Cocrystal Formation Research Articles

Separation of benzene and toluene associated with vapochromic behaviors by hybrid[4]arene-based co-crystals

The combination of macrocyclic chemistry with co-crystal engineering has promoted the development of materials with vapochromic behaviors in supramolecular science. Herein, we develop a macrocycle co-crystal based on hybrid[4]arene and 1,2,4,5-tetracyanobenzene that is able to construct vapochromic materials. After the capture of benzene and toluene vapors, activated hybrid[4]arene-based co-crystal forms new structures, accompanied by color changes from brown to yellow. However, when hybrid[4]arene-based co-crystal captures cyclohexane and pyridine, neither structures nor colors change. Interestingly, hybrid[4]arene-based co-crystal can separate benzene from a benzene/cyclohexane equal-volume mixture and allow toluene to be removed from a toluene/ pyridine equal-volume mixture with purities reaching 100%. In addition, the process of adsorptive separation can be visually monitored. The selectivity of benzene from a benzene/cyclohexane equal-volume mixture and toluene from a toluene/ pyridine equal-volume mixture is attributed to the different changes in the charge-transfer interaction between hybrid[4]arene and 1,2,4,5-tetracyanobenzene when hybrid[4]arene-based co-crystal captures different vapors. Moreover, hybrid[4]arene-based co-crystal can be reused without losing selectivity and performance. This work constructs a vapochromic material for hydrocarbon separation.

N-Alkylisoquinolinium bromides and α,ω-alkanediols: Eutectic systems with co-crystal formation

This research focuses on ionic liquids (ILs), specifically N-alkylisoquinolinium bromides with various chain lengths: octyl, decyl, dodecyl, and hexadecyl. The study covers the synthesis and thermophysical characterisation of these compounds, as well as crystal structure determination for all excluding N-decylisoquinolinium bromide ([i-QuinC10][Br]). The obtained thermophysical parameters were compared with the literature data and also within the extended homologous series.The solid–liquid phase equilibria (SLE) in mixtures of ILs with certain α,ω-alkanediols (1,6-hexanediol, 1,8-octanediol, 1,10-decanediol, 1,12-dodecanediol) were investigated. As a result of SLE studies, eutectic mixtures capable of acting as eutectic phase-change materials - ePCMs - were determined. Additionally, a self-organization phenomenon was observed between specific pairs, leading to the formation of co-crystals (solid-complex phase). All binary mixtures with [i-QuinC8][Br] formed a simple eutectic system, while in the case of [i-QuinC10][Br], the formation of a non-congruent melting compound was observed in the systems with 1,8-octanediol and 1,10-decanediol. Among the systems with [i-QuinC12][Br], congruent melting compounds were observed for mixtures with 1,8-octanediol, 1,10-decanediol and 1,12-dodecanediol, while a simple eutectic was recorded for 1,6-hexanediol. IL [i-QuinC16][Br] co-crystalised only with 1,12-dodecanediol, while with other diols formed simple eutectic systems. Calorimetric analysis (DSC) and crystal structure determination (X-ray diffraction) were used to characterize the obtained supramolecular compounds.As a result, a series of ePCMs with melting points ranging from 295 K to 343 K are presented, with the {[i-QuinC12][Br] + 1,10-decanediol} system showing the highest enthalpy of melting (173.5 J·g−1). The found features and correlations between structure and properties imply the necessity for additional investigation, indicating the potential for a new generation of compounds with customizable physicochemical properties.

Salt Effects on the Phase Behavior and Cocrystallization Kinetics of POCB-Water Mixtures.

Mixtures of water with polyoxacyclobutane (POCB) have a unique phase diagram which combines liquid-liquid equilibrium (LLE) at high temperatures and cocrystallization of a POCB-hydrate at low temperatures. Such cocrystal hydrate formation is extremely rare among polymers. We report on the effects of adding NaCl salt on the phase behavior of POCB-water mixtures and the kinetics of hydrate crystallization from such mixtures. Salt loadings of less than 0.1 wt % were found to greatly expand the LLE region. Salt loadings of ∼10 wt % were found to significantly decrease the melting temperature of the hydrate below its ∼37 °C value under salt-free conditions. The hydrate was found to be remarkably tolerant of salt and persists at room temperature even when equilibrated with salt-saturated water. Salt was found to slow down hydrate crystallization, and the degree of slowing was greater than that expected from the salt-induced decrease in undercooling due to melting point depression.

Efficient cocrystal coformer screening based on a Machine learning Strategy: A case study for the preparation of imatinib cocrystal with enhanced physicochemical properties

Cocrystal engineering, which involves the self-assembly of two or more components into a solid-state supramolecular structure through non-covalent interactions, has emerged as a promising approach to tailor the physicochemical properties of active pharmaceutical ingredient (API). Efficient coformer screening for cocrystal remains a challenge. Herein, a prediction strategy based on machine learning algorithms was employed to predict cocrystal formation and seven reliable models with accuracy over 0.890 were successfully constructed. Imatinib was selected as the model drug and the models established were applied to screen 31 potential coformers. Experimental verification results indicated RF-8 is the optimal model among seven models with an accuracy of 0.839. When the seven models were combined for coformer screening of Imatinib, the combinational model achieved an accuracy of 0.903, and eight new solid forms were observed and characterized. Benefiting from intermolecular interactions, the obtained multicomponent crystals displayed enhanced physicochemical properties. Dissolution and solubility experiments showed the prepared multicomponent crystals had higher cumulative dissolution rate and remarkably improved the solubility of imatinib, and IM-MC exhibited comparable solubility to Imatinib mesylate α form. Stability test and cytotoxicity results showed that multicomponent crystals exhibited excellent stability and the drug-drug cocrystal IM-5F exhibited higher cytotoxicity than pure API.

Effect of stoichiometry upon the characteristics of quercetin-arginine cocrystals formulated through solution crystallization

Objective The aim of this study is to demonstrate the effect of stoichiometry upon characteristics of quercetin-arginine (QCT-Arg) cocrystals. Significance Quercetin (QCT) is a most abundant flavonoid in vegetables and fruits and has been widely used as an antioxidant. However, its oral bioavailability remains low due to poor aqueous solubility. We illustrate that QCT-Arg cocrystals formulated through an optimized stoichiometry can be a useful approach for its solubilization. Method Cocrystals were prepared using solvent evaporation method. Characterizations were performed through microscopic, spectroscopic, and thermal techniques. The stoichiometry was confirmed from the binary phase diagram which was prepared using thermograms derived from differential scanning calorimetric experiments. Result Cocrystal formation was accompanied by the conversion of isotropic phase into anisotropic one. Thread-like cocrystals were formed, regardless of QCT-Arg stoichiometry and solvent’s polarity. Spectral analyses suggested that cocrystal structure was held together by hydrogen bonding between QCT and Arg. We ruled out the existence of eutectic mixture based on the observation of two eutectic points in the binary phase diagram. Conclusion Morphology of cocrystals remained unaffected by the solvent type, stoichiometry and the presence of surfactant. We noticed that the cocrystals could improve the aqueous solubility of QCT.

Investigation of the Storage and Stability as Well as the Dissolution Rate of Novel Ilaprazole/Xylitol Cocrystal.

Reflux esophagitis, a treatment for gastric ulcers known as Ilaprazole (Ila), is not stable during storage and handling at room temperature, requiring storage at 5 degrees Celsius. In this study, to address these issues with Ila, coformers rich in oxygen (O) and hydroxyl (OH) groups capable of forming hydrogen bonds with were selected. These coformers included Xylitol (Xyl), Meglumine (Meg), Nicotinic acid (Nic), L-Aspartic acid (Asp), and L-Glutamic acid (Glu). A 1:1 physical mixture of Ila and each coformer was prepared, and the potential for cocrystal formation was predicted using differential scanning calorimetry (DSC) screening. The results indicated the potential for cocrystal formation in the Ila/Xyl physical mixture. Subsequently, Ila and Xyl were mixed in ethyl acetate (EA) in a 1:1 ratio, and after 28 h of slurry, the formation of Ila/Xyl cocrystal was confirmed through solid-state CP/MAS 13C NMR spectrum analysis, showing intermolecular hydrogen bonding and conformational changes. Furthermore, the 1:1 ratio of Ila/Xyl cocrystal was confirmed through solution-state NMR (1H, 13C, and 2D) molecular structure analysis. To assess the stability of Ila/Xyl cocrystal at room temperature, it was stored and compared with Ila at 25 ± 2 °C and relative humidity (RH) of 65 ± 5% over three months. The results showed that the purity of Ila/Xyl cocrystal remained at 99.8% from the initial purity of 99.75% over the three months, while Ila was predicted to decrease from an initial 99.8% purity to 90% after three months. Additionally, at 25 ± 2 °C and RH 65 ± 5%, a specific impurity B in Ila/Xyl cocrystal was observed to be 0.03% over three months, whereas Ila was predicted to increase from an initial 0.032% to 2.28% after three months. To evaluate the dissolution rate of Ila/Xyl cocrystal, a formulation was prepared and compared with Ila at pH 10, with a dosage equivalent to 10 mg of Ila. The results showed that Ila/Xyl cocrystal reached 55% within 15 min and 100% within 45 min, while Ila was predicted to reach 32% at 15 min and 100% only after 60 min. However, overall, the Ila/Xyl cocrystal showed results equivalent to or exceeding the dissolution rate of Ila. Therefore, it is predicted that the Ila/Xyl cocrystal will maximize its effectiveness as a more convenient crystal structure for formulation development, allowing storage and preservation at room temperature without the need for the problematic 5 °C refrigeration during ambient conditions and storage, addressing the issues associated with Ila.

