International Journal of PharmTech Rearch
CODEN (USA): IJPRIF ISSN : 0974-4304 Development of Discriminating
Dissolution Method for an Insoluble Drug:
Nisoldipine
Amit Gupta*, Ram S. Gaud and Ganga S.
School of Pharmacy and Technology Management,SVKM’s NMIMS University,
Mumbai 400056, India
*Corres.author: , Phone number:9819981002
Abstract:Nisoldipine is poorly soluble drug. There is no official dissolution method available in the literature or recommended by regulatory agencies. In prent study dissolution method was developed. the media lection was done by solubility study of drug in different pH as well as in different surfactant solution. Volume of media was found by calculating sink condition. Sodium lauryl suphate, 1.0% was found to be most suitable surfactant. Further method lection at different rotation speed and volume of media and their discriminating power was evaluated using simple model independent approach. We obrved that higher paddle speeds result to flattering drug relea profiles and loss its discriminating power while at low paddle speed method was found to be more discriminating. Discriminating dissolution method for Nisoldipine is paddle at 60 rpm, 500 mL of 1.0% sodiul lauryl sulphate solution.
Keywords:Dissolution, similarity factor, dissimilarity factor.
Introduction
Development of the dissolution method for poorly soluble or insoluble drug has been a challenge for scientists. The objectives of challenge vary during the life cycle of a dosage form. The primary focus of objective during Phas 0 and I is to develop a method to establish the mechanism of in vitro drug
relea and solubilization. During Phas II and III, the objective includes identification of method providing IVIVC. At filling and during Pha IV, the goal is to identify a quality control (QC) dissolution test method to verify process and process parameter. Developed method should be able to satisfy all objectives makes dissolution method development challenging. Physicochemical solubility, logP value, pKa rves as guidelines for the method development (1). The solubility of the active ingredient(s) the most important aspects in the screening of possible dissolution media. USP favors media related to physiological conditions, for example buffer solutions or diluted HCl (0.01 N) (2). Importance of solubility study is to find suitable dissolution method, providing sink condition. The term sink conditions is defined as the volume of medium at least greater than three times that required to form a saturated solution of a drug substance.
For the same purpo solubility characteristics of the formulation are to be done over the physiologic pH range of 1.2 to 7.5 (3). For water-insoluble and sparingly water soluble drug products, u of a surfactant such as Sodium lauryl sulfate, Cetyl triammonium bromide and Tween 80 etc are recommended (4) in justified concentration. A maximum of 3.0% of SLS has been allowed for dissolution test of insoluble drugs like Acetracin & Orlistate (5).
Nisoldipine is a antihypertensive drug with poor solubility, high permeability & high hepatic metabolis
m (6) and belongs to Class II of Bio pharmaceutical system (BCS) and Biopharmaceutical drug disposition system (BDDCS). Since drug and its formulation is not official in any pharmacopoeia and also dissolution method recommendation is not made by Food Drug Administration, it becomes important to develop a discriminating dissolution method to support
product development and quality control for Nisoldipine Extended Relea Tablets. Experimental
Materials
Nisoldipine was procured from Shandong Boyuan Chemical Co.,Ltd, China. Carbopol and Polycarbophil were a gift samples from Lubrizol Advanced Material India Pvt Ltd, Mumbai, Hypromello was gift sample from Colorcon Asia Pvt Limited Pvt., Goa, Soldium lauryl sulfate (SLS), Tween 80, Cetyl Triammonium Bromide (CTAB), potassium dihydrogen orthophosphate, sodium dihydrogen orthophosphate (Qualigens,Mumbai), sodium hydroxide (S.D.Fine chemicals, Mumbai), methanol (AR grade), and hydrochloric acid (Merck, Darmstadt, Germany) were ud. Double-distilled water was ud throughout the solubility and dissolution study.
