2016 Volume 64 Issue 10 Pages 1421-1430
Recent active research and new regulatory guidance on pharmaceutical cocrystals have increased the rate of their development as promising approaches to improve handling, storage stability, and bioavailability of poorly soluble active pharmaceutical ingredients (APIs). However, their complex structure and the limited amount of available information related to their performance may require development strategies that differ from those of single-component crystals to ensure their clinical safety and efficacy. This article highlights current methods of characterizing pharmaceutical cocrystals and approaches to controlling their quality. Different cocrystal regulatory approaches between regions are also discussed. The physical characterization of cocrystals should include elucidating the structure of their objective crystal form as well as their possible variations (e.g., polymorphs, hydrates). Some solids may also contain crystals of individual components. Multiple processes to prepare pharmaceutical cocrystals (e.g., crystallization from solutions, grinding) vary in their applicable ingredients, scalability, and characteristics of resulting solids. The choice of the manufacturing method affects the quality control of particular cocrystals and their formulations. In vitro evaluation of the properties that govern clinical performance is attracting increasing attention in the development of pharmaceutical cocrystals. Understanding and mitigating possible factors perturbing the dissolution and/or dissolved states, including solution-mediated phase transformation (SMPT) and precipitation from supersaturated solutions, are important to ensure the bioavailability of orally administrated lower-solubility APIs. The effect of polymer excipients on the performance of APIs emphasizes the relevance of formulation design for appropriate use.
Cocrystals comprise multiple components forming a crystal lattice through non-ionic interactions. Recent active research on their development and application to pharmaceutical formulations has aimed at improving material handling during processing, storage stability, and dissolution of active pharmaceutical ingredients (APIs).1,2) Furthermore, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) regulatory guidance on the requirements and approval processes of pharmaceutical cocrystals should facilitate product development.3,4) Nonetheless, some concerns remain regarding the ability of standard development and manufacturing approaches originally designed for single-component or salt crystals to achieve the product quality required for safe and effective use of complex cocrystals. This review surveys the physical and functional properties of pharmaceutical cocrystals as well as their manufacture, with a focus on product quality. We discuss current physicochemical characterization methods in addition to in vitro (e.g., dissolution) and in vivo (e.g., bioavailability) performance tests. We also address the different FDA and EMA regulatory approaches to controlling the quality of pharmaceutical cocrystals; the differences in these approaches have caused some confusion in industry and academia. Some excellent reviews on the structure and properties of pharmaceutical cocrystals may provide deeper understanding.1,2,5,6)
Crystals comprising multiple ingredients have been extensively investigated. Pioneering works by Wöhler7) as well as a patent by F. Hoffman-La Roche & Co.8) are considered the origin of cocrystal studies. Cocrystals have been distinguished from salts and solvates since the 1990 s and have only been accepted as “crystalline solids composed of stoichiometric ratios of multiple ingredients that form the crystal lattice by non-ionic interactions” from as late as 2005.9,10) Some pre-1980 s studies referred to cocrystals in other terms (e.g., “complex crystals”).11) A recent study clarified that the structure of a pharmaceutical complex crystal (e.g., chloral betaine) developed in the 1960 s is properly categorized as a cocrystal according to the current definition.12)
Many pharmaceutical cocrystals are composed of an API moiety and coformer (cocrystal former, guest molecule). Recent studies have addressed various cocrystal formations by APIs and coformers as well as their diverse physical and chemical properties. Many pharmaceutical cocrystals contain physiologically non-active molecules (e.g., carboxylic acids, amides, amino acids, and polyols) as coformers, whereas others combine two active ingredients. Some other solids used for pharmaceutical formulations (e.g., salts, hydrates, and solvates) comprise multiple ingredients and possess crystal structures analogous to cocrystals. These solids present different interactions in their crystal lattice and physical properties of the guest molecules. Salt crystals are composed of anions and cations that interact through ionic interactions instead of non-ionic interactions. Hydrates and solvates contain guest components that are liquid in their isolated states. By contrast, guest molecules in cocrystals exist as individual solids under ambient conditions.
