Development and Validation of a Discriminating Method of Dissolution for Ropinirole Tablets Based on In Vivo Data

 

S. Poongothai¹* C.M. Karrunakaran² and R. Ilavarasan³

¹Bharath University, Selaiyur, Chennai-600 073, India

²SMK Fomra Institute of Technology, Chennai - 603 103, India

 

ABSTRACT:

The aim of this work is to develop and validate a dissolution test for ropinirole tablets based on in vivo data. The best dissolution conditions were USP apparatus 1, 500 ml of medium containing pH 4.0 deaerated citrate buffer at a speed of 50 rpm and detection was carried at 250 nm. The in vitro dissolution samples were analyzed and validated using HPLC method according to USP protocol. The method showed accuracy, precision, linearity and specificity within the acceptable range. The kinetics of dissolution was determined using model-dependent methods. The dissolution profiles were best described by Hixson–Crowell model.

 

 

 

INTRODUCTION:

One challenge that remains in biopharmaceutics research is that of correlating in vitro drug-release profiles with the in vivo pharmacokinetic data¹. The value of dissolution, as a quality control tool for predicting in vivo performance of a drug product, is significantly enhanced if an in vitro–in vivo relationship is established and the dissolution studies are used not only to assess batch-to-batch consistency of drug release from solid dosage forms, but they are also essential in several stages of formulation development, for screening and proper assessment of different formulations^2-4. IVIVC has been defined as a predictive mathematical model describing the relationship between an in vitro property of a dosage form and an in vivo response⁵. The biological properties most commonly used are one or more pharmacokinetic parameters, such as c_max, t_max or AUC, obtained following the administration of the dosage form. The in vitro dissolution behavior of an active pharmaceutical ingredient from a dosage form under a given set of conditions expressed as percent of drug released is the most commonly used physicochemical property.

 

The relationship between the two properties, biological and physicochemical, is expressed quantitatively^6-8 . Lack of a relationship between the dissolution test results and in vivo behavior would lead to inappropriate control of the critical production parameters by the test and also confound biopharmaceutical interpretation of the dissolution test results. Therefore, in vitro specification limits should be set according to an established relationship between in vivo and in vitro results, best reached through a well-designed IVIVC¹.

 

Ropinirole Hydrochloride, (Figure 1) 4-[2-(dipropylamino) ethyl]-1,3-dihydro-2H-indole-2-one hydrochloride,  is a non-ergoline D₂/D₃ dopamine agonist with the greatest affinity at the D₃ receptors and recently introduced to therapy for Parkinson’s disease⁹. Ropinirole is absorbed rapidly with peak plasma concentrations occurring in 1 to 2 hours. After two days of use, steady state concentrations are generally achieved. Nevertheless, no clinically significant differences in C_min, C_max or AUC₂₄ between fasting and fed states have been noted. It is being increasingly used as monotherapy in the initial treatment of Parkinson’s disease rather than as adjunct to levodopa. In addition, ropinirole is also efficacious in the management of more advanced Parkinson’s disease in patients experiencing motor complications after long-term levodopa use¹⁰.

 

Figure 1. Chemical structure of ropinirole

 

Drug absorption from a dosage form after oral administration depends on the release of the drug from the pharmaceutical formulation, the dissolution and/or its solubilization under physiological conditions, and the permeability across the gastrointestinal tract. Because of the critical nature of the first two of these steps, in vitro dissolution may be relevant to the prediction of in vivo performance^{11, 12}. The dissolution test is a very important tool in drug development and quality control, for this reason, there is a crescent number of works describing the development of dissolution test for deflazacort, citalopram, and citrizine^13-15. At the moment ropinirole is not described in any pharmacopoeia and there are no specifications for the dissolution test. In this context, the objective of this study was to develop and validate a dissolution test for ropinirole tablets (Requip®) based on IVIVC. The in vivo data was obtained from the literature ^16-18.The discriminatory power of the dissolution method was challenged. The kinetics of dissolution was determined using model-dependent approaches.

 

MATERIALS AND METHODS:

MATERIALS:

Ropinirole hydrochloride reference substance (purity, 99.65%) was purchased from Ind-Swift Laboratories Ltd., (Chandigarh, India). The Requip® (GlaxoSmithkline, India) tablets containing 4 mg of ropinirole base were obtained from commercial sources within their shelf life period. The excipients contained in the dosage form (lactose, cellulose microcrystalline, croscarmellose sodium, magnesium stearate, hypromellose, macrogol, titanium dioxide and indigo carmine aluminium) were all of pharmaceutical grade and acquired from different distributors. HPLC-grade acetonitrile, hydrochloric acid (HCl), monobasic potassium phosphate, sodium acetate and ammonium acetate were purchased from Merck (Mumbai, India). All chemicals used were of pharmaceutical or special analytical grade. For all the analyses, ultra pure water was purified using an Elix 3 coupled to a Milli-Q Gradient A10 system (Millipore, Bedford, USA). The 0.1 M HCl, citrate buffer (pH 4.0) and monobasic potassium phosphate buffer (pH 6.8) were prepared according to the directions specified in USP 32¹⁹.

