Initially, co-crystals are exploited in pharmaceutical analysis to change the chemistry properties of a drug like solubility, stability, temperature and shelf life.

Crystal engineering is generally considered to be the design and growth of crystalline molecular solids with the aim of impacting material properties. A principal tool is that the bond, that is answerable for the bulk of directed unit interactions in molecular solids. Co-crystals area unit multi-component crystals supported chemical element bonding interactions while not the transfer of chemical element ions to make salts; this is often a crucial feature, since bronsted acid-base chemistry isn't a demand for the formation of a co-crystal. Co-crystallization could be a display of directed self-assembly of various elements. Co-crystals have been described of various organic substances over the years [1, 2] and given numerous names, like addition compounds [3, 4] molecular complexes [5, 6] and hetero molecular co-crystals[7]. Despite naming convention, the essential which means is that of a multi-component crystal wherever no valency chemical modification of the constituents happens as a result of the crystal formation.

Pharmaceutical active ingredients (APIs) will exist in an exceedingly kind of distinct solid forms, as well as polymorphs, solvates, hydrates, salts, co-crystals and amorphous solids. Every kind displays unique physicochemical properties that can profoundly influence the bioavailability, manufacturability purification, stability and other performance characteristics of the drugs

2. Co-crystals, Salts, Solvates and Hydrates:

USFDA defined the co-crystal, salt and polymorphs in the draft guidance. The polymorphs are defined as the compounds which are present in different crystalline forms such as solvates or hydrates (also known as pseudo polymorphs) and amorphous forms. Polymorphs have different lattice arrangement and also, they have different physicochemical properties due to their crystal lattice structures. Salts are the compounds which are formed by complete transfer of proton from one compound to another [8].

Salts and co-crystals can be differentiated based by a proton transfer from an acid to base. A complete transfer of proton takes place between acid-base pairs, whereas, no proton transfer occurs during co-crystal formation. Two components are bound to each other by non-covalent interactions such as hydrogen bonding, π-π stacking, and Vander Waal forces. A prediction can be made by ΔpKa value whether co-crystals are formed or not. It is generally accepted that a salt will be formed if the ΔpKa value is greater than 3 and ΔP ^K^a value less than 0 will lead to the formation of co-crystals. This parameter is not accurate to predict the formation of co-crystals in solids between the ΔpKa values 0 and 3 but the possibility of salt formation will increase when the ΔpKa increases [9, 10].

Co-crystals and solvates can be differentiated based on their physical state of the components. The compounds which are liquid at room temperature are called as solvates whereas those compounds which are solid at room temperature are called as co-crystals. If the solvates contain water as a solvent in their crystal lattice then they are known as hydrates [11] Solvates/hydrates are commonly formed during the co-crystallization via solution or liquid assisted grinding and they can alter physicochemical properties of API’s. Stability of solvates will be different from un-solvated forms because of presence of solvent in crystal lattice.

Solvates/hydrates are quite unstable, because they lose solvent/water at high temperature and low humidity during storage and the physiochemical properties will be different for hydrated/dehydrated forms [12, 13]. Dissolution rate of the drug was enhanced by the solvated forms of spironolactone [14]. Different polymorphic co-crystals and solvates of caffeine and anthranilic acid were prepared by using different solvents via liquid assisted grinding. [15]

2.1 Advantages of Co Crystals:

Ÿ Stable crystalline form as compared to amorphous kind.

Ÿ Give exaggerated solubility; so exaggerated bioavailability.

Ÿ Technique is used for purification.

Ÿ Co-crystals having benefits like stable crystalline kind (as compared to amorphous solids).

Ÿ No need to make or break covalent bonds, theoretical capability of all types of API molecules (weakly ionizable/non-ionizable) to form co-crystals.

Ÿ The existence of diverse potential counter-molecules (food additives, preservatives, pharmaceutical excipients, and alternative APIs).

Ÿ The only solid form that is designable via crystal engineering patentable expanding IP portfolios and can be produced using solid-state synthesis green technologies high yield, no solvent or by-products.

2.2 Design of Co-Crystals:

The crystal engineering experiment usually involves the Cambridge Structural information (CSD) survey followed by the experimental work. Co-crystals designed on the principal of the supramolecular synthesis; it provides a strong approach for proactive discovery of novel pharmaceutical solid phases. Co-crystals incorporates multiple elements in given ratio quantitative relation, wherever completely different molecular species move by chemical element bonding and by non-hydrogen bonding.

