INTRODUCTION:

Dipyridamole is a thromboembolic risk preventive drug for heart valve replacement and long-term angina pectoris treatment will be well absorbed in the stomach. Chemically Dipyridamole USP is Pyrimido-Pyrimidine derivatives. It is a yellow, crystalline, odorless powder with a bitter taste. Drug is practically soluble in methanol, chloroform and dilutes acids, and is practically insoluble in water. Dipyridamole is a BCS class II drug i.e. low solubility and high permeability class. It has good solubility in acidic pH but at alkaline pH it is practically insoluble (i.e. small intestinal alkaline pH). Dipyridamole has a narrow window of absorption and is primarily absorbed in the stomach, Oral bioavailability is 38-65% and there is also a short half-life (45 min)^(1). There are many methods available for design of sustained release drug formulations and its development. These drug delivery systems are mainly intended to improve disease control by changes in pharmacokinetic profiles of drugs that are usually given as conventional tablets or capsules. It often occurs in traditional oral dosage formulations that, variations in the amount of the drug plasma either reaching the maximum therapeutic safe concentration or dropping rapidly under the sub therapeutic level; In general, that effect depends entirely on the biological half-life, duration of administration and release rate of the specific agent⁽²⁾. Many patients are known to benefit from drugs dosage form developed for chronic administration in a safe and effective range of plasma levels. Hydroxyl propyl methyl cellulose (HPMC) in different grades is representative example of the Hydrophilic polymers commonly used in the formulation of the sustained release matrix tablets. HPMC K4M is a semi-synthetic cellulose derivative popular as hydrophilic and swell able polymers⁽³⁾. It is a non-toxic substance and it is an excellent release retardant polymer that is easy to handle. The polymers hydrate when exposed to dissolution media and converted to a layer of viscous gel that releases the drug by diffusion and/or matrix erosion.

Response Surface Methodology (RSM) is most commonly used optimization methods for formulation development based on experiment design principles (DOE), The technique include the different experimental designs, the creation of statistical interaction in polynomial form and the mapping of the experimental domain response to choose the optimum formulation. The different design of RSM are accessible for formulation optimization are central composite design (CCD) and factorial design, Box Behnken design (BBD) and D-optimal design. Box-Behnken statistical design is a type of response surface methodology which is an isolated, rotatable quadratic design with combinations of responses at the midpoints of the corners of the box. It also requires less trial runs and short period of time and therefore offers a method that is much more reliable and cost-effective than traditional method for formulation and optimization processes for development of dosage form⁽⁴⁾.

The goal of present investigation was to develop and optimize Dipyridamole- tartaric acid cocrystals Matrix tablets (DYP-TA matrix tablets) by using the methodology of computer-assisted optimization i.e. Box Behnken Design with response as % in vitro drug release at 12h (98%-100%). Independent factors are the quantity of release retardant polymers like HPMC K4 M (X₁), MCC101 (X₂) and magnesium Stearate (X₃) and the dependent variable is the percentage release of drug after 12 h (Y₁) were studied^(5).

MATERIALS AND METHODS:

Dipyridamole was obtained from Micro Advanced Research Center (Bangalore, India) as a gift sample. HPMC K4M and Microcrystalline Cellulose 101, Lactose Monohydrate, were taken as a gift sample from Color on Asia (Put) Ltd, Mumbai, India, Talc and Magnesium stearate was purchased from new Neeta Chemicals, Pune, India.

Analytical method development:

0.01N HCl were used to prepare the drug stock solution and further dilution were done. The drug absorbance was determined at 282nm using UV double beam spectrophotometer (UV100 Cyber Lab). The linearity of the absorbance was found to be from the concentration between 10–50µg/ml (r2 = 0.9938)⁽⁶⁾⁽⁷⁾.

