Why spray drying should be on every formulator's mind

William Wei Lim Chin, technical specialist, Science and Technology at Catalent explains why spray drying is essential for overcoming solubility issues.

Developers and manufacturers are frequently turning to spray dried dispersions (SDDs) as a means of overcoming the solubility challenges presented by many new medicines. Spray-dried dispersions have some unique characteristics, and there are some important formulation and processing parameters to be considered when creating an amorphous solid dispersion (ASD) and incorporating ASDs into common dosage forms.

For formulators, solubility is a persistent challenge to delivering the therapeutic benefits of a treatment, and one that, if not properly addressed in the early stages of development, can be costly, both in terms of time and money to solve later. It is estimated that nearly 40% of the new chemical entities (NCEs) screened by pharmaceutical companies fail to progress to later stages of development due to poor aqueous solubility¹. This puts an onus on formulators to improve the bioavailability of poorly soluble drug molecules to ensure that life-changing drugs are not abandoned and can reach their true potential, and the patients who need them.

Since many of these insoluble drugs exist in crystalline form, creating an ASD using spray drying technology is one approach to improve solubility. Amorphous forms are intrinsically more soluble than crystalline materials, as there is no crystalline lattice energy to be overcome. An SSD is an amorphous molecular dispersion of a drug in a polymer matrix, created by dissolving drug and polymer in an organic solvent and subsequently atomising this liquid feed into very small droplets within a hot drying gas, leading to flash drying of the droplets into solid particles. This single-step, continuous process is very robust and stable and offers multiple opportunities for formulation development of dosage forms.

Processing parameter considerations for spray drying

Creating the ideal spray dried particles requires control over the critical processing parameters that influence radial distribution of the active pharmaceutical ingredient (API) and polymer components². During the rapid drying phase, the components tend to adsorb and diffuse on the surface of the droplet. Solvent evaporation, a balance between the solvent’s vapour pressure and partial pressure, causes the droplet surface to recede, leading to diffusion of components towards the interior. To avoid phase separation, evaporation must occur before the API crystallises, and this can be controlled by optimising the spray rates, feed solution concentration and processing temperature. By varying the parameters of the spray drying, it is also possible to engineer smaller particle size (typically between 1-5 µm) for inhaled drug products. The process allows for the formulation of products that may have unusual or difficult characteristics, including products that are difficult to handle, or are hygroscopic. Spray drying also offers advantages for materials that are particularly temperature sensitive, as the rapid drying involved in the process helps ensure the product is not degraded during processing.

Formulation considerations for spray drying

In the development of an SDD, it is crucial that the product is stable. The nature of the polymer used in the process must be considered to ensure that it is chemically stable with the API, while also being miscible and improving the supersaturation of the API in aqueous media. Selecting polymers that have a high glass transition temperature (T_g) could ensure that the rate of phase separation and crystallisation is substantially reduced. Though most polymers are relatively inert, some are hygroscopic or acidic and therefore inappropriate for compounds prone to hydrolysis or acid degradation.

Similarly, the choice of solvent is important as it must provide sufficient solubility and chemical stability for both the API and the chosen polymer. A wide range of organic solvents are suitable for spray drying, and often a combination of solvents can be the most appropriate.

Dosage form formulation

It is important to note that any instability previously observed in the crystalline form of the API will likely be more pronounced in the amorphous state. Specifically, hygroscopicity is usually worse in an amorphous form due to the hygroscopicity of some polymers, and the high surface area of the ASD particles. Reactivity with acids, bases, and oxidisers is also generally worse due to the high energy state of the amorphous material.

Once a physically and chemically stable SDD has been developed, formulating this into a solid dose form is the next step – which could be either a tablet, capsule or an alternative format. Excipients for dose form formulation however, must be selected and tested for compatibility with the spray-dried powder. Excipients that can provide the best chemical stability are often those that are pH neutral, low moisture content, and low hygroscopicity, such as mannitol as a tablet excipient and hydroxypropylmethyl cellulose (HPMC) capsules instead of gelatin for hard shell capsules.

For compounds that are pH-sensitive, excipients with pH buffering capacity, such as citric acid and sodium bicarbonate, can have a stronger stabilising effect on ASDs than on a crystalline API, and additionally, solid dosage forms can be coated with materials such as polyvinyl acetate (PVA) for further moisture protection.

It is important that formulation development efforts focus on fast-disintegrating dosage forms, otherwise the increased solubility of the spray-dried API can be quickly negated by its poor release into the body. It may be necessary to introduce aggressive disintegration approaches in the dose form if initial attempts produce long disintegration times, or slow dissolution rates.

All in vitro formulation development work needs to be confirmed with in vivo studies whenever possible, and comparison studies carried out between the neat dispersion suspended in water along with the formulated dispersion in a relevant model, to ensure poor disintegration is not leading to lower than expected exposure levels.

Conclusion

Typically, spray drying is unlikely to be a formulator’s first choice to overcome solubility issues, as other approaches such as salt forms, co-crystals, and micronisation require less technical expertise and are economically advantageous. However, developing an ASD should be considered if other approaches do not offer the desired solubility. With more molecules being developed with poor aqueous solubility, spray drying is becoming an important part of development “toolkits”, and investments across the industry are being made in increased capacity and expertise to ensure the technology is accessible to allow drugs to be taken through to commercialisation.

References

^{1: Roots Analysis Business Research & Consulting, Pharmaceutical Spray Drying Market, 2nd edition 2018-2028.}

^{2: Vehring R. Pharmaceutical particle engineering via spray drying. Pharm Res. 2008 May;25(5):999-1022. Doi: 10.1007/s11095-007-9475-1}