The use of chemical element bonding rules, synthons and graph sets could assist within the style and analysis of co-crystal systems. Normally tho', prediction of whether or not co-crystallization can occur isn't however attainable and should, at present, be answered through empirical observation. Co-crystal formation could also be rationalized by thought of the bond donors and acceptors of the materials that area unit to be co-crystallized and the way they may move. Following the intensive examination of discriminatory packing preferences and bond patterns in an exceedingly variety of organic crystals, Etter and associates projected the rules to facilitate the deliberate style of hydrogen-bonded solids.[16] All smart nucleon donors and acceptors area unit employed in chemical element bonding, membered ring unit chemical element bonds kind in preference to unit chemical element bonds, the most effective nucleon donor and acceptor remaining when unit chemical element-bond can form unit hydrogen bonds to 1 another (but not all acceptors can essentially move with donors). These observations facilitate to handle the difficulty of competitive bond assemblies ascertained once employing a specific co crystallizing agent.

A detailed understanding of the supramolecular chemistry of the functional groups present in a given molecule is the prerequisite for designing the co-crystals because it facilitates the selection of the suitable co-crystal former. Supramolecular synthons that can occur in common functional group in order to design new co-crystals and certain functional groups such as carboxylic acids, amides and alcohols are particularly amenable to formation of supramolecular heterosynthon.[17] The strong hydrogen bond includes (N-H---O), (O-H---O), (-N-H---N, ) and (O-H---N). The weak hydrogen bonds involves the −C-H---O and C-H---O=C [18]

2.3 Different Strategies of Co-crystals Formation:

Till date, completely different strategies are reported for the preparation of co-crystals by the researchers. Few ancient strategies supported the answer and grinding was reported for the synthesis of co crystals [19]. An appropriate form of solvent is employed in answer methodology for the preparation of co crystals. Differing kinds of strategies like solvent evaporation [20], crystallization technique [21], anti-solvent addition [22], suspension conversion methodology [23] and reaction crystallization methodology [24] area unit mentioned with appropriate examples in table 1. Grinding strategies area unit of 2 types: neat grinding and solvent drop grinding [25,26]. Some new rising strategies used for the formation of co crystals area unit ultrasound aided methodology [27,28], critical fluid atomization technique [29,30] spray drying technique [31,32] hot soften extrusion technique [33,34].

2.3.1 Solution-Based Strategies:

2.3.1.1. Solvent Evaporation method:

In solvent evaporation method, for both API and coformer are dissolved in a suitable solvent and the solution is allowed to evaporate the solvent slowly.

During dissolution, the functional groups in the drug and conformer interact with each other and form hydrogen bonds [30]. This is most commonly used method for the preparation of co-crystals by researchers [23,35].

In solution crystallization technique, drug and co-formers are dissolved in boiling solvent with stirring and the boiling of the solution would be continued until the volume of the solution become small Co crystallization takes place rapidly when the boiling solution is allowed to cool about 15 min. Co crystals are separated by filtration and kept in oven or air for drying [21,36].

2.3.1.7. Supercritical Fluid Atomization Technique:

In critical atomization technique, the drug and co-formers area unit mixed with one another by victimization high pressurized critical fluid i.e. CO2. Co-crystals area unit ready by atomizing this answer with the assistance of sprayer. In critical anti-solvent (SAS) methodology, the co-crystals area unit ready from answer by the anti-solvent result of critical fluid [47- 49].

2.3.1.8. Spray drying technique:

In spray drying method, Co-crystals area unit ready by spraying the answer or suspension of drug and coformer with hot air stream to evaporate the solvent. This is often the foremost most well-liked technology as a result of this is often a quick, continuous, and ballroom dancing method. Thus, spray drying method can supply a novel atmosphere for the preparation and scale-up of co-crystals. [30,31] (Figure 2)

2.3.1.9. Hot Soften Extrusion Technique:

In hot soften extrusion technique, the co-crystals area unit ready by heating the drug and co-formers with intense intermixture that improved the surface contacts while not use of solvent. The restrictions of this methodology embrace each coformer and API ought to be compatible in liquefied kind and not used for unstable medicine [32,33].

3. EVALUATION OF COCRYSTALS:

3.1. Fourier transforms infrared radiation (FTIR):

FTIR spectrographic analysis is employed to predict the unit interactions and compatibility study between drug and co-formers. This system is wide accustomed predict the chemical conformation of compounds. Aakeroy et al. used FTIR to tell apart the co-crystals from salts by evaluating the acid involvement within the bond formation [50,51]. Pure drug, coformer, physical mixture and co-crystals area unit analyzed by FTIR within they vary of 400-4000 cm-1. FTIR study is additionally used alongside alternative techniques like DSC or XRD for the screening of the co-crystals [52,53,54].