Computer aided optimization design:

3-factor, 3-level Box and Behnken design was employed for the optimization study. This is one of best suited optimization techniques of response surface methodology for development of sustained release matrix tablets. This method is ideal for exploring second-order polynomial model, quadratic response surfaces, with design expert (version 12) software gave a few number of experimental runs to define the process (13 runs). This cubic configuration is defined by a set of points at the midpoint of replicates of each edge of a multi-dimensional cube and center points (n=0). The polynomial equations for different models are given below,

Linear model; Y = A₁ X₁ + A₂ X₂ + A₃ X₃ Equation 1

Second order; Y = A₁ X₁ + A₂ X₂ + A₃ X₃ + A₁₂ X₁ X₃ Equation 2

Quadratic model; Y = A0 + A₁ X₁ + A₂ X₂+ A₃ X₃ + A₁₂ X₁ X₂ + A₁₃X₁ X₃ + A₂₃ X₂ X₃+ A₁₁ X₁² + A₂₂ X₂² +A₃₃ X₃ Equation 3

The Y is the determined response associated with each level of each factor combination; A₀is an intercept; A₁ to A₃₃ are regression coefficients derived from the observed experimental values of Y; and independent variables are coded in X1, X₂ and X₃. The terms X₁X₂ and X₂ n (n = 1, 2 or 3) represents the concepts of interaction and quadratic terms. For each formulation, the preliminary studies offered a level framework. This optimization design involves three variables and one response^{(8), (9)}.The variables and their levels measured are summarized in Table 1, the positive an d negative values of each factors based on preliminary experimental observation.

Table 1. Different levels of variables used in the formulations

Dependent Variables	Different levels (actual is coded)
	Low	Medium	High
X₁ – HPMC K4M	12 (-1)	22 (0)	32 (+1)
X₂ – MCC 101	95 (-1)	105 (0)	115 (+1)
X₃ – Magnesium Stearate	0.5(-1)	1 (0)	1.5 (+1)
Independent Variable		Target
Y₁ - % Dissolution after 12 hrs		99%-100%

Preparation of matrix tablets:

13 formulations proposed by response surface model - Box-Behnken design, each containing 75 mg of Dipyridamole were prepared with different ratio of matrix forming polymer such as HPMC K4M, MCC 101 and Magnesium stearate by direct compression technique. The previously sieved ingredients (# 60mesh) are mixed for 15 min in a planetary mixer and the tablets were punched using 10 mm punches in rotary tablet compression machine with high speed 8 station⁽¹⁰⁾.

Drug Content Analysis and Tablets Physical Evaluation:

Determinations of Drug content:

A quantity of tablet powder equivalent to label claim (75 mg) of for drug content analysis, Dipyridamole was extracted with methanol as a solvent and analysis of sample was done by double beam UV spectrophotometer (Shimadzu uv-100) at wavelength 282 nm. Calculation of drug content of formulation was done by given formula,

Drug Content= Drug Content/ Label Claim * 100 Equation 4

Physical evaluation⁽¹¹⁾

Evaluation of Tablets are done for their hardness using Monsanto hardness tester, friability by using Roche Friabilator, weight variation test, and thickness (zoom dial caliper).

FTIR study:

The FTIR spectra of Dipyridamole, drug in co crystals form and polymer blend of optimized tablet, was recorded on a Nicolet iS10 spectrophotometer from 4,000 cm-1 to 500 cm^-1 (Thermo Fisher Scientific, Madison, USA. With 40 scans per spectrum with 0.4 cm^-1 resolution. By using the DTGS KBr detector spectra were collected and analyzed.

Differential Scanning calorimetry:

Thermal analysis of pure drug, drug in cocrystals form and blend of tablet was done by using a differential calorimeter scanning (DSC7020 thermal analysis system HITACHI), Powder samples of about 2.0mg were mounted in open crucibles of aluminum and heated up to 400°C at a rate of 10°C/min.

Powder X-ray diffraction (PXRD):

DYP-TA pure drug, DYP-TA co crystals and tablets XRD patterns were achieved using Shimadzu XRD-6000X system at ambient temperature (Shimadzu, Japan). Samples with Ni-filtered Cu-K (α) radiations were irradiated at a voltage of 40.0 kV and a current of 40.0 mA. The scanning rate ranged from 3º to 50º over a diffraction angle of 2º/min.

In-vitro drug release study:

Studies of dissolution have been conducted using USP (II) standard dissolution apparatus at 37 ± 1ºC. The Tablets in triplicate were placed in 900ml of 0.01 N HCl dissolution medium and rotated at 50 rpm. A 5 ml of sample was collected at specific time intervals, 30 minutes, 1 hrs, 2 hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, 7 hrs and 8 hrs, till 12 hrs after each withdrawal, to preserve sink conditions, the same amount of fresh dissolution medium has been substituted. After that withdraw sample was diluted, and spectrophotometrically analyzed at 282nm. For the 13 formulations, the total percentage release of drugs was calculated and the responses observed by the design of Box-Behnken were reported⁽¹²⁾.

