01635nas a2200157 4500008004100000245009500041210006900136260000800205300001200213490000700225520106700232100002401299700001901323700002401342856011101366 2020 eng d00aCrystal structure of a 1:1 co-crystal of the anti-cancer drug gefitinib with azelaic acid 0 aCrystal structure of a 11 cocrystal of the anticancer drug gefit cJUN a884-8880 v763 a

In the title co-crystal, C22H24ClFN4O3·C9H16O4, gefitinib (GTB; systematic name: quinazolin-4-amine) co-crystallizes with azelaic acid (AA; systematic name: nona-nedioic acid). The co-crystal has the monoclinic P21/n centrosymmetric space group, containing one mol-ecule each of GTB and AA in the asymmetric unit. A structure overlay of the GTB mol-ecule in the co-crystal with that of its most stable polymorph revealed a significant difference in the conformation of the morpholine moiety. The significant deviation in the conformation of one of the acidic groups of azelaic acid from its usual linear chain structure could be due to the encapsulation of one acidic group in the pocket formed between the two pincers of GTB namely, the morpholine and phenyl moieties. Both GTB and AA mol-ecules form N-H⋯O, O-H⋯N, C-H⋯O hydrogen bonds with C-H⋯F close contacts along with off-stacked aromatic π-π inter-actions between the GTB mol-ecules.

1 aGeorge, Christy, P.1 aSangtani, Ekta1 aGonnade, Rajesh, G. uhttps://library.ncl.res.in/content/crystal-structure-11-co-crystal-anti-cancer-drug-gefitinib-azelaic-acid01834nas a2200193 4500008004100000022001400041245013200055210006900187260000900256300001400265490000700279520110900286100002401395700002501419700002501444700002001469700002401489856012701513 2020 eng d a1466-803300aDrug-drug cocrystals of anticancer drugs erlotinib-furosemide and gefitinib-mefenamic acid for alternative multi-drug treatment0 aDrugdrug cocrystals of anticancer drugs erlotinibfurosemide and  cOCT  a6137-61510 v223 a

Drug-drug cocrystals of anticancer drugs erlotinib and gefitinib with furosemide and mefenamic acid, respectively, have been synthesized. The 1:1 erlotinib-furosemide cocrystal crystallizes in the monoclinic centrosymmetric P2(1)/n space group containing one molecule of each component in the asymmetric unit. In contrast the 1:1 gefitinib-mefenamic acid cocrystal hydrate belongs to the monoclinic centrosymmetric P2(1)/c space group comprising one molecule of both drugs along with one water molecule in the asymmetric unit. The solubility and dissolution rate study revealed higher solubility for BCS class II drugs, furosemide, and mefenamic acid, while the solubility and dissolution rate of erlotinib showed a significant reduction in the cocrystal salt. Conversely, the solubility of gefitinib didn't reveal a substantial decrease; however, the dissolution rate has been reduced in the cocrystal hydrate. Further, an attempt has been made to correlate the crystal structures of the erlotinib-furosemide and gefitinib-mefenamic acid cocrystals with their solubilities and dissolution rate.

1 aGeorge, Christy, P.1 aThorat, Shridhar, H.1 aShaligram, Parth, S.1 aSuresha, P., R.1 aGonnade, Rajesh, G. uhttps://library.ncl.res.in/content/drug-drug-cocrystals-anticancer-drugs-erlotinib-furosemide-and-gefitinib-mefenamic-acid03089nas a2200181 4500008004100000245013200041210006900173260000800242300001400250490000700264520238600271100002502657700002402682700002502706700002002731700002402751856013202775 2021 eng d00aPolymorphs and hydrates of the anticancer drug erlotinib: X-ray crystallography, phase transition and biopharmaceutical studies0 aPolymorphs and hydrates of the anticancer drug erlotinib Xray cr cJUN a3961-39740 v233 a

