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PubMed2004

[Effect of programmed humidification and temperature on drug stability].

AIM: To simplify the study on the effect of relative humidity and temperature on drug stability. METHODS: The stability of penicillin potassium as a model was studied with programmed humidifying and heating. RESULTS: Results of our programmed humidifying and heating experiments are comparable to those of traditional experiment at constant humidity and temperature. CONCLUSION: Programmed humidifying and heating experiments are applicable to drug stability study.

Drug Stability↗
PubMed1984

Statistical prediction of drug stability based on nonlinear parameter estimation.

The classical approach in Arrhenius prediction of drug stability uses two sequential steps of linear regression involving (a) a function of drug content versus time to obtain the rate constants (k) at several elevated temperatures and (b) the relationship of logarithm of mean k versus reciprocal temperature to predict the room temperature rate constant and hence the shelf-life of the drug. Uncertainties in drug content determinations are often neglected in the second regression. The classical approach also provides a wide and unsymmetrical 95% confidence interval for the predicted shelf-life. We have developed equations which allow for direct statistical prediction of shelf-life using observed values of drug content, time, and temperature. Nonlinear regression analysis was employed to provide parameter estimates of drug shelf-life and the energy of activation. The developed approach was shown to provide good estimates of shelf-life with meaningful statistics of reactions over a wide range of stability and energetics, with various kinetic orders, with different levels of noise in the data, and with different types of data structure. Comparison between the nonlinear approach and the classical approach showed that the nonlinear approach provided better mean estimates of shelf-life with much smaller and more symmetrical 95% confidence intervals than the classical approach. The method appears sufficiently robust and wide-ranging as to be potentially applicable for the prediction of the drug stability of pharmaceutical products.

Chemistry, Pharmaceutical↗
PubMed1996

Median-based robust regression methods in prediction of drug stability.

The classical isothermal approach for the prediction of drug stability exploits least squares regression. In this paper the use of some robust regression techniques to estimate the rate constants at different temperatures has been evaluated. These techniques are able to give accurate estimates when data are contaminated by the presence of outliers. The successful application of two robust methods, single median and repeated median, to real stability data from the literature is shown. Moreover, the authors have modified the original methods in order to apply them to data sets with replicates, typical of stability studies. The performances of the modified techniques have been investigated with simulated data sets containing outliers and with real data. They appear suitable for preliminary stability studies, especially on solid dosage forms. For a quick implementation of these methods, macroprograms written for a widely used spreadsheet are reported.

Computer Simulation↗
PubMed1999

Incorporating batch effects in the estimation of drug stability parameters using an Arrhenius model.

The nonlinear estimation of drug stability parameters (energy of activation Ea and shelf-life tY) by conventional approaches employs equations relating drug content determination C at time t and temperature T. The identification procedures lead to the determination of only one initial drug content C0 for several different experiments. However, it is well known that because of experimental concentration variation or of intentional modification of the experimental schedule, there are as many initial drug contents as experiments. For these reasons, a method which takes into account batch effects is proposed to determine stability parameters and also all initial drug contents C0j where j is the index of experiment in one step. This method is more accurate from a statistical viewpoint and is suitable for data treatment in pharmaceutical industries where the initial drug content of each batch entering the stability program can be checked a posteriori. The application of this method is shown on real kinetic data from the hydrolysis of acetylsalicylic acid (ASA).

Algorithms↗
PubMedDate not supplied

Effect of drug stability on the analysis of release data from controlled release microspheres.

The objective of this study was to determine the effect of drug stability on the analysis of in vitro release data from controlled release microspheres. Amoxicillin was chosen as a model drug and its stability in various media determined. The in vitro release of amoxicillin from PLGA microspheres was investigated in phosphate buffered saline (PBS) containing either Tween-80 or Tween-80 + Na-azide. Drug concentration in the media and the amount remaining inside the microspheres were analysed using HPLC. Amoxicillin degraded rapidly in PBS. The rate of degradation was reduced in the presence of Tween 80 and Na-azide. Drug release from the microspheres was analysed with and without considering the drug degradation rate. Mass balance between released drug, drug remaining in the microspheres and initial drug loading was only achieved when drug degradation was accounted for. Drug stability should be considered in analysis of in vitro extended release data, since released drug may degrade with time. These results have implications for in vitro release studies for controlled release products that include drugs and other compounds which are susceptible to degradation during the course of the release study.

Amoxicillin↗
PubMed2007

Pooling batches in drug stability study by using constant-width simultaneous confidence bands.

One important study objective in drug stability studies is to estimate the shelf-life of a drug. A key statistical problem involved in this is how to assess the practical equivalence of different batches of the same drug so that different batches can be subgrouped to produce a single shelf-life for the drug. In this paper constant-width simultaneous confidence bands are proposed to quantify the magnitude of difference between different batches, with a particular view to establish the practical equivalence of different batches. This approach is suitable for the situation that the intercepts and slopes of the regression lines for the batches cannot be assumed to be equal. It is shown how constant-width simultaneous confidence bands can be easily constructed for the multiple comparison of several general linear regression models. In particular, it is shown that constant-width simultaneous confidence bands have a better chance to establish the equivalence than, and so are preferable to, the hyperbola-shaped simultaneous confidence bands considered.

Drug Stability↗
PubMed1969

[Drug stability].

Explore the source record for details and available documents.

Biological Products↗
PubMed2005

Stabilizing drug molecules in biological samples.

Stability is one of the basic parameters, along with accuracy, precision, selectivity, and sensitivity, for bioanalytic method validation in nonhuman and clinical pharmacology/toxicology, bioavailability (BA), bioequivalence (BE), and other studies related to the drug approval process. In the drug development stage where stability evaluation is obligatory, instability of drug candidates in biologic samples will seriously complicate assay validation. In this article, we review the general strategies and methodologies such as temperature adjustment, pH control, derivatization, and addition of inhibitors and oxidant that are commonly employed to stabilize pharmaceuticals that might be unstable in biologic samples.

