Enhancing the physicochemical properties of solid-state materials through crystal engineering enables optimization of these materials without covalent modification. Cocrystals have become a reliable means to generate novel crystalline forms with multiple components and they exhibit different physicochemical properties compared to the individual components. This dissertation exemplifies methodologies to generate cocrystals of active pharmaceutical ingredients (API's) based upon knowledge of supramolecular interactions (supramolecular synthons), while focusing on enhanced delivery through in vitro and in vivo processes with both salts and cocrystals respectively. The utility of mechanochemistry involving small amounts of an appropriate solvent, or solvent drop grinding (SDG), has been shown to reliably reproduce cocrystals with the anti-convulsant carbamazepine that were originally obtained by solution crystallization. This technique has been confirmed as a reliable screening method using solvents in which both components exhibit some solubility. The benefits of this technique lie in the time and cost efficiency associated with it as well as its inherently small environmental impact making it a "Green" method. SDG was also used as an efficient way to discover cocrystals of the anti-inflammatory meloxicam with carboxylic acids after analysis of existing reports and the analysis of structural data from the Cambridge Structural Database (CSD) to guide the choice of coformer. It has been shown that SDG can be used to screen for cocrystalline forms that are also obtainable by solution crystallization which is important in later stage development and manufacturing including but not limited to large scale up processes. Single crystals suitable for single crystal X-ray diffraction were obtained with meloxicam and two of the coformers, fumaric and succinic acid. Some of the meloxicam cocrystals exhibited enhanced pharmacokinetic (PK) profiles in rats exemplifying significantly higher serum concentrations after only fifteen minutes and consistently higher exposure over the time studied while others maintained lower exposure. This reveals that cocrystals can fine tune the PK profile of meloxicam in order to reduce or enhance exposure. Two different sulfonate salts, 4-hydroxybenzenesulfonate (p-phenolsulfonate) and 4-chlorobenzenesulfonate, of the anti-spastic agent (R,S) baclofen were developed by strategically interrupting the intramolecularly stabilized zwitterionic structure of baclofen. This zwitterionic structure results in low solubility associated with physiological pH required for intrathecal administration. Structural data for both salts in the form of single crystal X-ray diffraction data was successfully obtained. Solubility based on baclofen was assessed and shown to increase in pure water and at pH's 1 and 7. Only the 4-chlorobenzenesulonate salt maintained an increased solubility over two days at pH 7 making it a viable candidate for further study in terms of intrathecal administration. During crystallization experiments with (R,S) baclofen two polymorphic forms of the baclofen lactam were generated, Forms II and III. Both forms are conformational polymorphs confirmed by single crystal X-ray diffraction and Form II has a Z' of 4 with an unusual arrangement of enantiomers.

With a greater understanding of the fundamentals of crystal engineering lays the potential for the development of a vast array of novel materials for a plethora of applications. Addressed herein is the latent potential of the current knowledge base with an emphasis upon cocrystallization and the desire for scientific exploration that will lead to the development of a future generation of novel cocrystals. The focus of this dissertation is to expand the cocrystallization knowledge base in two directions with the utilization of cocrystals in the novel synthetic technique of cocrystal controlled solid-state synthesis and in the development of active pharmaceutical ingredients. Cocrystal controlled solid-state synthesis uses a cocrystal to align the reactive moieties in such a way that the reaction occurs more quickly and in higher yield than the typical solution methodology. The focus herein is upon cocrystal controlled solid-state synthesis of imides where an anhydride and primary amine were the reactive moieties. Forty-nine reactions were attempted and thirty-two resulted in successful imide formation. In addition, the cocrystal was isolated as part of the reaction pathway in three cases and is described in detail. The impact of cocrystals upon active pharmaceutical ingredients is also addressed with a focus upon generating novel crystal forms of lamotrigine and meloxicam. Cocrystallization attempts of lamotrigine resulted in ten novel crystal forms including three cocrystals, one cocrystal solvate, three salts, one solvated salt, a methanol solvate, and an ethanol hydrate. Additionally, cocrystallization attempts of meloxicam afforded seven novel cocrystals. Solubility and pharmacokinetic studies were conducted for a selected set of lamotrigine and meloxicam crystal forms to determine the crystal form with the most desirable properties. Properties between crystal form and cocrystal former were also examined.

