33 research outputs found
X-ray crystallography and its role in understanding physicochemical properties of pharmaceutical cocrystals
YesProperties of a matter are intrinsically dependent upon the internal arrangement of molecules in the solid state. Therefore, knowledge of 3-dimensional structure of the matter is prerequisite for structure-property correlations and design of functional materials. Over the past century, X-ray crystallography has evolved as a method of choice for accurate determination of molecular structure at atomic resolution. The structural information obtained from crystallographic analysis paved the way for rapid development in electronic devices, mineralogy, geosciences, materials science, pharmaceuticals, etc. Knowledge of the structural information of active pharmaceutical ingredients (APIs) is prerequisite for rational drug design and synthesis of new chemical entities for development as new medicines. Over the past two decades, X-ray crystallography has played a key role in the design of pharmaceutical cocrystals-crystalline solids containing an API and one or more of pharmaceutically acceptable coformers. These materials have proved promising for fine-tuning several important properties of APIs. This short review highlights the history of crystallography, early breakthroughs, and the role of crystallography in understanding physicochemical properties of pharmaceutical cocrystals.S. Aitipamula gratefully acknowledges the financial support from the Institute of Chemical and Engineering Sciences of A*STAR (Agency for Science, Technology and Research), Singapore. V. R. Vangala thanks Royal Society of Chemistry for Researcher Mobility Grant (2015/17)
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Resistant maltodextrin as a shell material for encapsulation of naringin: Production and physicochemical characterization
YesHerein the potential of a relatively new water soluble fiber, resistant maltodextrin (RMD) to encapsulate grapefruit polyphenol, naringin, using spray drying was evaluated. Full factorial Design Of Experiments (DOE) for spray drying with two levels of fiber–naringin ratio and spray dryer inlet temperature was executed. Resulting powders were characterized with respect to particle size and morphology, crystallinity, thermal properties, moisture sorption and naringin aqueous solubility increase. A 60–80% encapsulation was achieved. Thermal and moisture sorption behaviors of these dispersions were found to be dominated by RMD. By varying fiber–naringin ratio and spray drying temperatures, naringin was able to disperse in amorphous form in RMD matrix, which led to 20–55% increase in aqueous solubility. Solubility enhancement was found to correlate positively with increasing fiber: naringin ratio and spray drying temperature due to multiple factors discussed in this study. In conclusion, fiber–polyphenol bicomponent nutraceutical was successfully developed based on a well-established encapsulation technology i.e. spray-drying
Coformer Replacement as an Indicator for Thermodynamic Instability of Cocrystals: Competitive Transformation of Caffeine:Dicarboxylic Acid
yesThe thermodynamic stability of caffeine (CA) cocrystals with dicarboxylic acids (DAs) as coformers was investigated in the presence of a range of structurally related dicarboxylic acids (SRDs). Two experimental conditions (slurry and dry-grinding) were studied for mixing the cocrystal and the SRD additive. The additives oxalic, malonic and glutaric acid led to the replacement of the acid coformer for certain cocrystals. Interestingly, a change in stoichiometry was observed for the CA:maleic acid system. A stability order among the cocrystals was established depending on their tendency to replace the coformer. To understand the factors controlling the relative stabilities, lattice energies were calculated using dispersion corrected Density Functional Theory (DFT). Gibbs free energy changes were calculated from experimental solubilities. The observed stability order corroborated well with lattice energy and Gibbs free energy computations
Stability of Pharmaceutical Cocrystal During Milling: A Case Study of 1:1 Caffeine-Glutaric Acid
yesDespite 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
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Isomorphism: 'Molecular similarity to crystal structure similarity' in multicomponent forms of analgesic drugs tolfenamic and mefenamic acid
YesThe non-steroidal anti-inflammatory drugs mefenamic acid (MFA) and
tolfenamic acid (TFA) have a close resemblance in their molecular scaffold,
whereby a methyl group in MFA is substituted by a chloro group in TFA. The
present study demonstrates the isomorphous nature of these compounds in a