2.2 Pharmaceutical Applications of CocrystalsCocrystals find wide applications in pharmaceutical formulations. They improve the storage stability and dissolution of certain APIs. Some enable the preparation of solid formulations containing intrinsically liquid, semi-solid,13) or volatile APIs14) without handling difficulties. The association of some technically problematic APIs such as paracetamol with certain coformers (e.g., trimethylglycine) assists their appropriate tableting by enhancing compressibility.15,16) Other APIs exhibit better physical properties, such as improved flowability, that aid formulation processes.17)
Reducing the mobility of API molecules in the lattice of cocrystals improves storage stability of some oily and volatile APIs. The formation of cocrystals also stabilizes APIs that tend to form amorphous solids and/or unstable crystals by themselves. Superior physical properties and storage stabilities provide opportunities to improve current formulations and to develop dosage forms for new administration routes. Henck and Byrn have suggested that cocrystals be incorporated into formulations used for clinical trials of investigational new drugs.18)
Current studies on pharmaceutical cocrystals have mainly aimed at enhancing the bioavailability of biopharmaceutics classification system (BCS) class 2 and 4 APIs by increasing their solubility.19) This approach is considered a promising alternative to several dissolution-assisting technologies involving amorphous solids, salt crystals, micelles, and liposomes that provide adequate bioavailability to oral formulations comprising low-solubility APIs. Most importantly, pharmaceutical cocrystals are applicable to numerous non-ionic APIs and potential coformers compared to salt crystals. The early development stages of several new drugs include a screening of cocrystal formation and characterization of the resulting solids.
The regulation of pharmaceutical cocrystals and their formulations is expected to substantially affect development and quality control strategies in addition to the value of intellectual properties of related technologies.20) The FDA Center for Drug Evaluation and Research has issued industry guidance for the classification of pharmaceutical cocrystals to define a framework for their handling in new and generic drug applications.3) An EMA working group has also addressed the use of cocrystals and other solid-state forms of active substances in medicinal products.4) These guidelines emphasized the importance of characterization and quality control for the appropriate use of pharmaceutical cocrystals. Both agencies set the same scientific definition of cocrystals but opted for different regulatory approaches, which has led to some arguments in academia and industry (Table 1). In particular, these arguments pertain to the categorization of cocrystals as APIs or drug product intermediates (DPIs) and their potential recognition as new active substances. No official guidelines on the use of pharmaceutical cocrystals are currently provided in Japan.
| FDA guidance (2013) | EMA reflection paper (2015) | |
|---|---|---|
| Regulatory category | Drug product intermediate (DPI) | Active pharmaceutical ingredients (API)a) |
| Composed of: | API and neutral guest compound | Two or more components in definite stoichiometric ratio |
| Crystal lattice is based on: | Nonionic interactions | Nonionic interactions |
| Role of coformer | Excipient | Reagent |
| New active substance (NAS) or new chemical entity (NCE) registration | No | Possible |
| Sameness with parent API | Same | Same unless demonstrated different efficacy/safety |
| Treated in the same way with: | Polymorph of same API | Salts of same API |
| Cocrystal and salt | Strict discrimination by interaction | Some are difficult to discriminate from structure |
| Large difference in regulatory pathways | Regulatory pathways depend on efficacy/safety | |
| Mainly anticipated manufacturing sites | Drug product facilities | API manufacturing facilities |
| Drug master files (DMF) or active substance master file (ASMF) registration | No | Possible |
a) Depends on cocrystallization process.
These dissimilarities partly result from wide variations in cocrystal manufacturing methods and postulated processes. The FDA regards cocrystals as DPIs because they are often produced at formulation facilities using APIs and coformers synthesized upstream. By contrast, the EMA recognizes them mainly as APIs applicable to various formulations. FDA guidelines stress structure of cocrystals, such as interactions between components, to discriminate cocrystals from other crystals (e.g., salts). By contrast, the EMA emphasizes the evaluation of functional properties such as in vivo performance to determine regulatory pathways. Because current regulations set different ways of manufacturing controls and application documentations between regions, reasonable demands for international harmonization through scientific discussion have been made for avoiding delays in developing new clinically important pharmaceuticals and thus avoiding associated economic losses.
Understanding the structure and physical properties of cocrystals is critical for the development of new pharmaceutical solids based on the quality by design (QbD) concept.21,22) Various analytical techniques, including X-ray diffraction (XRD), thermal analysis, polarized-light microscopy, Raman spectroscopy, and solid-state NMR, have been used to achieve this goal.
4.1 Structure of CocrystalsCocrystals comprise stoichiometric amounts of various molecules interacting by non-ionic forces.23) They result from the combination of several acidic, neutral, or basic APIs with coformers. Some acidic and basic APIs form salts and cocrystals depending on their counterparts. Molecular components are often less packed in cocrystals than in other crystals (e.g., salts).24) Also, non-ionic interactions constructing the cocrystals, such as hydrogen bonding, halogen bonding, π–π stacking, and van der Waals forces, are weaker than ionic interactions. In addition to several cocrystals composed of non-ionic APIs and coformers, some crystals containing salts of APIs and coformers interacting in a non-ionic manner satisfy the aforestated definition (i.e., ionic cocrystals). Brittain have classified an FDA-approved valproic acid formulation in this category.2) Although most cocrystals contain uniform API and coformer distributions, some solids (e.g., solid solutions) show variations in component ratios depending on positions.25) Some new forms of multi-component crystals have been developed for pharmaceutical applications (e.g., BioMOFs); these materials are beyond the scope of this review.26)
Detailed crystal structures may provide a theoretical basis for the quality control of pharmaceutical cocrystals, which is achieved by the powerful single-crystal XRD technique. However, suitable large, high-quality cocrystals are often difficult to obtain because of their preparation methods. Recent advances in data processing provide reasonable structural information on cocrystals from powder XRD (PXRD) data.27) Raman spectroscopy and methods such as Fourier transform infrared spectroscopy (FT-IR) and solid-state NMR are also valuable structural elucidation techniques.
