1. INTRODUCTION:

Crystallization is a chemical process applied to separate solids from liquids involving the mass transfer of a solute from a liquid solution to a pure solid. The process of crystallization, which can occur naturally or artificially, results in a solid form with highly ordered atoms or molecules called crystals¹. There are two primary phases of crystallization. Nucleation is the first step in the process of generating crystals from a supercooled liquid or a highly saturated solvent.

The second phase, known as crystal growth, leads to particles of greater size and a crystalline state. It is important to remember that during this phase, loose particles adhere to exposed flaws like pores and fissures and form layers on the crystal's surface². Crystallization is one of the most important purification and separation steps in the generation of APIs, and it may drastically impact a product's quality in both direct and indirect ways. A number of variables including size, shape, humidity, time, melting point, and so forth, influence the crystallization process. To comprehend the fundamentals of crystallization, including theory, equipment, factors influencing crystallization, and the significance of crystallization, this literary analysis of the process has been taken into account.

X-ray diffraction analysis is required to examine the atomic arrangement, crystal size, flaws, and structure of crystalline materials³. X-ray crystallography is a technique used to find out the molecular and atomic structure of a crystal⁴. X-ray diffraction (XRD) and X-ray crystallography are essential in drug development, providing critical insights into the molecular structure and properties of pharmaceutical compounds. XRD characterizes crystalline structures and polymorphs, aiding in form selection, while X-ray crystallography visualizes atomic arrangements, crucial for understanding drug-target interactions. Together, they inform drug design, formulation, and quality control, advancing the discovery and optimization of new drugs⁵. Both the techniques X-ray crystallography and XRD both are essential to the effectiveness and safety of products. They play multifaceted roles in understanding the molecular characteristics of drug compounds, ensuring their quality, and optimizing their efficacy⁶.

2. Crystallization: Role in Pharmaceutical Manufacturing and Industrial Research:

In the chemical industry, one of the most extensively utilized technologies is crystallization, and process stability governs economics and productivity. Crystallization is of great benefit in the food and pharmaceutical industries for improved solid form selection, separation, and purification. Crystallization is the most popular means of generating pharmaceutical solids needed for generating Active Pharmaceutical Ingredients (API). Since the physical form of a pharmaceutical product influences its quality and efficacy, it is critical to improve the particulate characteristics, such as shape distribution and size⁷. A lot of pharmaceutical dosage forms have unfavorable physiochemical characteristics, such as a limited solubility in human body fluids. To facilitate in the synthesis of active pharmaceutical ingredients, a great deal of research and development has gone into developing a solid form ecosystem that includes all feasible solid structures, such as polymorphs, solvates, co-crystals, salts, and the amorphous phase. (APIs)⁸. Developing crystallization techniques requires continual control over a number of product traits such as molecular level solid structure, crystal size and shape, and purity. Typically, controlled cooling crystallization processes are the only method used by crystallization chemists to achieve high purity and high yield targets. This is difficult yet necessary for process control⁹.

3. Characteristics of Crystals:

The word “Crystal” comes from the Greek word Kristal’s, which means both “rock crystal” and “ice”. The study of crystals is named Crystallography.

3.1. Crystal Forms¹⁰

Table 1. Various Crystal Forms

Crystals	Axial relationship	Angles	Examples
Cubic	a = b = c	Α = β = γ = 90⁰	NaCl
Tetragonal	a = b ≠ c	Α = β = γ = 90⁰	TiO₂
Orthorhombic	a ≠ b ≠ c	Α = β = γ = 90⁰	MgSO_4.7H₂O
Hexagonal	a = b ≠ c	Α = β = 90⁰ γ = 120⁰	SiO₂
Trigonal	a =b= c	Α = β = γ ≠ 90⁰	CaCO₃
Monoclinic	a ≠ b ≠ c	Α = γ = 90⁰ ≠ β	CaSO₄. 2H₂O
Triclinic	a ≠ b ≠ c	Α ≠ β ≠ γ ≠ 90⁰	K₂Cr₂O₇

3.2. Crystal Habits¹¹

The structure and form of a crystal are referred to as its "crystal habit," and they are mostly influenced by the rates at which crystals develop in various directions as well as by outside variables including the solvent utilized, contaminants, and the physical circumstances surrounding the crystallization process. Different crystal habits describe a crystal's overall appearance.

