Raman Chemical Imaging - Shedding Light on Metered-Dose Inhalers with Multiple Active Pharmaceutical Ingredients
By Ryan J. Priore, Ph.D.
In today’s pharmaceutical market, the reach of respiratory drugs and associated delivery technologies is expanding due to their potential to increase drug uptake rates and improve bioavailability for certain drugs (relative to oral dosing), as well as their convenient administration. Most often limited to localized diseases (e.g. rhinitis), recent research and development activities of inhalable products point to opportunities in nontraditional therapeutic areas like motion sickness and seizures. As a result, the need to develop rapid, cost-effective methods of generating particle analysis data for active pharmaceutical ingredients (APIs) in pulmonary formulations is on the rise.
All Particles Are Not Created Equal
In pulmonary drug delivery, the drug particle size will determine the rate of dissolution, dosage and availability to sites of action within the lungs. With that in mind, particle size distribution (PSD) for the drug or drug aggregates should be characterized in the formulated product both within the primary container and within the aerosolised droplets. Aggregation between API and excipient ingredients bring about an increase in overall particle size and may cause a number of potential problems like changes in bioavailability and/or clogging of the delivery device.
Currently, multistage cascade impaction followed by High Performance Liquid Chromatography (CI-HPLC) is the accepted method for assuring that the aerodynamic size of inhaled particles falls into the optimal pulmonary delivery range of 1-5 µm. Humidity is strictly controlled during the cascade impaction measurements to minimize hygroscopic growth and aggregation of particles. These measurements provide only rudimentary, purely physical data and cannot differentiate between chemically different particles or particle aggregates. In addition, the U.S. Food & Drug Administration (FDA) recommends microscopic evaluation of the sample for “release and stability purposes” to check for the presence of large particles, aggregates and foreign contaminants, changes in morphology and crystal growth for both the drug substance and carrier particles. Neither method can be used for the Ingredient-Specific Particle Sizing™ (ISPS) of the drug substance nor to identify unique particles based on their underlying chemistry.
Although the PSD of the API can easily be determined prior to inclusion in a pressurized metered-dose inhaler (MDI) formulation, it is a challenge to establish the PSD in the finished product. Adding another API to the equation makes things even more complex. Enter Combivent®, an MDI that contains two active ingredients a microcrystalline suspension of ipratropium bromide (IB) and albuterol sulfate (AS) in a pressurized metered-dose aerosol unit (18 mcg/103 mcg per actuation). Additionally, the formulation contains soy lecithin as a surfactant and chlorofluorocarbon propellants. We’ll take a closer look at Combivent® in the next section.
Visualize Particle Chemistry with Raman Chemical Imaging
Previous ChemImage studies1, 2 have focused on using Raman Chemical Imaging (RCI) as a potential measurement tool for determining the PSD of a corticosteroid in nasal spray formulations like Rhinocort AQ® and Flonase®. These studies used RCI to combine the chemical specificity of Raman spectroscopy with digital image processing to evaluate the morphology of one or more target APIs even in the presence of a complex matrix. This presence or absence of API within individual particles can be determined by the Raman spectral features characteristic of the drug. Spectral shifts as small as 2 cm-1 can be detected, which also allows RСI to determine polymorphic and hydrated forms of a drug substance
Raman spectroscopy of non-volatile components of the formulation was performed to determine the optimal chemical imaging region. A significant spectral difference between AS and IB was observed in the spectral region from 960-1020 cm-1. Raman chemical images were collected in an automated fashion over this spectral range to obtain a statistically significant number of API particles for both drug components. The processed chemical images were then used to calculate the particle size of APIs independent of each drug.
In short, this RCI technique shows promise as a method for characterizing the ISPS of multiple drug substances in MDI formulations and could provide crucial support to drug formulators of both innovator and generic products.
For More Information
If you would like to see more information on the Combivent® study, ChemImage will be presenting a poster on this data at the Respiratory Drug Delivery 2010 Conference in Orlando, Florida, April 25-29, 2010. The poster will be available in our resources section for download after the show.
Questions for the author? Click here.
To sign up for Pharma Focus Click here.
To submit a topic for our e-newsletter Click here.
Additionally, you may contact us via phone: toll free at 1-877-241-3550 or email: firstname.lastname@example.org at any time with general questions.
1. Raman Chemical Imaging for Ingredient-specific Particle Size Characterization of Aqueous Suspension Nasal Spray Formulations: A Progress Report. Doub, William H., et al. Pharmaceutical Research. May 2007, Vol. 24, 5, pp. 934-945.
2. The Potential Use of Raman Imaging for Determination of the Particle Size Distribution of Active Pharmaceutical Ingredients in Metered-dose Inhalers . Guo, Changning. s.l. : The Third International Conference on Advanced Vibrational Spectros, 2005.
3. Ingredient-Specific Particle Sizing™ for Batch Comparison to Analyze the Drug Particle Size Distribution in Aqueous Nasal Spray Formulations. Priore, Ryan, Olkhovyk, Oksana and Klueva, Oksana. Lisbon, Portugal: Respiratory Drug Delivery (RDD) Europe Conference, 2009.