Solubility Enhancement of Clozapine Through Co-Crystal Formation with Isonicotinamide

Fikri Alatas, Hestiary Ratih, Hesti Kurnia, Sundani Nurono Soewandhi

Abstract

Clozapine (CLO) is an effective atypical antipsychotic to control the symptoms of psychosis and schizophrenia. Clozapine has low solubility and high permeability, so it is classified as a class II in the biopharmaceutical classification system. The aim of this study was to improve the solubility and dissolution rate of clozapine by clozapine-isonicotinamide (CLO-INA) co-crystal formation. CLO-INA co-crystal was prepared by solvent-drop grinding (SDG) method using water as a solvent. Characterization of SDG result was conducted by powder X-ray diffraction (PXRD) and Fourier transform infrared (FTIR).  Solubility test was performed in water at room temperature. The dissolution test was performed in 900 mL of pH 6.8 phosphate buffer solution, 50 rotation per minute of paddle rotation, and at 37±0.5 °C. The PXRD pattern of  SDG result of CLO-INA has many different peaks from its parent components, and this may indicate the co-crystal formation. The solubility of the co-crystal clozapine was fifteen folds higher than pure clozapine. The dissolution rate of CLO-INA co-crystal increased in the first 10 minutes compared to pure clozapine. Percentage of clozapine dissolved after 10 minutes from CLO-INA co-crystal and pure CLO were 10.2 and 2.4%, respectively. CLO and INA can form co-crystal by SDG method that can improve the solubility and dissolution rate of clozapine.

Keywords: Clozapine, Isonicotinamide, Co-crystal, Solubility, Dissolution

Full Text:

PDF HTML

References

Manu P, Sarpal D, Muir O, et al. When can patients with potentially life-threatening adverse effects be rechallenged with clozapine? A systematic review of the published literature. Schizophr Res 2012; 134: 180–186.

Dias SBT, Nascimento TG, Santos AFO, et al. Polymorphic characterization and compatibility study of clozapine: implications on its stability and some biopharmaceutics properties. J Therm Anal Calorim 2014; V.12x: X1.

Stahl SM. Antipsychotics and mood stabilizer. 3rd ed. New York: Cambridge University Press, 2008.

Chadha R, Saini A, Jain DS, et al. Preparation and solid-state characterization of three novel multicomponent solid forms of oxcarbazepine: Improvement in solubility through saccharin cocrystal. Cryst Growth Des 2012; 12: 4211–4224.

Babu NJ, Nangia A. Solubility advantage of amorphous drugs and pharmaceutical cocrystals. Cryst Growth Des 2011; 11: 2662–2679.

Rodríguez-Hornedo N, Nehm SJ, Jayasankar A. Cocrystals : design , properties and formation mechanisms. Encycl Pharm Technol 2007; 615–635.

Alatas F, Ratih H, Soewandhi SN. Enhancement of solubility and dissolution rate of telmisartan by telmisartan-oxalic acid co-crystal formation. Int J Pharm Pharm Sci 2015; 7: 423–425.

McNamara DP, Childs SL, Giordano J, et al. Use of a glutaric acid cocrystal to improve oral bioavailability of a low solubility API. Pharm Res 2006; 23: 1888–1897.

Tomaszewska I, Karki S, Shur J, et al. Pharmaceutical characterisation and evaluation of cocrystals: Importance of in vitro dissolution conditions and type of coformer. Int J Pharm 2013; 453: 380–388.

Zegarac M, Leksic E, Sket P, et al. A sildenafil cocrystal based on acetylsalicylic acid exhibits an enhanced intrinsic dissolution rate. CrystEngComm 2014; 16: 32–35.

Aher S, Dhumal R, Mahadik K, et al. Effect of cocrystallization techniques on compressional properties of caffeine/oxalic acid 2:1 cocrystal. Pharm Dev Technol 2011; 1–6.

Babu NJ, Sanphui P, Nangia A. Crystal engineering of stable temozolomide cocrystals. Chem - An Asian J 2012; 7: 2274–2285.

Wang L, Tan B, Zhang H, et al. Pharmaceutical cocrystals of diflunisal with nicotinamide or isonicotinamide. Org Process Res Dev 2013; 17: 1413–1418.

Dubey R, Desiraju GR. Structural landscape of the 1:1 benzoic acid:isonicotinamide cocrystal. Chem Commun 2014; 50: 1181–1184.

Madeley LG, Levendis DC, Lemmerer A. Isonicotinamide-2-naphthoic acid (1/1). Acta Crystallogr Sect E Struct Reports Online; 67.

Báthori NB, Lemmerer A, Venter GA, et al. Pharmaceutical co-crystals with isonicotinamide—vitamin B3, clofibric acid, and diclofenac—and two isonicotinamide hydrates. Cryst Growth Des 2011; 11: 75–87.

Sanphui P, Kumar SS, Nangia A. Pharmaceutical cocrystals of niclosamide. Cryst Growth Des 2012; 12: 4588–4599.

Takeru Higuchi, Kenneth A. Connors. Phase solubility techniques. In: Advances in Analytical Chemistry and Instrumentation. New York: Jonh Wiley & Sons, INC, 1965, pp. 117–212.

Mantri RV, Sanghvi R, Zhu H (Jim). Solubility of Pharmaceutical Solids. In: Yihong Qiu, Yisheng Chen, Geoff G.Z. Zhang, Lirong Liu WRP (ed) Developing Solid Oral Dosage Forms: Pharmaceutical Theory And Practice. New York: Academic Press, 2009, pp. 1–24.

Trask A V, Motherwell WDS, Jones W. Solvent-drop grinding: green polymorph control of cocrystallisation. Chem Commun (Camb) 2004; 890–891.

Rehder S, Klukkert M, Löbmann K a M, et al. Investigation of the formation process of two piracetam cocrystals during grinding. Pharmaceutics 2011; 3: 706–722.

Mahmoud A, Ali A, Ali AA, et al. Clozapine-carboxylic acid plasticized co-amorphous dispersions : Preparation, characterization and solution stability evaluation. 2015; 65: 133–146.

Aakeröy CB, Beatty AM, Helfrich BA, et al. Do polymorphic compounds make good cocrystallizing agents? A structural case study that demonstrates the importance of synthon flexibility. Cryst Growth Des 2003; 3: 159–165.

Qiao N, Li M, Schlindwein W, et al. Pharmaceutical cocrystals: An overview. Int J Pharm 2011; 419: 1–11.

Sarma B, Chen J, Hsi HY, et al. Solid forms of pharmaceuticals: Polymorphs, salts and cocrystals. Korean J Chem Eng 2011; 28: 315–322.

Saikia B, Bora P, Khatioda R, et al. Hydrogen Bond Synthons in the Interplay of Solubility and Membrane Permeability/Diffusion in Variable Stoichiometry Drug Cocrystals. Cryst Growth Des 2015; 15: 5593–5603.

DOI: https://doi.org/10.24198/idjp.v2i1.23957

Refbacks

  • There are currently no refbacks.