 

In vivo study:

The average plasma concentration versus time curve was fitted with a non-linear software (Micromath Scientist®, v.2.01) using a one-compartment open model, according to Eq. (1), and the resulting curve and parameters were used to estimate intermediate plasma concentration data points:

 

--------------------- (1)

 

where C is the plasma concentration at time t; k_e is the elimination rate constant; k_a is the absorption rate constant; V_d is the volume of distribution; D is the dose and F is the fraction of the dose absorbed. The percentage of drug absorbed (FA) versus time was calculated using the Wagner–Nelson method ²⁰.

 

In vitro study:

Dissolution test conditions:

The development and validation of the dissolution test was performed using a VANKEL^® VK 8000 dissolution auto-sampling station consisting of a VK type bidirectional peristaltic pump, VK 750D digitally controlled heater/circulator,VK7010 multi-bath dissolution testing station (n = 8) with automated sampling manifold. Dissolution was performed using 500 ml of dissolution medium pre-heated at 37±0.5°C. Influence of rotation speed, filters, dissolution medium and different apparatus (USP basket and paddle) were evaluated. Sample aliquots were withdrawn at 5, 15, 20, 30, 40, 50 and 60 min and replaced with an equal volume of fresh medium to maintain a constant total volume. An auto sampler was used to withdraw aliquots through a 0.45µm filter. All the dissolution samples were analyzed by HPLC.

 

HPLC analysis:

A Shimadzu Prominence HPLC system (Shimadzu, Kyoto, Japan) was used equipped with a SCL-10AVP system controller, LC-10 ADVP pump, DGU-14A degasser, CTO-10AVP column oven, SIL-10ADVP auto sampler and a SPD-M10AVP photodiode array (PDA) detector. Detector was set at 250 nm and peak areas were integrated automatically by computer using Shimadzu Class-VP software (version 6.14). Chromatographic analysis was carried out using a Vertical RP-18 column (150 mmx4.6 mm i.d., particle size 5µm and pore size of 110 Å), with a Xterra® C₁₈, column. A security guard holder was used to protect the analytical column. The Shimadzu Prominence HPLC system was operated  isocratically at controlled tem­perature of 30°C using a mobile phase consisted of a mixture of pH 6.5 potassium dihydrogen orthophosphate and triethylamine with acetonitrile (70:30 v/v). The flow rate was 1.2 ml/min and the injection volume was 100 μL. The detection of ropinirole was carried out by ultraviolet absorption at 250nm and all assays were performed at room temperature conditions. A Thornton T50 ultrasonic bath (Metler-Toledo, Bedford, MA) was used for deaeration. Elico pH analyzer (Model: Elico LII20) was used to determine the pH of all solutions.

 

Solubility:

Ropinirole sink conditions were determined in different media. The solubility of the drug was tested using an amount of ropinirole equivalent to three times the dose in the pharmaceutical formulation in 500 ml of medium. HCl 0.1 M, citrate buffer pH 4.0 and phosphate buffer pH 6.8 were tested. Vessels (n = 3) containing 250 ml of medium were pre-heated to 37°C±0.5 before adding one tablet of Requip® (4 mg). The samples were gently rotated. An aliquot (10 ml) was removed from each vessel after 1 and 2 h and filtered. 1ml of the filtered aliquots was pipette into 50 ml volumetric flask, neutralized, diluted with mobile phase and injected into the HPLC. The solubility in each medium was determined in triplicate.

 

In vitro–in vivo correlation:

An IVIVC for ropinirole was evaluated by plotting the mean percentage of drug absorbed (FA) versus the mean percentage of drug dissolved (FD). Linear regression analysis was used to evaluate the data.

 

Validation of the dissolution procedure:

The in vitro dissolution method developed was validated according to current  guidelines ^{2, 19, 21}. Specificity, linearity, accuracy and precision were evaluated. The chromatographic parameters monitored were peak  retention  time, capacity factor, tailing factor and theoretical plate number.

