Nucleotides as new co-formers in co-amorphous systems: Enhanced dissolution rate, water solubility and physical stability

Developing co-amorphous systems is an attractive strategy to improve the dissolution rate of poorly water-soluble drugs. Various co-formers have been investigated. However, previous studies revealed that it is a challenge to develop satisfied acidic co-formers, e.g., acidic amino acids showed much poorer co-former properties than neutral and basic amino acids. Only a few acidic co-formers have been reported, such as aspartic acid, glutamic acid, and some other organic acids. Thus, this study aims to explore the possibility of adenosine monophosphate and adenosine diphosphate used as acidic co-formers. Mebendazole, celecoxib and tadalafil were used as the model drugs. The drug-co-former co-amorphous systems were prepared via ball milling and confirmed using XRPD. The dissolution study suggested that the solubility and dissolution rate of the drug-co-formers systems were increased significantly compared to the corresponding crystalline and amorphous drugs. The stability study revealed that using the two nucleotides as co-formers enhanced the physical stability of pure amorphous drugs. Molecular interactions were observed in MEB-co-former and TAD-co-former systems and positively affected the pharmaceutical performance of the investigated co-amorphous systems. In conclusion, the two nucleotides could be promising potential acidic co-formers for co-amorphous systems.

Introduction

Nearly 40 % of marketed drugs and roughly 90 % of drug candidates exhibit inadequate solubility in water, leading to low and variable oral absorption rates and, inevitably, low bioavailability and unsatisfactory therapeutic outcomes [1], [2]. Therefore, enhancing the water solubility of these chemical compounds is an attractive research topic, and this is particularly important for drugs classified as biopharmaceutics classification system (BCS) II drugs, since the poor water solubility is the limited process for absorption. Converting crystalline drugs to their amorphous form can enhance their water solubility and dissolution rate, and consequently increase their oral bioavailability [3]. However, the amorphous form is unstable due to the higher Gibbs free energy than its crystalline form. It has the risk of reverting to the crystalline form during manufacturing and storage [4]. Thus, it is necessary to develop appropriate methods to improve the physical stability of amorphous drug systems.

In the past ten years, co-amorphous systems have been developed as an appealing substitute for amorphous solid dispersions (ASDs). The definition of co-amorphous systems is that the drug mixes with one or more co-formers at a defined ratio to form a single homogeneous phase amorphous system [5]. The co-formers are usually small molecular weight excipients. The co-formers can be the second drugs to form drug-drug co-amorphous systems [6], or they can be other small excipients, e.g., amino acids [7], citric acid [8], and saccharide [9]. Co-amorphous systems are usually prepared at a 1:1 M ratio of drug: co-former and, therefore, overcome the disadvantage of low drug-loading of ASDs [10]. The use of co-formers could improve the physical stability of amorphous drugs and enhance the dissolution rate of poorly water-soluble drugs [11]. The possible molecular interactions between the drug and the co-former, e.g., hydrogen bonding [12], salt formation [13] and π-π interactions [14], contribute significantly to the enhancement of physical stability [15], [16]. However, some co-amorphous systems without molecular interactions also exhibited enhanced physical stability compared to pure amorphous drugs [17].

Previous studies have shown that not all of the investigated co-formers are suitable for given drugs. Acidic co-formers, including acidic amino acids, some organic acids (such as benzoic acid and malic acid) and some other acidic excipients, showed poor co-formability with model drugs [18], [19]. Poor co-formability means it is difficult to form stable co-amorphous systems with given drugs, and shows no noticeable enhancement of the physical stability of amorphous drugs [11]. One of our previous studies has proved that salt formation between the drug and the co-former plays an important role in the formation and performance of co-amorphous systems [13]. However, preparing stable acidic co-formers-drug co-amorphous systems with an improved drug dissolution rate and water solubility remains challenging. Another previous study compared the co-former performance of single amino acids, amino acid physical mixtures, amino acid salts and dipeptides. It revealed that single acidic glutamic acid showed the worst co-former performance: MEB-glutamic acid mixture did not form amorphous after milling, while all other co-formers converted to amorphous form with MEB [20]. Biotin was used as a potential acidic co-former, but the biotin-valsartan co-amorphous system recrystallized within 40 d of storage under room temperature [21]. Thus, exploring a new series of acidic co-formers is important for developing co-amorphous systems, especially for basic drugs.

Nucleotides and their related metabolic products are essential in many biological processes and serve as the main components of DNA and RNA [22]. Nucleotides are abundant in the diets of adults and weaned infants. Thus, their safety as excipients in the food and pharmaceutical industry has been determined [25]. Both Adenosine diphosphate (ADP) and adenosine monophosphate (AMP) contain a phosphoric acid functional group and are generally more acidic than the mentioned amino acids and organic carboxylic acids. Thus, ADP and AMP may form salt more easily than the reported acidic co-formers. In addition, the purine ring offers a proton acceptor and donor, which might lead to hydrogen bonding with some given drugs. Considering that the potential molecular interactions between the drug and the co-former in co-amorphous systems could be beneficial to the formation and performance of co-amorphous systems [23], ADP and AMP were chosen and investigated to evaluate the possibility of using as new acidic co-formers for co-amorphous systems.

In this study, mebendazole (MEB, basic), celecoxib (CEL, acidic) and tadalafil (TAD, neutral) were used as the model drugs. The drug and the co-former were ball milled (BM) at a molar ratio of 1:1 to prepare co-amorphous systems. The solid-state properties of the prepared samples were analyzed using X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) to confirm whether a successful amorphization and a homogenous single-phase system had been formed. Fourier-transform infrared spectroscopy (FTIR) was used to investigate the potential molecular interactions between the drugs and the co-formers in co-amorphous systems. Moreover, powder dissolution and physical stability studies were performed to evaluate the pharmaceutical performance of the co-formers.

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Materials

Tadalafil (TAD, MW = 389.4 g/mol, pKa = 16.68 [24], form I [25], purity of 97 %), Adenosine-5′-monophosphate (5′-AMP, MW = 347.22 g/mol, pKa1 = 3.84, pKa2 = 6.21 [26], purity of 98 %), and Adenosine-5′-diphosphate (5′-ADP, MW = 427.2 g/mol, pKa1 = 3.83, pKa2 = 6.19 [27], purity of 98 %) were purchased from Aladdin Biochemical Technology (Shanghai, China). Mebendazole (MEB, MW = 295.29 g/mol, pKa = 9.93 [28], form A [29], purity of 98 %) was obtained from Saen Chemical Technology (Shanghai, China). Celecoxib (CEL, MW = 381.37 g/mol, pKa = 9.52 [30], form III [31], purity of 99 %) was bought from InnoChem Science & Technology Co., Ltd. (Beijing, China). The chemical structures of the materials used in this study are shown in Fig. 1. All materials were used as received.

Xianzhi Liu, Luyan Shen, Lin Zhou, Wencheng Wu, Guang Liang, Yunjie Zhao, Wenqi Wu, Nucleotides as new co-formers in co-amorphous systems: Enhanced dissolution rate, water solubility and physical stability, European Journal of Pharmaceutics and Biopharmaceutics, Volume 200, 2024, 114333, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2024.114333.

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