The Particle Articles

On July 10th, Oksana Olkhovyk, Ph.D., Senior Scientist  at Gateway Analytical hosted a webinar designed for scientists working to develop various pharmaceutical drug products. During this webinar, we discussed how Raman Chemical Imaging (RCI) is an effective tool that can be used to identify agglomerates by their chemical makeup in various drug formulations, and how it can benefit developers of OINDPs such as nasal spray suspensions, dry powder inhalers (DPIs), metered dosed inhalers (MDIs), as well as semi-solids: topical creams, emulsions and gels. We also discussed the validation of the RCI method to objectively and precisely evaluate the extent and size of drug to drug or drug to excipient aggregates and compare it to other methods for identifying agglomerates including, optical microscopy, Anderson Cascade Impaction, Raman Microscopy and Confocal Spectroscopy.

For more details on the webinar, you can use the links below.

• View the webinar
• Download the presentation slides

We received a number of questions from attendees during the Q&A segment, and you can find those questions and answers below. If you have any questions about this or any other topic, please contact us.

1. Can you identify the grade of lactose in DPI formulations?
   Yes, Raman spectroscopy and imaging may be used to identify the grade of lactose in DPI formulations.
2. Since the median is based on a specific size particle, how do you get a value for the standard deviation? Is it based on multiple FOVs?
   We determine the population size necessary to ensure representative sampling for each product. We typically evaluate statistically significant number of particles for reporting statistical data (i.e. 100 particles or more).
3. Will Raman only measure the surface of API particles, or how deep does the Raman go?
   We used 532nm laser for RCI analysis. So the depth of penetration will depend on refractive indices of material we analyze (chemical composition of drug particles).
4. How long does it take to analyze each field of view?
   Each FOV is analyzed by RCI over the spectral range defined to contain Raman bands specific to the component of interest and may contain one or multiple specific spectral ranges (multiple spectral ranges we use for dual-API formulations, or for polymorph determination of the drug particles). Each FOV may be analyzed in time frame from seconds to 1-2 minutes depending on integration time we sue, number of frames in the hypercube, photo bleaching time, averages, etc.
5. What is the field of view size and how does this translate to the size of the pixel?
   Raman camera we use for RCI analysis has 512x512 pixels and spatial resolution obtainable at 100x (NA 0.9) is approximately 350nm per pixel for the 532nm excitation. For 50x it is 41x41 microns FOV in the Raman camera EMCCD detector, for example.
6. For a DPI formulation where there will be a wide range of particle sizes, how does the RCI determine if particles are agglomerated?
   NIST-traceable PSMS of various sizes spanning the size range of DPI formulation can be measured. The specific sizes that can be measured at one magnification under same experimental conditions may be from 500nm to 10 µm.
7.  How small a particle can be accurately sized?
   NIST-traceable PSMS of 500nm to 1 µm can be measured. Accuracy, precision and limit of detection of the Chemically-Specific Particle Sizing analysis may be determined based on the bias parameters which are calculated as difference between stated by Vendor PSMS size and Measured Average PSMS size by RCI.
8. Do you have standards to cover submicron range?
   NIST-traceable PSMS of 500nm to 1 µm can be measured. Accuracy, precision and limit of detection of the Chemically-Specific Particle Sizing analysis may be determined based on the bias parameters which are calculated as difference between stated by Vendor PSMS size and Measured Average PSMS size by RCI.
9. I suppose that agglomerate size have to be validated on API in the formulation and not on PS spheres?
   RCI data sets of agglomerated PSMS of known values sizes spanning the size range of the API final nasal spray formulation can be collected, processed and compared for accuracy and precision for validation studies. Formulations with known sizes of micronized drug may be used for validation also.