International Journal of Innovative Pharmaceutical Sciences and Research

Transcription

1 International Journal of Innovative Pharmaceutical Sciences and Research FORMULATION AND EVALUATION OF NICARDIPINE HYDROCHLORIDE SUSTAINED RELEASE PELLETS 1 T.Nagendra Babu*, 2 K.Umasankar, 3 P.Jaya Chandra Reddy Department of pharmaceutics, Krishna Teja Pharmacy College, Chadalawada Nagar, Tirupati , INDIA Abstract The objective of the present study was to formulate and evaluate Nicardipine hydrochloride sustained release pellets which correlates the standards of marketed product by using HPMC and Ethyl Cellulose as polymers. And compare the in-vitro dissolution profiles of formulated pellets with various concentrations of HPMC and Ethyl cellulose. The in vitro drug release studies were carried out in ph 6.8 using dissolution test apparatus II. The pellets were placed inside the 900 ml dissolution medium and speed and paddle was set at 75 rpm. Samples (5 ml) withdrawn at a time interval of 0, 0.50, 1, 2, 6, 12 hours and same value of fresh medium were replaced. The samples were analysed for drug content ph 6.8 as blank at λ max 237 nm. The percentage drug release was plotted against time Compatibility study of drug and polymers were conducted by employing FTIR Spectral studies. In this FTIR studies along with drug, HPMC E5 and ethyl cellulose 7cps used. The order of drug release for optimised formulation followed first order. And the mechanism of drug release is non-fickian diffusion governed by Higuchi. In the drug loading stage total five formulations(f1,f2,f3,f4,f5) are formulated and in these F4 chosen as optimized formulation because of its % yield and assay were within the limits. Keywords: Nicardipine hydrochloride, HPMC, Ethyl Cellulose, Pellets, Higuchi, Non-fickian. Corresponding Author T.Nagendra Department of Pharmaceutics, Krishna Teja Pharmacy College, Tirupati, Andhra Pradesh, INDIA pharmauser05@gmail.com. Phone: Available online: March Issue 164

2 INTRODUCTION Incorporating an existing medicine into a novel drug delivery system (NDDS) can significantly improve its performance in terms of efficacy, safety and improved patient compliance. In the form of a NDDS, an existing drug molecule can get new life, thereby increasing its market value and competitiveness. Historically, the word pellet has been used by a number of industries to describe a variety of agglomerates produced from diverse raw materials. Pellets can be defined as agglomerates of fine powders or granules of bulk drugs and excipients. Multiparticulate dosage forms are pharmaceutical formulations in which the active substance is present as a number of small independent subunits with diameter of mm [1]. To deliver the recommended total dose, these subunits are filled into a capsule or compressed into a tablet [1,2]. They provide many advantages over single-unit systems because of their small size. Multiparticulates are less dependent on gastric emptying, resulting in less inter and intra-subject variability in gastrointestinal transit time. They are also better distributed and less likely to cause local irritation [3]. The pelletized products can improve the safety and efficacy of the active agent. Recently much emphasis is being laid on the development of multiparticulate dosage forms in preference to single unit systems because of their potential benefits such as increased bioavailability, reduced risk of systemic toxicity, reduced risk of local irritation and predictable gastric emptying [4]. Pellets offer a great flexibility in pharmaceutical solid dosage form design and development. They flow freely and pack easily without significant difficulties, resulting in uniform and reproducible fill weight of capsules and tablets.successful film coating can be applied onto pellets due to their ideal spherical shape and a low surface area-to-volume ratio [5]. Pellets composed of different drugs can be blended and formulated in a single dosage form. This approach facilitates the delivery of two or more drugs, chemically compatible or incompatible, at the same sites or different sites in the gastrointestinal tract. Even pellets with different release rates of the same drug can be supplied in a single dosage form. Sustained Release Sustained released means that the drug will be released under first order kinetics. Therefore if a drug starts out at 100mg and releases at a rate of 10% per unit time [6]. 100mg --> 90mg --> 81mg --> 72.9 mg. Available online: March Issue 165

