Optimizing the Role of Polymer Blend in the Preparation of Acyclovir Controlled-Release Tablets : An Approach for Better Patient Compliance ٭

Release Tablets: An Approach for Better Patient Compliance Barkat Ali Khan, Faheem Haider, Kifayat Ullah Shah. Bushra Uzair. Kaijian Hou, Muhammad Khurram Waqas, Akhtar Rasul Faculty of Pharmacy, Gomal University, Dera Ismail Khan 29500, Khyber Pakhtunkhwa, Pakistan Department of Pharmacy, Quaid I Azam University, Islamabad, Pakistan Department of Bioinformatics and Biotechnology, International Islamic University, Islamabad, Pakistan Shantou Traditional Chinese Medical Hospital, Guangdong, China Institute of Pharmaceutical Science, UVAS, Lahore, Pakistan Department of Pharmacy, GC University, Faisalabad, Pakistan Correspondence: barki.gold@gmail.com, Tel: +92-333-9732578 Abstract: This study was carried out to formulate and evaluate controlled release (CR) matrix tablets of Acyclovir using combination of hydrophilic and hydrophobic polymers. Acyclovir is a guanine derivative and is its half-life is short hence administered five times a day using immediate release tablets. Six formulations (F1-F6) were developed using Ethocel and Carbopol in equal combinations at drug-polymer (D:P) ratio of 10:5, 10:6, 10:7, 10:8, 10:9 and 10:10. Solubility study was performed using six different solvents. The compatibility studies were carried out using FTIR and DSC. According to USP, Quality Control and dimensional tests (hardness, friability, disintegration and thickness) were executed. In-vitro drug release studies of Acyclovir was carried out in dissolution apparatus using using 0.1 N HCl medium at constant temperature of 37 ± 0.5 oC. In order Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 10 July 2018 doi:10.20944/preprints201807.0165.v1


Introduction
The most frequently used route for administration of drugs is the oral route.The best and prevalent oral formulations available in the market are tablets and are favored by both patients and physicians equally.The most preferred formulations for chronic therapy are controlled release (CR) tablets for the reason that they offer better patient compliance [1].
The main objective of controlled release formulation is to offer appropriate carriage profiles in the range of therapeutic window [2][3][4].
The nature and characteristics of polymer play a significant role in release of Drug from reservoir, therefore their application can generate well branded dosage forms [1].
Among the most predominant means for oral controlled delivery of drug is the system of hydrophilic matrix and the principal of release of drug from hydrophilic matrices is based on swelling of the polymer when it interacts with the aqueous medium.The release of drug occurs then by means of diffusion, dissolution, and erosion [5][6][7][8].
The success of Acyclovir in treating Herpes simplex virus (HSV) has prompted the synthesis of several structural analogs, but none has shown to be as tolerable as and have shown to have such a high therapeutic index as acyclovir [9].
The most extensively used drug for genital herpes, cutaneous herpes, chicken pox, varicella zoster and herpes keratitis infections is Acyclovir.Generally acyclovir is used as 200 mg tablets orally, five times a day [8].Acyclovir is available in conventional immediate release tablet dosage form, Intravenous infusion (Zovirax ® ) and 3% ocular ointment, Liposomal, niosomal and magnet depot technology have also been investigated for the acyclovir by certain researchers [10,11].Ethyl cellulose is an important polymer excessively used as drug retarding ingredient in the formulating sustained and controlled release pharmaceutical drug products.Ethyl cellulose alters the length and size of the diffusion path thereby controlling the release of the drug from the dosage form.
Carbomer is soft and white colored powder which can easily absorb water forming thick solutions and/ or gels.Carbomer is an inert, unchanging or stable substance.It has no any toxic effects and repel putrefaction and spoilage.

Chemicals
Acyclovir was provided as a gift sample from Glitz Pharmaceuticals, Islamabad, Pakistan.Potassium Phosphate Monobasic and Sodium Hydroxide were purchased from CBW Chemie GmbH Bitterfeld-Wolfen, Germany, Magnesium Stearate and Lactose was obtained from BDH Chemical Ltd, Pool England while Ethocel and Carbopol were taken from Dow Chemical Co.Midland USA.All the stated above chemicals were used without any further purification.

Construction of Standard Calibration Curve of Acyclovir
For stock solution preparation 25 mg of Acyclovir was taken in 50 ml (0.5 mg/ml) of manobasic phosphate buffer (pH 7.4) and was placed in ultra sonifier until the drug dissolution ensured completely.Suitable dilutions were prepared from the stock solution in descending order and then analyzed by means of UV-Spectrophotometer at λ max (254 nm).The corresponding absorbance values were noted and documented.

Chemical Integrity
FTIR spectra were measured for CR tablets of Acyclovir in order to investigate the effect on the functional group of Acyclovir.All samples were analyzed by a universal FTIR spectrum series at a resolution of 4 cm −1 .For this purpose one sample of suitable quantity of pure drug and other containing pure drug along with polymers and excipients.