· Tabular Not as long as bladed, but book-like (tablets) with a thickness greater than platy. Tabular crystals formed by wolfenite are a good example of crystal structure.

· Bladed Like a grass blade, bladed crystals are longer as well as flat, thinner than tabular and more elongated than platy. Bladed crystals can be seen in the crystals formed by kyanite.

· Stalactitic A long, gently tapering, spherical mass generated in some cases by a concretionary growth encircling a hollow tube. Circular rings, resembling tree rings, are typically seen in cross-sections. It typically happens when a mineral precipitates from an evaporating fluid in caves or other rock voids. Aggregates of malachite and rhodochrosite are interesting examples of this type.

· Lamellar Bulk layers akin to paper sheets. Aggregates made of muscovite are an excellent illustration of this morphology.

· Prismatic Among the most popular crystal habits, Long, "pencil-like" crystals that are thicker than needles are called prismatic crystals. Elbaite crystals in the form of indicolite are excellent examples of prismatic crystals.

· Dendritic A crystal growth that branches out and usually forms a surface or inclusion that resembles plants and resembles arborescent crystals, but is less tree-like. Examples of such shapes include "Jack Frost" on windows and plant-like patterns. An excellent illustration of this shape is the aggregate that Sal ammoniac forms.

· Acicular Long and needle-shaped, thicker than fibrous yet thinner than prismatic. An excellent example of an acicular crystal would be a natrolite crystal¹².

3.3. Chemical Bonds in Crystals:

Crystals can be categorized based on the kinds of chemical bonds that exist between their atoms or ions¹³.

· Covalent Crystals: Covalent bonds hold the atoms in covalent crystals together. Both covalent substances, like zinc sulphide, and pure nonmetals, like diamond, are capable of prod6cing covalent crystals.

· Ionic Crystals: Ionic bonds are created between atoms with varying electronegativity capacities by electrostatic forces. A halite or salt crystal is a typical illustration of an ionic crystal.

· Metallic Crystals: Metals frequently crystallize into metallic states, in which valence electrons are allowed to travel freely throughout the lattice. Many kinds of metallic crystals can arise from a single metal. For example, iron can crystallize into a variety of metallic forms, such as a face-cantered cubic and a body-cantered cubic. E.g.: Iron crystal

· Molecular Crystals: In an ordered fashion, whole molecules are bound to one another. A sugar cube, which is made up of sucrose molecules, is an excellent example.

4. Mechanism of Crystallization:

The formation of crystal from solution involves three steps i.e., Supersaturation, Nucleation, Crystal growth.

4.1. Supersaturation:

Supersaturation is the difference between the solute concentration in a solution (where crystals are forming) and the solute concentration that is in equilibrium with the solution¹⁴. A coefficient is used to express the supersaturation and is provided as,

S = (Parts solute/100 Parts solvent) at equilibrium > 1.0/ (Parts solute/100 Parts solvent) at the current situation.

A non-supersaturated solution cannot support crystal nucleation and growth. For crystallization to take place, one of the following methods of producing supersaturation must be used.

a) By using indirect heat exchange, cool down a hot concentrated fluid.

b) By evaporating a solution or a portion of the solvent.

c) By adiabatically evaporating and cooling: This involves flashing a feed solution to a lower temperature and sequentially cooling and evaporating the solvent to induce/cause crystallization.

d) By incorporating an unfamiliar component that lessens the initial solute's solubility, such as salting¹⁵.

4.2. Nucleation:

Nucleation is the birth of very small bodies of a new phase in a supersaturated liquid phase. Among the atoms, the first to crystallize forms the nucleation center, around which other atoms are generated. Since it determines the general structure of the crystal, nucleation is the most crucial stage in the crystallization process¹⁶. The process of one phase forming inside another when there is a free energy barrier is called nucleation¹⁷. Nucleation is a random process that happens at a different time in two systems with the same conditions. Generally speaking, the nature and behaviour of the new thermodynamics known as classical nucleation theory, or CNT are included in the introduction when explaining this phenomenon¹⁸. In a supersaturated solution, new crystals can form either through primary nucleation when crystalline solids of the same substance are absent—or secondary nucleation—when crystalline solids of the same substance are present¹⁹. There are two types of nucleation

4.2.1. Primary Nucleation: It is occurred in the absence of crystalline material of its own kind and is a stochastic process. It again classified as homogenous and heterogenous nucleation²⁰. Primary nucleation has been given with the following power-law expression.