Erlotinib, a non-small cell lung cancer BCS class II drug, was found to occur as two polymorphs and two hydrates depending on the crystallization conditions. The monohydrate (form III), which has been reported in patents and publications, is the preferred crystalline phase from solution crystallization. The other forms (polymorphs, forms I and II, and a trihydrate, form IV) are solvent and condition-specific. Form I was exclusively and reproducibly obtained from dried non-polar solvents (viz. toluene, benzene, and xylene) using a solution crystallization method under controlled conditions. In contrast, form II was obtained by the rotary evaporation technique under reduced pressure from polar solvents (viz. dichloromethane, ethyl acetate, acetone, and acetonitrile). Slow evaporation from polar and non-polar solvents under open conditions yielded form III crystals, whereas evaporation from acetone-acetonitrile-water mixtures yielded form IV crystals. DSC and variable temperature PXRD studies revealed form I to be the most stable phase while the other solid forms displayed thermally induced polymorphic transitions into form I crystals. Further, form I and form III are found to be stable over the 30-90% RH range. Further, form I displayed solution-mediated transformation into form III (monohydrate) when left to stand in the mother liquor for a longer duration (1-2 days). Similarly, the unstable form IV crystals transformed into the stable form III crystals within 1-2 h when exposed to an open atmosphere. Fast crystallization from polar solvents using the rotary evaporation technique enabled us to capture the metastable polymorph, form II. Early separation of form I from its mother liquor prevented its solution-mediated transformation into the monohydrate, form III. The water activity study revealed that form III is the most preferred solid phase in the presence of water. Dissolution rate measurements showed that the rate of form II is almost comparable to that of the marketed erlotinib hydrochloride. In contrast, for the other forms, the dissolution profiles showed a considerable decrease. Although the crystal structures of form I and form III have been published previously, this manuscript gives a comprehensive overview of the free base solid forms of erlotinib, the phase transitions amongst them and their biopharmaceutical properties.

1 aThorat, Shridhar, H.1 aGeorge, Christy, P.1 aShaligram, Parth, S.1 aSuresha, P., R.1 aGonnade, Rajesh, G. uhttps://library.ncl.res.in/content/polymorphs-and-hydrates-anticancer-drug-erlotinib-x-ray-crystallography-phase-transition-and02013nas a2200229 4500008004100000245011400041210006900155260000800224300001400232490000700246520121200253100002301465700002401488700002101512700001901533700001701552700001901569700002101588700002401609700002401633856012601657 2022 eng d00aNovel crystal forms of Entresto: a supramolecular complex of trisodium sacubitril/valsartan hemi-pentahydrate0 aNovel crystal forms of Entresto a supramolecular complex of tris cOCT a7387-73930 v243 a

Entresto is a salt-cocrystal supramolecular complex with the chemical name trisodium sacubitril/valsartan hemi-pentahydrate for treating chronic heart failure and was approved by the US FDA in 2015. This multidrug complex was synthesized in our laboratory to investigate its polymorphic behavior. Different crystallization conditions, including various solvent systems, yielded different novel solid forms of Entresto (Form-I to Form-VI), including the reported form. All the novel solids are solvent-dependent and were reproducibly crystallized on a 10 g scale quantity. The 1H NMR spectra confirmed the 1 : 1 stoichiometry of the two drugs, namely, sacubitril and valsartan, in all the solid forms of the crystalline products. Powder X-ray diffraction and DSC analysis of the crystalline solids established that they are distinct crystalline forms. Stability studies under ambient conditions carried out over a one-year period showed higher stability for Form-I and Form-III compared to the other forms, including the innovator crystal form (labelled as Form-II). The novel crystal forms (notably Form-I and Form-III) exhibit higher stability and less hygroscopicity than the reported Form-II.

1 aShaikh, Tabrez, R.1 aGeorge, Christy, P.1 aBhukya, Priyanka1 aShelke, Nikita1 aPawar, Komal1 aGarai, Abhijit1 aDandela, Rambabu1 aGonnade, Rajesh, G.1 aNangia, Ashwini, K. uhttps://library.ncl.res.in/content/novel-crystal-forms-entresto-supramolecular-complex-trisodium-sacubitrilvalsartan-hemi01840nas a2200217 4500008004100000022001400041245012600055210006900181260000800250300001600258490000700274520107300281100002001354700001901374700001901393700002401412700002101436700001701457700001901474856012901493 2022 eng d a0020-166900aTridentate NacNac stabilized tin and nickel complexes: access to a monomeric nickel hydride and its catalytic application0 aTridentate NacNac stabilized tin and nickel complexes access to  cOCT a17370-173770 v613 a

The transmetalation reaction of picolyl-supported tridentate nacnac germylene monochloride [2,6-iPr2-C6H3NC-(Me)CHC(Me)NH(CH2py)]GeCl (1) (py = pyridine) with SnCl2 results in an analogous stannylene chloride (2). The three -coordinated stannylenium cation [{2,6-iPr2-C6H3NC(Me)CHC-(Me)NH(CH2py)}Sn]+ with SnCl3- as a counteranion (3) has been generated through the abstraction of chloride ligand from 2 using an additional equivalent of SnCl2. Instead of forming a donor-acceptor complex, 2 undergoes a facile redox trans-metalation reaction with Ni(COD)2 (COD = cyclooctadiene) and CuCl to afford analogous nickel and copper complexes [2,6-iPr2-C6H3NC(Me)CHC(Me)NH(CH2py)]MCl [M = Ni (4) and Cu (5)]. The reactions of 4 with potassium tri-sec-butylborohydride (commonly known as K-selectride) and AgSbF6 provide access to monomeric Ni(II) hydride, [2,6-iPr2-C6H3NC(Me)CHC(Me)NH(CH2py)]NiH (6) and a Ni(II) cation, [{2,6-iPr2- C6H3NC(Me)CHC(Me)NH(CH2py)}Ni][SbF6] (7), respectively. 6 was found to be an effective catalyst for the hydroboration of amides.

