Issue:April 2023

FORMULATION FORUM - Tackling Challenging Molecules by Spray Drying: Making the Impossible Possible


As we continue our research in drug discovery, more than 80% of new molecular entities (NMEs) are poorly soluble, often making it impossible to formulate by using the conventional technologies, such as micro-milling, salt formation, or complexation. That has triggered a range of enabling formulation options, including non-conventional technologies, such as amorphous solid dispersions (ASDs) or liquid dispersions and co-precipitation.1 Polymer-based amorphous solid dispersion (ASD) technology is an innovative approach that converts highly crystalline insoluble molecules resembling “brick dust” to highly amorphous powders, making them highly water soluble.2 Others like liquid dispersions resulting from emulsifying systems require a significant amount of solubilizers and surfactants lipophilic in nature, enabling the formation of microemulsions or nanoemulsions for faster dispersibility in waters that lead to faster absorption in the gastrointestinal tract often independent of pH.3

For polymer-based ASDs, polymeric excipients play a crucial role in helping convert highly crystalline APIs into amorphous states, making them more water soluble. For development of NCEs requiring medium to high doses, solid dispersion technologies are highly desirable for designing better and smarter oral dosages with higher efficacy that increase patient compliance by reducing the pill burden. Of several marketed ASD drugs, spray drying remains the most popular approach to convert crystalline drugs into amorphous powder, mainly due to a simpler downstream process to formulate ASDs into oral dosage forms.4

Spray drying formulas appear simple, but they can bring challenges in selecting suitable excipient solvents and processing conditions that match those API properties during the formulation design and manufacturing of ASDs. The product’s quality attributes depend on several factors, including the intrinsic instability of amorphous dispersions resulting from conversion or nucleation to original stable crystalline state.

Furthermore, controlling the level of residual solvents requires a paramount task to meet the ICH guidelines. In addition, longer solvent removal time during secondary drying may potentially lead to the API’s degradation and compromised efficacy of drug due to moisture and temperature effects. In spite of all these challenges, spray drying is an ideally accepted technology for preparing amorphous dispersions and improving and enhancing solubility and bioavailability, thus, making them possible from impossible for some of difficult molecules.5

This article will focus on spray drying technology with special reference to polymers and solvents selection, processing conditions, and the challenges with downstream manufacturing, stability, and degradation of APIs in oral dosages.


Spray drying requires polymers or blends of polymers for enhancing miscibility of drugs fully dispersed in the matrix. The composition and nature of the polymers and polymeric solubilizers are critical for processing and manufacturing of drugs in ASD powders. For example, higher polymer-to-drug ratios generally help provide stronger interactions of drug with polymer and yield stable formulations. Longer and higher molecular weight polymers provide stronger intermolecular interactions and protection of drug in the polymeric matrices. On the other hand, short-chain polymers affect the weaker intermolecular interactions of drug, resulting in poor entanglement and poor solubility and stability of drugs in the ASD powders. Therefore, polymer selection remains one of the important criteria in creating and developing a robust ASD formulation. For instance, long-chain polymers with higher molecular weight, for example, Soluplus®, will probably have much better and stronger interactions, and likely better solubilization capabilities, than those with low molecular weight due to lack of stronger entanglement of drug with polymer.6

A number of polymers are available commercially and also marketed in ASD drug products. The criteria for selecting polymers for spray drying include solubility of polymer and drugs in compatible organic solvents, thermal stability, and ease of processibility. All these criteria affect the in vitro and in vivo performances of drugs. The glass transition temperature (Tg) and chemistry and functional group of polymers and melting and Tg of drugs are all important factors in selection of appropriate polymeric excipients for spray drying. For instance, drugs with H-donor abilities can be stabilized with polymers having H-accepting ability via H-bonding. Thus, H-donor and acceptor criteria can stabilize the drug within the polymeric matrix by intermolecular interactions. For instance, copovidone (PVP/VA 64), may lead to stable formulations by inhibiting the recrystallization and leading the API in supersaturation without precipitation.7

Polymeric excipients used for ASDs are often amorphous in nature, while the drugs are highly crystalline. The API’s compatibility with polymers depends on the physico-chemical properties of APIs. In cases in which the drugs are like “brick dust” or highly “lipophilic,” finding the appropriate polymers with understanding of higher drug loading and maintaining thermodynamic and kinetic stability over extended periods in powders and in aqueous solution/biorelevant media are challenging because all factors lead to critical quality attributes for a robust formulation. The greater solubility of amorphous drug, compared to its stable crystalline form, is primarily due to minimal energy barrier required to dissolve in water.8