There is heightened interest to diversify the range of crystal forms exhibited by active pharmaceutical ingredients (APIs) in the pharmaceutical industry. The crystal form can be regarded as the Achilles' heel in the development of an API as it directly impacts the physicochemical properties, performance and safety of the API. This is of critical importance since the crystal form is the preferred method of oral drug delivery by industry and regulatory bodies. The ability to rationally design materials is a lucrative avenue towards the synthesis of functional molecular solids with customized physicochemical properties such as solubility, bioavailability and stability. Pharmaceutical cocrystals have emerged as a new paradigm in pharmaceutical solid form development because they afford the discovery of novel, diverse crystal forms of APIs, generate new intellectual property and modify physicochemical properties of the API. In addition, pharmaceutical cocrystals are amenable to design from first principles of crystal engineering. This dissertation focuses on the crystal engineering of multi-component crystal forms, in particular pharmaceutical cocrystals and crystalline hydrates. It addresses: (i) the factors involved in the selection of cocrystal formers (ii) design strategies for APIs that exhibit complexity, (iii) the role of water molecules in the design of multi-component crystal forms and (iv) the relationship between the crystal structure and thermal stability of crystalline hydrates. In general, cocrystal former libraries have been limited to pharmaceutically acceptable substances. It was investigated to expand this library to include substances with an acceptable toxicity profile such as nutraceuticals. In other words, can nutraceuticals serve as general purpose cocrystals formers? The model compounds, gallic acid and ferulic acid, were selected since they possess the functional moieties carboxylic acids and phenols, that are known to form persistent supramolecular synthons with complementary functional groups such as basic nitrogen and amides. The result yielded pairs of cocrystals and revealed the hierarchical nature of hydrogen bonding between complementary functional groups. In general, pharmaceutical cocrystals have been designed by determining the empirical guidelines regarding the hierarchy of supramolecular synthons. However, this approach may be inadequate when considering molecules that are complex in nature, such as those having a multiplicity of functional groups and/or numerous degrees of conformational flexibility. A crystal engineering study was done to design multi-component crystal forms of the atypical anti-psychotic drug olanzapine. The approach involved a comprehensive analysis and data mining of existing crystal structures of olanzapine, grouped into categories according to the crystal packing exhibited. The approach yielded isostructural, quaternary multi-component crystal forms of olanzapine. The crystal forms consist of olanzapine, the cocrystal former, a water molecule and a solvate. The role of water molecules in crystal engineering was addressed by investigating the crystal structures of several cocrystals hydrates and their related thermal stability. The cocrystal hydrates were grouped into four categories based upon the thermal stability they exhibit and it was concluded that no structure/stability correlations exist in any of the other categories of hydrate. A Cambridge Structural Database (CSD) analysis was conducted to examine the supramolecular heterosynthons that water molecules exhibit with two of the most relevant functional groups in the context of active pharmaceutical ingredients, carboxylic acids, and alcohols. The analysis suggested that there is a great diversity in the supramolecular heterosynthons exhibited by water molecules when they form hydrogen bonds with carboxylic acids or alcohols. This finding was emphasized by the discovery of two polymorphs of gallic acid monohydrate to it the first tetramorphic hydrate for which fractional coordinates have been determined. Analysis of the crystal structures of gallic acid monohydrate polymorphs revealed that forms I and III exhibit the same supramolecular synthons but different crystal packing and forms II and IV exhibit different supramolecular synthons. Therefore, the promiscuity of water molecules in terms of their supramolecular synthons and their unpredictable thermal stability makes them a special challenge in the context of crystal engineering.

