These patterns cause the crystals to show many sorts of unique shapes which for thousands of years have drawn our attention for their colors and outer beauty. With the crystallographic tools developed during the 20th century, we can find out the inner structure of matter, living or inanimate, from which crystals are formed. To know the inner structure of matter means to determine the positions of all atoms and how they are linked together, in many cases forming atomic clusters known as molecules.
The atomic structure of matter generates knowledge that is used by chemists, physicists, biologists, and other scientists. This allows us not only to understand the properties of matter, but also to modify them for our benefit. The two figures on the left show the molecular structure of penicillin, in the form of a diagram and its corresponding three-dimensional real shape. Only after the molecular structure of penicillin was unambiguously determined in by Dorothy C. Hodgkin using crystallography, chemists could start the quick synthesis of this compound, thus saving millions of lives.
The first big step forward: A new light to "look" inside crystals? The discovery of X-rays in To understand how Crystallography became an important branch of science, you should continue reading He showed that X-rays are electromagnetic waves with a wavelength of about 10 meters and that the internal structure of crystals is regular, as if they had tiny slits of that order of magnitude, formed by the distances between atoms.
Indeed, after lighting a crystal of copper sulfate with X-rays Laue found that a photographic plate showed black spots not only at its center as due to the fact that the incident beam passes directly through the crystal , but also in other places of the photographic plate, far away from the center.
This result was interpreted as a consequence of the phenomenon called diffraction , whereby the X-ray beams scattered by the atoms interfere with each other inside the crystals and deviate from the central beam. Representation of a wave. It did not take long until the Max von Laue's discovery was recognized as very important.
In fact, in the same year of Laue's experiment, William Henry Bragg and his son William Lawrence Bragg realized that if atoms inside crystals diffract X-rays and give rise to a diffraction pattern, this pattern should contain enough information to extract the relative positions of atoms in the crystal, that is to go backwards and retrace the path of diffraction.
These scientists interpreted the phenomenon of diffraction with a simple geometric law: atoms in crystals occupy virtual planes that behave as mirrors, but reflecting X-rays only for certain angular positions of incident X-rays Bragg's law. Father and son shared the Nobel Prize for Physics in for demonstrating the usefulness of the phenomenon discovered by von Laue in studying the internal structure of crystals.
The importance of Bragg's work cannot be overstated, for it heralded a revolution in the scientific understanding of crystals and their atomic arrangements. In biology, x-ray diffraction can be used to observe the complex structures of proteins, and has led to an in depth understanding of DNA and other biomolecules. From this, diseases and new ways to counteract them can be researched, improving the standard of healthcare in the world today. Large scale X-ray and neutron sources have furthered our understanding of the properties of materials by using crystallography to explore their structures.
By analysing this with state of the art neutron detectors researchers can obtain structures in minutes that would have taken months to achieve 20 years ago. Crystallography has advanced dramatically in recent decades and this huge leap forward in our ability to understand the fine detail of materials is playing a big role in finding new, cleaner energy solutions, and ways to combat the growing problem of environmental pollution and climate change.
Careers Media Office. While the biological action of the drug product depends on the activity of the API, its physicochemical properties determine how well the API is absorbed in the body to perform its action.
Therefore, it is important to understand the physical description of the API prior to development of a dosage form. As discussed in the previous section, a given API can form a wide variety of solid forms and each has its own physicochemical properties, which could impact the formulation development. Thus, the complex nature of formulation development and manufacturing operations demands a closer look at how the properties of a given drug vary from one solid form to the other.
Pharmaceutical salts are by far the most commonly used solid forms for development of drug formulations. For example, salts are known to improve solubility, dissolution rate, melting point, photostability, processability, better taste, etc.
A large number of monographs and books highlight the importance of salt formation in drug development. Despite widespread application of salt formation in drug development, the technique is limited to only APIs that are ionizable under normal pH conditions. Many drug products and drug substances in the developmental stages contain APIs that fall into this category. Therefore, alternative technique such as pharmaceutical cocrystallization is important for probing solid-form diversity of APIs.
Cocrystallization scores additional advantages over salt formation as it can be applied even to non-ionizable APIs. GRAS chemicals are food additives considered safe for human consumption 35 and their list constitutes a wide range of chemicals like aldehydes, alcohols, carboxylic acids, amides, and sweeteners.
Therefore, the diversity of GRAS chemicals in terms of their structure and physicochemical properties provides an additional means of selecting a suitable coformer for a target change in the API.
Physicochemical properties of an API differ from one solid form to the other which is often a consequence of the way the API molecules are arranged in the crystal lattice of that solid form. Hence, selection of a solid form has profound implications in clinical, legal, and regulatory perspective. Poor solubility is the characteristic nature of the drugs that fall into these classes. Drug formulators often rely on techniques such as micronization, solid dispersion, encapsulation, salt formation, amorphous forms, etc.
However, these techniques have inherent drawbacks in manufacturing and additional risk of stability of resulting formulations. In addition, many solid-state problems such as physical stability, hygroscopicity, melting point, and dissolution rate could be modified by selecting an appropriate coformer.
