Int J Pharm Pharm Sci, Vol 8, Issue 8, 342-346Original Article



Departement of Pharmaceutical and Technolgy Formulation of University of Gadjah Mada, Yogyakarta 55281 and University of Padjadjaran, Bandung, Indonesia

Received: 26 May 2016 Revised and Accepted: 20 Jun 2016


Objective: The main objective of this study was to explore co-crystallization as an effort to enhance the solubility of simvastatin (SV) using tartaric acid (TA) as co-former.

Methods: The simulation of molecular modeling of TA against SV has been done by in silico using auto dock 4.2. A preparation of co-crystal carried out by using solvent drops grinding (SGD) with an equimolar ratio. A co-crystal formed was confirmed by scanning electron microscopy (SEM), saturated solubility test, in vitro dissolution test, infrared spectrophotometry (FTIR), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC).

Results: The in silico studies showed that the interaction of TA and SV has synthon molecular by hydrogen bonding. An increasing of solubility and in vitro dissolution profile of co-crystal resulted as compared to the value of pure SV and its physical mixer. Characterizations of a co-crystal SV: TA (1: 1) including SEM, FTIR, PXRD, and DSC have indicated the formation of new solid crystal phase that different compared to SV, TA, and its physical mixture.

Conclusion: The co-crystallization has been used to enhance the solubility and dissolution of simvastatin. All characterization either in silico and in vitro has shown the formation of co-crystal SV: TA (1:1).

Keywords: Simvastatin, Co-crystal, Solubility, Dissolution


A drug with good solubility properties will show better absorption and bioavailability. Almost 40% of the drug in the market exhibit a low solubility in water. It is causing the drug slowly to be absorbed. In addition, the levels of the drug in the blood lower than levels that should be [1]. In the pharmaceutical industry, the shortage of properties of biopharmaceutical drugs such as toxicity and less effective medication is 1% of the major cases in a market [2]. It is due to the nature of the solubility of the drug. The effectiveness of drug therapy highly depends on the level of drug in the blood, thus directly depends on the nature of drug solubility [3, 4]. Approximately 70% of drug candidates have problems with the solubility. It is a big challenge in the field of pharmaceuticals to developing drugs and drug dosage form to obtain a good profile of the solubility and dissolution rate, especially for oral dosage forms [4].

Base on biopharmaceutical classification system (BCS), drugs are classified into four classes, including drugs with low solubility problems, such as simvastatin (SV). SV (fig. 1) is the drug in the BCS class II. It has a problem with the low solubility of about 30 µg/ml and a bioavailability is only 5% [5, 6]. Several methods have been developed to increase the solubility of SV such as the technique of forming an inclusion complex of cyclodextrin [7], solid dispersion [8], an addition of a surfactant, particle size reduction by microemulsion [9,10], and supercritical antisolvent (SAS) [11]. These methods have lacked, such as using the number of matrices and the energy of the process is high. According to the knowledge of the researchers, co-crystallization has not been applied to increase the solubility of the SV.

Fig. 1: Stucture of SV

The Top of Form

co-crystallization method is commonly used in the pharmaceutical field to change the features of the active pharmaceutical ingredients become a material with the desired properties [12]. Co-crystallization can generally be applied to acid, alkaline, neutral and ionic compounds [13]. Co-crystallization can improve the properties of the physiochemistry such as the level of solubility and the rate of dissolution using the simple technique [14, 15]. Co-crystal is complex solid compounds at room temperature. It is formed by two or more compounds with a co-former and connected by a synthon with certain of stoichiometry ratio [16, 17]. Synthon is a noncovalent interaction, including hydrogen bonds, Van der Walls and π-π electron [18-20]. The interaction of synthon can be predicted by in silico method. It is conducted to ensure the interactions of a active pharmaceutical ingredient (API) and co-former [21, 22].

