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Atomic force microscopy-based screening of drug-excipient miscibility and stability of solid dispersions.

Lauer ME, Grassmann O, Siam M, Tardio J, Jacob L, Page S, Kindt JH, Engel A, Alsenz J - Pharm. Res. (2010)

Bottom Line: Their potential to phase separate is determined through imaging at molecular length scales, which results in short observation time.De-mixing is quantified by phase separation analysis, and the drug/polymer combinations are ranked to identify the most stable combinations.The assay allows to identify well-miscible and stable combinations within hours or a few days.

View Article: PubMed Central - PubMed

Affiliation: Center for Cellular Imaging and Nanoanalytics, Biozentrum, University of Basel, Mattenstrasse 26, CH 4006 Basel, Switzerland. Matthias.Lauer@roche.com

ABSTRACT

Purpose: Development of a method to assess the drug/polymer miscibility and stability of solid dispersions using a melt-based mixing method.

Methods: Amorphous fractured films are prepared and characterized with Raman Microscopy in combination with Atomic Force Microscopy to discriminate between homogenously and heterogeneously mixed drug/polymer combinations. The homogenous combinations are analyzed further for physical stability under stress conditions, such as increased humidity or temperature.

Results: Combinations that have the potential to form a molecular disperse mixture are identified. Their potential to phase separate is determined through imaging at molecular length scales, which results in short observation time. De-mixing is quantified by phase separation analysis, and the drug/polymer combinations are ranked to identify the most stable combinations.

Conclusions: The presented results demonstrate that drug/polymer miscibility and stability of solid dispersions, with many mechanistic details, can be analyzed with Atomic Force Microscopy. The assay allows to identify well-miscible and stable combinations within hours or a few days.

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Related in: MedlinePlus

Nanometer homogeneity is shown with phase maps recorded with tapping-mode AFM on fracture surfaces of the blank excipients (a–e), and corresponding combinations with NK1(1) (f–j), and with CETP(2) at the bottom (k–o). The numbers visible in the image rows (f–j, and k–o) relate the number of comparably structured places with the number of investigated places. The scale bars as shown throughout all images are the same and correspond to a length of 1 μm.
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Fig4: Nanometer homogeneity is shown with phase maps recorded with tapping-mode AFM on fracture surfaces of the blank excipients (a–e), and corresponding combinations with NK1(1) (f–j), and with CETP(2) at the bottom (k–o). The numbers visible in the image rows (f–j, and k–o) relate the number of comparably structured places with the number of investigated places. The scale bars as shown throughout all images are the same and correspond to a length of 1 μm.

Mentions: All fractured films were then analyzed by Atomic Force Microscopy with respect to their molecular homogeneity; the results are summarized in the Table 2. Combinations thereby judged homogenous at the nanometer scale fulfill two additional criteria: i) Ten different regions on each combination were analyzed with respect to their molecular fracture roughness and with respect to the roughness variations of the different sample regions. A homogenous film combination has to have a roughness, and a variation of roughness not significantly bigger than on the corresponding excipient blank (Fig. 3b). ii) The surface contact properties as visualized by phase maps with tapping mode AFM need to scale only with molecular morphological variations or fracture roughness. This means that a fracture surface was not picked if it exhibits islands, droplets, and domains with distinct mechanical property contrast, because such surfaces were related to separated, and nanometers-sized phases, clearly larger than a single polymer molecule (Fig. 4).Table II


Atomic force microscopy-based screening of drug-excipient miscibility and stability of solid dispersions.

Lauer ME, Grassmann O, Siam M, Tardio J, Jacob L, Page S, Kindt JH, Engel A, Alsenz J - Pharm. Res. (2010)

Nanometer homogeneity is shown with phase maps recorded with tapping-mode AFM on fracture surfaces of the blank excipients (a–e), and corresponding combinations with NK1(1) (f–j), and with CETP(2) at the bottom (k–o). The numbers visible in the image rows (f–j, and k–o) relate the number of comparably structured places with the number of investigated places. The scale bars as shown throughout all images are the same and correspond to a length of 1 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3044090&req=5

Fig4: Nanometer homogeneity is shown with phase maps recorded with tapping-mode AFM on fracture surfaces of the blank excipients (a–e), and corresponding combinations with NK1(1) (f–j), and with CETP(2) at the bottom (k–o). The numbers visible in the image rows (f–j, and k–o) relate the number of comparably structured places with the number of investigated places. The scale bars as shown throughout all images are the same and correspond to a length of 1 μm.
Mentions: All fractured films were then analyzed by Atomic Force Microscopy with respect to their molecular homogeneity; the results are summarized in the Table 2. Combinations thereby judged homogenous at the nanometer scale fulfill two additional criteria: i) Ten different regions on each combination were analyzed with respect to their molecular fracture roughness and with respect to the roughness variations of the different sample regions. A homogenous film combination has to have a roughness, and a variation of roughness not significantly bigger than on the corresponding excipient blank (Fig. 3b). ii) The surface contact properties as visualized by phase maps with tapping mode AFM need to scale only with molecular morphological variations or fracture roughness. This means that a fracture surface was not picked if it exhibits islands, droplets, and domains with distinct mechanical property contrast, because such surfaces were related to separated, and nanometers-sized phases, clearly larger than a single polymer molecule (Fig. 4).Table II

Bottom Line: Their potential to phase separate is determined through imaging at molecular length scales, which results in short observation time.De-mixing is quantified by phase separation analysis, and the drug/polymer combinations are ranked to identify the most stable combinations.The assay allows to identify well-miscible and stable combinations within hours or a few days.

View Article: PubMed Central - PubMed

Affiliation: Center for Cellular Imaging and Nanoanalytics, Biozentrum, University of Basel, Mattenstrasse 26, CH 4006 Basel, Switzerland. Matthias.Lauer@roche.com

ABSTRACT

Purpose: Development of a method to assess the drug/polymer miscibility and stability of solid dispersions using a melt-based mixing method.

Methods: Amorphous fractured films are prepared and characterized with Raman Microscopy in combination with Atomic Force Microscopy to discriminate between homogenously and heterogeneously mixed drug/polymer combinations. The homogenous combinations are analyzed further for physical stability under stress conditions, such as increased humidity or temperature.

Results: Combinations that have the potential to form a molecular disperse mixture are identified. Their potential to phase separate is determined through imaging at molecular length scales, which results in short observation time. De-mixing is quantified by phase separation analysis, and the drug/polymer combinations are ranked to identify the most stable combinations.

Conclusions: The presented results demonstrate that drug/polymer miscibility and stability of solid dispersions, with many mechanistic details, can be analyzed with Atomic Force Microscopy. The assay allows to identify well-miscible and stable combinations within hours or a few days.

Show MeSH
Related in: MedlinePlus