One of the largest obstacles in drug development is to overcome solubility and bioavailability problems. Preformulation strategies such as nanoparticle formation are often employed but sometimes create new issues and are limited in their effectiveness and applications. Since the majority of drugs are marketed and sold as solid forms, drug delivery systems are not always desirable. This is where solid-state chemistry becomes important. Traditional solid-state chemistry approaches are often successful but are sometimes too restrictive and cannot be applied to certain compounds. Cocrystals have emerged as an alternative solid-state technique that can be applied to a broad range of compounds. However, the technology is still very new and its effectiveness in certain conditions had previously not been evaluated. The studies detailed herein investigated the ability of two different technology platforms for overcoming drug design challenges for two promising bioflavonoids: EGCg and quercetin. Studies have shown that EGCg might be useful for the treatment of Alzheimer's disease and other neurodegenerative diseases. Quercetin is being investigated for numerous bioactivities and is currently being marketed as an energy dietary supplement. Both of these bioflavonoids exhibit poor bioavailability and water solubilities that are at opposite ends of the spectrum. In the chapters to follow, nanoparticle technology was applied to EGCg and evaluated in cell models of AΒ production, a hallmark of Alzheimer's disease. Bioavailability improvements were also evaluated in rats. Additionally, new forms of both flavonoids were created using cocrystallization. These new cocrystals were characterized using powder and single crystal x-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. Solubility and bioavailability changes were also evaluated. These data have strong implications in drug development since they elucidated the strengths and weaknesses of two major technologies in compounds with different design challenges.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2017-02-15T11:48:36Z No. of bitstreams: 2 Dissertação - Romayne Paniago França - 2016.pdf: 1501835 bytes, checksum: 413c74416f9a069ed5fcaa317d37d106 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-02-15T11:49:02Z (GMT) No. of bitstreams: 2 Dissertação - Romayne Paniago França - 2016.pdf: 1501835 bytes, checksum: 413c74416f9a069ed5fcaa317d37d106 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-02-15T11:49:02Z (GMT). No. of bitstreams: 2 Dissertação - Romayne Paniago França - 2016.pdf: 1501835 bytes, checksum: 413c74416f9a069ed5fcaa317d37d106 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2016-10-07 / Polymorphism is the capability of an element or compound in crystallizing itself into more than one distinct crystal species, it affects not only the speed in which a substance acts in the organism, but also its chemical stability along time. There is a great problem that has been of considerable importance in the pharmaceutical industry, it is the development of a new drug. The realization of this research is justified by the fact that, according to the literature, the crystalline form or presence of polymorphism alters the solubility and the physical-chemical properties of drugs, being able to cause deviations of quality by the bioavailability of drugs, influencing the performance of the medicines and the bioequivalence. The objective of the research is to synthesize and characterize crystalline forms of the drugs Glicosamine and Tolbutamide, therefore having the polymorphism and the crystalline structure of these drugs analyzed. The experiments were performed in the Laboratory of Development of New Drugs of UFG/Regional Jataí, where the essays of crystallization for the obtainment of cocrystals of the drugs Glicosamine and Tolbutamide were performed. I was chosen the Tolbutamide, drug used as oral hypoglycemic agent and the Glycosamine used in the treatment of arthrosis, articular rheumatism and regeneration of damaged cartilage. The choice