Several techniques had been developed to synthesize co-crystal such as melting by using heat [23, 24], supercritical fluid (SFC) [25], slurrying assisted ultrasound [26], solvent evaporation, solid grinding [27], spray drying [28], liquid-assisted grinding (LAG) [29] and solvent drops grinding (SGD) [30]. An SGD is a co-crystal preparing method that employs a few chemical solvents, requires a less energy, having a good repeatability in the formation of crystals and could be used for a co-crystal screening [31]. In this project, we developed a simple method of co-crystallization in the terms procedures, process and it is also able to produce an increased solubility of API up to fifty times as much as previous studies [25]. In this work, we use a simple in silico method as a tool to ensure SV and TA interactions, especially for hydrogen bonds in the co-crystal form.


Molecular docking simulation

The 3D-chemical structures of the SV and TA were designed using Hyperchem 7.0 (Ref) and energy minimization by MM+. Furthermore, the compound conformations were produced using the Discovery Studio 2.5 with CATALYST finest conformation module. CHARMM forced field was applied for energy optimization. The resulting compounds which had higher than 20 kcal/mol as compared to the global minimum of conformation l minimum were refused, The utmost number of conformations was adjusted to 255 [32]. Docking simulations of the molecules were conducted using AutoDock 4.2 [33]. The AutoDockTools (ADT) script was employed to transform the ligand PDB to the pdbq format with adding Gasteiger charges, inspecting polar hydrogens and setting ligand flexibility.

Synthesis of co-crystal

Accurately weighed simvastatin (purity>99%, Teva, Belgium) and TA (Merck, Germany) equivalent to a molar ratio (1: 1), afterwards carried by grinding of the mixture of SV and TA assisted by methanol pro analysis (Merck, Germany) as solvent for 10 min, later stored in a water bath at 30 °C for 24 h.

Characterization of co-crystal

Scanning electron microscopy (SEM)

The surface of morphology of the samples was analyzed using a scanning electron microscopy SEM analytis (JSM6360A, JEOL, USA), Samples were measured with a double-faced adhesive tape, sputtered with platinum. Scanning electron photographs were taken at an accelerating voltage of 5 kV.

Saturated solubilty studies

Accurately weighed of dried co-crystal equivalently to SV 100 mg, then input into vial and reconstituted with 50 ml of distilled water, later shaken for 24 h using an agitator shaker, afterward calculate the amount of SV was dissolved by validated spectrophotometric Uv-Vis method using Spectrophotometry UV-Vis (Analytical Zena, Germany). The same way was done for pure SV, and a physical mixture of SV: TA (1:1).

In vitro dissolution studies

The in vitro release behaviors of the SV and its co-crystals were measured using a dissolution tester (USP type two paddle apparatus). A typical experiment equal consisted of 40 mg crystal powders SV in a 900 ml simulated intestinal fluid (less enzyme) pH 6,8, stirred at 100 rpm. Sampling (5 ml) was done until 60 min at pre-determined time points, and a fresh 5 ml SIF solution was added into the system after each sampling. Each sampled solution was filtered through a syringe filter of 0.45 μm pore size, and its UV absorbance were measured at 240 nm. A concentration of the SV was calculated using a validated pre-constructed calibration curve.

Powder x-ray diffraction (PXRD)

The powder X-ray diffractometer (X Philips Analytical PW1710, Germany) patterns were collected using Cu Ka radiation (l = 1.54 Å), a tube voltage of 40 kV and a tube current of 40 mA. Data were collected from 2Ɵ angle 5 ° to 48 ° at a continuous scan rate of 4 °/minute.

FT-IR spectrophotometry

Samples in the form of powder mixed with potassium bromide crystal with the molar ratio (1:10) and crushed until homogeneous and then compressed to a pressure of 20 psi. The spectra were analyzed over a range of wavenumbers 4000-400 cm–1 using FT-IR (Specord 200, Germany)

Differential scanning calorimetry (DSC)

The thermal analysis was performed on a DSC/TGA apparatus (Linseis PTA ST 1600, USA) that was calibrated for temperature and cell constants using indium. Samples (1–3 mg) crimped in the aluminum pan were analyzed from 50 °C to 300 °C with a heating rate of 10 °C/min. Samples were continuously purged with nitrogen at 50 ml/min.


