Research Article SIMULTANEOUS IMPROVEMENT OF DISSOLUTION RATE AND STABILITY OF RAMIPRIL BY FORMATION OF UREA INCLUSION COMPLEXES VIKAAS BUDHWAAR*, ARUN NANDA Department of Pharmaceutical Sciences, Mahrshi Dayanand University, Rohtak, Haryana, India. Received: 24 Nov 2011, Revised and Accepted: 05 Jan 2013 ABSTRACT Ramipril is an angiotensin-converting enzyme (ACE) inhibitor, used to treat high blood pressure and congestive heart failure. In the present study, urea, a well-known adductor for linear compounds was successfully employed for inclusion of Ramipril—a substituted cyclic organic compound through a modified technique using oleic acid as rapidly adductible endocyte (RAE).The proportion of oleic acid and urea in the inclusion compounds was optimized for maximum dissolution of ramipril using 2 2 factorial design. Formation of urea inclusion compounds was confirmed by FTIR, DSC and XRD. Urea–Ramipril–RAE inclusion compounds containing varying proportions of guests were prepared and their thermal behavior studied by DSC. The inclusion compounds were also found to exhibit high content uniformity and markedly improved dissolution profile as demonstrated by increased dissolution efficiency in acidic , neutral and alkaline medium. Stability studies revealed that lesser amount of Ramipril in urea inclusion compounds degraded at 4 o C, 25 o C and 40 o C than pure drug kept under same conditions. Studies reveal the possibility of exploiting co-inclusion of the drug in urea host lattice for simultaneous improvement of dissolution and stability. Keywords: Adduction; Ramipril; Complexation; Dissolution; Dissolution rate; Inclusion compounds; Urea inclusion compounds, Normally Non- adductible endocyte, Rapidly adductible endocyte. INTRODUCTION Ramipril, inhibits the actions of angiotensin converting enzyme(ACE), thereby lowering the production of angiotensin II and also decreasing the breakdown of bradykinin which ultimately results in relaxation of arteriole smooth muscle leading to a decrease in total peripheral resistance, reducing blood pressure as the blood is pumped through larger diameter vessels. It is used in the management of mild to severe hypertension and myocardial infraction. It is a prodrug which after absorption, undergo rapid metabolism by ester hydrolysis to the active diacidic form ramiprilat[1,2] by liver esterase enzymes. Ramiprilat is mostly excreted by the kidneys. The half-life of ramiprilat is variable (3–16 hours), and is prolonged by heart and liver failure, as well as kidney failure. Even though ramipril is without question one of the most important ACE inhibitors available today, current ramipril formulations show considerable problems like poor water solubility (3.5 mg/L) and wettability , poor bioavailability and susceptibility to undergo degradation. The degradation of ramipril is believed to occur mainly via two pathways: (a) hydrolysis to ramipril–diacid and (b) cyclization or condensation to ramipril–diketopiperazine[3]. The poor solubility and wettability of Ramipril leads to poor dissolution and hence, variations in bioavailability. It suffers from low bioavailability of 28%, two main reasons contributing towards the same being its poor aqueous solubility and high first pass metabolism[5]. Thus, increasing the aqueous solubility and shelf life of Ramipril is of therapeutic importance[4]. The complexation of drugs under hydrophilic carriers is one of the selective approaches to achieve this ideal therapy particularly for drugs with poor aqueous solubility and stability. There are few works related with stability studies of ramipril: accelerated stability studies for the simultaneous determination of ramipril/moexipril[6], ramipril/ telmisartan[7], and ramipril/hydrochlorothiazide[8], a forced degradation study of ramipril in Altace capsules[9], a stability study of ramipril in solvents of different pH[10], a study of stability of ramipril over time in water apple juice and applesauc[11]and a comparative study of stability over time of marketed generics of ramipril tablets versus reference ramipril tablets[12] . Among some of the recent efforts to increase the solubility of ramipril tablets are formulation of ramipril containing solid self microemulsifying drug delivery system by adsorbent technique[13],formulation of inclusion complexes of ramipril using β-cylcodextrin (β-CD) and hydorxypropyl β- cylcodextrin (HPβ-CD) [14], formulation and evaluation of Chitosan Loaded Mucoadhesive Microspheres of Ramipril to enhance its solubility[15], designed and development of oral oil in water ramipril nanoemulsion containing Ramipril[16], production of Multiple Unit Particle System (MUPS) of stabilized Ramipril pellets[17] etc. Inclusion compounds were first observed by Mylius in 1886[18]as unusual complexations occuring between hydroquinone and several volatile compounds. Urea inclusion compounds were first reported by Bengen from experiments on the effect on the addition of urea to pasteurized milk[19]. Bengen was able to separate quantitavely the butter fat by formation of its urea inclusion compounds. In the conventional urea inclusion compounds, the host structure comprises a hydrogen-bonded arrangement of urea molecules that contain hexagonal, non-intersecting, linear, parallel tunnels [20] of diameter varying between about 5.5 and 5.8Å according to the position of guest along the tunnel and this structure is stable only when the tunnels are filled with a dense packing of guest molecules. Linear molecules are included along the tunnel in an extended planar zigzag conformation[18,21] As the cross-section of the channels in urea inclusion compounds (defined by the van der Waals surface of the tunnel wall) is 5.5–5.8 A ° , only guest molecules that have a molecular size smaller than this area can fit into these cavities. More specifically, the molecules having a sufficiently long n-alkane chain with a limited degree of substitution can fit within these channels[22,23] .There are two main criteria which determine whether or not a particular urea inclusion compound will be formed, a) the length of the carbon backbone of the guest, and b) the degree of branching or substitution in the guest carbon skeleton. More specifically the adductible guests must have a carbon skeleton consisting of six or more atoms with little or no branching or substitution is usually a requirement for urea inclusion compound formation[24]. In general, molecules containing benzene or cyclohexane rings do not form inclusion compounds with urea, presumably because these structural components are too wide to fit comfortably inside the tunnel[25]. If however benzene carries a long chain substituent, then an inclusion compound may be formed because the long chain of this compound is readily adducted and apparently the unit cell can easily withstand the distortion caused by an occasional benzene group[26]. Similarly normally a non-adductible endocyte (NNAE) like 3-methyl heptane forms an adduct with urea only when a more slender hydrocarbon (e.g. n-C6H14)—a rapidly adductible endocyte (RAE) serves as a ‘‘pathfinder’’[26,27]. The endocytes possessing a A A c c a a d d e e m mi i c c S Sc c i i e e n n c c e e s s International Journal of Applied Pharmaceutics ISSN- 0975-7058 Vol 5, Issue 3, 2013