Recent Innovations And Enhancements To Pharmaceutical Spray Drying

Spray drying has been used in the pharmaceutical industry for a variety of particle engineering and bioavailability enhancing applications. The process is continuous and readily scalable to accommodate the needs of programs from early feasibility assessments through large-scale commercial launch.

Recent advances in spray drying have allowed for additional degrees of freedom in selecting solution compositions to avoid solvents that are either hard to remove from the spray dried powders, are not compendial, or are environmentally harmful and challenging to achieve from a waste management perspective. Lonza, a global contract development and manufacturing organization (CDMO), possesses a wealth of expertise in spray drying, including recent advancements in simultaneous spray drying for combination dry powder formulations to treat lung cancer.

In a recent webinar, “Pharmaceutical Spray Drying: Sustainable Commercial Best Practices to Continuous Project-Focused Innovation,” experts from Lonza explored the spray drying process, including recent enhancements and the approach that Lonza uses to scale up programs using this technology, as well as recent developments to enable processing of extremely poorly soluble (aqueous and organic) molecules into amorphous dispersions for oral bioavailability enhancement. This webinar also explored heated solution processing approaches, novel solvents, and solution preparation techniques that can be used to process extremely poorly soluble molecules or eliminate the need to use undesirable solvents such as tetrahydrofuran (THF) and dichloromethane (DCM). Speakers for the event included:

• Travis Harrer, Manager, Process Engineering, Lonza
• Jason Bertola, Head of Commercial Development North America, Lonza

Attempts to overcome poor organic solubility often involve use of less desirable solvents, particularly DCM and THF, which both pose health and environmental concerns. DCM, an ozone-depleting greenhouse gas, has seen its usage increase significantly in recent years, owing to the rise in very insoluble APIs entering development. It is also a chlorinated solvent that is thought to have neurotoxicological effects in both humans and animals. THF, while not chlorinated and much less toxic, has a tendency to form peroxides, which can be a significant safety problem when processing at a large scale. Finding alternative solvent approaches would allow lower volumes of less toxic solvents to be used, significantly improving both the environmental and human health implications of new drugs produced.

Key Market Drivers Shaping the Small Molecules Landscape

The small molecules space has been shaped by a number of key drivers in recent years – the early phase pipeline for these drug products has grown by more than five percent CAGR since 2014, and more than 8,000 of the new chemical entities (NCEs) in development today are small molecules. Additionally, the majority of this pipeline is comprised of oral formulations, creating solubility and bioavailability issues as developers wrestle with increasingly complex molecules. Currently, more than 75 percent of NCEs in solid oral dosage forms have issues with bioavailability; more than 80 percent of the companies investigating these NCEs are small biopharmaceuticals that may lack the expertise or capabilities to address these issues efficiently and effectively.

While oral solid dosage forms remain the preferred route of administration for most drug developers, the issues surrounding bioavailability for these therapeutics must be addressed. There are several approaches that developers can take to increase an active pharmaceutical ingredient’s (API) solubility to enhance absorption, including crystal form selection, size reduction, amorphous materials, or solvation. The focus of this presentation, amorphous solid dispersions (ASDs) manufactured through spray drying, place API into a higher energy state versus crystalline APIs, but commonly present risk for physical and chemical stability. ASDs have been proven to be an effective formulation strategy throughout a product’s lifecycle. During ASD processing, excipients are utilized to sustain supersaturation of the API in the intestine, providing a significantly higher driving force for absorption over the crystalline API. Some of the key advantages of ASDs manufactured via spray drying include their broad applicability for a range of diverse compounds, their capacity to accommodate high-dose compounds, and their flexibility for use in tablets, encapsulations, or in extended-release combination formulations.

Lonza provides integrated services for poorly soluble molecules by first addressing solubility challenges and modulating pharmacokinetics to meet a client’s target product profile. Its Small Molecule Division is comprised of five sites in three geographical regions, two in Switzerland and China focusing on drug substance, one focused on particle engineering and jet milling, and two specializing in drug product. Lonza possesses more than 25 years of experience enhancing the solubility of drugs for oral delivery through innovations in spray drying and other technologies. It continues to investigate novel spray drying techniques to improve its applicability and address increasingly poorly soluble APIs.

