1. Introduction
Despite their wide acceptance, higher dose frequency is the main limitation of oral solid dosage forms [
1], resulting in missed doses and variation in drug concentration in blood. This phenomenon is to be critically considered in the case of drugs with a narrow therapeutic window and in conditions where the drug concentration in blood is required to be consistent. In conventional dosage forms, the drug is immediately released after oral administration, is absorbed from the gastrointestinal tract (GIT), and reaches the general circulation. The drug produces its response after achieving a therapeutic concentration in blood, and is metabolized and eliminated from the body [
2,
3]. The drug response peaks when its concentration in blood is high, and thereafter gradually declines to a sub-therapeutic level. To provide a longer-term effect, the drug concentration needs to be maintained at a certain level for a longer period of time.
During the past few decades, a number of strategies have been adopted by the pharmaceutical scientist to maintain therapeutic drug concentration in blood. Among these, the most simple and robust method is to sustain the drug release to maintain a constant drug concentration in blood for a longer period. The sustained-release dosage form remains in the GIT and releases the drug at the rate equal to its elimination rate, thereby maintaining the required amount of the drug in blood for a long time. The main objective of designing a sustained-release dosage form is to achieve a therapeutic drug concentration in blood, maintain it for longer time, and overcome its fluctuation [
4]. Some of the benefits of sustained-release formulations are:
Reduced dose frequency, leading to no chance of a missed dose and subsequent enhancement in the patients’ compliance [
5];
Fluctuations in concentration of the drug in blood are overcome and a uniform level is maintained [
6];
Potent drugs can be administered in a safe way by controlling their release [
5].
Polymers (large molecules made up of many small repeating units) have a variety of applications in pharmaceuticals, and their importance is steadily increasing. The characteristics of polymers are dependent on their molecular weight, chain length, and branching [
7]. On the basis of solubility, polymers may be water soluble or soluble in organic solvents.
Among hydrophilic polymers, hydroxypropyl methylcellulose (HPMC) has been widely used in the formulation of dosage forms for different purposes, such as a binder, monolithic matrix, and release modifier [
8], due to its compatibility, better safety profile, and easy availability [
9,
10]. HPMC is a derivative of cellulose and forms a swollen gel upon contact with water. Water penetration into the core of the matrix and subsequent drug release are controlled by the swollen gel layer. Release of the drug from the HPMC matrix is based on:
The dissolution rate of the drug from polymeric matrices is governed by physico-chemical characteristics of the active pharmaceutical ingredient (API), and the nature and quantity of the excipients included in the formulation. Generally, the process of diffusion is observed during the release of hydrophilic drugs. Upon penetration of water, the matrix becomes swollen, and the drug is dissolved and diffuses out of the matrix [
11] at a pre-determined rate. In the case of hydrophobic drugs, the drug release occurs after erosion of the matrix. Similarly, water-soluble excipients present in matrix tablets dissolve earlier and micro-channels are developed, which increase water penetration into the core of the matrix and increase the dissolution rate. A number of studies have reported an increase in the dissolution rate by increasing the quantity of lactose (a water-soluble excipient) in the matrix tablets [
12], and a decrease in the dissolution rate with the inclusion of di-basic calcium phosphate (a water-insoluble excipient) [
13]. Changes in the GIT conditions can also affect the mechanism of the dissolution rate due to enzymatic activity and variation in pH of the medium from highly acidic to alkaline. Alcohol has a solubilizing effect on HPMC, and the Food and Drug Administration (FDA) has issued a warning about dose dumping due to rapid drug release from the matrix upon alcohol consumption.
Clarithromycin is an erythromycin derivative (6-
O-methylerythromycin) macrolide [
14]. The molecular formula of clarithromycin is C
38H
69NO
13, with corresponding molecular weight equal to 747.96 g/mol. Physically, clarithromycin is a white or off-white powder with a crystalline nature. It is insoluble in water and can be solubilized in different organic solvents such as ethanol, acetone, acetonitrile, and methanol [
15]. The structural formula of clarithromycin is presented in
Figure 1.
Clarithromycin is prescribed twice or three times per day, depending upon the severity of the infection. During antibiotic therapy, a consistent blood concentration of the drug is desired, whereas divided doses lead to a variation in blood plasma concentration. There is a need for a controlled-release dosage form of clarithromycin that can avoid the problems of multiple dosing and provide a consistent drug concentration in blood. The current study aimed to control the drug release of clarithromycin after oral administration via formulation as polymeric matrix tablets. Different formulations were developed using HPMC as a release-controlling polymer and evaluated for quality control parameters as per the official compendia. Dissolution profiles of the developed formulations were compared with conventional marketed products using a model-independent approach.