Methods
Saturation Solubility Study
The saturation solubility of Nisoldipine (NS) was determined in double-distilled water, anionic surfactant solution: SLS (0.25, 0.5, 0.75, 1.0, 2.0 and 3.0% W/V), Cationic surfactant solution: CTAB (0.25, 0.5, 0.75, 1.0, 2.0 and 3.0% W/V), Non-inoninc surfactant solution: Tween 20 (0.25, 0.5, 0.75, 1.0, 2.0 and 3.0% W/V), Hydrochloric Acid solution (pH 1.2) & Phosphate buffer (pH 2.0, 4.0, 6.0. 6.4, 6.8, 7.2, 7.6 and 8.0) at 37°C. To find saturated solubility, excess of NS was added to 50 mL of above mentioned solutions/ buffer in a conical flask and agitated continuously at room temperature for 24h using an orbital shaker Orbitek (Scigeneics Biotech). The solutions were kept aside for 6 h for equilibrium. The solutions were then filtered through Whatman filter paper No. 41 followed by filtration through whattman fiters (0.45micron) and filtrates were suitably diluted and analyzed spectrophotometrically at 238 nm (UV–vis spectrophotometer, Perkin-Elmer).
Formulation design
A total of six formulation were prepared using single polymer (E1, E3) and Progressive hydration technology (E5) along with sligh change in each technology (E2, E4 and E6) to challenge dissolution method for their discrimination power. Compositions of formulations are given in Table-1.
Tablets were prepared by compression using twelve station compression machines (Karnavati- Minipress) using 8.0 mm Flat face punches to hardness of 40-55 kp.2012杭州中考英语>dslam
In Vitro Drug Relea Study
Prepared batches of NS were taken for in vitro drug relea study. The dissolution experiments were conducted in eight station bath dissolution apparatus (Electrolab, TOD-08L). Four dissolution methods were designed in USP Apparatus II (paddles) as mentioned below:
Method 1: Volume: 1000ml, 100± 2 rpm, 370±0.50C Method 2: Volume: 500ml, 100± 2 rpm, 370±0.50C Method 3: Volume: 1000ml, 60± 2 rpm, 370±0.50C Method 4: Volume: 500ml, 60± 2 rpm, 370±0.50C
A 5-mL sample was withdrawn using sampling cannula fitted with cannula filter (35 micron) at different time intervals and withdrawn samples were filtered through No. 41 Whatman filter paper. The same volume of fresh medium was replaced. The sample was directly analyzed without dilution using a UV–vis spectrophotometer at 238 nm.
Stability Study
Standard solutions of pure NS and sample solutions from dissolution study of formulation containing high polymer E2, E4 & E6 in 1%w/v SLS were stored in the dark at ambient temperature
and at 2–8°C for up to ven days. Sample aliquots of 5 mL were withdrawn and analyzed spectrophotometrically after every 24-h period. Each day the concentrations of drug found in the standard and sample were compared. The absolute differences between the results at time zero and the time indicated for stability were determined by analysis.
Comparison of Dissolution Profiles by Model-Independent Method
A simple model independent approach using a difference factor (f1) and a similarity factor (f2 ) to compare dissolution profiles was ud (2, 7). The difference factor (f1) calculates the percent difference between the two curves at each time point and is a measurement of the relative error between the two
curves:
where n is the number of time points, Rt is the dissolution value of the reference (prechange) batch at time t, and Tt is the dissolution value of the test (postchange) batch at time t.
The similarity factor (f2) is a logarithmic reciprocal square root transformation of the sum 2 of squared error and is a measurement of the similarity in the
percent (%) dissolution between the two curves.
For curves to be considered similar, f1 values should be clo to 0, and f2values should be clo to 100. Generally, f1values up to 15 (0-15) and f2 values greater than 50 (50-100) ensure sameness or equivalence of the two curves and, thus, of the performance of the test (postchange) and reference (prechange) products (2).