A New Look at the Mechanism of Cocrystal Formation and Coformers Exchange in Processes Forced by Mechanical and/or Thermal Stimuli - ex situ and in situ Studies of Low-Melting Eutectic Mixtures.

Three different devices: ball mill, hot stage melting, and magic angle spinning (MAS) NMR rotor were used for the preparation of ethenzamide (ET) cocrystals with glutaric acid (GLU), ethylmalonic acid (EMA) and maleic acid (MAL) as coformers. In each case, well-defined binary systems (ET:EMA, ET:GLU, ET:MAL) were obtained. The common features of the two solvent free methods of cocrystal formation (grinding, melting) are presented on the basis of arguments obtained by solid state NMR spectroscopy. Thermal analysis (Differential Scanning Calorimetry) proved that the eutectic phase arises over a wide range of molar ratios of components for each of the binary systems. NMR techniques, supported by theoretical calculations, allowed to provide details about the pathway of the reaction mechanism with atomic accuracy. It was found that the formation of ET cocrystals is a complex process that requires five steps. Each step has been recognized and described. Variable temperature 1D and 2D MAS NMR experiments allowed to track physicochemical processes taking place in a molten state. Moreover, it was found that in a multicomponent mixture consisting of all four components, ET, EMA, GLU, and MAL, ET in the molten phase behaves as a specific selector choosing only one partner to form binary cocrystals according to energy preferences. The process of exchange of coformers in binary systems during grinding, melting, and NMR measurements is described. The stabilization energies (Estab ) and molecular electrostatic potential (MEP) maps computed for the cocrystals under discussion and their individual components rationalize the selection rules and explain the relationships between individual species.

Development of direct compression Acetazolamide tablet with improved bioavailability in healthy human volunteers enabled by cocrystallization with p-Aminobenzoic acid

Pharmaceutical cocrystallization has been widely used to improve physicochemical properties of APIs. However, developing cocrystal formulation with proven clinical success remains scarce. Successful translation of a cocrystal to suitable dosage forms requires simultaneously improvement of several deficient physicochemical properties over the parent API, without deteriorating other properties critical for successful product development. In the present work, we report the successful development of a direct compression tablet product of acetazolamide (ACZ), using a 1:1 cocrystal of acetazolamide with p-aminobenzoic acid (ACZ-PABA). The ACZ-PABA tablet exhibits superior biopharmaceutical performance against the commercial tablet, DIAMOX® (250 mg), in healthy human volunteers, leading to more than 50 % reduction in the required dose.

Pyrazine 1,4-Dioxide is a Prolific Cocrystal Former and Energetic Material Itself

Pyrazine 1,4-Dioxide is a Prolific Cocrystal Former and Energetic Material Itself

Improving the sublimation stability of ligustrazine with gallic acid by forming pharmaceutical cocrystal based on the Etter's rules

