Volume 1, Number 1, June 2017 Science & Development A Journal of the College of Basic and Applied Science (CBAS), University of Ghana Quashie et al Mechano synthesis of co-crystals of Sulfamethoxazole and 8-Hydroxy-7-Iodoquinoline-5-Sulfonic acid based on Green Chemistry principles Andrews Quashie1, Robert Kingsford-Adaboh2, Victor P. Y. Gadzekpo1 1 University of Cape Coast, Cape Coast, Ghana 2 University of Ghana, Legon, Accra, Ghana *Corresponding author: andy.quash@gmail.com Abstract Co-crystals have been used to produce new drugs and to improve the physical properties of drugs. Some disease causing germs have developed resistance to newer drugs, hence there is a general trend to take ‘old’ but efficacious drugs, improve their properties and use them to treat the conditions. This study used mechano-synthesis to produce a co-crystal of two active pharmaceutical ingredients (API), Sulfamethoxazole and 8-hdroxy-7-iodoquinoline-5-sulfonic acid (Ferron), based on Green Chemistry principles. The two APIs were combined by mixing, grinding and kneading. The resulting co-crystals were characterized using analytical methods such as spectroscopy, thermal analysis and diffractometry. In-Silico techniques based on computer modelling using Gaussian 09 and VEDA 4 software were used to interpret the vibrational spectrum of the co-crystals. The study found that kneading gave the highest yield compared to mixing and grinding. The study also confirmed that a combination of the analytical methods was necessary to characterize a co-crystal. Co-crystals of Sulfamethoxazole and 8-Hydroxy-7-Iodoquinoline- 5-Sulfonic acid can therefore be formed by kneading, implying that the production of the co-crystals can be done using a process that reduces pollution by the minimal use of solvents. Another implication is that Sulfamethoxazole, whose use has been minimised because of problems such as allergic reactions from patients, can be looked at again and used to produce ‘polydrugs’ which can be used to manage conditions at relatively cheaper costs. Keywords: Mechano-synthesis, co-crystallization, DSC, VEDA 4, Green Chemistry, Sulfamethoxazole, 8-Hydroxy-7- Iodoquinoline-5-Sulfonic acid Introduction Co-crystals have been defined differently by several Crystalline salts on the other hand interact electrostatically authors, but in all these definitions, a common theme and the components are ionized (Stahly, 2007). Co- is that a co-crystal consists of two or more non-ionic crystals are useful especially in the pharmaceutical compounds in a single crystalline phase in a given industry in the design and preparation of drug forms in stoichiometric ratio held together by hydrogen bonds or which one or more of active pharmaceutical ingredients other non-covalent bonds (Dunitz, 2003 ; Rodríguez- or components are non-ionic. Hornedo, et al., 2007).The components in a co-crystal maintain their chemical properties even after the process This usefulness stems from the possibility of improving since no covalent bonds are broken or formed. the properties of drugs by forming co-crystals of the APIs. Some of the documented properties of drugs which have Science and Development Volume 1, No. 1, 2017 Science and Development 89 been improved are bioavailability and/or dissolution of Hornedo et al., 2007). Here the components are ground drugs which have poor solubility; chemical stability and together with a mortar and pestle or in a mixer mill to melting point (Blagden et al., 2007; Kotak et al., 2015). induce co-crystal formation. This method uses at least Old drugs whose use has been discontinued either due two of the Green Chemistry principles: low temperature to the discovery of newer drugs or because of some and very little or no crystallization solvent (Alatas, et al., unfavourable properties discovered in their use have 2013). recently attracted renewed attention. This is because of A complex set of reactions take place when two solid the emergence of drug-resistant strains of the disease substances are ground together, from the breaking of causing agents. Antibiotics and antibacterials fall in this category (Falagas et al., 2008; Maviglia et al., 2009; the crystalline structure to the production of cracks and Falagas & Kasiakou, 2005; Giamarellou & Poulakou, the development of new surfaces (Fernández-Bertran, 2009). 