Research Article Preparation and Optimization of Meropenem-Loaded Solid Lipid Nanoparticles: In Vitro Evaluation and Molecular Modeling Ellen K. G. Mhango, 1 Rahul S. Kalhapure, 1,2 Mahantesh Jadhav, 1 Sandeep J. Sonawane, 1 Chunderika Mocktar, 1 Suresh Vepuri, 1 Mahmoud Soliman, 1 and Thirumala Govender 1,2 Received 11 August 2016; accepted 18 November 2016 Abstract. Encapsulation of antibiotics into nanocarriers has the potential to overcome resistance and disadvantages associated with conventional dosage forms as well as increase half-life of an antibiotic. Encapsulation of meropenem (MRPN) into solid lipid nanoparticles (SLNs) remains unexplored among the limited work reported on nanoformulation incorporating MRPN. The study aimed to use an experimental design, to optimize MRPN- loaded SLNs, and to undertake in vitro and in silico evaluations. A Box-Behnken design (BBD) was used to optimize manufacturing conditions of glycerol monostearate (GMS) SLNs loaded with MRPN. The SLNs were prepared using hot homogenization and ultrasonication method. Optimized MRPN-SLNs showed particle size, zeta potential, and entrapment efficiency of 112.61 ± 0.66 nm, -20.43 ± 0.99 mV, and 89.94 ± 1.26%, respectively. The morphology of the SLNs revealed nearly spherical shaped particles. Differential scanning calorimetry and X-ray diffraction analysis showed that meropenem was present in amorphous form in the SLNs. Controlled in vitro MRPN release from SLNs was achieved and followed the Korsmeyer-Peppas model (R 2 = 0.9679). Prolonged in vitro antibacterial activity against Escherichia coli was also observed. The molecular modeling showed that both hydrophobic interactions and hydrogen bonding led to a stable MRPN-GMS complex formation, which was confirmed by its low heat of formation (-5536.13 kcal/mol). This stable complex could have contributed to the controlled release of MRPN from the SLNs and subsequent sustained antibacterial activity. KEY WORDS: antibacterial; Box-Behnken design; meropenem; molecular modeling; solid lipid nanoparticles. INTRODUCTION Infections are the leading cause of the burden of diseases globally despite the use of vaccines and antibiotics, improved hygiene and sanitation practice, and vector control (1,2). Globally, infectious diseases cause more than 13 million deaths annually (3). Many of these infections, such as respiratory and gastrointestinal, are of bacterial origin (4), and some are associated with noncommunicable diseases, such as diabetes mellitus, peptic ulcer, cardiovascular, asthma, and cancer among others (2,5–7). Escherichia coli is a major cause of hospital and community-acquired infections such as neonatal meningitis, bacteremia, and intra-abdominal infections (8). Although the discovery of antibiotics led to a reduction in morbidity and mortality by combating these bacterial infectious diseases (9), several disadvantages of current antibiotic use exist. These include their poor intracellular penetration (10), low concentration at infection sites (11), frequent high doses being needed to attain the desired concentrations (12), serious adverse effects, and toxicity (12,13) which have left clinicians with few therapeutic options. In addition, the current rise in bacterial resistance to antibiotics has made even the main antibiotics that are in current use invalid (9). The slow and declining development of new antibiotics is another challenge (14,15). The current limitations of antibiotic delivery, the emergence of multidrug- resistant strains of bacteria, and the declining and slow development of new classes of antibiotics highlight the need to explore new ways of overcoming bacterial infections and prevent further spread of resistance to the currently used antibiotics. Nanosystems can be used to overcome challenges of conventional antibiotic therapy as they possess unique physicochemical properties and a high surface area to volume Electronic supplementary material The online version of this article (doi:10.1208/s12249-016-0675-z) contains supplementary material, which is available to authorized users. 1 Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, 4000, South Africa. AAPS PharmSciTech ( # 2016) DOI: 10.1208/s12249-016-0675-z 1530-9932/16/0000-0001/0 # 2016 American Association of Pharmaceutical Scientists