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Influence of drug load on dissolution behavior of tablets containing a poorly water-soluble drug: estimation of the percolation threshold.
Drug Dev Ind Pharm. 2017 Aug; 43(8):1265-1275.DD

Abstract

Drug load plays an important role in the development of solid dosage forms, since it can significantly influence both processability and final product properties. The percolation threshold of the active pharmaceutical ingredient (API) corresponds to a critical concentration, above which an abrupt change in drug product characteristics can occur. The objective of this study was to identify the percolation threshold of a poorly water-soluble drug with regard to the dissolution behavior from immediate release tablets. The influence of the API particle size on the percolation threshold was also studied. Formulations with increasing drug loads were manufactured via roll compaction using constant process parameters and subsequent tableting. Drug dissolution was investigated in biorelevant medium. The percolation threshold was estimated via a model dependent and a model independent method based on the dissolution data. The intragranular concentration of mefenamic acid had a significant effect on granules and tablet characteristics, such as particle size distribution, compactibility and tablet disintegration. Increasing the intragranular drug concentration of the tablets resulted in lower dissolution rates. A percolation threshold of approximately 20% v/v could be determined for both particle sizes of the API above which an abrupt decrease of the dissolution rate occurred. However, the increasing drug load had a more pronounced effect on dissolution rate of tablets containing the micronized API, which can be attributed to the high agglomeration tendency of micronized substances during manufacturing steps, such as roll compaction and tableting. Both methods that were applied for the estimation of percolation threshold provided comparable values.

Authors+Show Affiliations

a Formulation Research and Development , F. Hoffmann-La Roche Ltd , Basel , Switzerland.a Formulation Research and Development , F. Hoffmann-La Roche Ltd , Basel , Switzerland.b Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University , Düsseldorf , Germany.a Formulation Research and Development , F. Hoffmann-La Roche Ltd , Basel , Switzerland.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28398095

Citation

Wenzel, Tim, et al. "Influence of Drug Load On Dissolution Behavior of Tablets Containing a Poorly Water-soluble Drug: Estimation of the Percolation Threshold." Drug Development and Industrial Pharmacy, vol. 43, no. 8, 2017, pp. 1265-1275.
Wenzel T, Stillhart C, Kleinebudde P, et al. Influence of drug load on dissolution behavior of tablets containing a poorly water-soluble drug: estimation of the percolation threshold. Drug Dev Ind Pharm. 2017;43(8):1265-1275.
Wenzel, T., Stillhart, C., Kleinebudde, P., & Szepes, A. (2017). Influence of drug load on dissolution behavior of tablets containing a poorly water-soluble drug: estimation of the percolation threshold. Drug Development and Industrial Pharmacy, 43(8), 1265-1275. https://doi.org/10.1080/03639045.2017.1313856
Wenzel T, et al. Influence of Drug Load On Dissolution Behavior of Tablets Containing a Poorly Water-soluble Drug: Estimation of the Percolation Threshold. Drug Dev Ind Pharm. 2017;43(8):1265-1275. PubMed PMID: 28398095.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Influence of drug load on dissolution behavior of tablets containing a poorly water-soluble drug: estimation of the percolation threshold. AU - Wenzel,Tim, AU - Stillhart,Cordula, AU - Kleinebudde,Peter, AU - Szepes,Anikó, Y1 - 2017/04/19/ PY - 2017/4/12/pubmed PY - 2017/9/15/medline PY - 2017/4/12/entrez KW - Roll compaction KW - dissolution KW - particle size KW - percolation threshold KW - poorly soluble drug SP - 1265 EP - 1275 JF - Drug development and industrial pharmacy JO - Drug Dev Ind Pharm VL - 43 IS - 8 N2 - Drug load plays an important role in the development of solid dosage forms, since it can significantly influence both processability and final product properties. The percolation threshold of the active pharmaceutical ingredient (API) corresponds to a critical concentration, above which an abrupt change in drug product characteristics can occur. The objective of this study was to identify the percolation threshold of a poorly water-soluble drug with regard to the dissolution behavior from immediate release tablets. The influence of the API particle size on the percolation threshold was also studied. Formulations with increasing drug loads were manufactured via roll compaction using constant process parameters and subsequent tableting. Drug dissolution was investigated in biorelevant medium. The percolation threshold was estimated via a model dependent and a model independent method based on the dissolution data. The intragranular concentration of mefenamic acid had a significant effect on granules and tablet characteristics, such as particle size distribution, compactibility and tablet disintegration. Increasing the intragranular drug concentration of the tablets resulted in lower dissolution rates. A percolation threshold of approximately 20% v/v could be determined for both particle sizes of the API above which an abrupt decrease of the dissolution rate occurred. However, the increasing drug load had a more pronounced effect on dissolution rate of tablets containing the micronized API, which can be attributed to the high agglomeration tendency of micronized substances during manufacturing steps, such as roll compaction and tableting. Both methods that were applied for the estimation of percolation threshold provided comparable values. SN - 1520-5762 UR - https://www.unboundmedicine.com/medline/citation/28398095/Influence_of_drug_load_on_dissolution_behavior_of_tablets_containing_a_poorly_water_soluble_drug:_estimation_of_the_percolation_threshold_ L2 - https://www.tandfonline.com/doi/full/10.1080/03639045.2017.1313856 DB - PRIME DP - Unbound Medicine ER -