3.2. Differential scanning colorimetry (DSC):

DSC has been used for screening of co-crystal formation. Screening of co-crystals formation is determined by the presence of heat-releasing peak followed by endoergic peak in DSC spectra. The presence of those peaks within the physical mixture of elements indicates the chance of formation of co-crystals. Pure drug, coformer, physical mixture and co-crystals were weighed out (1.5-2.5 mg) in atomic number 13 pans and analyzed with heating rates of five-30° victimization similar empty pan as a reference. The gas with rate of flow fifty ml/min maintained the inert atmosphere. Temperature, glass transition temperature, polymorphic nature, heat of fusion, endoergic or heat-releasing behavior is determined by victimization DSC [42,55].

3.3. Thermo gravimetric analysis (TGA):

Physical and chemical properties of solids area unit determined by victimization thermal analysis as a operate of skyrocketing temperature (with constant heating rate) or as a operate of your time (with constant temperature and/or constant mass loss). TGA could be a appropriate methodology for determination of hydrates/solvates sorts of co-crystals or presence of volatile elements still as decomposition or sublimation temperature. Thermal stability, compatibility and purity of co-crystals is foretold by TGA analysis. The burden losses of sample mass throughout the TGA analysis is that the indication of loss of volatile part or decomposition of co-crystal [56,57,59].

3.4. Terahertz time domain-spectroscopy (THz-TDS):

Terahertz time-domain-spectroscopy (THz-TDS) is another tool to PXRD for the characterization of co-crystals. Chiral and racemic molecular and supramolecular structures is distinguished by rate spectrographic analysis [52] rate spectrographic analysis was accustomed distinguish the identical molecular structure co-crystals of bronchodilator with completely different co-formers (such as malic acid and salt acid) that were gift in chiral and racemic forms [60].

3.5. Solid-state NMR:

Solid-state NMR (SSNMR) is employed to characterize solid phases that can't be studied by SXRD [52]. SSNMR was accustomed investigate the character of complicated by crucial degree of nucleon transfer. Thus, SSNMR is a crucial tool for the identification of co-crystal or salt. SSNMR may be accustomed appraise the co-crystal structure by estimating chemical element bonding and native conformation changes by couplings [61,62].

3.6. Powder x-ray diffractometer:

PXRD is often used for screening and determination of co-crystal structure [29]. The PXRD patterns obtained from diffractometer were compared to every alternative for analyzing the structure of co-crystals. The various PXRD pattern of co-crystals from their elements is that the indication of co-crystal formation [47,63]. Crystal structure of solids at atomic level co-crystals is set by victimization single crystal X-ray diffraction (SXRD). The most important downside associated with this system is that usually single co-crystal cannot be made that is appropriate for SXRD analysis [52]. Scanning microscope is that the instruments accustomed verify the particle size and morphological analysis of co-crystals. A high energy lepton beams scan the atoms that give the knowledge regarding the sample surface’s topography. [31,52].

3.7. Invitro Dissolution:

Dissolution study is employed to work out the quantity of drug enhances with time in dissolution medium and predict the in vivo performance of the formulation. Dissolution studies for the co-crystals are performed with the assistance of the dissolution equipment. The dissolution study for the co-crystals is done at intervals the acceptable dissolution medium delineated in drug protocol of referred assemblage. The drug samples is collected within the appropriate amount at preset measure and might be examined with the assistance of appropriate suggests that like HPLC or UV. [64,65]

3.8. Solubility study:

Solubility study is assessed by Higuchi and tennis player methodology for solubility determination. The solubility of pure drug, physical mixture and co-crystals is determined in water or appropriate medium given within the referred assemblage. Drug sample and medium ought to be extra in an exceedingly cone-shaped flask, and will be agitated for twenty-four h at temperature on rotary flask shaker. The complete samples ought to be protected against light-weight by wrapping the flask by aluminum foil if the drug is sensitive to light-weight. When twenty four h samples area unit filtered through Whatman paper and aliquots area unit befittingly diluted and assayed by HPLC or actinic radiation at appropriate wavelength [66,67].

3.9. Stability study:

Stability study provides the knowledge regarding time period of drug product below completely different storage conditions. Medicine product ought to be unbroken in glass vials below variable environmental factors (such as wetness, temperature, light) for various intervals of time. After that, the samples area unit analyzed for thermal study, drug dissolution study, XRD study and FTIR study and compared with the results obtained before stability study [68].

