CRYSTAL STRUCTURE PREDICTION IN THE CONTEXT OF PHARMACEUTICAL POLYMORPH SCREENING AND PUTATIVE POLYMORPHS OF CIPROFLOXACIN

Molecular simulation is increasingly used by medicinal chemists in the process and product development. Reliable computational predictions are of great value not only for the design of an active pharmaceutical ingredient with novel properties but also for the avoidance of an undesirable change of form in the late stages of development of an industrially important molecule. In the pharmaceutical industry, drug polymorphism can be a critical problem and is the subject of various regulatory considerations. This contribution tried to review the fuzzy frontiers between the chemical structure of the molecule and its crystal energy landscape with a particular focus on the crystal structure prediction (csp) methodology to complement polymorph screening. A detailed application of csp in the pharmaceutical industry is illustrated on ciprofloxacin; describing its putative polymorphs. This approach successfully identifies the known crystal form within this class, as well as a large number of other low-energy structures. The performance of the approach is discussed in terms of both the quality of the results and computational aspects. csp methods are now being used as part of the interdisciplinary range of studies to establish the range of solid forms of a molecule. Moreover, further methodological improvements aimed at increasing the accuracy of the predictions and at broadening the range of molecules i.e. cocrystals, salts and solvates

PHYSICOCHEMICAL CHARACTERIZATION AND EVALUATION OF TELMISARTAN: HYDROXYPROPYL-β-CYCLODEXTRIN: TWEEN 80 INCLUSION COMPLEX

Objective: The present work was aimed to study the effect of the ternary component on complexation efficiency of cyclodextrins towards telmisartan which is a poorly soluble anti-hypertensive agent.Methods: The elucidation of inclusion complexation of telmisartan (TEL) with hydroxypropyl-β-cyclodextrin (HP-β-CD) in the presence and absence of tween 80 was done by investigating their interactions in solid and solution state. The solid state characterization was performed using differential scanning calorimetry (DSC), powder X-ray diffraction studies (PXRD) fourier transform infra-red spectroscopy (FTIR) studies. The host guest stoichiometry was confirmed in solution state by proton nuclear magnetic resonance (1HNMR) and solution calorimetry studies. The improvement in solubility was evaluated through dissolution studies, which was further confirmed by in vivo studies.Results: In solution state, the phase solubility studies indicated 1:1 stoichiometry between TEL and HP-β-CD both in presence and absence of tween 80. The NMR and molecular modelling studies indicated the insertion of N-methyl benzimidazole and biphenyl carboxylate regions of TEL into HP-β-CD cavity suggesting the coexistence of two 1:1 complexes in equilibrium with each other. The stability constants, K1 (imidazole region of TEL-CD) and K2 (biphenyl acetic acid region of TEL-CD), were enhanced in the presence of tween 80 as evident by the higher value of stability constants. Efficacy of ternary complex was established by a significant decrease in the systolic blood pressure of deoxycorticosterone acetate (DOCA) induced hypertensive rats.Conclusion: It can be concluded that solubility of TEL was increased by encapsulation with HP-β-CD. Tween 80 further increased the complexation efficiency and decreased the bulk of cyclodextrin

Characterisation and evaluation of pharmaceutical solvates of Atorvastatin calcium by thermoanalytical and spectroscopic studies

BACKGROUND: Atorvastatin calcium (ATC), an anti-lipid biopharmaceutical class II drug, is widely prescribed as a cholesterol-lowering agent and is presently the world’s best-selling medicine. A large number of crystalline forms of ATC have been published in patents. A variety of solid forms may give rise to different physical properties. Therefore, the discovery of new forms of this unusual molecule, ATC, may still provide an opportunity for further improvement of advantageous properties. RESULTS: In the present work, eight new solvates (Solvate I-VIII) have been discovered by recrystallization method. Thermal behaviour of ATC and its solvates studied by DSC and TGA indicate similar pattern suggesting similar mode of entrapment of solvent molecules. The type of solvent present in the crystal lattice of the solvates is identified by GC-MS analysis and the stoichiometric ratio of the solvents is confirmed by (1)HNMR. The high positive value of binding energy determined from thermochemical parameters indicates deep inclusion of the solvent molecules into the host cavity. The XRPD patterns point towards the differences in their crystallanity, however, after desolvation solvate II, III, IV, V and VIII transform to isostructral amorphous desolvated solvates. The order of crystallinity was confirmed by solution calorimetric technique as the enthalpy of solution is an indirect measure of lattice energy. All the solvates behaved endothermically following the order solvate-VIII (1-butanol solvate) < solvate-I (isoproplyate) < solvate-V (methanol solvate) < solvate-III (ethonalate) < solvate-VI (acetone ethanol solvate) < solvate-IV (t-butanol solvate) < solvate-II (THF solvate) < solvate-VII (mixed hemi-ethanol hydrate). The positive value of the heat capacity of the solvate formation provides information about the state of solvent molecules in the host lattice. The solvents molecules incorporated in the crystal lattice induced local chemical environment changes in the drug molecules which are observed in (13)CP/MAS NMR spectral changes. CONCLUSIONS: Aqueous solubility of solvate-VIII was found to be maximum, however, solvate-I and VIII showed better reduction in total cholesterol and triglyceride levels as compared to atorvastatin against triton-induced dyslipidemia

