Amino Acids for Cocrystal Development

Cocrystals are one of the most commonly used methods to alter the physicochemical properties of active pharmaceutical ingredients (APIs) through non-covalent interactions with one or more ligands, without changing their pharmacological activity. Recently, green methods have prompted many researchers to develop solvent-free or minimized solvent techniques for designing more eco-friendly cocrystal processes. Researchers have also been looking for ligands that pose lower risks while achieving the desired physicochemical properties of APIs. Structurally, amino acids are promising candidate ligands because they possess functional groups that can form hydrogen bonds and increase stability through zwitterionic groups that support strong interactions. Cocrystals and deep eutectic solvents derived from these natural compounds have been shown to enhance drug performance. For example, L-glutamine can reduce the side effects of mesalazine by stabilizing it in gastrointestinal fluids through acid-base interactions. Moreover, certain amino acids, particularly L-proline, enhance the solubility and absorption of APIs in their natural deep eutectic solvents and cocrystal systems. Additionally, ion cocrystals of some amino acids have been designed to improve chiral resolution. Therefore, amino acids are safe potential ligands that can improve the physicochemical properties of APIs and hold promise for further development in formulations and solid-state synthesis.

What is Cocrystal?

Cocrystals were first discovered in 1844, but their structure was not characterized until 1958, and the term "cocrystal" was first used by Lawton and Lopez in 1963. According to the U.S. Food and Drug Administration (FDA), a cocrystal is a multicomponent solid crystalline supramolecular complex composed of two or more components within the same lattice, where each component is in a neutral state and interacts via non-ionic interactions. Generally, cocrystals are classified into two main categories: molecular cocrystals and ionic cocrystals. Molecular cocrystals contain two or more different neutral components, held together by hydrogen bonds or halogen bonds. In contrast, ionic cocrystals contain at least one ionic component and are supported by charge-assisted hydrogen bonds or coordination bonds (if metal cations are present).

Fig. 1. Cocrystal structure (Molecules. 2021, 26(11): 3279).

Cocrystals provide a new and effective way to modulate the physicochemical properties of APIs while maintaining their therapeutic activity. This makes cocrystals more accessible than other methods, such as micronization, solid dispersions, salt formation, nanoparticle formation, and other approaches. When altering the physicochemical properties of a drug without changing its pharmacological activity, important factors to consider include the characteristics of the API and the ligand used, the molecular interactions that occur, and the synthetic steps. Unlike salt formation, which can only be applied to ionizable APIs and involves the transfer of hydrogen atoms between acidic and basic functional groups, cocrystal technology can be used for both ionizable and non-ionizable APIs. Cocrystals are also different from other solid forms, such as solvates and hydrates. Solvates are solids containing organic solvent molecules, while hydrates are solids containing water molecules. Additionally, combinations of hydrates or salts with cocrystals may also occur.

Cocrystal Technology

Currently, many cocrystal technologies have been reported, including dry grinding (NG), liquid-assisted grinding (LAG), solvent evaporation (SE), gas antisolvent precipitation (GAS), and other techniques. Recently, the success of green cocrystal methods has encouraged many researchers to seek other more eco-friendly cocrystal technologies. Mechanochemical reactions, including grinding with minimal or no solvent, have become an effective alternative method for cocrystal synthesis due to their environmentally friendly processes. Researchers are also looking for less hazardous ligands with hydrogen bonding sites that can interact with the functional groups of APIs, including amino acids. Most amino acids are soluble and stable in water, making them suitable for green method cocrystal synthesis. Functional groups that can form supramolecular assemblies, such as acid−acid, acid−pyridine, acid−amide, amide−amide, amide−pyridine, and others, are important factors in the formation of intermolecular hydrogen bonds in cocrystal synthesis. Moreover, molecules capable of forming double hydrogen bonds are more likely to form cocrystals. The amino and carboxyl groups of amino acids act as donor and acceptor groups, respectively, and tend to form hydrogen bonds with other groups, such as hydroxyl, carboxyl, pyridine, and phenolic hydroxyl groups.