1 aPahar, Sanjukta1 aSharma, Vishal1 aMahata, Biplab1 aGeorge, Christy, P.1 aSharma, Himanshu1 aVanka, Kumar1 aSen, Sakya, S. uhttps://library.ncl.res.in/content/tridentate-nacnac-stabilized-tin-and-nickel-complexes-access-monomeric-nickel-hydride-and00976nas a2200193 4500008004100000245006800041210006800109260000800177300001400185490000700199520034000206100001900546700001900565700002600584700002400610700002400634700002400658856010000682 2023 eng d00aPolymorph II of hydroxyurea 150 years after its first synthesis0 aPolymorph II of hydroxyurea 150 years after its first synthesis cMAY a2712-27160 v253 a

A new polymorph of hydroxyurea (HU) was crystallized 150 years after its first synthesis. Due to its medicinal use in neoplastic diseases and sickle cell anemia, a high throughput screen of HU binary cocrystals was attempted. Instead of a cocrystal, an isoenergetic form II crystallized concomitantly with urea in methanol.

1 aRai, Sunil, K.1 aTothadi, Srinu1 aArhangelskis, Mihails1 aGeorge, Christy, P.1 aGonnade, Rajesh, G.1 aNangia, Ashwini, K. uhttps://library.ncl.res.in/content/polymorph-ii-hydroxyurea-150-years-after-its-first-synthesis02779nas a2200217 4500008004100000245010100041210006900142260000900211300001400220490000700234520201600241100002502257700002402282700002102306700002702327700001902354700001702373700001802390700002402408856012902432 2023 eng d00aRivaroxaban eutectics with improved solubility, dissolution rates, bioavailability and stability0 aRivaroxaban eutectics with improved solubility dissolution rates cJUN  a3253-32630 v253 a

Rivaroxaban (RXB) is a direct factor Xa inhibitor used for the treatment of deep vein thrombosis (DVT, a blood clot in the leg) and pulmonary embolism (PE, a blood clot in the lung) and to prevent blood clots in atrial fibrillation following hip or knee surgery. However, RXB suffers from poor solubility that hinders its broader application. Although its cocrystals are reported for solubility enhancement, the methodology used to prepare multi-component crystals is complex. Also, it uses hazardous solvents to develop cocrystals. We have prepared eutectics of RXB with caffeic acid (CAA), coumaric acid (CA), fumaric acid (FA), succinic acid (SA), mandelic acid (MA) and trimesic acid (TA) and analyzed them using hot stage microscopy (HSM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and fourier transform infrared spectroscopy (FTIR) techniques. The saturation solubility and dissolution rate profiles were also obtained to investigate the effect of eutectics on these parameters. Amongst all the coformers tested, coformers CAA, CA, and FA showed significant enhancement in the solubility of RXB. The powder dissolution rate of the eutectics showed considerable enhancement compared to that of RXB. In vivo pharmacokinetic study was carried out for RXB-CAA, RXB-CA and RXB-FA in rats and compared with RXB, which showed 1.5 and 1.4 times enhancement in relative bioavailability for RXB-CAA and RXB-CA, respectively. Stability studies were carried out as per ICH guidelines for all the eutectics, which revealed excellent stability over six months under accelerated (40 degrees C and 75%) conditions and twelve months under long-term (30 degrees C and 60% RH) conditions. The DFT studies carried out using the B3LYP/TZVP level of theory revealed higher Gibbs free interaction energy (Delta G(int)) for homosynthons (drugMIDLINE HORIZONTAL ELLIPSISdrug and coformerMIDLINE HORIZONTAL ELLIPSIScoformer) than heterosynthons (drugMIDLINE HORIZONTAL ELLIPSIScoformer).

