Biomedical subjects

D L Massart

Publications and source records attributed to D L Massart.

At least 19 recordsLinked to original sources

PubMed2002

Principal component analysis of dissolution data with missing elements.

The use of principal component analysis (PCA) for incomplete dissolution data sets is examined. The PC space is constructed using a reference set and the test set is projected in that space. Several cases such as a reference set with missing data, an incomplete test set and both sets measured at different time points, are discussed using two examples: one simulation and one obtained from the pharmaceutical practice. From the many possibilities to deal with missing data, the expectation-maximization algorithm in combination with PCA was chosen. The influence on the similarity or f2 factor is examined too. The sampling with replacement or bootstrap technique, which can be used to obtain confidence limits, can also be used when missing data are present in one of the data sets.

Algorithms↗

PubMed2002

Screening approach for chiral separation of pharmaceuticals. Part I. Normal-phase liquid chromatography.

A strategy for rapid screening for the separation of chiral molecules of pharmaceutical interest by normal-phase liquid chromatography using three cellulose/amylose stationary phases is proposed. In a first step, the most important parameters for the separations were determined and studied for their effects by means of experimental designs. Results showed that the cellulose tris-(3,5-dimethylphenylcarbamate), the amylose tris-(3,5-dimethylphenylcarbamate) and the cellulose tris-(4-methylbenzoate) stationary phases have very broad and complementary enantiorecognition properties. The type of organic modifier used in the mobile phase appeared to have a dramatic influence on the quality of the separation. Based on the results of the preliminary study, a screening strategy was developed and successfully applied to a set of 36 diverse drugs. Enantiomeric separation was observed in 89% of cases and the analysis times were usually shorter than 20 min.

Chromatography, Liquid↗

PubMed2002

Knowledge-based system for method development of chiral separations with capillary electrophoresis using highly-sulphated cyclodextrins.

Method development for chiral separations is not easy because it requires experience and many experimental possibilities can be chosen. In order to help the analyst, a knowledge-based system (KBS) for the rapid determination of experimental parameters, which allow a baseline separation of enantiomers, has been developed. On the basis of own laboratory knowledge, completed with literature data, rules were defined and a KBS was built. Five different techniques are considered in this KBS. This paper describes the capillary electrophoresis (CE) section, in which a strategy has been defined based on the use of highly-sulfated cyclodextrins as chiral selectors. A structured representation of the knowledge and its implementation in Toolbook software is presented.

Artificial Intelligence↗

PubMed2001

Heroin impurity profiling: trends throughout a decade of experimenting.

Heroin is still one of the most frequently abused drugs of today. All over the world, law enforcement agencies try to eradicate the illicit production and trafficking of this potent and highly addictive narcotic. To this aim, important information is provided by physical and chemical toxicological analysis of confiscated samples, with special attention for the identification and the quantification of minor components, such as the impurities related to the origin and manufacturing. By combining these data complex characterisations, i.e. impurity profiles, chemical signatures or fingerprints, can be obtained and used for comparative analysis. This review focuses on heroin impurity profiling during the 1990s, proclaimed by the United Nations as the 'Decade for Eradicating Drug Abuse'. Special attention will be given to the new trends in analytical techniques as well as in data handling strategies, so called chemometrics, to produce these profiles. The latter can be used in comparative analysis of seized heroin samples for tactical (batch-to-batch comparison) and strategic (origin determination) intelligence purposes.

Chemistry Techniques, Analytical↗

PubMed2001

The use of wavelets for signal denoising in capillary electrophoresis.

The discrete wavelet transform was applied to denoise electropherograms in capillary electrophoresis (CE). The use of the Haar wavelet and translation invariant denoising were found to be very efficient for this purpose. An important improvement was obtained, as compared with Savitzky-Golay and Fourier, which are the most commonly used techniques for denoising in the instrumentation software packages. A better removal of the noise and, especially, a better preservation of the shapes of very sharp peaks was achieved. Removal of the baseline variations was also investigated.

Journal Article↗

PubMed2001

Application of linear mixed effects models to the evaluation of dissolution profiles.

The performance of linear mixed effects models for the comparison of dissolution profiles is examined. This type of model is frequently used by statisticians, but is rather unknown to people that work in dissolution laboratories. Hence, an extensive theoretical part was introduced to make the methodology more accessible. Firstly, repeated measures ANOVA is discussed, followed by the "real" linear mixed effects models. The theory is applied to two types of dissolution data: one corresponding to an immediate and another to a slow release formulation. We tried to use as much as possible the standard settings of the statistical software (S-plus). Suggestions are given to solve problems encountered during model fitting. It was found that the statistical limits are much more discriminative than the similarity factor.

Analysis of Variance↗

PubMed2001

Using experimental design to optimize the process parameters in fluidized bed granulation on a semi-full scale.

