Over the years, various techniques and formulations have been employed to enhance the bioavailability of drugs without disturbing patient acceptability and compliance.[1,2]
The gastrointestinal tract continued to be the major and most common route of drug entry to the systemic circula-tion.[3,4] However, a delay in the onset time might happen to drugs taken orally due to interpersonal variation in the gastric emptying, creating a lag time between adminis-tration and onset of intestinal absorption.[5]Moreover the blood that drains from the gastro intestinal tract (GIT) goes directly to the liver giving chance to many drugs to lose some to most of their bioavailability if swallowed by this route due to first-pass metabolism.[6–8]
Currently there was a growing interest to use other administration routes where rapid and effective drug absorption occurs.[9]
Many drugs were successfully formulated and absorbed through the mucosal cells of the oral cavity, mainly by the buccal or sublingual mucosa.[10–12]
Both absorption sites share common benefits includ-ing rapid onset of action with increased blood levels. Furthermore, drugs are protected from the hostile envi-ronment of the GIT, bypass first-pass effect and hence save their bioavailability.[9,13]
Among the different pharmaceutical forms that were found applicable in the oral cavity,[14–18] rapidly disintegrating tablets continued to gain much popularity and clinical usefulness among patients,[19–22] especially with children and elderly who experience problems in swallowing.
Metoclopramide hydrochloride (MH) is an antido-paminergic and gastrointestinal stimulant that exerts antiemetic properties through antagonism of central and peripheral dopamine receptors. Onset time was found to be between 30 and 60 min after oral tablet intake.[23]
ReseaRch aRtIcle
Zero-order release profile of metoclopramide hydrochloride sublingual tablet formulation
Randa Latif
1Department of Pharmaceutics, Faculty of Pharmacy, Cairo University, Egypt
abstractThis report describes zero-order approximation for metoclopramide hydrochloride sublingual tablet formulation. Effects of type and concentration of excipients on release were investigated. Study revealed that highest rate of dissolution was attained with crosspovidone and decreased in the order crosspovidone > sodium starch glycolate > ac-di-sol. All formulations demonstrated flush release, except the one containing 10% crosspovidone where a lag time of 0.5 min. was depicted. Increasing the concentration of crosspovidone from 5 to 10% gave the same half-life, whereas kinetics of release changed to zero order. Differential scanning colorimetry and infrared spectroscopy did not reveal any sign of physical or chemical interaction between drug and crosspovidone. In order to study the alignment of polymeric network inside tablet matrix, scanning electron microscopy was performed on the tablet and its cross-section. Matrix with 10% crosspovidone showed higher density of interconnections extending to the interior of core enabling fast and constant release. Hence physicochemical characteristics of crosspovidone could be tailored by varying its concentration, in a way that provided a porous matrix with tight arrangement of polymeric chains, resembling to an assemblage of cylinders with constant apertures, from which zero-order release was approached.
Address for Correspondence: Dr. Randa Latif, Faculty of Pharmacy, Department of Pharmaceutics, Cairo University, 47 Maamal El Alban Street, Khalafawi, Shoubra 11241, Egypt. Tel: +20 1222863930/+20 222022299. E-mail: [email protected]
(Received 16 May 2012; revised 07 July 2012; accepted 23 July 2012)
Zero-order release profile of metoclopramide hydrochlride sublingual tablet formulation
R. Latif
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2 R. Latif
Pharmaceutical Development and Technology
Attempting to decrease onset time by proper optimi-zation of the formulation parameters would be benefi-cial especially in case of critical situations with patients receiving anticancer drugs or those suffering from severe dehydration.
Beside, it is noteworthy that ideal delivery of drugs would follow zero-order kinetics, so that blood level of drugs could be maintained constant throughout the delivery period. This concept was mostly applicable in controlled delivery devices, where gradual release of can-didate drug overtime would be done at constant rate.[24–26]
The new objective of our present work was to design a sublingual tablet formulation of MH, possessing both fast and constant zero-order release profile, through proper optimization of different formulation excipients.
