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)

HELLP syndrome, associated with eclampsia, preeclampsia, in one hundred cases, the complications, maternal morbidity and mortality: the near miss and missed obstetric scenarios

Background: The investigations done, complications observed, mode of delivery, management of complications, the perinatal outcome, the maternal mortality, the lessons learnt have been outlined. The referral to higher tertiary care Institutes has been analysed. The goals of management were, control of hypertension, prevention of convulsions, assessment of the severity of HELLP syndrome, identification of associated complications and chances of fetal salvage, a decision to be made regarding the mode of delivery, keeping the blood products ready, anaesthetist and paediatrician to be informed, consultation of nephrologist, cardiologist, neurophysician, ophthalmologist, gastroenterologist, surgeon as required in the particular case and continued vigilance in the postpartum period. Methods: This is a prospective observational study of one hundred cases of HELLP syndrome managed at two tertiary care Institutes. Twenty-five cases, managed at CARE Institute of Medical sciences, during the years 2011 to 2013 and 75 cases from the Institute of Obstetrics and Gynaecology at Modern Government Maternity Hospital, MGMH, Osmania Medical College, OMC, between 2021 to 2023, were included in the study. Results: Labour was induced, in 47.29%, vaginal delivery in 28 cases, 37.83% and lower segment caesarean section (LSCS) was needed in 46, 62.16% in the study. A total of 90.66% of HELLP have occurred in the third trimester of pregnancy. Eclampsia was associated with HELLP syndrome in 39/100=39%. The remaining 61 cases had preeclampsia associated HELLP syndrome. PRAKI in 31/100=31%, DIC in 19%, PRES in 7/100, PPCM 2%, PPH in 18=24%, maternal mortality in 17/100=17%. Conclusions: Delivery by 37 weeks would have clearly prevented 36% of cases. Delivery by 35 weeks would have prevented 61% of cases of HELLP syndrome

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

Indirect Wafer Bonding and Epitaxial Transfer of GaSb-Based Materials

Results from a study of indirect wafer bonding and epitaxial transfer of GaSb-based materials are presented. Benzocyclobutene (BCB) was used as a bonding agent to bond GaSb and epitaxial structures lattice matched to GaSb onto Si, GaAs, and sapphire carrier substrates. To better understand sources of stress during the bonding process, which can result in cracking and subsurface damage of the GaSb-based materials, BCB’s hardness and reduced elastic modulus were measured at various stages during the curing process. Based on the results of curing experiments, a bonding and epitaxial transfer process for GaSb-based materials was then developed. Following bonding, using an experimentally determined low-stress cure cycle, GaSb substrates were removed from epitaxial layers of InAsSb using a combination of mechanical thinning and polishing followed by selective chemical etching using a hydrofluoric and chromic acid solution. Etch selectivity data are also presented where selectivity greater than 100:1 is achieved for GaSb:InAsSb

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

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

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