Some API–coformer combinations, such as caffeine–glutaric acid28) and carbamazepine (CBZ)–malonic acid,29) give rise to multiple cocrystal forms or polymorphs depending on the production methods and process parameters (e.g., solvent choice). Multiple functional groups in several well-known coformers, such as organic acids, and their ability to form multiple hydrogen bonds offer varied stacking arrangements through several combinations of interactions composing the crystal lattice.30) FT-IR spectroscopy serves as a simple and powerful tool for evaluating the state of carboxylate groups. Stable-form crystal solids are usually preferred compared with other polymorphs for developing pharmaceutical formulations to avoid unexpected property changes during processing, storage, and clinical use. Some other forms of cocrystals that are practically stable would be also applicable to achieve specific purposes, such as increasing solubility. Some cocrystals such as sulfadimidine–4-aminosalicylic acid crystals present the same crystal lattice but vary in appearance (e.g., morphology, surface topology) and formulation-relevant physical properties (e.g., flowability) when produced by different methods.31)
4.2 Salts, Hydrates, Solvates, and CocrystalsSalts, hydrates, solvates, and cocrystals have similar crystal structures comprising an API and a second component. Cocrystal lattices are held together by relatively weak interactions, whereas salts rely on stronger ionic forces. However, ascertaining whether a particular crystal is a salt or a cocrystal is frequently difficult. Crystals containing certain active ingredients (e.g., minoxidil) and organic acids are categorized as salts, cocrystals, or solvates depending on the nature of the organic acid.32) The boundary between salts and cocrystals and methods to distinguish them have attracted increasing attention because of both scientific interest and their different regulatory requirements.22,33)
The occurrence of proton transfer in ionic interactions between components is a characteristic feature of salt crystals.34) Reliable and precise information on proton transfer in multi-component crystals is available by neutron diffraction; however, this technique remains difficult to access.33,35) Solid-state NMR associated with new data processing methods, such as cross-polarization magic angle spinning, offers a more practical characterization approach.36) Methods such as FT-IR vibrational analysis of carboxyl groups,33) Raman spectroscopy, and X-ray photoelectron spectroscopy combined with solid-state density functional theory (DFT) have also been applied to the characterization.37) FDA guidance clearly separates regulatory pathways for salts and cocrystals. It proposed the difference between active moiety and coformer pKa values as a simple way to categorize crystals as salts (1< ΔpKa) or cocrystals (ΔpKa <1). Despite its usefulness, this criterion accounts for individual component properties in aqueous solutions instead of multi-component crystals.
The necessity for a strict discrimination between salts and cocrystals through extensive experiments in the development of pharmaceuticals has led to some controversy. Proton transfer strongly depends on temperature, and no apparent differences in pharmaceutical properties are observed between salts and cocrystals at the boundary, making a clear distinction impossible.38) Certain complex-structure multi-component crystals, including those containing amphoteric components, are also difficult to categorize according to interactions. EMA recommendations emphasize differences in the material properties of the crystal to set regulatory requirements. Cocrystals, solvates, and hydrates exhibit similar structures and interactions. Therefore, their main difference is the physical state of the isolated second component under ambient conditions. Some cocrystals, such as theophylline–citrate crystals, may also form hydrates and solvates containing water or solvent molecules, respectively, as third components, depending on the raw material, preparation method, and storage conditions.39)
In addition to the designed substance, pharmaceutical cocrystals prepared by various methods may exhibit variations in the physical states or compositions besides the objective cocrystal (Table 2). They may also contain production-related impurities or degradation products. Because of this complexity, the management of pharmaceutical cocrystal quality requires appropriate physical characterization methods.
| Objective substance |
| Cocrystal |
| Variation in physical states |
| Different crystal form of the cocrystal (polymorph) |
| Coamorphous solid |
| Variation in compositions |
| Solvates or hydrates of the cocrystal |
| Cocrystals consisting varied component molar ratio |
| Coformer-exchanged cocrystal |
| Incomplete crystallization or degradation products |
| Chemically altered cocrystal |
| Crystal of individual components, their variations |
| Non-crystalline individual components |
| Production-related impurities |
| Residual water, solvent |
Several methods have been developed to screen cocrystal formation using defined APIs and coformers. Liquid-assisted grinding (LAG) has proven most appealing because of its wide range of applicable chemicals, small sample sizes, and short processing times.40) Its application to mixtures combining an API with a cocktail of possible coformers facilitates the efficient screening of stable cocrystals.41) Another way to obtain cocrystals is to maintain suspensions or slurries at equilibrium until the solvent is evaporated. Cooling the molten mixtures of chemically stable and low-melting-point materials is also a simple way to induce cocrystallization.