B = dN/dt = kn (c−c∗) n Eq. (1)

Equation (1) demonstrates that the rate constant, the solute concentration at the instantaneous concentration, the concentration during the saturation phase, and the empirical exponent which often falls between three and four are all necessary for nucleation. In general, the kinetics of nucleation for the crystallization process and the metastable zone width (MSZW) data can be studied using primary nucleation theories. The gap of supersaturation between the super solubility curve and the solubility curve is known as MSZW²¹.

4.2.2. Secondary Nucleation:

It is believed that secondary nucleation is the primary source of nuclei for the majority of crystallization processes. Secondary nucleation can also lead to polymorphism, "whether contact secondary nuclei originate from semi-ordered solute clusters at the parent crystal interface or from parent crystals via micro-attrition²². Low supersaturation is the ideal growth rate for good quality, when nucleation occurs; lower energy is required when a crystal strike prevents an existing crystal from breaking to form a new one; lower kinetic order and rate-proportional to supersaturation allow for easy control without unstable operation; and the quantitative fundamental have been demonstrated and are being used in real-world applications²³. The following model, although somewhat simplified, is often used to model secondary nucleation.

B = dNdt = k1MjT(c−c∗) bB = dNdt = k1MTjc−c∗b E2 Eq. (2)

where k1 is a rate constant, MT is the suspension density, j is an empirical exponent that can range up to 1.5, and b is an empirical exponent that can range up to 5. One of the primary processes in the industrial crystallization process is secondary nucleation. The process and dynamics of the secondary nucleation of the crystallization of aluminium hydroxide are the main areas of interest for researchers. Furthermore, it has to do with how the surface nucleation mechanism promotes the growth of the crystal process. Other than that, secondary nucleation is referred as removal-limited and chemical reaction-controlled²⁴.

4.3. Crystal Growth:

It is diffusion process and surface phenomenon. From solution, solute molecule or ions reach the faces of a crystal by diffusion²⁵.

5. Miller Indices and X-Ray Techniques:

The orientation of a plane or group of parallel planes of atoms in a crystal is represented by the Miller indices, a set of three numbers²⁶. In the event when every atom in the crystal is represented by a point and these points are connected by lines, the Miller indices can be discovered by finding the intersection of the plane with a set of crystallographic axes.

X-ray crystallography is processing those entails shining an X-ray beam onto a crystal. The regularly spaced atomic planes within the crystal lattice are the diffracting surfaces for the X-rays. The distance between these planes, which is indicated by their Miller indices, determines the angles and intensities of the diffracted X-rays²⁷. Scientists can determine the Miller indices of the crystallographic planes causing the diffraction by examining the diffraction pattern. The configuration of atoms inside the crystal lattice is then ascertained using this information²⁸. X-ray Diffraction is the technique used to examine how atoms are arranged within crystals. The periodic arrangement of atoms in the crystal lattice causes X-rays to scatter when they strike a crystal in different directions. The scattered X-rays constructively interfere with one another, producing spots or peaks in the resulting diffraction pattern. The diffraction peaks' locations and intensities reveal details about the symmetry of the crystal lattice as well as the distances between crystallographic planes. These diffraction peaks are labelled with Miller indices, which enables scientists to pinpoint the crystallographic planes that gave rise to each peak²⁹. Miller indices provide an organized way of characterizing the orientation of crystallographic planes and directions within a crystal lattice, an essential tool in X-ray diffraction and X-ray crystallography. They are necessary for interpreting diffraction patterns and identifying the atomic composition of crystalline substances³⁰.

5.1. Applications of Miller indices:

· Miller indices are crucial in describing the orientation of crystal planes and directions within crystals.

· They are used in determining crystal symmetry, understanding crystal growth patterns, and analysing crystal structures using techniques like X-ray diffraction.

· Miller indices play a significant role in material science, mineralogy, and various fields of engineering where crystallographic information is essential.

· Understanding Miller indices is fundamental for crystallographers and materials scientists as they provide a standardized and concise notation for describing the complex three-dimensional structures of crystals³¹.