Materials and methods
MaterialsDisodium hydrogen phosphate, dihydrogen
potassium phosphate, and magnesium stearate (Adwic Co., Cairo, Egypt)
Crosscarmelose sodium (ac-di-sol) type SD-711 (FMC Corporation, Philadelphia, PA)
Glycolys, pearlitol flash and mannitol BP (Roquette, France)
MH was kindly supplied from Cid Pharmaceutical Co. (Guiza, Egypt)
MethodsPreparation of tabletsSeven formulations F1 to F7 containing each 10 mg MH along with different types & percent of excipients were directly compressed using a single punch tablet press (KorschEK0, Germany) using 6 mm flat level edged punch. A moderate compression force (3–5 KN) was applied so as to provide a constant value for hardness (~3 kg) for all tested formulae (measured with Monsanto hardness tester). The total weight of the compressed tab-lets was maintained at 80 mg.
Evaluation of tablet characteristicsFriabilityThe friability of tablets was measured according to the USP methods & criteria.[27] Tablets were weighed before and after the measurement and the weight loss was cal-culated. Results were mean of four determinations.
Weight variationWeight of tablets was determined according to USP spec-ifications,[28] where the mean weight of 20 tablets (±SD) was calculated.
Content uniformityEach tablet was crushed and then dissolved in buffer pH 6.8 by the aid of magnetic stirring (Pierce, Rokford).The content of MH was then assayed spectrophoto-metrically at wave length of 272 nm using a Shimazu UV-160 V ultraviolet/visible spectrophotometer (Shima Corp, Tokyo, Japan). Results were mean of six determi-nations (±SD) for each formulation.
Disintegration timeA simple method for determination of disintegra-tion time (DT) of sublingual tablets was performed according to Rawas Qalajii et al. in two successive publications.[29,30]where in brief; each tablet was dropped into a 10-ml glass test tube filled with 2 ml distilled water. The time required for complete tablet disintegration (i.e completely dispersed fragments were obtained) was observed and recorded with a stop wash. The test tube was gently rotated at 45° during the visual inspection. Results were mean of six determina-tions (±SD).
Wetting timeBy a slight deviation from the method reported by Schiermeier et al.,[31] wetting time of tablets was mea-sured by a rather simple and discriminating procedure such that each tablet was placed in a circular glass petri dish. By the aid of a dropper, one drop of methelyne blue solution was allowed to fall on the center of the tablet. The spreading of the dye was visually observed and the time for complete propagation of the dye at the upper surface of the tablet was recorded with a stop wash. Results were expressed as mean of ten determi-nations (±SD).
Water absorption ratioTablets were weighed before and after wetting procedure. Water absorption ratio was determined according to the following equation:
R w w= 100 ( )wa b b− /
were wb and w
a are the weight before and after water
absorption, respectively.[32–34]
In vitro release studyThe release study was carried out using USP dissolution apparatus ll at a rotation speed of 50 rpm.[35]The dissolu-tion medium was phosphate buffer pH 6.8 (300 ml)[36,37] equilibrated at 37°. Samples were withdrawn at suitable time intervals and determined spectrophotometrically at 272 nm. Each experiment was performed in triplicate. The mean and SD were calculated.
Kinetic analysis of release dataKinetic analysis was performed using linear regression analysis, adopting models for zero order, first order, and Higuchi diffusion model.
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Zero-order release profile of metoclopramide hydrochlride sublingual tablet formulation 3
Differential scanning colorimetryThe possibility of interaction and/or complexation between CP and MH was studied using differential scanning colorimetry (DSC) (DSC- 60, Shimazu, Kyoto). Physical mixtures of drug and CP at two predetermined weight ratios viz: 1:0.8 (F5) and 1:0.4 (F6) along with drug and CP alone were sealed each in an aluminum pan. The samples were heated at 10°C/min to 250°C.
FTIR analysisInfrared (IR) spectra was recorded for MH and CP alone besides a physical mixture of drug and CP at ratios equiv-alent to that present in F5 and F6 with a FT-IR spectro-photometer (Perkin Elmer Co, CA, USA). Samples were scanned from 500 to 4000 cm−1.
SEM analysisThe surface topography of tablet formulations (F5 & F6) before and after wetting as well as a cross section in
tablet matrix was studied by SEM (Jeol Ltd, Tokyo, Japan). Samples were sputter- coated with a layer of Au under argon atmosphere, 20 kV acceleration voltages was used.