PXRD and thermal analysis have been used to characterize solids during the screening process.42) Raman spectroscopy has attracted growing interest to meet the need for faster cocrystal detection in small solid samples containing high water residue.43) It benefits from limited requirements for standard materials or complex data processing (e.g., principal component analysis), which are necessary for near infrared (NIR) analysis. Other methods enable the observation of the cocrystal formation process. Hot-stage thermal microscopy shows the occurrence of a new phase at material interfaces.44) Solid-state NMR studies provide detailed information on the cocrystal formation process during in situ monitoring.45)
Predictions based on structural information offer insights into potential cocrystal arrangements and appropriate coformer choice.46,47) Structure predictions based on synthon concepts or functional group compatibility are valuable for designing new cocrystals because various APIs and coformers form cocrystals through a network of non-covalent and non-ionic interactions, such as hydrogen bonding and supramolecular synthon, between certain functional groups. Crystal structure information resources, such as the Cambridge Structural Database, assist the search for stable hydrogen bonding motifs to form cocrystals.
Coformers can be chosen from any chemical but are usually restricted to excipients already used in some drug products to avoid additional safety studies. Chemicals that have been registered as generally recognized as safe (GRAS) by the FDA are also popular coformer choices because many of them have substantial amounts of available safety data.48) Other coformers can be used for some specific purposes, such as visible clinical advantages, albeit with supporting evidence for their pharmaceutically acceptable safety and quality. Cocrystals containing multiple physiologically active substances, such as theophylline and caffeine, have been widely studied partly because of academic interests. Some incorporate two APIs to make fixed-dose combinations, whereas others use “mild” chemicals such as nutraceuticals. Their development requires a justification of their clinical relevance as well as their component ratios.
4.4 Physical Properties of Pharmaceutical CocrystalsProduct quality hinges on understanding and controlling the physical properties of pharmaceutical cocrystals by multiple characterization methods.49) Chemical compositions are rather simple to analyze and control. Required information and applied analytical methods depend on the cocrystal nature and development stage. The solid structure and physical properties of cocrystals are roughly characterized at the milligram scale in the early stages of development. Determining the quantity of physically varied possible minor components remains a challenge in the development of pharmaceutical cocrystals (Table 2).
Thermal analysis by differential scanning calorimetry (DSC) and thermal gravimetry (TG) provides valuable information about cocrystals, such as their melting temperature, enthalpy of fusion, thermal transition temperature, crystallinity, and solvate or hydrate formation.42,50) Several cocrystals melt at temperatures different from their API and conformer components. Thermal scans using temperature-controlled PXRD or simultaneous DSC–PXRD systems directly detect physical changes occurring during measurements. Chemical analysis of thermally altered materials by suitable methods, such as HPLC, Raman, and FT-IR, helps elucidate these changes. TG and residual water measurements facilitate solvate and hydrate characterization. Phase diagrams describing the relation between the compositions and melting temperatures provide insight into particular products and rational process design.42,49) Melting and thermal transitions also help predict the storage stability of cocrystals and their formulations.
Crystallinity plays an important role in the stability and clinical performance of pharmaceutical cocrystals. The amount of target cocrystal in solids is usually determined by PXRD and DSC. Diffraction peak intensities specific to the target cocrystal in the PXRD patterns and cocrystal melting enthalpy have provided the crystallinity of CBZ–saccharin and indomethacin–saccharin cocrystals.51) Crystallinity is also measured to assess cocrystal stability.52) Accurate crystallinity determinations to widen pharmaceutical cocrystal use can be challenging, especially for complex solid formulations containing excipients.
4.5 Stability of Pharmaceutical CocrystalsCocrystals present complex structures that substantially affect their clinical performance, highlighting the importance of their physical and chemical stability during processing and storage. Their lattice reduces molecular mobility, enhancing the chemical stability of some oily and amorphous APIs under various storage conditions.53) Several pharmaceutical cocrystals show relatively lower propensity to absorb water vapor in high-humidity environments compared to amorphous solids or metastable crystals of their corresponding APIs, which represents an apparent advantage with respect to chemical and physical stability.54) In some cocrystals, the API component shows variable chemical stability depending on the coformer.55) Chiral and racemic components also affect chemical stability.56) Intermolecular and intramolecular factors, which influence molecular packing and conformational strain, respectively, also affect cocrystal stability.
