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Next Generation Metrology for Drug Delivery Systems

Summary:

A critical metrology issue for pharmaceutical industries is the application of analytical techniques to the characterization of drug delivery systems in order to address the interrelationships between processing, structure and drug release. Because modern drug delivery systems such often have complex designs involving multiple polymeric layers and compositions, it is important that the final product as well as all formulation steps be analyzed to determine the functional integrity and reliability of the device for product development and quality control purposes. Dissolution studies can monitor the rate of drug release, however these studies need to be correlated with structural information, such as compositional variations and defects within the device. We have been working closely with the Food and Drug Administration (FDA), Medtronic Inc., and Surmodics Inc., to study the release of drugs from various polymeric matrices using multiple imaging modalities, including laser scanning confocal microscopy (LSCM), confocal Raman Microscopy, Atomic force microscopy (AFM) and cluster Secondary Ion Mass Spectrometry (cluster SIMS). Here we will describe our attempts to develop cluster SIMS technology for 3-D characterization of these devices. It is our primary goal to aid in developing new technologies and methodologies for the characterization of these complex drug delivery systems in hopes of gaining a better understanding of the structure-property relationships.

Description:

Secondary Ion Mass Spectrometry (SIMS) is a mass spectrometric-based analytical technique that provides information about the molecular, elemental and isotopic composition of a surface. In a conventional SIMS experiment, an energetic primary ion beam, such as Ga+, Cs+ or Ar+ is focused onto the sample surface. The interaction of this beam with the sample results in the desorption of secondary ions from the surface of the material, which are then extracted into a mass spectrometer. Widespread use of SIMS for imaging and depth profiling of organic systems has historically been limited by low secondary ion yields and beam-induced damage effects. One potential solution to this limitation is to use cluster or polyatomic primary ion beams. With the application of cluster primary ion sources, such as C60+, C8-, Au3+, SF5+ and more recently Bi3+, one typically achieves significant improvements in characteristic molecular secondary ion yields (greater than 1000-fold in some cases), and also decreased beam-induced sample damage in organic and polymeric materials. With cluster SIMS, the distribution of both drugs and excipients within selected drug delivery system can be determined with a high degree of spatial resolution (100 nm - 500 nm), sensitivity (as low as ppm (µg/g)) and depth resolution (5 nm -10 nm). We have been developing this technique for in-depth characterization of various polymeric-based drug delivery systems. An example is shown in the Figure, which shows depth profiles obtained from model drug eluting films cast on silicon substrates. The films are comprised of a poly(lactic-co-glycolic acid) (PLGA) polymer containing 25% w/w Rapamycin (used to prevent restenosis in drug eluting stents). In the examples shown, two beams were used, one for sputtering (SF5+) and another for analysis (Bi3+). The sample was maintained at -100 degrees Celsius during the analysis to minimize beam-induced damage accumulation. The diffusion profile of the drug is clearly observed. Though the results in the Figure indicate that cluster SIMS is useful for thin film characterization, more often than not, the coatings used for drug delivery applications are much thicker. The release characteristics of these devices indicate that the 50 % rapamycin coating shows a large initial burst release of drug, consistent with the coating having a “thick” enrichment layer of drug at the surface. The 25 % rapamycin and 5 % rapamycin formulations show much smaller bursts at the initial timepoint, and correspondingly have thinner drug enrichment layers at the surface.

Major Accomplishments:

Have determined the important chemistries of polymeric biomaterials that make them amenable to cluster SIMS depth profiling.

Have determined important parameters in depth profiling including temperature, beam chemistry, beam size, beam angle and beam energy.

Have characterized several model and real drug delivery systems with industrial clients, such as Medtronic Inc. and Surmodics (drug eluting stent manufacturers).

Have worked closely with the FDA to characterize and predict drug elution characteristics for drug eluting stent applications.

Cluster SIMS depth profile of PLGA (m/z 56) thin film (200nm) containing 25 % rapamycin (m/z 84) spincast on silicon (m/z 28).

Start Date:

February 19, 2008

End Date:

ongoing

Lead Organizational Unit:

mml

Facilities/Tools Used:

Advanced Measurement Laboratory

TOF-SIMS

Confocal Raman Microscope

Secondary Electron Microscope

Staff:

Christine Mahoney

Contact

Christine Mahoney
301-975-8515 Telephone
cmahoney@nist.gov