A Case for Solid Dispersions

Advances in combinatorial chemistry and high-throughput screening have led to an increasing number of poorly soluble drugs in the development pipeline and the need to develop technologies that address solubility issues has never been more crucial. One approach that is becoming increasingly popular is the use of amorphous solid dispersions because of their broad applicability, observes Kevin O’Donnell, PhD, Associate Research Scientist at Dow Pharma & Food Solutions. Traditional methods rely on certain API properties to be successful, according to O’Donnell. “For example, salt formation requires the API to be ionizable and complexing agents such as cyclodextrins require the drug to fit within the complexing ring.”

“For solid dispersions, it is a matter of rendering and maintaining the drug in the amorphous state and/or adequately dispersing it within a carrier matrix using one of many available technologies,” O’Donnell explains. “While drug-carrier incompatibilities may exist, requiring careful excipient selection, there is no distinct property required of the API for formulation into a solid dispersion.”

“Solid dispersions can often provide a significant increase in solubility compared to other formulation approaches,” O’Donnell adds. “This advantage is largely due to the amorphous state of the API and to the hydrophilic nature of the surrounding matrix material that can aid in wetting once exposed to the aqueous biological media. Furthermore, solid dispersions allow for unique intellectual property to be obtained, thereby aiding in the lifecycle management of existing compounds and maximizing a drug’s economic potential.”

Methods to produce solid dispersions

O’Donnell notes that until recently, the number of methods available to a formulator to generate an amorphous solid dispersion was limited. “However, recent growth in the techniques capable of generating an amorphous solid dispersion-such as spray drying, hot melt extrusion (HME), precipitation methods, co-milling, KinetiSol dispersing, cryogenic methods, and others-has created processing flexibility, allowing almost any API to be formulated into a solid dispersion.”

Spray drying and HME are currently the most commonly used methods to produce solid dispersions. “Spray drying is highly effective at generating the amorphous form of an API and can be used for APIs that have low degradation temperatures,” says William 'Trey' Porter III, PhD, Associate Research Scientist at Dow Pharma & Food Solutions. “Furthermore, with appropriate polymer and solvent selection, the resulting product will be homogeneous.” Porter adds that HME is also effective in converting a crystalline API into the amorphous form and has the advantage of being a continuous process with significant versatility in the final dosage form.

An important consideration for solid dispersions is the pairing of the API to the optimal polymer for solubility enhancement, Porter points out. “This, combined with an in-depth understanding of the API physical properties, allows for selection of an appropriate technology for the generation of the amorphous solid dispersion. By letting the API and matched polymer guide the formulator to an optimal technology, rather than force-fitting a formulation to a technology, the likelihood of success increases.”

Another primary challenge for solid dispersions is the stability of the amorphous drug, according to Porter. “Improperly formulated systems may recrystallize into more thermodynamically stable and less soluble forms, resulting in dramatic changes in the dissolution, absorption, and therapeutic effect of the API,” he explains. “The stability of crystalline formulations is also of great concern if a high energy polymorph is selected because polymorphic transformations can have similar negative effects.”

Understanding the API is key

A number of tools can be used to improve the likelihood of success of early formulations and for selection of an appropriate technology, says Porter. “A strong understanding of the API including the melting point, glass transition temperature, lipophilicity, and Tm/Tg ratio will provide insight into the propensity for recrystallization of an amorphous API as well as drug loading limitations in the final formulation. Additionally, the organic solubility and thermal decomposition temperatures are important factors in selecting a technology by which to produce the amorphous solid dispersion.”

“At Dow, our primary screening tools for amorphous solid dispersion formulation include high throughput precipitation inhibition screening for polymer selection,” says Porter. “Furthermore, small-scale spray drying/HME and microcentrifuge dissolution testing are performed on leading candidates to ensure that the proper polymer structure has been selected for maximum dissolution performance and formulation stability.”

One of the most significant advances in recent years is the introduction of small-scale spray drying and HME equipment capable of reducing API consumption and increasing technology availability for formulators, observes Porter. “However, despite significant advances such as the use of high throughput screening methods for polymer selection and formulation design, the number of available excipients and new excipients entering the market hinders formulation optimization,” says Porter. “With no definitive approval pathway for newly designed excipients, the ability to gain acceptance and broad use of an excipient is reliant upon its use in an approved product, thus creating lengthy timelines to market.”