Results and discussion
Disintegration timeValues for disintegration time of tested formulae ranged between 1.16 and 1.51 min with an average (Av) of 1.28 ± 0.12 min. (Figure 1). This could ensure the suit-ability of all tested superdisintegratants for sublingual application. However, different types and percent of excipients contributed differently in the extent and rate of drug dissolution from tablet formulations. Therefore, discrimination was performed on the light of the calcu-lated dissolution rate constants.
Wetting timeFive percent Glycolys (F7) in tablet formulations gave the fastest wetting time if compared with ac-di-sol and CP at the same tested concentration (Table 2). The addi-tional amount of mannitol present in F7 might be the cause of enhanced wetting. It was also remarkable that for ac-di-sol and Cp, complete wetting of tablet surface was accelerated by the increase in the percent of added superdisintegratant. This could be reasonable due to their well known strong hydration capacity. Affinity to drag water into their porous structure was enhanced with increase in concentration, thereby allowing water to spread and absorb more rapidly into tablet matrix. However, 10% CP was superior to the same concentra-tion of ac-di-sol in fastening the wetting of tablet prob-ably due to less swelling energy and hence easier water uptake (Table 1 and Figure 2).
Figure 1. Disintegration time for tablet formulae. (See colour version of this figure online at www.informahealthcare.com/phd)
Table 1. Physicochemical characteristics of tablet formulations.Formula Code Weight %a %Friabilitya Disintegration time (min, s) Wetting time (min, s) Water absorption ratio Drug contentb
Friability percentThe use of mannitol in formulations might be accused for poor tablet cohesion (Table 1). Addition of 1% of the latter in formulae (F2, F3, and F6) (Table 2) caused a significant increase in percent friability if compared to F1 devoid of mannitol. The use of 45% Pearlitol flash in F7 resulted in the highest record. On the other hand, the good compac-tion property of cross povidone and ac-di-sol seemed to overshadow the effect of added mannitol. This was elu-cidated by a less friability percent upon increasing the
concentration of the two latters to 10% of tablet weight (F4 and F5, respectively).
In vitro release studyKinetic treatment of release data (Table 3 and Figure 3) revealed that tablet formulation (F
1) containing only MCC
and HPC had the lowest release rate constant. This was reflected on dissolution half-life which showed the high-est value (~16 min.). Hence, MCC & HPC alone were not sufficient to attain the goal for a fast release sublingual tablet.
Addition of 1% mannitol to the formulation (F2)
caused a slight decrease in t1/2 to 9 min. Being an osmotic diuretic,[38] mannitol might drag more effec-tively dissolution medium inside the tablet, where it dissolved first, leaving behind a porous matrix with more channels. Faster disintegration with subse-quent drug dissolution occurred in consequence. Furthermore, the facilitated inward diffusion of dis-solution medium caused an amount of drug (5%) to dissolve from the surface layer of tablet matrix giving a higher percent of flush release than that present in F1 devoid of mannitol.
For more enhancement of drug release rate, ac-di-sol was added in formulations F
3 and F
4 in concentrations, 5
and 10%, respectively. Although a slight fastening in t1/2 occurred to 5.6 min in F
3, doubling the % of the excipi-
ent did not further enhance the rate of drug release. This might be interpreted on the light of the dual action of the added excipient on drug disintegration and dissolution. The well known fibrous nature of ac-di-sol might cause a water wicking effect that pulled aqueous medium into the core of the tablet thereby enabling faster drug dissolution. Its cross linked chemical structure created an insoluble hydrophilic and highly adsorbent matrix, which upon swelling to many times its original volume caused a rapid disintegration of tablet with subsequent outer release of the drug included.[39] Therefore, the enhancing in rate of drug dissolution was partially limited by the swelling capacity of ac-di-sol, that might attain equilibrium at the lower concentration used.
On the other hand, drug release at zero time (flush release) increased from 0.4 to about 1.9 mg% by increasing the % of ac-di-sol from 5 to 10%, respectively (Table 3). This
Figure 2. Photomicrograph of tablet formulation (F5) before (a) and after (b) wetting with dye. (See colour version of this figure online at www.informahealthcare.com/phd)
Figure 3. Release profile for tablet formulae. (See colour version of this figure online at www.informahealthcare.com/phd)
Figure 4. DSC thermograms for (a) MH, (b) CP, (c) F5, (d) F6 at a rate of 10°C/min. (See colour version of this figure online at www.informahealthcare.com/phd)
Table 3. Kinetic treatment of dissolution data.
