Dengue Fever: A Continuous Threat

Dengue fever is a vector borne disease and is caused by DEN Virus. This virus has four different serotypes. The vectors are two mosquitoes known as Aedesaegypti (the yellow fever mosquito) and Aedesalbopictus(the Asian tiger mosquito).  First case of dengue fever was reported back in 1994 in Karachi. A complete outbreak of this epidemic shook the whole nation in 2012. Uptill now, Lahore a city full of culture, witnessed about 16,580 confirmed cases and 257 deaths. About 5000 confirmed cases with 60 deaths were reported from the rest of the provinces. Under guidelines of WHO, Government has made efforts to combat this epidemic. Although the overall efforts have minimized the outbreak on controllable levels but dengue fever is a continuous threat. Since no permanent cure is available, the transmission of DEN virus is controlled indirectly. So the prime focus is to control mosquito population and decrease the possible hot spots i.e. Mosquito breeding sites in human habitations. Every year, the country witnesses monsoon season which brings vast areas full of clear standing waters providing breeding sites for mosquitoes which ultimately leads to increased number of patients suffering from dengue fever. Efforts have been made to fight against dengue including formation of dengue wards in hospitals, vector surveillance, community education, reactive vector control etc. A study has shown prevalence of four mosquito genera in Pakistan including Aedes, Culex, Armigeresand Anopheles. All of the above mentioned genera are associated with disease transmissions as they are the vectors of different viruses and parasites. It is the need of hour to do a collaborative effort stressing the community mobilization and management in war against dengue.

Pharmaceutical Co-Crystals: A New Paradigm of Crystal Engineering to Modify Physicochemical and Pharmaceutical Properties of Paracetamol and Naproxen

Co-crystals are of considerable relevance to the drug development as they offer the ability of optimizing the physicochemical properties of an active pharmaceutical ingredient by incorporation of a second component (a co-former), while retaining the biological function of the parent material. Co-crystals have been emerged as an alternative approach when salt or polymorph formation does not meet the required targets. Furthermore co-crystals also represent a broad patent space because of the availability of a large number of co-formers. The aim of the present study was to synthesize and delineate co-crystals of paracetamol (a frequently used antipyretic and analgesic drug) and naproxen (a nonsteroidal anti inflammatory drug). Both paracetamol and naproxen had dissolution limited absorption and poor compressional behavior owing to low plasticity. A screening process, employing various methods namely dry grinding, liquid assisted grinding, solvent evaporation and anti solvent addition, was carried out with different ratios of paracetamol and caffeine. Implementation of the screen resulted in paracetamol-caffeine co-crystals by liquid assisted grinding and solvent evaporation methods with 1:1 and 2:1 ratios of paracetamol and caffeine respectively. Naproxennicotinamide co-crystal was generated by liquid assisted grinding in 2:1 molar ratio. Cocrystals gave characteristic PXRD patterns and DSC endotherms that were distinctive from the starting materials. Mechanical properties of paracetamol-caffeine and naproxennicotinamide co-crystals were analyzed by in-die Heckel model and tabletability curves respectively. Mean yield pressure, an inverse measure of plasticity, obtained from the Heckel plots decreased significantly for paracetamol-caffeine co-crystals than pure paracetamol. Over the entire range of compaction pressure used, tensile strength of naproxen was poor and lamination and sticking occurred in some tablets. Tensile strength of naproxennicotinamide co-crystal gradually increased with pressure achieving a desirable value of more than 2 MPa which was ~ 1.80 times that of naproxen at 5000 psi. Moreover, cocrystal pellets did not show any signs of cracking. Intrinsic dissolution rates of co-crystals of both drugs showed more than 2 fold faster dissolution compared to that of the respective pure drugs. Co-crystals were successfully formulated into tablets by direct compression which was not possible to employ for pure paracetamol and naproxen without extensive chipping. In-vitro dissolution studies of paracetamol-caffeine and naproxen-nicotinamide co-crystals based formulations also showed enhanced dissolution profiles in comparison to reference formulations. In a single dose oral exposure study conducted in sheep model both cocrystals revealed a significant increase (p < 0.05) in peak plasma concentration and area under the curve. For selected paracetamol-caffeine and naproxen-nicotinamide cocrystals, peak plasma concentrations were 2.45 and 1.61 times higher corresponding to 2.47 and 1.63 times higher area under the curve as compared to pure paracetamol and naproxen. Relative bioavailability was also found to be ~ 2 and 1.6 times enhanced for PCM and NAP co-crystals, respectively. In conclusion, liquid assisted grinding was found to be a robust and easy method and caffeine and nicotinamide as suitable co-formers for the synthesis of co-crystals of paracetamol and naproxen, respectively. Co-crystals illustrated improved physicochemical and mechanical properties. An enhancement in formulation performance and in-vivo oral bioavailability was also shown by co-crystals.