1999). This method of synthesis is already in use in the local pharmaceutical industry since it does not require An additional advantage that drugs formed using co- sophisticated machinery and/or solvents which may be crystals have over crystalline salts is that many more needed when using solvent evaporation methods. numerous neutral compounds (mainly GRAS1) can be used in drug formulations, rather than the relatively This study is, therefore, aimed at co-crystallizing Sulfa- fewer counterions which are used in crystalline salts methoxazole, a well-known Active Pharmaceutical Ingre- (Halden, 2014). dient (API), used as an antibiotic, with a lesser known but old API, 8-Hydroxy-7-Iodoquinoline-5-Sulfonic The use of co-crystallization in the design and production acid, which has anti-protozoan properties, using Green of drugs is one of the ways that scientists can protect Chemistry principles. people and the environment at the same time since it promotes the use of Green Chemistry principles. Green Chemistry uses methods and conducts reactions at low Experimentals or ambient temperatures; reduces the use of chemicals, which in turn reduces the generation of hazardous wastes Sulfamethoxazole (SMX), 98% purity Analar grade, or substances that must be safely disposed of (Anastas & was purchased from Central Drug House (CDH), New Warner, 1998). Delhi, India, and was used without further purification. 8-Hydroxy-7-Iodoquinoline-5-Sulfonic acid (8H7QS), Though the production of co-crystals by the slow Spot-Test reagent grade, was purchased from BDH evaporation of a solvent in which the components Chemicals Ltd., Poole, England, and was used without are dissolved is very common, solid grinding of the further purification. Ethanol, 99.7 – 100%, Analar components has also been used and is still being grade, was purchased from Pharmacos Banbury, United used to produce co-crystals. In some instances, co- Kingdom, and was used without further purification. Distilled water was prepared using an Accumax (India) crystals produced by solid-grinding exhibit different stainless steel water distillation unit. characteristics from those produced using solvent evaporation (Bruni et al., 1999). A solvent system consisting of Ethanol and distilled Water in a 1:1 volume ratio was prepared and used in the Mechano-synthesis is defined as co-crystal formation in study. the solid state based on mechanical activation of materials by processes such as grinding or milling (Rodrίguez- 1 Generally Recognised as Safe Science and Development Volume 1, No. 1, 2017 90 Science and Development Mechano-Synthesis the powdered co-crystals of 8H7QS and SMX were in- troduced into a PANalytical Empyrean X-ray Diffractom- A Fritsch ‘Pulverisette 2’ Mortar Grinder was used for eter with a copper anode. The K –alpha1 wavelength was both grinding and kneading. The ground sample was 1.54060Å and the K-alpha2 wavelength was 1.39225Å. prepared by weighing 0.5020 g of SMX and 0.6978 g of 8H7QS into the mortar bowl and grinding for 30 minutes. Each sample was scanned continuously in steps of .08o The kneaded sample was prepared by weighing 0.5020 g in 3 seconds with 2θ from 5.04o to 80o while spinning of SMX and 0.6978 g of 8H7QS into the mortar bowl, to acquire the Powder X-ray Diffractograms. Spekwin adding 5 drops of the solvent system and kneading for 30 32 (Menges, 2015) software was used to sketch the minutes. The ‘mixed’ sample was prepared by weighing diffractograms. 