of these had as basis the availability of these substances in the Laboratory of Development of New Drugs of UFG/Regional Jataí, and the fact of not having been, yet, totally explored by the literature. Essays of crystallization for obtainment of cocrystals in different solvents were performed and the structures were characterized by monocrystal X-ray diffraction (MXRD) and Infra-red. The raw material Glicosamine and Tolbutamide were acquired at Pharma/China Zhejiang Golden- Shell and Sigma-Aldrich Co., USA, respectively. The behavior of solubility of Glicosamine and Tolbutamide were observed experimentally in the solvents: deionized water, methanol, ethanol, isopropyl alcohol, butyl alcohol, acetone, dimethyl formamide, ethyl acetate, ethyl ether, acetonitrile, chloroform, dichloromethane, tetrahydrofuran, hexane and n-heptane. It has been observed that Glicosamine is slightly soluble in the solvents deionized water, isopropyl alcohol, butyl alcohol, dimethyl formamide, and chloroform at room temperature, after the heating of the solutions, Glicosamine was only soluble in deionized water. However, it is insoluble in the solvents: methanol, ethanol, acetone, ethyl acetate, ethyl ether, acetonitrile, dichloromethane, tetrahydrofuran, hexane and n-heptane. In the results of the essays of crystallization for obtainment of cocrystals of Glicosamine, from the solution of Glicosamine and deionized water with salicylic acid and other solvents there was the formation of 2-aminobenzoic acid. It was observed that the Tolbutamide is soluble, at room temperature, in methanol, ethanol, isopropyl alcohol, acetone, dimethyl formamide, ethyl acetate, acetonitrile, chloroform, dichloromethane and tetrahydrofuran. It is slightly soluble in the solvents: deionized water, butyl alcohol, ethyl ether and insoluble in the solvents hexane and n-heptane and became soluble in butyl alcohol after heating. In the results of crystallization for obtainment of cocrystals of Tolbutamide, from the solution of Tolbutamide and methanol with salicylic acid in the solvents methanol, ethanol, isopropyl alcohol, acetonitrile and dichloromethane, there was the formation of 2aminobenzoic acid, however, there was no crystallization in the solvents ethyl acetate, chloroform and tetrahydrofuran. In the results of the essays of crystallization for obtainment of cocrystals of Tolbutamide, from the solution of Tolbutamide and ethanol with salicylic acid in the solvents ethanol, ethyl acetate, acetonitrile, dichloromethane and tetrahydrofuran there was the formation of 2aminobenzoic acid, however, there was no crystallization in the solvents methanol, isopropyl alcohol and chloroform. In the essays of crystallization it was found the polymorph I and the polymorph III of Tolbutamide. In the results of the essays of crystallization for obtainment of cocrystals of the solution of Tolbutamide, from the solution of Tolbutamide and ethanol with maleic acid in the solvents methanol and ethyl acetate there was the crystallization of Tolbutamide in the monoclinic system and in the spatial group /n group, while in the solvents butyl alcohol, acetone and tetrahydrofuran, there was the crystallization of Tolbutamide in the orthorhombic system and spatial group in the . The essays performed with tartaric acid and oxalic acid have great evidence of the formation of cocrystals of Tolbutamide with oxalic acid and Glicosamine with tartaric acid, identified by the measures of Infrared Spectroscopy. / O polimorfismo é a capacidade de um elemento ou composto em cristalizar-se em mais do que uma espécie distinta de cristal, este afeta não apenas a velocidade com que uma substância age no organismo, mas também sua estabilidade química ao longo do tempo. Existe um grande problema que tem sido de importância considerável na indústria farmacêutica, é o desenvolvimento de um novo fármaco. A realização dessa pesquisa se justifica pelo fato de que, de acordo com a literatura, a forma cristalina ou presença de polimorfismo alteram a solubilidade e as propriedades físico-químicas