2. Material and Methods
2.1. Material and Instrumentation
Clarithromycin (99.95% pure with respect to the USP standard; Wuxi Hexia Chemica Company, Wuxi, China) was the model drug, and excipients included lactose (Kerry company, Raunheim, Germany), HPMC (Dow Chemical Company, Wiesbaden, Germany), magnesium stearate (Linghu xingwing Chemical Co., Ltd., Huzhou, China) and talc. Different instruments, such as a rotary compression machine (Yenchen, Taiwan), digital tablet testing apparatus (PharmaTest, Hainburg, Germany), dissolution testing apparatus (Pharma Test, Hainburg, Germany), friabilator (Pharma Test, Hainburg, Germany), super mixing granulator (Yenchen, Taiwan), IR spectrophotometer (FTIR Prestige, Shimadzu, Japan), and HPLC (Perkin-Elmer, Langenfeld, Germany), were used in the preparation and evaluation of polymeric matrix tablets.
2.2. Evaluation of Compatibility of Drug and Polymer
The compatibility of clarithromycin with HPMC and other excipients was evaluated on the basis of a drug excipient compatibility study. Samples were prepared using the binary mixture approach [
16], subjected to stress conditions, and checked for physical consistency, clarithromycin content, and FTIR spectra. Samples were prepared as per
Table 1, by physical mixture, using 2 g of each material.
Samples were prepared as per
Table 1 and packed in air-tight glass containers. Samples were stored at stress conditions (40 ± 2 °C and 75 ± 5% R.H.) for 90 days and checked at regular intervals, i.e., at days 1, 30, 60, and 90.
The physical consistency (color and physical appearance) of each sample was evaluated by visual inspection. The drug content in each drug-containing sample was determined by HPLC. An FTIR spectrophotometer (Shimadzu, Japan) was used for recording the IR spectra of each sample using a KBr disc. A small quantity of the sample was mixed with KBr and crushed to a fine powder. A mixture of the sample and KBr was loaded to the sample folder with gentle tapping and spectra were recorded at 4000–400 cm−1 in transmittance mode. Data were processed using I.R. Solutions software, version 1.10.
2.3. Preparation of Clarithromycin Matrix Tablets
Matrix tablets of clarithromycin were prepared via high-shear wet granulation using HPMC as the matrix-forming polymer. The main steps of the process were mixing all of the ingredients (drug, polymer, and other excipients) in a dry state; wet massing with the binder; and drying, sizing, lubrication, and compression of granules. All the ingredients, as listed in
Table 2, were weighed accurately, sifted through a mesh having a 600 µm pore, and loaded into a lab-scale high-shear wet granulator (Yenchen, Taiwan). All the ingredients were mixed in a dried state by rotating the main impeller at 150 rpm, while the speed of the chopper was 2200 rpm. Water was used as the binder and was added at the rate of 1 L/20 s. Wet granulation was performed at high speeds (150 and 2500 rpm) of the main impeller and chopper. Drying of wet granules was achieved in a fluidized bed drier by a stream of hot air. Initially, simple air was passed for one minute and then the temperature of the inlet air was increased to 80 °C. Sizing of the dried granules was carried out using a cone mill having a rotating mesh of 2 mm pore, revolving at 800 rpm. Granules were lubricated and compressed using a rotary compression machine. The compression machine was fitted with oblong shallow concave punches (19 mm), with an engraved “
f” on one side. The compression weight of tablets was 900 mg/tablet and, for each formulation, a minimum of 250 tablets was prepared. In the formulation of sustained-release clarithromycin tablets, lactose monohydrate was used as a diluent to make up the bulk. This was added in different quantities in different formulations to make the final weight of tablet equal to 900 mg/tablet. Talcum was used as an anti-adherent and magnesium stearate was used as a lubricant.
2.4. Pre Compression Evaluation
Granules for all the formulations were tested for their flow parameters as per USP [
17]. Bulk density and tapped density of granules were determined by placing a weighed quantity of granules in a graduated cylinder [
17]. For determination of the tapped volume, known quantity of granules was placed in a cylinder and tapped manually. Reduction in the volume of granules was noted after each 100 taps, until the volume became constant; this volume was noted as the tapped volume. The weight and tapped volume of the granules were used for the calculation of the tapped density. The mean values of the bulk and tapped density were used to calculate Car’s Index and the Hausner ratio [
17] using Equations (1) and (2), respectively.
where “Dc” and “Da” denote the tapped and bulk density of the granules, respectively.