Thermodynamic Behavior
The thermal behavior of the prepared pure acyclovir powder and CR tablets of Acyclovir (Pure Acyclovir+polymers) was tested by Differential Scanning Calorimeter (DSC).
Samples of specified quantity were placed in platinum crucible with heating range of 25-500 °C having a heating rate of 10 °C min -1 .

Solubility Study of Acyclovir
According to the technique described by Higuchi and Connors solubility study was performed.Six different solvents i.e.Monobasic potassium phosphate buffer having pH 7.4, 7.2 and 6.8, purified water, 0.1 N Hydrochloric acid (HCl) solution and 0.1 N Sodium hydroxide (NaOH) solution were used for solubility.

Acyclovir Tablet Formulation
Acyclovir controlled release tablets (500 mg), comprising 200 mg of Acyclovir and copolymers Ethocel and carbopol were formulated.The tablets were prepared at several drug-to-polymer ratios (D:P ratio of 10:5, 10:6, 10:7, 10:8, 10:9, and 10:10) using the slugging method and wet granulation method.Lactose was added as a diluent and magnesium Stearate (0.5% w/w) was used as a lubricant as given in table 1. Formulations of all D:P ratios were mixed in a geometrical manner with the help of pestle and mortar for obtaining uniform mixture.The lubricant (Magnesium stearate) was not added in this mixture.10% Poly Vinyl Pyrolidone (PVP-K 30) solution was used as wetting agent.Subsequently the resultant humid mass was forcefully passed through sieve having mesh size number 8 for obtaining uniform size granules.The granules were kept for drying in tray dryer and sieving process was repeated with mesh size number 12.
After drying, these granules were again passed through #12 mesh screens to avoid formation of any lumps agglomerates.Later on when dried uniform size granules were obtained, lubricant was added to the dried granules of all formulations in specified amount.Final formulations of all ratios were eventually compressed into CR tablets of Acyclovir by single punch tablet machine.

Determination of Tabletting Parameters
After preparation of CR tablets of Acyclovir using wet granulation technique, they were subjected to various quality control tests for their physical characteristics investigation.
Using standard operating procedure as described in USP their disintegration, thickness,, friability and hardness were determined.Digital vernier caliper was used for the thicknesses determination of all formulations.Friability, hardness and disintegration of all formulation were performed according to the standards of United State Pharmacopoeia (USP) protocol;s using hardness Apparatus, Friabililator and Disintegration Apparatus.

In Vitro Drug Release
Acyclovir CR tablets of all formulations were examined using USP Method-1 (Rotating Basket Method) for in vitro release studies.The media used, was 0.1 N HCl which was kept at temperature of 37± 0.5 ºC. 5 ml sample was taken with the help of syringe from each basket at definite intervals of time (1, 2, 3, 6, 8, 9, 10, 12, 15, 18, 24 hours).5 ml solvent was added to each basket so that net volume remains constant.All the samples were filtered by membrane filter having size of 0.45 µm before taking their absorbance so that any extra particles or can be removed from samples.Absorbance of all sample were obtained with the help of UV-Visible Spectrophotometer at 254 nm and their percentage releases of each formulation were determined.

In-vitro Release Kinetics
In order to predict the physical mechanism of the Acyclovir in-vitro release behavior of all the formulations prepared with different D:P ratios (10:5, 10:6, 10:7, 10:8, 10:9, and 10:10), release data were compared using the following mathematical models [12].

Standard Calibration Curve of Acyclovir
The standard calibration curve of Acyclovir was obtained using the method mentioned in previous section.
Using UV-Visible spectrophotometer, absorbance valves of stock solution of Acyclovir and its different dilutions were taken and plotted against its respective concentrations.These findings are in accordance with previous findings reported by Musumeci et al and Prerak et al [16,17].The physical mixture of acyclovir and polymers showed the same thermal behavior as the individual components, indicating that there was no interaction between the drug and the polymer in the solid state.The results suggested that the drug was molecularly dispersed in the polymers matrix and it might exhibit amorphous or disordered crystalline state as reported previously by Prerak et al [17].

Solubility of Acyclovir
The

All values expressed in mean ± SD
The mean hardness of CR tablets of Acyclovir of all formulations with Carbopol and Ethocel, waw in the range from 12-16 which were within the USP satisfactory limits i.e.
(10-20 kg/cm 2 ), the hardness of formulation 10:10 D: P ratio was maximum as compared to rest of formulations due to use of high fraction of polymers.
Disintegration tests were then applied to all formulations as given in table 3. Tablets with Carbopol and Ethocel were disintegrated within 15 minutes.The friability tests were performed after disintegration tests for all formulations of Acyclovir with Carbopol and Ethocel.The results of all formulations were within USP satisfactory friability range, the mean value of friability was less than 0.8%.

