Sugars and Polyols of Natural Origin as Carriers for Solubility and Dissolution Enhancement

Abstract

Crystalline carriers such as dextrose, sucrose, galactose, mannitol, sorbitol, and isomalt have been reported to increase the solubility, and dissolution rates of poorly soluble drugs when employed as carriers in solid dispersions (SDs). However, synthetic polymers dominate the preparation of drugs: excipient SDs have been created in recent years, but these polymer-based SDs exhibit the major drawback of recrystallisation upon storage. Also, the use of high-molecular-weight polymers with increased chain lengths brings forth problems such as increased viscosity and unnecessary bulkiness in the resulting dosage form. An ideal SD carrier should be hydrophilic, non-hygroscopic, have high hydrogen-bonding propensity, have a high glass transition temperature (T_g), and be safe to use. This review discusses sugars and polyols as suitable carriers for SDs, as they possess several ideal characteristics. Recently, the use of low-molecular-weight excipients has gained much interest in developing SDs. However, there are limited options available for safe, low molecular excipients, which opens the door again for sugars and polyols. The major points of this review focus on the successes and failures of employing sugars and polyols in the preparation of SDs in the past, recent advances, and potential future applications for the solubility enhancement of poorly water-soluble drugs

Introduction

Poor aqueous solubility is a major concern for new chemical entities (NCEs) and many of the existing active pharmaceutical ingredients (APIs) developed for oral drug delivery, where these substances have great pharmacological and permeability potential. An increasing proportion of potential new drug candidates (40–70%) are classified as Biopharmaceutical Classification System (BCS) Class II or IV drugs, and the formulation and commercialisation of these as oral dosage forms presents great challenges as they show sub-optimal dissolution; absorption; and, hence, bioavailability [1]. The poor aqueous solubility has a negative effect on dissolution, resulting in the incomplete absorption of these APIs in the gastrointestinal tract; hence, the bioavailability is affected detrimentally [2,3]. Several techniques are used to overcome this problem, which include physical and chemical modifications of the drug through micronization, crystal engineering, salt formation, the addition of surfactants, solid dispersions with hydrophilic carriers, complexation, hydrotropy, eutectic mixtures, and amorphous systems, to mention but just a few [2,4]. Among these solid-state alterations, solid dispersions and co-amorphous and co-crystal systems have taken the lead over the past two decades. One of the common factors among these techniques that plays a significant role in solubility and bioavailability enhancement is the type of carrier, co-former, or excipient used [5,6]. In the selection of a carrier, preference is given to carriers that are hydrophilic in nature [5], have high hydrogen bonding propensity, have higher glass transition temperatures (Tg), are non-hygroscopic [7], and form part of the United States Food and Drug Administration (FDA)-approved Generally Recognized as Safe (GRAS) list [8].

Naturally occurring sugars of several types, such as monosaccharides (glucose, fructose, galactose); disaccharides (sucrose, maltose, lactose); and sugar alcohols (polyols) such as sorbitol, mannitol, xylitol, erythritol, maltitol, lactitol, and isomalt, have been reported to enhance the solubility of drugs. The FDA designates sugars and polyols as GRAS excipients [9,10], and in addition to their proven safety, these compounds exhibit good water solubility [11] and possess hydroxyl groups (-OH) attached to each carbon atom in the molecule, which, in theory, provides hydrogen-bonding sites for drug molecules, thereby already meeting three of the abovementioned criteria in terms of suitable solid-state co-formers.

There are several ways in which sugars and polyols have been used to enhance the solubility of drugs. One predominant method used is to form solid dispersions of the drug [12]; another approach is the formulation of eutectic mixtures [13,14]. Polyols such as xylitol [15,16], mannitol [15], and sorbitol [17] have been reported as potential co-formers for developing co-crystalline systems. However, efforts made in exploring sugars and polyols in the making of co-crystals and co-amorphous systems are few to none. The low molecular weight, safety, good glass-forming ability, and (in some instances) high Tg of sugars [18] make them an interesting option to explore as excipients for drug–excipient co-amorphous and co-crystalline systems. The current review focuses on summarising the use of naturally occurring sugars and polyols for the enhancement of solubility and the dissolution rate of poorly soluble drugs. Furthermore, it seeks to understand the pros and cons in relation to the various techniques used; to provide a theoretical basis for their application in the formulation of co-amorphous and co-crystalline systems; and finally, to identify potential opportunities for future research.

Table 2. Summary of SDs reported in the literature obtained by using various sugars as carriers.

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Poka, M.S.; Milne, M.; Wessels, A.; Aucamp, M. Sugars and Polyols of Natural Origin as Carriers for Solubility and Dissolution Enhancement. Pharmaceutics 2023, 15, 2557. https://doi.org/10.3390/pharmaceutics15112557