Pharmaceutical Cocrystals: An Emerging Strategy for Improving Solubility of BCS Class II Drugs

One of the persistent challenges in pharmaceutical development is the poor ability of many drug molecules to dissolve effectively in aqueous environments, such as biological fluids. Since oral drug absorption largely depends on the drug being in a dissolved state, insufficient solubility can significantly hinder the dissolution process. This, in turn, limits the amount of drug available for absorption across biological membranes. As a consequence, inadequate dissolution directly impacts bioavailability, leading to reduced therapeutic effectiveness and potentially inconsistent clinical outcomes. [1,2].

According to the Biopharmaceutics Classification System (BCS), Class II drugs are characterized by high membrane permeability but low aqueous solubility. Although these drugs can readily cross biological membranes once dissolved, their limited solubility restricts the rate at which they dissolve in gastrointestinal fluids. As a result, the dissolution process becomes the rate-limiting step in drug absorption. Consequently, the overall bioavailability of Class II drugs is primarily governed by their dissolution behavior rather than their permeability, making enhancement of solubility and dissolution rate a critical focus in their formulation development. [3].Although a variety of techniques—such as particle size reduction, salt formation, and solid dispersion—have been widely explored to address poor solubility, their effectiveness is often variable and formulation-dependent. While these approaches can enhance dissolution to some extent, the results are not always consistent across different drug candidates. In certain cases, they may introduce additional challenges, such as physical or chemical instability, recrystallization, or difficulties in maintaining improved performance over time. Consequently, these limitations can prevent such methods from delivering reliable and long-term enhancement in drug solubility and overall therapeutic performance. [4–6].

These limitations have driven the need to explore alternative solid-state strategies that can offer more reliable and consistent improvements in drug properties. Among these, cocrystallization has emerged as a promising approach that specifically targets the modification of the internal molecular arrangement within a crystal lattice. In cocrystallization, the drug molecule interacts with a suitable coformer to form a well-defined crystalline structure. This association is governed by non-covalent intermolecular interactions, such as hydrogen bonding or π–π stacking, which help stabilize the new crystal lattice. By altering the molecular packing without changing the chemical identity of the drug, this technique enables the fine-tuning of physicochemical properties, ultimately enhancing drug performance [7–9].

This rearrangement of molecules within the crystal lattice can significantly influence important physicochemical properties, especially solubility and dissolution rate. By altering how the molecules are packed and interact with each other, the drug can exhibit improved interaction with the surrounding aqueous environment, leading to enhanced dissolution behavior. Importantly, these modifications occur without changing the drug’s chemical structure, ensuring that its pharmacological activity and therapeutic effect remain unaffected while its performance is improved [10].

From a formulation perspective, this makes cocrystals a highly adaptable and versatile option compared to conventional techniques. Unlike traditional methods, which may be limited by drug-specific constraints or stability issues, cocrystallization offers greater flexibility in selecting suitable coformers to tailor desired properties. This adaptability allows formulators to optimize key characteristics such as solubility, dissolution rate, and stability in a more controlled and predictable manner, making cocrystals an attractive alternative in modern drug development.

2. Methods of Cocrystal Formulation

2.1 Solvent Evaporation Approach

In this method, the drug and coformer are first dissolved together in a suitable solvent to create a homogeneous solution. As the solvent is gradually removed under controlled conditions, the solute molecules begin to organize and form a crystalline structure. This slow and controlled evaporation promotes the orderly arrangement of the drug and coformer within the crystal lattice, leading to the formation of cocrystals.

Although the technique is relatively simple and widely used, it requires careful optimization of critical parameters such as the choice of solvent, concentration, temperature, and rate of evaporation. Improper control of these factors may result in non-uniform crystal formation, incomplete cocrystallization, or the formation of unwanted phases, making process optimization essential for achieving consistent and high-quality crystals. [11–16].

Fig. 1: Solvent Evaporation Method

2.2 Grinding-Based Methods

Grinding is widely employed as an initial screening technique for the formation of pharmaceutical cocrystals due to its simplicity, speed, and minimal requirement for specialized equipment. It enables rapid evaluation of potential drug–coformer combinations and is particularly useful during early-stage development.