4. APPLICATIONS OF CO-CRYSTALS:

Ÿ Co crystallization has a bonus to optimize the chemistry properties of medicine while not sterilization the molecular structure of medicine.

Ÿ The chew over whether co-crystals or salts will have the desired properties depends upon the API and specific project.

Ÿ Co-crystals with negative ΔpKa value will give non-ionized drug when dissolved whereas salt will give ionized API, which is more soluble in water.

Ÿ Whenever dissolution rate of drug should be important rather than equilibrium solubility, co-crystals can be better than salt form of drug.

Ÿ Co crystallization is an alternative way to enhance the solubility and bioavailability of poorly water soluble drugs, especially for those compounds which are neutral or weakly ionized in nature [68-70]. Further, co-crystallization also offers possibility of altering improving the melting point, tablet ability, solubility, stability, bioavailability and permeability.

5. CONCLUSION:

Co-crystals are very interesting and useful product. The co-crystals are solid substances, which consist of few components mixed together; the co-crystals can be applied in medicine and pharmaceutical industry for improving different properties such as dissolution rate, melting point, solubility, chemical stability and decreasing dose size. Co-crystal produced supersaturating with respect to the parent drug and improving the drug penetration and diffusion due to an enhanced amount of free drug in the medium. Moreover, the co-crystal intrinsic solubility, dissolution and coformer ionization reduced the media pH, enhancing the proportion of the unionized species and thus drug transport through passive diffusion absorption mechanism. Co-crystallization is a very useful method for a crystal engineer to change the physical properties of solid materials. In current the results of applications of co-crystallization in pharmaceuticals are useful only at microscopic level. Strategies to produce co-crystals in larger scales are yet to be focused into, in order to get maximum useful results of whatever has been achieved at microscopic level.

6. ACKNOWLEDGEMENT:

The Authors are thanks full to Sree Vidyanikethan College of management Dr M. Mohanbabu and Principal Dr. Anna Balaji for providing necessary facilities and infra structure.

7. DECLARATION OF INTEREST:

Nil.

8. REFERENCE:

1. Kobell FV, Prakt JF. D-glucose: Sodium chloride monohydrate.Chemie.1843; 28:489.

2. Wöhler F. Untersuchungen über das Chinon Quinhydrone. Annalen. 1844; 51:153.

3. Buguet A. Cryoscopy of Organic Mixtures and Addition Compounds. Compt Rend. 1910; 149:857.

4. Grossmann H. Thiourea. Cryoscopy of organic mixtures and addition compounds. Chemiker-Zeitung. 1908; 31:1195.

5. Damiani A, De Santis P, Giglio E. The crystal structure of the 1:1 molecular complex between 1, 3, 7, 9-tetramethyluric acids and pyrene. Acta Crystallogr. 1965; 19:340. DOI.org/10.1107/S0365110X67003470.

6. Ramu Samineni, Anil Kumar M, Malisha J, Pavani K, Bhavyasree K, Nithin E. R. Formulation and Evaluation of Topical Solid Lipid Nanoparticulate System of Aceclofenac. Int J Pharma Res Health Sci.2018 6 (4): 2647-2650

7. Pekker S, Kovats E, Oszlanyi G, Benyei G, Klupp G. Rotor-stator molecular crystals of fullerenes with cubane. Nat Materials. 2005; 4:764–7. DOI: 10.1038/nmat1468.

8. Ramu samineni, Gopal Reddy, Chandra P, Srinivasa Rao D, Ramakrishna G. Formulation And Evaluation Of Lansoprazole Delayed Release Pellets. International Journal of Pharmaceutical, Chemical & Biological Sciences.2015 5 (4): 860-878

9. Bhogala BR, Basavoju S, Nangia A. Tape and layer structures in cocrystals of some di- and tricarboxylic acids with 4, 4-bipyridines and isonicotinamide. From binary to ternary cocrystals. Cryst Eng Comm 2005:7; 551-62. DOI:10.1039/B509162D.

10. Childs SL, Stahly GP, Park A. The salt-cocrystals continuum: The influence of crystal structure on ionization state. Mol Pharm 2007:4; 323-38. DOI: 10.1021/mp0601345.

11. Morissette SL, Almarsson O, Peterson ML, Remenar JF, Read MJ, Lemmo AV, et al. High-throughput crystallization: polymorphs, salts, cocrystals and solvates of pharmaceutical solids. Adv Drug Deliv Rev 2004:56; 275-300. DOI.org/10.1016/j.addr.2003.10.020.