5.2. Applications of X-Ray Crystallography and X-Ray Diffraction in Pharmaceuticals:

X-ray diffraction through the application of X-ray beams to compound crystals provides detailed diffraction patterns that show the spatial arrangement of atoms, clarifying bond lengths, angles, and interactions that are essential for comprehending pharmacological processes. X-ray crystallography and X-ray diffraction are fundamental methods in drug development, provide unparalleled insights into the molecular structures of both target proteins and potential drug candidates. Scientists can see the three-dimensional configuration of atoms inside a crystal lattice by using X-ray crystallography, which gives important details on the size, shape, and orientation of molecules. Through the exact structural analysis of pharmacological targets, such as enzymes or receptors implicated in disease processes, scientists can develop more potent and targeted therapeutic medicines. These methods improve the process of finding new drugs by directing the logical design and optimization of pharmaceuticals, making it easier to find attractive lead compounds, and refining molecular interactions to maximize benefits and reduce drawbacks^32,33. X-ray crystallography and X-ray diffraction widely use in pharmaceutical applications for a multiple purpose:

5.2.1. Determination of Structure:

X-ray diffraction and X- ray crystallography Both methods are essential for identifying the exact three-dimensional configurations of biological entities. Drug compounds can be structurally determined in three dimensions using X-ray diffraction and crystallography methods³⁴. The exact atomic arrangement of the drug compound can be revealed by reconstructing the electron density map of the molecule by crystallizing it into a regular lattice and examining the scattering patterns that are created when X-rays contact with the crystal. The ability to directly visualize the molecular structure not only verifies the medicine's identification and purity but also sheds light on its structural flexibility, enabling researchers to record the molecule in a variety of conformations and tautomeric forms. Furthermore, X-ray crystallography is essential for researching how the medication molecule interacts with its target protein. Understanding the fundamental of drug-target interactions is aided by the ability to visualize the binding mechanism, which includes hydrogen bonding, van der Waals interactions, and hydrophobic contacts, when the drug-protein complex co-crystallizes. Moreover, by clarifying how structural alterations affect binding affinity and selectivity, X-ray crystallography directs lead optimization efforts and makes it easier to create compounds that are more powerful and selective. It also helps in the identification of binding sites on target proteins, including allosteric sites, which presents chances for the creation of innovative treatments. Finally, based on experimental data, X-ray crystallography is a vital validation tool for computer models used in drug discovery, enabling researchers to increase and refine prediction accuracy. All things considered, these methods are crucial to pharmaceutical research's comprehension of molecular interactions, optimization, and logical drug design^35,36.

5.2.2. Drug Formulation Characterization:

X-ray diffraction is a crucial technique for characterizing medication formulation which provides important information about the crystalline structure and polymorphic forms of the drugs. Through X-ray exposure of a sample and subsequent analysis of the diffraction pattern, scientists are able to determine the exact spatial arrangement of atoms in the formulation. This is especially important for the pharmaceutical industry, as several physicochemical qualities, such solubility, stability, and bioavailability, are greatly impacted by the crystallinity and polymorphism of active pharmaceutical ingredients (APIs) and excipients³⁷. X-ray diffraction (XRD) facilitates the identification and measurement of many polymorphic forms that are present in a formulation, providing uniformity from batch to batch and assisting in the creation of stable and effective pharmaceutical products³⁸. Furthermore, XRD makes it easier to identify amorphous areas, crystallite sizes, and crystallinity levels, all of which are vital details for formulation optimization and quality assurance. In addition, XRD can be used to investigate the physical stability of formulations under various storage circumstances, which can aid in the prediction and advertence of undesired phase transitions or degradation routes. All things considered, X-ray diffraction is a vital instrument for the characterization and quality control of medication formulations, helping to create safe and effective pharmaceuticals³⁹.

5.2.3. Identification of Drug Target:

X-ray crystallography is an important tool in structural biology offers precise structural details about proteins and other macromolecules. It makes it possible for scientists to ascertain the three-dimensional atomic structures of enzymes, proteins, and receptors that could be targets for pharmaceuticals⁴⁰. Through the process of crystallization and X-ray diffraction analysis, scientists are able to determine the exact configuration of atoms within these biomolecules. Determining the structure of proteins implicated in disease pathways or biological activities is a significant use of X-ray crystallography⁴¹. Analysts can find important structural elements, active sites, and binding pockets that could be targets for therapeutic intervention by deciphering the crystal structures of these proteins. Protein-ligand interactions can also be studied via X-ray crystallography by co-crystallizing the target protein with pharmacological or small molecule ligands⁴². By co-crystallizing the target protein with small molecule ligands or therapeutic candidates, X-ray crystallography can also be utilized to analyze protein-ligand interactions. This data is crucial for logical drug design and optimization, directing the creation of more effective and targeted medicinal substances⁴³.