Pharmaceutical cocrystals exhibit specific physical stability issues. Certain API and coformer components tend to dissociate during storage, particularly in high-humidity and high-temperature environments (i.e., they tend to undergo disproportionation)57) (Table 3). Some excipients formulated with a cocrystal can replace the original coformer during storage.38) Coformer removal and/or alteration result in the parent API crystals, API hydrate crystals, or other cocrystals that may show lower solubility and reduced bioavailability. The occurrence and effects of solid-state phase transformation depend on the type of coformers in cocrystals.58) Grinding mixtures of particular cocrystals and potential coformers provide information on the stability of interactions between APIs and coformers. The sonication of aqueous suspensions or slurries generally facilitates the evaluation of possible water-induced structural changes.
| Environment | Changes | Resulting solids |
|---|---|---|
| Solid (high humidity) | Removal of coformer (disproportionation) | API, API hydrate |
| Coformer exchange | Different cocrystals | |
| Contact with water | Solution-mediated phase transformation | API, API hydrate, API salts |
| Supersaturated solutions | Precipitation of lower solubility solids | API, API hydrate, API salts |
Certain physical mixtures comprising an API and a potential conformer, such as theophylline–oxalic acid and theophylline–nicotinamide mixtures, generate cocrystals during storage in high-humidity environments.59) This cocrystallization usually slowly proceeds through successive absorption, dissolution, nucleation, and crystal growth steps on the solid surface via the same mechanism observed in slurries and aqueous dispersions.58,60) Storage of some tablets containing hydrated API or coformer crystals, such as theophylline monohydrate–anhydrous citric acid formulations, have also produced cocrystals.61)
Various physical stresses involved in the formulation process and storage (e.g., exposure of cocrystals to water, heat, high pressure) affect pharmaceutical cocrystal structure.62) Environmental changes, such as variations in local pH and residual water amount, and direct interaction with excipients may also alter storage stability. Understanding the process and appropriately characterizing the physical, chemical, and functional properties is expected to enable the rational formulation and process design of effective and safe products (Table 4). Raman transmission studies of cocrystal-containing tablets provide ingredient compositions.63) Ultra-low frequency Raman spectroscopy is gaining increasing attention as a new technique to characterize crystal polymorphs in pharmaceutical formulations. This method provides information on the lattice vibrations of cocrystals in the solid states without large interference by excipients that often perturb the analysis in FT-IR, conventional Raman, and terahertz spectroscopy.64) Some mapping techniques by FT-IR, Raman, and terahertz spectroscopies provide valuable information regarding the component distribution in solid formulations.65)
| Crystal structure |
| Single crystal XRD, Solid-state NMR, PXRD, FT-IR |
| Interaction between API and coformer (Salt/Cocrystal discrimination) |
| Newtron diffraction, Solid-state NMR, Raman, FT-IR |
| X-ray photoelectron spectroscopy (XPS) |
| Cocrystal formation screening |
| Raman, PXRD, DSC, Solid-state NMR, Hot-stage microscopy |
| Melting temperature |
| DSC |
| Crystallinity |
| PXRD, DSC |
| Solvate/Hydrate formation |
| Raman, FT-IR, TG, DSC |
| Chemical composition |
| HPLC |
| Mixing in formulation |
| Raman, NIR, Terahertz imaging |
| Solubility/dissolution |
| Shake-flask method |
| Dissolution tests (paddle, bascket, flow-through) |
| Intrinsic dissolution measurement (UV, HPLC) |
| Precipitation/insoluble solid |
| PXRD, Raman |
Information related to how the coformer and formulation factors affect in vitro and in vivo behaviors of cocrystals are pivotal for their design and appropriate use. Cocrystal formation improves the solubility and/or dissolution profile of many low-solubility APIs, such as indomethacin and saccharin.21) It has also increased the in vivo bioavailability of these APIs in animal models.66,67) The solubility and dissolution profiles of solid pharmaceuticals depend on the interactions between components in solids (e.g., crystal lattice energy) as well as in the solvent, which are determined by the hydrophobicity of the active ingredient.68) The solubility of APIs in the given media and at given temperatures was mainly evaluated by the shake-flask method. The increased dissolution of pharmaceutical cocrystals mainly results from reduced interactions in solids. The ionization of certain active components and coformers in aqueous solutions, such as basic coformers in high-pH solutions, also contributes to the dissolution of cocrystals involving non-ionic APIs.69,70) Many acidic and basic APIs generating both salts and cocrystals present higher solubility in their salts.49) Cocrystals containing coformers exhibiting a lower intrinsic melting temperature tend to exhibit relatively higher solubility in aqueous solutions.