Drug Release Studies
As displayed in figure 4  The results of in vitro dissolution study of each formulation (D:P ratio 10:10) are taken with the help of USP method 1 according to the procedure mentioned in methodology section.The results of each formulation have been shown individually in figure 6.The rate of the drug release (until 24 hours) tended to decrease with increase amounts of either Carbapol or ethocel.According to literature findings, the slowing effect of both polymers is due to increases in the viscosity of the gel layer around the matrix tablet [18,19].Both polymers have a affinity of making gel when they come into contact with aqueous layer.So, at high levels, polymer concentrations are increased around the tablet, and so is the viscosity of the outer layer, which results in decreases in the release of the drug, which then subsequently limits the release of the drug from the matrix [18].Gel creation occurs due to dissociation of the carboxyl groups of Carbapol at a pH above their pKa (i.e., 6.0±0.3),which causes uncoiling and the development of molecules due to the

Kinetic Analysis of Drug Release Data
Kinetic analysis of drug release data was done by using the mathematical models [19].It was found that the formulation F6 followed zero order release and formulations F1, F2, F3, F4 and F5 followed first order release as shown in table 4. The data of the various models revealed that formulations F1, F2, F3, F4 and F5 followed Higuchi matrix model whereas formulations F6, follows Korsmeyer-Peppas model.In case of formulation F6 the n value for Korsmeyer-Peppas model was found to be in range less than 0.5, which indicates mechanism of drug release by Fickian diffusion whereas in case of formulations F1, F2, F4 and F5 the n value for Korsmeyer Peppas model was found to be more than 0.5, which indicates mechanism of drug release by non fickian diffusion by those formulations.
Acyclovir was constructed using Microsoft Excel and presented in Fig 1 along with equation of regression and (R 2 ) value.

Figure 3 :Figure 4 :
Figure 3: Acyclovir pure drug DSC thermogram results obtained from solubility study are depicted by fig 6. Acyclovir has highest solubility in 0.1 N HCl at 37 ºC.Among several phosphate buffers the solubility of Acyclovir was highest at pH 7.4.The least solubility has been observed in 0.1 N NaOH at 25 ºC as shown in fig 6.

Figure 5 :Figure 6 :
Figure 5: Solubility study results of Acyclovir in different solvents stored at 25 and 37 °C CR Acyclovir tablets formulations prepared by wet granulation method at different drug to polymer ratio of 10:5, 10:6, 10:7, 10:8, 10:9, and 10:10.The formulations of D: P ratio 10: 10 prolong the release of Acyclovir drug to a more extent and the 96% of whole the drug was released in 24 hours.The release from 10: 5 was extended only up to 1 hour and 84.39% drug was released.The second formulation 10:6 extended the release up to 2 hours.The third formulation 10: 7 prolonged the release time to 6 hours.The release of drug was extended up to 12 hours by fourth formulation.From formulation of 10: 9 the release was much slower and extended to 18 hours.Final formulation 10:10 gave us the desired result and release of drug was extended up to 24 hours.

Table 2 :
presented the thickness, hardness and friability, while table 3 shows the disintegration applied to CR tablets of Acyclovir with Carbopol and Ethocel.All the tablets of above mentioned formulations were well-made in look and were having smooth shiny surfaces.As displayed in table 2, the mean thickness of CR tablets of Acyclovir of all formulations, prepared by wet granulation technique with Carbopol and Ethocel were about 5mm which are within the USP range (2-6mm).Results of Tabletting Parameters of Acyclovir CR tablets prepared by Wet granulation Method Preprints (www.

Table 3 :
Results of Disintegration Test of Acyclovir CR tablets prepared by Wet granulation Method

Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 10 July 2018 doi:10.20944/preprints201807.0165.v1 production
[20,21]lectrostatic repulsive force between the negatively charged carboxyl groups.Uncoiling and expansion of the molecules result in polymer swelling and, consequently, gel is formed, which consists of closely packed swollen particles.With increases in the amount of polymer, this gelling property increases, and thicker gel restrains water penetration, which ultimately reduces the release of the drug.At high levels of both polymers, a considerable fraction of the drug (~16%) remained unreleased until 24 hours, which may result in reductions in the extent of bioavailability significantly.Charyulu et al prepared acyclovir controlled release tablets using HPMC K15M and sustained the release for 10 hrs.Similarly CHAUDHARI et al formulated controlled release tablets of acyclovir using hydrophilic polymer, polyethylene oxide and the maximum sustained action was observed for 12 hrs[20,21].Acylex ® by Ferozsons (pvt) Ltd Noshehra, Pakistan was used as a reference drug which gave 100% release after 40 Minutes.

Table 4 :
Kinetic models Parameters applied to release profile of CR tablets4.ConclusionBased on the results of these studies, it was concluded that the blend of Ethocel and Cabapol polymers can be used as efficient matrix former to provide controlled release of acyclovir.The formulation F6 can retard the drug release rate up to 24 hours which can lead to OD dose and can enhance patient compliance as the usual dose is QID.In the present work, 1 st time the attempt has been made, formulating CR tablets of acyclovir using blend of hydrophillic and hydrophobic polymers.It is suggested to perform pharmacokinetic parameters (t1/2, Cmax, Tmax ) and IVIVC in-vivo.