The Importance of Bioavailability Enhancement

Many enabling technologies are available to facilitate optimized drug solubility – from various crystallization forms, including salts, cocrystals, and polymorphs, to size reduction technologies such as micronization and techniques like solid dispersions and solvation. Lonza has amassed an array of expertise to help clients achieve the right formulation.

The amorphous form of many drugs can provide significant solubility enhancement, enabling paths to greater efficacy for novel and innovative treatments. The process of creating an amorphous dispersion involves increasing from a low-energy polymorph that is very stable through a high-energy polymorph to an amorphous material. This increase in free energy is achieved through spray drying, which entails combining an active drug with excipients, dissolving them into a common volatile solvent, and rapidly drying this mixture to kinetically trap the matrix and prevent crystallization. The rapid drying time, coupled with evaporative cooling of the process solvent, ensures that the product never experiences temperatures higher than the spray drying outlet temperature, typically 30 – 50C, reducing thermal exposure over ASD manufacturing techniques. The solvent rapidly evaporates in the drying chamber to form amorphous powders, which are subsequently separated from the gas stream using a cyclone. This technique minimizes API degradation by limiting heat exposure, incorporating stabilizing excipients, and controlling shear exposure through the selection of pumps and atomizers.

Unparalleled Process Control for Unparalleled Results

The two processes that are considered during a spray drying process scale-up are drying kinetics and atomization. Lonza’s approach to scaling drying kinetics relies on controlling the key parameters that impact the SDD quality attributes; in this case, outlet temperature is the primary variable affecting both particle morphology and bulk density. Gas flow rate is typically scale dependent. Liquid flow is scaled linearly to ensure a similar outlet relative saturation. Generally, cooler process temperatures result in higher density, less compressible morphologies, while higher temperatures lead to less dense, less flowable materials.

The key variables to control in the atomization process are solution rheology, atomization pressure, and geometry. To scale atomization, typically atomization geometry is modified to increase the flow rate at larger scales. The atomization pressure is adjusted accordingly to match the particle size from smaller scale; particle size often impacts dissolution performance and downstream manufacturing. In a typical workflow, Lonza’s experts will begin with the kinetic assessment, and an operating space is determined for a given API based on the API chemical properties and the process solvent used. Then an atomization assessment is performed, confirming SDD acceptability and studying a range of droplet sizes in order to determine particle size impacts on the dosage form’s performance. That lead material is then put through extensive demonstration batches to establish yield, perform stability testing, and conduct other robustness testing as determined by the initial screening process.

Enabling Technologies: Amorphous Solid Dispersions

At Lonza’s drug product facility in Bend, Oregon, operators utilize multiple spray scales and can help clients optimize their formulation through a holistic evaluation of an API’s needs. Lonza does this by evaluating a wide range of variables, including:

• volume
• mixing equipment and time
• nozzle size and type
• residence time
• solution properties
• liquid pressure
• particle size distribution
• cyclone dimensions
• gas velocity

Additionally, Lonza experts work to identify product attributes and make a preliminary assessment of whether they are critical quality attributes (CQAs), outline formulation components and materials attributes and identify risk of impact on CQAs, and define process steps and process parameters to determine the risk of impact on CQAs. Lonza then uses this evaluation to define the studies required for risk reduction prior to formulation lock.

Conclusion

Ultimately, there is a large industry need for bioavailability enhancing technologies. Spray drying is one such technique to improve bioavailability through producing amorphous dispersions that lead to supersaturation in the intestine, driving higher rates of absorption when compared to the crystalline drug. Additionally, techniques have been developed to allow greater degrees of freedom when selecting process solvents for spray dried dispersion manufacture, including heated processing and volatile acidic/basic compounds to dissolve API in a wider range of less toxic or hazardous solvents. Spray drying is a readily scalable process for which Lonza is able to support development activities and commercialization activities in quantities from <1g to metric tons of material.