de fármacos, podendo ser capazes de causar desvios de qualidade através da biodisponibilidade dos fármacos, influenciando o desempenho dos medicamentos e a bioequivalência. O objetivo da pesquisa é sintetizar e caracterizar formas cristalinas dos fármacos Glicosamina e Tolbutamida, desta forma analisou-se o polimorfismo e a estrutura cristalina destes fármacos. Os experimentos foram realizados no laboratório de desenvolvimento de novos fármacos da UFG/Regional Jataí, onde se realizou os ensaios de cristalização para a obtenção de cocristais dos fármacos Glicosamina e Tolbutamida. Foram escolhidos a Tolbutamida, fármaco utilizado como hipoglicemiante oral e a Glicosamina usada no tratamento de artrose, reumatismo articular, e regeneração de cartilagem danificada. A escolha destes teve como base a disponibilidade destas substâncias no Laboratório de Desenvolvimento de Novos Fármacos da UFG/Regional Jataí, e o fato de não terem sido, ainda, totalmente explorados na literatura. Foram realizados ensaios de cristalização para obtenção de cocristais em diferentes solventes e caracterizadas as estruturas por difração de raios X por monocristal (DRXM) e infravermelho (IV). As matérias primas Glicosamina e Tolbutamida, foram adquiridas na Pharma/China Zhejiang Golden- Shell e Sigma-Aldrich Co., USA, respectivamente. Os comportamentos de solubilidade da Glicosamina e Tolbutamida foram observados experimentalmente para os solventes: água deionizada, metanol, etanol, isopropanol, butanol, acetona, dimetil-formamida, acetato de etila, éter etílico, acetonitrila, clorofórmio, diclorometano, THF, hexano e heptano. Observou-se que a Glicosamina é pouco solúvel nos solventes água deionizada, isopropanol, butanol, dimetil-formamida e clorofórmio à temperatura ambiente, após aquecimento das soluções a Glicosamina, apresentou ser solúvel apenas em água deionizada. Entretanto, é insolúvel nos solventes: metanol, etanol, acetona, acetato de etila, éter etílico, acetonitrila, diclorometano, THF, hexano, heptano. Nos resultados de ensaios de cristalização para obtenção de cocristais de Glicosamina, a partir da solução de Glicosamina e água deionizada com ácido salicílico e outros solventes obteve a formação do ácido 2aminobenzoico. Observou- se que a Tolbutamida se solubiliza, à temperatura ambiente, em metanol, etanol, isopropanol, acetona, dimetil-formamida, acetato de etila, acetonitrila, clorofórmio, diclorometano e THF. É pouco solúvel nos solventes: água deionizada, butanol e éter etílico e insolúvel nos solventes hexano e heptano e passou a ser solúvel em butanol após aquecimento. Nos resultados de ensaios de cristalização para obtenção de cocristais de Tolbutamida, a partir da solução de Tolbutamida e metanol com o ácido salicílico nos solventes metanol, etanol, isopropanol, acetonitrila e diclorometano, obteve-se a formação do ácido 2-aminobenzoico, porém não houve cristalização nos solventes acetato de etila, clorofórmio e THF. Nos resultados de ensaios de cristalização para obtenção de cocristais de Tolbutamida, a partir da solução de Tolbutamida e etanol com ácido salicílico nos solventes, etanol, acetato de etila, acetonitrila, diclorometano e THF, obteve a formação do ácido 2-aminobenzoico, porém não houve cristalização nos solventes metanol, isopropanol e clorofórmio. Nos ensaios de cristalização foram encontrados o polimorfo I e o polimorfo III da Tolbutamida. Nos resultados de ensaios de cristalização para obter cocristais da solução de Tolbutamida, a partir da solução de Tolbutamida e etanol com ácido maleico nos solventes metanol e acetato de etila ocorreu a cristalização da Tolbutamida no sistema monoclínico e no grupo espacial P21/n, enquanto nos solventes butanol, acetona e THF, ocorreu a cristalização da Tolbutamida no sistema ortorrômbico e no grupo espacial Pna21. Nos ensaios realizados com ácido tartárico e ácido oxálico, temos fortes evidências da formação de cocristais de Tolbutamida com ácido oxálico e Glicosamina com ácido tartárico, constatadas pelas medidas de Espectroscopia de Infravermelho.

