Shaukat Ali, PhD, FAAPS - Sr. Director, Scientific Affairs & Technical Marketing, Ascendia® Pharma.
Over 80% of new molecular entities (NMEs) are poorly soluble, often making it impossible to formulate them using 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. 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.
Successful spray drying takes more than equipment. Ascendia® Pharmaceuticals blends modern equipment with its B.E.S.T. (Brilliant Technology, Excellent Service, Superior Quality, Trust) approach to provide advanced small-batch spray drying services. In fact, Ascendia® has a proven track record of spray-drying molecules that have not traditionally been thought to be candidates for the process.
Spray Drying Process
Spray drying is a gentle one-step continuous manufacturing process that involves creating dry powder directly from a fully dispersed one-phase mixture of drug and polymer dissolved in a common solvent or slurry 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 powder dries rapidly, as the solvent evaporates and the product is collected in a cyclone, and the solvent is reconciled after condensing through a chiller.
Spray drying factors affect the product’s quality in general. Figure 1 outlines some of the main factors.
Spray Drying Considerations
Spray drying requires polymers or blends of polymers to enhance the miscibility of drugs fully dispersed in the matrix. The composition and nature of the polymers and polymeric solubilizers are critical for the processing and manufacturing of drugs in ASD powder. Therefore, polymer selection remains one important criterion in creating and developing a robust ASD formulation.
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
- Ease of processability
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 the selection of appropriate polymeric excipients for spray drying.
Polymeric excipients used for ASDs are often amorphous, 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 an understanding of higher drug loading and maintaining thermodynamic and kinetic stability - in powder and aqueous solution/biorelevant media, is challenging because all factors may impact the critical quality attributes of a robust formulation. The greater solubility of an amorphous drug, compared to its stable crystalline form, is primarily due to minimal energy barrier required to dissolve in water.
Screening of APIs with Polymers
Since 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 physio-chemical properties, their high-solubilization characteristics must be considered.
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. This process is simple and rapid, which allows screening of multiple compounds with polymers at different drug: polymer ratios simultaneously within a short time.
Polymer selection and choice of compatible solvents are an important first step in spray drying. 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 powder.
Solvent Selection for Spray Drying
Spray drying requires a significantly large amount of solvents, which can be an impediment in developing an amorphous drug because of incomplete drying of ASD powder. At a smaller scale, it is highly feasible to save time and cost, but for scale-up, large amounts of solvent are required; therefore a more efficient drying process is necessary to control the residual solvents per ICH guidelines. In such cases, solvents with low boiling points and APIs with higher solubility are preferred to control particle size and produce higher ASD yield.
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.
The Ascendia® Difference
Ascendia has become the “go-to” CDMO for small-batch spray drying projects, using advanced expertise and experience to implement processes that lead to effective scale-up. Our proficiency helps us recognize formulations that will have issues – such as viscosity – later in the drug development process and optimize them for success.
Ascendia is adept at conducting spray drying in a number of different environments, including aseptic. Our expertise includes transitioning formulations from non-cGMP environments to cGMP environments at a small scale. Such proficiency helps create a seamless transition of formulations from Ascendia to pharmaceutical companies for larger-scale production.
Contact Ascendia at www.ascendiapharma.com
[email protected] or 732-640-0058
Publication Detail
This article appeared in American Pharmaceutical Review:
Vol. 26, No. 8
Nov/Dec 2023
Pages: 48-49
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