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The opportunistic pathogen Streptococcus pneumoniae has dual lifestyles: one of an asymptomatic colonizer in the human nasopharynx and the other of a deadly pathogen invading sterile host compartments. The latter triggers an overwhelming inflammatory response, partly driven via pore forming activity of the cholesterol dependent cytolysin (CDC), pneumolysin. Although pneumolysin-induced inflammation drives person-to-person transmission from nasopharynx, the primary reservoir for pneumococcus, it also contributes to high mortality rates, creating a bottleneck that hampers widespread bacterial dissemination, thus acting as a double-edged sword. Serotype 1 ST306, a widespread pneumococcal clone, harbours a non-hemolytic variant of pneumolysin (Ply-NH). Performing crystal structure analysis of Ply-NH, we identified Y150H and T172I as key substitutions responsible for loss of its pore forming activity. We uncovered a novel inter-molecular cation-π interaction, governing formation of the transmembrane β-hairpins (TMH) in the pore state of Ply, which can be extended to other CDCs. H150 in Ply-NH disrupts this interaction, while I172 provides structural rigidity to domain-3, through hydrophobic interactions, inhibiting TMH formation. Loss of pore forming activity enabled improved cellular invasion and autophagy evasion, promoting an atypical intracellular lifestyle for pneumococcus, a finding that was corroborated in in vivo infection models. Attenuation of inflammatory responses and tissue damage promoted tolerance of Ply-NH-expressing pneumococcus in the lower respiratory tract. Adoption of this altered lifestyle may be necessary for ST306 due to its limited nasopharyngeal carriage, with Ply-NH, aided partly by loss of its pore forming ability, facilitating a benign association of SPN in an alternative, intracellular host niche., Competing Interests: The authors have declared that no competing interests exist.

Polymorphs enable us to gain molecular insights into the compaction behavior of pharmaceutical powders. Two polymorphs (α and γ) of indomethacin (IMC) were investigated for in-die and out-of-die compaction behavior using compressibility, tabletability and compactibility (CTC) profile, stress-strain relationship, and Heckel, Kawakita and Walker equations. Compaction studies were performed on a fully instrumented rotary tabletting machine. CTC analysis revealed that the γ-form has increased compressibility while the α-form showed greater compactibility. The α-form also showed increased tabletability over the γ-form at all the compaction pressures. Lower values of Py (Heckel parameter) and 1/b (Kawakita parameter) indicated increased deformation behavior of γ-form. Stress-strain analysis also supports the increased compressibility of γ-form. In addition, Walker analysis showed higher compressibility coefficient (W) for α-form, consistent with its greater tabletability. Thus, tabletability of IMC polymorphs was governed by the compactibility of the material. Detailed examination of crystallographic data revealed that the presence of a slip plane system in the γ-form offered it increased compressibility and deformation behavior. However, the α-form showed greater compactibility by virtue of closer molecular packing (higher true density). Hence, although direct correlation between tabletability and the presence of slip planes in the crystals has been reported, prediction solely based on this crystallographic feature must be avoided. The present work reiterates the influence of the crystal packing on the tabletability of the pharmaceutical polymorphs.

Good flow and compaction properties are prerequisites for successful compaction process. Apart from initial profile, mechanical properties of pharmaceutical powders can get modified during unit processes like milling. Milled powders can exhibit a wide range of particle size distribution. Further downstream processing steps like compaction can be affected by this differential particle size distribution. This has greatest implications for formulations like high dose drugs wherein the active pharmaceutical ingredient (API) contributes the maximum bulk in the final formulation. The present study assesses the impact of dry coating with ultrafine particles of same material, on the flow and compaction properties of the core material. Ibuprofen was selected as model drug as it has been reported to have poor mechanical properties. Ultrafine ibuprofen (average size 1.75 μm) was generated by Dyno(®) milling and was dry coated onto the core ibuprofen particles (average size 180 μm). Compaction studies were performed using a fully instrumented rotary tablet press. Compaction data was analyzed for compressibility, tabletability, compactibility profiles and Heckel plot. Dry coating of the ibuprofen exhibited greater compressibility and tabletability, at lower compaction pressure. However, at compaction pressure above 220 MPa, compressibility and tabletability of coated as well as uncoated materials were found to be similar. Heckel analysis also supported the above findings, as P(y) value of uncoated ibuprofen was found to be 229.49 MPa and for 2.0% ultrafine coated ibuprofen was found to be 158.53 MPa. Lower P(y) value of ultrafine coated ibuprofen indicated ease of plastic deformation. Superior compressibility and deformation behaviour of ultrafine coated ibuprofen attributed to increased interparticulate bonding area. This strategy can also be explored for improving tabletability of high dose poorly compressible drugs., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Being a density violator, clopidogrel bisulfate (CLP) polymorphic system (forms I and II) allows us to study individually the impact of molecular packing (true density) and thermodynamic properties such as heat of fusion on the compaction behavior. These two polymorphs of CLP were investigated for in-die and out-of-die compaction behavior using CTC profile, Heckel, and Walker equations. Compaction studies were performed on a fully instrumented rotary tabletting machine. Detailed examinations of the molecular packing of each form revealed that arrangement of the sulfate anion differs significantly in both crystal forms, thus conferring different compaction behavior to two forms. Close cluster packing of molecules in form I offers a rigid structure, which has poor compressibility and hence resists deformation under compaction pressure. This results into lower densification, higher yield strength, and mean yield pressure, as compared with form II at a given pressure. However, by virtue of higher bonding strength, form I showed superior tabletability, despite its poor compressibility and deformation behavior. Form I, having higher true density and lower heat of fusion showed higher bonding strength. Hence, true density and not heat of fusion can be considered predictor of bonding strength of the pharmaceutical powders., (Copyright © 2012 Wiley Periodicals, Inc.)