Pharmaceutical cocrystals mainly aim to improve the dissolution of low-solubility APIs; however, some cocrystals achieve the opposite effect. Their formation may explain the complexation of gentisic acid and caffeine that reduces the dissolution and bitter taste upon oral intake.11) Low solubility may even cause a few safety problems. Severe kidney damage was observed in dogs upon pet-food intake in Canada between 2004 and 2007 as a result of the formation of practically insoluble cocrystals between cyanuric acid and melamine, which had been added to temper the protein content.71)
In vitro evaluation of dissolution is key to the development of pharmaceutical cocrystals. Published solubility and dissolution profiles are helpful, while they may be often obtained using low-purity crystals. In vitro characterizations are typically conducted through intrinsic dissolution-rate measurements72,73) and conventional dissolution tests using a paddle or rotating basket apparatus in pharmacopeia. The intrinsic dissolution of a pure drug substance is often a good parameter for in vivo API performance prediction because measurements provide dissolution propensities regardless of particle size and various formulation factors.74) However, it is not applicable to some cocrystals that display limited compressibility, perturbing the preparation of appropriate disk samples. Coformer loss during dissolution studies can also prevent solubility data acquisition for the original material.
Animal studies provide valuable insight into the actual behavior of formulations. They have shown that higher API concentrations in main absorption regions, such as the small intestine, increase the bioavailability of low-solubility APIs in certain cocrystals (e.g., itraconazole–dicarboxylic acids).66,67,75) These data require a careful evaluation of their relevance to humans because factors influencing in vivo absorption, such as structure and fluid content of the gastrointestinal tract, dramatically vary among species. The large difference in hydrophobic API dissolution between fed and fasted conditions with respect to bile acid concentration serves as an apparent factor affecting bioavailability. Therefore, the increase in API solubility upon cocrystal formation may reduce the dependence of API solubility and bioavailability on feeding conditions.64)
6.2 Solution-Mediated Phase Transformation and Physical Stability of Cocrystal SolutionsSome pharmaceutical cocrystals undergo two physical changes, including solution-mediated phase transformation of the solids and precipitation from supersaturated solutions, which may alter their bioavailability. Contact with water during oral administration often removes or alters coformers in cocrystals in the same manner as that under high-humidity storage conditions, leading to low-solubility and practically insoluble solids, such as API crystals, hydrate crystals, and other cocrystals.57,76) Some cocrystals, such as those comprising CBZ, form metastable intermediates upon exposure to aqueous solutions.77) The solid transformations may decrease the dissolution of large particles of cocrystals to greater degrees compared with the dissolution of smaller particles. The variable balance between insolubilization and dissolution speeds highlights the importance of choosing appropriate particles while developing pharmaceutical cocrystal formulations.
The oral administration of pharmaceutical cocrystals often causes API supersaturation at dissolving sites or upon pH change during their transition through the gastrointestinal tract.78) When the API concentration surpasses its solubility in particular environments, phase separation is induced by precipitation or crystallization of API alone or associated with salts or hydrates79) (Fig. 1). Active ingredients in celecoxib–nicotinamide, indomethacin–saccharine, and CBZ–cinnamic acid cocrystals have precipitated after dissolution.80) Some APIs form salts with buffer components. A similar precipitation has occurred in several formulations designed to achieve higher dissolution but containing high-energy solids such as amorphous and metastable crystal forms.
