EVALUATION OF SPRAY AND FREEZE DRIED EXCIPIENT BASES 119
EVALUATION OF SPRAY AND FREEZE DRIED EXCIPIENT BASES CONTAINING DISINTEGRATION ACCELERATORS FOR THE FORMULATION OF METOCLOPRAMIDE ORALLY
DISINTEGRATING TABLETS
Fars K. Alanazi
Orally disintegrating tablets (ODT) are gaining attractiveness over conventional tablets specially for patients having difficulty in swallowing such as pediatric, geriatric, bedridden and disable patients. ODT technologies render the tablets disintegrate in the mouth without chewing or additional water intake. So far there have been many patents for ODT, but only few publications are dealing with this dosage form. The aim of the present study was to formulate metoclopramide in ODT with sufficient mechanical strength and fast disintegration from bases prepared by both spray (SD) and freeze drying (FD) techniques. Different disintegration accelerators (DA) were utilized to prepare the proper ODT using various super-disintegrants (Ac-Di-Sol, Kollidon and sodium starch glycolate), a volatilizing solvent (ethanol) and an amino acid (glycine). Metoclopramide, an antiemetic medication, was used as a model drug in the formulated ODT. It was noted that the disintegration of ODT depends on utilization of DA in both SD and FD techniques to prepare tablet bases for ODT and so many other factors such as drying process, type of DA, and the addition of DA before or after the drying processes. The good disintegration property of the prepared tablets was related to the excellent wettability of the ingredients after being subjected to the drying processes. Results also showed that the addition of DA to the tablet bases before drying process results in lengthening of the disintegration time in comparison to their addition to the tablet bases after the drying process. These findings could be utilized for many
drugs and they may be considered versatile in the applications. Also, the disintegration of the ODT in the buccal cavity may favor fast absorption via the mucus membrane in the oral cavity.
Key words: Spray drying, Freeze drying, Orally disintegration tablet, Metoclopramide, Disintegration accelerators, Dissolution rate, Super-disintegrants.
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
EVALUATION OF SPRAY AND FREEZE DRIED EXCIPIENT BASES 119
Introduction
Recent advances in drug delivery systems seek enhancing the safety and efficacy of drug molecules by formulating them in conveniently administrated dosage forms (1). Dysphagia, difficult in swallow-wing, is common among all age groups and it is experienced by patients such as pediatric, geriatric, bedridden and disabled patients (2). The most common complaint about the difficulty in swallow-wing of tablets is their large sizes (3). Therefore, improving the compliance and quality of life of such patients by using orally-fast disintegrating tablet is a promising alternative to conventional tablets (4).
During the last decade, great deal of attention has been drawn to orally disintegrating tablet (ODT) technologies that make such tablets disintegrate in the mouth without chewing or additional water intake (5). These tablets disintegrate into smaller granules or melt in the mouth from a hard rigid solid to a gel like structure, allowing easy swallowing by patients. The saliva of patients (1-2 ml) is the dissolving medium and it would be enough to disintegrate these tablets (4).
Orally disintegrating tablets (ODT) have been reported to be prepared by different technologies including molding, sublimation, direct compression, wet granulation, freeze drying and spray drying (6). So far there have been many patents for ODT, but only few publications are dealing with this dosage form (7). Spray drying (SD) and freeze drying (FD) are considered novel techniques to prepare excipients for ODT. SD technique provides a fast and economic way of evaporating solvents, subse-quent drying and producing highly amorphous spherical, fine powders suitable for ODT (8). On the other hand, FD; lyophilization, is a process in which the solvent is sublimed from a frozen drug solution or suspension containing structure-forming excipi-ents. Glassy amorphous porous structure of excipi-ents as well as the drug substance produced with FD leading to the enhancing of dissolution (9). In the literature, there is no study comparing between SD and FD as techniques in the efficiency of preparation of ODT bases. In addition, there is lack of information about the effect of SD and FD
techniques on the efficiency of disintegration accele-rators (DA).
The aim of the present study was to formulate
ODT with sufficient mechanical strength and fast
disintegration from bases prepared by both SD and FD techniques. Different disintegration accelerators (DA) were also utilized to prepare the proper ODT using various super-disintegrants (Ac-Di-Sol, Kollidon and sodium starch glycolate), a volatile solvent (ethanol) and an amino acid (glycine).
Metoclopramide, an antiemetic medication, was used in the present study as a model drug. It is administrated by group of patients who have motion sickness (10) and may not have an access to water at the time of administration. Examples of these patients are aeroplane passengers and pregnant women during walking. In the light of that, metoclopramide is a good candidate for ODT and formulating it in ODT is beneficial for certain patients.