3 MATERIALS AND METHODS: List of Materials Used: Nicardipine hydrochloride, Sugar sphres, Sodium lauryl sulphate, Inf-10, Lactose, Mannitol, Sucrose, Pvp K-30, Tween 80, HPMC E5, Methylene dichloride, Iso propyl alcohol, Ethyl cellulose 7 cps, Di ethyl phthalate Analytical Methods for Estimation of Nicardipine The following analytical methods are reported for the estimation of Nicardipine 1. UV Spectroscopy 2. High Performance Liquid Chromatography 3. Reverse phase High performance Liquid Chromatography 4. Visible Spectroscopy. In the present investigation UV.Spectrophotometer method was used for the estimation of Nicardipine Hydrochloride Assay Standard preparation Weigh accurately about 100 mg of Nicardipine hydrochloride working standard into 100 ml of volumetric flask add 50 ml of Methanol,sonicate and shake well and dilute to volume with Methanol. Mix well. Pipette 2 ml of this solution in to 100 ml volumetric flask dilute to volume with distilled water and mix well. Sample Preparation Weigh accurately about 20 mg drug equivalent pellets in a 50 ml volumetric flask, add 10 ml of Methanol, sonicate for 10 minutes. Cool and dilute to volume with Methanol. Filter the solution through what man filter paper. Then take 2 ml of filtrate into 50 ml volumetric flask and dilute to volume with distilled water. Measure the absorbance at 237 nm. Calculation Assay = Std.Wt S.Abs P S.Wt 2 Std.Abs Std.Wt. = standard weight S.Wt. = sample weight Std.Abs. = standard absorbance S.Abs= sample absorbance P= purity of substance Available online: March Issue 166

4 STANDARD CURVE FOR NICARDIPINE HYDROCHLORIDE Table 1: Analytical profile for Nicardipine hydrochloride Fig.1: Standard curve Nicardipine hydrochloride Concentration (µg/ml) Absorbance Table 2: Formulation of Nicardipine Hydrochloride Pellets NICARDIPINE HCl 22%W/W BATCH SIZE 1KG FORMULATION CODE F1 F2 F3 F4 F5 DRUG LOADING NICARDIPINE HCL SUGAR SPHERES SLS INF LACTOSE MANNITOL SUCROSE PVP K TWEEN P.WATER QS QS QS QS QS THEORICAL YIELD SEAL COATING HPMC E5(3%) MDC 0.18 IPA THEORITICAL YIELD SR COATING EC 7CPS 0.50% 1% 1.50% 2% 2..5 EC 7CPS DEP IPA MDC THEORITICAL YIELD Available online: March Issue 167

5 FORMULATION OF NICARDIPINE HYDROCHLORIDE PELLETS Nicardipine Hydrochloride Sustained Release Pellets: In this work, the method used for preparing Nicardipine Hydrochloride sustained release pellets was powder layering followed by solution/suspension-layering technique. Solution / suspension-layering technique: The three main steps followed in suspension layering technique to prepare sustained release pellets of Nicardipine were, 1. Drug coating 2. Sub coating 3. Functional coating 1. Drug coating: A coating solution containing appropriate concentration of drug, binder, and other excipients was prepared. Then, the solution was sprayed on to the nonpareil seeds by using Wruster bottom spray (FBP), by maintaining all appropriate parameters like spray rate, bed temperature, inlet temperature, exhaust and RPM. Dried forms of coated pellets were obtained. Samples were withdrawn at different areas and tested for content uniformity and assay. Std.Wt. = standard weight S.Wt. = sample weight Std.Abs. = standard absorbance S.Abs. = sample absorbance P = purity of Nicardipine hydrochloride Table 3: Process parameters during drug loading S.No Name of the parameter Operation parameter 1 Inlet temp C 2 Exhaust Temp C 3 Pump RPM Atomization air pressure kg/cm2 5 Spray rate gm/min 6 Drying Time 30 min Available online: March Issue 168

6 2. Sub coating The calculated quantity of drug loaded pellets was taken into FBC bowl. After ensuring the integrity of the apparatus the operation was started by setting the temperature, spray pressure, spray rate etc. Coating was done by wurster coating method. Coating process was started maintaining the temperature between C and continued until the required weight gain and coating of the material is achieved. After completing the process the pellets were allowed to dry in the bowl itself by air blowing for 15 min. The critical parameters include bowl temperature and spray rate. After drying the pellets were unloaded from the bowl and collected for sifting. Sifting The dried pellets were passed through the sieves 12# and 18#. The ups and downs of each sieve were collected separately. Pellets retained on 18# are used for further process. Samples were taken from each batch and subjected for assay and dissolution test. 3. Functional coating: Table 4: Process parameters during barrier coating After drug and seal coating this step plays most important role in sustaining the drug release. This is also called as polymer coating, where a coating solution containing appropriate concentration of polymer was prepared and sprayed on seal coated pellets. The coating solution was sprayed on the pellets using same mechanism and by maintaining the appropriate parameters.the development of present study was mainly based on the process of binding of drug to non-pareil seeds and binding of polymer on to drug coated non-pareil seeds. During this process, a variety of possible binders were used in order to bind the drug onto the NPS. The main aim was to sustain the release of drug. S.No Name of the parameter Operation parameter 1 Inlet temp C 2 Exhaust Temp C 3 Pump RPM Atomization air pressure kg/cm2 5 Spray rate gm/min 6 Drying Time 15 min Sifting: The dried pellets were passed through the sieves 12# and 16#. The ups and downs of each sieve were collected separately. Pellets retained on 16# are used for further process. Samples were taken from each batch and subjected for assay and dissolution test. Available online: March Issue 169