Swelling Index Determination:

The swelling and erosion studies were performed to determine the influence of swelling and erosion behavior of the formulation on its drug release. Under the same set of conditions as agreed for drug release rate studies, matrix tablets were inserted into the dissolution apparatus. Using small basket, the tablets were removed and the swollen weight of each tablet was assessed⁽¹³⁾.

Swelling Index= Wt-W0/Wt X 100 Equation 5

where,

Wt is the weight of Tablet at time ‘t’.

Wo is the weight of Tablet at time t = 0.

Optimization and data analysis:

Based on the ANOVA provision in the program, polynomial equations which were statistically validated developed by Design Expert (version 12) has been provided. Total 13 runs of Box Behnken Design created with one center point. In terms of statistically significant parameters, standardized main effects (SME) and R² values, the models were evaluated. Different software experiments were performed to determined optimal formulation compositions and specific 3D response surface graphs were drawn using Design Expert software. The optimized formulations of the checkpoint have been prepared and evaluated for different response properties. The resulting experimental values of the responses were compared quantitatively with those of the predicted values. In addition, linear regression plots were produced using MS-Excel between actual and predicted response values^(14,15,16).

Stability studies:

The stability analysis of the tablets of optimized formulation according to the ICH guidelines was carried out at 25^oC±2 ^oC/60% ± 5% Relative Humidity. Physical attributes of tablets, shape, size, % drug content and drug release dissolution profile have been analyzed over a 3-month duration.⁽¹⁷⁾

RESULT AND DISCUSION:

Drug Content Analysis and Tablets Physical Evaluation:

Spectrophotometrically assayed the % drug content of tablets at 282nm. The Dipyridamole quantity in different trial batches varied between 93.4% and 99.65% (average 95.50%). The formulations drug content was spectrophotometrically analyzed at 282nm. The drug content ranged from 93.4% to 99.65% (average 95.50%) in different formulations. Tablet weights varied between 262 and 285mg, hardness between 5 and 7kg/cm2 (average 6kg/cm²), thickness between 3.20 and 3.60mm (average 3.4mm) and friability ranged from 0.04% and 0.13% (average 0.40%). All formulations identified to be effectively within the official limits as the results of drug content and physical examination. The drug content and physical evaluation values obtained are tabulated in Table 2. From all the 13 batches of formulations Batch F4 shows all the result within specification⁽¹⁸⁾.

Table 2: Drug content and Physical evaluation of 13 runs

Formulation	Weight Variation (%)	Hardness (kg/cm²)	Thickness (cm)	Friability (%)	Drug Content (%)
F 1	277 ±0.03	5±0.28	3.45 ±0.03	0.03 ±0.06	98
F2	270 ±0.11	6±0.35	3.22 ±0.03	0.07 ±0.10	98.5
F3	274 ±0.08	5±0.31	3.42 ±0.03	0.05 ±0.16	97.6
F4	275 ±0.06	6±0.49	3.50 ±0.03	0.05 ±0.01	99.90
F5	280 ±0.12	6±0.28	3.56 ±0.03	0.05 ±0.18	99.65
F6	282 ±0.34	7±0.35	3.22 ±0.03	0.11 ±0.21	96.5
F7	268 ±0.28	7±0.36	3.60 ±0.03	0.13 ±0.34	95.5
F8	279 ±0.11	6±0.72	3.45 ±0.03	0.11 ±0.32	98.3
F9	280 ±0.21	6±0.30	3.53 ±0.03	0.09 ±0.24	98.6
F10	262 ±0.06	7±0.30	3.21 ±0.03	0.05 ±0.12	94.5
F11	265 ±0.10	5±0.36	3.38 ±0.03	0.14±0.09	97
F12	285 ±0.13	5±0.40	3.30 ±0.03	0.05 ±0.11	97
F13	282 ±0.32	7±0.45	3.20 ±0.03	0.05 ±0.17	93.4

Figure 1: IR Spectra of a) Dipyridamole b) DYP-TA cocrystals c) DYP-TA Tablet

Differential Scanning calorimetry:

Figure 2: DSC thermographs of a) Dipyridamole b) DYP-TA cocrystals c) Blend of DYP-TA cocrystals matrix tablets

Figure 2 a), 3 b), 3 c) demonstrates pure Dipyridamole DSC thermographs, thermograph of API in cocrystals form and in tablet formulation. Based on DSC studies, thermographs revealed that the pure drug shows melting point at 122.5 ° C, pure drug in cocrystal form shows melting point at 124.5°C and that of the drug in the formulation shows melting point at 122.5°C. From DSC thermographs, it is demonstrated that the melting point of the pure drug and melting point of drug in tablet formulation does not differ significantly. It can be inferred that, even in the formulation without interfering with the polymers, the drug is in the same state of purity.

FTIR study:

Dipyridamole FTIR spectrum Figure 1 a) (shows a broad peak at 2888 cm^-1 may be due to O-H stretching, 1362 cm-¹for C-H stretching and 1630 cm^-1 Ar-H stretching, 1342 cm^-1 may be due to C=C stretching of aromatic, 1060cm^-1 may be due to C-H bending. – C-O-C group shows peak at 962cm^-1. Substituted benzene ring shows peak at 947 cm^-1. FTIR spectral analysis cleared that the configurations of the characteristic drug bands along with the FTIR spectrum of the optimized formulation generated during this investigation are not significantly changed. Since the origin and state of the bands does not change in the formulation, the drug may be expected to maintain its crude nature without any chemical interaction with the polymer.⁽¹⁹⁾

Swelling index studies:

The swelling index was calculated for the validated 13 formulations. Increased percentage swelling index of the tablets was observed up to 6 h due to weight gain by tablets. Later, the weight gain was decreased gradually due to dissolution medium and slow erosion of the gelled layer up to 8 h. Erosion of the optimized formulation after 8 h was found to be 26%, this low erosion due to the polymer concentration used in the formulation. The percentage swelling index of the optimized formulation (Batch F4).

In-vitro dissolution studies:

DYP-TA cocrystals matrix tablet comprising Dipyridamole cocrystals, and hydrophilic polymer HPMC K4m for the matrix release under investigation, sustained release matrix tablets release the drug in three steps, First step is to penetrate the dissolution medium (hydration) into the tablet matrix. Second step is the swelling of the matrix with co-dissolution or subsequent erosion. The third step is to transfer the dissolved substance to the surrounding dissolution medium, either by the hydrated matrix or from the sections of the eroded tablet. 13 runs are provided by a 3-factor, 3-level Box-Behnken experimental statistical model as the response surface methodology and Table 3 shows the independent variables and the responses for all 13 runs. All batches showed the drug release at 12 h (Y) in the range between 85.50% - 101%. The DYP-TA matrix tablets dissolution data is obtained by plotting graph as concentration (mg / L) vs. time (h) shown in Figure 3 for predictive completion of release.⁽²⁰⁾

Table 3: The 13 runs and the responses observed by Box-Behnken design

Formulation	Dependent Variable			Independent Variables
	X1(%)	X2(%)	X3(%)	Y1 (%)
F1	12	105	0.5	95
F2	22	95	1.5	96
F3	12	95	1	98
F4	22	105	1	101
F5	22	115	1.5	90
F6	32	115	1	85.4
F7	32	95	1	87.5
F8	22	115	0.5	94.5
F9	22	95	0.5	97
F10	32	105	0.5	98.5
F11	12	105	1.5	97.5
F12	12	115	1	96.5
F13	32	105	1.5	89

Figure 3: In vitro drug release of DYP-TA cocrystal matrix tablets (F1 – F13)

A 3-factor, 3-level Box-Behnken experimental statistical design as the RSM provides 13 runs and the independent variables and responses for all 13 runs are given in Table 3. All batches showed the drug release at 12 h (Y₁) in the range between 85.50% - 101 %. All the result for 13 formulations were fitted in both quadratic and second order simultaneously, when using Design Expert (State ease-Ver. 12) and Comparative R² and standard deviation values are given in Table 4 including the regression equation developed for Y₁ responses found to follow quadratic, only statistically significant coefficients (p < 0.05) are included in the equations. A positive value is influences that support optimization, whereas a negative value is an inverse relationship between variables and responses.

