Effect of Different Types of Polymers as Well as Different Preparation Techniques on the In-Vitro Release of Dyphylline Controlled Release Matrix Tablets


 Dyphylline, xanthine derivatives, is used to manage asthma, cardiac dyspnea, chronic bronchitis, and emphysema. This work aimed to develop controlled release matrix tablets of Dyphylline using different types of polymers, and different preparation techniques such as direct compression, wet granulation, and hot melt methods. The prepared matrix tablets were evaluated by Infrared spectral analysis, differential thermal analysis, evaluation which included hardness, friability, content uniformity, and the in-vitro drug release. Kinetic analysis of the release profiles was investigated using different kinetic orders. All Dyphylline formulae obey Higuchi’s diffusion model. The diffusion is the mechanism of Dyphylline release from its controlled matrix tablets. IR and DSC revealed no incompatibility between Dyphylline and the polymers used in the prepared formulae. The obtained results revealed that the wet granulation technique using water as the granulating liquid is the best method for the formulation of Dyphylline hydrophilic matrix tablets compared with the other techniques. The high content of polymers led to the high value of T1/2, and a decrease in Dyphylline's extent due to the improvement of the retention of drug release. A synergistic effect was obtained using PVP-K-25 in the hydrophilic matrix tablets, which led to the retention of the drug release.

2 Controlled-release of the drug means the extending of the duration of the drug delivery, as in the prolonged-release system, as well as implying predictability and reproducibility of drug release kinetics (5). There are many techniques by which tablets are suitable drug delivery system can be obtained.

Wet granulation technique:
Granules are formed by adding the liquid of granulation onto powder, which is under the, Effect of an impeller, screws, and air. The agitation obtained from the wetting process leads to the aggregation of the primary powder particles and producing the wet granules. The solvents used as liquids of granulation must be volatile, non-toxic, and can be removed by drying. The liquid of granulation includes water, ethanol, and isopropanol either alone or in combination. The liquid of granulation may be aqueous solvents or non-aqueous solvents. Aqueous solutions are safer than non-aqueous solvents (6).

Direct compression technique:
Direct compression is the technique by which tablets are compressed directly using mixtures of the drug and excipients (7). The simple formula consists of an active constituent, a lubricant, and a diluent (8). Direct compression technique has many advantages over the other manufacturing techniques used for tablet preparations and provides high efficiency (9). Tablets prepared by this technique give minimal microbial levels than others prepared by the wet granulation technique. The compaction process exerts a fatal effect on the survival of microorganisms (10, 11). The main limitation of this technique is using more than 30% of the drug in the formulation, mainly for drugs with low segregation and flowability (12, 13).

Hot-melt technique:
Hot-melt granulation is a technique by which the powders are agglomerated using meltable binders, which may be hydrophilic or hydrophobic, preferred in the preparation of the controlled-release formulations (14, 15).

Figure 1
3 Thus, the present work aimed to develop Dyphylline controlled release matrix tablets which release their contents over for 12 hours using different polymers and different preparation methods as well as studying the, Effect of different types of polymers and different preparation techniques on the invitro release of the drug from its controlled release matrix tablets. All tablet formulae prepared will be evaluated when freshly prepared, and promising tablet formulae that release their contents over 12 hours will be selected and subjected to scaling-up.

Design of Dyphylline controlled release matrix tablets:
Ten different hydrophilic, and hydrophobic polymers were used alone and in combination to prepare several tablet formulae applying three methods of preparation (direct compression, wet granulation, and hot melt). All formulae contained 100 mg Dyphylline per tablet. Two hundred tablets were prepared for each formula using suitable filler to obtain the constant weight of the tablet at 850mg. Talc (1%) was used as a glidant, and magnesium stearate (0.25%) was also used as a lubricant. The composition of the prepared formulae is illustrated in Table (1).

Preparation of Dyphylline controlled-release tablets using direct compression technique:
Twenty-seven tablet formulae were prepared by direct compression applying two variables, namely, polymer type (9 polymers) and polymer concentration (7, 14, and 21%) using the single punch tablet machine (Type AR 400, Erweka Heusenstamm, Germany). Tables (1-3) exhibit the composition of the designed formulae. Avicel PH 102 was used as the filler, where it was mixed with Dyphylline using a mortar and a pestle for 5 minutes, then, mixed with the specified polymer by geometric dilution for extra 5 minutes. The obtained blends were mixed with magnesium 4 stearate and talc and then compressed in a single 20 mm oblong punches. The force of compression at ten kpsi was kept constant.

