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In order to ensure efficient and safe drug dosage, predictable shelf life and consistent product quality, product screening is employed.
Today’s pharmaceutics are delivered either orally (eg pills or suspensions) or as injectables. In both cases a prolonged exposure to low dose of the active component is preferable to short-burst high dosage treatment to minimize undesirable side effects of the active. This controlled drug release is influenced by particle size and formulation stability. Colloidal dispersion such as microemulsions are used to solubilise drugs and ensure safe and consistent drug release. In order to accomplish this formulation goal, both the particle size and the particle charge (zeta potential) need to be monitored.
For the end product on the shelf, further screening is utilized to ensure adequate shelf life, batch to batch consistency and predictable drug performance. Particle size is easily and quickly studied by dynamic light scattering (DLS). The particle stability (zeta potential) is detected by electrophoretic light scattering (ELS).
Therapeutic proteins are an example of how DLS may help in effective product screening. The thermal melting point of proteins can be related to the shelf-life of the product. The exquisite sensitivity of the technique allows the ability to distinguish different oligomeric and quaternary protein states and easily confirms denaturing conditions. External solution/preparation conditions (buffer, pH, salts, temperature, storage, freezing, lyophilization) may show a significant influence on the protein size as the Dynamic Light Scattering technique is ideally suited to monitor small changes.
Protein interaction detection for example between antibody and antigen may be used to confirm the activity or expected behaviour of a selected compound, not as easily available with other assays.
Protein crystallography screening has become popular in recent years to find and optimize solution conditions for enhanced success in structural biology. A homogenous protein solution increases the chances of obtaining well-refracting protein crystals to find the molecular structure needed for structure based drug design (SBDD).
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Presentations:
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On demand presentation on "Predicting Formulation Stability with the Zetasizer Nano System ".
For industries involved in the production of colloidal dispersions, the long-term dispersion stability is an important characteristic of the final product. The stability of a particle dispersion will depend upon the balance of the repulsive and attractive forces that exist between particles as they approach one another. The magnitude of the electrostatic interactions between particles can be determined by measuring the zeta potential of the particle dispersion and hence zeta potential measurements can be used to predict dispersion stability. This presentation describes the application of zeta potential measurements in predicting dispersion stability.
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On demand presentation on "Why measure Zeta Potential?".
This presentation provides an overview of what zeta potential is, what affects it and how it is measured. The use of zeta potential in predicting dispersion stability is also discussed and illustrated with application examples.
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On demand presentation on:"What Affects Dispersion Stability and How Can We Predict It?".
The stability of a particle dispersion is determined by the balance between repulsive and attractive forces which the particles experience as they approach one another. This presentation discusses how dispersion stability can be achieved, what factors influence it and how an understanding of these factors can be used to predict the shelf life of a product.
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Application notes:
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Photon Correlation Spectroscopy and Microemulsions.
Microemulsions are colloidal dispersions that can be used for the solubilisation of drugs. In order to ensure safe and efficient dosage, predictable shelf life and batch to batch consistency, particle size must be closely controlled. One technique that can be used for size determination of microemulsions is that of Photon Correlation Spectroscopy (PCS).
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Characterization of Protein Melting Points.
The sensitivity of Dynamic Light Scattering (DLS) is sufficient to distinguish different oligomeric and quaternary protein states, and is ideally suited for monitoring the stability of the protein structure to denaturing conditions.
Proteins are composed of polypeptide chains with unique 3-dimensional structures in the native state. These structures are stabilized by a combination of electrostatic and hydrophobic interactions, combined with a large degree of flexibility inside the structure of the molecule. If solution conditions change, denaturation or unfolding can quickly occur, along with a subsequent change in size. The sensitivity of dynamic light scattering is ideally suited for monitoring the stability of a protein to denaturing conditions. The protein melting point temperature is indicative of the thermal stability of a protein. Modifications (such as glycosylation) can influence the stability and are easily observed with dynamic light scattering. |
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Pharmaceutical Drug Development Screening for Promiscuous Inhibitors.
New lead compounds for drug design are typically discovered using high throughput combinatorial techniques that utilize large screening databases of known compounds. These small molecule databases however, have been shown to contain promiscuous inhibitors that function as effective enzyme inhibitors, while exhibiting non drug-like traits such as poor specificity and uncorrelated structure-function relationships. Recent studies indicate that the concentration dependent inhibitory nature of these promiscuous inhibitors is a direct consequence of non-specific aggregation, i.e. when the molecule is aggregated it functions as an effective inhibitor; when aggregation is absent, so is the inhibitory activity of the compound. While the mechanism for this aggregation controlled inhibition is still under examination, the suggested pathway is one wherein the enzyme absorbs either onto the surface or into the interior of the drug aggregate, which subsequently restricts active site access. Photon correlation spectroscopy or dynamic light scattering (DLS) is an analytical technique capable of measuring the size of very small particles, at low sample concentrations. Because of the molecular weight dependence of the particle scattering intensity, the technique is extremely sensitive to the presence of aggregates. As such, DLS is an ideally suited screening tool for identifying promiscuous inhibitors from the cache of lead compound candidates selected from
small molecular databases. This application note summarizes measurements performed on a candidate drug that exhibits inhibitory behavior at certain concentrations..
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Study of Antibody:Antigen Interactions Using Light Scattering Techniques.
Published in "International LabMate" August 2000.
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Dynamic Light Scattering - The Silver Bullet for Crystal Screening?.
In the early 1990s, dynamic light scattering (DLS) was introduced as a screening tool for crystallography. Over the past decade DLS has become widely accepted in this role and dynamic light scattering instruments are now routinely integrated into X-ray crystallography research centers. A common misconception however, is that dynamic light scattering can tell the researcher which samples are likely to yield high quality crystals. In practice, DLS is more appropriately used as a tool for screening out samples that are unlikely to yield crystals. In this article, we address the subtle difference in these two points, and examine the value of light scattering techniques as crystal screening tools.
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