 

Specificity:

Specificity was evaluated by preparing samples of placebo. The placebo consisted of all the excipients (lactose, cellulose microcrystalline, croscarmellose sodium, magnesium stearate, hypromellose, macrogol, titanium dioxide and indigo carmine aluminium). The estimated concentrations in pharmaceutical formulation (Requip®) were based on the literature data²² and calculated for a medium weight of content (~1.203 mg) for the tablets. The samples of the placebo were transferred to separate vessels (n = 3), filled with 500 ml of dissolution medium at 37±0.5°C and stirred for 1 h at 150 rpm using basket (USP apparatus 1). Aliquots were withdrawn and analyzed by HPLC.

 

Linearity:

A stock solution containing 200µg/ml of ropinirole was prepared in methanol. The linearity of the method was evaluated in the 1.0–30.0µg/ml range using stock solution and dissolution medium. The solutions were injected in triplicate every day, for three consecutive days. The mean peak area versus concentration data was treated by least-squares linear regression analysis.

 

Accuracy/precision:

Accuracy was accomplished by adding known amounts of ropinirole reference substance to placebo. Aliquots of 0.6, 0.8 and 1.0 ml of a 5 mg/ml ropinirole standard solution dissolved in methanol were added to vessels containing dissolution medium for a final volume of 500 ml (final concentrations were 6.4µg/ml, 8.0µg/ml and 9.6 µg/ml, respectively), pre-heated at 37°C and rotated for 1 h at 150 rpm. Aliquots were withdrawn and analyzed by HPLC. These studies were performed on three different days and the recovery of the added drug substance (n = 9) was determined. Placebo samples were prepared in the same way described in the specificity test. The same solutions used in the accuracy test were analyzed in order to assess the precision of the method. Intra and inter day precision was established based on RSD of the results.

 

Stability studies:

Stability of ropinirole in the dissolution medium was evaluated using standard and sample. The solutions were kept at 37±0.5°C for 1 h under light shaking, and were then left at room temperature for 24 h. The sample solution was stored in a glass test tube wrapped securely in paraffin. Aliquots of the samples were tested at time 0, and after 1 and 24 h. The responses for the aged solutions were evaluated using a freshly prepared standard. The assay was performed in triplicate.

 

Evaluation of release kinetic:

Four mathematical models were applied to evaluate the kinetics of drug release: zero order, first order, Higuchi and Hixon–Crowell, whose equations are shown in Table 1. The curves were constructed applying the kinetic models cited, considering only one point above 80% of the drug released. The mathematical model that best expressed the dissolution profile of ropinirole tablets was selected based on the coefficient of determination (R²) ^{19, 23}. The suitability of models to experimental data was evaluated using the software Scientist TM (Micromath, EUA), based on the model selection criteria (MSC).

 

Table 1. Mathematical models used:

Zero order kinetics	Qt =Q0 + K0t
First order kinetics	Log Qt = log Q0 + (K1t)/2.303
Higuchi model	ft = KHt1/2
Hixson–Crowell model	W01/3 −Wt1/3 = Kst

 

Q_t, amount of drug dissolved in time t; Q₀, initial amount of drug in the solution; K₀ and K₁, zero order and first order release constants, respectively; f_t, amount of drug released in time t by surface unity; K_H, Higuchi dissolution constant; W₀, initial amount of drug in the pharmaceutical dosage form; W_t, remaining amount of drug in the pharmaceutical dosage form at time t; K_s, a constant incorporating the surface–volume relation.

 

Discriminating power of the test:

The discriminatory power of the proposed dissolution test was challenged. Changes in the biopharmaceutical performance of ropinirole tablets caused by aging (validity time expired) and temperature storage and humidity (40°C and 75% RH for 1 and 2 months) were evaluated.

 

Evaluation of dissolution profiles:

The dissolution profiles obtained were compared using model independent method, in which the two profiles were compared only at the observed time points²³. The model-independent approach includes the difference factor (f₁) and the similarity factor (f₂). The f₁ factor measures the percent error between two curves over all time points (Eq. (2)):

                  (2)

 

where n is the number of time points, R_t and T_t are the percent dissolved of the reference and test product, respectively, at each time point. The percent of error is zero when the test and drug reference profiles are identical and increase proportionally with the dissimilarity between the two dissolution profiles ²³. The f₂ factor is a logarithmic transformation of the sum-squared error of differences between the test and the reference products over all time points (Eq. (3)):

 

    (3)

 

This factor is 100 when the test and reference profiles are identical and moves toward 0 as the similarity decreases¹⁹. According to the FDA, two dissolution profiles are declared similar if f₁ is between 0 and 15 and if f₂ is between 50 and 100³.

