Limits...
Hot-stage microscopy for determination of API particles in a formulated tablet.

Simek M, Grünwaldová V, Kratochvíl B - Biomed Res Int (2014)

Bottom Line: In each case, hot-stage micrographs, taken before and after the API melting point, were compared with image analysis software to obtain the PSDs.Then, the PSDs of the APIs from the disintegrated tablets were compared with the PSDs of raw APIs.Good agreement was obtained, thereby confirming the robustness of our methodology.

View Article: PubMed Central - PubMed

Affiliation: Department of Solid State Chemistry, Institute of Chemical Technology Prague, Technická 5, 166 28 Prague, Czech Republic.

ABSTRACT
Although methods exist to readily determine the particle size distribution (PSD) of an active pharmaceutical ingredient (API) before its formulation into a final product, the primary challenge is to develop a method to determine the PSD of APIs in a finished tablet. To address the limitations of existing PSD methods, we used hot-stage microscopy to observe tablet disintegration during temperature change and, thus, reveal the API particles in a tablet. Both mechanical and liquid disintegration were evaluated after we had identified optimum milling time for mechanical disintegration and optimum volume of water for liquid disintegration. In each case, hot-stage micrographs, taken before and after the API melting point, were compared with image analysis software to obtain the PSDs. Then, the PSDs of the APIs from the disintegrated tablets were compared with the PSDs of raw APIs. Good agreement was obtained, thereby confirming the robustness of our methodology. The availability of such a method equips pharmaceutical scientists with an in vitro assessment method that will more reliably determine the PSD of active substances in finished tablets.

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Comparison of PSD of raw API used in generic drug, API in generic tablet, and API in the RLD tablet.
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fig8: Comparison of PSD of raw API used in generic drug, API in generic tablet, and API in the RLD tablet.

Mentions: The aim of this part is to demonstrate the application of hot-stage microscopy analysis as a routine analytical method in the pharmaceutical industry. Bioequivalence studies are performed to demonstrate in vivo that two pharmaceutically equivalent products (in the US) or alternative pharmaceutical products (in the EU) are comparable in their rate and extent of absorption [22]. For reaching the bioequivalence, values of the maximal concentration in blood (Cmax⁡), the area under the curve of pharmacokinetic profile (AUC), and their deviations, must be situated inside the tolerance limit. Width of the limit (from 80 to 125%) is defined by the regulatory authorities and center point (100%) represents relative values of Cmax⁡ and AUC of the reference listed drug (RLD). As shown in Figure 7, the bioequivalence study of generic and reference listed drug (RLD) was not reached. We used hot-stage microscopy to compare API PSD in the RLD and generic tablet and raw API used in the generic tablet (Figure 8). The results showed a difference in PSDs of API used in the RLD and generic tablet and helped to find out why the bioequivalent study had not matched in Cmax⁡. Higher Cmax⁡ of the generic tablet was truly caused by the smaller size of API particles, as the smaller particles dissolved faster and led to higher Cmax⁡. API particles in the RLD are roughly double the size of the particles in the generic tablet. Almost identical PSDs of the raw API and API in the generic product confirm the robustness of the method.


Hot-stage microscopy for determination of API particles in a formulated tablet.

Simek M, Grünwaldová V, Kratochvíl B - Biomed Res Int (2014)

Comparison of PSD of raw API used in generic drug, API in generic tablet, and API in the RLD tablet.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4127278&req=5

fig8: Comparison of PSD of raw API used in generic drug, API in generic tablet, and API in the RLD tablet.
Mentions: The aim of this part is to demonstrate the application of hot-stage microscopy analysis as a routine analytical method in the pharmaceutical industry. Bioequivalence studies are performed to demonstrate in vivo that two pharmaceutically equivalent products (in the US) or alternative pharmaceutical products (in the EU) are comparable in their rate and extent of absorption [22]. For reaching the bioequivalence, values of the maximal concentration in blood (Cmax⁡), the area under the curve of pharmacokinetic profile (AUC), and their deviations, must be situated inside the tolerance limit. Width of the limit (from 80 to 125%) is defined by the regulatory authorities and center point (100%) represents relative values of Cmax⁡ and AUC of the reference listed drug (RLD). As shown in Figure 7, the bioequivalence study of generic and reference listed drug (RLD) was not reached. We used hot-stage microscopy to compare API PSD in the RLD and generic tablet and raw API used in the generic tablet (Figure 8). The results showed a difference in PSDs of API used in the RLD and generic tablet and helped to find out why the bioequivalent study had not matched in Cmax⁡. Higher Cmax⁡ of the generic tablet was truly caused by the smaller size of API particles, as the smaller particles dissolved faster and led to higher Cmax⁡. API particles in the RLD are roughly double the size of the particles in the generic tablet. Almost identical PSDs of the raw API and API in the generic product confirm the robustness of the method.

Bottom Line: In each case, hot-stage micrographs, taken before and after the API melting point, were compared with image analysis software to obtain the PSDs.Then, the PSDs of the APIs from the disintegrated tablets were compared with the PSDs of raw APIs.Good agreement was obtained, thereby confirming the robustness of our methodology.

View Article: PubMed Central - PubMed

Affiliation: Department of Solid State Chemistry, Institute of Chemical Technology Prague, Technická 5, 166 28 Prague, Czech Republic.

ABSTRACT
Although methods exist to readily determine the particle size distribution (PSD) of an active pharmaceutical ingredient (API) before its formulation into a final product, the primary challenge is to develop a method to determine the PSD of APIs in a finished tablet. To address the limitations of existing PSD methods, we used hot-stage microscopy to observe tablet disintegration during temperature change and, thus, reveal the API particles in a tablet. Both mechanical and liquid disintegration were evaluated after we had identified optimum milling time for mechanical disintegration and optimum volume of water for liquid disintegration. In each case, hot-stage micrographs, taken before and after the API melting point, were compared with image analysis software to obtain the PSDs. Then, the PSDs of the APIs from the disintegrated tablets were compared with the PSDs of raw APIs. Good agreement was obtained, thereby confirming the robustness of our methodology. The availability of such a method equips pharmaceutical scientists with an in vitro assessment method that will more reliably determine the PSD of active substances in finished tablets.

Show MeSH
Related in: MedlinePlus