<p>The thermal decomposition of four energetic cocrystals composed of 4-amino-3,5-dinitropyrazole (ADNP)/diaminofurazan (DAF), 2,4,6-trinitrotoluene (TNT)/ 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL20), 1,3,5,7-tetranitro-1,3,5,7-tetrazacyclooctane (HMX)/CL20, and 1-methyl-3,5-dinitro-1,2,4-triazole (MDNT)/CL20 were studied using simultaneous differential scanning calorimetry (DSC), thermogravimetry analysis (TGA), and hot-stage microscopy. The kinetic parameters of their thermal decomposition reaction were determined using the Kissinger and Ozawa kinetic analysis methods. Each cocrystal’s peak exothermic temperature (decomposition temperature), activation energy, and pre-exponential constant are reported. Furthermore, these parameters from each cocrystal were compared to the same parameters from the corresponding stoichiometric physical mixture in order to identify changes in behavior attributable to the cocrystallization process. For ADNP/DAF, the cocrystal shows an 8% increase in the peak exotherm temperature and a 11-13% decrease in peak activation energy as compared to its physical mixture. For TNT/CL20, this comparison shows a much smaller change in the peak exotherm temperature (<1%) but shows a 5% decrease in activation energy. This cocrystal also experiences phase stabilization—where a phase transition of one or both coformers is omitted from the decomposition process. The HMX/CL20 cocrystal shows a 1% change in the peak exotherm temperature and shows a 2% increase in activation energy. Finally, for MDNT/CL20, this comparison shows nearly a 4% increase and a drastic decrease in peak activation energy by 42-44%. Cocrystallization clearly affects the thermal decomposition and reaction kinetics of these materials, offering the potential to create a hybrid-class of energetic materials which combines the high performance of an energetic material with the safety and insensitivity of another. </p>

Halogen bonding to phosphorus atoms remains uncommon, with relatively few examples reported in the literature. In part 1 of the thesis, the preparation and investigation of the cocrystal (dicyclohexylphenylphosphine)(1,6-diiodoperfluorohexane) by X-ray crystallography and solid-state multinuclear magnetic resonance spectroscopy is described. The crystal structure features two crystallographically unique C-I···P halogen bonds (dI···P = 3.090(5) Å, 3.264(5) Å) and crystallographic disorder of one of the 1,6-diiodoperfluorohexane molecules. The first of these is the shortest and most linear I···P halogen bond reported to date. 13C, 19F, and 31P magic-angle spinning solid-state NMR spectra are reported. A 31P chemical shift change of -7.0 ppm in the cocrystal relative to pure dicyclohexylphenylphosphine, consistent with halogen bond formation, is noted. This work establishes iodoperfluoroalkanes as viable halogen bond donors when paired with phosphorus acceptors, and also shows that dicyclohexylphenylphosphine can act as a practical halogen bond acceptor. In part 2 of the thesis, computational work was done on nuclides of atoms which engage in the strongest halogen bonds (iodine, bromine, chlorine) that are all quadrupolar (spin I > ½). Previous group work reported extensive experimental NMR and NQR data relating 35/37Cl, 79/81Br, and 127I quadrupolar coupling information to local molecular structure in halogen bonded systems. Here, we make use of a new parameter, the valence p-orbital population anisotropy (VPPA), reported by Rinald and Wu, to increase our understanding of the origins of the electric field gradients (EFG) in halogen-bonded systems. Computations on model and real halogen-bonded cocrystalline systems using standard hybrid DFT methods are used to generate p-orbital populations and to compute the VPPA. We discuss the utility of the VPPA, and hence the EFG, as a tool to assess the ability of particular donors to engage in halogen bonds.