In silico modeling

An In silico studies by molecular modeling (fig. 2) has been employed as a simple tool to make sure the hydrogen bonding interactions of the SV-TA [21]. The lowest Gibbs-free energy of molecule conformation was-1,8 kcal/mol. The negative value indicates SV and TA interactions has occurred. The interaction type of the SV and TA is the hydrogen bond with bond distances 2, 27 Å. It is indicated a very close bond and allow hydrogen bonds.

Fig. 2: In silico interaction model of (A) SV and (B) TA

An SV has a lactone group that contains a carbonyl, ether, and hydroxyl groups. TA has carboxylic acid and hydroxyl groups. Therefore, both of compounds could be as hydrogen donor and acceptor for hydrogen bonds. Analysis of molecular structure to design a co-crystal is very important to predict a synthon [34].

Preparation of co-crystal SV: TA (1:1)

A preparation of co-crystal had been carried out by SGD. It is done because SGD method was more effective and environmentally friendly [30, 35]. SGD method was also reliable for the discovery of a new co-crystal when a presence of a small amount of the liquid phase can improve the rate of co-crystal formation [36]. Photo of SEM (fig. 3) had revealed a comparison of particle size and surface morphology of pure SV and its co-crystal. The co-crystal of SV-TA (1:1) had displayed a more compact structure with a higher density. It was due to the interaction of hydrogen bonding of the SV and TA in co-crystal form. As we knew, a hydrogen bonding has a dominant role in the intermolecular interaction of co-crystallization [37].

Fig. 3: Photo of SEM (a) pure SV and (b) co-crystal SV-TA (1:1)

Evaluation of co-crystal of SV-TA (1:1)

Saturated solubilty studies

Top of Form

Test of saturated solubility has conducted to the SV, a physical mixture of SV-TA and co-crystal SV-TA (1:1) (fig. 4). Evaluation of the saturated solubility of co-crystal SV-TA (1:1) has shown an increase up to 2.4 fold as compared to the physical mixture and SV. It is due to an affinity of the solvent against SV was more intense and another factor was a decrease in energy of crystal lattice by co-crystal formation [38, 39].

Bottom of Form

Fig. 4: Saturated solubility profiles (A) pure SV, (B) co-crystal SV: TA (1:1) and (C) physical mixture SV: TA (n=6)

In vitro dissolution studies

In vitro dissolution studies had been carried out to pure SV and co-crystal SV-TA 1: 1 (fig. 5). The dissolution profile of co-crystal SV-TA (1:1) has shown the increasing approximately twofold compared to the dissolution profile of the pure SV in 60 min. The Increasing of dissolution rate was correlated with a function of surface area, a diffusion constant, boundary-layer thickness as well as solubility [40]. SGD also could modify the diffusion of a molecule of the API by affecting the hydrodynamic properties and to influence the release behavior of the API [41].

Fig. 5: Dissolution profile of (a) SV and (b) co-crystal SV: TA (1:1) (n=6)

FT-IR studies

FT-IR analysis of co-crystal was employed to determine the hydrogen bonding between the SV and TA (fig. 6). The spectrum overlay of pure SV, TA and co-crystal SV-TA (1:1) has exhibited the tape widening of the co-crystal absorption band at 3600-3200 cm-1. It is specific for intermolecular hydrogen bonding. The characteristic peak absorption of an SV was found at 3,545 cm−1(free O-H stretch), 2,970 cm−1 (methyl C-H asymmetric stretch), 1,695 cm−1 (ester C=O stretch, associated), 1,265 cm−1(l-C-O-C stretch) [42]. In co-crystal form, the peaks of a SV were not prone and intensively also reduced.

Fig. 6: FT-IR spectrum (a) TA, (b) co-crystal SV: TA (1:1) and (c) pure SV
The absorption band of free OH will be observed at the wavenumber 3500 cm-1. A widening of OH peak on wavenumber 3500 cm-1 was due to the interaction of hydrogen bonding of co-crystal SV–TA 1:1.