12. Vishweshwar P, McMahon JA, Bis JA, Zaworotko MJ. Pharmaceutical cocrystals. J Pharm Sci 2006; 95:499-516. DOI: 10.4172/pharmaceutical-sciences.1000302.

13. Blagden N, Matas M, Gavan PT, York P. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Adv Drug Deliv Rev 2007:59; 617-30. DOI: 10.1016/j.addr.2007.05.011.

14. Ross SA, Lamprou DA, Douroumis D. Engineering and manufacturing of pharmaceuticals cocrystals: a review of solvent free manufacturing technologies. Chem Commun 2016; 52:8772-86 DOI: 10.1039/C6CC01289B.

15. Salole EG, Al-Sarraj FA. Spiranolactone crystal forms. Drug Dev Ind Pharm 1985:11; 855-64 DOI.org/10.3109/03639048509057461.

16. Madusanka N, Eddleston M, Arhangelskis M, Jones W. Polymorphs, hydrates and solvates of a co-crystal of caffeine with anthranilic acid. Acta Crystallogr B Struct Sci Cryst Eng Mater 2014:70; 72-80 DOI: 10.1107/S2052520613033167.

17. Nair RH, Sarah JN, Adivaraha J, Swarbreek, editors. Co-crystals: design, properties and formulation mechanism, in Encyclopedia of Pharmaceutical Technology. 3rd ed. Vol. 1. New York: Informa Healthcare; 2007. p. 615.

18. Burton WK, Cabrera N, Frank FC. The growth of crystals. Phil Tran R Soc Lond A. 1951; 243:299–358. DOI.org/10.1016/0001-8686(79)87007-4.

19. Ning S, Michael JZ. The role of co-crystals in pharmaceutical science. Drug Discov Today. 2008; 13:440–6. DOI: 10.1016/j.drudis.2008.03.004.

20. He GW, Jacob C, Guo LF, Chow PS, Tan RBH. Screening for cocrystallization tendency: the role of intermolecular interactions. J Phys Chem 2008; 112:9890-5. DOI: 10.1021/jp803019m

21. Lin HL, Hsu PC, Lin SY. Theophylline-citric acid co-crystals easily induced by DSC-FTIR microspectroscopy or different storage conditions. Asian J Pharm Sci 2013; 8:19-27. DOI.org/10.1016/j.ajps.2013.07.003.

22. McNamara DP, Childs SL, Giordano J, Iarriccio A, Cassidy J, Shet MS, et al. Use of a glutaric acid cocrystal to improve oral bioavailability of a low solubility API. Pharm Res 2006; 23(8):1888-97 DOI: 10.1007/s11095-006-9032-3.

23. Manin AN, Voronin AP, Drozd KV, Manin NG, Bauer-Brandl A, Perlovich GL. Cocrystal screening of hydroxy benzamides with benzoic acid derivatives: a comparative study of thermal and solution based methods. Eur J Pharm Sci 2014; 65:56-64 DOI: 10.1016/j.ejps.2014.09.003.

24. Chun NH, Lee MJ, Song GH, Chang KY, Kim CS, Choi GJ. Combined anti-solvent and cooling method of manufacturing indomethacin-saccharin (IMC-SAC) co-crystal powders. J Cryst Growth 2014; 408:112-8. DOI.org/10.1016/j.jcrysgro.2014.07.057.

25. Zhang S, Chen H, Rasmuson AC. Thermodynamics and crystallization of a theophylline–salicylic acid cocrystal. Cryst Eng Comm 2015; 17:4125. DOI:10.1039/C5CE00240K.

26. Alhalaweh A, George S, Basavoju S, Childs SL, Rizvi SAA, Velaga SP. Pharmaceutical cocrystals of nitrofurantoin: screening, characterization and crystal structure analysis. Cryst Eng Comm 2012; 14:5078-88. DOI:10.1039/C2CE06602E.

27. Karki S, Friscic T, Jones W, Motherwell WDS. Screening for pharmaceutical cocrystal hydrates via neat and liquid-assisted grinding. Mol Pharm 2007; 4(3):347-54. DOI: 10.1021/mp0700054.

28. Karki S, Friscic T, Jones W. Control and interconversion of cocrystal stoichiometry in grinding: stepwise mechanism for the formation of a hydrogen-bonded cocrystal. Cryst Eng Comm 2009; 11:470-81. DOI:10.1039/B812531G.

29. Kotak U, Prajapati V, Solanki H, Jani G, Jha P. Co-crystallization technique its rational and recent progress. World J Pharm Pharm Sci 2015; 4(4); 1484-508.