0.5020 g of SMX and 0.6978 g of 8H7QS into the mortar bowl and mixing with a spatula for 10 minutes. The Thermal Analysis powdered products were then analysed. An appropriate quantity of crystalline Sulfamethoxazole (SMX), 8-Hydroxy-7-Iodoquinoline-5-Sulfonic acid Infra-Red Spectroscopy (8H7QS), and the co-crystals of 8H7QS and SMX were analysed using the thermal analytical methods of Thermo The infra-red spectra of a suitable quantity of crystalline Gravimetry, TGA, and Thermal Calorimetry, DSC. The Sulfamethoxazole (SMX), crystalline 8-Hydroxy-7- equipment used was TA Instruments SDT-Q600 V20.9 Iodoquinoline-5-Sulfonic acid (8H7QS) and co-crystals Build 20 (Bernstein, 2002). (of 8H7QS and SMX) were measured in the 4000 – 400 cm-1 region at 4 cm-1 resolution and an average The DSC results were collected on a Mettler DSC 822e of 23 scans on a Perkin Elmer Spectrum Two FT-IR under an inert atmosphere (nitrogen at 20 ml/Min) at a Spectrophotometer. The spectra were elaborated using heating rate of 10 deg C per minute (Lu et al., 2008).  the Spekwin 32 (Menges, 2015) software to convert the transmittance to absorbance. Crystal Structure The crystal structure for Sulfamethoxazole was acquired Ultraviolet Spectroscopy from Crystallography Open Database (Gražulis et al., A 0.0128M solution of each of the pure compounds 2012; Grazulis et al., 2009; Downs & Hall-Wallace, and the co-crystals was prepared by dissolving the 2003) as determined and published by Perlovich G. compound/powdered co-crystal in a mixed solvent L. et al., 2013), was visualized using OLEX 2 software system of Ethanol:Water (1:1 by vol.). The solution (Dolomanov, Bourhis, Gildea, Howard, & Puschmann, was used subsequently for the Ultraviolet spectroscopy. 2009) and plotted using ORTEP-plot in PLATON The UV spectra of Sulfamethoxazole, 8-Hydroxy-7- version 271014. Iodoquinoline-5-Sulfonic acid and the co-crystal were X-ray crystal structure data on 8-Hydroxy-7-Iodoquin- determined using a Spectroquant Pharo 300 UV-Vis oline-5-Sulfonic acid was obtained from Crystal Open Spectrophotometer in the region 190 nm – 1100 nm. The Database (COD) (Information card for 2005313) as spectra were elaborated using the Spekwin 32(Menges, published by Balasubramanian and Muthiah (1996), was 2015) software. visualized using OLEX 2 software (Dolomanov et al., 2009) and plotted using ORTEP-plot in PLATON ver- Powder X-ray Diffraction: sion 271014. Suitable quantities of Sulfamethoxazole (SMX), 8-Hy- droxy-7-Iodoquinoline-5-Sulfonicacid (8H7QS) and Science and Development Volume 1, No. 1, 2017 Science and Development 91 Results and Discussions the stretching of the bond between C6 and H6. There wasM aelcshoa nao csoynntthreisbisu otfio cno- cfrryosmtal st hofe S tuolfrasmioenth oinxavzoollveainndg 8H-H2y,d roxy-7- C2, C3 and C4. Infra-Red Spectroscopy iodoquinoline-5-Sulfonic acid based on Green Chemistry principles The experimentally determined infra-red spectrum of 8-Hydroxy-7-Iodoquinoline-5-Sulfonic acid showed no distinct peaks above the 3000 cm-1 wavenumber. This confirms the IR spectrum as reported in the data base of NIST (8-Hydroxy-7-iodo-5-quinoline sulfonic acid, 2011) Using IR spectroscopy, the structural consequences of combining the two compounds using mechano-synthe- sis were shown using the vibrational modes of the bonds maintained or newly formed in the process (Thanigaima- ni et al., 2015). The number of atoms in 8-Hydroxy-7-Iodoquinoline-5- Sulfonic acid, 8H7QS, is 22 and that of Sulfamethoxazole, SMX is 28. The degrees of freedom