To improve the high sublimation characteristics of ligustrazine (TMP), an unreported ligustrazine-gallic acid pharmaceutical cocrystal (C7H6O5·2(C8H12N2)·H2O, TMP-GA) was synthesized by using a virtual cocrystal screening method based on the rules of hydrogen bonding formation (Etter's rules). The results of the molecular surface electrostatic potential (MEPS) of TMP-GA showed that the actual hydrogen bonding sites of TMP-GA were the same as the predicted ones, and the calculated ΔE was not much different from the predicted ones. The results of physicochemical properties showed that TMP-GA had better physical stability against TMP sublimation without reducing the solubility and permeability of TMP. Combined with the interaction force analysis of the crystals, the reason may be that compared with the TMP monomer pharmaceutical structure, the intermolecular hydrogen bonding of the TMP-GA pharmaceutical cocrystal is increased, the structure is more stable, and the increase in the energy required for TMP sublimation makes the tendency to sublimate of the TMP-GA significantly lower. This suggests that we can utilize the virtual cocrystal screening method based on Etter's rules to introduce suitable cocrystal formers to reduce the sublimation tendency of active pharmaceutical ingredients.

Exploring polymorphism, stoichiometric diversity and simultaneous existence of salt and cocrystal during cocrystallization using mechanochemistry

We demonstrate here the mechanochemical cocrystallization of trans-aconitic acid with nicotinamide that resulted salt and cocrystal forms with stoichiometric diversity, polymorphism and high Z′′.

Vacuum-ultraviolet irradiation of pyridine:acetylene ices relevant to Titan astrochemistry.

Nitrogen-containing polycyclic aromatic hydrocarbons (NPAHs) are important molecules for astrochemistry and prebiotic chemistry, as their occurrence spans from interstellar molecular clouds to planetary systems. Their formation has been previously explored in gas phase experiments, but the role of solid-state chemical reactions in their formation under cryogenic conditions remains elusive. Here, we explore the formation of NPAHs through vacuum ultraviolet (VUV) irradiation of pyridine:acetylene ices in amorphous and co-crystalline phases, with the aim to simulate conditions relevant to the interstellar medium and Titan's atmosphere. Our results show that the synthesis of ethynylpyridines from VUV-irradiated pyridine:acetylene amorphous ices is achievable at 18 K. In the co-crystal phase, photolysis at 110 K leads to the formation of NPAHs such as quinolizinium+ and precursors, reflecting a dynamical system under our conditions. In contrast, irradiation at 90 K under stable conditions did not produce volatile photoproducts. These results suggest that such chemical processes can occur in Titan's atmosphere and potentially in its stratosphere, where the co-condensation of these molecules can form composite ices. Concurrently, the formation of stable co-crystals can influence the depletion rates of pyridine, which suggests that these structures can be preserved and potentially delivered to Titan's surface. Our findings provide insights into the molecular diversity and chemical evolution of organic matter on Titan, crucial for future space exploration missions, such as the Dragonfly mission, which may uncover higher-order organics derived from pyridine precursors on Titan's surface.

Karakterisasi Pembentukan Ko-kristal Tenoksikam-Asam Malat dan Evaluasi Kompresibilitas dan Tabletabilitasnya

Tenoxicam is a non-steroidal anti-inflammatory drug which has poor compressibility and compactibility. One way to change the compressibility and compactibility of a material is to use co-crystallization techniques The aim of this research is to characterize the formation of co-crystal between tenoxicam and malic acid and evaluate their compressibility and tabletability. Tenoxicam-malic acid co-crystal were prepared using the ultrasound-assisted solution co-crystallisation (USSC) method with the addition of ethanol solvent at the same molar ratio. The USSC result was characterized by polarization microscopy, powder X-ray diffraction, and thermal analysis methods. Evaluation of compressibility and tabletability (tensile strength and elactic recovery) was carried out on tenoxicam-malic acid co-crystal and intact tenoxicam. Characterization of the USSC result indicated the formation of tenoxicam-malic acid co-crystal, which were characterized by crystal habit, powder X-ray diffraction patterns, and DSC thermograms that were specific and different from intact tenoxicam and malic acid. Compressibility evaluation results show that the tenoxicam-malic acid co-crystal is in the good flow properties category, while the intact tenoxicam is in the poor flow properties category. The tensile strength of tenoxicam-malic acid co-crystal is higher than that of intact tenoxicam at the same compression strength (40 kg/cm2). Tenoxicam-malic acid co-crystal showed lower elastic recovery compared to intact tenoxicam. These results can be concluded that tenoxicam-malic acid co-crystals have been successfully prepared using the USSC method and have better compressibility and tabletability than intact tenoxicam.

New Perspectives for Antihypertensive Sartans as Components of Co-crystals and Co-amorphous Solids with Improved Properties and Multipurpose Activity.

