The problem of supersaturating drug products might loosely be summed up as:
“If you’re not part of the solution, you’re part of the precipitate!”
Indeed, more than 60% of new drug candidates are poorly soluble1 which can severely limit their bioavailability. To ameliorate this issue, a common approach is formulating to create supersaturated solutions of drug. Widely used approaches include, for example, using amorphous solid dispersions, where the amorphous solid has higher solubility than a more stable crystalline form or formulating the drug as a salt. In both cases, the dissolution of the formulation results in concentrations of dissolved drug that exceed the thermodynamic solubility. Such supersaturated solutions therefore carry a precipitation risk which can severely limit the intended benefits of this approach but which can be ameliorated through additional formulation strategies such as the addition of precipitation inhibitors. In addition, poorly soluble, low basic pKa drugs, which tend to have significantly higher solubility at the low gastric pH typical of fasted conditions compared to the elevated pH of the small intestine, are also susceptible to precipitation. Thus, anticipating these properties and reacting accordingly, for example through adding precipitation inhibitors, can be critical to successful drug development.
The Office of Generic Drugs (OGD) at the US Food and Drug Administration (FDA) recently awarded Certara’s Simcyp group a multi-year research grant to create and validate a physiologically-based pharmacokinetic (PBPK) modeling and simulation framework to predict and simulate the behaviour of supersaturating, orally dosed drug products in the human gastro-intestinal tract. This platform will also permit assessing and comparing new products to reference products.
We aim to further develop state-of-the art mechanistic models and workflows to improve predicting the in vivo behavior of supersaturating drugs. The models should help sponsors to employ appropriate formulation strategies and either prevent precipitation or mitigate its impact earlier than before.
The Simcyp® Population-based Simulator is designed to simulate clinical trials and predict variability between individuals in different populations rather than just for an “average person”. The Simulator already includes a sophisticated and well recognized oral absorption module – the Advanced Dissolution Absorption and Metabolism (ADAM) model2-7. The Simulator is complemented by the separate Simcyp In Vitro Data Analysis (SIVA) Toolkit.5 This tool is essential for gaining/confirming mechanistic understanding, model validation and in certain situations for extracting appropriate parameters from in vitro experiments for use as input for in vivo simulations.
Predicting supersaturation and precipitation kinetics of drugs and drug products in the complex, variable GI luminal environment is a challenging task requiring both suitable mechanistic models and detailed descriptions of physiology and its patient to patient variability. Precipitation from supersaturated solutions is usually characterised by two processes viz. a nucleation step and precipitation step. Many mechanistic models are available for handling nucleation; the most well-known is Classical Nucleation Theory (CNT). We will also investigate alternatives as part of this project including tools to deal with liquid-liquid phase separation phenomenon which cannot be dealt with using CNT. The relevant physiological parameters for modeling events in the GI tract include: luminal fluid volumes and their dynamic changes when a glass of water is taken with a dosage form; pH and bile salt concentrations; transit rates including gastric emptying; luminal fluid viscosity and flow rate; buffer capacity; gut wall permeability (both passive and active), and a number of other factors ALL with inter-individual variability.
The mechanistic supersaturation and precipitation models and the supporting physiology and variability database will be validated against clinical studies performed under the auspices of Professor Augustijns of the Drug Delivery and Disposition Unit in the Department of Pharmaceutical and Pharmacological Sciences at the University of Leuven. Some of the clinical studies available with supersaturating formulations include simultaneous measurements of drug concentration in luminal fluids4 and in the plasma providing dual endpoints against which to assess the PBPK models.
Given the complexity of the nucleation process and crystal growth, this project is not expected to solve all the associated issues. However, the undertaking will be a significant advance both in terms of identifying appropriate and sufficient mechanistic models and the provision of tools to enable the transfer of information from appropriate in vitro experiments to simulations of in vivo behaviour within a PBPK modeling framework.
To learn more about how the SIVA Toolkit can help you gain mechanistic understanding of in vitro experiments, please watch this webinar. Let me know what you think in the comments section!
 Almeida e Sousa et al. (2016) Supersaturation Potential of Salt, Co-Crystal, and Amorphous Forms of a Model Weak Base. Cryst. Growth Des. 16, 737.
 Jamei et al. (2009) Population-based mechanistic prediction of oral drug absorption. AAPS J. 11, 225.
 Patel et al. (2014) Quantitative prediction of formulation-specific food effects and their population variability from in vitro data with the physiologically-based ADAM model: a case study using the BCS/BDDCS Class II drug nifedipine. Eur J Pharm Sci. 16, 240.
 Turner et al. (2016) Comment on “In Silico Modeling of Gastrointestinal Drug Absorption: Predictive Performance of Three Physiologically-Based Absorption Models”. Mol Pharm. 14, 336.
 Cristofoletti R, Dressman JB. (2016) Bridging the Gap Between In Vitro Dissolution and the Time Course of Ibuprofen-Mediating Pain Relief. J Pharm Sci.105, 3658.
 Hens et al. (2016) Gastrointestinal and Systemic Monitoring of Posaconazole in Humans After Fasted and Fed State Administration of a Solid Dispersion. J Pharm Sci. 105(9):2904.
 Hens et al. (2017) In Silico Modeling Approach for the Evaluation of Gastrointestinal Dissolution, Supersaturation and Precipitation of Posaconazole. Mol Pharmaceut (ms. submitted).