantiotropic phase relationship, with form I stable at room temperature and form III stable above 37 degrees C. Its melting temperature was found at 67.3 +/- 0.5 degrees C. Cysteamine hydrochloride is hygroscopic and immediately forms a concentrated saturated solution in water with a surprisingly high concentration of 47.5 mol % above a relative humidity of 35%. No hydrate has been observed. A temperature composition phase diagram is presented that has been obtained with the unary pressure temperature phase diagram, measurements, and calculations. For development, form I would be the best form to use in any solid dosage form, which should be thoroughly protected against humidity

An Integrated View of the Influence of Temperature, Pressure, and Humidity on the Stability of Trimorphic Cysteamine Hydrochloride

Understanding the phase behavior of pharmaceuticals is important for dosage form development and regulatory requirements, in particular after the incident with ritonavir. In the present paper, a comprehensive study of the solid-state phase behavior of cysteamine hydrochloride used in the treatment of nephropathic cystinosis and recently granted orphan designation by the European Commission is presented employing (high-pressure) calorimetry, water vapor sorption, and X-ray diffraction as a function of temperature. A new crystal form (<i>I</i>2/<i>a</i>, form III) has been discovered, and its structure has been solved by X-ray powder diffraction, while two other crystalline forms are already known. The relative thermodynamic stabilities of the commercial form I and of the newly discovered form III have been established; they possess an overall enantiotropic phase relationship, with form I stable at room temperature and form III stable above 37 °C. Its melting temperature was found at 67.3 ± 0.5 °C. Cysteamine hydrochloride is hygroscopic and immediately forms a concentrated saturated solution in water with a surprisingly high concentration of 47.5 mol % above a relative humidity of 35%. No hydrate has been observed. A temperature–composition phase diagram is presented that has been obtained with the unary pressure–temperature phase diagram, measurements, and calculations. For development, form I would be the best form to use in any solid dosage form, which should be thoroughly protected against humidity