Materials and Methods
Materials:
Metoclopramide and glycine were purchased from Sigma (USA). Crosslinked sodium carboxy-methyl cellulose (Ac-Di-Sol), sodium starch glycol-late (SSG), and Kollidon CL (crosslinked polyvinyl pyrrolidone) were kindly donated from Al-Jazerah Pharm. Ind. (Riyadh, Saudi Arabia). All other chemicals and solvents used were of pharmaceutical grades.
Methods
A. Preparation of spray-dried tablet bases:
Tablet bases, composed of microcrystalline cellulose, mannitol, saccharine and DA (Table 1), were suspended in deionized water and then heated to 40 oC bending to SD process. All batches of suspension bases were spray-dried using Buchi 190 mini spray drier (Büchi Labortechnik AG, Germany) with 0.5mm nozzle. The suspension bases were fed to the nozzle via peristaltic pump (spray flow rate of 12 ml/min.). The suspension was sprayed as atomized droplets by the force of the compressed air
(air flow rate of 4 pound per square inch). The solvent in the droplets was evaporated in the drying chamber by the blown hot air (inlet air temperature of 135 oC and outlet air temperature of 70 oC). The dried tablet bases were collected in collection vessel and stored at room temperature for further manipulation.
B. Preparation of freeze-dried tablet bases:
The tablet bases, composed of microcrystalline cellulose (MCC), mannitol, saccharine and DA (Table 1), were suspended in deionized water and the suspensions were heated to 40 o C. Suspension bases were pre-cooled (-5 o C) prior to FD. The frozen bases were lyophilized using freeze dryer (ALPHA 1-4LD-2, Martin Christ, Osterode, Ger-many) under the following conditions (temperature = -59, vacuum = 0.001 mp) for 48 hrs. The dried bases were collected and transferred to well-closed containers and stored at room temperature (25 o C) bending to evaluation and formulation experiments.
C. Particle size analysis of the prepared tablet bases:
The samples were dispersed in liquid paraffin (1 mg/ 1 ml) and mounted on microscopic slides. Particle diameters of the bases were measured using Reichert Microscope (Depew, NY, USA) and using eyepiece of magnification of 40X. The microscope is equipped with a special projection system connected to the eyepiece which allows the measurement on the surface of the projection screen. The readings were measured in millimeter and converted to micrometer using the microscope provided equation [diameter (mm) = measurement in mm X (1000/ magnification power)]. The diameters measured are number parameters (i.e. numbers distribution) (11). The mean particle diameters were the average of at least 100 particles.
D. Measurement of Angle of repose of the prepared tablet bases:
The angle of repose was measured for the SD and FD bases, so as to observe the flow properties of such bases. The method employed a funnel secured with its tip at a given height (H), above the graph paper placed on horizontal surface. Treated base powders were poured through the funnel until the apex of conical pile touched the tip of the funnel. The angle of repose was calculated using the following formula, tan a = H/R where a is the angle of repose and R is the radius of conical pile (12). The angle of repose was calculated as the mean of three determinations.
E. Determination of moisture content of the prepared tablet bases:
Weight loss on drying was determined using a Mettler moisture balance (Meltter PM 480 Delta Range, Switzerland). Five gms of each prepared base powder was put in the pan of the balance. Heating temperature was set at 100 oC and the time mode was set at 30 seconds which means continuous heating of the sample after removal of the free water content for the 30 seconds (13). The percentage moisture content was directly recorded. The test was carried out on triplicate for each base and the mean values were considered.
F. Determination of bulk density and compressibility of the prepared tablet bases:
The bulk density was determined by filling the processed base powders into a tarred graduated cylinder to the 100 ml mark. The graduated cylinder was weighed and the bulk density (VB) was calculated as the ratio of the sample weight to the sample volume (14). The graduated cylinders were then tapped (for 3 mins which was found practically to be enough time) from a height of about 2 inches till constant volume was obtained. The tap density (VT) was calculated as the ratio of the sample weight to the final sample volume. The trial was carried out on triplicate and the mean values were calculated. Carr’s Index and Hausner factor were calculated for the prepared ODT bases as evaluation parameters for compressibility (15). The changes occurring in packing arrangement during the tapping procedure were expressed as Carr’s Index (I) as shown by the following equation , I = [( 1- VB)/ VT] X 100. Hausner factor (HF) was calculated from the following equation, HF = VT/ VB.