30. Aher S, Dhumal R, Mahadik K, Paradkar A, York P. Ultrasound assisted cocrystallization from solution (USSC) containing a non-congruently soluble cocrystal component pair: Caffeine/maleic acid. Eur J Pharm Sci 2010; 41:597-602. DOI: 10.1016/j.ejps.2010.08.012.

31. Padrela L, Rodrigues MA, Velaga SP, Fernandes AC, Matos HA, Azevedo EG. Screening for pharmaceutical cocrystals using the supercritical fluid enhanced atomization process. J Supercrit Fluids 2010; 53:156-64. DOI.org/10.1016/j.supflu.2010.01.010.

32. Yadav S, Gupta PC, Sharma N, Kumar J. Co-crystals: An alternative approach to modify physicochemical properties of drugs. Int J Pharm 2015; 5(2):427-36.

33. Alhalaweh A, Velaga P. Formation of cocrystals from stoichiometric solutions of incongruently saturating systems by spray drying. Cryst Growth Des 2010; 10(8):3302-5. DOI: 10.1021/cg100451q.

34. Grossjohann C, Serrano DR, Paluch KJ, O’connell P, Vella-zarb L, Manesiotis P, et al. Polymorphism in sulfadimidine/4-aminosalicylic acid cocrystals: solid-state characterization and physicochemical properties. J Pharm Sci 2015; 104:1385-98. DOI: 10.1002/jps.24345. Epub 2015 Jan 20.

35. Boksa K, Otte A, Pinal R. Matrix-assisted cocrystallization (MAC) simultaneous production and formulation of pharmaceutical cocrystals by hot-melt extrusion. J Pharm Sci 2014; 103:2904-10. DOI: 10.1002/jps.23983.

36. Daurio D, Medina C, Saw R, Nagapudi K, Alvarez-Nunez F. Application of twin screw extrusion in the manufacture of cocrystals, Part-1: Four case studies. Pharmaceutics 2011; 3:582-600. DOI: 10.3390/pharmaceutics.

37. Abourahma H, Cocuzza DS, Melendez J, Urban JM. Pyrazinamide cocrystals and the search for polymorphs. Cryst Eng Comm 2011; 13:1-22. DOI:10.1039/C1CE05598D.

38. Bhatt PM, Azim Y, Thakur TS, Desiraju GR. Cocrystals of the anti-HIV drugs lamivudine and zidovudine. Cryst Growth Des 2009; 9(2):951-7. DOI: 10.1021/cg8007359.

39. Skorepova E, Husak M, Cejka J, Zamostny P, Kratochvil B. Increasing dissolution of trospium chloride by co-crystallization with urea. J Cryst Growth 2014; 399:19-26. DOI.org/10.1016/j.jcrysgro.2014.04.018.

40. Aher NS, Shinkar DM, Saudagar RB. Pharmaceutical cocrystallization: A review. J Adv Pharm Educ Res 2014; 4:388-96. DOI.org/10.1016/j.ijpharm.2018.06.024.

41. Yadav AV, Shete AS, Dabke AP, Kulkarni PV, Sakhare SS. Cocrystals: A novel approach to modify physicochemical properties of active pharmaceutical ingredients. Indian J Pharm Sci 2009; 71(4):359-70. DOI: 10.4103/0250-474X.57283.

42. Vaghela P, Tank HM, Jalpa P. Cocrystals: A novel approach to improve the physicochemical and mechanical properties. Indo Am J Pharm Res 2014; 4(10):5055-65.

43. Mutalik S, Prambil A, Krishnan M, Achuta NU. Enhancement of dissolution rate and bioavailability of aceclofenac: A chitosan based solvent change approach. Int J Pharm 2008; 350: DOI.org/10.1016/j.ijpharm.2007.09.006.

44. Sugandha K, Kaity S, Mukherjee S, Isaac J, Ghosh A. Solubility enhancement of ezetimibe by cocrystal engineering technique. Cryst Growth Des 2014; 14:4475-86 DOI: 10.1021/cg500560w.

45. Nehm SJ, Rodriguez-Spong B, Rodríguez-Hornedo N. Phase solubility diagrams of cocrystals are explained by solubility product and solution complexation. Cryst Growth Des 2006; 6:592-600. DOI: 10.1021/cg0503346.

46. Bysouth SR, Bis JA, Igo D. Cocrystallization via planetary milling: enhancing throughput of solid state screening methods. Int J Pharm 2011; 411:169-71. DOI.org/10.1016/j.ijpharm.2011.03.037.