yes / Despite the rising interest in pharmaceutical cocrystals in the past decade, there is a lack of research in the solid processing of cocrystals downstream to crystallization. Mechanical stress induced by unit operations such as milling could affect the integrity of the material. The purpose of this study is to investigate the effect of milling on pharmaceutical cocrystal and compare the performance of ball mill and jet mill, using caffeine-glutaric acid (1:1) cocrystal as the model compound. Our results show that ball milling induced polymorphic transformation from the stable Form II to the metastable Form I; whereas Form II remained intact after jet milling. Jet milling was found to be effective in reducing particle size but ball milling was unable to reduce the particle beyond certain limit even with increasing milling intensity. Heating effect during ball milling was proposed as a possible explanation for the difference in the performance of the two types of mill. The local increase in temperature beyond the polymorphic transformation temperature may lead to the conversion from stable to metastable form. At longer ball milling duration, the local temperature could exceed the melting point of Form I, leading to surface melting and subsequent recrystallization of Form I from the melt and agglomeration of the crystals. The findings in this study have broader implications on the selection of mill and interpretation of milling results for not only pharmaceutical cocrystals but pharmaceutical compounds in general.

Yes / Insights into structure–mechanical property correlations in molecular and multicomponent crystals have recently attracted significant attention owing to their practical applications in the pharmaceutical and specialty fine chemicals manufacturing. In this contribution, we systematically examine the mechanical properties of dimorphic forms, Forms I and II of 1:1 caffeine-glutaric acid cocrystal on multiple faces using nanoindentation to fully understand their mechanical anisotropy and mechanical stability under applied load. Higher hardness, H, and elastic modulus, E, of stable Form II has been rationalized based on its corrugated layers, higher interlayer energy, lower interlayer separation, and presence of more intermolecular interactions in the crystal structure compared to metastable Form I. Our results show that mechanical anisotropy in both polymorphs arises due to the difference in orientation of the same 2D structural features, namely the number of possible slip systems, and strength of the intermolecular interactions with respect to the indentation direction. The mechanical properties results suggest that 1:1 caffeine-glutaric acid cocrystal, metastable form (Form I) could be a suitable candidate with desired tablet performance to that of stable Form II. The overall, it demonstrates that the multiple faces of nanoindentation is critical to determine mechanical anisotropy and structure- mechanical property correlation. Further, the structural-mechanical property correlations aids in the selection of the best solid phase for macroscopic pharmaceutical formulation.

Yes / In a competitive coformer exchange reaction, a recent topic of interest in pharmaceutical research, the coformer in a pharmaceutical cocrystal is exchanged with another coformer which is expected to form a cocrystal that is more stable. There will be a competition between coformers to form the most stable product through formation of hydrogen bonds. Thus, to monitor each and every step of such reactions, employing a very sensitive technique is crucial. 1H nuclear magnetic resonance (NMR) is a very powerful technique that is very sensitive to the hydrogen bond interactions. In this study, an in situ monitoring of a coformer exchange reaction is carried out by 1H magic angle spinning (MAS) solid-state NMR (SSNMR) at a spinning frequency of 60 KHz. The changes in caffeine maleic acid cocrystals on addition of glutaric acid, and caffeine glutaric cocrystal on addition of maleic acid were monitored. In all the reactions, it has been observed that caffeine glutaric acid Form I is formed. When glutaric acid was added to 2:1 caffeine maleic acid, the formation of metastable 1:1 caffeine glutaric acid Form I was observed, at the start of the experiment, indicating that the centrifugal pressure is enough for the formation. The difference in the end product of the reactions with similar reaction pathway of 1:1 and 2:1 reactant stoichiometry indicate that a complete replacement of maleic acid has only occurred only in the 1:1 stoichiometry of the reactants. The polymorphic transition of caffeine glutaric acid Form II to Form I at higher temperature was crucial reason which triggers the exchange of glutaric acid with maleic acid in the reaction of caffeine glutaric acid and maleic acid. Based on these results, new reaction pathways in competitive coformer exchange reactions could be distinguished, and the remarkable role of stoichiometry, polymorphism, temperature and centrifugal pressure could be established. / C.H. acknowledges Department of Science and Technology, India (DST), for the grant of Inspire Fellowship. T.G.A. acknowledges Council of Scientific and Industrial Research, India (CSIR) for research grants under the 12th 5 year plan project (Grant No. CSC0405). / The full-text of this article will be released for public view at the end of the publisher embargo on 19 Feb 2025.