Because APIs are available in small quantities, an efficient screening method is required to identify the appropriate polymers with higher drug loading or exposure. It is important because marketed ASD drugs are typically available in large pills (>1 g). Thus, when screening the APIs with a range of polymers structurally different from each other and having different properties, their high-solubilization capabilities must be considered.9 It is achieved by dissolving the compounds and polymers in polar organic solvents and by casting clear films on drying in an oven at 50°C.10 This process is simple and rapid, which allows screening of multiple compounds with polymers at different drug:polymer ratios simultaneously within a short time. Kolter et al. have used this method to screen a range of polymers to identify lead formulations.9 Likewise, others have used the same procedure for selection of polymers for lead formulations. Dai et al. also used solvent evaporation in 96 wells for screening a range of polymers and solubilizers for APIs.11 Others have also used several polymers and solubilizers for screening a range of APIs varied in structures and functions.12,13 There is no data available on structure-function relationship of polymers and APIs on solubility. Other methods also include hot-stage microscopy for screening of drug molecules, but again, all these methods remain laborious and empirical that require good amounts of compounds in which polymer selection for ASD remains “hit and miss.”14 Like polymer selection, solvent selection remains at the highest priority because its solvation capability and compatibility for polymers and drugs are at the forefront of spray drying technology.

This column is focused on polymer selection and the solvents used in spray drying technology. Because it is quite different from hot-melt extrusion, the polymer’s Tg is of lesser significance than solubility in organic solvents; therefore, Tg is not the prime concern with exceptions of drugs with very low melting temperatures and Tg.


Polymer selection and choice of compatible solvents are an important first step requirement for the spray drying process. It may bring enormous challenges as the processing conditions for spraying amorphous powders out of solvents/co-solvents can lead to immediate re-crystallization of drugs to their most stable state. Thus, spray rate, temperature, and atomization rate can all impact the outcome of amorphous dispersion powders. Table 1 shows the list of commonly used polymers and stabilizers for spray drying dispersions.4

Commonly used polymers for spray drying


The spray drying process requires a significantly large amount of solvents, which could be an impediment in development of an amorphous drugs because of incomplete dry powders. At a smaller scale, it is highly feasible to save time and cost, but for scale-up, it requires large amounts of solvent that necessitates a more efficient drying process to control the residual solvents per the ICH guidelines. In such cases, solvents with low boiling and API’s with higher solubility are preferred over high-boiling solvents for controlled particle size and higher yield.4 The drug’s stability in the solvent feed requiring a longer spray drying process can lead to generating impurities by thermal degradation; therefore, care must be taken to minimize the undesired side reactions and related impurities. Table 2 lists solvents and their boiling temperatures used in spray drying and are selected based on solubility of APIs and safety to maximize the output or yield of spray dried powders.15

Commonly used solvents for spray drying


Critical processing parameters for spray drying depend on several factors, including but limited to, spray rate, nozzle size, inlet and outlet temperature, humidity, drug and polymer amounts, and atomization rate among others. As indicated, the following critical parameters are used for spray dried formulations.

Spray Rate – faster rate helps improve the particle size and shape upon atomization.

Nozzle Size – spray rate through the nozzle aperture determines the shape and size of the spray dried powder and is critical for product’s performance.

Polymer & Drug Concentrations – higher solid content is important to cut down the solvents that further improve faster evaporation and less exposure of drug in solvent for extended periods during spray drying and to maintain droplet size upon atomization.

Viscosity – lower viscosity over higher viscosity of feed is preferred as it requires low energy and pressure to yield desired spray patterns and particle sizes.

Humidity – controlling humidity is necessary to reduce the adherence of the powders with the vessels thereby improving the yields and decreasing the chances for agglomeration.

Inlet Temperature of Air – higher inlet temperature leads to faster evaporation of solvents and moisture, but it should be controlled to drugs sensitive to higher temperature to prevent degradation of drugs.

Outlet Temperature of Air – controlling it by adjusting the gas flow which in turn atomizes the droplets out of the nozzle and controls the particle size and moisture in spray dried powders.

Organic Solvents – organic solvents with lower boiling temperature control the particle size, yield smaller particles due to reduced surface friction through the nozzle compared with water, and help drying the powders faster

Feed Rate – higher feed rate leads to increasing the droplet size, and hence, the particle size of spray dried powders.


The spray drying process is a gentle one-step continuous manufacturing process that involves creating dry powders directly from a fully dispersed one-phase mixture of drug and polymer dissolved in a commonly solvent or slurry of mixture of drug and polymer. The slurry is subjected to spray as fine droplets by atomization controlled with a stream of hot drying gas (nitrogen) typically carried out between 50°C-100°C. The spray dried powders are dried rapidly as the solvent evaporates and product is collected in a cyclone, and the solvent is reconciled after condensing through a chiller as shown in Figure 1.16

Illustration of the Spray Drying Process

Spray nozzles and their apertures are important for creating spherical and hollow smooth spray dried powders following atomization. Thus, a careful selection of nozzle is required for achieving the desired particle size from the droplets by adjusting the appropriate atomization pressure. To alleviate these challenges, hollow cone pressure one or multiple nozzles (eg, Schlick nozzles) are typically used for atomization of spray dried feed with viscosity of 50-100 mPas and at pressure range of 20-200 bar with a throughput of 500-kg liquid per hour.9 Powders collected in a cyclone require post drying or cooling by fluid bed to keep them moisture free as they can lead to agglomeration of particles forming lumps and possibly leading to degradation of APIs upon storage.

