Comparative dissolution studies of an extended release formulation of Tolterodine tartrate and Tamsulosin Hcl

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1 Research Article Supriya M. Mhamunkar et al. /BioMedRx 2013,1(3), Available online through Comparative dissolution studies of an extended release formulation of Tolterodine tartrate and Tamsulosin Hcl Supriya M. Mhamunkar 1*, Ganga Srinivasan 2, Tabassum Khan 3, Suvarna I. Bhoir 4 1 School of Science, NMIMS University, III Floor, Bhaidas Hall Bldg., JVPD Scheme, Vile Parle (W), Mumbai , Maharashtra state, India. 2 VES College of Pharmacy, Hashu Advani Memorial Complex, Behind Collector Colony, Chembur (E), Mumbai Dr. Bhanuben Nanavati College of Pharmacy, Gate No.1, 1 st Floor, Mithibai College Campus, V.M. Road, Vile Parle (W), Mumbai Shri C. B. Patel Research Centre s Analytical Laboratory, 3 rd floor, Bhaidas Sabhagriha Building, Juhu Scheme, Vile Parle (W), Mumbai , Maharashtra state, India. Received on: ; Revised on: ; Accepted on: ABSTRACT A comparative study was undertaken on dissolution studies of marketed formulations which contain Tamsulosin HCl (TAM) and Tolterodine Tartrate (TOL) in a combination of 0.4 mg and 4.0 mg respectively in an extended release form. The dissolution method developed was then used to study three marketed formulations, quantification being done using a validated HPLC method. Comparison of dissolution data was done using the Moor and Flanner model independent method which included determination of Similarity factor and Difference factor. The kinetics of the dissolution process were determined by analyzing the dissolution data using four kinetic equations; namely zero order, first order, higuchi square root and hixson Cube root equation. The results obtained were within the acceptance criteria. The kinetic study indicated that the dissolution data followed first order kinetics and hixson Crowell cube root equation as straight line were obtained with a slope of approximately one and small value of intercept. Keywords: Dissolution, HPLC, Kinetic Study, Tolterodine Tartrate, Tamsulosin HCl INTRODUCTION: TAM (Fig 1) [1] is a selective, potent and competitive α1 adrenoreceptor antagonist and has a great affinity for these receptors, predominantly present in the human prostate. Chemically, TAM Fig. 1. Chemical Structure of Fig. 2. Chemical Structure Tamsulosin HCl of Tolterodine Tartrate is 5 [(2R) 2- [[2-(2-ethoxy phenoxy) ethyl] amino] propyl] 2 methoxy benzene sulfonamide hydrochloride. TAM is used in men to treat the symptoms of an enlarged prostate which leads to difficulty in urination, painful urination, and urinary frequency and urgency [2]. *Corresponding author. Supriya M. Mhamunkar, School of Science, NMIMS University, III Floor, Bhaidas Hall Bldg., JVPD Scheme, Vile Parle (W), Mumbai , Maharashtra state, India. TOL (Fig 2) [3], chemically designated as (R)-N,N-di-isopropyl- 3-(2- hydroxy-5-methylphenyl)-3-phenylpropanamine L-hydrogen Tartrate is a new muscarinic receptor antagonist intended for the treatment of urinary urge incontinence and other symptoms related 7to an unstable bladder [4, 5]. It is used to treat an overactive bladder with symptoms of urinary frequency, urgency, and incontinence. Both, urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors [6]. Both of these drugs i.e. TAM and TOL are marketed fixed dose combination tablet in the ratio 0.4:4mg respectively. It has been reported that the diverse manufacturing techniques employed in the manufacture of Controlled Release (CR) dosage forms of Theophyllin preparations gave very different release patterns [7, 8]. Bioavailability of orally administered drugs can be influenced by a number of factors including release from the formulation, dissolution, stability in the gastrointestinal (GI) environment, permeability through the gut wall and first-pass gut wall and hepatic metabolism [9]. When the same drug is manufactured by different manufacturers, it is usually prepared by different manufacturing processes. These different tablets or capsules also contain different excipients, which have an effect on the release pattern of the tablet or capsule in the body. This difference can be evaluated with the help of a kinetic study. Hence,