A face-centered central composite design was applied in order to optimize the granulation process on a semi-full scale (30-kg batch) for the geometric mean granule size. The granulation process variables investigated were: inlet air temperature, inlet airflow rate, spray rate and inlet air humidity. Based on the process variables, the theoretical powder bed moisture content after the spraying process and a measure for the droplet size were determined. Multiple regression modeling was used to develop two models for the granule size: an empirical model, based on the four process parameters, and a fundamental model, based on the balance between the granule growth affected by the theoretical powder bed moisture content and the droplet size and the breakage effect of the airflow rate. These regression models were used to optimize the granulation process to obtain a granule size between 300 and 500 microm. Additional experiments confirmed that these models were valid. Other granule properties, namely the geometric standard deviation, the Hausner index, the angle of repose and the moisture content, were evaluated at the optimal operation conditions.

Research Design↗

PubMed2001

Influence of the roll compactor parameter settings and the compression pressure on the buccal bio-adhesive tablet properties.

Miconazole buccal tablets were prepared via a dry granulation process. By applying a factorial design (2(4)), the roll compactor parameters (compaction force, gap between the rolls, type of the rolls (smooth, ribbed) and the sieve aperture) were optimised for the tablet strength. The compaction force and the roll type significantly affected the tablet strength. Afterwards, a quarter fractional factorial design (2(5-2)) was applied, consisting of the four compactor parameters and additionally the compression pressure, in order to optimise these parameters for the dissolution profile and the buccal bio-adhesion characteristics (bio-adhesive force and energy). In order to evaluate the dissolution profiles properly, the similarity factor between sample and a zero-order release reference profile was used. The compression pressure and the roll type significantly affected the dissolution profile. The sieve aperture had a significant effect on the buccal adhesion properties and the compaction force had a significant effect on the dissolution profile and the bio-adhesive energy. The gap between the rolls affected the bio-adhesive force significantly.

Antifungal Agents↗

PubMed2001

Quantitative structure-retention and retention-activity relationships of beta-blocking agents by micellar liquid chromatography.

Sixteen beta-blocking agents (acebutolol, alprenolol, atenolol, bisoprolol, carteolol, celiprolol, esmolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, practolol, propranolol, sotalol and timolol) showing a large range of hydrophobicity (octanol-water partition coefficients, log P between -0.026 and 2.81) were subjected to micellar liquid chromatography with sodium dodecyl sulfate as micelle forming agent, and n-propanol as organic modifier. The correlation between log P and the retention factor extrapolated to a mobile phase free of micelles and organic modifier was investigated. The use of an interpolated retention factor or the retention factor for specific individual experimental mobile phases was however advantageous since the retention factors of all beta-blocking agents were measurable in the selected mobile phases. Good correlations with log P and with in vitro biological parameters (cellular permeability coefficients in Caco-2 monolayers and apparent permeability coefficients in rat intestinal segments) were found.

Adrenergic beta-Antagonists↗

PubMed2001

Evaluation of dissolution profiles using principal component analysis.

The performance of principal component analysis (PCA) for the evaluation of dissolution profiles is examined and compared with other methods such as the similarity factor and the calculation of the area under the curve. Both simulated and real data from the pharmaceutical industry are used. The PCA scores plots of the dissolution curves provide information about the between- and within-batch variations. Differences in level or shape can be observed in the first two principal components (PCs). Irrelevant irregularities, which have a strong influence on the similarity factor, are neglected in PC1/PC2. To detect outliers in a set of dissolution curves, PCA was preferred above Hotelling's T2 test. In general, PCA is found to be a useful technique to examine dissolution data visually, but however, it does not contain criteria to decide if batches are similar or not. This can be done by combining PCA with the resampling with replacement or bootstrap method to construct confidence limits.

Solubility↗

PubMed2001

Rapid screening for chiral separations by short-end injection capillary electrophoresis using highly sulfated cyclodextrins as chiral selectors.

Two series of amino acid derivatives and phenylamines were used to evaluate the potential of highly sulfated cyclodextrins (HS-CDs) for the screening for chiral separations by capillary electrophoresis (CE). HS-CDs showed to be very versatile and to exhibit very high enantioselectivity. The use of short-end injection allowed to reduce dramatically the analysis time. From the results obtained, a scheme for the rapid screening of enantiomeric molecules was developed and applied to various chiral drugs. Results are very satisfying as almost all compounds (62 out of 67) could be baseline-resolved. Usually, less than three experiments were necessary to obtain very good separation.

Acids↗

PubMed2001

Assessing molecular similarity/diversity of chemical structures by FT-IR spectroscopy.

FT-IR spectra have been investigated for their ability to distinguish compounds which are chemically diverse and to produce clusters of compounds which makes sense chemically. Principal component analysis (PCA) was applied to the analysis of a small database of FT-IR spectra. The effect of the data pretreatment step of log transformation on spectral data pattern was also visualized by using PCA plots. The method of sequential projection pursuit (SPP) was applied to detect inhomogeneities in the data. Finally, cluster analysis of these spectra, depending on unweighted pair-group average linkage, was carried out.

Cluster Analysis↗

PubMed2001

Guidance for robustness/ruggedness tests in method validation.