47. Mukaida M, Watanabe Y, Sugano K, Terada. Identification and physicochemical characterization of caffeine-citric acid cocrystal polymorphs. Eur J Pharm Sci 2015; 79:61-6 DOI: 10.1016/j.ejps.2015.09.002.

48. Shan N, Toda F, Jones W. Mechanochemistry and cocrystal formation: effect of solvent on reaction kinetics. Chem Commun 2002; 2372-73. DOI:10.1039/B207369M.

49. Cuadra IA, Cabanas A, Cheda JAR, Martinez-Casado FJ, Pando C. Pharmaceutical cocrystals of the anti-inflammatory drug diflunisal and nicotinamide obtained using supercritical CO2 as an antisolvent. J CO2 Util 2016; 13:29-37. DOI.org/10.1016/j.jcou.2015.11.006.

50. Mutalik S, Prambil A, Krishnan M, Achuta NU. Enhancement of dissolution rate and bioavailability of aceclofenac: A chitosan based solvent change approach. Int J Pharm. 2008; 350:279–90. DOI: 10.1016/j.ijpharm.2007.09.006.

51. Aakeroy CB, Salmon DJ, Smith MM, Desper J. Cyanophenyloximes: reliable and versatile for hydrogen bond directed supramolecular synthesis of cocrystals. DOI: 10.1021/cg0600492.

52. Qiao N, Li M, Schlindwein W, Malek N, Davies A, Trappitt G. Pharmaceutical cocrystals: An overview. Int J Pharm 2011; 419:1-11. DOI.org/10.1016/j.ijpharm.2011.07.037.

53. Lin HL, Hsu PC, Lin SY. Theophylline-citric acid co-crystals easily induced by DSC-FTIR microspectroscopy or different storage conditions. Asian J Pharm Sci 2013; 8:19-27. DOI.org/10.1016/j.ajps.2013.07.003.

54. Wu TK, Lin SY, Lin HL, Huang YT. Simultaneous DSC-FTIR microspectroscopy used to screen and detect the cocrystal formation in real time. Bioorg Med Chem Lett 2011; 21:3148-51. DOI.org/10.1016/j.bmcl.2011.03.001.

55. Lu E, Rodriguez-Hornedo N, Suryanarayanan R. A rapid thermal method for cocrystal screening. Cryst Eng Comm 2008; 10:665-68. DOI:10.1039/B801713C.

56. Yamashita H, Hirakura Y, Yuda M, Terada K. Coformer screening using thermal analysis based on binary phase diagram. Pharm Res 2014; 31:1946-57. DOI: 10.1007/s11095-014-1296-4

57. Steed JW. The role of cocrystals in pharmaceutical design. Trends Pharmacol Sci 2013; 34(3):185-93. DOI.org/10.1016/j.tips.2012.12.003.

58. Basavoju S, Bostrom D, Velaga SP. Indomethacin-Saccharin cocrystal: Design, synthesis and preliminary pharmaceutical characterization. Pharm Res 2008; 25(3):530-41. DOI: 10.1007/s11095-007-9394-1.

59. Jiang L, Huang Y, Zhang Q, He H, Xu Y, Mei X. Preparation and solid state characterization of dapsone drug-drug cocrystals. Cryst Growth Des 2014; 14:4562-73. DOI: 10.1021/cg500668a.

60. Parrott EPJ, Zeitler JA, Friscic T, Pepper M, Jones W, Day GM, et al. Testing the sensitivity of terahertz spectrocopy to changes in molecular and supramolecular structure: a study of structurally similar cocrystal. Cryst Growth Des 2009; 9:1452-60. DOI: 10.1021/cg8008893

61. Vogt FG, Clawson JS, Strohmeier M, Edwards AJ, Pham TN, Watson SA. Solid state NMR analysis of organic cocrystals and complexes. Cryst Growth Des 2009:9; 921-37. DOI: 10.1021/cg8007014.

62. EL-Gizawy SA, Osman MA, Arafa MF, El-Maghraby GM. Aerosil as a novel co-crystal co-former for improving the dissolution rate of hydrochlorothiazide. Int J Pharm 2015; 478:773-8. DOI: 10.1016/j.ijpharm.2014.12.037.

63. Li J, Liu P, Liu JP, Zhang WL, Yang JK, Fan YQ. Novel Tanshinone II A ternary solid dispersion pellets prepared by a single-step technique: In vitro and in vivo evaluation. Eur J Pharm Biopharm 2012; 80(2):426-32. DOI: 10.1016/j.ejpb.2011.11.003.

