Ternary Co-Amorphous Systems of Glimepiride Incorporating Microenvironmental pH Modulators for Solubility Enhancement: A Review

Glimepiride is a third-generation sulfonylurea that is frequently used to treat type 2 diabetes because of its strong Hypoglycaemia effects and extended half-life. Glimepiride's poor water solubility limits its therapeutic efficacy in clinical setting [17,18]. The Biopharmaceutics Classification System (BCS) classifies glimepiride as a Class II medication due to its high permeability and low solubility [6]. These medications have inconsistent and occasionally insufficient oral bioavailability because the dissolution rate becomes the limiting step for absorption. Glimepiride behaves as a weakly acidic chemical with a pKa of about 6.2, which results in high pH-dependent solubility [16]. The drug mostly stays in its unionized form in the stomach's acidic environment, which leads to incredibly low solubility. Higher pH levels cause solubility to somewhat rise, although this improvement is frequently insufficient to guarantee quick dissolution in gastrointestinal fluids. As a result, the rate-limiting step for medication absorption is dissolution, which could result in a delayed commencement of action and inconsistent therapeutic response [13]. To overcome these limitations, various formulation strategies have been explored to enhance the solubility and dissolution rate of glimepiride. These approaches include solid dispersions, complexation with cyclodextrins, lipid-based formulations, nanosuspensions, and particle size reduction techniques [26]. While these methods have shown some improvement in dissolution behaviour, they often present challenges such as physical instability, recrystallization, high polymer requirement, complex manufacturing processes, and scalability issues. Additionally, some techniques fail to maintain supersaturation during dissolution, resulting in precipitation of the drug and reduced bioavailability [19]. Therefore, there is a need for more effective formulation strategies capable of simultaneously improving solubility, maintaining supersaturation, and ensuring long-term physical stability. Advanced approaches such as co-amorphous systems and microenvironmental pH modification have emerged as promising alternatives. These strategies aim to enhance dissolution by stabilizing the drug in a high-energy amorphous state while improving ionization through localized pH adjustment. The integration of these approaches offers a potential solution to overcome the solubility limitations of glimepiride and improve its oral delivery performance [20].

Concept of Amorphization and Limitations of Polymeric Amorphous Solid Dispersions

Amorphization, which transforms a crystalline medicine into a high-energy amorphous state, is a well-known method of improving the solubility of poorly water-soluble medications. Amorphous materials have a greater Gibbs free energy and lack long-range molecular order in contrast to crystalline solids, which have an ordered lattice structure. Since drug molecules do not need lattice breaking during dissolving, this higher energy state enhances perceived solubility and dissolution rate. As a result, amorphous systems can produce supersaturated solutions, which improve medication absorption and concentration gradients [22,23]. Physical stability and dissolving performance may be jeopardized by the amorphous state's thermodynamic metastability and tendency to recrystallize over time. Polymers like hydroxypropyl methylcellulose (HPMC) or polyvinylpyrrolidone (PVP) stabilize the amorphous drug by decreasing molecular mobility and preventing nucleation in polymeric amorphous solid dispersions (ASDs), which have been developed to solve this problem. Polymeric ASDs have a number of drawbacks despite these benefits, such as the need for a high polymer content, a lower drug loading capacity, the possibility of phase separation, sensitivity to moisture, and recrystallization during storage. Large polymer amounts may also make processing and scale-up more difficult, and sustaining supersaturation during dissolution is still difficult [26,32]. These drawbacks emphasize the need for different stabilization techniques, like co-amorphous systems, which stabilize the amorphous state while improving dissolving performance by using low-molecular-weight co-formers [30].