Animals↗
PubMed2001

Tetraspan protein CD151: a common target of mood stabilizing drugs?

The latency in onset of antimanic and mood stabilizing effects of lithium suggest that long-term neuronal adaptations mediated by changes in gene expression may be important to the therapeutic action of lithium treatment. Using differential display-polymerase chain reaction, several novel, hitherto unexpected lithium-regulated genes have been isolated, all of which would not have been predicted with the candidate gene approach. During the process of characterizing one of these novel genes, we have identified a cDNA clone, a homolog of human/mouse transmembrane-4-superfamily (also known as tetraspan) protein, CD151, the expression of which was significantly decreased in rat frontal cortex following chronic (five weeks) lithium treatment. The reduction of CD151 mRNA levels was also observed following chronic administration of carbamazepine and valproate. Conversely, the expression of CD151 was not altered by short-term (one week) lithium treatment and by chronic administration of the tricyclic antidepressant, imipramine, or the typical antipsychotic, haloperidol, further demonstrating time dependence and pharmacological specificity of this effect. Our studies, thus, indicate that CD151 may represent a therapeutically relevant target common to lithium and the anticonvulsant mood stabilizing drugs, carbamazepine and valproate.

Affect↗
PubMed2003

Gene expression and mitotic exit induced by microtubule-stabilizing drugs.

To explore the molecular mechanisms underlying the actions of Taxol and the functionally related molecule epothilone B (EpoB), we have analyzed the gene expression profiles in A549 cells in response to increasing concentrations of these microtubule-stabilizing drugs. An almost identical expression pattern was observed in cells treated with either Taxol or EpoB. Low concentrations of the drugs induced aberrant mitosis including asymmetric and multipolar cell divisions. At drug concentrations that triggered G(2)-M arrest, cells escaped from a prolonged mitotic arrest without cell division, resulting in tetraploid G(1) cells. This mitotic slippage is correlated with diminished expression of cdc2 kinase, topoisomerase IIalpha, BUB3, and BUB2-like protein 1, as well as with an increased expression of 14-3-3-sigma. Poly(ADP-ribose) polymerase cleavage, an early indicator of apoptosis, occurred in cells undergoing mitotic slippage and in aneuploid cells resulting from aberrant mitosis. In contrast, cells arrested in mitosis demonstrated no signal for apoptosis but had an increased expression of survivin, an inhibitor of apoptosis. Induction of aneuploid or tetraploid G(1) cells was accompanied by increased expression of CD95, p21, and BTG2 that may contribute to cell death because their expression was diminished in an EpoB-resistant cell line. In contrast, expression of GADD45 and PTGF-beta could promote cell survival. We conclude that abnormal mitotic exit is required for apoptotic cell death induced by microtubule-stabilizing drugs.

Antineoplastic Agents↗
PubMed1999

The use of isothermal heat conduction microcalorimetry to evaluate drug stability in tablets.

Isothermal heat conduction microcalorimetry was used to evaluate chemical stability of a solid drug in tablets. A variety of mixtures were compressed to flat faced tablets of 300 mg weight and 10 mm diameter. The content of drug amounted to 10%. Besides drug containing tablets, also placebo tablets as well as the non compressed mixtures were examined by microcalorimetry at 80 degrees C. The excipient Emcompress exhibited a substantially high exothermic heat flow that was due to a change in crystallinity. For Emcompress containing tablets this interfering signal resulted in such a way that the calorimetric data did not reflect the drug decomposition with sufficient accuracy. In the case of the other preparations the heat flow of the excipients were low, and the calorimetric data did reflect the drug decomposition. The stability increased with increasing content of CaHPO4, respectively, with decreasing content of water.

Calcium Phosphates↗
PubMed1987

A critical appraisal of drug stability testing methods.

The determination of potency or shelf life, impurity limit testing, and study of reaction mechanisms are considered as different aspects of drug stability. These aspects traditionally have been treated in isolation. The current criterion for a stability-indicating assay is criticized and the merits of choosing reactant or decomposition product for monitoring decomposition are discussed. The initial-rate method of determining reaction order and rate constants by analysis of decomposition product is described and its potential advantages over traditional integral methods are discussed. Examples of the application of the initial-rate method to simple and complex drug decomposition systems for the determination of decomposition rate constants are given. Applications to limit testing and study of reaction mechanisms are outlined and the dependence of the initial-rate method and decomposition product analysis on modern chromatographic methods is emphasized.

Drug Stability↗
PubMed1981

[The influence of several membrane stabilizing drugs on the induced hereditary myotonia--a methodic way to test the effectiveness of drugs on myotonia (author's transl)].

The therapeutic effectiveness of several membrane stabilizing drugs was investigated on experimentally induced myotonia by 2,4-Dichlorophenoxyacetate (2,4-D) and in 20 patients with myotonia congenita. Procainamide and quinine showed a better antimyotonic effect in-vitro- as well as in-vivo-experiments on the cold blood muscle and the rat than Sparteine sulfate and Tachmaline (Ajmalin). The two last-mentioned drugs had nearly the same effect. Because of these experimental results only procainamide and sparteine sulfate were clinically used. Quinine was not used because of the well known side-effects. Mention is made of the fact, that the therapeutic effect depends on the dose or the concentration. The results support not only the theoretic considerations on the pathogenesis of myotonia but also recommend to carry out further pharmacological investigations with this method.

2,4-Dichlorophenoxyacetic Acid↗