2 Supriya M. Mhamunkar et al. /BioMedRx 2013,1(3), the aim was to develop a dissolution method and compare dissolution data of an extended release capsule formulation containing Tamsulosin HCl and Tolterodine Tartrate in combination. The comparative dissolution and kinetic study of TAM and TOL in fixed dose combinations has not been reported. In a literature search it was found that an in vitro study of TAM and release kinetics from Biodegradable PLGA in situ implants has been reported [10]. Some reported dissolution studies on a commercially available formulation of TAM in which quantification was done by HPLC has been reported [11, 12]. A dissolution method for TAM pellets has been reported [13]. There are reported dissolution methods for commercial formulations as well as transdermal films developed for TOL [14, 15]. A study was thus initiated on extended release formulations of different commercial brands which contained Tamsulosin HCl and Tolterodine tartrate in combined extended release dosage form. Dissolution release data of these brands were compared using similarity and difference factor by considering one formulation as a standard. Kinetic equations were applied to study the physical behavior of drug released. MATERIAL AND METHODS: Materials: The products tested included controlled release capsules listed in Table 1. Reference standards of Tamsulosin HCl and Tolterodine tartrate were gift samples from Corporate Analytical Development Lab. Methanol, acetonitrile used were of HPLC grade (Ultra pure) obtained from E. Merck (India) Ltd., having a minimum assay 99.8% by GLC. Ammonium acetate used was of E. Merck (India) Ltd and di- potassium hydrogen ortho phosphate, potassium dihydrogen phosphate and sodium chloride and triethylamine were obtained from Qualigens. Table 1: Details of formulations used in the dissolution study Sr. Brands Content (mg) Manufacturer No. Tamsulosin Tolterodine HCl Tartrate 1 Roliflo Ranbaxy Laboratories Ltd. 2 Tamlet Sun Pharmaceutical Industries Ltd 3 Bapter Dr. Reddy s Methods: Laboratories Ltd. Solubility Study: The solubility class boundary is based on the highest dose strength of a drug product that is the subject of a biowaiver (drug product approval without a pharmacokinetic BE study) request. According to USFDA BCS guidelines [16] a drug substance is considered highly soluble when the highest dose strength is soluble in 250 ml or less of an aqueous medium over the ph range of Thus according to the guidelines four different ph solutions were prepared to dissolve the drug i.e. 1.2, 4.5, 6.8 and 7.2. Tamsulosin HCl and Tolterodine tartrate were dissolved in these ph solutions and further diluted with mobile Table 2: Dissolution conditions Parameter Dissolution Medium phase to obtain the desired concentrations (TAM 0.4 µg/ml and TOL 4.0 µg/ml). Dissolution Studies: Dissolution studies were performed at ph 6.8 for 24 hours at 100 rpm using 900 ml of the dissolution medium i.e. a mixed phosphate buffer system [for 6 L medium ml KH 2 PO 4 (1 M) ml K 2 HPO 4 (1 M) ml NaCl (5 M) + remaining volume of water ] at a 37.0 o C in a thermostated water bath. The USP dissolution apparatus I (Basket, Lab India) was used. Manual sampling was undertaken at 1, 2, 3, 4, 6, 8, 12, 24 hours intervals where the filtered portions (around 10 ml) were analyzed on a HPLC system (Agilent 1100 series) using a validated HPLC method [17]. Dissolution study was done according to dissolution conditions mentioned in Table 2. To maintain constant volume of a medium in the bowl, replacement was done using fresh medium. This guaranteed a constant volume and constant drug content throughout the dissolution test. Each point in the data represents the average of 12 individual measurements. In all cases, the relative S.D. was less than 20% for earlier points and 10% for the other remaining points. Calculations were done using Excel MS office. Similarity factor and Difference factor were calculated using excel sheet. Condition 900 ml of mixed phosphate buffer system Medium ph 6.8 USP Apparatus USP I Basket Medium Volume 900 ml RPM 100 RPM Temperature 37.0 C Sampling Volume 10 ml RESULT AND DISCUSSION: Eq. 1 Eq. 2 Solubility Study: The result of the solubility study (Table 3) showed that ph 6.8 was suitable for the dissolution study of Tamsulosin HCl and Tolterodine Tartrate. Table 3: Solubility data for Tamsulosin HCl and Tolterodine tartrate at four different ph values Compound ph % Release Result n=3 Tamsulosin HCl 1.2 0% % % % Tolterodine Tartrate 1.2 0% % % %