Cocrystals that show improved physicochemical properties satisfy the three criteria required for issuing a patent: 1 novelty, every cocrystal is novel as it is not possible to predict whether a combination of an API and coformer forms a cocrystal, 2 non-obviousness, the physicochemical and pharmacokinetic properties of APIs are difficult to predict unless detailed experiments were conducted, 3 utility, the main motivation in the development of cocrystals is due to their ability to improve the performance of the parent drug.
Trask puts forth the patentability aspects of pharmaceutical cocrystals. The potential applications of cocrystals in the development of drug formulations has been recognized by several pharmaceutical companies and many have even recognized the need for their screening as part of solid-form screening for identifying an optimal solid form for development. The importance of pharmaceutical cocrystals has been recognized recently by the US Food and Drug Administration FDA, 37 and European Medicines Agency EMA, , 38 which released draft guidelines on the subject of regulatory classification of pharmaceutical cocrystals.
While FDA classified pharmaceutical cocrystals as drug product intermediates and the coformers used to make the cocrystals are defined as excipients, EMA defined them as being solid-state variants of the APIs, aligning them with salts, polymorphs, hydrates, or solvates.
The views of the regulatory bodies, in particular FDA, are contrary to what the current understanding of the concept of pharmaceutical cocrystals is that the second component in a cocrystal is a pharmaceutically acceptable coformer.
In addition, by classifying them as drug product intermediates, cocrystals have to comply with additional current good-manufacturing practice requirements cGMPs. Therefore, to address the industry concerns and also to ease the regulatory burden, the FDA has most recently reclassified them August as a special class of solvates in which the second component is non-volatile. Cocrystals are defined as multi-component crystals composed of two or more solid components in stoichiometric ratio.
Therefore, knowledge of intermolecular interactions between the molecular components is a prerequisite for a successful cocrystal design. In this regard, G. Recurring intermolecular interactions in a crystal structure are termed supramolecular synthons and are further classified into two basic types. One that involves the same functional groups is called supramolecular homosynthon and the one that involves different but complementary functional groups is called supramolecular heterosynthon.
As the cocrystals are formed due to intermolecular interactions between two or more different molecules, the supramolecular heterosynthons of the type that involve functional groups of different molecules play an important role in the design of cocrystals. Crystal engineering was defined by G. The knowledge obtained from the analysis of the crystal structures deposited in the Cambridge Structural Database CSD is used in the selection of coformers for cocrystal formation.
A successful cocrystal design demands supramolecular synthons that are observed most frequently between the functional groups present on the components of cocrystals.
Hence, the design of cocrystals for a given molecule starts with analyzing the functional groups available on that molecule and finding complementary functional groups which would likely form predictable supramolecular synthons. Thus, the coformer selection in a cocrystal design strategy reinforces a greater role of the knowledge of intermolecular interactions which is often drawn from X-ray crystal structure analysis.
Cocrystallization is the result of molecular recognition between two or more different molecules through energetically favorable intermolecular interactions. The strength of intermolecular interactions and the way that the constituents of the cocrystal arranged in the crystal lattice determine its physicochemical properties. Hence, it is important that a detailed structural analysis is a prerequisite for understanding the physicochemical properties, which not only results in structure—property correlation, but also aids in subsequent design of cocrystals for fine-tuning the API properties.
Over the past century, single-crystal X-ray diffraction has proven to be an important tool for unambiguous determination of crystal structures, and thus, assisted in ground-breaking analysis of material properties.
With respect to cocrystals, structural characterization a establishes the reliability of cocrystal design strategy, b reveals hydrogen-bond preferences of the functional groups, and c provides insights into structure—property correlation. The existing vast literature on cocrystals provides a breadth of knowledge on their diverse applications. These primarily deal with improvement in solubility, dissolution rate, stability, color, melting point, mechanical strength, etc.
Solubility is an important parameter in determining the bioavailability of a drug. Pharmaceutical cocrystals have proven to be valuable for addressing solubility and dissolution rate issues of several BCS Class II and IV drug substances, for which low solubility is a serious concern in development of drug formulations.
While a large number of cocrystals have been reported that showed improved solubility of API, attempts to reduce the solubility of an API through cocrystallization are seldom reported. One such study that has demonstrated the application of cocrystallization technique in controlling the solubility of an API was reported by A.
Nangia and coworkers using an antibiotic, sulfacetamide SACT. Such a limitation necessitates frequent dosing, which is often inconvenient to patients and amounts to excess drug loading. The authors have hypothesized that if the weaker hydrogen-bonding synthons in the crystal structure of SACT are replaced with stronger hydrogen bonds by way of cocrystallization, then the resulting stable cocrystal may be useful to lower the solubility of the parent drug.
By employing a crystal engineering strategy, the authors have prepared a series of cocrystals and analyzed crystal structures and evaluated the physicochemical properties. Interestingly, the cocrystals showed low solubility and dissolution rate compared to the parent API.