Formula Code k
Kinetic order t½ (min)
Y interceptValue Significance
F1 0.0438a first 15.8 1.6873 2.05c
F2 0.0742a first 9.34 1.2706 5.36c
F3 0.124a first 5.59 2.3672 0.43c
F4 0.124a first 5.59 1.7254 1.88c
F5 58.69b zero 0.9 -34.003 0.57d
F6 0.846a first 0.819 2.4189 0.38c
F7 0.165a first 4.21 1.9102 1.23c
aUnits for k are min−1.bUnits for k are mg/min.cValues represent flush release at zero time in mg %.dValue represents lag time in min.
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Zero-order release profile of metoclopramide hydrochlride sublingual tablet formulation 5
could be a result of more water uptake into the tablet caus-ing instant drug dissolution from the superficial layers of the matrix before swelling and subsequent disintegration took place.
The addition of 5% CP into the tablet core (F6) resulted in a flush release almost the same as in F3 having 5% ac-di-sol, indicating possible similarity in efficiency of water uptake for the two tested superdisintegrants. However, F6 showed a much faster release as t1/2 dropped from 5.6 min (F3) to 0.8 min. This result could be due to the higher porous nature of CP, creating a matrix from which MH could be released much faster, before disintegration could even be completed.
Increasing the concentration of CP to 10% (F5) did not cause a remarkable variation in t1/2, only a change in drug release mechanism occurred from first to zero-order kinetics (Table 4) accompanied by a disappearance
of flush release and a lag time of 0.57 min. appeared instead.
Attempting to explore a reasonable interpretation for such result, one or more suggestions were expected to influence the change in release kinetics of MH at higher concentration of CP.
• Existence of physical and/or chemical interaction between the drug and excipient, which was concen-tration dependent.
• Contribution of the spacial alignment of polymeric network inside tablet matrix at either concentration studied.
In order to study the first suggestion, DSC and IR spectra were performed for MH, CP each alone and their physical mixture corresponding to weight ratios in F5 and F6. However, according to Figures 4 and 5 no sign of
Table 4. Statistical treatment of dissolution data.
Formula code
Linear regression analysis of dataSlope Y intercept r
Figure 5. IR spectra for optimized tablet formulae.
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6 R. Latif
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chemical or physical interaction between the drug and excipient was revealed.
Second, the spacial alignment of polymeric network inside tablet matrix was elucidated by SEM analysis (Figure 6). Surface topography of tablet at lower CP concentration (F6), showed almost smooth non porous surface. However, increasing the concentration of CP (F5) revealed a significant change, in the form of rough reticulations with occasional pores on the surface. These porous reticulations were extending to the inte-rior of tablet core as shown in the cross-section.
Tablet matrix also showed narrow passages in F6, which were changed to wide interconnected pores at high concentration of the excipient (F5). Furthermore the observed pores became much wider after inward access of dissolution medium into the core.
From the previous observations it could be reasonable to postulate that, inward diffusion of buffer system was facili-tated through such wide interconnected pores, without preliminary dissolution of drug from tablet surface. That’s why flush release was eliminated and instead a lag time appeared. This was equivalent to the time taken by dissolu-tion medium to access tablet core before fast outward drug release was achieved. Furthermore, the alignment of poly-meric network could match with the geometrical model proposed by Landgraf et al.[40] In this model, polymeric structure resembled an infinite number of superimposed cylinders creating almost equal path lengths for the outward emergence of the drug. In such case a constant zero-order
release profile could be approached. The presence of large number of interconnected cavities[41] permitted fast release of the drug from tablet matrix which was completed almost before disintegration went to completion.
conclusion
Polymers possessing highly porous nature like cross povi-done could be helpful in the design of a proper formula-tion. The physicochemical properties of such polymer could be tailored at optimum concentration so as to create a variation in the geometry inside tablet matrix offering a well organized interconnected structure. Release of drug from such assembly could satisfy the goal of the present research being fast and constant zero order with time.
Declaration of interest
The author reports no conflicts of interest. The protocol of the present work was approved by Experiments and Advanced Pharmaceutical Research Unit (EAPRU), Faculty of Pharmacy, Cairo University.
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