5.2.4. Elucidation of Protein-Ligand Complex Structures:

An important technique in structural biology and drug development, X-ray crystallography offers a thorough understanding of the molecular interactions that tiny compounds have with target proteins. It makes it possible to use crystallization and X-ray diffraction analysis to determine the three-dimensional structure of protein-ligand complexes, which reveals the spatial arrangement of atoms within the crystal⁴⁴. With the use of this data, scientists are able to piece together the complex's electron density map and pinpoint with extreme precision the locations of the solvent molecules, protein, and ligand. Crucial details regarding the binding mechanism and interactions between the ligand and its target protein are also revealed by X-ray crystallography. In order to guide the creation and development of drug candidates with increased affinity and selectivity, researchers can identify critical residues in the protein binding site that interact with the ligand through hydrogen bonding, hydrophobic interactions, salt bridges, and other chemical forces⁴⁵. The study of ligand binding kinetics and thermodynamics is made possible by X-ray crystallography's ability to characterize the conformational changes that ligand binding induces in proteins. Quantitative structure-activity relationship (QSAR) research and the thoughtful design of ligands with ideal binding kinetics and pharmacological characteristics⁴⁶.

5.2.5. Crystal forms and polymorphs characterization:

In the pharmaceutical sector, X-ray diffraction (XRD) is an essential technique for identifying the crystal forms and polymorphs of medicinal ingredients and excipients. Drug development and formulation are greatly impacted by polymorphism, the capacity of a substance to exist in several crystalline forms with distinct molecular configurations in the crystal lattice⁴⁷. Researchers can measure the relative abundance of several polymorphic forms in a sample by using XRD to identify and differentiate them. For batch-to-batch consistency and to comprehend how polymorphism affects drug stability, solubility, dissolution rate, and bioavailability, this information is essential⁴⁸. Additionally, XRD improves in the characterization of amorphous regions in a sample, which can have an impact on the solubility, stability, and processing behaviour of drug formulations. Researchers can improve formulation tactics by identifying and quantifying amorphous content. In addition to identifying possible problems with formulation stability, XRD helps in the investigation of the physical stability of drug formulations under various storage circumstances. Researchers can evaluate the long-term stability of pharmaceutical items and create suitable packaging and storage plans to reduce deterioration and guarantee product efficacy and safety by keeping an eye on these changes⁴⁹. In the pharmaceutical sector, XRD is also essential for intellectual property rights and patent protection⁵⁰.

5.2.6. Stability studies of drug formulation:

X-ray diffraction (XRD) is an essential method used in stability studies in the pharmaceutical industry to evaluate the long-term physical stability of medication formulations. XRD provides insights into alterations that may impact medication qualities like solubility and bioavailability by allowing the detection and characterization of polymorphic transformations through periodic study of crystalline structures. Researchers can assess changes in medicinal components and excipients by using XRD to estimate crystallinity, which provides crucial information on formulation stability.[64] Furthermore, XRD is useful for detecting impurities or crystalline degradation products that might appear during storage, which helps evaluate formulation integrity and degradation pathways. Furthermore, XRD helps assess physical alterations like the distribution of particle sizes, which are essential to comprehending formulation behaviour. XRD data from stability investigations ultimately help determine shelf-life ^51-55.

6. CONFLICT OF INTEREST:

None.

7. REFERENCES:

1. Helmenstine, Anne Marie. Crystallization Definition. Thought Co, Aug. 29, 2020, thoughtco.com/definition-of-crystallize-605854.

2. Reviewed by BD editors, Crystallization, April 22, 2018.

3. Bunaciu AA, UdriŞTioiu EG, Aboul-Enein HY. X-ray diffraction: instrumentation and applications. Critical Reviews in Analytical Chemistry. 2015; Oct 2; 45(4): 289-99.

4. Smyth MS, Martin JH. x Ray crystallography. Molecular Pathology. 2000; Feb; 53(1): 8.

5. Blundell TL, Patel S. High-throughput X-ray crystallography for drug discovery. Current Opinion in Pharmacology. 2004; Oct 1; 4(5): 490-6.