Formulation of Dyphylline controlled release matrix tablets using wet granulation technique:
Preliminary studies were done to determine the optimum preparation conditions using 14% xanthan gum as a model polymer. To determine the optimum amount of the granulating agent, three different volumes of water were applied (250, 300, and 375 mg/tablet), and the produced tablets were evaluated for their release profile. Granules with three different mean particle sizes (780, 950 and, 1350 um) were tested. The effect of the tablet surface area was studied using three punches (16 mm circular, 20 mm oblong plain, and 20 mm oblong bisected punches). Similarly, the compression force was varied 8, 10, and 12 kpsi, and the tablets were evaluated.
Forty-two Dyphylline tablet formulae were prepared using the wet granulation technique with seven different types of polymers, each at three concentrations, and applying water or isopropyl alcohol as the granulating agent. The used polymers were: Xanthan gum, Sodium alginate, Alginic acid, HPMC K100M CR, HPMC E4M CR, HPC and HEC, formulae, numbers 1ww-21ww and 1wi-21wi (Table 1). Lactose monohydrate was selected as the filler in all formulae. A mixture of the drug and the filler was mixed geometrically with the specific amount of the polymer and then kneaded using the selected granulating liquid. The obtained mass was passed through a 1cm sieve and dried in a hot air oven at 60°C for 20 minutes in case of isopropyl alcohol and 60 minutes in case of water.
The dried mass was then passed through a 1mm sieve. Finally, the obtained blends were mixed with magnesium stearate (0.25%) and talc (1%) and then compressed in a single 20 mm oblong punch.
The force of compression at ten kpsi was kept constant.
For further optimization of the tablets, a set of four tablet formulae was prepared to apply mixtures of polymers, ( Table 2). Another set of five tablet formulae was prepared with the addition of 1% PVP K-25, (Table 3).

Preparation of Dyphylline controlled-release tablets using a hot-melt technique
Six formulae were prepared by the hot-melt method applying two preparation variables (polymer type and polymer concentration). Formulae number 22H -27H, ( Table 1). The drug was mixed with the waxy polymer (Compritol ATO 888 or Precirol ATO 5) using a mortar and a pestle for 5 minutes, poured in open Petri dishes, and placed in a hot air oven at 80°C ±2 for 30 minutes with occasional mixing every 5 minutes, then cooled to room temperature. The obtained mass was passed through a 1 mm sieve and mixed with the diluent (Avicel PH 102) and lubricants in a mortar. The obtained blends were compressed in a single 20 mm oblong punches and dies. The force of compression at ten kpsi was kept constant. Table 1   Table 2   Table 3 3

.2. Infrared spectral analysis (FTIR):
The spectrum of FTIR was applied to know if any types of interactions were found between the drug and the polymers used in the prepared formulae. The infrared spectra of the samples were by the use of a spectrophotometer (Espectrómetro Vertex 70, France). Samples were mixed with potassium bromide (spectroscopic grade) and then compressed into discs using a hydraulic press. Finally, the samples were scanned in the range of 4000 and 400 cm -1 (19).

Differential Scanning Calorimetry (DSC):
The physical state of the drug in the prepared formulae was analyzed by Differential Scanning Calorimeter Analyzer (DSC 204 F1 Nevio, Proteus ® software extensions). The thermograms of the samples were determined at a temperature range of 10°C to 300°C and a scanning rate of 20°C/min (20).

Evaluation of the blends to be compressed:
The flowability of the tablet blends prepared by direct compression was evaluated by using the fixed height cone method. The angle of repose was determined by the use of the following equation: Tan ɵ = 2h/d, Where (h) and (d) are the cone height and diameter, respectively (21).

In-vitro; Evaluation of the prepared tablets:
The following quality control tests were done on the prepared formulae:

Hardness:
Hardness demonstrates the ability of a tablet to withstand mechanical shocks while handling. This test is carried out using a TestCoat hardness tester (Digital Vickers Hardness Tester LHV -50Z, Motorized Turret Function, 16.5 MSH, USA). The value is expressed in kg.cm -2 . Ten tablets were chosen randomly, and the Hardness of the formulated tablets was calculated (22).

Friability:
Grace Digital Friabilator, USA, was used for testing the strength of tablets. Friability is calculated in percentage (%). Ten tablets were weighed and put into the apparatus (23). The Friabilator was operated at 20 rpm for 5 min or run up to 100 revolutions. The tablets were weighed again. The percentage friability was then determined by: Eq. (1) Where Wo: the initial weight of tablets, W: the final weight of tablets % friability of tablets less than 1% are in the accepted range.