PXRD evaluation

A PXRD had performed to define the crystallinity of co-crystal of SV: TA (1:1) as compared to SV and its physical mixture. The overlay of diffractogram has showen distinct peaks and intensity at an angle 2Ɵ: 11 °, 35-37 °, and 39-41 °. A Powder x-ray diffraction is a specific technique to confirm the new solid state. All crystal forms of a compound have produced its own characteristic X-Ray diffraction pattern [43]. The difference of peaks indicates the formation of new solid crystalline phases [44] and it also allows for differences physiochemistry properties between co-crystal, pure SV, and TA.

Thermal analysis

The DSC studies can be used to observe of co-crystal formation from the difference in melting point of co-crystal as compared to its own constituent via the endotherm phase [45]. Thermogram (fig. 7) had revealed the melting point (endotherm phase) of co-crystal SV-TA (67 °C)<pure SV (133 °C). The enthalpy of SV (87 Joule/g)>co-crystal SV-TA 1:1 (67,2 Joule/g). A decrease in melting point and heat content of co-crystal will directly correlate to increased solubility of API in the co-crystal. The melting point co-crystal will fall between melting point API and its co-former [2, 15]. We could predict to desire physiochemistry of co-crystal by a polarity of co-former [45].

Fig. 7: Diffractogram of (a) TA, (b) SV, (c) physical mixture SV-TA and (d) co-crystal SV-TA (1:1)

Fig. 8: Diffractogram pattern of (A) physical mixture SV: TA (1:1), (b) pure SV, and (c) co-cystal SV: TA (1:1)


Preparation of co-crystal SV with co-former TA (1:1) had been done with solvent drops grinding. The saturated solubility and in vitro dissolution evaluation of co-crystal SV: TA (1:1) had exhibited the rate of solubility and release behavior of co-crystal SV-TA (1: 1) increased significantly compared to pure SV. All confirmations against co-crystal SV: TA (1:1) had indicated the formation new solid crystalline phases that differ from SV, TA, and its physical mixture. Overall any linear correlation of in silico and in vitro evaluation.


The authors acknowledge of PT. Gracia pharmindo


SV-Simvastatin, TA-Tartaric Acid, API-Active Pharmaceutical Excipient, SGD-Solvent Drops Grinding, DSC-Differential Scanning Calorimetry, SEM-Scanning Electrons Microscopy, FT-IR-fourier Transform Infra Red Spetroscopy, PXRD-Powder X-ray Diffraction.