This paper is intended to give guidance in setting-up and interpreting a robustness test. The different steps in a robustness test are discussed and illustrated with examples. The recommendations given for the different steps are based on approaches found in the literature, several case studies performed by the authors and discussions of the authors within a commission of the French SFSTP (Société Française des Sciences et Techniques Pharmaceutiques). In the end of the paper a worked-out example is given of a robustness test case study set up and interpreted according to the guidelines.

Chemistry, Pharmaceutical↗

PubMed2001

Combining spectroscopic data (MS, IR): exploratory chemometric analysis for characterising similarity/diversity of chemical structures.

Combined infrared--mass spectra (IR--MS) have been used to examine a small data set of synthetic substances in order to elucidate whether a combination of spectral descriptors yield better classification and similarity predictions than their corresponding individual spectral descriptors. To eliminate differences in variation, a logarithmic transformation or log double-centering pretreatment was necessary. Principal component analysis (PCA) was applied to observe clusters of similar compounds. Hierarchical upgma-cluster analysis was also used for data classification.

Mass Spectrometry↗

PubMed2001

Using experimental design to optimize the process parameters in fluidized bed granulation.

In this study many parameters were screened for a small-scale granulation process for their effect on the yield of granules between 75 and 500 microns and the geometrical granule mean size (d50). First a Plackett-Burman design was applied to screen the inlet air temperature, the inlet flow rate, the spray rate, the nozzle air pressure, the nozzle spray diameter, and the nozzle position. The Plackett-Burman design showed that the key process parameters were the inlet flow rate and the spray rate and probably also the inlet air temperature. Afterward a fractional factorial design (2(5-2)) was applied to screen the remaining parameters plus the nozzle aircap position and the spraying time interval. The fractional factorial design showed that the nozzle air pressure was also important. As the target values for the granule yield (between 75 and 500 microns) and the geometric mean granule size (between 300 and 500 microns) were reached during the screening experiments, further optimization was not considered necessary.

Air Movements↗

PubMed2001

Susceptibility testing of pathogenic fungi with itraconazole: a process analysis of test variables.

A 2(10-5) fractional factorial model was used to investigate the influence of 10 process variables in broth microdilution susceptibility tests with itraconazole against eight isolates of Candida species and six isolates of filamentous fungi in two growth media. An analysis of variance (ANOVA) indicated that glucose concentration and incubation time both significantly influenced control turbidity optical density (OD) values for most of the Candida spp. isolates, while incubation in >10% CO(2) versus ambient air, incubation temperature and inoculum size significantly influenced these OD values for about half of the yeast isolates. Control OD values for the mould isolates were most influenced by incubation time and temperature, and by occlusion of the wells with an adhesive sticker. Three statistical approaches, ANOVA, rank transformation and Mann-Whitney U-test, were used to assess the influence of the variable combinations on MIC, determined with a 50% growth reduction end-point. Incubation temperature and time, glucose concentration and inoculum size were the variables that most often affected susceptibility results to the level of statistical significance; however, the supplier of RPMI 1640 medium, the use of adhesive stickers and the atmosphere of incubation significantly influenced the MIC for some isolates. The medium used to prepare the test inoculum, the solvent used to prepare the stock solution and the shape of the microdilution plate wells significantly affected outcome, but only sporadically. A principal component analysis of the data matrix confirmed this order of relative influence of the test variables on the MIC. Since each fungal isolate responded differently to combinations of process variables in the test, we conclude that any unified method for antifungal susceptibility determination represents a compromise, rather than an idealized system.

Antifungal Agents↗

PubMed2000

Exploratory chemometric analysis of the classification of pharmaceutical substances based on chromatographic data.

A chemometric study has been conducted on a published data set consisting of the retention times of 83 substances, from five pharmacological families, on eight HPLC systems. Principal component analysis, clustering and sequential projection pursuit were applied. In this way it was investigated to what extent the combination of chromatography and chemometrics allows one to make conclusions about pharmacological activities of (candidate) drugs and what the contribution is of the different HPLC systems considered.

Chromatography, High Pressure Liquid↗

PubMed2000

Development and optimisation of a flow injection assay for fluticasone propionate using an asymmetrical design and the variable-size simplex algorithm.

A flow injection analysis method is described to determine fluticasone propionate, based upon a novel adaptation of the reaction of o-phthalaldehyde with a thiol and a primary amine. The method, which allows both UV and fluorescence detection, has been optimised using experimental design. First a screening is executed to select the significant factors and in a second step these factors are optimised with the variable-size simplex algorithm. In the screening step, a two-level fractional factorial design is compared with an asymmetrical design containing the same number of experiments, but in which one factor is at three levels. It was found that in both designs the same significant variables are detected for the two-level factors, but that for the three-level factor the asymmetrical design confirms an expectation of having a (local) optimum in the examined domain, whilst from the two-level design this is not at all apparent. Complete optimisation was carried out for both UV and fluorescence detection. The two detection methods did not have the same significant variables. For the UV detection, the temperature and the pH adjustment on-line (concentration of sodium hydroxide and amount of boric acid) were the most critical parameters. For the fluorimetric detection the temperature and the fraction of methanol were critical. Moreover the conditions found to be optimal are different for both detection methods.

Algorithms↗