Interaction of artesunate with β-cyclodextrin: Characterization, thermodynamic parameters, molecular modeling, effect of PEG on complexation and antimalarial activity

AbstractInclusion of artesunate in the cavity of β-cyclodextrin (β-CD) as well as its methyl and hydroxypropyl derivatives was investigated experimentally and by molecular modeling studies. The effect of PEG on the inclusion was also studied. A 1:1 stoichiometry was indicated by phase-solubility studies both in the presence and absence of PEG and suggested by the mass spectrometry. The mode of inclusion was supported by 2D NMR and results were further verified by docking studies utilizing Fast Rigid Exhaustive Docking acronym. The thermodynamic parameters were determined for both binary and ternary systems using solution calorimetry and were found to be best for the methyl-β-cyclodextrin (Me-β-CD) system. However, the presence of PEG improves the complexation ability as evident from elevation in the numerical value of the stability constant (K). Solubility and dissolution profile of binary complex is enhanced in the presence of PEG, which is approximately at par with drug Me-β-CD complexes. In vivo studies showed 100% survivability in artesunate–Me-β-CD complexes

Dynamic Patterns of Circulating Seasonal and Pandemic A(H1N1)pdm09 Influenza Viruses From 2007–2010 in and around Delhi, India

Influenza surveillance was carried out in a subset of patients with influenza-like illness (ILI) presenting at an Employee Health Clinic (EHS) at All India Institute of Medical Sciences (AIIMS), New Delhi (urban) and pediatric out patients department of civil hospital at Ballabhgarh (peri-urban), under the Comprehensive Rural Health Services Project (CRHSP) of AIIMS, in Delhi region from January 2007 to December 2010. Of the 3264 samples tested, 541 (17%) were positive for influenza viruses, of which 221 (41%) were pandemic Influenza A(H1N1)pdm09, 168 (31%) were seasonal influenza A, and 152 (28%) were influenza B. While the Influenza viruses were detected year-round, their types/subtypes varied remarkably. While there was an equal distribution of seasonal A(H1N1) and influenza B in 2007, predominance of influenza B was observed in 2008. At the beginning of 2009, circulation of influenza A(H3N2) viruses was observed, followed later by emergence of Influenza A(H1N1)pdm09 with co-circulation of influenza B viruses. Influenza B was dominant subtype in early 2010, with second wave of Influenza A(H1N1)pdm09 in August-September, 2010. With the exception of pandemic H1N1 emergence in 2009, the peaks of influenza activity coincided primarily with monsoon season, followed by minor peak in winter at both urban and rural sites. Age group analysis of influenza positivity revealed that the percent positivity of Influenza A(H1N1)pdm09 influenza virus was highest in >5–18 years age groups (OR 2.5; CI = 1.2–5.0; p = 0.009) when compared to seasonal influenza. Phylogenetic analysis of Influenza A(H1N1)pdm09 from urban and rural sites did not reveal any major divergence from other Indian strains or viruses circulating worldwide. Continued surveillance globally will help define regional differences in influenza seasonality, as well as, to determine optimal periods to implement influenza vaccination programs among priority populations

Karakterizacija solvatomorfa metotreksata pomoću termoanalitičkih i drugih metoda

Identification and characterization of different forms of methotrexate were carried out by crystallization from different solvents. Five different forms of the drug were obtained. Appearance of a desolvation endotherm in the DSC accompanied by mass loss in TGA for forms I, II, IV and V showed these forms to be acetonitrile solvate hydrate (form I), trihydrate (forms II and IV) and dimethylformamide solvate (form V), respectively. However, the desolvation peak was absent in form III (obtained from methanol) indicating the absence of any solvent of crystallization. This form was found to be partially crystalline by its XRPD pattern. Solution calorimetry was further used to differentiate between the forms as they differ in lattice energy, resulting in different enthalpies of solution. The dissolution and solubility profiles were correlated with the enthalpy of solution and subsequently with crystallinity of all the forms; the least endothermic form (form III) had the highest dissolution rate.U radu je provedena identifikacija i karakterizacija pet različitih formi metotreksata dobivenih kristalizacijom iz različitih otapala. Desolvatacijska izoterma u DSC popraćena gubitkom mase u TGA za forme I, II, IV i V ukazuje da su te forme solvati s acetonitrilom: hidrat (forma I), trihidrat (forma II i IV) i solvat s dimetilformamidom (forma V). Međutim, desolvatacijski pik je odsutan u formi III (dobivenoj iz metanola) što ukazuje na odsutnost otapala u kristalnoj formi. Ta forma je parcijalno kristalna i pokazuje odgovarajući XRPD uzorak. Energija kristalne ćelije je za različite forme različita, što ima za posljedicu različite entalpije otapanja te omogućava primjenu kalorimetrije otopine za diferencijaciju formi. Topljivost je korelirana s entalpijom otopine i kristaliničnosti svih formi. Najmanje endotermna forma (forma III) je najbolje topljiva