1 aShaligram, Parth, S.1 aGeorge, Christy, P.1 aSharma, Himanshu1 aMahadik, Kakasaheb, R.1 aPatil, Sharvil1 aVanka, Kumar1 aArulmozhi, S.1 aGonnade, Rajesh, G. uhttps://library.ncl.res.in/content/rivaroxaban-eutectics-improved-solubility-dissolution-rates-bioavailability-and-stability02167nas a2200289 4500008004100000022001400041245005500055210005200110260000800162490000700170520133100177653002301508653002401531653001901555653001101574653002201585100002001607700001901627700001501646700002301661700002401684700002101708700001701729700002401746700001901770856008801789 2024 eng d a0947-653900aTridentate NacNac tames T-shaped nickel(I) radical0 aTridentate NacNac tames Tshaped nickelI radical cFEB0 v303 a

The reaction of a nickel(II) chloride complex containing a tridentate beta-diketiminato ligand with a picolyl group [2,6-iPr2-C6H3NC(Me)CHC(Me)NH(CH2py)]Ni(II)Cl (1)] with KSi(SiMe3)3 conveniently afforded a nickel(I) radical with a T-shaped geometry (2). The compound's metalloradical nature was confirmed through electron paramagnetic resonance (EPR) studies and its reaction with TEMPO, resulting in the formation of a highly unusual three-membered nickeloxaziridine complex (3). When reacted with disulfide and diselenide, the S-S and Se-Se bonds were cleaved, and a coupled product was formed through carbon atom of the pyridine-imine group. The nickel(I) radical activates dihydrogen at room temperature and atmospheric pressure to give the monomeric nickel hydride. A thermally stable, T-shaped, nickel(I) radical was straightforward obtained by reduction of a tridentate nacnac nickel(II) chloride with KSi(TMS)3. The metalloradical character of the compound was demonstrated by the formation of a highly unusual nickeloxaziridine complex upon addition of TEMPO. The Ni(I) species displays a rich chemistry towards activation S-S, and Se-Se bond leading to unusual C-C coupled product as well as dihydrogen activation at room temperature and atmospheric pressure to generate monomeric nickel hydride.+image

10aC-C Bond formation10aHydrogen Activation10aMetalloradical10aNickel10aTridentate nacnac1 aPahar, Sanjukta1 aSharma, Vishal1 aRaj, Vipin1 aSangole, Mayur, P.1 aGeorge, Christy, P.1 aSingh, Kirandeep1 aVanka, Kumar1 aGonnade, Rajesh, G.1 aSen, Sakya, S. uhttps://library.ncl.res.in/content/tridentate-nacnac-tames-t-shaped-nickeli-radical02855nas a2200181 4500008004100000022001400041245017200055210006900227260000800296300001400304490000700318520213300325100002002458700002302478700002402501700002402525856012402549 2025 eng d a1528-748300aCocrystals of the highly potent sickle cell anemia drug voxelotor with trimesic acid: a substantial enhancement in in vitro dissolution performance at physiological pH0 aCocrystals of the highly potent sickle cell anemia drug voxeloto cMAY a4405-44250 v253 a

Global Blood Therapeutic's (GBT's) Voxelotor is an investigational oral therapy for treating sickle cell anemia. It functions by increasing the affinity between hemoglobin and oxygen, thereby preventing the sickling of red blood cells and altering the disease's pathology. The US FDA has approved Voxelotor for the treatment of sickle cell anemia and granted it an orphan drug status. However, Voxelotor is classified as a BCS class II, indicating poor water solubility. The current study explores the enhancement of Voxelotor's water solubility by forming cocrystals with trimesic acid (TMA). Novel cocrystals, cocrystal solvates, and hydrates of Voxelotor (Vox) with trimesic acid (TMA) have been developed to improve their solubility. The new solids were characterized using PXRD, DSC, TGA, XPS, HSM, and single-crystal X-ray diffraction studies, and the intermolecular interactions were quantified using Hirshfeld surface analysis. Detailed crystallographic analysis revealed strong O-H center dot center dot center dot N hydrogen bonding interactions between Vox and TMA, primarily involving the COOH functional group of TMA and the pyridine or pyrazole groups of Vox. Additionally, TMA molecules participate in further hydrogen bonding-either with themselves or with solvates, including hydrates, through mono- or dimeric O-H center dot center dot center dot O H-bonding synthons. In vitro solubility studies demonstrated a significant increase in the solubility of Voxelotor in the Vox-TMA cocrystals compared to the pristine drug at physicochemical pH 4.5 and 6.8. Stability studies confirmed that the nonsolvated multicomponent crystal retains their structural integrity under nonambient conditions without undergoing polymorphic phase transitions. In contrast, the solvated crystals, including hydrates, undergo phase transitions within the temperature range of 100-130 degrees C, losing solvents and converting into one of the nonsolvated cocrystal forms. These findings suggest that the novel Vox-TMA cocrystals have the potential to enhance the therapeutic performance and clinical utility of Voxelotor.

1 aKhan, Akram, A.1 aShaikh, Tabrez, R.1 aGeorge, Christy, P.1 aGonnade, Rajesh, G. uhttps://library.ncl.res.in/content/cocrystals-highly-potent-sickle-cell-anemia-drug-voxelotor-trimesic-acid-substantial