Fundamentals of Co-Amorphous Systems

Co-amorphous systems (CAMs) are homogeneous amorphous solid systems consisting of an active pharmaceutical ingredient (API) and a low-molecular-weight co-former such as amino acids, organic acids, bases, or another drug molecule. Unlike polymeric amorphous solid dispersions, CAMs use small molecular stabilizers to maintain the amorphous state. The absence of crystalline order produces a high-energy metastable state that improves apparent solubility and dissolution rate compared with crystalline drugs. However, the amorphous state is inherently unstable and requires effective stabilization to prevent recrystallization. Physical stability of CAMs mainly arises from intermolecular interactions between the drug and the co-former. Hydrogen bonding between complementary functional groups enhances miscibility and stabilizes the amorphous matrix [4,14]. Ionic interactions or amorphous salt formation may occur when acidic and basic components are combined, providing stronger stabilization by increasing the glass transition temperature (Tg) and reducing molecular mobility [30,29]. In addition, π–π stacking between aromatic structures may further inhibit crystallization [1,3]. Selection of a suitable co-former is essential for successful CAM development. Important criteria include pKa compatibility, hydrogen bonding ability, molecular flexibility, high intrinsic Tg, and the capacity to maintain supersaturation during dissolution. Compared with polymeric amorphous dispersions, CAMs require lower excipient content and allow higher drug loading, although careful design is required to ensure adequate physical stability.

Microenvironmental pH (µpH)

Microenvironmental pH (µpH) refers to the localized pH at the solid–liquid interface of a dissolving drug particle, which can differ significantly from the bulk dissolution medium [13,35]. This localized pH is influenced by the diffusion layer, accumulation of ionized species, and limited mixing near the particle surface. For weakly ionizable drugs, µpH strongly affects dissolution because ionization and solubility depend on local hydrogen ion concentration. In weakly acidic drugs such as glimepiride, insufficient alkalinity in the diffusion layer restricts ionization and results in poor solubility in acidic and neutral conditions [35]. Modifying µpH can enhance ionization, promote supersaturation, and improve dissolution performance.[7]

pH-Modulating Co-Formers

pH-modulating co-formers provide dual functionality in co-amorphous systems by stabilizing the amorphous phase and improving dissolution [7,8]. For weakly acidic drugs like glimepiride, basic co-formers increase the local pH at the dissolution interface, enhancing drug ionization and apparent solubility [3,4] . Effective co-formers should possess suitable pKa compatibility, buffering capacity, good miscibility, and strong intermolecular interaction potential. Basic amino acids such as arginine and lysine are widely investigated because they combine strong molecular interactions with localized alkalization effects[11]. Upon dissolution, these co-formers modify the microenvironmental pH, promote supersaturation, and reduce precipitation, thereby improving dissolution and potential oral absorption of pH-dependent drugs [1] .

Table 1: Reported pH-Modulating Co-formers in Co-Amorphous Systems and Their Effect on Solubility Enhancement [1-20].

Numerous investigations have shown that in co-amorphous systems, pH-modulating co-formers greatly improve the solubility and dissolution of weakly water-soluble medications. Organic acids, inorganic bases, amino acids, drug-drug combos, and neutral co-formers that alter the pH of the microenvironment and encourage drug ionization are among the co-formers that have been documented. Among these, basic agents like meglumine, sodium carbonate, magnesium oxide, and L-arginine are frequently used for weakly acidic medications, whereas organic acids like citric acid, tartaric acid, succinic acid, and saccharin are frequently used for Weakly basic drugs. The drug co-former interaction and preparation technique such as ball milling, melt quenching, spray drying, solvent evaporation, and solid dispersion techniques determine the degree of solubility augmentation [1]. The majority of systems displayed a 3–8-fold increase in solubility. This is explained by enhanced ionization and amorphous stabilization [3]. However, because of considerable salt creation and microenvironmental pH rise, amino acid co-formers like L-arginine showed noticeably better solubility augmentation, especially for acidic medications. Indomethacin–L-arginine complexes, for instance, showed incredibly high solubility improvement; ibuprofen, zaltoprofen, and curcumin also showed significant increase [7,8]. Overall, these investigations demonstrate that pH-modulating co-formers enhance solubility via a variety of processes, such as salt creation, hydrogen bonding, microenvironmental pH alteration, enhanced wettability, and supersaturation stability. Amino acids, especially L-arginine, are thought to be very successful among the different co-formers, which makes them attractive options for improving the solubility of medications that are weakly acidic, such glimepiride [13,34].