Dry grinding: The drug and coformer are mechanically mixed using methods such as mortar–pestle or ball milling without the addition of any solvent. The applied mechanical energy facilitates close contact between the molecules, promoting intermolecular interactions that may lead to cocrystal formation.

Liquid-assisted grinding (LAG): It involves the addition of a small amount of solvent during the grinding process. This minimal solvent acts as a facilitator, enhancing molecular mobility and interaction between the drug and coformer. As a result, LAG often leads to improved efficiency, faster cocrystal formation, and better reproducibility compared to dry grinding, making it a preferred approach in many cases. [17].

Fig. 2: Neat Grinding and Liquid Assisted Grinding

Fig. 3: Grinding Based Methods

2.3 Slurry Technique

In this method, the drug and coformer are dispersed in a solvent in which both components exhibit limited solubility, rather than being completely dissolved. As the system is maintained over time, a state of equilibrium is gradually established between the dissolved and undissolved phases. This controlled environment allows the molecules to interact and reorganize, ultimately leading to the formation of cocrystals.

Because the process occurs under near-equilibrium conditions, it often promotes the development of well-ordered and thermodynamically stable crystalline forms. As a result, this method is commonly preferred when the goal is to obtain stable and reproducible cocrystals with desirable physicochemical properties. [18].

Fig. 4: Slurry Method

2.4 Hot Melt Extrusion

Hot melt extrusion involves the simultaneous heating and mixing of the drug and coformer under carefully controlled conditions, typically using an extruder. The applied heat softens or melts the components, allowing them to mix at a molecular level and form a homogeneous system. Upon cooling, this mixture solidifies, leading to the formation of cocrystals or solid dispersions depending on the system.

As a solvent-free technique, hot melt extrusion is considered environmentally friendly and well-suited for continuous, large-scale manufacturing. However, the process requires exposure to elevated temperatures, which can pose a limitation for thermolabile compounds that are prone to degradation under heat. Therefore, its applicability depends on the thermal stability of the drug and coformer involved [19].

Fig. 5: Hot Melt Extrusion Method

2.5 Supercritical Fluid Processing

In this method, supercritical carbon dioxide (CO?) is employed as a processing medium to promote cocrystal formation. When CO? is brought above its critical temperature and pressure, it exhibits unique properties—combining gas-like diffusivity with liquid-like solvating ability—which enhances mass transfer and facilitates intimate interaction between the drug and coformer. Depending on the specific approach used (such as supercritical anti-solvent or gas antisolvent techniques), cocrystallization occurs as the components precipitate out in a controlled manner.

One of the key advantages of this technique is the precise control it offers over particle size, morphology, and crystal habit, leading to uniform and high-quality cocrystals. However, the requirement for specialized high-pressure equipment, along with strict control of operating conditions such as temperature and pressure, makes the process more complex and costly compared to conventional methods [20].

Fig. 6: Supercritical Fluid Processing Method

2.6 Recent and Emerging Approaches

Recent advancements in cocrystal research have introduced innovative approaches such as nano-cocrystal systems, microfluidic technologies, and green synthesis methods. Nano-cocrystals focus on reducing particle size to the nanometer range, which significantly enhances surface area and, consequently, improves dissolution rate and bioavailability. This makes them particularly useful for poorly soluble drugs.

Microfluidic technologies, on the other hand, enable precise control over mixing, temperature, and reaction conditions at a microscale level. This results in uniform crystal formation, improved reproducibility, and better control over particle characteristics. Such systems are also advantageous for continuous processing and scale-up with consistent quality.

In addition, environmentally friendly or “green” synthesis methods aim to reduce or eliminate the use of harmful organic solvents. Techniques such as solvent-free grinding or the use of safer solvents contribute to more sustainable manufacturing practices. Collectively, these modern approaches not only enhance the efficiency and quality of cocrystal production but also address scalability challenges while minimizing environmental impact [28–30].