A glass funnel was used for determination of the angle of repose of the granules, as per USP [
17]. The glass funnel was fitted to a stand at the height of 5 cm from the table top and its lower opening was closed with a cotton plug. Granules were placed in the funnel and allowed to flow by removing the cotton plug. The radius and height of the powder heap was measured and the angle of repose was calculated using the following equation:
In Equation (3), α denotes the angle of repose, and “H” and “r” are the height and radius of the granule heap, respectively.
2.5. Evaluation of Matrix Tablets
2.5.1. Physical Parameters of Tablets
Physically, the matrix tablets of clarithromycin were checked for appearance and surface characteristics. The thickness and diameter of randomly selected tablets (
n = 10) were measured with a digital hardness and thickness tester (Pharma Test, Hainburg, Germany), and their average values were calculated. For calculation of weight variation, tablets were randomly selected and weighed individually, and average weight was calculated. The difference in the individual weight of tablets and the average weight were used for the calculation of the percent weight variation using Equation (4) [
17]:
2.5.2. Mechanical Strength of Tablets
The mechanical strength of matrix tablets of clarithromycin was evaluated by determining their crushing strength, specific crushing strength, and tensile strength, and friability testing, as per USP [
17]. The crushing strength of tablets (
n = 10) was measured via digital tablet hardness, and the specific crushing strength and tensile strength were calculated using the mean values of the crushing strength and the thickness of tablets, as per USP, using the following equations:
and
where “F” denotes the crushing strength of the matrix tablets, “D” is the diameter, and “H” denotes its thickness; π is the constant of proportionality.
For determination of friability, tablets (
n = 10) were randomly selected, dedusted, and subjected to 100 rotations in a Roche friabilator at 25 rpm [
17]. When rotations completed, tablets were evaluated for physical defects (breakage, chipping, capping, and lamination) and reweighed, and percent weight loss was calculated as follows:
where:
Wb = weight of tablets before subjecting to friability
Wa = weight of tablets after friability testing.
2.5.3. Determination of Drug Content
The amount of clarithromycin in the sustained-release matrix tablets was determined as per USP [
17]. Matrix tablets were taken and crushed, and powder containing about 2000 mg of clarithromycin was placed in a flask (capacity = 500 mL). Methanol (350 mL) was added to the flask and shaken for 30 min. Further methanol was added to the solution to make up the volume. An aliquot (3 mL) of this solution was diluted to 100 mL by adding a mobile phase and analyzed by HPLC. A mixture of methanol and mono-basic potassium phosphate (0.067 M) in 65:35 by volume was used as the mobile phase. The stationary phase consisted of a 4.6 mm × 150 mm column with L1 packing and was eluted with the mobile phase at the rate of 1 mL/min. The temperature of the column oven was kept at 50 °C and the detection wavelength was 210 nm. For the preparation of a standard solution, a weighed quantity of clarithromycin (250 mg) was dissolved in a sufficient quantity of methanol to obtain a concentration of 625 µg/mL. An aliquot (10 mL) of the solution was placed in a volumetric flask of 50 mL capacity and the volume was made up with the mobile phase. The final concentration of the standard solution was 125 µg/mL. Analysis of the standard and sample solutions was carried out by HPLC, and their peak areas were compared to obtain the percent concentration of clarithromycin in the sample preparation.
2.5.4. Determination of Dissolution Rate
The dissolution rate of the controlled-release clarithromycin tablets was studied in 900 mL of 0.1M acetate buffer (pH 4.6) [
17]. One tablet was placed in each flask containing dissolution media at 37 ± 2 °C. USP dissolution apparatus II (peddle) was used at 50 rpm for stirring the dissolution media. Samples were collected at specified time intervals and analyzed for drug content using HPLC. Details of chromatographic conditions and the mobile phase are mentioned in the Section “Determination of drug content”. The volume of the dissolution media was corrected with fresh dissolution media after each sampling.
2.5.5. Comparison of Dissolution Profiles
A model-independent approach was used for comparing dissolution profiles of matrix tablets with each other and with conventional tablets of clarithromycin. The model-independent approach is based on the similarity factor (
f2), dissimilarity factor (
f1) and dissolution efficiency (D.E.). The dissimilarity factor (
f1) and similarity factor (
f2) were calculated by Equations (8) and (9), respectively [
18,
19,
20]:
In Equations (8) and (9) “Rt” and “Tt” denote the dissolution rate of the standard and tested product at time “t”, respectively. Similarity of the two dissolution profiles was ensured by a value of “f2” equal to or greater than 50.
In addition to the mentioned parameters, time taken by each formulation to release 50% (T50%) and 100% (T100%) of the drug was also determined. Similarly, the quantity of drug released at different time points was also compared.