Components of Ternary Co-Amorphous System

L-arginine is the pH-modifying co-former, hydroxypropyl methylcellulose (HPMC) is the polymeric stabilizer, and glimepiride is the model drug in the suggested ternary co-amorphous system [16]. These components are chosen based on their complementing physicochemical characteristics and their capacity to increase solubility via a variety of methods.
The Biopharmaceutics Classification System (BCS) Class II drug glimepiride is mildly acidic and poorly soluble in water; the rate-limiting step for absorption is dissolution. Because of its pKa (~6.2), glimepiride has limited dissolving and variable oral bioavailability due to its pH-dependent solubility and preferential unionization in acidic gastrointestinal environments. Therefore, to improve ionization and dissolving performance, an appropriate pH-modifying agent must be incorporated. Because it is a basic amino acid with a high-water solubility and potent buffering ability, L-arginine is chosen as the co-former. L-arginine improves glimepiride's ionization and apparent solubility by raising the pH of the microenvironment surrounding the drug particles after it dissolves. Furthermore, L-arginine can interact with glimepiride through ionic or hydrogen bonding interactions, which maintain the amorphous state and lessen the tendency toward recrystallization. To improve system stability and dissolution behaviour even more, hydroxypropyl methylcellulose (HPMC) is added as a hydrophilic polymer. HPMC accelerates drug release by increasing wettability and facilitating the dissolving medium's penetration into the matrix. Additionally, the polymer decreases molecular mobility and inhibits precipitation. As a result, the combination of glimepiride, L-arginine, and HPMC creates a logical ternary co-amorphous system in which L-arginine alters the pH of the microenvironment, HPMC improves wettability and stabilization, and glimepiride gains from improved ionization and decreased crystallinity, which improves solubility and dissolution performance.

Mechanism of Action: Mechanism of Action

Co-formers in co-amorphous systems improve drug solubility by controlling the microenvironment dynamically while the drug dissolves. When the co-amorphous matrix is exposed to aqueous fluids, the pH-modulating co-former and glimepiride are released simultaneously as the matrix dissolves at the molecular level. The co-former acts in the stationary diffusion layer around the dissolving particle, where the microenvironmental pH (µpH) can be modified locally due to limited mixing [13].  According to the principles of acid–base balance, an increase in µpH within this diffusion layer +increases drug ionization for weakly acidic medicines like glimepiride. The concentration gradient that propels drug diffusion from the particle surface into the bulk dissolution liquid is strengthened and apparent solubility is improved by increased ionization. Reducing precipitation and extending the supersaturated state are achieved by delaying nucleation and crystal development through the maintenance of a suitable microenvironmental pH [34].

Thus, in co-amorphous systems, pH-modulating co-formers serve two purposes:

1. stabilize the amorphous solid by means of intermolecular interactions like hydrogen bonding or ionic interactions; and
2. control the microenvironmental pH during dissolution to promote drug ionization and preserve supersaturation [35]

Other mechanisms contribute to the improvement of solubility in the presence of HPMC and L-arginine. L-arginine is evenly distributed throughout the system, while glimepiride molecules are scattered within a hydrophilic matrix created by HPMC. In addition to increasing the surface area accessible for dissolving, this molecule dispersion decreases crystallinity. The hydrophilic HPMC matrix quickly hydrates and dissolves in aqueous environments, releasing glimepiride and L-arginine at the same time. Since L-arginine is a basic amino acid, the diffusion layer around the dissolving particles has a higher µpH[11]. Glimepiride's ionization is improved by the elevated pH, which leads to increased apparent solubility and quicker dissolution.
Moreover, glimepiride, L-arginine, and HPMC engage in intermolecular interactions such hydrogen bonding and ionic interactions. These interactions stop the medication from aggregating or recrystallizing and stable it in a scattered state. HPMC's hydrophilic properties increase wettability, which makes it easier for the dissolution medium to penetrate and encourages drug release [27,28]. A supersaturated solution is created when ionized glimepiride dissolves quickly. By decreasing molecular mobility and postponing nucleation and crystal formation, HPMC functions as a precipitation inhibitor. The drug's dissolved form is prolonged and dissolving performance is enhanced when this supersaturated condition is stabilized [3].
Thus, L-arginine's microenvironmental pH adjustment, intermolecular interactions, enhanced wettability from HPMC, decreased crystallinity, and stabilization of supersaturation all work together to increase glimepiride's solubility and rate of dissolution [4].

Fig 1: proceudre of soild dispersion

Table 2: method of solid dispersion

Table 3 : Micro-pH detecting methods.