series of their multicomponent solids. Furthermore, the unique nature of MFA
and TFA has been demonstrated while excavating their alternate solid forms in
that, by varying the drug (MFA or TFA) to coformer [4-dimethylaminopyridine
(DMAP)] stoichiometric ratio, both drugs have produced three different types
of multicomponent crystals, viz. salt (1:1; API to coformer ratio), salt hydrate
(1:1:1) and cocrystal salt (2:1). Interestingly, as anticipated from the close
similarity of TFA and MFA structures, these multicomponent solids have shown
an isomorphous relation. A thorough characterization and structural investigation of the new multicomponent forms of MFA and TFA revealed their
similarity in terms of space group and structural packing with isomorphic nature
among the pairs. Herein, the experimental results are generalized in a broader
perspective for predictably identifying any possible new forms of comparable
compounds by mapping their crystal structure landscapes. The utility of such an
approach is evident from the identification of polymorph VI of TFA from
hetero-seeding with isomorphous MFA form I from acetone–methanol (1:1)
solution. That aside, a pseudopolymorph of TFA with dimethylformamide
(DMF) was obtained, which also has some structural similarity to that of the
solvate MFA:DMF. These new isostructural pairs are discussed in the context of
solid form screening using structural landscape similarityDepartment of Science and Technology (DST/SJF/CSA-02/2014–15); Royal Pharmaceutical Society of Great Britain for seed corn funding (2018–19); INSPIRE fellowship from Department of Science and Technology, Government of India; IISER-Kolkata (instrumental facilities and fellowships
Nitrofurantoin methanol monosolvate
The antibiotic nitrofurantoin {systematic name: (E)-1-[(5-nitro-2-furyl)methylideneamino]imidazolidine-2,4-dione} crystallizes as a methanol monosolvate, C8H6N4O5·CH4O. The nitrofurantoin molecule adopts a nearly planar conformation (r.m.s. deviation = 0.0344 Å). Hydrogen bonds involve the co-operative N—H⋯O—H⋯O heterosynthons between the cyclic imide of nitrofurantoin and methanol O—H groups. There are also C—H⋯O hydrogen bonds involving the nitrofurantoin molecules which support the key hydrogen-bonding synthon. The overall crystal packing is further assisted by weak C—H⋯O interactions, giving a herringbone pattern
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Structural and reactivity analyses of nitrofurantoin 4 dimethylaminopyridine salt using spectroscopic and density functional theory calculations
YesPharmaceutical salt, nitrofurantoin–4-dimethylaminopyridine (NF-DMAP), along with its native components NF and DMAP are scrutinized by FT-IR and FT-Raman spectroscopy along with density functional theory so that an insight into the H-bond patterns in the respective crystalline lattices can be gained. Two different functionals, B3LYP and wB97X-D, have been used to compare the theoretical results. The FT-IR spectra obtained for NF-DMAP and NF clearly validate the presence of C33–H34⋅⋅⋅O4 and N23–H24⋅⋅⋅N9 hydrogen bonds by shifting in the stretching vibration of –NH and –CH group of DMAP+ towards the lower wavenumber side. To explore the significance of hydrogen bonding, quantum theory of atoms in molecules (QTAIM) has been employed, and the findings suggest that the N23–H24⋅⋅⋅N9 bond is a strong intermolecular hydrogen bond. The decrement in the HOMO-LUMO gap, which is calculated from NF → NF-DMAP, reveals that the active pharmaceutical ingredient is chemically less reactive compared to the salt. The electrophilicity index (ω) profiles for NF and DMAP confirms that NF is acting as electron acceptor while DMAP acts as electron donor. The reactive sites of the salt are plotted by molecular electrostatic potential (MEP) surface and calculated using local reactivity descriptors.SERB, DST, India, for providing the National Post-doctoral Fellowship (Project File Number: PDF/2016/003162); Central Facility for Computational Research (CFCR), University of Lucknow; Newton-Bhabha Ph.D. placement award (2017); Royal Society seed corn research grant (2018-19
Study of hydrogen bonding interactions and chemical reactivity analysis of nitrofurantoin–3-aminobenzoic acid cocrystal using quantum chemical and spectroscopic (IR, Raman, 13C SS-NMR) approaches