Content uniformity:
The drug content uniformity was calculated by crushing ten tablets from each formula, and the content of each tablet was determined individually (24). The powder equivalent to one tablet was dissolved in 50 ml water. The solution was then filtered through a 0.45 um Millipore filter and adequately diluted with water. The absorbance was Spectrophotmetrically measured at the predetermined λmax of 276 nm (Single Beam UV-VIS Spectrophotometer, (LT-291), Japan) drug content of each tablet was determined. The results were presented as the mean drug content ± SD.
The tablets meet the test if the average drug content lies within the range of 85 -115% of the label claim and the standard deviation is less than 6%.

In-vitro drug release studies:
The cumulative release of Dyphylline from its tablets was performed according to the general USP keep the sink condition. The filtered samples were analyzed using a UV spectrophotometer by measuring the absorbance of Dyphylline at λmax276nm using 0.1N HCl, phosphate buffer pH 6.8, and phosphate buffer pH 7.4 as blanks respectively. Each experiment was carried out three times.
The mean dissolution time (MDT) was calculated for all in-vitro dissolution profiles using the next equation:

Eq. (2)
Where i represents the number of the dissolution sample, n represents the dissolution sample time number, tmid represents the midpoint time between i and i-1, and ∆M represents the extra amount of drug dissolved between i and i-1; the higher the MDT, the slower the dissolution rate of the drug.
A hypothetical target release profile was designed and used as a reference to evaluate the prepared tablets. This target profile assumed that 100% of the drug content is released from the tablets after 12 hours following Higuchi release kinetics. The percent drug released at the intermediate time intervals was based on the USP official drug monograph. For selecting the most promising tablet 7 formula, the similarity factor f2 was determined according to the next equation: Where n represents the sample point's number, wt represents the optional weight factor, Rt represents the reference profile, the f2value should be between 50 and 100. An f2 of 100 suggests that the test and reference profiles are the same.

Kinetic models of the In-vitro release data:
To investigate the possible kinetic model of drug release from tested formulations, the release data obtained were fitted into various kinetic models, namely, Korsmeyer-Peppas, zero-order, Higuchi model, and first-order.  (4) exhibits that the release rate of the drug is concentration-independent (25).

Eq. (5)
Where Q 0 represents the initial amount of drug and k is the rate constant of the first-order. In the first-order release kinetics, the Log cumulative % drug remaining (Log Q 0 -Log Q) was plotted against the time. The rate constant of the first-order k1 and the regression line (R 2 ) values were also determined from the graph. The first-order equation (5)  Where Mt represents the percent of drug released at time t, Mo, corresponds to the initial amount of drug released after an infinite time, Kp represents constant incorporating structural and geometric characteristics of the release device, and n is the release exponent indicates of the mechanism of release. The n values used to illustrate the drug release mechanism from the tablets were determined from the cumulative log percentage of drug released versus log time plots (28)(29)(30).
The correlation coefficient in each of the four cases was determined. The kinetic parameters: Rate constants (K) and half-lives (t 1/2 ) were then computed according to the determined order.

4-Statistical Analysis:
One way ANOVA test was used for comparisons between the different prepared formulae. Data were presented as Mean ± SD. The P values <0.05 were considered as the significance level during this study.

Infrared spectral analysis (FTIR):
The FT-IR spectra of Dyphylline with HPMC, HPC, HEC, compritol, and precirol are illustrated in   FTIR studies showed no appearance of any new peaks or disappear off the original peaks, which confirmed that there is not any type of interactions or any incompatibility between Dyphylline and the chosen polymers.  Differential scanning calorimetric analysis was done to emphasize the absence of any interaction between the drug and polymer used and was done for the same samples tested by the FTIR technique. DSC thermograms exhibited that is no interaction between Dyphylline and the chosen polymers. Drug excipient interaction may lead to peak appearance or disappearance, change in peak 9 shape, size, and position. Dyphylline showed melting at about 163 °C. In all the thermograms of mixtures, the drug peak was retained. The peaks were somewhat broadened and shifted to lower temperatures. However, shifts were only less than 10 o C. Peak broadening and shift of the endothermic peak were probably due to the intermixed nature of the components, not interaction.

Differential Scanning Calorimetry (DSC):
These small shifts of the values should signify minor interactions of the components. However, this could only be due to physical interaction without changing the chemical nature of the components. Table 4 represents the angle of repose of Dyphylline tablet blends intended for preparation by direct compression.