6. Spiliopoulou M, Valmas A, Triandafillidis DP, Kosinas C, Fitch A, Karavassili F, Margiolaki I. Applications of X-ray powder diffraction in protein crystallography and drug screening. Crystals. 2020 Jan 21; 10(2): 54.

7. Schiele, S. A., Bier, R., Ommert, A., and Briesen, H. (2023). Direct Crystal Growth Control: Controlling Crystallization Processes by Tracking an Analogue Twin. Industrial and Engineering Chemistry Research. https://doi.org/10.1021/acs.iecr.2c04648

8. Guo M, Sun X, Chen J, Cai T. Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications. Acta Pharmaceutica Sinica B [Internet]. 2021; Aug 1; 11(8): 2537–64. Available from: https://doi.org/10.1016/j.apsb.2021.03.030

9. Kramer HJM, Van Rosmalen GM. CRYSTALLIZATION. In: Elsevier eBooks [Internet]. 2000. p. 64–84. Available from: https://doi.org/10.1016/b0-12-226770-2/00031-4

10. Cressey, G.; Mercer, I.F. (1999). Crystals. London. Natural History Museum.

11. Praveen Chaudhari, Pravin Uttekar, Nishant Waria, Amit Ajab. Study of Different Crystal Habits Formed by Recrystallization Process and Study Effect of Variables. Research J. Pharm. and Tech. 2008; 1(4): Oct.-Dec. 381-385. Available from:

12. Pevelen DDL. 8.4 Physical separations: Solid-State forms and habits of chiral substances. In: Elsevier eBooks. 2012. p. 54–62. Available from: https://doi.org/10.1016/b978-0-08-095167-6.00813-2

13. Okuno T. A review of: “Crystals and Crystal Structures, by Richard Tilley.” Molecular Crystals and Liquid Crystals. 2007; 469(1): 131–2. Available from: https://doi.org/10.1080/15421400701431661

14. Linnikov OD. Mechanism of precipitate formation during spontaneous crystallization from supersaturated aqueous solutions. Russian Chemical Reviews. 2014; 83(4): 343–64. Available from: https://doi.org/10.1070/rc2014v083n04abeh004399

15. Supersaturation crystallization, Methods of Supersaturation, https://www.chemicalslearning.com/2022/07/supersaturation-methods-of.html

16. David Williamson, Stages or Process of Crystallization. 2021

17. Vekilov PG. Nucleation. Crystal Growth and Design [Internet]. 2010; 10(12):5007–19. Available from: https://doi.org/10.1021/cg1011633

18. Wan Nur Athirah Mazli, Mohd Afnan Ahmad and Shafirah Samsuri, 2019 eISBN: 978-1-78801-358-1 DOI: 10.5772/intechopen.90164.

19. Barrett M, McNamara M, Hao H, Barrett P, Glennon B. Supersaturation tracking for the development, optimization and control of crystallization processes. Process Safety and Environmental Protection/ Transactions of the Institution of Chemical Engineers Part B, Process Safety and Environmental Protection/Chemical Engineering Research and Design/Chemical Engineering Research and Design. 2010; 88(8): 1108–19. Available from: https://doi.org/10.1016/j.cherd.2010.02.010

20. Wan Nur Athirah Mazli, Mohd Afnan Ahmad and Shafirah Samsuri, 2019 eISBN: 978-1-78801-358-1 DOI: 10.5772/intechopen.90164

21. Bian C, Chen H, Song X, Yu J. Metastable zone width and the primary nucleation kinetics for cooling crystallization of NaNO3 from NaCl-NaNO3-H2O system. Journal of Crystal Growth. 2019; 518:5-13

22. John McGinty, Nima Yazdanpanah, Chris Price, Joop H. ter Horst and Jan Sefcik, Chapter 1: Nucleation and Crystal Growth in Continuous Crystallization† , in The Handbook of Continuous Crystallization, 2020, pp. 1-50 DOI: 10.1039/9781788013581-00001

23. Fersht AR. Nucleation mechanisms in protein folding. Current Opinion in Structural Biology. 1997;7(1):3-9

24. Xue J et al. Secondary nucleation and growth kinetics of aluminum hydroxide crystallization from potassium aluminate solution. Journal of Crystal Growth. 2019; 507:232-240