3. Characterization of Cocrystals

3.1 FTIR Spectroscopy

Fourier Transform Infrared (FTIR) analysis is widely used to detect changes in functional group interactions during cocrystal formation. By comparing the infrared spectra of the pure drug, coformer, and the resulting cocrystal, it becomes possible to identify modifications in vibrational frequencies associated with specific functional groups.

Shifts in characteristic absorption peaks—such as those corresponding to hydroxyl, amine, or carbonyl groups—often indicate the formation of new intermolecular interactions, particularly hydrogen bonding between the drug and coformer. These spectral changes provide strong evidence of cocrystal formation, as they reflect alterations in the molecular environment without any change in the chemical structure of the components [21].

3.2 Differential Scanning Calorimetry (DSC)

Differential Scanning Calorimetry (DSC) is commonly used to study the thermal behavior of materials by monitoring heat flow associated with temperature changes. In the context of cocrystals, DSC helps identify phase transitions such as melting, crystallization, or glass transitions.

When a cocrystal is formed, it typically exhibits a distinct melting endotherm that differs from the melting points of the pure drug and the coformer. The appearance of this new, single melting peak indicates the formation of a new crystalline phase rather than a simple physical mixture. This provides strong thermal evidence that a unique and well-defined cocrystal structure has been successfully created [22].

3.3 Thermogravimetric Analysis (TGA)

Thermogravimetric Analysis (TGA) is used to monitor changes in the weight of a sample as a function of temperature or time under controlled conditions. In the study of cocrystals, TGA is particularly useful for assessing thermal stability by identifying temperatures at which decomposition or mass loss occurs.

Additionally, TGA can detect the presence of residual solvents or moisture within the crystal structure. Any observed weight loss at lower temperatures is often attributed to the evaporation of trapped solvent or water molecules, while weight loss at higher temperatures may indicate decomposition of the material. This information is essential for evaluating the purity, stability, and overall quality of the cocrystal system [22].

3.4 Powder X-ray Diffraction (PXRD)

Powder X-ray Diffraction (PXRD) is regarded as one of the most definitive techniques for the identification of cocrystals. It works by analyzing how X-rays are diffracted by the crystal lattice, producing a characteristic pattern based on the arrangement of atoms within the structure.

Each crystalline material generates a unique diffraction pattern, often referred to as its “fingerprint.” When a cocrystal is formed, its PXRD pattern will be distinctly different from those of the pure drug and the coformer. The appearance of new peaks, along with the disappearance or shifting of existing ones, confirms the formation of a new crystalline phase. This makes PXRD a highly reliable method for verifying the presence and purity of cocrystals [23].

3.5 Single Crystal X-ray Diffraction

This technique offers detailed insight into the molecular arrangement within the crystal lattice, revealing how the drug and coformer are spatially organized. It enables precise determination of atomic positions, orientation of molecules, and the nature of packing within the structure.

Additionally, it helps identify and characterize intermolecular interactions—such as hydrogen bonding, van der Waals forces, and π–π stacking—that play a crucial role in stabilizing the cocrystal. Such in-depth structural information is essential for understanding the properties and behavior of the crystalline system [23].

3.6 Scanning Electron Microscopy (SEM)

Scanning Electron Microscopy (SEM) is used to examine the surface morphology and particle shape of cocrystals at high resolution. It provides detailed visual information about the size, texture, and structural features of the particles.

In many cases, the morphology of cocrystals differs significantly from that of the pure drug and coformer. Changes in shape—such as from irregular to more defined crystalline forms—or variations in surface texture can indicate successful cocrystal formation. These morphological differences help support other characterization techniques in confirming the development of a new solid-state form [24].

3.7 Transmission Electron Microscopy (TEM)

Transmission Electron Microscopy (TEM) allows analysis at the nanoscale by transmitting electrons through an ultra-thin sample, providing highly detailed images of internal structure and particle size. This makes it especially valuable for studying nano-cocrystal systems, where precise characterization at the nanometer level is essential.

