**1. Introduction**

Malaria deaths and cases have decreased dramatically in the last 15 years, yet it remains one of the leading tropical diseases in terms of reported deaths [1]. Accordingly, the World Health Organization (WHO) recorded up to 216 million cases of malaria and about 445,000 deaths in 2016 only [1]. Development of antimalarial medicine resistance, as well as dramatically diminished sensitivity to artemisinin combination therapy (ACT), is the primary cause of this trend [2–6]. Apart from

that, the chemotherapeutic choices for treating and preventing malaria are limited [4]. In light of these circumstances, novel antimalarial drug discovery, particularly medicines associated with multiple mode of action and versatility in terms of efficacy against resistant *Plasmodia* spp., is critical. Surprisingly, due to poor physicochemical characteristics and pharmacokinetic profiles, many novel prospective antimalarial medicines are overlooked [7, 8]. In accordance with this, novel studies are being performed on the prospect of producing antimalarial salts and co-crystals [4]. The fundamental goal of these investigations is to enhance the physiochemical characteristics of antimalarial medicines without interfering with their bioactivity [9–11].

The search for APD-APIs is motivated by previous studies, which have revealed the existence of two important plant-based antimalarial drugs (1) quinine and (2) artemisinin from *Cinchona* spp. stem bark and *Artemisia annua*, respectively [12–14]. It is envisaged that bioprospecting of existing enormous plant biodiversity can come up with novel antimalarial drugs. More importantly, the quest for novel plant-based antimalarial drugs is based on ethnopharmacological studies, which are critical in drug development and discovery [15]. The basic idea in an ethnopharmacological study in this case is to come up with inexpensive and easily used antimalarial therapies, which subsequently limit the cost of drug discovery and development research [16–18]. However, only approximate of 6 and 15% of all land plants have been analyzed for pharmacological activity and have an elucidated phytochemistry, respectively [17]. The main reasons for considering APD-APIs in malaria treatment include low cost, effectiveness, easy availability, safety, and cultural preferences [19].

Interestingly, plants are important sources of APIs, which can be utilized in treatment and prevention many human health problems including malaria [17]. Generally, up to 25% of known plant species are exploited in medicine production worldwide and approximately 65% of the global population count on plants for their basic health care [20, 21]. These plants have been identified as rich sources of template compounds for synthesis of other important drugs and in the prevention as well as fight against many infectious diseases including malaria. In the case of malaria, two lead antimalarial drugs, quinine and artemisinin, have been utilized as derivatives of chloroquine and artemether, respectively. Additionally, antimalarial drugs such as primaquine, amodiaquine, and mefloquine are synthesized based on quinine and in antimalarial drugs including arteether, and sodium artesunate, where artemisinin is the lead compound [7, 22]. Plants are associated with potential antimalarial APIs classified into major groups including flavonoids, alkaloids, glycosides, terpenoids, and phenolic acids [23].

Co-crystals are solid compounds that show promise in drug development, particularly in terms of improving physicochemical properties such as drug solubility. Generally, co-crystals are formed due to the interactions between (1) active pharmaceutical ingredients (APIs) and (2) co-crystals forming agents (normally solid under ambient conditions) [24, 25]. Normally, H-bond holds the two components of co-crystals, and this is facilitated by functional groups of APIs, e.g., carboxylic acid functional group. Moreover, APIs are associated with other function groups such as amine and amide groups [26]. Co-crystallization is performed under relatively mild reaction conditions. The techniques for preparing co-crystals are classified into (1) solid-state and (2) solution-based [27–30].