25. Gavezzotti A. Organic crystal nucleation and growth: Little knowledge, much mystery. In: Theoretical and Computational Chemistry. 2021. p. 201–29. Available from: https://doi.org/10.1016/b978-0-12-823747-2.00004-4

26. Vigneron JP, Lousse V. Variation of a photonic crystal color with the Miller indices of the exposed surface. Proceedings of SPIE, the International Society for Optical Engineering/Proceedings of SPIE. 2006; Available from: https://doi.org/10.1117/12.646835

27. Wood EA. Vocabulary of surface crystallography. Journal of Applied Physics. 1964; 35(4): 1306–12. Available from: https://doi.org/10.1063/1.1713610

28. Schwarzenbach D. Note on Bravais–Miller indices. Journal of Applied Crystallography. 2003; 36(5): 1270–1. Available from: https://doi.org/10.1107/s0021889803014778

29. X-Ray diffraction: A practical approach. Choice/Choice Reviews. 1999; 36(06): 36-3382. Available from: https://doi.org/10.5860/choice.36-3382

30. Crystals and crystal structures. Materials Today [Internet]. 2006; 9(9):51. Available from: https://doi.org/10.1016/s1369-7021(06)71624-8

31. Sun S, Zhang X, Cui J, Liang S. Identification of the Miller indices of a crystallographic plane: a tutorial and a comprehensive review on fundamental theory, universal methods based on different case studies and matters needing attention. Nanoscale [Internet]. 2020 Jan 1;12(32):16657–77. Available from: https://doi.org/10.1039/d0nr03637d

32. Bunaciu AA, Udriştioiu EG, Aboul-Enein HY. X-Ray diffraction: instrumentation and applications. Critical Reviews in Analytical Chemistry. 2015; 45(4): 289–99. Available from: https://doi.org/10.1080/10408347.2014.949616

33. Smyth MS. x Ray crystallography. Molecular Pathology. 2000; 53(1):8–14. Available from: https://doi.org/10.1136/mp.53.1.8

34. Kermani AA, Aggarwal S, Ghanbarpour A. Advances in X-ray crystallography methods to study structural dynamics of macromolecules. In: Elsevier eBooks. 2023. p. 309–55. Available from: https://doi.org/10.1016/b978-0-323-99127-8.00020-9

35. Brunger AT, Adams PD, Clore GM, DeLano WL, Gros P, Grosse-Kunstleve RW, et al. Crystallography and NMR System: A New Software Suite for Macromolecular Structure Determination. Acta Crystallographica Section D, Biological Crystallography. 1998; 54(5):905–21. Available from: https://doi.org/10.1107/s0907444998003254

36. Neutze R, Wouts R, Van Der Spoel D, Weckert E, Hajdu J. Potential for biomolecular imaging with femtosecond X-ray pulses. Nature. 2000; 406(6797): 752–7. Available from: https://doi.org/10.1038/35021099

37. Rodríguez I, Gautam R, Tinoco AD. Using x-ray diffraction techniques for biomimetic drug development, formulation, and polymorphic characterization. Biomimetics. 2020; 6(1):1. Available from: https://doi.org/10.3390/biomimetics6010001

38. Bergese P, Colombo I, Gervasoni D, Depero LE. Assessment of the X-ray diffraction–absorption method for quantitative analysis of largely amorphous pharmaceutical composites. Journal of Applied Crystallography. 2003; 36(1): 74–9. Available from: https://doi.org/10.1107/s002188980201926x

39. Chernyshev VV. Structural Characterization of Pharmaceutical Cocrystals with the Use of Laboratory X-ray Powder Diffraction Patterns. Crystals [Internet]. 2023; Apr 9; 13(4): 640. Available from: https://doi.org/10.3390/cryst13040640

40. Carvalho AL, Trincão J, Romão MJ. X-Ray crystallography in drug discovery. In: Methods in Molecular Biology. 2009. p. 31–56. Available from: https://doi.org/10.1007/978-1-60761-244-5_3

41. Maveyraud L, Mourey L. Protein x-ray crystallography and drug discovery. Molecules/Molecules Online/ Molecules Annual. 2020; 25(5): 1030. Available from: https://doi.org/10.3390/molecules25051030

42. Mazzorana M, Shotton EJ, Hall DR. A comprehensive approach to X-ray crystallography for drug discovery at a synchrotron facility — The example of Diamond Light Source. Drug Discovery Today Technologies. 2020; 37:83–92. Available from: https://doi.org/10.1016/j.ddtec.2020.10.003