64. Gurunath S, Nanjwade BK, Patila PA. Enhanced solubility and intestinal absorption of candesartan cilexetil solid dispersions using everted rat intestinal sacs. Saudi Pharm J 2014; 22(3):246-57. DOI.org/10.1016/j.jsps.2013.03.006.

65. Sathali AA, Selvaraj V. Enhancement of solubility and dissolution rate of racecadotril by solid dispersion methods. J Curr Chem Pharm Sci 2012; 2(3):209-25.

66. Fukte SR, Wagh MP, Rawat S. Coformer selection: An important tool in cocrystal formation. Int J Pharm Pharm Sci 2014:6; 9-14.

67. Cocrystals continuum: The influence of crystal structure on ionization state. Mol Pharm 2007:4; 323-3819:1-11. DOI: 10.1021/mp0601345.

68. Prabhakar Panzade, et, al, Pharmaceutical Cocrystal of Piroxicam: Design, Formulation and Evaluation, 2017, sep, v.3(7) 399–408, Journal of advanced pharmaceutical bulletin. DOI: 10.15171/apb.2017.048.

69. Ramu S, Shamili M.R., Ravindra Babu M, Latha Sri K, Ishwarya. M. Formulation and Evaluation of Sustained Release Vildagliptin Microspheres, International Journal of Pharmacy and Pharmaceutical Research. 2016, 8 (1): 275-294

70. Hao Zhang, 1, et al Preparation and Characterization of Carbamazepine Cocrystal in Polymer Solution, 2017, dec1, 9(4), 1-13, pharmaceutics DOI: 10.3390/pharmaceutics9040054.

71. Stevanus Hiendrawan, et al Physicochemical and mechanical properties of paracetamol cocrystal with 5-nitroisophthalicacid, 2017, 30, jan, v(497), issues1-2, 106-113, international journal of pharmaceutics. DOI: 10.1016/j.ijpharm.2015.12.001.

72. Jignasa Ketan Savjani, et al Improvement of physicochemical parameters of acyclovir using cocrystallization vol. 52(4)oct./dec., 2016, Brazilian Journal of Pharmaceutical Sciences. DOI.org/10.1590/s1984-82502016000400017.

73. Yori Yuliandra, et al Cocrystal of Ibuprofen–Nicotinamide: Solid-State Characterization and In Vivo Analgesic Activity Evaluation2018, 4, june, 1-11, Scientia Pharmaceutica. DOI: 10.3390/scipharm86020023.

74. Shigeru Ando, et al, Physicochemical Characterization and Structural Evaluation of a Specific 2:1 Cocrystal of Naproxen Nicotinamide, 2012, 29, march, 1-8, wiley online library. DOI: 10.1002/jps.23158.

75. Min-Sook Jung, et al Bioavailability of indomethacin-saccharin cocrystals, 2010, 11, 1560–1568, Journal of Pharmacy and Pharmacology. DOI:10.1111/j.2042-7158.2010.01189.

Received on 15.02.2019 Modified on 28.03.2019

Research J. Pharm. and Tech. 2019; 12(7):3117-3124.

DOI: 10.5958/0974-360X.2019.00527.4

S. No	Drug name	Conformer/ Polymer	Method of preparation	Results	Reference
1	Piroxicam	Piroxicam Sodium acetate	Dry grinding method	Improve the solubility and dissolution.	68
2	Clarithromycin	Erythromycin, common solvents	Solvent evaporation technique	Improved solubility of CLN and in turn higher dissolution rate than the pure drug	69
3	Carbamazepine	Nicotinamide (NIC) and saccharin (SAC	Solution methods	Characterization results show that in ethanol-water solvent mixture, pure CBZ-NIC co-crystal can be prepared	70
4	Paracetamol	5-Nitro isophhthalic acid (5NIP)	Solvent evaporation technique	Improves its tablet ability	71
5	Acyclovir	Common solvents	Solvent evaporation technique	improved solubility which may result in improvement of bioavailability	72
6	Ibuprofen-nicotinamide	Nicotinamide	Slow evaporation method.	Improves the in vivo analgesic effect, as compared with intact ibuprofen and its physical mixture.	73
7	Naproxane-nicotinamide	Sodium naproxen anhydrate	solid-state nuclear magnetic resonance (NMR)	Improved initial naproxen dissolution and less water vapor adsorption, indicating better pharmaceutical properties of naproxen	74
8	Indomethacin-Saccharin	Saccharin	Cooling batch crystallization without seeding	Improved aqueous solubility of the co-crystals leads to improved bioavailability of IND.	75