Hardness and Friability:
The mean hardness values of ten tablets of each formula are presented in Table 5. Different formulae of Dyphylline controlled release matrix tablets prepared by different polymers showed closely related hardness values ranging from 13-16 kg, with a standard deviation of less than 2%.
Friability measurement is the most common experimental procedure to determine if the tablet is prone to erode mechanically during handling and determine the attrition resistance of tablets. The friability of all formulae was determined and listed in Table 5. The Friability percentage of the prepared formulae was less than 1%, which confirms that the compressed tablets are in the acceptable range (31). Table 5 shows the drug content average of 10 tablets from each formula. It is worthy to note that all formulae comply with the pharmacopeia limits, i.e., the drug content average of all formulae is in between the range of 85%-115% of the label claim, and the standard deviation was less than 4%.

In-vitro drug release studies:
The In-vitro release of the Dyphylline controlled-release tablets was studied in a pH-gradient dissolution medium. The dissolution profiles were exhibited in Figure 4. It is worthy to note that the percentage of drug dissolved was determined according to the percentage drug content determined for each formula. For assessment and comparison, the MDT and the similarity with the reference release profile were calculated. The Effect of type and content of controlled release matrix on the release of Dyphylline from the prepared formulae was assessed individually.

Fig. 4
From Figure (4), it is evident that the increase in xanthan gum, alginic acid, HEC, and HPC did not show any change in percent Dyphylline released. This was attributed to the hydrophilic nature of these polymers as they need water to hydrate and produce the gel layer responsible for drug retardation. Those four polymers, at their three concentrations, failed to control the drug release.
They released 100% of their drug loadings in less than one h. it was recording short MDT values All tablets prepared by direct compression except for formula F24d (prepared using 21% Compritol ATO 888) recorded f2 value below 50, indicating significant differences from the reference release profile. Formula F24d showed a high f2 value (82.61) and was considered promising and selected for further scaling. Table 6 From Table 6, it is evident that the increase in the water volume from 250 to 300 and 375 mg/tablet increased MDT values indicating better retardation of drug release. This may facilitate proper wetting of the polymer, such as adding a higher amount of water, may reduce the rehydration rate of the xanthan gum matrix and decrease the time for gel layer formation and increase gel layer rigidity leading to a decrease in the percent drug released. These results were following those recorded for Niacinamide CR matrix tablets (33), which showed that increasing the water percentage produced more compact particles with a fewer of large fibers. On the other hand, the dissolution profiles of HPMC CR matrix tablets were independent of the amount of water during granulation (34).

Selection of the optimum conditions for wet granulation:
By increasing the mean particle size of the prepared granules from 780 um to 950 um, the MDT decreased, and drug retardation ability also decreased. Tablets prepared using granules of mean particle size 1350 um entirely dissolved in 10 min, indicating non-controlled release behavior.

11
These results may lead to increasing the porosity of tablets and thus a decrease in the tortuosity of the gel layer and an increase in release rate. The smaller size of the granule range leads to a closer and more intimate packing (35). These results are in agreement with those obtained with Diclofenac sodium CR matrix tablets (36), Propranolol hydrochloride (37), and Aspirin CR matrix tablets (38).
Increasing the compression force resulted in more retardation of drug release (higher MDT values).
The reduction in the matrix's porosity leads to slower water uptake and waterfront moving into the matrix, which in turn leads to slower drug release ( The disruption of the tablet surface by bisection led to disruption in the gel layer's tortuosity and thus increases in amounts of Dyphylline released.

Hardness and Friability:
The Friability and mean Hardness values of the prepared tablet formulae are presented in Tables 7 and 8. the high content of polymer resulted in an external wet and highly viscous layer. This layer prevented the complete hydration of the inner parts of the granules formed and resulted in more friable and weak granules after drying.