Results
Solubility study and Medium Selection
周圆The results of the solubility study and the influence on sink conditions for lowest strength and highest strength are summarized in Table 2. NS solubility is 1.1394 mcg/mL. pH-Solubility profile shows solubility does not changes significantly in pH range 1-9 and solubility was found to be pH-independ
ent (Figure -1) to provide sink condition having Cs/Cd (S value) less than 0.20 in 500mL of same media. Significant increas in solubility was found when surfactants were added in media. Selection of surfactant was bad on critical micelle concentration (CMC) of each of surfactant. A linear relation was obrved between surfactant concentration and solubility enhancement (Figure-2). Similar relation was obtained for Aceclofenac also (8). Non-inoinc surfactant: Tween 20 incread solubility around 150 times in concentration of 3.0% w/v. Ionic surfactant provided great enhancement in solubility than that of by non ionic one and increa in solubility was 314 folds and 165 folds for SLS and CTAB. Maximum effect on solubility was found by SLS indicating minimum amount required to bring sink condition in limited volume of dissolution media. Also being most popular surfactant suggested by FDA to u in dissolution media, SLS was lected as suitable surfactant for dissolution method development. Further amongst various concentrations of SLS, 1.0% w/v gave sink condition to lowest strength of NS (S value 13.79, Table-2) and highest strength (S value 3.45) of NS tablet. Hence 1.0% SLS was lected as satisfactory dissolution media. Dissolution Method lection and In Vitro Drug Relea Study
Results of dissolution study of all six formulation in method I, method II, method III and method IV are given in Figure 3, 4, 5 and 6. Comparison of obtained dissolution curves for method discriminatio
n is done by Model-Independent analysis using F1 and F2 value. F1 value more than 15 indicates significant dissimilarity and F2 value more than 50 indicates significant similarity in results (2).
A comparison of similarity and disimmilarity for all formulation in different dissolution method are mention in table 3 and 4.
Dissolution Method I in 1000mL of 1.0% SLS, paddle speed 100rpm is not able to distinguish between any of the formulation and F1 values are found in the range of 2-5.3. Also F2 shows significant similarity since all values are more than 50.
Dissolution Method II in 500mL of 1.0% SLS, paddle speed 100rpm could differentiate between formulations with single polymer with F1 value 16.8 and 21.3 for E1-E2 and E3-E4 respectively. Also F2 value found to be less than 50 confirming discriminating power of method for the formulations but for formulation E5-E6, progreressive hydration technique, F1 and F2 values are not able to discriminate between formulations.
Dissolution Method III in 1000mL of 1.0% SLS, paddle speed 60rpm also gave same statistical result as that of method II reprenting unsatisfactory discriminating power for formulation E5-E6 showing F1 14.4 and 65.8.
Dissolution Method IV in 500mL of 1.0% SLS paddle speed 60rpm found to be most satisfactory in terms of discrimination since method discriminated between formulation E1 and E2, E3 and E4 also E5 and E6 with F1 value 34.8, 45.5 and 21.3 and F2 value 27.8, 22.4 and 43.2 respectively.
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Another statistical tool of student’s t-test was ud to find maximum significant difference in dissolution profile. The minimum P value reprents maximums significant difference in the drug relea in formulations at varying speeds of rotation. Minimum P values i.e 0.132, 0.292 and 0.159 were found in method IV for formulations E1-E2, E3-E4 and E5-E6 indicating maximum significant difference.
Stability Study
Results from stability study are mentioned in Table 5. The absolute difference between the concentrations of drug stored at 2–8 °C were found to be less than 1.75% and the same solution at room temperature over the period of 7 days was found to be less than 3.0% to that of reference solution in 1%w/v SLS.
Discussion
Reference compendia and guidelines of Food drug administration, United States Pharmacopeia, Federation International Pharmaceutique, World Health Organization, European Pharmacopoeia and Japane Pharmacopoeia recommend u of rotating paddle between 50 to 100rpm with volume of 500 to 1000ml along with surfactant to provide sink condition for insoluble drug products (9).
Surfactants can be ud as either a wetting agent below its CMC or beyond CMC to solubilize the drug substance(9) and further their lection should satisfy two factors i.e cost and concentration. (10). Three surfactants approved by regulatory agencies for dissolution media were lected. Suitable concentration required for sink condition were found by solubility study and sink condition. Becau of the nature of the NS and micelle interaction, there is typically a linear dependence between solubility and surfactant concentration above the CMC as it en in Figure-2. The ratio of solubility to drug concentration (do), expresd as S value which is calculated from Cs/Cd, reprents the cloness to sink conditions (9).
