Understanding the Effect of API Properties on Bioavailability Through Absorption Modeling

Abstract

Abstract. Selection of API phase is one of the first decision points in the formulation development process. Subsequent to phase selection, the focus shifts to the API physical properties such as particle size. Oftentimes, such properties are closely monitored throughout the drug development, as they can have a direct impact on the formulation bioperformance. The purpose of this mini-review was to describe the potential for application of absorption modeling in understanding the effect of API properties on bioavailability. Examples are provided to demonstrate how absorption modeling can be applied both early on to set the formulation strategy as well as during the development process to help with setting of specifications around the API. Limitations of the existing models and areas of possible expansion of such tools are also discussed.

Evaluation of Dissolution Enhancement of Aprepitant Drug in Ternary Pharmaceutical Solid Dispersions with Soluplus® and Poloxamer 188 Prepared by Melt Mixing

“…It is a lipophilic compound supplied in the form of a white to off-white crystalline solid powder with pKa value of 9.7 within the pH range 2 to 12. It is considered as practically insoluble in water with low free base aqueous solubility of (3-7 μg/mL) over the physiological pH range [6][7][8]. In vivo absorption of APT through first pass metabolism leads to low bioavailability while the API is considered as having intermediate permeability across Caco2 [9,10].…”

Practical Anticipation of Human Efficacious Doses and Pharmacokinetics Using In Vitro and Preclinical In Vivo Data

“…Since exposure is apparently solubility rate-limited, solubility scenarios chosen were (a) 0.002 mg/mL, which represents minimal formulation efforts and (b) 0.01 mg/mL assuming a 10-fold increase in solubility due to formulation optimization (28). An IR capsule and a default average particle size of 25 μm was assumed.…”

“…This case illustrates that biorelevant solubility data are crucial for accurate human predictive PK/PD modeling. Measuring relevant solubility remains a challenge (45), and more work is needed to refine the models, including precipitation kinetics (28).…”

“…We report examples for the practical projection of human PK and PK/PD concentration and effect time profiles based on preclinical PK/PD and absorption models (27,28). We illustrate modeling approaches which can be readily implemented by pharmaceutical scientists utilizing common tools such as allometric scaling (11)(12)(13)(14)29,30), the Wajima et al method (23,26), and GastroPlus™ including its PBPK, PK/ PD, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) Predictor™ software modules (31).…”

Amorphous Solid Dispersions or Prodrugs: Complementary Strategies to Increase Drug Absorption

“…Several publications have shown the ability of dissolution to provide discriminatory data on comparing factors such as particle size and to use these data as input in PBPK type of models to forecast clinical pharmacokinetics. 18,138 However, traditional dissolution tests may not be sufficient to fully reflect the behavior of solubilizing formulation. For ASDs, the ability of the system to capture the supersaturation generated is a critical aspect of the in vitro evaluation.…”