**1. Introduction**

Neglected tropical diseases are infectious diseases that affect a sixth of the world population, more than a billion people, mainly in poor populations of tropical countries in Africa, Latin America, Asia and the Middle East. Their prevalence increases with the absence of salubrious water and adequate sanitation conditions and the most vulnerable population are children in contact with contaminated water [1].

Schistosomiasis is the second neglected tropical disease with the highest prevalence, widespread mainly in tropical Africa. Therefore, the improvement of the existing treatment with the praziquantel (PZQ) drug is very important for saving lives. Since schistosomiasis is in the expansion phase and currently affects 240 million people in the world, of which only 88 million receive adequate treatment, it is estimated that it produces more than 200,000 deaths annually, and it is extended in 78 countries around the world, mainly in the tropical and subtropical region, being in Africa the second most prevalent disease in children. This disease is acquired by contact with fresh water infested with larvae of the parasite [2–5].

PZQ is the recommended treatment against all forms of schistosomiasis. It has high efficacy, low toxicity and is administered orally. In addition, the cost of production and sale of PZQ is low [2,6]. However, it has a few disadvantages. First, it is a racemic compound, with only one of its enantiomers being pharmacologically active [7,8]. In addition, it is a Class II drug of the Biopharmaceutical Classification System (BCS) and has very low aqueous solubility and high permeability, so that the dissolution is the factor limiting the rate of absorption [9–11]. Its low solubility in water makes it necessary to administer high oral doses, which gives rise to secondary effects that increase the therapeutic noncompliance and favor the appearance of resistant forms of the parasite. For these reasons, the use of low-cost natural inorganic excipients was proposed as a starting hypothesis to improve the aqueous solution profile of the PZQ, maintaining the final cost of the drug, which is very important given the population to which it is subject destined.

Montmorillonite and sepiolite are innocuous, non-toxic, biocompatible and low-cost clay minerals. Additionally, clays have high adsorbent properties that allow them to encapsulate drugs in nanometric spaces present between the layers in the case of the montmorillonite or in the channels in the case of the sepiolite [12–17].

The interaction between PZQ and other excipients was also studied in order to improve the low solubility of the drug, for example, with calcium carbonate [18–20], β-cyclodextrins [21–23], polyvinylpyrrolidone [24,25], polyethylene glycols [26–28], sodium starch glycolate [29], phosphatidylcholine– containing liposomes [30], layered double hydroxides [31], among others. Specifically, the interaction between PZQ and montmorillonite in aqueous medium was previously studied, although no improvements of in vitro dissolution and absorption rates were observed [32]. The lack of relevant biopharmaceutical improvements was explained by the absence of PZQ in the interlayer space of montmorillonite. Water molecules present in the clay interlayer space would be blocking the entrance of the drug, thus PZQ would be solely absorbed in the external surface of montmorillonite. Therefore, in our previous studies [33,34], the interactions between PZQ and montmorillonite and sepiolite in absence of water were studied as a strategy for enhancing the aqueous solubility of the drug. To do this, ethanol 99% (*v*/*v*) was used as a solvent increasing the interaction between the drug and the excipient. The results showed a great increase in the dissolution rate of the drug and the total amount of drug dissolved in vitro in the interaction products, due to the high interaction between both components. Therefore, this new procedure was found to be an effective strategy to improve the biopharmaceutical profile of the PZQ.

Hence, in this work, the preparation of interaction products is studied following the previously described procedure [33,34] comparing the use of different organic solvents, like ethanol, acetonitrile and dichloromethane. The aim is to prepare and characterize these systems and, by these means, to determine the potential influence of the organic solvent on the release and solubility of the drug. In particular, the results were compared with those obtained with ethanol in which a significant improvement in the biopharmaceutical profile was described. As well as this, in vitro cytotoxicity and cell cycle studies are carried out for checking if these systems are biocompatible and suitable for human use.