Despite the various studies that have been conducted on a wide range of pharmacological molecules, plant-derived antimalarial drug molecules appear to have been neglected [10]. Many current antimalarial drugs are becoming ineffective owing to the drug resistance. For instance, *Plasmodium spp.* and *Plasmodium falciparum* have shown resistance to the antimalarial quinine derivatives such as chloroquine

*Co-Crystallization of Plant-Derived Antimalarial Drugs: An Alternate Technique for Improved… DOI: http://dx.doi.org/10.5772/intechopen.106200*

and an increase in resistance to the artemisinin-based therapies, respectively [2, 3]. The aim of this chapter is to explore multicomponent crystal structures utilization in antimalarial treatment and review the literature that addresses the feasibility of this therapeutic option. Up to date, there is no structured literature that relates to the co-crystallization of APD-APIs. Therefore, this chapter identifies the research gaps and outlines (1) APD-APIs, (2) limitations of single APD-APIs in the treatment of malaria, (3) techniques in the development and properties of APD-APIs co-crystals.

## **2. Summary of main APD-APIs**

According to Ungogo [31], statistics for pharmaceuticals authorized by the U.S Food and Drug Administration (1981–2010) suggested that around 35% of approved new medicines were derived from natural sources, with plants-derived drugs contributing 25%. Phenolics, quinones, alkaloids, saponins, terpenes, and their derivatives are examples of APD-APIs. Notably, these APD-APIs can be utilized as both crude phytomedicines and pure pharmaceuticals. They can, nevertheless, serve as basis for the production of synthetic pharmacologically complex active compounds, models for designing lead molecules, and taxonomic markers for the discovery of novel drugs [31].

#### **2.1 Alkaloids**

Alkaloids are a group of diverse plant secondary metabolites characterized by a basic nitrogen associated with a carbon ring [32]. The classification of these APD-APIs is on the basis of the principal C-N skeleton, and in certain instances, classification is according to biological origin. Using the first classification system, alkaloids are classified into 13 classes: pyrroles, pyrrolines, pyrrolidines, pyrrolizidines, indoles, pyridines, pyrimidines, piperidines, quinolones, isoquinolines, quinolizidines, tropanes, and imidazoles [31]. Antimalarial alkaloids have been reported in several studies, for instance, Iwu and keayman [33] isolated alkaloids (which are antimalarial) from *Picralima nitida* fruits. The authors reported IC50 values in the range 1.6–2.4 μg/ ml when crude dichloromethane extracts were tested for antiplasmodial action. Additionally, indole alkaloids including akuammicine and alstonine were isolated with aid of chromatographic technique, and these alkaloids were inhibitory against *P. falciparum* strains (1) D6 and (2) W2 as indicated by IC50 values ranging from 0.01 to 0.9 μg/ml [5]. More recently, *Holarrhena africana* bark and leaves' alkaloid fractions showed antiplasmodial activity (**Figure 1**) [34].

#### **2.2 Terpenoids**

Terpenoids are compounds of plant essential oils and terpene hydrocarbons derivatives, and according to [35], these APD-APIs are classified into eight categories: monoterpenoids, diterpenoids, triterpenoids, tetraterpenoids, hemiterpenoids, sesquiterpenoids, sesterterpenoids, and polyterpenoids. Notably, in several studies, terpenoids were identified in antimalarial plant essential oils [35–38], and most of the plants from which essential oils are extracted have been exploited as traditional antimalarial and antipyretic medicines [39]. One of the most common antimalarial terpenoids is artemisinin, which is classified as sesquiterpenoid. This sesquiterpenoid (artemisinin) as well as bioactive compounds derived from this antimalarial is highly antimalarial especially against *P. falciparum* that is chloroquine-resistant.

**Figure 1.** *Some examples of the antimalarial alkaloids.*

**Figure 2.** *Some examples of the antimalarial terpenoids.*

A study by [40] identified several diterpenoids, for example, (13S)-ent-7β-hydroxy3 cleroden-15-oic acid and (13S)-ent-18-(E)-coumaroyloxy-8(17)-labden-15-oic acid from a plant, *Nuxia sphaerocephala* in Madagascar. The identified diterpenoids were antiplasmodial as indicated by IC50 values ranging from 4.3 to 21.0 μgml−1 against FcB1 *P. falciparum*. Several studies have identified different classes of plant derived terpenoids and their antimalarial activities (**Figure 2**) [40–45].