In-vitro release studies:
The data of the release of the prepared tablets were illustrated in Figures 5 and 6.  comparing with other tablets prepared by using isopropyl alcohol. This may lower the solubility of the used polymers in isopropyl alcohol relative to better solubility in water; thus the granulation with water tends to increase the magnitude of polymer hydration than granulation with isopropyl alcohol leading to a more intact gel layer, which decreases the rate of release. However, these results are not by those obtained with Pentixifylline CR matrix tablets prepared using either water or IPA as granulating liquids and HPMC or HEC as gum type CR matrix, where both fluids gave near related profiles (49).
Better retardation of the drug release (higher MDT values) is obtained by increasing polymer content. Tablets prepared at 7% polymer content showed short MDTs. During the dissolution of tablets with higher polymer contents (14 and 21%), the outer hydrated layer showed a progressive increase in size, followed by a loss in integrity. So, it still unchanged until the end of the dissolution process when wetting the dry inner core till the entire tablet disappeared (50 similarity factor values (>65) indicating good similarity to the reference release profile, and thus they were selected to be further studied and scaled up. Table 9 shows that combining polymers did not affect the Friability, Hardness, and content uniformity values of the produced tablets.

Table 9
The data of the release of the prepared tablets were illustrated in Figure 7

Figure 7
On the other hand, Fig. 7 shows that drug's release was significantly faster from all tablets obtained by using combined polymers about the corresponding formulae containing each of the polymers alone. This may attribute a less rigid gel layer formation with a consequent decrease in retardation capacity. Different results were reported for Tramadol hydrochloride CR tablets (57), and Diclofenac sodium CR tablets (58), were a combination of xanthan gum and HPMC led to a more significant retarding effect.

Effect of addition of extra binder:
For further optimization, the five selected formulae were prepared by adding 1% PVP as a binder. Table 10 shows no significant change was recorded for the Friability, Hardness, and content uniformity values. Table 10 14 The data of the release of the prepared tablets were illustrated in Figure 8

Figure 8
It is shown from Figure 8  indicating good similarity to the reference release profile, and thus, they were selected to be further studied and scaled up. Table 11 represents that the prepared formulae showed very closely and officially accepted Friability and Hardness values. Table 11 shows that all formulae are complying with the pharmacopeia limits. Table 11 5.5.3. In-vitro release studies:

Content Uniformity:
The data of the release of the prepared tablets were illustrated in Figure 9 It is shown from Figure 9 that preparing tablets using hydrophobic polymer by hot melt method succeeds in retarding the Dyphylline release. This was attributed to the heat treatment which, caused the melting of the wax, redistribution, coating both the drug and diluents as well as forming a network structure that increased tortuosity of the matrix and delayed-release (61). Similarly, the phenylpropanolamine hydrochloride release was retarded by the heat treatment with Compritol ATO 888 (62).
Increasing the hydrophobic polymer content led to a decreasing in the percent Dyphylline released and better retardation of drug release. The lipophilic controlled release matrix makes the wetting of the factual matrix difficult and subsequently allows a slower release rate (63). Theophylline controlled release matrix tablets showed a closely related behavior where the drug release was delayed when lipophilic controlled release matrix content increased.
Formula F 2 4 H (prepared using 21% Compritol ATO 88 8) had an f2 value of 81.52 and was selected for further scaling.

Kinetic analysis of the release profile of the selected tablet formulae:
The most suitable kinetic model for the Dyphylline in-vitro release formulae can be determined from the highest values of the correlation coefficients obtained (Table 12).

Table 12
Table (12) shows that all Dyphylline formulae obey Higuchi's diffusion model, explaining the diffusion-controlled release mechanism.
The difference in mean of First-order, Zero-order, Higuchi-kinetics, and Korsmeyer-Peppas between the different formulae "K" was indicating significant (p < 0.05).

6-Conclusion:
Formulation of Dyphylline hydrophilic matrix tablets is better achieved with a wet granulation technique using water as granulating liquid. The increase in the polymer content led to increasing in t1/2 value and a decrease in the Dyphylline's extent released due to the improved retardation of drug release. The rate of the Dyphylline release from hydrophilic matrix tablets prepared by the wet granulation method and using either: xanthan gum, sodium alginate, alginic acid, and hydroxyethylcellulose as the hydrophilic polymer was lower upon using water as the granulation liquid compared to results obtained upon using isopropyl alcohol. This was attributed to the 16 minimal solubility of these polymers in isopropyl alcohol compared to good solubility in water, which led to a decrease in the polymer hydration and the production of a less intact gel layer manifested as a decrease of drug retardation. The synergistic effect of the PVP-K-25 combined with other binders leads to retention of the release of the drug from hydrophilic matrix tablets. Diffusion is the mechanism of Dyphylline release from the controlled release tablets prepared by direct compression, wet granulation, and hot melt techniques. The formulations exhibited release profiles close to the reference release profile and recorded high similarity factor values (>65) indicating good similarity to the reference release profile, and thus, they were selected to be further studied and scaled up designated.