**Preface to "Pharmaceutical Crystals (Volume II)"**

We are delighted to deliver the second reprint of the series of "Pharmaceutical Crystals (Volume II)", a Special Issue of *Crystals*.

The crystalline state is the most used and essential form of solid active pharmaceutical ingredients (APIs) in manufacturing, processing, storing, and administering. The center of the characterization of pharmaceutical crystals is crystal structure analysis, which reveals the molecular structure and the alignment of the molecules of important pharmaceutical compounds. This structural information is the key to understanding intermolecular interactions, and a wide range of physicochemical and biological properties of the APIs (e.g., solubility, stability, tablet ability, color, hygroscopicity, etc.).

The second reprint of the Special Issue series on "Pharmaceutical Crystals" aimed to publish novel molecular and crystal structures of pharmaceutical compounds, especially new crystal structures of APIs, including polymorphs and solvate crystals, and multi-component crystals of APIs, such as co-crystals and salts.

Thus, this Special Issue demonstrates the importance of crystal structure information in many sectors of pharmaceutical science. Ten articles present the latest research findings, including in areas of morphology, spectroscopic, theoretical calculation, and thermal analysis with the crystallographic study. This wide variety of studies is the essence of this Special Issue, presenting current trends in the structure-property study of pharmaceutical crystals.

This Special Issue focuses on physicochemical properties and crystal structure, correlating various physical properties to crystal structure.

Multi-component crystals (MCCs), a generic term for crystals, such as co-crystals, salt crystals, and hydrates, have been the focus of recent research on pharmaceutical crystals. Half of the articles in this Special Issue deal with MCCs. MCCs are essential for improving other crystals' properties with challenging physical properties since they can contain the same drug substance but have different physicochemical properties due to their unique crystal structure.

Tamboli et al. [1, 2] newly synthesized 1:1 salt crystals (MCC) of the anti-arrhythmic drug, Disopyramide, with phthalates and studied their crystal structures in detail. Strong charge-assisted hydrogen bonding interactions are observed between ionized molecules in the crystal. The conformations of the API molecules in the "mother crystal" and in the MCC are different. The differences in physicochemical properties between these two crystals were further characterized by differential calorimetric analysis, thermal gravimetric analysis, powder X-ray diffraction and infrared spectroscopy. It is important to analyze and evaluate crystals using various methods, along with crystal structure analysis.

Research to improve the solubility of drug crystals by MCC formation is one of the most exciting topics because crystals with low solubility result in low bioavailability of the API. For example, Enrofloxacin is an antibacterial drug of fluoroquinolones, and its low solubility is a problem. Pang et al. [3] synthesized three new organic salt crystals of Enrofloxacin (with tartaric acid, nicotinic acid, and suberinic acid). They performed crystal structure analysis to compare the structures and study the molecular interactions' characteristics. Solubility measurements revealed that these new salt crystals exhibit excellent water solubility. Combined crystal characterization (field emission scanning electron microscopy, powder X-ray diffraction, Fourier transform infrared spectroscopy, and differential scanning calorimetry) was also performed in this research, and new data were reported.

A wide variety of intermolecular interactions are observed in MCC, and, in recent years,

halogen bonding has been attracting attention in addition to traditional hydrogen bonding, which is understood as an electrostatic attraction interaction between a positive region on a halogen atom and a negative part on another molecule, which has strength and directionality similar to hydrogen bonds. Kryukova et al. [4] targeted anastrozole, a well-known aromatase inhibitor, and successfully made MCCs by halogen bonding. This research used advanced analysis using quantum chemical calculations and QTAIM analysis to study the intermolecular interactions quantitatively.

Hydrate crystals are important MCCs. By studying the relative positions and interactions between API molecules and water molecules in crystals and comparing them to the structure of anhydrous crystals, we can gain insight into the stability of hydrate crystals. In addition, by making hydrate crystals with various hydration numbers and examining the conditions of dehydration, one can establish a landscape encompassing various crystals of the API molecule and gain insight into the stability of the crystals. Stefan et al. [5] synthesized chemical derivatives of the thyreostatic ˇ drug methimazole and successfully made tetrahydrate, dihydrate, and anhydrous crystals, which were analyzed for crystal structures. These crystal structures are being evaluated with spectroscopy, microscopy, and thermal analysis.

The sodium salts of pharmaceutical molecules often form hydrate crystals. Hydrate crystals are considered potentially unstable because they dehydrate depending on environmental conditions such as temperature and humidity. To utilize sodium salt hydrates as pharmaceuticals, it is important to clarify the changes in crystal structure by dehydration/hydration via crystallographic analysis. Oyama et al. [6] studied the structural change of diclofenac sodium salt 4.75 hydrate, a non-steroidal anti-inflammatory drug, to 3.5 hydrates and then to anhydrate crystals upon dehydration. They elucidated the complex mechanism of dehydration and hydration involving the coordination of water to sodium ions.

Determination of the three-dimensional structure of molecules is important in docking research of drug molecules for developing novel anticancer drugs. Shin et al. [7] synthesized an isoflavone compound and revealed its crystal structure by single crystal X-ray structure analysis. Interestingly, they found two independent molecules in the crystal, each with its disorder, and compared their molecular structures. Information on crystal structures leads to research on intermolecular interactions and then to intermolecular docking studies. This study suggests that this isoflavone compound has the potential to bind to the active site of IKKβ, which may be explored as an anticancer drug targeting IKKβ inhibition.

On the other hand, crystallographic analysis of protein complexes in which disease-related protein molecules and API molecules are docked has been performed. Would the structure of the API molecule change with or without docking? For example, Venetoclax is an API molecule used as a selective inhibitor of B-cell lymphoma-2 that can be administered orally. Until now, only the molecule's structure docked with a protein molecule was known, but Perdih et al. [8] reported the first crystal structure of API alone. By comparing the conformations of two independent molecules with the molecular structure of the bound state, they revealed that the supramolecular structure is achieved through various intermolecular interactions.

The elucidation of molecular and crystal structures is also important for developing new pharmaceuticals. Crystal structure analysis is an essential tool to confirm the chemical synthesis of compounds, and it can also provide information on intermolecular interactions in solids, such as hydrogen bonding. Furthermore, the three-dimensional structure of a compound can be used for research on the expression of its activity as a drug. Xiong et al. [9] designed and synthesized two fenclorim derivatives and revealed their molecular structures by crystallographic analysis. These compounds showed superior in vitro activity compared to known pharmaceuticals, suggesting their potential as new pyrimidine fungicides.

As a parallel topic to the detailed discussion on crystal structures, we present an important, review of crystals in the last article.

Nanocrystalline materials (NCMs) are crystalline materials composed of nanoparticles with dimensions less than 1000 nm. Their application in drug crystals and co-crystals is an example of NCMs with attractive physicochemical properties. They have attracted significant attention as an important material class with great potential in drug delivery. This review article by Witika et al.[10] summarizes recent advances in therapeutic options using drug NCMs. It also provides a detailed description of the basic characterization methods of drug NCMs and their applications, as well as their impact on the performance of NCMs after formulation.

In conclusion, this Special Issue presents a wide range of recent studies about pharmaceutical crystals and provides valuable information for future studies in the related field. The guest editors hope the readers enjoy this fruitful Special Issue of "Pharmaceutical Crystals (Volume II)".