A sink condition occurs when the amount of drug that can be dissolved in the dissolution medium is at least three times greater than the amount of drug to be
dissolved. A low Cs/Cd ratio shows non-sink condition.The rate of drug dissolution will be slowed by t
he limited solubility of the drug in the medium. Proper sink condition was maintained in current study using 1% w/v SLS since concentration required was least amongst other surfactant to provide sink condition.The most common way to check the discriminatory power of the method is to test formulations with differences resulting forms, changes in the characteristics of the API, drug product composition,product manufacturing process, and stability conditions (2,9,11–14). Discriminating power can be statistically analyze by model independent mathematic approach as recommended by FDA for development of Solid oral dosage Forms and guidelines on Scale-up post approval changes (2,15) and bioavailability and bioequivalence (14), This approach is widely accepted in method developments(7, 16–20). In prent study,change in formulation by changing type of polymers and their concentrations were taken into account to validate the discriminating power of dissolution method. Most commonly mild agitation condition and lesr volume of dissolution media is considered as more discriminating and dissolution method tends less
discriminating if operated at faster speed which shows flatter relea profile. Conducted experiment shows the similar obrvation in which Method IV (Volume:500ml, 60± 2 rpm) could show the maximum discrimination obrved using F1 and F2 factor.
Stability of drug substance in dissolution media alone and with formulation components are importan
t factor to assure accuracy of obrved dissolved amount and thus a minimum of 24hr stability of drug is recommended in dissolution media (21,22). NS was found to be stable in 1%w/v SLS solution in solution form and along with excipients.
Conclusion
Discrimination of dissolution is a very important in vitro test for evaluating drug products to encounter change in formulation or process. Since there is no dissolution method specified for NS ER Tablets in the literature, an attempt was made to develop a discriminating dissolution method. The u of 500 mL of 1.0% w/v SLS at 37 ± 2 °C, paddle speed of 60 ± 2rpm found to be satisfactory.
Table 1. Composition of Formulation to Challenge Dissolution for Discriminating Power.Composition E1E2E3E4E5E6Nisoldipine 10.110.110.110.110.110.1HPMC 15K 1030002525Corn Starch 0000515DCL 1175.955.975.955.930.920.9Aerosil 222222Carbopol 974P 0010302525Talc 111111Mg stearate 111111
商谈Table 2. Saturation Solubility of NS and Sink Conditions in Different Dissolution Media for lower and higher strengths (n=3).Sink Cs*/Cd #Medium Solubility (mcg/mL)Solubility enhancement 10mg 40mg DD water 1.1394±0.56210.110.030.1 1.4684±0.852 1.30.150.04Acid solution 1.2 1.3597±0.698
1.20.140.032 1.2500±0.590 1.10.130.034 1.2175±0.743 1.10.120.036 1.2983±1.0432 1.10.130.036.4 1.1599±0.74710.120.03Phosphate buffer, pH
6.8 1.0400±0.572
0.9
0.10.03
7.2 0.8913±0.4910.80.090.02
7.6 0.8559±0.5630.80.090.02
80.7463±0.5090.70.070.02
0.25 27.6580±1.69824.3 2.770.69
0.5 55.0929±5.12148.4 5.51 1.38
0.75 93.7175±15.012 82.39.37 2.34
1137.9182±16.923 12113.79 3.45
2263.7546±20.623 231.526.38 6.59
SLS3357.9368±16.239 314.135.798.95
own goal0.25 12.125±1.69810.62214 1.2110.27
0.5 20.7751±3.04518.2 2.0750.52
0.75 26.7751±7.68223.5 2.680.67
185.9108±10.098 75.48.59 2.15
2133.2528±15.176 116.913.33 3.33info是什么意思
CTAB3188.5595±18.935 165.518.86 4.71
fireflies
0.25 19.8699±0.96417.4 1.990.5
0.5 40.1487±2.00635.2 4.011
0.75 49.4981±5.96743.4 4.95 1.24
推荐信格式
158.9591±11.970 51.7 5.9 1.47
2110.6320±13.672 97.111.06 2.77
alana evans
Tween 203172.5836±16.050 151.517.26 4.31
#Cd do of NS in tablet formulation;
D.D indicates double-distilled;
SLS is sodium lauryl sulfate.
CTAB is cetyl triammonium bromide
Table 3. Comparison of Tablet Dissolution Profiles using dissimilarity Factor (f1) at Different dissolution methods.
Dissolution methods E1-E2E3-E4E4-E6 Method I 2.0 5.3 4.5 Method II16.821.3 3.9 Method III33.355.814.4 Method IV34.845.521.3
Table 4. Comparison of Tablet Dissolution Profiles using similarity Factor (f2)
at Different dissolution methods.
E1-E2E3-E4E4-E6 Dissolution
methods
Method I82.564.675.0 Method II42.638.376.4 Method III28.426.065.8 Method IV27.822.443.2