which constitute vibrational motion for each of the compounds are therefore 60 and 78 respectively (Banks et al., 2010). The Total Energy Distribution, TED data generated Fig. 1: Labelled molecule of 8-hydroxy-7- Figure 1: labelled molecule of 8-hydroxy-7-iodoquinoline5-sulfonic acid (8H7QS) from the Potential Energy Distribution, PED, was iodoquinoline5-sulfonic acid (8H7QS) used in discussing the IR spectrum of the two starting -1 compounds. The PED analysis is more accurate than A C - C pure mode was determined at 1401 cm to be the visualization of an atom movement to interpret a due to stretching between C4 and C7. This was shown -1 theoretical vibrational spectrum of a molecule. It also experimentally at 1383 cm . Most of the C – C bonds quantitatively describes the contribution to movement of gave peaks theoretically varying from 850 cm -1 to 1500 -1 a given group of atoms in a normal mode ( Jamróz, 2013). cm , but these were mixed with other modes. The PED analysis is indispensible tool in serious analysis C – H had a pure stretching mode at a calculated of the vibrational spectra. To perform the PED analysis wavelength of 1037.18 cm-1; experimentally it was it is necessary to define 3N-6 linearly independent local shown at 1042 cm-1. At a wavelength of 707.52 cm-1 mode coordinates. Already for 20-atomic molecules it is (experimentally at 726 cm-1), the stretching of both C-H a difficult task. The VEDA program reads the input data and N-H were mixed, though the N-H contributed more automatically from the Gaussian program output files. to the absorbance. Then, VEDA automatically proposes an introductory The stretching of the O8-H8 bond was assigned the set of local mode coordinates. Next, the more adequate wavelengths 3254, 1710, 237 and 209 cm-1, but these coordinates are proposed by the program and optimized were not shown clearly experimentally. This may be to obtain maximal elements of each column (internal due to the location of the lone pair of electrons in the coordinate. antibonding orbital of H8 as determined with the NBO Figure 1 is a labelled molecule of 8H7QS based on its analysis. crystal structure. The highest peak from the experimental The stretching of the S –O bond gave a pure mode at data for 8H7QS was at 598 cm-1 and this was shown in 397.3 cm-1 (experimentally at 403 cm-1). the calculated data at 600.82 cm-1. This was attributed to Science and Development Volume 1, No. 1, 2017 92 Science and Development Figure 2 below is a labelled molecule of SMX based on The peak at 1509.14 cm-1 in the calculated spectrum, its crystal structure. The highest peak in the calculated corresponding to the peak at 1501 cm-1 in the spectrum of Sulphamethoxazole is at a frequency of experimental spectrum, is also due to a pure mode 507.75 cm-1 corresponds to the peak at 561.84 cm-1 in the of torsion in the plane C1-C6-C5-C8. The stretching experimental spectrum. This is attributed to the torsion modes between atoms in the group frequency region are of the planes which pass through H2-C2-C3-C4 and H3- mainly mixed with other modes except for the calculated C3-C4-S1. The peaks around 3000 cm-1 frequency are modes at 1053.32 cm-1 and 1038.59 cm-1 which are single due mainly to torsion of some planes in the molecule. For modes attributed to the stretching of the C3-H3 bond example, the peaks at 3377 cm-1 and 3298 cm-1, calculated and the O2-N2 bonds respectively. These bonds are seen to be at 3354.13 cm-1 and 3262.24 cm-1 respectively, are around the 1000 cm-1 in the experimental spectrum. due in part to torsion in the plane through H1B-N1- The pure bending mode between atoms H10A-C10-C9 C1-C2. However, the peaks at calculated frequencies gives a peak at a calculated frequency of 1300.24 cm-1 of 3171.04 cm-1 and 3088.09 cm-1 