Continued advancements in drug discovery have yielded a wide range of new, yet complex molecules in today's growing pipeline. However, many of these products demonstrate poor aqueous solubility during development, which leads to poor bioavailability and, hence, efficacy. A portion of these compounds, known as brick dust compounds, are poorly soluble in both water and organic solvents, potentially leading to even greater challenges for drug product manufacturers.


Three enabling technologies to improve drug solubility in organic solvents

In the webinar, "Enabling Technologies to Increase Spray Drying Throughput for Brick Dust Compounds," David Lyon, Ph.D., Senior Fellow, and Molly Adam, R&D Spray Drying Expert, Bioavailability Enhancement, Lonza Small Molecules, discussed three enabling technologies designed to improve drug solubility in organic solvents for spray drying, as well as case studies detailing the process for each one. These methods include heating a drug slurry to a temperature below the solvents boiling point, which increases its solubility; using an in-line heat exchanger to rapidly increase the temperature of the solution above the boiling point immediately before atomization, dissolving the drug at a higher concentration (known as temperature shift) and using volatile processing aids, with no need for heating or other changes to the normal spray drying process. Not only can these methods increase solubility in compounds with poor solubility, but they can also increase throughput, ultimately reducing solvent consumption, cycle times, and costs.

The following Q&A session was held after this webinar, where Lyon and Adam addressed attendees questions about the details of the methods and case studies.

How do you select a temperature and residence time for the temperature shift process?

Adam: It depends on your API, its solubility, and the heat source being used. Lonza's heat exchangers are inline tube-in-tube heat exchangers, and they are heated using hot water; therefore, the attainable drug solubility depends on how much heat is available and what temperature you can achieve. You want to look at drug solubility as a function of temperature and the target solubility as well as a safety factor to ensure everything is dissolved, so you would select the drug concentration you want in your solution, a temperature based on your solubility curve, and a heat source. If you have a compound that's sensitive to heat, you can also minimize residence time. We do have a commercial process that has some thermal degradation risk, and we were able to minimize the residence time while still increasing the temperature and achieving higher drug solubility and throughput for this drug.

How do you optimize the solvent ratio and solids content in the spray solution?

Adam: Normally, we screen several different solvents and solvent-water ratios to determine the highest solubility. We don't like to add a lot of water into our solvent blends because water isn't as volatile, so we can't achieve as high a throughput. Our target is a range between 0% and 20% water. You also need only a small amount of acetic acid or ammonia. For your solids loading, we like to maximize the drug loading in the solution, but as I already said, we like to have a safety factor in, so around 80% of your maximum drug solubility. In addition, you can run into viscosity limits with the polymer concentration, so if the viscosity is too high, the atomization isn't sufficient and the liquid doesn't break up into droplets as well. However, that's only at an extremely high weight percent of polymer in solution, so we typically target a max polymer concentration around 9% to 12%, depending on your polymer.

When using the volatile aids technology, how do you know if the ingoing form of the drug is in the final product?

Adam: Lonza secondary dries our products because there can be residual solvent left in the powder after the spray drying process. In this case study, we used spray drying and measured the amount of the volatile aid at different time points in order to confirm it was removed to below our target limits. Those results were compared to controls, and they had similar performance and purity, so we were able to determine the ingoing form, not the ionized form, as in the final drug product.

What pKa ranges will work for the acetic acid or ammonia volatile processing aids?

Adam: We don't really want to limit this technology to a certain pKa range. We have a rule of thumb of a few pKa units compared to the volatile aid, like acetic acid and ammonia, so you know your compound is deprotonated or protonated. If you have more than that, you may not be able to remove the aid during the drying process.

Can you elaborate on what exactly brick dust compounds are?

Adam: Brick dust compounds are compounds that have poor solubility in not only water but also organic solvents, which makes them really difficult to process. In addition, the drug doesn't dissolve in the body, so the patient must take a really large dose for it to have an effect. Therefore, they need some bioavailability enhancement, but the poor organic solubility makes them hard to process, which creates challenges during spray drying. The technologies discussed in the webinar can be enabling for these molecules and make them easier to process.

Is the permeability discussed in the webinar in regard to human cell membranes?

