DEVELOPMENT AND VALIDATION OF SPECTROPHOTOMETRIC METHODS FOR THE DETERMINATION OF RISPERIDONE IN PURE AND TABLET DOSAGE FORMS

ABSTRACT

Two simple, sensitive, accurate and extraction-free spectrophotometric methods were developed and described for the determination of risperidone in pure and in tablet dosage forms. The methods are based on the formation of ion-pair complex between risperidone and the dyes bromocresol green in method A and thymol blue in method B at room temperature to form yellow coloured products having absorption maxima at 414 nm and 404 nm respectively. The composition of the ion-pairs was established by Job’s method and it was found to be 1:1 for both methods. Different variables affecting the reaction conditions such as diluting solvents, concentration of dye, reaction time were studied and optimized. Under the optimal conditions, linear relationship with good correlation coefficients (0.994 and 0.995 for methods A and B respectively) was found between absorbance and the concentrations of risperidone in the range of 2-20 µg/ml and 20-40 µg/ml respectively. The assay limits of detection (LOD) and limits of quantification (LOQ) were 1.27 and 3.84 µg/ml for method A and 7.00 and 21.15 µg/ml for method B. The precision of both methods did not exceed 15% likewise the percentage relative error was within the accepted range of 1-5%. No interference could be observed from the excipients commonly present in tablet or liquid dosage forms. The methods developed have been validated and there is no significant difference (P < 0.05) between the methods and the reference (BP) method. The methods can be successfully applied for the analysis of risperidone in pure and tablet dosage forms.

CHAPTER ONE

1.0 INTRODUCTION

1.1 Preamble

Risperidone is a psychotropic (antipsychotic) agent used in the treatment of schizophrenia. The action is mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism. It is a selective monoaminergic antagonist with high affinity for 5HT2, D2 and H1 histaminergic receptors (Potter and Hollister, 2001). It belongs to the chemical class of benzisoxazole derivatives. The chemical name of risperidone is 3-[2-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6, 7, 8, 9-tetrahydro-2-methyl-4H-pyrido-[1,2-a]-pyrimidin-4-one) while the molecular formula is C23H27FN4O2 with the molecular weight of 410.49g (The Merck Index, 2001).

Fig 1.1 Chemical structure of Risperidone

According to the British Pharmacopoeia (2009), risperidone contains not less than 99.0 per cent and not more than the equivalent of 101.0 per cent of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidin-4-one, calculated with reference to the dried substance (BP, 2009). The absolute oral bioavailability of risperidone is 70% and a half life of 20 hours. It is rapidly distributed with the volume of distribution being 1-2 L/kg. In plasma, risperidone is bound to albumin.

It is extensively metabolized in the liver (USP/NF, 2006).

Risperidone was first developed by Janssen-Cilag from 1988 to 1992 and was approved by the Food and Drug Administration in 1994. However, Janssen-Cilag’s patent on risperidone expired on December 29, 2003 which paved the way for the introduction of cheaper generics into the world market. Some of these cheaper generics, though affordable often fall short of their required efficacy. Simple “on-spot” assessment of these brands of risperidone has therefore become paramount (www.naminh.org).

1.2 Research Problem

The dearth of equipment employed in the determination of risperidone with methods like high performance liquid chromatography (HPLC) (Woestenborghs et al., 1992; Balant-Gorgia et al., 1999; Schatz and Saria, 2000; Zhou et al., 2004; El-Sherif et al., 2005; Huang et al., 2008; Kirschbaum et al., 2008; Baldaniya et al., 2008; Yunoos et al., 2010; Prakash et al., 2014), liquid chromatography (LC) (Avenoso, et al., 2000; Aravagiri and Mander, 2000; McClean et al., 2000; Zhang et al., 2005; Bhatt et al., 2006; Zhang et al., 2007; Locatelli et al., 2009), chemiluminescence assay (Song and Wang, 2004), pulse polarography (Joshi et al., 2006), and the cost of executing these methods constitute an enormous challenge in developing countries like Nigeria. The use of visible spectrophotometric methods reported for the determination of risperidone in its pure form and pharmaceutical preparations have complex procedures and/ or utilization of expensive chemicals and solvents (Hassan, 2008; Narayana and Shetty, 2011; Deepakumari et al, 2013; Archana et al, 2013; Hassouna et al, 2014). This has prompted the call for the development of sensitive, simple and economical ultraviolet-visible (UV)-spectrophotometric methods for the determination of risperidone which can be used to assay risperidone in pharmaceutical formulations available in the market and achieving precise and accurate results with less difficulty and cost.

Risperidone has fewer side effects and has benefitted refractory psychotic patients compared to the typical antipsychotics like haloperidol (Shengquan, 2011). This has contributed to its widespread use. In addition, with the introduction of newer and cheaper generics into the market, it is imperative to develop simple, accurate, precise and cost effective methods for the determination of risperidone to ensure routine quality assessment.

1.4 Theoretical Framework

The basic nature of the risperidone (pka- 8.24) makes it possible to utilize an anionic dye (bromocresol green and thymol blue) to form an ion-pair complex. Due to resonance effect, protonation of the benzisoxazole ring and pyrimidin-4-one is very difficult. Thus, there is only one site which is susceptible to protonation and that is the nitrogen in the piperidine ring (Harikrishna et al., 2008). Among the two tautomers of the dyes (bromocresol green and thymol blue) present in equilibrium, the quinoid ring must predominate because of the strong acidic nature of the sulfonic group. Finally, protonated risperidone form ion-pairs with the dyes Bromocresol green and Thymol blue in 1:1 ratio. The possible reaction pathway is depicted below: