Daryl A. Roston

Characterization of polymorphs of a new anti-inflammatory drug

The present study demonstrates the utility of a diversified analytical approach for the characterization and quantitative analysis for two polymorphs of a new anti-inflammatory agent, (+/-)-7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy-3,4-dihydro -8-propyl- 2H-1-benzopyran-2-carboxylic acid (SC-41930). The existence of two distinct crystal polymorphs of SC-41930 was qualitatively indicated through microscopy and application of thermal methods of analysis. The application of TGA was important for establishing that the two solid forms were, in fact, polymorphs, as opposed to solvated and unsolvated drug substances. The application of IR spectrometry revealed spectral features in the carbonyl stretching region, which were characteristic and unique to the two SC-41930 polymorphs. DRIFT spectrometry was implemented as the sampling method of choice to eliminate the possibility of polymorphic transformations during conventional mulling or KBr pellet sampling procedures. The DRIFT spectrometry procedure permitted development of a quantitative assay for detection of the low-melting polymorph (as an impurity) in high-melting samples. Calibration plots showed acceptable linearity of response from 0 to 25% (w/w) low-melting samples spiked into the high-melting polymorph. The performance characteristics of the method indicated good run-to-run and day-to-day consistency for its intended use.

Comparison of drug substance impurity profiles generated with extended length columns during packed-column SFC

The current study assesses the effect of extending column length during gradient packed column sub/supercritical fluid chromatography (PCSFC) experiments on the detection of known and unknown impurities in a drug substance sample. Quantitative drug substance impurity profiles were generated and compared using multiple column PCSFC and HPLC conditions. Also, chromatographic figures of merit were estimated and compared for components of a standard mixture during PCSFC experiments, which used one column, four columns, and six columns in series.

Demonstrative validation study employing a packed column pressurized fluid chromatography method that provides assay, achiral impurities, chiral impurity, and IR identity testing for a drug substance

Assay development, assay validation, and documentation are reported here for a single packed column pressurized fluid chromatographic/ultraviolet (UV) method that provides: (1) simultaneous detection and quantification for the chiral drug, the chiral impurity and seven achiral impurities; and (2) a Fourier transform infrared (FT-IR) spectrometric identification test result for the Searle drug substance sample, xemilofiban. The separation is achieved in less than 30 min with three columns in tandem and a gradient of CO2-CH3OH. The post-column flow is split between UV (assay) and FT-IR (identification). Precision and accuracy are consistent within figures of merit obtained by liquid chromatographic-ultraviolet assays on analogous drug substances. The reported procedure combines three typical drug substance tests into one test (e.g. chiral impurities, achiral impurities, and infrared identification).

Supercritical fluid extraction—Supercritical fluid chroomatography for analysts of a prostglandin: HPMC dispersion

AbstractAn on-line SFE-SFC system was used to extract and chromatograph a synthetic prostaglandin from hydroxypropyl methylcellulose (HPMC), which is a widely used material in controlled-release drug formulations. The only sample preparation for the on-line SFE-SFC analysis of the dispersion was weighing the sample into the extraction vessel insert. The extraction efficiency for a four-minute extraction was approximately 65%.

Evaluation of HPLC with Pulsed-Amperometric Detection for Analysis of an Aminosugar Drug Substance

Abstract The present report describes development of a reversed-phase, ion-pairing, high-performance liquid chromatographic method with pulsed amperometric detection for analysis of a new aminosugar drug substance, N-butyldeoxynojirimycin, which has been identified as an anti-viral agent. the method has been used to determine the purity of chemical lots prior to formulation for use in clinical trials. Elements of the method development and validation described include selectivity optimization, linearity of response, and precision.

Supercritical fluid extraction-liquid chromatography method development for a polymeric controlled-release drug formulation

We have recently been involved in the development of a method for assaying the active component in a controlled-release drug formulation, which is composed of a drug substance covalently bonded to polymer matrix. The drug substance in the formulation is the active enantiomer of misoprostol, a synthetic analog of natural prostaglandins and the active ingredient in Cytotec. Our method development consisted of a systematic evaluation of dynamic, off-line supercritical fluid extraction (SFE) as sample preparation for the formulation assay. Extracts were analyzed with normal phase and reversed-phase HPLC methods. The reversed-phase system utilized postcolumn reaction to provide selective detection of the extracted prostaglandin sample components. Several SFE parameters were investigated to optimize the recovery of the drug substance from the formulation, including sample quantity, extraction cell volume, extraction duration, supercritical carbon dioxide modifier, temperature, pressure, and collection solvent. The SFE experiments were completed with a commercially available multicell extractor. Preliminary validation studies utilized a formulation made with radiolabeled drug to determine the recovery achieved under the optimized SFE conditions and assessed the precision of replicate determinations. Analysis was completed under the optimized conditions to quantitate levels of the active component and related compounds in lots of the experimental polymeric formulation and to determine the total weight per cent extracted.

Matrix effects during standard addition quantitation of a trace volatile impurity in a drug substance sample

Abstract Matrix effects during standard addition analysis were studied through the determination of trace amounts of butyric acid (a reagent in the synthesis of an experimental drug substance and a residual component affecting the drug quality). By studying the calibration curves with the same concentrations of added component (butyric acid) and different concentrations of drug matrix, it was found that the y -intercept in standard addition analysis is comprised of three factors: (1) y -intercept from a pure analyte calibration curve (without matrix substance), (2) matrix effect from the matrix substance and (3) analyte in the matrix substance. As the matrix effect was quantitatively determined, the absolute value (without matrix effect) of butyric acid in the drug sample could be obtained. Use of an internal standard greatly improved the linearity of the calibration curve and was necessary in this determination. The combination of internal standard and standard addition approaches yielded high accuracy in the determinations.

HPLC Method Development for a New Antiarrhythmic Drug

Abstract The present report concerns HPLC method development for chemical samples of a new antiarrhythmic drug 2-methyl-5-phenyl-5-[2-[2-N, N-bis (1-methylethyl amino] ethyl]-1,3 diazabicyclo [4.4.0] octen-4-one (MPMED). Selectivity optimization for MPMED and several synthetic process intermediates with reversed-phase HPLC conditions is described. Also, the use of electrochemical and UV absorption detection for MPMED samples has been evaluated. The developed method has been validated for generation of assay data for chemical lots of MPMED.