What is the solubility of fluticasone in pMDI propellants?
April 03, 2016
A fundamental property to be measured when developing pMDI formulations is the solubility of APIs and excipients in propellants. It is not easy and no commercial solution exists to measure it in situ, under pressure in HFA134a or HFA227 propellants ... until now!
Solubility in HFAs is routinely overlooked. It is assumed that nothing is soluble in HFAs, therefore measuring a solubility is said to makes no sense. That is wrong, even a low solubility, e.g. < 100 ppm, can destabilise a suspension. What really matters is the dose/solubility ratio. Because of the low doses used in pMDI products, even a low solubility can lead to a substantial portion of the API go into solution and modify the behavior of the formulation; e.g. up to 12% of budesonide is in solution in a typical budesonide pMDI HFA suspension, more if water or other components are present such as excipients or other APIs. These 12% destabilise a formulation over time, and must therefore be quantified to be controlled.
To measure API solubility in HFAs, formulators have traditionally relied on filtering a large amount of an HFA-API suspension (50 to 100 ml) at a more or less controlled temperature, vent off the propellant form the filtrate, dry the residue, dilute it in a solvent and sample this solution to quantify by HPLC with a suitable detection method the amount of API that was filtered. Cost of the operation: may be 500 mg of sample, up to 6 hours of preparation per sample, a full detection method development and calibration (2 days?). The issues with these measurements are numerous mostly due to sample handling; measurements are inaccurate and will depend on the validation of the filtering method, and contamination during sample handling is highly likely. Did we mention you would need to build your own filtration tools and vessels?
An effective way to measure API solubilities in propellants
Aedestra is offering an alternative way to measure API and excipient solubilities in HFA propellants. Based on a H-NMR method, and existing pressurized NMR technology, Aedestra can measure the solubility of your APIs and excipients in pressurized HFA propellant easily and accurately. Very little sample is required, typically < 250 mcg. Measurements can be done in both HFA134a and HFA227, as well as mixtures, and with solvents and excipients (subject to confirmation that a useful signal can be detected). Measurements can be performed at different temperature points.
The method relies on the natural contrast between the fluorinated propellants and the solutes to quantify their concentration, as well as variation of the signals from the few hydrogen atoms in the fluorinated molecules to detect transition in the mixture API/excipient/propellant, making it a useful tool to study phase diagrams as well.
The method is precise and can yield routine accuracy of 0.2% per measurement.
A brief description of the method was published a few years ago (Determination of Drug Solubility in HFA Propellant Using a Novel Reverse Coaxial NMR Method), and Aedestra is pleased to make this method available commercially.
Advantages of Aedestra's method:
In situ pressurized measurement
Very little sample required <250 mcg
No sample filtering
No water contamination
Determinations at different temperature possible
Possibility to map phase diagrams
What about fluticasone?
We could indeed give you the value of the solubility of Fluticasone in HFA propellants, but would it be relevant to your source of API? Far better is to measure what you need in a way that will help you develop your own products.
Get in touch for prices and T&C to measure the solubility of your APIs and excipients in pMDI propellants: firstname.lastname@example.org.
Aedestra is a product development company in the field of inhaled drug product. We make developing inhaled products easy, so you can focus on delivery. We drive initiatives; you realise opportunities. We can help you develop the right product in the right way by providing strategic and technical expertise: reducing cost, time and risk. Get in touch now to expand and develop your inhaled portfolio.