Ascendia’s GMP Spray Dryer

Taken collectively, the product’s quality parameters should be monitored for hygroscopicity, moisture content, bulk and tapped density, flowability, particle size and morphology, amorphization, and encapsulation and complete miscibility of drugs by physical techniques. Spray drying factors, such as operation conditions and feed characteristics, affect the product’s quality in general. The operation conditions include inlet and outlet temperatures, feed flow rate, drying gas flow rate, atomizing gas flow rate, feed temperature, and atomizer speed; and the feed characteristics include feed composition, carrier’s type and concentration, density, and viscosity.17

Table 3 may help guide to achieve spray drying formulations with desired characteristics using the right processing conditions.18,19

A guide to achieve spray drying formulations with desired characteristics using the right processing conditions.18,19


Spray dried powders are fine and often contain the residual solvents (ca. 1%-10%) regardless of the drying conditions.20 The evaporation of solvents from dried powders requires elevated temperature under vacuum/pressure. In such cases, drying by traditional methods of spray dried powders can take several days; therefore, more efficient methods are warranted to improve stability of drugs in bulk powders. To drive off the residual solvents and attain the minimal levels to meet the ICH guidelines, traditional methods like the use of conventional ovens may be time-consuming and costly. Furthermore, longer evaporation time under higher temperature could also be detrimental for stability, integrity, and stability of drug products. Thus, there is a continued effort to find the ideal evaporation method to minimize the exposure of amorphous drug in powders to alleviate re-crystallization and avoid degradation and/or conversion into different polymorphs. Shepard et al. used a solvent-assisted secondary drying method.21 The solvent-assisted method is carried out in an Ekato VPT3 agitated dryer that allows the removal of residual solvents from bulk powder by purging of solvents (eg, methanol) with dry nitrogen bubbles. The stability challenges, if not controlled, can lead to compromised potency or generation of undesired impurities that could pose safety risks upon storage over extended periods. In such cases, careful selection of the drying methods for evaporation of residual solvents are highly desired to shorten the exposure by an efficient drying process to reduce the solvent levels and hygroscopicity.

Spray dried powders can be directly compressed into tablets, minitablets, or pellets. Because the powder flowability of SD powders are poor, use of appropriate excipients lead to increased flowability for compression. Lin and Kao compressed spray dried sodium diclofenac enteric-coated microcapsules into tablets with neocel and flo-starch (weight ratio, 1:1).22 Al Zoubi et al. investigated a number of directly compressible excipients for compressing SD powders into oral tablets


As new molecules coming out of discovery require enabling, non-conventional formulation technologies for developing drugs for unmet medical needs, Ascendia continues to be on the forefront serving the pharma and biotech industry by employing its proprietary technologies, such as NanoSol®, EmulSol®, LipidSol®, and AmorSol®. The latter is widely applicable as some of the other technologies may require challenges with stability and special facilities for sterile and aseptic filling/processing for parenteral and oral liquids. Ascendia’s AmorSol® can help find the appropriate solutions by screening different compatible polymers listed in the inactive ingredient database (IID) for an individual compound by using a film-casting approach to streamline and optimize the process amenable to ASDs by the spray drying or hot-melt process. In addition, AmorSol® could potentially reduce or eliminate the food effect for certain type of drug candidates. Its state-of-the-art cGMP manufacturing facility can handle ASD projects from early stage in pre-IND to clinical Phase 1 and Phase 2 development.


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Jim Huang, PhD
Founder & CEO
Ascendia Pharmaceuticals

Dr. Jim Huang is the Founder and CEO of Ascendia Pharmaceuticals, Inc. he earned his PhD in Pharmaceutics from the University of the Sciences in Philadelphia (formerly Philadelphia College of Pharmacy and Sciences) under Joseph B. Schwartz. He has more than 20 years of pharmaceutical experience in preclinical and clinical formulation development, manufacturing, and commercialization of oral and parenteral dosage forms. His research interests are centered on solubility/bioavailability improvement and controlled delivery of poorly water-soluble drugs through nano-based technologies.

Shauket Ali, PhD
Sr. Director, Scientific Affairs & Technical Marketing

Ascendia Pharmaceuticals

Dr. Shaukat Ali joins Ascendia Pharmaceuticals Inc. as Senior Director of Scientific Affairs and Technical Marketing after having worked in the pharma industry for many years. His areas of expertise include lipid chemistry, liposomes, lipid nanoparticles, surfactant-based drug delivery systems, SEDDS/SMEDDS, oral and parenteral, topical and transdermal drug delivery, immediate- and controlled-release formulations. He earned his PhD in Organic Chemistry from the City University of New York and carried out his post-doctoral research in Physical Biochemistry at the University of Minnesota and Cornell University. He has published extensively in scientific journals and is inventor/co-inventor of several US and European patents.