Research Article In silico Tools at Early Stage of Pharmaceutical Development: Data Needs and Software Capabilities Juliet Obianuju Njoku, 1 Daniela Amaral Silva, 1 Dwaipayan Mukherjee, 2 Gregory K. Webster, 2 and Raimar Löbenberg 1,3 Received 1 April 2019; accepted 18 June 2019 Abstract. In early drug development, the selection of a formulation platform and decisions on formulation strategies have to be made within a short timeframe and often with minimal use of the active pharmaceutical ingredient (API). The current work evaluated the various physicochemical parameters required to improve the prediction accuracy of simulation software for immediate release tablets in early drug development. DDDPlus™ was used in simulating dissolution test profiles of immediate release tablets of ritonavir and all simulations were compared with experimental results. The minimum data requirements to make useful predictions were assessed using the ADMET predictor (part of DDDPlus) and Chemicalize (an online resource). A surfactant model was developed to estimate the solubility enhancement in media containing surfactant and the software’s transfer model based on the USP two-tiered dissolution test was assessed. One measured data point was shown to be sufficient to make predictive simulations in DDDPlus. At pH 2.0, the software overestimated drug release while at pH 1.0 and 6.8, simulations were close to the measured values. A surfactant solubility model established with measured data gave good dissolution predictions. The transfer model uses a single-vessel model and was unable to predict the two in vivo environments separately. For weak bases like ritonavir, a minimum of three solubility data points is recommended for in silico predictions in buffered media. A surfactant solubility model is useful when predicting dissolution behavior in surfactant media and in silico predictions need measured solubility data to be predictive. KEY WORDS: dissolution; DDDPlus; model fitting; simulation; ADMET predictor. INTRODUCTION Ritonavir is an HIV-1 protease inhibitor which is used in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and children of 2 years of age and older (1). Ritonavir also has a potent inhibitory effect on CYP3A4 (2), which is a major human hepatic drug- metabolizing enzyme. Ritonavir is a lipophilic drug with a LogP of 4.2 (ADMET Predictor) and a weak base with pKa values of 2.84 and 13.68 (Chemicalize) (3). Systematic studies by Law et al. (2001) (4) show that ritonavir has a LogD of 4.3 at 25°C at pH 6.8. It is poorly soluble at a high pH (400 μg/mL in 0.1 N HCl, 1 μg/mL at pH 6.8, 37°C) (4), and has a slow dissolution rate (0.03 mg/cm 2 -min in 0.1 N HCl at 37°C) (5). The chemical structure of ritonavir is shown in Fig. 1. Compounds with low aqueous solubility often suffer from limited bioavailability. If a low solubility drug candidate has reasonable membrane permeability, then often the rate- limiting process in absorption is the dissolution of the drug dose in the gastrointestinal tract (6,7). This is often the case for poorly soluble drugs (8). It is estimated that up to 40% of drug candidates have been abandoned due to insufficient solubility and associated poor pharmacokinetics under phys- iological conditions (8). Hence, approaches such as the use of in silico simulations based upon the drug’s physicochemical properties promise an option to accelerate the selection between drug candidates, with less intensive in vitro testing. Solubility screening of compounds can reduce considerably the time and effort required to identify a lead compound (9). A fundamental understanding of the physicochemical prop- erties such as logD, solubility, and excipient effects is imperative to develop a formulation strategy. In vitro dissolution characteristics must be thoroughly assessed; each step of the in vitro dissolution process must be studied under a variety of physiologically relevant conditions and multiple pH values need to be tested (10). The 1 Faculty of Pharmacy and Pharmaceutical Sciences, Katz Group Centre for Pharmacy and Health Research, University of Alberta, Edmonton, Alberta T6G 2H5, Canada. 2 Research and Development, AbbVie Inc., North Chicago, llinois, USA. 3 To whom correspondence should be addressed. (e–mail: Raimar.Loebenberg@ualberta.ca) AAPS PharmSciTech (2019) 20:243 DOI: 10.1208/s12249-019-1461-5 1530-9932/19/0000-0001/0 # 2019 American Association of Pharmaceutical Scientists