Declared none


  1. Rinaki E, Valsami G, Macheras P. Quantitative biopharmaceutics classification system: the central role of dose/solubility ratio. Pharm Res 2003;20:1917–25.
  2. Aakeröy CB, Forbes S, Desper J. Using co-crystals to systematically modulate aqueous solubility and melting behavior of an anticancer drug. J Am Chem Soc 2009;131:17048–9.
  3. Blagden N, De Matas M, Gavan PT, York P. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Adv Drug Delivery Rev 2007;59:617–30.
  4. Hu J, Johnston KP, Williams RO. Nanoparticle engineering processes for enhancing the dissolution rates of poorly water soluble drugs. Drug Dev Ind Pharm 2004;30:233–45.
  5. Dahan A, Miller JM, Amidon GL. Prediction of solubility and permeability class membership: provisional BCS classification of the world’s top oral drugs. AAPS J 2009;11:740–6.
  6. Murtaza G. Solubility enhancement of simvastatin: a review. Acta Pol Pharm 2012;69:581–90.
  7. Zhang Y, Zhang J, Jiang T, Wang S. Inclusion of the poorly water-soluble drug simvastatin in mesocellular foam nanoparticles: drug loading and release properties. Int J Pharm 2011;410:118–24.
  8. Mandal D, Ojha PK, Nandy BC, Ghosh LK. Effect of carriers on solid dispersions of simvastatin (Sim): physico-chemical characterizations and dissolution studies. Pharm Lett 2010;2:47–56.
  9. Margulis-Goshen K, Magdassi S. Formation of simvastatin nanoparticles from microemulsion. Nanomed Nanotechnol Biol Med 2009;5:274–81.
  10. Zimper U, Aaltonen J, Krauel-Goellner K, Gordon KC, Strachan CJ, Rades T. The influence of milling on the dissolution performance of simvastatin. Pharmaceutics 2010;2:419–31.
  11. Hiendrawan S, Veriansyah B, Widjojokusumo E, Soewandhi SN, Wikarsa S, Tjandrawinata RR. Simultaneous co-crystalization and micronization of paracetamol-dipicolinic acid co-crystal by supercritical antisolvent (SAS). Int J Pharm Pharm Sci 2016;8:89–98.
  12. Padrela L, Rodrigues MA, Velaga SP, Fernandes AC, Matos AH, de Azevedo EG. Screening for pharmaceutical co-crystals using the supercritical fluid enhanced atomization process. J Supercrit Fluids 2010;53:156–64.
  13. Zaworotko M. Crystal engineering of co-crystals and their relevance to pharmaceuticals and solid-state chemistry. Acta Crystallogr 2008;64:11–2.
  14. Schultheiss N, Newman A. Pharmaceutical co-crystals and their physicochemical properties. Cryst Growth Des 2009;6:2950–67.
  15. Blagden N, de Matas M, Gavan PT, York P. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Adv Drug Delivery Rev 2007;59:617–30.
  16. Aakeröy CB, Salmon DJ. Building co-crystals with molecular sense and supramolecular sensibility. CrystEngComm 2005;7:439–48.
  17. Bethune SJ, Schultheiss N, Henck JO. Improving the poor aqueous solubility of nutraceutical compound pterostilbene through co-crystal formation. Cryst Growth Des 2011;11:2817–23.
  18. Aakeröy CB, Fasulo M, Schultheiss N, Desper J, Moore C. Structural competition between hydrogen bonds and halogen bonds. J Am Chem Soc 2007;129:13772–3.
  19. Miroshnyk I, Mirza S, Sandler N. Pharmaceutical co-crystals-an oportunity for drug product enhancement. Expert Opin Drug Delivery 2009;6:333–41.
  20. Cinčić D, Friščić T, Jones W. A stepwise mechanism for the mechanochemical synthesis of halogen-bonded co-crystal architectures. J Am Chem Soc 2008;130:524–5.
  21. Price SL. The computational prediction of pharmaceutical crystal structures and polymorphism. Adv Drug Delivery Rev 2004;56:301–19.
  22. Karamertzanis PG, Kazantsev AV, Issa N, Welch GW, Adjiman CS, Pantelides CC, et al. Can the formation of pharmaceutical co-crystals be computationally predicted? 2. Crystal structure prediction. J Chem Theory Comput 2009;5:1432–48.
  23. Dhumal RS, Kelly AL, York P, Coates PD, Paradkar A. Co-crystalization and simultaneous agglomeration using hot melt extrusion. Pharm Res 2010;27:2725–33.
  24. Jung S, Choi I, Kim I. Liquid-assisted grinding to prepare a co-crystal of adefovir dipivoxil thermodynamically less stable than its neat phase. Crystals 2015;5:583–91.