43. Panzade P, Wagh A, Harale P, Bhilwade S. Pharmaceutical cocrystals: a rising star in drug delivery applications. Journal of Drug Targeting. 2024; 32(2):115–27. Available from: https://doi.org/10.1080/1061186x.2023.2300690

44. Kumar R, Moche M, Winblad B, Pavlov PF. Combined x-ray crystallography and computational modeling approach to investigate the Hsp90 C-terminal peptide binding to FKBP51. Scientific Reports. 2017; 7(1). Available from: https://doi.org/10.1038/s41598-017-14731-z

45. Hough MA, Prischi F, Worrall J a. R. Perspective: Structure determination of protein-ligand complexes at room temperature using X-ray diffraction approaches. Frontiers in Molecular Biosciences. 2023; 10. Available from: https:// doi.org/ 10.3389 /fmolb.2023.1113762

46. Hansch C, Li R, Blaney JM, Langridge R. Comparison of the inhibition of Escherichia coli and Lactobacillus casei dihydrofolate reductase by 2,4-diamino-5-(substituted-benzyl)pyrimidines: quantitative structure-activity relationships, x-ray crystallography, and computer graphics in structure-activity analysis. Journal of Medicinal Chemistry [Internet]. 1982; 25(7):777–84. Available from: https://doi.org/10.1021/jm00349a003

47. Bunaciu AA, Udriştioiu EG, Aboul-Enein HY. X-Ray diffraction: instrumentation and applications. Critical Reviews in Analytical Chemistry. 2015; 45(4):289–99. Available from: https://doi.org/10.1080/10408347.2014.949616

48. Roberts SNC, Williams AC, Grimsey IM, Booth SW. Quantitative analysis of mannitol polymorphs. X-ray powder diffractometry—exploring preferred orientation effects. Journal of Pharmaceutical and Biomedical Analysis. 2002; 28(6):1149–59. Available from: https://doi.org/10.1016/s0731-7085(02)00053-5

49. Newman AW, Byrn SR. Solid-state analysis of the active pharmaceutical ingredient in drug products. Drug Discovery Today. 2003; 8(19): 898–905. Available from: https://doi.org/10.1016/s1359-6446(03)02832-0

50. Ahn H. Second generation patents in pharmaceutical innovation. 2014. Available from: https://doi.org/10.5771/9783845250861

51. Sarmah KK, Sarma P, Rao DR, Gupta P, Nath NK, Arhangelskis M, et al. Mechanochemical synthesis of olanzapine salts and their hydration stability study using powder x-ray diffraction. Crystal Growth and Design. 2018; 18(4): 2138–50. Available from: https://doi.org/10.1021/acs.cgd.7b01593

52. Yonemochi E, Hoshino T, Yoshihashi Y, Terada K. Evaluation of the physical stability and local crystallization of amorphous terfenadine using XRD–DSC and micro-TA. Thermochimica Acta. 2005; 432(1): 70–5. Available from: https://doi.org/10.1016 /j.tca.2005.02.023

53. Braham Dutt, Manjusha Choudhary, Vikas Budhwar. Enhancement of Stability profile of Aspirin through Cocrystallization Technique. Research Journal of Pharmacy and Technology. 2022; 15(2): 768-2. Available from: 10.52711/0974-360X.2022.00081

54. Madhuri Gaddam, Nagaraju Ravouru. A Crystal Engineering design to enhance the Solubility, Dissolution, Stability and Micromeritic properties of Omeprazole via Co-crystallization Techniques. Research J. Pharm. and Tech. 2021; 14(1): 356-362. Available from: 10.5958/0974-360X.2021.00001.9

55. Thimmasetty J, Shashank NN, Abdul Raheem T, Shwetha SKK, Tanmoy G. Modafinil Cocrystals for Altered Physicochemical Properties. Research Journal of Pharmacy and Technology. 2021; 14(9): 4891-6. Available from: 10.52711/0974-360X.2021.00850

Received on 27.06.2024 Revised on 16.10.2024

Accepted on 24.12.2024 Published on 10.04.2025

Available online from April 12, 2025

Research J. Pharmacy and Technology. 2025;18(4):1906-1912.

DOI: 10.52711/0974-360X.2025.00272

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.