3 Comparison Study: Comparing the in vitro dissolution profiles of a tablet, powder, or capsule provides the formulator with critical information necessary for screening formulations during product development; for evaluating stability; and optimizing dosage forms. For this the Difference factor f 1 and the Similarity factor f 2 were calculated. The dissolution profiles of all three brands were compared using the Similarity Factor and the Difference factor. Among the three brands, i.e. Roliflo-OD, Tamlet 4 and Bapter, Roliflo-OD was used as the reference for the other two brands. Results are shown in Table 4. Table 4: Comparison data of Dissolution Profile of Tamsulosin HCl and Tolterodine Tartrate with their f1 and f2 values Supriya M. Mhamunkar et al. /BioMedRx 2013,1(3), Drug Tamsulosin HCl Tolterodine Tartrate Time Roliflo-OD Tamlet-4 Bapter Roliflo-OD Tamlet-4 Bapter Point n=12 n=12 n=12 n=12 n=12 n=12 Fig. 3. Comparative of % Cumulative Release vs. Time with SD bars for Tamsulosin HCl for all three brands f f Kinetic Study: In order to describe the kinetics of the release process of drugs formulated in CR preparations, various equations are normally used such as the zero-order rate equation (Q = Q 0 + K 0 t) which describes the systems where the release rate is independent of the concentration of the dissolving species [18]. The first-order equation (Log C = Log C 0 - kt / 2.303) describes the release from systems where dissolution rate is dependent on the concentration of the dissolving species [19-21]. The Higuchi square root equation [22] (Q t = k H (t) 0.5 ) describes the release from systems where the solid drug is dispersed in an insoluble matrix and the rate of drug release is related to the rate of drug diffusion [23, 24]. The Hixson-Crowell cube root law (Q 0 1/3 Q t 1/3 = K HC t) describes the release from systems where there is a change in surface area and diameter of the particles or tablets. Such a change in area and diameter is reflected by a change in the weight of the particles. The applicability of all of these equations was tested in this work. Fig. 4. Comparative of % Cumulative Release vs. Time with SD bars for Tolterodine Tartrate for all three brands A comparative dissolution profile of Tamsulosin HCl and Tolterodine Tartrate for all three brands with the values of SD (n=12) at each time point is shown in Fig. 3 and 4 respectively; the plot is of % Cumulative release vs. Time in hours. The dissolution data obtained for all brands (for TAM and TOL) at ph 6.8 were plotted in accordance with the zero order equation i.e. percent dissolved as a function of time (Fig. 5 and 6). It was evident from the figure that the plots are curvilinear suggesting that the release process is not zero-order in nature. This indicated that the dis- Fig. 5. Comparative of % Cumulative Release vs. Time for Tamsulosin HCl for Zero Order Equation

4 Supriya M. Mhamunkar et al. /BioMedRx 2013,1(3), Fig. 6. Comparative graph of % Cumulative Release vs. Time in hours for Tamsulosin HCl for Zero Order Equation solution rate of the drug was dependent on the amount of drug available for dissolution and diffusion from the matrix. The plot also exhibited a large degree of brand-to-brand variation. Fig. 8. Comparative of Log % Cumulative Remaining vs. Time for Tolterodine Tartrate for all three brands for First Order equation The dissolution results for Tam and Tol (Fig. 9 and 10) were plotted in accordance with the Higuchi square root equation, i.e., percent dissolved as a function of the square root of time. A linear relationship was obtained after an initial lag time had lapsed in all cases. This lag time is a measure of the time needed by the drug to diffuse from the matrix interior through the boundary layer and then to the dissolution medium. The linearity of the plots indicated that the release process