The insolubilization and precipitation of active ingredients and their resulting variations in bioavailability are major risk factors in pharmaceutical cocrystal applications.79,81,82) The dissolution tests of pharmaceutical cocrystals often show a rapid increase of the API concentrations and a subsequent decrease in the solubility of the API crystal.83) The highest achievable concentration and the stability of the dissolved states play important roles in determining cocrystal bioavailability. Bioequivalent media may help elucidate dissolution and precipitation behaviors.64) Small-scale dissolution assays have appropriately provided the dissolution properties and precipitation behavior of pharmaceutical cocrystals.84) Solids precipitated at the bottom of vessels exhibit changes in crystal form and composition that insolubilize APIs in test solutions (e.g., API hydrate crystal), as characterized by PXRD and Raman spectroscopy. Further studies on the dissolution and solution stability of cocrystals in physiological conditions are expected to ensure API safety and efficacy in large patient groups under various feeding conditions.85)
The stabilization of supersaturated states in the use of pharmaceutical cocrystals has also attracted recent research. Some polymers such as polyvinylpyrrolidone and hydroxypropyl methylcellulose enhance the physical stability of supersaturated solutions, reducing precipitation-induced variations in bioavailability.80,83,86) The improved physical stability of the supersaturated cocrystal solutions through combined effects of hydrophobic interactions and steric hindrance should contribute to reducing the variation in bioavailability caused by the precipitation. The addition of some surfactants generates cocrystal transition points, at which the API and cocrystal solubilities are equal and above which the cocrystal solubility advantage over the API is eliminated.87) Understanding the complex effect of the excipients on the solubility of the cocrystals and the stability of the supersaturated solutions are critical for the rational development of pharmaceutical cocrystal formulations.84)
6.3 API–Coformer Interactions in SolutionMany API–coformer combinations in orally administrated pharmaceutical cocrystals are considered to dissociate upon dissolution and dilution in the gastrointestinal tract, as suggested by studies on the relation between cocrystal in vitro dissolution and in vivo pharmacokinetics.5) Cocrystal regulation pathways mainly target these APIs. However, some API–coformer combinations exhibiting high binding constants form stable complexes after dissolution in aqueous solution.86,88) The effect of this potential complexation on the physical stability of supersaturated states and API absorption has emerged as an interesting topic in cocrystal studies.
The drug–coformer binding may positively or negatively affect API bioavailability of orally administrated pharmaceutical cocrystals by stabilizing supersaturated solutions or disturbing membrane permeation through diffusion. Binding with certain coformers may increase the absorption of some APIs by transporters.89) Some cocrystals even damage cell membranes.85) The measurement of dissociation constants in aqueous solutions may provide insight into API and coformer behaviors in a simple manner. Low dilution in some routes of administration, such as dermal formulations and inhalations, may reduce the chances of API–coformer dissociation. Complexation enhances skin permeability and diffusion through synthetic membranes as compared to formulations containing API alone.90) The control of pharmaceutical cocrystal performance in vivo through formulations needs further clarification.84)
Methods to prepare pharmaceutical cocrystals are selected according to API and coformer properties, required cocrystal amount, anticipated formulation, and development stage (Table 5). Required cocrystal amounts range from milligram levels for simple early-stage characterizations to multi-kilogram batches for commercial production. Different approaches are applied for archiving the targeted quality of products. Technical improvements should also alter the appropriate methods used to prepare the pharmaceutical cocrystals.
| Physical/chemical purity | Scalability | Applicable APIs | |
|---|---|---|---|
| Crystallization from solution | ◎ | ◎ | △ |
| Spray-drying | ○ | ◎ | △ |
| Freeze-drying | ○ | ○ | △ |
| Liquid-assisted grinding | △ | △ | ◎ |
| Hot-melt extrusion | ○ | ○ | ◎ |
| Microwave heating | ○ | ○ | ○ |
| Melt mixture cooling | △ | △ | ○ |
△: Fair, ○: Good, ◎: Very good. Ratings may vary depending on the cocrystals and required amount.
Cocrystals are typically obtained by crystallization from aqueous or organic solvent solutions containing the active component and coformer. Crystallization processes relying on cooling, antisolvent addition, and seed crystal addition have proven cost-effective and eligible for scale-up.91) The resulting high-purity cocrystals may find wider distribution and application in formulations similar to that of other API crystals. However, this approach presents limitations because certain components display lower solubility than their corresponding cocrystals, which often leads to their precipitation. Phase diagrams including changes caused by temperature and crystal growth facilitate an effective cocrystal production.60) Reaction–crystallization produces cocrystals wherein the components exhibit nonequivalent solubility, preventing low-stability components from crystallizing.91) The monitoring of the changing solute compositions by spectroscopic methods assists process control.92) Some approaches have reduced inorganic solvent use during cocrystal production. Specifically, carbon dioxide gas addition effectively induces itraconazole–succinic acid cocrystal formation and precipitation from aqueous solution (e.g., gas antisolvent (GAS) method).93)
2) Spray- and Freeze-Drying TechniquesCocrystals, such as CBZ–nicotinamide, can also be formed by spray-drying or freeze-drying API–coformer solutions.94) These processes feature faster solute solidification compared to crystallization in aqueous solutions, which may promote cocrystal production by reducing the phase separation and precipitation of low-solubility components. They are also compatible with scale-up and with the addition of a third component that improves pharmaceutical properties, such as a bulking agent. Spray-drying is expected to facilitate the large-scale production of pharmaceutical cocrystals by fast, cost-effective solvent evaporation. Freeze-drying is suitable for the aseptic production of injectable solid formulations. Nonetheless, these techniques also present some drawbacks. They require sufficient API and coformer solubilities in applicable solvents, especially water and t-butanol. The rapid solidification may also generate less stable amorphous solids or metastable crystals.95)
3) Grinding and Hot-Melt ExtrusionMechanochemical methods, such as grinding and hot-melt extrusion, have proven appealing for pharmaceutical cocrystal production because of their applicability to a wide range of chemicals. Liquid-assisted and neat grinding are performed using a mill or mortar with or without a small amount of solvent, respectively. Some chemical mixtures such as piracetam and citric acid form cocrystals by neat grinding the solids.96) Solvent addition enables a much faster cocrystal formation than neat grinding while controlling crystal form and particle size.97) These solvent effects result from the API and coformer dissolution on the solid surface. The speed of cocrystal formation increases with the grinding force.98) However, grinding often encounters difficulties during scale-up because of its sensitivity to raw material quality and various process parameters. Related technologies such as solvent-added high-shear grinding99) and polymer-assisted grinding40) have also been explored.