are due to pure which corresponds the peak at 1303 cm-1 determined bending modes between O3-N3-C7 and H2A-N2-O2 experimentally. The is a pure bending modes between respectively. the atoms H6-C6-C1 and N1-C1-C6 give peaks at calculated frequencies of 1361.9 cm-1 and 1358.44 cm-1 respectively. These peaks correspond to the peak at the frequency of 1363 cm-1 determined experimentally. Vibrational modes from bonds in 8H7QS, especially in the ‘fingerprint’ zone, which were not available when the co-crystal was formed by Grinding, Kneading and ‘Mixing’ have been given in Tables 1 to 3 respectively below. Also shown are the assignments as determined from PED calculations using the VEDA 4 software ( Jamróz, 2015). FFiiggu.r e2 2:: LLaabeblleedl mleodlec muleo ofl eSuclfuamleet hoofx aSzoulel f(SaMmX)e thoxazole (SMX) Table 1: Vibrational modes of absorptions of 8H7QS remaining after Grinding Calculated Experimental No. IR Absorbance Wavenumber IR Absorbance Wavenumber Assignment (cm-1) (cm-1) 1 53.1 1449.47 0.816 1459 13δHNC 2 18.56 1342.05 0.8246 1348 11τCCCS+11τCNCC 3 141.36 1291.64 0.8529 1298 4 55.53 1181.96 0.9561 1174 12νCC+11νCC+11δHCC 5 8.69 950.05 0.8817 956 78δOOS 6 40.33 867.54 0.857 936 11δHCC+22δHCC Figure 3: IR spectra of both compounds and Co-crystals 7 3.87 856.15 0.8839 917 11νCC+10δHCC+16δICC 8 11.25 801.96 0.8565 847 11δHCC+16τHOCC+18τHCCC+18τHCCN Science and Development Volume 1, No. 1, 2017 Science and Development 93 Table 2: Vibrational modes of absorptions of 8H7QS remaining after Kneading Calculated Experimental No. IR Absorbance Wavenumber IR Absorbance Wavenumber Assignment (cm-1) (cm-1) 1 53.1 1449.47 0.816 1459 13δHNC 2 18.56 1342.05 0.8246 1348 11τCCCS+11τCNCC 3 141.36 1291.64 0.8529 1298 4 55.53 1181.96 0.9561 1174 12νCC+11νCC+11δHCC 5 40.33 867.54 0.857 936 11δHCC+22δHCC 6 3.87 856.15 0.8839 917 11νCC+10δHCC+16δICC 7 11.25 801.96 0.8565 847 11δHCC+16τHOCC+18τHCCC+18τHCCN Table 3: Vibrational modes of absorptions of 8H7QS remaining after ‘Mixing’ Calculated Experimental No. IR Absorbance Wavenumber (cm-1) IR Absorbance Wavenumber (cm-1) Assignment 1 127.36 1616.22 0.8461 1621 12δHOC 2 53.1 1449.47 0.816 1459 13δHNC 3 18.56 1342.05 0.8246 1348 11τCCCS+11τCNCC 4 40.33 867.54 0.857 936 11δHCC+22δHCC 5 3.87 856.15 0.8839 917 11νCC+10δHCC+16δICC 6 11.25 801.96 0.8565 847 11δHCC+16τHOCC+18τHCCC+18τHCCN 7 29.99 707.52 0.8658 726 10νCH+18νNH 8 23.56 620.03 0.8954 624 16τHNCC 9 182.25 600.82 1 598 10νCH+13τHCCC Co-crystals from all mechano-synthesis methods used Under all three syntheses, the 8H7QS bonds which were have similar IR spectra, especially in the ‘finger print’ de-emphasised in the co-crystallization process were region. the bending of HNC, HCC, ICC, the twisting of CCCS, CNCC, HOCC, HCCC, and HCCN; and the stretching The wavenumbers at which the co-crystals absorbed of CC. which are not in the starting compounds are highest for the kneading method; these were at 3105 cm-1, 1502 Similar vibrational modes of both 8H7QS and SMX cm-1, and 571 cm-1. In the case of grinding, there was were not available in the co-crystals formed through an absorption at only one new wavenumber, 3070 cm-1. either grinding or kneading. For example, the vibrational Similarly, when the compounds were mixed, there was modes which absorbed between wavenumbers 1830 cm-1 only one new wavenumber with absorption at 3104 cm- and 2170 cm-1 in the spectrum of 8H7QS were all absent 1. in the co-crystals, no matter the method of production. This is shown in Figure 3. This implies that new bonds are formed by kneading whose vibrational modes are at those wavenumbers. Science and Development Volume 1, No. 1, 2017 94 Science and Development Figure 2: Labelled molecule of Sulfamethoxazole (SMX) When the compounds were ‘mixed’ together, the peak w