The heteromeric interactions afford the cocrystal better packing efficiency and stronger crystal lattice, which showed lower solubility and dissolution rate of SACT. It has also been found that the cocrystal is stable under slurry and accelerated test conditions—a consequence of the stronger crystal lattice of the cocrystal. Permeability across barrier tissue, for instance, gastrointestinal mucosa, determines absorption and distribution of drugs.
To improve permeability, lipophilic and non-ionizable drugs are preferred, but such drugs can cause poor solubility and thus result in low oral absorption.
Permeability along with solubility may provide an insightful understanding of bioavailability. The amount of drug transported at the membrane is a function of the concentration gradient. Hence, high-soluble drugs may be absorbed well. The diffusion behavior is also dependent on the particle size. The in vitro diffusion measurements are commonly performed using parallel artificial membrane permeability assay and Caco-2 cells. Cocrystallization of APIs for improving aqueous solubility has been a well-established technique; however, studies on improving drug permeability through cocrystallization have been reported only recently.
The solubility and permeability product best represents the impact of cocrystallization on pharmacokinetic properties of HCT. The observed improvement in solubility and permeability of the cocrystals is due to the disruption of sulfonamide—sulfonamide homosynthon in API by the coformer molecules.
The authors proposed that the higher concentration of cocrystals in solution leads to amorphous cocrystal formation in solution with moderate or weak hydrogen bonds, which could generate high concentration gradient at the membrane site. Thus, the resulting high transient concentrations overcome lipophilicity and particle size effects and provide improved permeation. Results of permeability studies on HCT and its cocrystals, a cumulative amounts of cocrystals diffused vs time.
Metaxalone MTX is a muscle relaxant used to relieve discomfort associated with acute and painful musculoskeletal conditions. Its effects have been reasoned to depression of central nervous system.
It has also been reported that the oral bioavailability of MTX is greatly influenced by food, which impacts dosing needs of a patient. The previous attempts to make a sufficiently bioavailable form of MTX have not been successful.
MTX exists in two polymorphic forms. Oxazolidone group of the MTX was exploited to form a series of cocrystals with dicarboxylic acids such as, succinic acid, fumaric acid, maleic acid, adipic acid, and salicylic acid.
The presence of coformer in the crystal lattice resulted in a significant change in the bioavailability of the MTX. Pharmacokinetic PK studies in beagle dogs using cocrystals with succinic and fumaric acids revealed higher plasma concentration and the area under the curve AUC for cocrystals than the MTX.
Hydrogen bonding in MTX polymorphs and its cocrystals. Notice that the imide—imide dimer synthon is retained in all the crystal structures of the cocrystals. The exposure of photons on pharmaceutical materials can have destructive effects impacting quality and efficacy of drug products.
As per International Conference on Harmonisation ICH guidelines, photostability testing is an integral part of pharmaceutical development process. The drug products undergo a variety of complex photochemical reactions depending upon the chemical and physical structure of the materials, such that the labile functionalities, such as conjugated double bonds or aromatic residues containing N, S, or O, are prone to photochemical degradation.
Applications of cocrystals in modulating photochemical reactivity of pharmaceuticals have been paid less attention until recently. For example, V. Vangala and coworkers demonstrated for the first time that the improvement in photostability of an antibiotic drug, nitrofurantoin NF , can be achieved via cocrystallization. By following a crystal engineering strategy, the authors have made a series of cocrystals and studied their photostability. As shown in Fig. The greater photostability of the cocrystals was rationalized on the basis of crystal structures.
Materials undergo deformation on applying stress; this includes elasticity, plasticity, viscoelasticity, brittle fracture, fragmentation, or a combination of these based on the nature of applied stress and internal structure of the material. A proper understanding of these mechanical properties and material deformation phenomena is important for powder compaction and secondary processes such as milling.
The previous studies on single-component systems are aimed at correlating compaction properties and plasticity of materials. The presence of slip planes and crystallographic planes with weakest interactions or adjacent planes with higher d-spacing in the crystal structure affords greater plasticity and better tabletability.
Studies concerning mechanical properties of cocrystals have been conducted only recently. For example, W.
Jones and coworkers have found that the cocrystals of paracetamol PRA showed better tabletability than the marketed polymorph. Velaga et al. A closer look into the crystal structures of the cocrystals and Form I revealed that the crystal structure of Form I has no slip plane and consisted primarily of interlocked PRA molecules held strongly by hydrogen bonds.
The rigid hydrogen-bonded network affords poor tableting properties that resulted in brittleness to the compressed tablets. On the other hand, the cocrystal with oxalic acid features catemeric arrangement of oxalic acid and PRA molecules that generate layers parallel to and planes.
The perfect layered structure of the cocrystal explains the greater plastic deformation and better tabletability. These studies underscore the role of crystal packing and the strength of intermolecular bonding in determining tablet formation and its mechanical strength. Notice that the perfect layered structure of the cocrystal affords improved tabletability. Reprinted with permission from reference Marketability of a solid form depends on several factors and its promising physicochemical properties are undoubtedly the prime consideration.
As detailed in Sects.
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