Selecting the Appropriate Technology for Oral Bioavailability Enhancement

Model-based formulation and technology selection methodologies facilitate rapid product development.
Nov 02, 2017
Volume 41, Issue 11, pg 28-31

alice-photo/Shutterstock.comA large percentage of new chemical entities (NCEs) have physicochemical properties that require enabling formulations to achieve acceptable oral bioavailability and the associated therapeutic efficacy. Because of the increasing need for enabling formulations, several new drug-delivery technologies have been developed and commercialized. However, although commercial precedence of a number of enabling technologies has been established, significant expertise is required to identify and apply the most appropriate technology to a given drug candidate. 

There has been a recent emphasis on efficiently evaluating the safety and efficacy of compounds in preclinical and early clinical studies to save time, money, and resources. For NCEs requiring enabling formulations, formulation identification and development are based on a clear understanding of gastrointestinal (GI) tract physiology; the physicochemical properties of the drug molecule; and the target product profile (TPP), including dose, optimal pharmacokinetics profile, and preferred final dosage form. With this knowledge, key technical challenges associated with the drug candidate can be addressed early in formulation development.

In addition to bioavailability enhancement (BAE), many TPPs also require modified-release (MR) or targeted GI delivery technologies. Site-specific release in the GI tract may be desired to avoid API exposure to the gastric environment to limit acid-catalyzed degradation, to maximize exposure in the lower intestine for local-acting treatments, or to release solubilized API in the gut over an extended timeframe to achieve an optimal pharmacokinetics profile. Antiviral molecules are often dosed with a cytochrome P450 inhibitor acting as a pharmacokinetic “booster.” Fixed-dose combinations (FDCs) requiring BAE and MR are increasingly common for therapeutic effect or reduced dosing regimens. Dosage forms designed for specific patient population groups (e.g., pediatric or geriatric) may also be required to address dosing issues. Simultaneously achieving TPPs involving both BAE and MR or targeted delivery for one or multiple APIs, as well as developing a robust formulation that can be effectively advanced in an efficient manner, requires innovative formulations based on mechanistic models.

The mechanistic delivery challenge 

The first step in formulation development is to identify the technical challenge to be addressed, which may include low aqueous solubility, low permeability, slow dissolution rate, significant metabolism or efflux, requirements for site-specific release in the GI tract, and/or the need to maximize or minimize systemic absorption. Mechanistic understanding of the drug-delivery problem statement early in the candidate development program minimizes iteration of technology and formulation screening. It also directs experimentation to critical aspects of formulation performance, stability, or manufacturability, which increases efficiency by focusing on the most critical factors for compound progression. Formulation experience is crucial to quickly identify and address bioavailability challenges. By leveraging extensive institutional knowledge of molecules with similar properties and TPPs in the form of compound property maps and other physical models, formulation scientists can rapidly identify key problem statements for the NCE, and therefore better select formulation approaches likely to address the particular formulation challenge.

In-vitro testing 

Models of varying levels of sophistication guide technology and formulation selection for drug-delivery applications. Simple models include guidance maps based on large and diverse historical data sets of molecules that have been successfully formulated. Such maps can be used to identify formulation starting points using the knowledge generated for similar molecules and formulations. Quantitative mechanistic models include maximum absorbable dose (MAD) estimates based upon a few easily ascertained molecular properties that can be used early in development to obtain initial estimates of absorption. For programs in later stages of development, more detailed mathematical models based on a larger number of fundamental physical properties of the drug and formulation can be used to refine predictions of relative or absolute performance characteristics, such as percent dose absorbed or pharmacokinetic profiles. The best use of in-vitro tests is to generate key physical parameters that are used as inputs to these mechanistic models to identify rate-limiting steps to absorption, to rank-order formulations for parameter sensitivity analysis, and/or to otherwise understand the impact of a key property on performance, manufacturability, or stability. 

A variety of both well-established and novel in-vitro tests are used to measure compound or formulation physical properties that are used as model inputs. The utility of specific tests depends on the properties of the compound, the limiting mechanism to absorption, and the type of formulation. For example, measurement of the drug molecule’s amorphous solubility can be used to estimate the maximum improvement in absorption of a low-solubility compound using an amorphous drug form, such as a solid amorphous dispersion, relative to absorption from the crystalline drug form. Similar screening tests can be used to select polymers to maximize sustainment of supersaturation prior to manufacturing any formulations as part of the preformulation work flow. In evaluating solubilization performance, an assessment of drug speciation is crucial because the concentration of drug dissolved versus that incorporated into solubilized species such as micelles, colloids, and nanocrystals can have a large impact on performance. 