Sartans (angiotensin II receptor blockers, ARBs), drugs used in the treatment of hypertension, play a principal role in addressing the global health challenge of hypertension. In the past three years, their potential use has expanded to include the possibility of their application in the treatment of COVID-19 and neurodegenerative diseases (80 clinical studies worldwide). However, their therapeutic efficacy is limited by their poor solubility and bioavailability, prompting the need for innovative approaches to improve their pharmaceutical properties. This review discusses methods of co-crystallization and co-amorphization of sartans with nonpolymeric, low molecular, and stabilizing co-formers, as a promising strategy to synthesize new multipurpose drugs with enhanced pharmaceutical properties. The solid-state forms have demonstrated the potential to address the poor solubility limitations of conventional sartan formulations and offer new opportunities to develop dual-active drugs with broader therapeutic applications. The review includes an in-depth analysis of the co-crystal and co-amorphous forms of sartans, including their properties, possible applications, and the impact of synthetic methods on their pharmacokinetic properties. By shedding light on the solid forms of sartans, this article provides valuable insights into their potential as improved drug formulations. Moreover, this review may serve as a valuable resource for designing similar solid forms of sartans and other drugs, fostering further advances in pharmaceutical research and drug development.

Quabodepistat (OPC-167832), a Novel Antituberculosis Drug Candidate: Enhancing Oral Bioavailability via Cocrystallization and Mechanistic Analysis of Bioavailability in Two Cocrystals.

Quabodepistat (code name OPC-167832) is a novel antituberculosis drug candidate. This study aimed to discover cocrystals that improve oral bioavailability and to elucidate the mechanistic differences underlying the bioavailability of different cocrystals. Screening yielded two cocrystals containing 2,5-dihydroxybenzoic acid (2,5DHBA) or 2-hydroxybenzoic acid (2HBA). In bioavailability studies in beagle dogs, both cocrystals exhibited better bioavailability than the free form; however, the extent of bioavailability of cocrystals with 2HBA (quabodepistat-2HBA) was 1.4-fold greater than that of cocrystals with 2,5DHBA (quabodepistat-2,5DHBA). Dissolution studies at pH 1.2 yielded similar profiles for both cocrystals, although the percent dissolution differed: quabodepistat-2HBA dissolved more slowly than quabodepistat-2,5DHBA. The poor solubility of quabodepistat-2HBA is likely the primary factor limiting dissolution at pH 1.2. To identify a dissolution method that maintains the bioavailability in beagle dogs, we performed pH-shift dissolution studies that mimic the dynamic pH change from the stomach to the small intestine. Quabodepistat-2HBA demonstrated supersaturation after the pH was increased to 6.8, while quabodepistat-2,5DHBA did not demonstrate supersaturation. This result was consistent with the results of bioavailability studies in beagle dogs. We conclude that a larger quantity of orally administered quabodepistat-2HBA remained in its cocrystal form while being transferred to the small intestine compared with quabodepistat-2,5DHBA.

Supramolecular Nature of Multicomponent Crystals Formed from 2,2'-Thiodiacetic Acid with 2,6-Diaminopurine or N9-(2-Hydroxyethyl)adenine.

The synthesis and characterization of the multicomponent crystals formed by 2,2'-thiodiacetic acid (H2tda) and 2,6-diaminopurine (Hdap) or N9-(2-hydroxyethyl)adenine (9heade) are detailed in this report. These crystals exist in a salt rather than a co-crystal form, as confirmed by single crystal X-ray diffractometry, which reflects their ionic nature. This analysis confirmed proton transfer from the 2,2'-thiodiacetic acid to the basic groups of the coformers. The new multicomponent crystals have molecular formulas [(H9heade+)(Htda-)] 1 and [(H2dap+)2(tda2-)]·2H2O 2. These were also characterized using FTIR, 1H and 13C NMR and mass spectroscopies, elemental analysis, and thermogravimetric/differential scanning calorimetry (TG/DSC) analyses. In the crystal packing the ions interact with each other via O-H⋯N, O-H⋯O, N-H⋯O, and N-H⋯N hydrogen bonds, generating cyclic hydrogen-bonded motifs with graph-set notation of R22(16), R22(10), R32(10), R33(10), R22(9), R32(8), and R42(8), to form different supramolecular homo- and hetero-synthons. In addition, in the crystal packing of 2, pairs of diaminopurinium ions display a strong anti-parallel π,π-stacking interaction, characterized by short inter-centroids and interplanar distances (3.39 and 3.24 Å, respectively) and a fairly tight angle (17.5°). These assemblies were further analyzed energetically using DFT calculations, MEP surface analysis, and QTAIM characterization.