Hot-melt extrusion is recognized as a scalable mechanochemical method for producing cocrystals.100) Several modified procedures, such as the addition of matrix polymers (e.g., polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol-graft-copolymer),101,102) have been reported. Applying process analytical technologies, such as Raman and near-IR spectroscopies, that enables in situ monitoring of product changes provides valuable information for controlling the mechanical manufacturing methods.103) Recent improvements in screw assembly design and operating temperature control enhance cocrystal purity during hot-melt extrusion, reducing component degradation caused by heat and shear force.102)
4) Other MethodsPharmaceutical cocrystals are also produced by microwave heating, melt mixture cooling, the use of supercritical fluid, and ultrasound.104) The choice of manufacturing methods depends on various factors, such as process reproducibility, as well as the purity and physical states of the resulting solids. Some methods are only applicable to cocrystals comprising chemically stable and low-melting-point materials. A process that satisfies the target product profile is expected to generate a constant production of formulations.
7.2 Quality Control of Pharmaceutical CocrystalsPharmaceutical cocrystals are produced by unit operations that usually apply to the manufacturing of APIs and their formulations. The crystallization process from solutions is expected to provide high-quality solids, enabling extensive characterization of the cocrystals, as described in the EMA guidelines. On the contrary, cocrystals prepared by typical formulation processes, such as grinding and spray-drying, may exhibit small size, lower purity, and excipient inclusion, which hinder their isolation and full characterization. A clear control strategy that fits product characteristics and manufacturing is important for the development of pharmaceutical cocrystals. Fitting this strategy with good manufacturing practices may assure a continuous production of pharmaceutical cocrystals and formulations that satisfy target quality profiles. Control strategies may also depend on whether they are used for a particular formation or distributed as raw materials for multiple generic formulations. Regulations defining cocrystals as APIs and provision of active substance master files may assist their distribution for formulation manufacturing. A clear definition of some terms related to the quality of pharmaceutical cocrystals should assist their applications.
Rules regarding pharmaceutical cocrystals affect the development of innovator and generic formulations in different ways. The QbD approach of formulation design and rigorous assessment of the resulting formulations should provide sufficient information to adapt various regional regulation rules in the development of cocrystals containing new active molecules. Schulthesis et al. proposed a priority of various factors (melting point, solubility, stability, scalability) in a choosing appropriate pharmaceutical cocrystal in a typical development process.49) They recommended early physical characterization during product development. Another prospective approach by innovative companies is the application of cocrystals to the lifecycle management of their registered API to improve the products and to add new administration routes.
The application of cocrystal technologies to off-patent APIs in generic pharmaceutical formulations has attracted increasing attention.105,106) Cocrystals may serve as alternatives to other formulation technologies used in reference innovator products to achieve clinical performance, such as dissolution assistance, potentially avoiding infringement of intellectual property rights. An appropriate characterization of physical properties and performance is needed to ensure the therapeutic equivalence and mitigate the potential risks of pharmaceutical cocrystals in generic formulations. Understanding the regional differences in regulations regarding cocrystals and generic products should enable rational developments.
Technical bases and issues regarding the appropriate use of pharmaceutical cocrystals were introduced and discussed with a focus on physical characterization and quality management. Pharmaceutical cocrystals provide versatile applications in the development of new chemical entities and improvement of products containing already registered APIs. A better understanding of complex physical properties and in vivo performance is expected to aid the rational design of pharmaceutical cocrystals and their formulations. Studies on cocrystals should clarify the practical relevance of potential risk factors listed in this review. Product quality should be managed in flexible ways, depending on characteristics and manufacturing.
This study was partly supported by the Japan Agency for Medical Research and Development and the Pharmaceutical and Medical Device Regulatory Science Society of Japan. We thank members of Focus group on Pharmaceutical Profiling of the Academy of Pharmaceutical Science and Technology (Japan) for valuable discussions.
The authors declare no conflict of interest.