7 Table 5: Process parameters during sub coating S.NO Name of the parameter Operation parameter 1 Inlet temp C 2 Exhaust Temp C 3 Pump RPM Atomization air pressure kg/cm2 5 Spray rate gm/min 6 Drying Time 30 min Preformulation Studies Preformulation study is an investigation of physical and chemical properties of a drug substance alone and when combined with excipients. It is the first step in the rationale development of dosage form. The overall objective of preformulation study is to generate information useful to the formulation development for a stable and bioavailable dosage forms. The use of Preformulation parameters is to maximize the chances in formulating an acceptable, safe, efficient and stable product. Physical Drug Excipient Compatibility Studies Excipients were important ingredients of almost all pharmaceutical dosage form. The successful formulation of a stable and effective solid dosage form depends on the selection of excipients, so it is necessary to know the inherent stability of the drug substance and possibility of interaction with excipients. The physical compatibility studies were coupled with the stability studies at higher temperature and humidity conditions.physical observation of sample was done every week for any color change or lumps formation and flow, for three months stored at 40 o C/75% RH. Table 6: Protocol for drug-excipients compatibility Batch Drug-Excipients combination D:ERatio no. 1 Nicardipine hydrochloride alone - 2 Nicardipine hydrochloride + sls 1:5 3 Nicardipine hydrochloride +Inf-10 1:5 4 Nicardipine hydrochloride +lactose 1:5 5 Nicardipine hydrochloride + mannitol 1:5 6 Nicardipine hydrochloride +sucrose 1:5 7 Nicardipine hydrochloride +pvp k-30 1:5 Available online: March Issue 170

8 Drug Release Kinetics Data obtained from the in-vitro release studies were fitted to various kinetic equations such as zero order, first order, Higuchi model and Korsmeyer- Peppas model Zero order equation Q = Q 0 K0t ¾ First order equation Higuchi equation In Q = In Q 0 K1t Q = K2t1/2 Korsmeyer - Peppas equation Q/Q 0 = K tn Where, K 0 to K2 were release rate constan t s, Q/Q 0 was fraction of drug released at tim e t, K was a constant and n was diffusion constant that indicates general operating release mechanism. For Fickian (diffusion controlled), n 0.5; for non- Fickian (anomalous) release, n value is in between 0.5 to 1.0; for zero order release, n=1.0; for super case transport II, n > EXPERIMENTAL RESULTS Organoleptic Characters of Nicardipine Hcl Table 7: Nicardipine Specifications S.No. TEST SPECIFICATION RESULT 1 Description 2 Solubility Greenish yellow colour crystalline powder Soluble in water and slightly soluble in methanol An off-white to cream colored crystalline hygroscopic powder Complies 3 Water Content (by Karl-Fisher) NMT 3% 1% w/w 4 LOD by IR moisture analyzer, at C 1.37 % w/w 5 Bulk density Tapped density Haussner s Ratio Carr s/compressibility Index (%) 0.21 gm/ml 0.27 gm/ml Melting Point O C 136 o C 7 Assay on Anhydrous Basis (Potentiometric) <98% and not more than 102% w/w 98.9%w/w Available online: March Issue 171

9 FTIR Scan of Nicardipine Hydrochloride Table 8: FTIR Scan Of Nicardipine Hydrochloride Wave number (cm -1 ) Functional group 1356 NO 2 stretching 3070 C-H stretching 1637 C=C stretching 3182 N-H stretching 1703 C=O stretching Fig 2: FTIR Scan of Nicardipine Hydrochloride Table 9: FTIR spectrum of physical mixture (NicardipineHCl, HPMCE5 and ethyl cellulose) Wave number (cm -1 ) Functional group 1357 NO 2 stretching 3064 C-H stretching 1633 C=C stretching 3182 N-H stretching 1701 C=O stretching Fig 3: FTIR spectrum of physical mixture (NicardipineHCl, HPMC E5 and ethyl cellulose) Available online: March Issue 172