Cocrystal Screening

Pharmaceutical cocrystals alter the arrangement and packing of API molecules by introducing cocrystal ligand molecules, thereby changing the interaction patterns of the APIs. From the perspective of crystal engineering design, the formation of pharmaceutical cocrystals involves two processes: first, the API and ligand molecules recognize each other through hydrogen bonds or other interactions to form supramolecular assemblies; second, the supramolecular assemblies stack and assemble to form the pharmaceutical cocrystal. A supramolecular assembly refers to a structure where units are assembled through interactions to form a supramolecule. Supramolecular assemblies play an important role in cocrystal synthesis. Common supramolecular assemblies in cocrystals include carboxyl−carboxyl, carboxyl−amide, carboxylic acid−aromatic nitrogen, amide−amide, amide−aromatic nitrogen, and phenolic hydroxyl−aromatic nitrogen. Pharmaceutical cocrystals can regulate the solubility and dissolution rate of poorly soluble drugs without changing the chemical structure of the drug molecule. For example, the cocrystals of quercetin−theophylline and soybean flavone−theophylline increase the inherent dissolution rate of the raw drug by approximately 8.4 and 2.3 times, respectively. Pharmaceutical cocrystals can also improve the stability, mechanical properties, and biological properties of drugs. For instance, McKellar et al. synthesized propofol−isoniazid cocrystals, which significantly increased the melting point of propofol, converting it from a liquid form to a solid form at room temperature, greatly enhancing the thermal stability of the drug.

Amino Acids

Amino acids are essential components for the synthesis of proteins, enzymes, hormones, peptides, neurotransmitters, and other mediators. They contain one amino group and one carboxyl group. Twenty amino acids are found in many natural peptides, and they can be classified based on their side chains and physiological functions. According to their side chains, amino acids are categorized into three groups: amino acids with non-polar and uncharged side chains, amino acids with polar and uncharged side chains, and amino acids with charged side chains. Based on their physiological functions, amino acids can also be divided into three groups: essential amino acids, which cannot be synthesized in the body; non-essential amino acids, which can be produced in the body; and semi-essential amino acids, which can be produced in limited amounts by the body. In addition to being components of proteins, several amino acids also play a role in regulating key metabolic pathways required for maintaining health, growth, reproduction, and immunity. These amino acids are functional amino acids, including arginine, cysteine, glutamine, leucine, proline, and tryptophan. In the field of pharmaceutical research, amino acids are also considered Generally Recognized As Safe (GRAS), meaning they are low in toxicity and can be easily found in natural products such as wheat, rice, and corn. Therefore, amino acids are an excellent choice and potential ligand for cocrystals. Based on their suitability, amino acids have recently been developed for the cocrystal design of more drugs.

Amino Acids from BOC Sciences

BOC Sciences has extensive amino acid supply and customization capabilities, offering a variety of natural and non-natural amino acids to meet the needs of different APIs. By working closely with clients, BOC Sciences is able to select the most suitable amino acids as cocrystal ligands based on the specific properties of the drug to optimize its solubility and bioavailability. Our amino acid range includes non-polar amino acids as well as other amino acids with unique structures that have been shown to be effective in cocrystal formation. With advanced synthesis techniques and extensive chemical reaction experience, BOC Sciences is able to provide customers with high-purity, highly stable amino acids, offering strong support for cocrystal development.

Amino Acids as Ligands for Co-crystal Development

Amino acids as ligands in cocrystal development have increasingly attracted attention in the pharmaceutical field, especially for their significant advantages in addressing low drug solubility. Amino acids can form cocrystals with poorly soluble APIs, significantly improving their solubility and bioavailability, thus enhancing the physicochemical properties and efficacy of the drug. The advantage of using amino acids as ligands lies in their amino and carboxyl groups, which can form stable cocrystal structures with APIs through interactions such as hydrogen bonding. Particularly, non-polar amino acids such as L-phenylalanine, L-tryptophan, and L-proline, which have cyclic or pyrrole groups, can provide faster dissolution rates and enhance drug solubility. In addition, the amphoteric ion nature of amino acids gives them a unique advantage in forming chiral cocrystals, especially in the application of "green methods," which reduce environmental harm. As natural compounds, amino acids generally have low toxicity, further increasing their potential in pharmaceutical applications. For example, research has shown that the cocrystal of febuxostat and glutamic acid improves solubility in water and various pH buffer solutions, while cocrystals of itraconazole with amino acids (such as L-proline, glycine, etc.) not only enhance solubility but also improve drug permeability and antibacterial effects. Moreover, amino acid cocrystals with APIs can reduce side effects; for instance, the cocrystal of mesalazine with glutamine enhances its bioavailability and alleviates side effects such as bloating.

What is the Role of Cocrystals in Pharmaceutical Design?