YesInvestigations of structural reactivity, molecular interactions and vibrational characterization of pharmaceutical drugs are helpful in understanding their behaviour. The aim of this study is to determine the molecular, electronic and chemical properties of the antibiotic drug nitrofurantoin (NF), after cocrystallisation with 3-aminobenzoic acid (3ABA) and to understand how those changes lead to variation of properties in the cocrystal NF–3ABA. NF–3ABA formation is explained by stabilization via the hydrogen-bond network between NF and 3ABA molecules. It is thoroughly characterized by IR, Raman and CP-MAS solid-state 13C NMR techniques, along with quantum chemical calculations. The results of IR, Raman, and 13C NMR analyses showed that imide N–H23 and C12[double bond, length as m-dash]O of NF interact with the acid C[double bond, length as m-dash]O and –OH groups in 3-ABA, respectively. Therefore the IR, Raman, and 13C NMR spectra verified the formation of N–H⋯O and O–H⋯O hydrogen bonds. To study hydrogen bonding interactions theoretically in NF–3ABA, two functionals B3LYP and wB97X-D have been used. A comparison is made between the results obtained by B3LYP and those predicted at the wB97X-D level. It is found that wB97X-D is best applied density functional theory (DFT) functional to describe the hydrogen bonding interactions. The strength and nature of hydrogen bonding in NF–3ABA have been analysed by quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis. To validate the results obtained by QTAIM theory and to study the long-range forces, such as van der Waals interactions, the steric effects in NF–3ABA, the reduced density gradient (RDG) and the isosurface have been plotted using Multiwfn software. QTAIM and isosurface analysis suggested that the hydrogen bonding interactions present in NF–3ABA are moderate in nature. The calculated HOMO–LUMO energy gap shows that NF–3ABA is more active than NF and 3ABA. Chemical reactivity descriptors are calculated to understand the various aspects of pharmacological sciences. Chemical reactivity parameters show that NF–3ABA is softer and chemically more reactive than NF. The results suggest that cocrystals can be a feasible alternative for positively changing the targeted physicochemical properties of an active pharmaceutical ingredient (API).V. R. Vangala acknowledges the financial support of the Royal Society of Chemistry for mobility grant (2015/17)
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Intriguing High Z'' Cocrystals of Emtricitabine
YesEmtricitabine (ECB) afforded dimorphic cocrystals (Forms I, II) of benzoic acid (BA), whereas with p-hydroxybenzoic acid (PHBA), p-aminobenzoic acid (PABA) are resulted in as high Z'' cocrystals. Intriguingly, the Z'' of cocrystals are trends from two to fourteen based on the manipulation of functional groups on the para position of BA (where H atom is replaced with that of OH or NH2 group). ECB‒PABA cocrystal consists of six molecules each and two water molecules in the asymmetric unit (Z''=14) with 2D planar sheets represents the rare pharmaceutical cocrystal. The findings suggest that the increment of H bond donor(s) systematically via a suitable coformer are in correspondence with attaining high Z'' cocrystals. Further, solid state NMR spectroscopy in conjunction with single crystal X-ray diffraction are demonstrated as significant tools to enhance the understanding of the number of symmetry independent molecules in the crystalline lattice and provide insights to the mechanistic pathways of crystallization.Department of Science and Technology (DST) Fund for improvement of S & T Infrastructure (FIST) with grant no. SR/FST/CST-266/2015(c) to PS and VP. AN and VV acknowledge the Government of India under National Overseas Scholarship (2012-13) and High Commission of India, London UK for PhD studentship
Thermal and in situ x-ray diffraction analysis of a dimorphic co-crystal 1:1 caffeine-glutaric acid
YesSpurred by the enormous interest in co-crystals from the pharmaceutical industry, many novel co-crystals of active pharmaceutical ingredients have been discovered in recent years and this has in turn led to an increasing number of reports on polymorphs of co-crystals. Hence, a thorough characterization and understanding of co-crystal polymorphs is a valuable step during drug development. The purpose of this study is to perform in situ structural analysis and to determine thermodynamic stability of a dimorphic co-crystal system, 1:1 caffeine-glutaric acid (CA-GA, Forms I and II). We performed thermal and structural characterizations by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy (HSM), slurry and in situ variable temperature X-ray diffraction (VTXRD). For completeness, we have also re-determined crystal structures of CA-GA Forms I and II at 180 K using single crystal X-ray diffraction. Our results revealed that Form II is stable and Form I is metastable at ambient conditions. Further, the results suggest that the dimorphs are enantiotropically related and the transition temperature is estimated to be 79 Celcius degrees.This work was supported by Science and Engineering Research Council of A*STAR (Agency for Science, Technology and Research), Singapore