Lyon: Yes, that was in reference to permeability of the drug across the gut wall. The compounds we've discussed are BCS [Biopharmaceutical Classification System] II compounds.

How do you handle compounds that are temperature sensitive? Are cold temperatures preferred for solubilization?

Lyon: Chemists look at the temperature sensitivity of the molecule in the desired spray solvent and can quickly identify parameters that allow us to be predictive of degradation as a function of temperature, concentration, and solvent composition. These are API-sparing techniques that can be done on milligrams of material using high pressure NMR [nuclear magnetic resonance] spectroscopy techniques. Once we understand time and temperature dependence of degradation, we can then translate that into a processing space. As mentioned previously, we have an in-house commercial product that allows the temperature shift process to be economical because the cost of goods relationship to processing throughput is so critical. Therefore, once we understand the degradation as a function of time and temperature, we're able to optimize residence time in the heat exchanger to ensure the drug is dissolved, not degraded. As discussed in the case study, we were eventually able to commercialize the product, which proves that these temperature shift processes are still feasible for temperature-sensitive compounds.

Adam: And just to clarify, we do use heated nitrogen gas, but the temperature of the gas does go down quickly once it enters the chamber. We assume the chamber temperature is the same as the outlet temperature of the spray dryer. For methanol, we typically aim for 45°C and 35°C for acetone. Once those droplets contact the heated gas, they do not experience those high temperatures due to evaporative cooling, so particles and solids are not exposed to extremely high temperatures nor are they exposed for very long.

Are the volatile processing aids biocompatible, and do you have to consider the concentration that ends up in the final spray dried dispersion for regulatory limits?

Adam: Yes, they are biocompatible. Acetic acid is a Class 3 solvent, so it does have an ICH limit of below 0.5 weight percent. Ammonia does not have an ICH limit, but it is used in other pharma applications, such as in the manufacturing of capsules. Our target weight percent for ammonia is to be below 50 parts per million. We use spray drying standard conditions for secondary drying. This depends on the drug, though. If it holds onto the aid a bit more, you can use more aggressive conditions like higher temperatures, humidity, or even a step change in your process, such as starting at lower temperatures and then increasing throughout the run. Lonza also uses another method for secondary drying called an Ekato dryer, which is a batch mixer that uses nitrogen sweep gas and heat to remove residual solvent.

In the technology using the volatile processing aid, does the aid itself partition into the polymer excipient?

Adam: The answer depends on whether the polymer is neutral or enteric. If the polymer is neutral, it does not partition, but it can if the polymer is enteric. In our case study, we did add enough ammonia to the solution to react with the drug and the HPMCAS [hydroxypropyl methylcellulose acetate succinate], which is an enteric polymer. We did this because we wanted to confirm that all of the drug was ionized. Even though we added more ammonia for this solution, we were able to remove it to below 50 PPM.

How critical is the spray drying process for increasing solubility and bioavailability?

Adam: Around 70% of compounds in today's pipeline are in need of bioavailability enhancement. Spray drying can address this by manufacturing the amorphous phase, which increases solubility, so it is critical to addressing a key challenge in drug development today. There are other methods, such as hot melt extrusion, but spray drying is the most commonly used.

Lyon: Bioavailability enhancement can be accomplished through a variety of techniques. Amorphous solid dispersions is one of them. Other techniques, such as solubilization using lipid formulations or solvents, have been used and have been commercialized, but if you look at the last five years, spray drying for making an amorphous solid dispersion seems to be the most commercially relevant.

Does API concentration change during the heating process, and is there a tolerance limit?

Adam: The temperature shift process begins with a slurry of the drug in the organic solvent containing the polymer, which is then pumped up to the heat exchanger, where the drug is dissolved when the temperature increases. So, yes, the API concentration does change during heating.

Do you need to use a pressurized tank for the heating application?

Adam: If you're using the warm process, you do not need to use a pressurized tank because you're heating it just below the boiling point; however, if you are using the temperature shift process, you don't pressurize the tank, but rather the solution as it's pumped into the dryer. This is done because the solution could boil if it isn't pressurized high enough. Once it goes to the dryer, the flash atomizer atomizes the droplets.

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