Scalability of Pharmaceutical Co-Crystal Formation by Mechanochemistry in Batch.

The development of mechanochemistry is considerably growing. Benign by design, this technology complies with several principles of green chemistry, contributing to the achievement of the United Nations Sustainable Development Goals (UN SDGs) and the European Green Deal objectives. Herein, we report the use of mechanochemical processes in batch to prepare kilogram-scale of the Active Pharmaceutical Ingredient (API): Ibuprofen-Nicotinamide (rac-IBP:NCT) co-crystal in an industrial eccentric vibration mill. This scenario shows a sustainable approach to the industrial up-scaling of pharmaceutical co-crystals by a solvent-free mechanochemical process in batch. The quantitative assessment of the greenness of the mechanochemical process against the Twelve Principles of Green Chemistry was performed using the DOZN 2.0 Green Chemistry Evaluator.

Machine Learning Prediction of Flavonoid Cocrystal Formation Combined with Experimental Validation

Machine Learning Prediction of Flavonoid Cocrystal Formation Combined with Experimental Validation

Metolazone co-crystals-loaded oral fast dissolving films: Design, optimization, and in vivo evaluation

This study aimed to formulate and optimize metolazone (MLZ) co-crystals incorporating fast-dissolving films (OFDFs) as an agreeable oral formulation for improving the bioavailability of the drug. The co-crystal formation between MLZ and different co-formers was performed using the solvent evaporation method. The MLZ co-crystal formula (MLZ-nicotinamide) with the highest dissolution parameters was loaded into OFDFs by the solvent casting method after being characterized by FT-IR, DSC, and PXRD. The formulated OFDFs were evaluated for their physicochemical properties. Using Statgraphics Centurion software, a full factorial design was used to examine the impact of formulation variables on the swelling index, the disintegration time, and the cumulative MLZ percent release after 10 min. The optimized OFDF was subjected to palatability, stability, and in vivo studies. Various co-formers lowered the melting point of MLZ, suggesting the development of different crystalline packing arrangements and the formation of co-crystals. All developed co-crystal formulations had higher values for relative dissolving rate (RD) and dissolution efficiency (DE%) when compared to pure MLZ. The obtained FTIR data could reflect the co-crystallization process between MLZ and nicotinamide, which was confirmed by the change of the PXRD pattern and the shift of the endothermic peak obtained by DSC. The optimized OFDF loaded with MLZ had a 4.57 swelling index, a 23.7 s disintegration time, and 99.8% MLZ released after 10 min. The optimized formula was stable for six months under the specified storage conditions. When evaluated in rabbits, the relative bioavailability of the optimized MLZ-OFDF was calculated to be approximately two-fold higher than that of the commercially available Efectinix® tablets.

BIOAVAILABILITY AND POLYMORPHIC STABILITY CHALLENGES AFFECTING DRUG PRODUCT’S POTENTIAL: A CRITICAL EVALUATION AND PERTINENT SOLUTION

Clinical failure remains an ongoing challenge in pharmaceutical drug product development. Solubility and permeability therefore play a very critical role in achieving desired bioavailability and pharmacological response, which in turns affects clinical safety and efficacy significantly. The situation becomes more critical when the drug candidate exhibits polymorphism and undergoes polymorphic transformation due to its meta-stable nature. This review article outlines the available technologies, pertinent regulations, the concepts involved in the enhancement of bioavailability and polymorphic stability to overcome the clinical failures. Various available technologies for bioavailability enhancement such as salification, micronization, complexation, microemulsification, nano emulsification, cocrystal formation, and amorphous solid dispersion with their advantage and disadvantage in formulating a stable drug product containing a polymorphic and meta-stable drug substance. Thermodynamic and kinetic aspects of polymorphic transformation are discussed to understand different excipient and process-induced transformation during manufacturing and shelf life of the drug product. Selecting the right instrument from the analytical toolbox is equally important to understand the diverse nature of polymorphic transformation. This review provides state-of-the-art information available on advanced analytical tools along with their capabilities, advantages, and disadvantage with respect to physical/structural analysis of polymorphs and polymorphic transformation.