10 INFO: The FTIR spectra show the peaks in pure drug of Nicardipine hydrochloride are not disutrubed in the mixture. So that it indicates they are compatible Dissolution Data of Nicardipine Pellets All values are expressed as mean ±S.D, n=3 Drug Release Comparison of Optimized Formulation F4 With Marketed Product Fig 4: Drug Release Comparison of Optimized Formulation F4 with Marketed Product Table 10: Dissolution Data Of Nicardipine Pellets DISSOLUTION PROFILE % drug release TIME(hr) F1 F2 F3 F4 F5 MARKETED PRODUCT ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.16 Assay: Table 11: Assay values Formulation F1 F2 F3 F4 F5 Assay 86% 80% 92% 95% 90% Available online: March Issue 173

11 The limits of assay was 95% to 105% The labeled Nicardipine concentration was22.0% The F4 formulation was 20.9%(95%) In-vitro dissolution studies The release profiles of Nicardipine from pellet coated with ethyl cellulose. The entire pellet disintegrates during the dissolution test, and no gel like structure remained, indicating complete dissolution at different coating levels. As the coating level increased, the drug release decreased. The reduction in the release rate with increasing coating level may be due to the increased diffusional path length with increase in the thickness of the coat. The effect of coating level on release of Nicardipine from pellets coated with ethyl cellulose. It was observed from the results that the coating levels had a major effect on the ultimate rate of drug release and the duration of the release. The entire pellet remained intact during the dissolution test, indicating that the ethyl cellulose coating layer controlled the drug release. Generally, in dosage forms that have a water insoluble polymer as the rate controlling membrane, since diffusion through the membrane controls the overall release rate of the drug, the layer properties and geometry, such as coating porosity, internal structure, and coating thickness, may be critical factors in determining the release rate of drug Kinetics of In-Vitro Dissolution: The drug release for the optimized formulation (F4) followed first order kinetics shown in Figure No.20,21 As the graph was drawn between the log % of drug unreleased verses time were found to be linear. To ascertain the mechanism of drug release data was subjected to Higuchi shown in Figure No22,23&Korsmayer,peppas equation shown in Figure No 24,25 From the regression coefficients the plots shows highest linearity with first order followed by Higuchi model. Determination of Assay: The assay of Nicardipine Hydrochloride was determined by using UV-spectrophotometric method. The result obtained within the specified limits(95%-105%). CONCLUSION The in-vitro dissolution studies of all formulations were carried out in simulated intestinal fluid for 12 hours and the formulations met the standard results. Nicardipine HCl sustain released pellets were formulated by solution layering technique by using HPMC E5 and Ethyl cellulose Available online: March Issue 174

12 7cps as polymers of release retarding. The preformulation studies of API were found to be within limits. Those are bulk density, tapped density, compressibility index, hausner s ratio and angle of repose. The stability studies were conducted for optimized formulation (F4) as per ICH guidelines at 25 0 C±2/60±5% RH and 40 0 C±2/75±5% RH for 3 months and no changes were observed. The optimised formulation F4 had the similar dissolution properties with that of marketed formulation The conclusion of this dissertation was by preparing the noval dosage forms like sustain released pellet formulations, can improve the drug availability in the plasma for more than conventional dosage forms. ACKNOWLEDGEMENT I express my deep sense of gratitude and indebtedness to my most respected teacher, research guide and mentor, Mr. P. Jayachandra Reddy for his untiring guidance, unmitigated encouragement, for inculcating confidence and for being a great source of inspiration and keen interest in making this thesis a reality. It would not have been possible to achieve this goal without his support, care and affection. I express my sincere thanks to to Dr.K.Umasankar, M.Pharm, Ph.D,HOD, Krishna Teja Pharmacy College,Tirupati for granting permission to carry out my research work in industry. REFERENCE 1. Shaji J., Chadawar V., Talwalkar P., Multiparticulate Drug Delivery System, The Indian Pharmacist, June 2007, 6: Preparing Modified Release Multiparticulate Dosage Forms With Eudragit Polymers, Pharma Polymers, November 2002, 9: Gajdos, B.,. Rotary granulators - Evaluation of process technology for pellet production using factorial design Drugs Made Ger. 27: Tang E. S.K., Chan L.W., Heng P.W.S, Coating of Multiparticulates for Sustained Release, Amer J Drug Delivery 2005: 3: Tang E. S.K., Chan L.W., Heng P.W.S, Coating of Multiparticulates for Sustained Release, Amer J Drug Delivery 2005: 3: Ozturk. A.G., Ozturk. S.S, Palsson. B.O, Wheatley. T.A, Dressman. J.B., Mechanism of release from pellets coated with an ethyl cellulose-based film. Journal of Controlled Release,1990: 14,203. Available online: March Issue 175