Tackling Solubility in Drug Development

The proportion of poorly soluble molecules entering the drug development pipeline is increasing year-on-year, raising the bar for pharmaceutical companies in terms of how best to approach the challenge of improving solubility and bioavailability. “Over the past 20 years, drug development pipelines have been filled with drugs that present solubility issues,” confirms Márcio Temtem, site manager, R&D Services, Hovione. “It is estimated (1,2) that the current proportion of poorly soluble compounds in the development pipeline is between 70% and 90%.”

“Where APIs have poor solubility, this has a marked effect on a drug’s efficacy within the body and can lead to poor absorption, poor bioavailability, and increased pharmacokinetic variability,” adds William Wei Lim Chin, technical specialist, Science and Technology, Catalent. “Since many of these drugs exist as crystalline materials, one approach to improve the API’s performance is to create an amorphous solid dispersion (ASD), for which spray drying technology is a key part of the manufacturing process.”

An approach with merit

“Solubility, bioavailability, and stability are some of the most difficult formulation challenges faced by the pharmaceutical industry at present, and spray drying offers a very suitable solution,” explains Manuel Leal, business development director, Idifarma. “The process involves spraying a solution or suspension that contains the excipient and active substance inside a drying chamber. Dry particles are dispersed and collected by a cyclone as the solvent is evaporated at high speed. The ASDs with different particle sizes obtained after spray drying achieve better solubility than the API alone.”

The rates of spraying and evaporation in spray drying are crucial, according to Chin, who notes that evaporation must take place before either crystallization or phase separation has time to occur. “Amorphous forms are intrinsically more soluble than crystalline materials, as there is no crystalline lattice energy to be overcome,” he says. “Spray drying also gives a finely divided powder that can be processed into any dosage form that can incorporate powders, including capsules and tablets.” 

Adding to Chin’s point, Temtem notes that the flexibility afforded by spray drying is a clear advantage of the technique over others that are currently available. “Spray drying enables development across a broad range of drug delivery options,” he says. “Additionally, as it is a flash drying process, it can be applied to many different molecules, such as those that have a thermally labile character, as the drug product will not be exposed to the high temperatures itself.”

There are significant benefits of spray drying, specifies Leal. “As is the case with many common technologies, batch size is not limited by the equipment capacity as spray drying operates on a continuous production process, which can be easily re-run. This scalability means that spray drying represents a swift, cost-effective solution,” he confirms.

“Another advantage spray drying has is in the formulation of products that have unusual or difficult characteristics,” continues Chin. “Products that may be sticky or hygroscopic, slow to crystallize, or difficult to isolate are all good candidates for spray drying.”

For Temtem, one of the most important advantages of spray drying over other techniques is that process development can be achieved using minimum quantities of materials. “For example,” he continues, “comparing with other available technologies, it is possible to perform process development with just a few grams of materials with spray drying, whereas to get the same information with other techniques, such as hot-melt extrusion or co-precipitation, you would potentially need from hundreds of grams to kilos of material. This is a big advantage, particularly in the processing of new chemical entities where API availability is limited.”

Multiple applications

“The quality achieved through spray drying a powder can influence the drug’s preparation downstream and how it is administered to patients,” explains Chin. “For example, particle engineering by spray-drying enables further development for inhaled delivery, which is the cornerstone in the management of patients across a spectrum of respiratory diseases.”

Concurring, Temtem also notes the increased traction that is being seen in the field of inhalation. “Spray drying is particularly beneficial in the preparation of composite particles for inhalation, both from a product stability and product performance perspective. During the spray drying process, ingredients are combined at the molecular level, improving the stability of the API and adjusting the cohesive‑adhesive balance of the materials,” he says. 

“The advantages of spray drying can be applicable to multiple drug products, from over-the-counter to prescription, and in a wide variety of therapeutic areas,” adds Leal. “One therapeutic area that can reap the advantages of spray drying is oncology. By altering the pharmaceutical form of the final product, spray drying can facilitate different administration routes.” If solubility of a drug substance can be improved and the route of administration can be changed from injection to oral, then patient compliance and quality of life will also be positively impacted, he confirms.

“In antibodies, protein, and vaccine therapies, the drug substance is usually in a liquid state,” asserts Chin. “To improve its stability and to have the flexibility to administer it via dosage routes other than injectable and oral suspension, a spray dried powder offers many advantages and can be manufactured into conventional oral solid dose forms, which are more acceptable to patients with chronic diseases.”

Furthermore, as more companies are looking to tackle more rare disease areas and are approaching drug development and approval via the fast track or breakthrough regulatory programs, spray drying can provide an enabling option, emphasizes Temtem. “For instance, by employing spray drying combined with modeling, for both product and process development, it is possible to accelerate the development lifecycle significantly, while also improving the drug’s performance.”

An attractive investment choice

The broad applications and ability of spray drying to improve solubility have made it an attractive choice for investment by companies and outsourcing partners throughout the industry. “As the industry struggles to find new drugs that improve existing therapies, the need for more innovative processes to advance the galenic formulation of a finished product has become essential,” states Leal. “As spray drying can achieve this, it has naturally become one of the top investment choices for many companies focusing on complex development projects.”

“Identifying a suitable dispersion is not necessarily easy, but the benefits it offers in terms of scalability of manufacture and dose form development has led to spray drying becoming a crucial tool within a formulator’s toolkit,” adds Chin. However, Chin iterates that industry has also experienced issues in the development of spray-dried formulations as a result of a lack of capacity at the commercial scale. “This issue has been addressed by some contract development and manufacturing organizations (CDMOs) investing in additional capacity,” he says.

The move towards fast-track programs and breakthrough therapies is also driving investment in spray drying, states Temtem, echoing his earlier thoughts. “The ability to move quickly through the development lifecycle is critical for companies at the moment,” he says. “Spray drying has clear advantages to help in the area of time efficiencies, and as a consequence, the number of programs using spray drying as a technique are increasing exponentially.”

Trends driving adoption

“Both versatility and speed are driving adoption of spray drying techniques,” says Chin. “The technique offers versatile formulation options and flexible downstream dose form manufacturing into tablets, powder‑filled capsules, and inhaled drug products. It is a highly scalable process too, that allows for precision control of particle engineering, including particle size, bulk density, the degree of crystallinity, and levels of both organic volatile impurities and residual solvents.”

The ability to enhance the physical properties of drug products, particularly when looking at the ability to change parenterally delivered products to those that can be administered orally or by inhalation, will also lead to greater adoption by the industry of spray drying. “It’s important for the industry to continue to support patient adherence by looking for ways to improve comfort such as offering products in forms that patients can take at home,” adds Leal.

For Temtem, the combination of spray drying and drug productivity will become more prominent in the future, along with continuous manufacturing in the downstream processing, both of which will enable accelerated development. “Additionally, another trend for the future is the use of Big Data and the associated digital transformation. With a simple click of a button, it will be possible to gain information about the most adequate process conditions for a molecule, and when combined with empirical and mechanistic modeling, [Big Data and digital transformation] will also be able to speed up development,” he adds. “Speed and agility are key to what comes next in the area of spray drying.”  

References

1. R. Lipp, Am. Pharm. Rev., 16 (3) 10–16 (2013).
2. A.M. Thayer, Chem. Eng. News, 88 (22) 13–18 (2010).

Article Details

Pharmaceutical Technology
Vol. 43, No. 12
December 2019
Pages: 24–25

Citation 

When referring to this article, please cite it as F. Thomas, “Tackling Solubility in Drug Development,” Pharmaceutical Technology 43 (12) 2019.