  25. Basavoju S, Boström D, Velaga SP. Indomethacin-saccharin co-crystal: design, synthesis and preliminary pharmaceutical characterization. Pharm Res 2008;25:530–41.
  26. Dhumal RS, Biradar SV, Paradkar AR, York P. Ultrasound assisted engineering of lactose crystals. Pharm Res 2008;25:2835–44.
  27. Dwi Setyawan RS. Preparation and characterization of artesunate-nicotinamide co-crystal by solvent evaporation and slurry method. Asian J Pharm Clin Res 2014;7 Suppl 1:62–5.
  28. Alhalaweh A, Kaialy W, Buckton G, Gill H, Nokhodchi A, Velaga SP. Theophylline co-crystals prepared by spray drying: physicochemical properties and aerosolization performance. AAPS PharmSciTech 2013;14:265–76.
  29. Takata N, Shiraki K, Takano R, Hayashi Y, Terada K. Co-crystal screening of stanolone and mestanolone using slurry crystallization. Cryst Growth Des 2008;8:3032–7.
  30. Trask AV, Motherwell WDS, Jones W. Solvent-drop grinding: green polymorph control of co-crystallisation. Chem Commun 2004;7:890–1.
  31. Basavoju S, Boström D, Velaga SP. Indomethacin-saccharin co-crystal: design, synthesis and preliminary pharmaceutical characterization. Pharm Res 2008;25:530–41.
  32. Ikram NKK, Durrant JD, Zalaludin AS, Purwitasari N, Mohamed N, Rahim ASA, et al. A virtual screening aroach for identifying plants with anti H5N1 neuraminidase activity. J Chem Inf Model 2015;55:308–16.
  33. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 2009;30:2785–91.
  34. Desiraju GR. Crystal and co-crystal. CrystEngComm 2003;5:466–7.
  35. Braga D, Maini L, Grepioni F. Mechanochemical preparation of co-crystals. Chem Soc Rev 2013;42:7638–48.
  36. Shan N, Toda F, Jones W. Mechanochemistry and co-crystal formation: effect of solvent on reaction kinetics. Chem Commun 2002;20:2372–3.
  37. Etter MC, Reutzel SM. Hydrogen bond directed co-crystallization and molecular recognition properties of acyclic imides. J Am Chem Soc 1991;113:2586–98.
  38. Serajuddin ATM. Salt formation to improve drug solubility. Adv Drug Delivery Rev 2007;59:603–16.
  39. Good DJ, Rodríguez-Hornedo N. Solubility advantage of pharmaceutical co-crystals. Cryst Growth Des 2009;9:2252–64.
  40. Dokoumetzidis A, Macheras P. A century of dissolution research: from noyes and whitney to the biopharmaceutics classification system. Int J Pharm 2006;321:1–11.
  41. Jung S, Choi I, Kim I. Liquid-assisted grinding to prepare a co-crystal of adefovir dipivoxil thermodynamically less stable than its neat phase. Crystals 2015;5:583–91.
  42. Pandya P, Gattani S, Jain P, Khirwal L, Surana S. Co-solvent evaporation method for enhancement of solubility and dissolution rate of poorly aqueous soluble drug simvastatin: in vitro-in vivo evaluation. AAPS PharmSciTech 2008;9:1247–52.
  43. Parmar VK, Shah SA. Hydrochloride salt co-crystals: preparation, characterization and physicochemical studies. Pharm Dev Technol 2013;18:443–53.
  44. Sanphui P, Goud NR, Khandavilli UR, Nangia A. Fast dissolving curcumin co-crystals. Cryst Growth Des 2011;11:4135–45.
  45. Lu E, Rodríguez-Hornedo N, Suryanarayanan A. A rapid thermal method for co-crystal screening. CrystEngComm 2008;10:665–8.
  46. Fayos J. Molecular crystal prediction approach by molecular similarity: data mining on molecular aggregation predictors and crystal descriptors. Cryst Growth Des 2009;9:3142–53.

How to cite this article

  • Iyan Sopyan, Achmad Fudholi, Muchtaridi, Ika Puspitasari. A simple effort to enhance solubility and dissolution rate of simvastatin using co-crystalization. Int J Pharm Pharm Sci 2016;8(8):342-346.

About this article




Simvastatin, Co-crystal, Solubility, Dissolution



Additional Links

Manuscript Submission


International Journal of Pharmacy and Pharmaceutical Sciences
Vol 8, Issue 8, 2016 Page: 342-346

Online ISSN


Authors & Affiliations

Iyan Sopyan

Achmad Fudholi
Departement of Pharmaceutical and Technolgy Formulation of University of Gadjah Mada, Yogyakarta, 55281, Indonesia.

Muchtaridi Muchtaridi

Ika Puspitasari

Article Tools


  • There are currently no refbacks.