 

RESULTS AND DISCUSSION:

In vivo study:

The pharmacokinetic data used to develop the IVIVC was obtained from the literature^16-18. Based on these results, the plasma concentration versus time profile curve was transformed into percentage of drug absorbed versus time, using the Wagner–Nelson method (Figure 2). According to the FDA⁵  model-dependent techniques such as the Wagner–Nelson and Loo–Riegelman method or model-independent numerical deconvolution are utilized to calculate absorption profiles. Wagner–Nelson and Loo–Riegelman methods are both dependent, the former being used for as a one-compartment model and the latter for two-compartment systems¹¹. Considering that the best fit for the in vivo data was obtained using an open one-compartment body model equation, the Wagner–Nelson method was used to obtain the fraction of dose absorbed.

 

Figure 2. Percent of dose absorbed vs. time curve for ropinirole tablets using Wagner-Nelson method

 

Solubility determination:

The solubility test showed that ropinirole was soluble in 0.1 M HCl, citrate buffer pH 4.0 and phosphate buffer pH 6.8. The solubility in water was not tested, since it is not an ideal dissolution medium ^{2, 19}. The solubility of ropinirole hydrochloride is strongly pH dependent, being low at pH 6.8 (114 mg/ml) as compared with peak solubility between pH 3 and 4 (172 mg/ml at pH 4.0). Thus, the solubility data obtained were used as the basis for the selection of dissolution medium for ropinirole tablets and also ensured sink conditions. 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^2,19

 

Development of the dissolution test:

Test conditions were selected based on a screening study with USP apparatus 1 (25/50 rpm, baskets). The tablets were tested in 500 ml of 0.1 M HCl, citrate buffer pH 4.0 and phosphate buffer pH 6.8. Dissolution aliquots were analyzed at several time points (5, 15, 30, 40, 50 and 60 min) to generate dissolution profiles in each medium. Each experiment was performed with 12 tablets.

 

Dissolution profile of ropinirole tablets:

The USP apparatus 1 (basket) was chosen due to its acceptance as a standard procedure for tablets, and the stirring speed was used at 25 and 50 rpm. Thus, significant difference was observed in the total drug released from the pharmaceutical formulation using 25 or 50 rpm, but based on the solubility the stirring rate of 50 rpm was selected as mild condition that allowed maximum discriminating power. The influence of rotation speed at 25 and 50 rpm in citrate buffer pH 4.0 was evaluated and the results are shown in Figure 3. The dissolution profile obtained using citrate buffer pH 4.0 were almost similar to the in vivo absorption whereas the dissolution rate was quite lower by using the other medias like 0.1 M HCl and phosphate buffer pH 6.8 and the results are presented in Figure 4.

 

Figure 3. Mean dissolution profiles of Requip® tablets (n = 12) using pH 4.0 citrate buffer using apparatus 1 rotating at 50 rpm and 25 rpm

 

Figure 4. Mean dissolution profiles in different media (DPDM) of ropinirole tablets using 500 mL medium with basket apparatus at stirring rate of 50 rpm

 

The results demonstrated that the in vitro dissolution profile was similar to the in vivo dissolution profile in the three media tested and a good correlation was obtained (Table 2). Deaerated citrate buffer pH 4.0 demonstrated the best correlation (level-A) with the in vivo data (Figure 5). The level-A correlation was linear and represents a point-to-point relationship between in vitro dissolution and the in vivo dissolution rate⁶. The choice of medium will depend on the purpose of the dissolution test. For batch-to-batch quality testing, selection of the dissolution medium is based, in part, on the solubility data and the dose range of the drug product to ensure sink conditions. On the other hand, when the dissolution test is used to indicate the biopharmaceutical properties of the dosage form, it is more important that the proposed biorelevant test closely simulate the environment in the gastrointestinal (GI) tract than necessarily produce sink conditions^{2, 20, 11}. Thus, citrate buffer pH 4.0 was chosen as the dissolution medium since it is considered to be biorelevant and the best correlation was obtained using basket at 50 rpm (R² = 0.9992). The drug dissolution results were reproducible. The RSD was lower than 20% at the first time point (10 min) and lower than 10% RSD at later time points.

 

Table 2. Regression analysis^a for the IVIVC

^ay= m. x + b

 

Validation of dissolution method:

Specificity:

No chromatographic peak from the placebo formulation was observed with the same retention time (3.843 min) as ropinirole standard (Figure 6a and 6b). The purities of peak were higher than 0.999 and were obtained using a PDA detector. According to the Pharmacopoeial Forum and USP 32, the lack of chromatographic peaks from the placebo formulation demonstrates the specificity of the method.