TEM helps in determining particle size distribution, crystal structure, and degree of crystallinity, while also revealing fine structural details that are not visible through other microscopy techniques. As a result, it plays a crucial role in confirming the successful formation and uniformity of nano-cocrystals, as well as in understanding their potential impact on drug performance [24].

3.8 Nuclear Magnetic Resonance (NMR)

Nuclear Magnetic Resonance (NMR) techniques are valuable for confirming both the molecular composition and the nature of interactions within a cocrystal system. By analyzing the chemical environment of atomic nuclei—commonly hydrogen (^1H) and carbon (^13C)—NMR provides detailed information about how the drug and coformer are associated.

In cocrystals, shifts in chemical signals (chemical shift changes) compared to the pure components often indicate the presence of intermolecular interactions such as hydrogen bonding or other non-covalent forces. Additionally, NMR can help verify the stoichiometric ratio of the components, ensuring the correct composition of the cocrystal. This makes it a powerful complementary technique for confirming successful cocrystal formation and understanding molecular-level interactions [25].

3.9 Raman Spectroscopy

Raman spectroscopy serves as a complementary technique to FTIR by offering additional insight into molecular vibrations and structural modifications within a cocrystal system. While FTIR is sensitive to changes in dipole moment, Raman spectroscopy is based on changes in molecular polarizability, allowing it to detect vibrational modes that may be weak or inactive in FTIR.

In the context of cocrystals, shifts in Raman peaks, changes in intensity, or the appearance of new bands can indicate alterations in molecular environment and the formation of intermolecular interactions between the drug and coformer. This complementary nature makes Raman spectroscopy particularly useful for confirming structural changes and providing a more comprehensive understanding of cocrystal formation [26].

3.10 UV–Visible Spectroscopy

This method is primarily employed for quantitative analysis in dissolution and solubility studies, where accurate measurement of drug concentration is essential. It enables the determination of how much drug is dissolved in a given medium over time, allowing for the evaluation of dissolution rate and extent.

By providing precise and reproducible data, this technique helps in comparing the performance of cocrystals with that of the pure drug. It is particularly useful for assessing improvements in solubility and bioavailability, making it an important tool in the characterization and evaluation of pharmaceutical formulations [27].

3.11 Dynamic Vapor Sorption (DVS)

Dynamic Vapor Sorption (DVS) is used to study how cocrystals interact with moisture under controlled humidity conditions. In this technique, the sample is exposed to systematically varying relative humidity levels, and changes in its weight are continuously monitored.

This analysis helps determine the hygroscopic nature of the cocrystal, including its tendency to absorb or release moisture. Such behavior is critical for assessing physical and chemical stability, as exposure to humidity can lead to phase transformations, degradation, or loss of crystallinity. Therefore, DVS plays an important role in predicting storage conditions, packaging requirements, and overall stability of cocrystal formulations [31–33].

3.12 Particle Size and Zeta Potential Analysis

These parameters are particularly important for nano-cocrystals because they directly affect how well the particles remain dispersed and how efficiently they dissolve. At the nanoscale, properties such as particle size, size distribution, surface charge (zeta potential), and surface characteristics play a crucial role in determining stability in suspension.

Well-dispersed nano-cocrystals with optimal surface properties are less likely to aggregate, which helps maintain a high surface area and ensures consistent dissolution. Conversely, poor dispersion stability can lead to particle agglomeration, reducing effective surface area and negatively impacting dissolution behavior. Therefore, careful control and evaluation of these parameters are essential to achieve improved solubility, enhanced bioavailability, and reliable performance of nano-cocrystal formulations [34–36].

4. Applications in BCS Class II Drugs

Cocrystals have demonstrated considerable success in improving the performance of poorly soluble drugs such as fenofibrate, carbamazepine, and indomethacin [37–40]. The enhancement in dissolution is often attributed to improved wettability and lower lattice energy.

Beyond conventional formulations, recent research indicates potential applications in antimicrobial systems and advanced delivery platforms such as transdermal and inhalation-based systems [41–45].

Fig. 7: Applications of Co-Crystals Formulation