A brief case study demonstrates the importance of careful use of in-vitro measurements in conjunction with quantitative models to design enhanced formulations. Figure 1 shows the solubilized drug concentration from the spray-dried dispersions (SDD) of a poorly water-soluble API relative to that provided by the crystalline form. Analysis by centrifugation or filtration showed a large enhancement in solubilization for the enabled formulation. A MAD calculation based on this analysis predicted an eight-fold enhancement in absorption in dogs due to solubilization. However, as shown in Figure 2, the area under the curve (AUC) provided by the SDD was only a little more than two-fold higher than that from the crystalline suspension. A more careful assessment of the drug speciation in vitro using spectroscopic analysis of data from fiber optic probes (see Figure 3) showed that nanocrystalline drug particles rapidly form in the dissolution media, quickly reducing the drug activity and the driving force for absorption. Using the time-concentration profiles of dissolved drug from this in-vitro analysis gave an accurate prediction of the enhanced absorption provided by the SDD, and guided development of a formulation that better sustained high dissolved drug concentrations.

Figure 1: The initial spray-dried dispersion formulation provided high concentrations
of solubilized drug. (All figures courtsey of the author.)

Applying the mechanistic models and testing described here at the earliest phases of feasibility increases the likelihood of developing robust and scalable formulations, leading to lower risk, faster development timelines, and lower development costs. This approach is used routinely to assess applicability of technologies for the required performance, manufacturability, and product stability. It ensures that even at the initial formulation feasibility stage there is line of sight to the commercial product, reducing the risk that reformulation will be needed later in the drug development program. 

Figure 2: In-vivo plasma profile in dogs (left) and the maximum absorbable
dose (MAD) estimate based on the solubilization profile in
Figure 1 (right). AUC is area under the curve.

To optimally formulate based on mechanistic science requires having a breadth of formulation technologies available to take advantage of the unique characteristics of various solubilization approaches. For example, if analysis suggests that modest dissolution rate enhancement is sufficient to give adequate oral exposure for a compound that also has chemical stability risks, then crystalline particle size reduction is likely a better choice than lipid/liquid-based or solid amorphous formulations. Having a range of technologies available aids in advancement of the most appropriate technology. Likewise, the availability of a range of technologies also allows formulating in a phase-appropriate manner. For example, SDDs are ideal for early stage work, as they can be manufactured quickly using only a small quantity (10s of mg) of API. Depending on the application, SDDs can then be scaled up and advanced through later development, or potentially transferred to a hot-melt extrusion (HME) process, depending on technical and commercial considerations. Therefore, strategic application of enabling technologies based on the technical considerations, the phase of the development program, and the TPP is a generally advantageous approach for the rapid and efficient progression of challenging drug candidate programs.

Figure 3: Spectral analysis of the solubilized species identified rapid formation
of nanocrystalline drug suspended in the dissolution media (top).
Based on characterization of the dissolved drug concentration profile,
the revised maximum absorbable dose (MAD)
calculation is in good agreement with the in-vivo data (below).
The in-vitro analysis was used to develop a non-crystallizing formulation.
AUC is area under the curve.


The majority of drug compounds in the pharmaceutical pipeline require bioavailability enhancement and/or modulation of the pharmacokinetic profiles in order to achieve successful formulations. Efficient and robust development of these increasingly demanding drug products requires fundamental mechanistic understanding of the barriers to absorption, and of the interplay between formulation attributes and GI physiology. Physical and mathematical models informed by data collected from an array of appropriately chosen in-vitro tests guide technology and formulation selection, allowing for rapid and effective product development. Experience and process capabilities across the range of enabling BAE and MR/targeted technologies and formulations are prerequisites for developing and applying advanced modeling and testing in meeting challenging TPPs.

Article Details

Pharmaceutical Technology
Vol. 41, No. 11
November 2017
Page: 28–31


When referring to this article, please cite it as M. Morgen, M. Grass, and D. Vodak, “Selecting the Appropriate Technology for Oral Bioavailability Enhancement,” Pharmaceutical Technology 41 (11) 28–31 (2017).

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