 

Figure 5. Plot of mean percentage of dose absorbed vs. mean percentage of dose dissolved for ropinirole tablets.

 

Figure 6a. Typical ropinirole standard chromatogram in pH 4.0 citrate buffer showing λ_max at 250 nm

 

Figure 6b. Specificity of method showing no interference at the retention time of standard ropinirole (3.84 min) in pH 4.0 citrate buffer at 250 nm

 

Linearity:

The recommended range for the calibration curve is from ±20% below the lowest expected concentration to ±20% above the highest expected concentration of the dissolution test^{2, 19}. The method showed good linearity at concentrations ranging from 1.0 to 30.0µg/ml. The correlation coefficient was 0.9998 and the linear regression is also calculated and the obtained equation is y=1.0171x-0.1544. The analysis by ANOVA showed significant linear regression and no significant deviation from linearity (p<0.05). These data indicate that the method is linear for ropinirole.

 

Accuracy/precision:

The accuracy was demonstrated by the recovery of known amounts of ropinirole in the dissolution vessels. Percentage recoveries from 80.0% to 120.0% are recommended for the accuracy test^{2, 21}. In the accuracy test three concentrations were evaluated (6.4, 8.0 and 9.6 µg/ml) and mean recoveries were 100.8±0.60, 100.4±0.64 and 100.5±1.05 %, respectively, corroborating the accuracy of the method.

 

Repeatability was determined by triplicate injection of standard solutions (6.4µg/ml, 8.0µg/ml and 9.6µg/ml) and the intermediate precision was evaluated for 3 days. The low RSD values obtained for repeatability and intermediate precision show the good precision of the method (Table 3).

 

 

Table 3. Precision of dissolution method

Concentration (µg/mL)		Precision
		RSD  intra-day	RSD inter-day
Day 1	6.4	0.35	1.02
Day 2	6.4	0.42
Day 3	6.4	1.02
Day 1	8.0	0.28	0.84
Day 2	8.0	1.13
Day 3	8.0	0.52
Day 1	9.6	1.42	1.56
Day 2	9.6	1.06
Day 3	9.6	0.68

 

Standard and sample solution stability:

Ropinirole was found to be stable under dissolution test conditions. There was no evidence of degradation of ropinirole under these conditions. The results demonstrate that sample and standard solutions remained at 100.0±2.0% over a period of 24 h.

 

Evaluation of release kinetic:

The dissolution profile (Figure 4) was used to evaluate the kinetics of drug release. The determination coefficient (R²) and model selection criteria (MSC) are presented in Table 4. According to the R² and MSC, dissolution profiles were better described by the Hixson–Crowell model (Table 4). When this model is used, it is assumed that the release rate is limited by the drug particle dissolution rate and not by diffusion that might occur through the polymeric matrix²³ .

 

 

Table 4. Coefficient of determination (R²) and model selection criteria (MSC).

 

Discriminating power of the test:

The discriminating power of the dissolution method is the method’s ability to detect changes in the drug product^{2, 19}. If significant changes in the drug dissolution characteristics are observed over long-term storage of the dosage form, this would indicate that functional changes are occurring in the drug product, and may compromise its performance in vivo ²⁴. Thus, the dissolution method developed was challenged. The pharmaceutical dosage forms exhibited a decrease in dissolution rate after storage at 40°C and 75% RH for 1 and 2 months, as well as for the tablets past their expiration date, as shown in Figure 7. The dissolution profiles obtained were compared using the difference factor (f₁) and similarity factor (f₂). The results confirmed that the profiles obtained are not similar (Table 5).

 

Figure 7. Changes in the dissolution rate of ropinirole tablets after storage and date expired

 

Table 5. Comparison of tablets dissolution profiles through difference factor (f₁) and similarity factor (f₂)

 

CONCLUSIONS:

A level-A in vitro–in vivo correlation was established for ropinirole tablets (Requip®). The in vitro dissolution profile for ropinirole was obtained using 500 ml of dissolution medium containing deaerated citrate buffer pH 4.0, USP apparatus 1 at 50 rpm and 37±0.5°C. Kinetics of drug release was best described by the Hixson–Crowell model. The validation results demonstrate that the in vitro dissolution method was accurate, precise, linear and specific. Both the HPLC analytical method and in vitro dissolution test were validated and can be used to evaluate the release profile of ropinirole tablets.

 

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Received on 06.09.2014          Modified on 15.09.2014

Accepted on 19.09.2014          © RJPT All right reserved