G. Scanning electron microscopic (SEM) examination for the prepared bases:
SD and FD tablet base morphologies were examined under the scanning electron microscope (Jeol, JSM-6360LV scanning microscope, Tokyo, Japan). Before microscopy, the base powders were mounted at carbon tape and were sputter-coated using gold (Jeol, JFC-1100 fine coat ion sputter, Tokyo, Japan). The photomicrographs were taken at an acceleration voltage of 20 kV (16).
H. Preparation of ODT by direct compression technique:
The ODT were prepared using the SD and FD processed bases after the addition of metoclopramide and sodium stearyl fumarate (SSF), (Table 1). The tablet constituents were weighed and mixed first in the mortar (triturating) and mixed furtherly in tubula mixer (Erweka S27, Frankfort, Germany) for 2 mins which was found practically as the efficient mixing time. The tablet ingredients after mixing were compressed by EKO single punch tablet machine (Korsch, Berlin, Germany) using punch 0.6 cm in diameter and weighing 110 mg.
I. Determination of the prepared ODT hardness:
The hardness of the ODT was measured using Erweka TBH-28 hardness tester (Frankfort, Ger-many). Hardness is the breaking strength value of the tablet reported in kilograms (12). Minimum of six tablets were used and the mean value was considered.
J. Determination of the prepared ODT friability:
Friability (f) of the tablets was determined using Erweka TA3R friabilitor (Frankfort, Germany) at 25 rpm/min for 4 min. The tablets were weighed and loss in weight (%) was calculated (17). Twenty tablets were used in such determination.
K. Determination of wetting time for the prepared ODT:
Wetting time was determined by the method described previously (18). In brief, a piece of tissue paper folded twice was placed in small culture dish (internal diameter = 6.5 cm) containing 6 ml of water. Then, the tablet was placed on the wetted paper and the time for complete wetting was calculated. The test was carried out on triplicate and the mean value was considered.
L. Measurement of disintegration time for the prepared ODT:
Disintegration time was determined using USP disintegration test apparatus (Erweka ZT4, Frankfort, Germany) without disk for six tablets. The disintegration medium was 900 ml of distilled water kept at 37 ± 0.5 oC and stirred at a rate of 30 ± 2 cycles/ min (13).
M. Measurement of in vitro drug dissolution from the prepared ODT:
The dissolution measurements were performed
using USP dissolution apparatus II (Caleva Ltd., Model 85T, Philips, UK) adopting a continuous automated monitoring system which consists of an IBM computer PS 830 series and PU 860/60 dissolution test software, Philips VIS/UV single beam, six cells, spectrophotometer model PU 8620, Epson FX 850 printer, and Waston-Marlow peristaltic pump. In each flask, 1 L of distilled water was used as the dissolution medium (USP 23). The temperature was maintained at 37 ± 0.5 oC and paddles speed was kept at 50 rpm. Percent drug dissolution was determined at specified time intervals by assaying the collected samples spectrophotometerically for drug content at 308 nm (19). It was found that all additives included in the tablet formulation didn’t interfere with the spectrophotometric assay of the drug. The dissolution studies were carried out in triplicate. The time required for 50% of the drug to be dissolved (T50 %) was calculated graphically (16) which was used as a comparison parameter in drug dissolution evaluation. Relative dissolution rate (RDR) was obtained by dividing the dissolution percent of the drug in the specific formula at the determined time by the dissolution percent of the pure drug which processed under the same condition (SD and FD) at the same time. Dissolution efficiency (DE) is defined as the area under dissolution curve up to the time (t) which was expressed as a percentage of the area of the rectangular described by 100 % dissolution in the same time (10).
N. Statistical analysis of the obtained results:
One-way analysis of variance (ANOVA) and t-test were performed using Statgraphics plus 2 software to compare the mean values for all formulations. Multiple Range Test (Fisher’s least significant difference procedure, LSD) was also used to determine which means are significantly different from the others. The level of confidence was set to be 95% (20).
Results and Discussions
SD technique yielded spherical particles as shown in Fig 1. However, in case of FD technique the products were in the form of spongy matrices with very porous structures. Exception to these findings is in case of glycine, SD powder is not spherical but tubular like structure (Fig 2: SD-F). It was also observed that SD powder containing SSG is spherical in shape (Fig 2: SD-B2), yet their base surface is not smooth like the rest of super-disintegrants (Fig 1: SD-B1 and SD-B3). This surface is composed of small tubular particles joined together to form bigger spherical particles. This could be because SSG may adsorb water during its presence in the sprayed suspension which results in resistance in water removal by SD due to SSG high water affinity. This finding can be also supported by the data obtained from the moisture content (Table 2) in which SSG has the highest moisture content (1.8 %) compared to other SD bases. It worth mentioning that the particle morphology, structure and shape of these bases affect their compressibility