Cocrystallization of pharmaceuticals is a great way to make a pharma-quality drug product with a better physicochemical profile without compromising the pharmacokinetics of the API. Other physical features like hygroscopicity, stability, crystallinity, particle size, flowability, filterability, density, and flavour can shift as well for improved therapeutic effects.

• Improving Solubility and Bioavailability

The most prominent application of cocrystals is the enhancement of the drug molecule's solubility. By altering its basic crystal structure, cocrystals have different solubility characteristics than their constituent drug molecules. Cocrystals can modify solubility, pharmacokinetics, and bioavailability, thereby improving drug administration and clinical efficacy. Using cocrystals to enhance the oral drug delivery of Class II and IV drugs (low solubility) in the Biopharmaceutics Classification System (BCS) has become a common approach to overcome traditional drug property limitations. For example, ketoconazole is a broad-spectrum imidazole antifungal agent and a BCS Class II drug (low solubility, high permeability). It has hydrophobic sites and a low alkaline nature (containing an imidazole ring), leading to poor water solubility. Studies have found that cocrystallizing ketoconazole with ascorbic acid increases its solubility by 50% compared to pure ketoconazole.

• Improving Other Physicochemical Properties

Many drug molecules have multiple physical and chemical properties that can be altered by forming cocrystals. Drug cocrystals can modify solubility, bioavailability, permeability, melting points, compressibility, and other properties.

• Melting Point: A high melting point in drug molecule cocrystals is generally favorable but may lead to low solubility and limit certain formulation processes. Conversely, a low melting point of cocrystals may cause drying and stability issues for the drug product. A high melting point indicates the thermodynamic stability of the new molecule. By using cocrystal formers with a higher melting point, the thermal stability of the API can be improved.
• Permeability: Permeability plays a crucial role in drug absorption and distribution through biological membranes, generally correlating with the octanol/water partition coefficient (logP). Studies have found that the permeability of 5-fluorouracil (a BCS Class III drug, high solubility, low permeability, an anti-metabolite drug primarily used for cancer treatment) is improved through cocrystallization with various coformers like 4-aminobenzoic acid, cinnamic acid, and 3-hydroxybenzoic acid.
• Stability: Stability is a key factor in the development of new chemical entities (NCEs). Stability studies in drug development include chemical stability, light stability, relative humidity stability, and thermal stability. One study found that cocrystallizing glutaric acid with a drug molecule provided the best chemical stability, showing no chemical degradation under various conditions. Another study found that the cocrystal of carbamazepine (used for treating epilepsy and neuropathic pain) and saccharin exhibited strong chemical stability and good physicochemical stability under high-temperature conditions.
• Improving Mechanical Properties: The mechanical properties of drug products, such as tensile strength, breaking force, thermal deformation, compressibility, and tablet material capacity, are also key quality attributes. The mechanical properties of drug molecules can be modified by changing their crystal structures. Tablet pressing is a widely accepted dosage form due to its high production yield, ease of use, lower manufacturing cost compared to other forms, and ease of storage and handling.
• Multi-Drug Cocrystals: A new trend in drug development is combining multiple active pharmaceutical molecules into a single dosage unit, forming combination therapies. For example, the anti-SARS-CoV-19 drug Paxlovid contains both nirmatrelvir and ritonavir, two peptide-like active substances. The growing trend for combination therapies is driven by two key factors: 1) the need to target multiple receptors for successful treatment of chronic diseases such as HIV/AIDS, cancer, and diabetes, and 2) reducing drug development costs. Combination therapy drugs can either be used in separate doses, as in Paxlovid, or combine different APIs into a single delivery system, using models like salts, cocrystals, and co-amorphous systems.
• Masking the Taste of Oral Formulations: Oral disintegrating tablets require fast dissolution. These tablets do not require chewing or water, increasing drug consumption levels and being suitable for elderly, pediatric, and travel patients. However, to improve patient comfort, disintegrating tablets often require flavor masking agents. While sugar-based excipients can be used for masking flavors, they also have limitations, such as reducing the dissolution rate of the tablet. Drug cocrystals can partially solve this issue. For example, the cocrystal of hydrochlorothiazide with sucralose as the coformer has a flavor-masking effect and exhibits a high dissolution rate.
• Patentability: Intellectual property is crucial for pharmaceutical companies. Innovative solid drug types, including polymorphs, salts, and cocrystals, can provide new intellectual property for certain drugs, extending their patent lifecycle.

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