Lately, as has been widely documented, there appears to be an ever increasing number of compounds in discovery and development that are water-insoluble. This fraction is clearly increasing over time, and is at least in partly due to the need for novel compounds that have specific and potent interactions with modern biological targets. Many estimates are that 30-40% of compounds in many modern discovery libraries are essentially insoluble in water.
So, if our goal is to maximize oral bioavailability, what do we do with these molecules? Traditionally, identifying a more soluble salt form, micronizing to improve dissolution rate and lipid/oil-based solutions have been used with reasonable success. However, these traditional approaches have limitations and essentially don’t work for many insoluble molecules.
The use of amorphous solid dispersions (ASD) has recently been quite successful in advancing water-insoluble and hence poorly bioavailable molecules into the market. In these systems, the drug is combined with a water-soluble polymer to ideally produce a single-phase amorphous mixture of the drug and the polymer. Since the drug is amorphous, it has a higher free energy, and hence provides a much higher aqueous solubility and dissolution rate compared to other approaches. Recent drug approvals using this approach include Kalydeco (cystic fibrosis, Vertex) and Incivek (Hepatits C, Vertex).
In this blog post, we review ASDs at a high level and provide a basic overview of this formulation approach. Let us know your opinion below.
An Overview
A bit of background. Unlike crystalline forms, amorphous forms lack a highly-ordered crystal lattice and thus exhibit a decrease in intermolecular interactions (and a corresponding increase in enthalpy) that must be overcome to achieve the solution state, resulting in rapid dissolution and high levels of supersaturation in aqueous media. Since the vast majority of drugs are passively absorbed in the gastrointestinal (GI) tract, supersaturation increases the flux of drug across the intestinal wall, which leads to greater absorption in the GI tract.
In general, ASDs combine the drug and key excipients together to form a homogeneous amorphous material. Polymers are usually preferred over small molecule excipients as they generally can simultaneously produce enhanced solubility in water and achieve acceptable amorphous physical and chemical stability. Both of these are required to achieve a practical and commercializable drug product.
More technically, these amorphous materials should possess a high glass transition temperature, which minimizes drug mobility in the solid state, and ideally non-covalent interactions between the drug and polymer. These drug-polymer interactions can enable physical and chemical stability of the drug in the ASD.
When properly designed, ASDs dissolve rapidly and supersaturate (relative to the crystalline solubility of the drug) when they encounter aqueous intestinal environment. Ideally, supersaturation is sustained for several hours to ensure maximum bioavailability. Polymers in solution prevent crystallization of a supersaturated drug solution, although the extent of inhibition depends on both drug and polymer. For example, hydroxypropyl methylcellulose acetate succinate (HPMCAS) is well known to be especially effective at reducing solution precipitation of the drug, although depending on the specific molecular structure of the drug, other polymers may be preferred. Some other amphiphillic polymers include povidone (PVP), povidone-co-vinyl acetate (PVP-VA), HPMCAS, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC), polymethacrylates, and methacrylate copolymers. A carefully designed formulation screening process is required to identify the preferred polymer (or combination of polymers) and polymer amount to ensure optimum performance and stability. Surfactants can also enhance dissolution and slow solution crystallization in some cases.
The nature of ASDs necessitates certain analytical methods to ensure success. Some of these are thermal analysis (e.g., differential scanning calorimetry, thermogravimetric analysis, microcalorimetry, etc.), X-ray diffraction, spectroscopy (infrared, Raman, solid-state NMR), microscopy (optical, SEM and TEM), dissolution, and solubility. When designing an ASD formulation, it is very important to utilize these methods to provide a clear understanding of potential performance and stability. A particularly vexing issue is prediction of in vivo performance from in vitro dissolution data. Dissolution methods and media specific to ASDs are required to gain some understanding of how a given formulation may perform in vivo, and is largely poorly applied. In addition, it is important to gain a clear understanding of the physical state and stability of the ASD prior to scale-up, and ideally early in the development process.
Preferred Processes
There are many processes and manufacturing methods that have been used to make ASDs. However, there are clearly a few preferred process methods. These are scalable and well understood and routinely used to manufacture ASDs. Preferred processes include spray drying, melt extrusion, and co-precipitation.
Spray drying is broadly applicable as long as the drug has sufficient solubility in the spray solution. The process involves dissolving drug and excipients in a solvent and forcing this solution through a nozzle which produces small droplets in a drying chamber of heated gas. The droplets dry rapidly resulting in small particles, typically 1-50 microns in diameter. The particles are collected using a cyclone and a filter system. The major benefit of this approach is the ability to form true uniform molecular dispersions for almost any drug due to very rapid solvent removal (10–100 milliseconds). An example of a marketed ASD formulation made using spray drying is Incivek® (telapravir), discussed below.
Melt extrusion utilizes high-shear induced transient heating to form a uniform molecularly dispersed solid state of drug and excipient. Typically, crystalline drug, a polymer, and in some cases a plasticizer are combined via blending and then fed continuously using a powder feeder into a twin screw extrusion system. In a melt extrusion process, this heat is produced primarily in a high-shear zone (although heat can be applied directly to the extruder barrel), followed by relatively rapid cooling, preventing thermal degradation of the drug and/or excipients. Benefits of this approach are the avoidance of volatile organic solvents in the process, while challenges include the need to use heat, which can limit applicability to heat sensitive materials. Extrusion technology for manufacture of ASDs at commercial scale is common, an example being Kaletra, which is a combination tablet containing ritonavir and lopinavir for AIDS therapy.
A less common approach, but one which has had recent commercial success, is co-precipitation. In this process, drug and excipient are dissolved in a solvent followed by rapid precipitation using an anti-solvent (typically water). A commercially scaled version of this process has recently been used to manufacture Zelboraf®, a treatment for metastatic melanoma, which was approved in the United States in 2011. A key limitation of this approach is the formation of completely amorphous materials, and for many drugs, this cannot be achieved using precipitation methods.
The selection of the preferred process can be accomplished early in the development process by using key physical chemical properties of the drug and by understanding of how the drug may interact with various excipients and in various process methods. This is a critical issue when selecting a service provider.
Challenges of ASD Formulations
ASDs have demonstrated their utility to improve bioavailability of poorly water soluble drugs and are becoming the go-to approach for insoluble molecules. However, ASD technology development requires a unique set of skills and methods, and knowledge is limited in the service-provider community. As such, they present a certain level of increased risk for those pursuing clinical and commercial development. One key to reducing risk is early assessment of the preferred approach, which can be accomplished with careful analysis of the compound, proper solid-state and in vitro screening, and understanding of development goals, such as dose and manufacturing costs. Additionally, developing analytical methods and cGMP operations that are unique to ASDs is critical for successful development.
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