Figure 4: Response (Y₁): % Drug Release at 12 hours

% Drug Release at 12 hours (%DR_12h) = -450.80875 + 14.55875 X₁ + 7.52125 X₂ + 20.82500 X₃ - 0.038750 X₁* X₂ + 0.025000 X₁* X₂ - 0.241250 X₁² - 0.032500 X₂² - 15.00000 X₃² Equation 6

Table 4: Results of regression analysis for response % drug release at 12 hrs (Y₁)

Models

R²

Adjusted

R²

Predicted

R²

S.D

Remarks

Second order Quadratic

0.9247

0.7742

0.7941

Suggested

From the response surface plot (Figure 4) and the polynomial equation (Eq. no. 06), it was found that the in case of %DR 12h values increment of concentration of HPMC K4M (X₁). This can be attributed that as the concentration of hydrophilic polymer (X₁) increases ultimate resulting increase in viscosity of the gel layer and internal strength, which in turn delays the spread of water into the core of the tablet, resulting in a more consistent and sustained release of the drug. Increasing the concentration of Magnesium Stearate (X₃) showed the major effect on the drug release. As reflected by the prominent negative value for X₃ delayed drug release is caused by the polymers hydrophobic nature and may have retarded the drug release dissolution.

Drug Release Kinetics:

In the in-vitro release profile of 13 box Behnken design, separate dissolution models were applied to study the release mechanism of formulations. The kinetic model includes Zero order, First order, Korsemayer-Peppas and Higuchi, model was evaluated by using PCP Disso software based on MS-Excel. Table 5 displays the equations used to evaluate the related models and the R² values for optimized formulation of 13 runs and the release profile is shown in Figure 5 a), b), c), d). The overall fitting of the curve demonstrated that Higuchi model preceded drug release from optimized formulation (Batch F4) from the sustained release matrix tablet (n=0.9862 indicating Fickian diffusion). As the dissolution continues, outer layer incremental swelling produces proportionately new drug diffusion zones. Since the matrix is hydrophilic, the dissolution medium permeation occurs in the matrix and allows the drug to detach from the inner layer. As shown in Figure 5a), b), c), d) plots drawn in linear relationships according to specific kinetic models. In the plot of zero order (Figure. 5 a) the obtained r² value is 0.9629 and the first order (Figure. 5 b) was 0.5511 defining the relationship between drug release rate and drug concentration. Equation generated during the plot of Higuchi (Figure. 5 d) (r2 = 0.9833) indicated that best linearity showing the release of drug from matrix as a square root of time i.e., diffusion-based time-dependent mechanism. ^{(21, 22)}

Table 5: Result of DYP-TA co-crystal matrix tablets curve fitting of dissolution data (final optimized Batch F4).

Sr. No.	Drug Release Model	Equation	Correlation Coefficients (R²)
1.	Zero order	y = 8.0385x + 14.692	0.9629
2.	First Order	y = 0.102x + 1.0447	0.5504
3.	Korsemeyer-Peppas model	y = 0.0804x + 0.1469	0.9629
4.	Higuchi model	y = 31.385x - 7.6907	0.9833

Stability studies:

As per the ICH accelerated stability study guideline, stability test of the optimized batch formulation did not shows any drug degradation and release profile of same batches was also within the specification after the 3 months of storage condition. Tablets were also tested for the physical evaluation, result for the same was recorded and are within the specification. Weight variation, hardness, drug content, friability, thickness test was done found to be statistically significant (ANOVO p>0.05) ⁽²¹⁾_.

CONCLUSION:

Dipyridamole-TA cocrystals matrix tablets were successfully prepared by direct compression method. Optimization was done with the 3-factor, 3-level response surface methodology (Box Behnken design) with 13 runs. The quadratic surface response technique analyzed helped with release rate to understand the effects of interaction between the three polymers combination and ratio. The linearity between the real and expected values for variables responses showed the predictive potential of the box Behnken design of response surface methodology. Along with the stability analysis of the optimized Batch F4 formulation, FTIR reports, the DSC research demonstrated the durability of the hydrophilic sustained release tablets. High degree of prediction obtained using surface response methodology is therefore very effective in optimizing DYP-TA matrix tablets formulation that shows second order quadratic in responses.

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Received on 03.01.2020 Modified on 08.03.2020

Research J. Pharm. and Tech. 2021; 14(2):610-616.

DOI: 10.5958/0974-360X.2021.00109.8