was diffusion-controlled. The dissolution data of all brands (for Tam and Tol) were plotted in accordance with the first order equation, i.e. the logarithm of the percent remaining as a function of time (Fig. 7 and 8). It is evident from the figure that a linear relationship was obtained for all brands showing that the release is an apparent first-order process. This indicated that the amount of drug released was dependent on the matrix drug load. Fig. 9. Comparative % Cumulative release vs. Square root of time for Tamsulosin HCl for all three brands for Higuchi square root model Fig. 7. Comparative of Log % Cumulative Remaining vs. Time for Tamsulosin HCl for all three brands for first Order equation Fig. 10. Comparative % Cumulative release vs. Square root of time for Tolterodine Tartrate for all three brands for Higuchi square root model

5 Supriya M. Mhamunkar et al. /BioMedRx 2013,1(3), The dissolution data were also plotted in accordance with the Hixson- Crowell cube root law, i.e. the cube root of percent remaining, as a function of time. Fig. 11 and 12 indicates that a linear relationship was obtained in all cases. A small non-zero intercept was noticed in most of the plots. This was not, however, unexpected since the particles are not isometric. Such a non-zero intercept was reported earlier [25]. Statistical Data of all equations are shown in Table 5. CONCLUSION: The dissolution method developed for evaluation of TAM and TOL from a pharmaceutical formulation is also rugged and gives 100 % release for both the compounds. Fig. 11. Comparative Cube root of % cummulative remaining vs. time for Tamsulosin HCl for all three brands for Hixson Crowell cube root model A comparative study of all brands shows that these brands are equivalent to each other as their f 1 value is between 0-15 and f 2 value is between For Tamlet-4 though the f 1 and f 2 values are not within the acceptance criteria, these values are very close to 80 % and above for both the drugs during the period under study From the regression values and graphs it is clear that the formulations follow first order kinetics up to 12 hours as they gave a linear relationship with small non zero intercepts for Tamsulosin HCl and Tolterodine Tartrate. Same is the case with the Hixson Crowell equation; it also shows a good regression value with a small non zero intercept for both the drugs. ACKNOWLEDGEMENT: We are grateful to Dr. A.M. Bhagwat, Director of C. B. Patel Research Centre and the staff members of C.B. Patel Research Centre for their encouragement in carrying out this work. We also express gratitude towards our colleagues for their valuable inputs. Fig. 12. Comparative Cube root of % cummulative remaining vs. time for Tolterodine Tartrate for all three brands for Hixson Crowell cube root model Table 5: Statistical data of Tamsulosin HCl and Tolterodine Tartrate Molecules Brands Zero First Higuchi Hixson Order Order Model Crowell Model Tamsulosin Roliflo OD Regression HCl Slope Intercept Tamlet-4 Regression Slope Intercept Bapter Regression Slope Intercept Tolterodine Roliflo OD Regression Tartrate Slope Intercept Tamlet-4 Regression Slope Intercept Bapter Regression Slope Intercept REFERENCES: 1. tamsulosin-hydrochloride.htm (Access on April 2012) 2. National Center of Biotechnology information. Available at: (access on April 2012) 3. (Access on April 2012) 4. Nilvebrant L, Glas G, Jonsson A, Sparf B, The in vitro pharmacological profile of tolterodine - a new drug for the treatment of urinary urge incontinence, Neurourol Urodyn, 13,1994, Nilvebrant L, Stahl M, Andersson K E, Interaction of tolterodine with cholinergic muscarinic receptors in human detrusor, Neurourol Urodyn, 14,1995, Nilvebrant L, Andersson K E, Gillberg P G, Stahl M, Sparf B, Tolterodine a new bladder-selective antimuscarinic agent, European Journal of Pharmacology, 327, 1997, Ibrahim Jalal R, Zmaily Z, Najib N, Dissolution kinetics of commercially available Controlled release theophylline preparations, International Journal of Pharmaceutics, 52, 1989, Buckton G, Ganderton D, Shah R, In vitro dissolution of some commercially available sustained-release theophylline

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