as at 296 nm and the shoulder between 315 nm and 3Fi5gu0re 4n: ImR s.p eThctra oef CUo-cVrys taslsp sheocwitnrga re liastiv eg iinvtenesintie si onf e Fachi gtyupe re 5. FiguFrei 3g: .IR 3 sp:e cItRra osf pboethc ctomrapo uondfs b anod tCoh-c rcysotamls pounds and Co-crystals At wavenumbers common to all products of the mechano synthesis, the lowest absorption were from the FigureF 5:i UgV. s p5e:c trUa oVf C somppeoucndtsr and o Cof- cCrysotamls pounds and Co-crystals kneaded products as shown in Figure 4. This supports the conclusion that the kneading process produces the most co-crystals since the formation of the co- Differential Scanning Calorimetry crystals has the effect of reducing the amount of starting compounds available which could have absorbed at those The melting point of 8H7QS was found to be 269.25 oC, wavenumbers. while the decomposition temperature of the 8H7QS was determined to be 283.07oC. The literature value for the melting point of 8H7QS is 269-270oC. The literature value is close to the laboratory determined value of 268- 270oC using the capillary method. The melting point of SMX on the other hand is 168.30oC which is close to the literature value of 166-171.5oC and to that determined in the laboratory which was 170oC. The decomposition temperature was determined to be 250.07oC. FFiiggu.re 4 4:: I RIR sp esctpra eof cCto-rcarys toalsf sbhoowitngh re clatoivem intpenositiuesn ofd easch a tynped Co-crystals The melting point of the co-crystal produced is lower than the melting points of the starting materials and decreases in the order ‘Mixed’> Ground>Kneaded as UV Spectra given in Table 4. The 8H7QS had a peak at 297 nm and a shoulder between 325 nm and 345 nm while the SMX had a single peak at The latent heat of the co-crystals formed using the 300 nm. different synthesis methods is approximately the same, though it decreases slightly in the order ‘Mixed’> When the two compounds were ground together for 30 Ground>Kneaded. This implies that the products are minutes, the peak was at 292 nm and a shoulder between 320 nm and 350 nm. the same, but with different impurities which may be remnants of the starting compounds. W hen the compounds were kneaded together, the peak wFigausre a5: tU V2 sp9e7ctr an ofm Com aponundd s aan ds Cho-ocruystladls er between 315 nm and 345 nm. Science and Development Volume 1, No. 1, 2017 Science and Development 95 Table 4: Melting point and Latent Heat of compounds of the co-crystal. Likewise, peaks at 2θ = 42o, 7.36o and and co-crystals 35.20o in the diffractogram of SMX did not appear in the diffractogram of the co-crystal. Sample Melting point Latent Heat(oC) (J/g) In the case of the co-crystal formed by grinding, the 8H7QS 269.25 diffractograms showed fewer peaks at angles common to SMX 168.30 -112.34 both 8H7QS and SMX on one hand and the co-crystal 8H7QS + SMX ‘Mixed’ 167.50 -38.85 on the other. For example, the peaks at 2θ = 28.80o, 8H7QS + SMX Ground 166.32 -38.96 17.76o and 21.52o of the diffractogram of the co-crystal 8H7QS + SMX Kneaded 156.92 -40.25 had no corresponding peaks at the same angles for either 8H7QS or SMX. Conversely, most of the major peaks Co-crystals were formed under the various synthesis in the diffractogram of either 8H7QS or SMX did not conditions with the highest yield being when the appear in the diffractogram of the co-crystal. powders were kneaded. The different forms of co-crystals In the case of the co-crystal from kneading, the five peaks all decomposed at temperatures (between 193-196oC) with the highest intensities of 8H7QS were not found far lower than the decomposition temperatures of the in the diffractogram of the co-crystal, though three of starting compounds. Table 5 below gives the latent heat the highest peaks of SMX were visible. The co-crystal of decomposition of the co-crystals. had characteristic peaks at 2θ = 17.52o and 22.56o. The characteristic intense peak of SMX at 2θ = 24.08o was Table 5: Decomposition point of compounds and also not visible in the diffractogram of the co-crystal. co-crystals When the diffractogram of the co-crystals from the different synthesis were compared, characteristic peaks Onset Decom- Latent Heat of o o o o Sample position Point Decomposition were found at 2θ = 9.92 , 17.52 , 27.60 , 28.60 and (oC) (J/g) 40.30o. 8H7QS 283.07 -375.87* This indicates the formation of a product, in this case, a co- SMX 250.07 471.65 crystal, when the two compounds are brought together, 8H7QS + SMX ‘Mixed’ 195.81 159.01 with the best method of synthesis being kneading. 8H7QS + SMX Ground 193.16 230.91 8H7QS + SMX Kneaded 194.66 298.60 Conclusion * Latent heat of melting and decomposition Co-crystals of 8-Hydroxy-7-Iodoquinoline-5-Sulfonic acid and Sulfamethoxazole were successfully produced Powder X-Ray Diffractometry using Green Chemistry principles by applying mecha- no-synthesis methods. Generally, the intensities of the peaks were lowered when the co-crystals were formed. Kneading of the compounds together gives the highest yield of the co-crystals compared to mixing which gave All the major peaks in the diffractogram of the co-crystal the least. formed by ‘mixing’ of 8H7QS and SMX are found as peaks at the same angles, 2θ, in the diffractograms of Using UV spectroscopy alone does not show clearly the 8H7QS and/or SMX except for the peak at 2θ = 6.88o. formation of the co-crystals. Peaks at 2θ = 11.76o and 20.56o found in the diffractogram of 8H7QS however did not appear in the diffractogram Science and Development Volume 1, No. 1, 2017 96 Science and Development References analysis program. J. Appl. Cryst. Retrieved from support@olex2.org. Alatas, F., Soewandhi, S. N., Sasongko, L., Ismunandar, & Uekusa, H. (2013). Cocrystal Formation Downs, R. T., & Hall-Wallace, M. (2003). The American Between Didanosine And Two Aromatic Mineralogist Crystal Structure Database. 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Crystal Growth & Design, 13, 4002–4016. http://doi.org/10.1021/ cg400666v. Science and Development Volume 1, No. 1, 2017 BIOLOGICAL SCIENCE 2 An Integrated Education Intervention Improves the Feeding Frequency of Infants and Young Children in the Upper Manya Krobo District of Ghana Agartha Ohemeng (PhD), Grace S. Marquis (PhD) and Anna Lartey (PhD) 14 Understanding the smallholder farmers’ crop production choices in the forest-savanna transition zone of Ghana Jesse S. Ayivor, Benjamin D. Ofori, Opoku Pabi and Chris Gordon 29 n dynamics of aphids, Lipaphis erysimi pseudobrassicae (Davis) and Myzus persicae (Sulzer) (Hemiptera: Aphididae), their natural enemies and the yield of cabbage Ethelyn Echep Forchibe, Ken Okwae Fening and Kwame Afreh-Nuamah VETERINARY SCIENCE 45 Gross and Histo-Pathologic Findings in Goats with Plastic bags in the Rumen Otsyina, H. R., Mbuthia, P. G., Nguhiu-Mwangi, J., Mogoa, E. G. M. and Ogara W. O. PHYSICAL SCIENCE 59 Estimating Exceedance Probability of Extreme Water Levels of the Akosombo dam Eric Ocran, Kwabena Doku-Amponsah and Ezekiel N. N. Nortey 68 Leaching of trace metals from mixed electronic waste using four extraction methods Stephen Nyarko, Rose Tawiah, Isaac Asante and Frank Nyame 79 Public Perception of E-Waste Management and Disposal Practices in Accra Metropolis, Ghana Bonzongo, Brajesh Dubey, Isaac Asante and Frank Nyame 88 Mechano synthesis of co-crystals of Sulfamethoxazole and 8-Hydroxy- 7-Iodoquinoline-5-Sulfonic acid based on Green Chemistry principles Andrews Quashie, Robert Kingsford-Adaboh and Victor P. Y. Gadzekpo College of Basic and Applied Science University of Ghana