Evaluation of floating floting tablets

                 Various parameters17 that need to be evaluated in gastro-retentive formulations include floating duration, dissolution profiles, specific gravity, content uniformity, hardness, and friability in case of solid dosage forms. In the case of multiparticulate drug delivery systems, differential scanning calorimetry (DSC), particle size analysis, flow properties, surface morphology, and mechanical properties are also performed.

A) Floating Ability and Dissolution Test
                  The tests for floating ability (Table 2) and drug release are generally performed in simulated gastric fluids at 37ºC.
Table 2. In Vitro Floating and Dissolution Performance
Drug (Polymer Used)    Floating Media/Dissolution Medium and Method    Ref
Pentoxyfillin
(HPMC K4 M)    500 mL of artificial gastric fluid pH 1.2 (without pepsin) at 100 rpm using USP XXIII dissolution apparatus. The time taken by the tablet to emerge on the water surface (floating lag time) and time until it floats on water surface was measured.

Amoxicillin beads
(Calcium alginate)    For dissolution: 900 mL of deaerated 0.1 M HCl (pH 1.2) at 37ºC ± 1ºC in USP XXII dissolution tester at 50 rpm.

Ketoprofen
(Eudragit S100
Eudragit RL)    20 mL of simulated gastric fluid without pepsin, 50 mg of floating microparticles in 50-mL beakers were shaken horizontally in a water bath.
% age of floating micro particles was calculated.
For dissolution: 900 mL of either 0.1 N HCl or the phosphate buffer (pH 6.8) at 37ºC ± 0.1ºC in USP dissolution apparatus (I) at 100 rpm.    49

Verapamil
(Propylene foam, Eudragit RS,
ethyl cellulose, poly methyl meth acrylate)    30 mL of 0.1 N HCl (containing 0.02% wt/wt Tween 20), pH 1.2. Floatation was studied by placing 60 particles into 30-mL glass flasks. Number of settled particles was counted.

Captopril
(Methocel K4M)    900 mL of enzyme-free 0.1 N HCl (pH 1.2) in USP XXIII apparatus II (basket method) at 37ºC at 75 rpm. 

Theophylline
(HPMC K4M,
Polyethylene oxide)    0.1 N HCl in USP XXIII Apparatus II at 50 rpm at 37°C.
Its buoyancy to upper 1/3 of dissolution vessel was measured for each batch of tablet.  

Furosemide
(β Cyclodextrin, HPMC 4000, HPMC 100,CMC, Polyethylene glycol)    For dissolution: continuous flow through cell gastric fluid of pH 1.2, 45–50 m N/m by adding 0.02% Polysorbate 20 (to reduce the surface tension), the flow rate to provide the sink conditions was 9mL/min.    32

Aspirin, Griseofulvin,
p-Nitro Aniline
(polycarbonate, PVA)    For dissolution: 500 mL of simulated gastric and intestinal fluid in 1000-mL Erlenmeyer flask. Flasks were shaken in a bath incubator at 37ºC. 

Piroxicam (microspheres)
(Polycarbonate)    For dissolution: 900 mL dissolution medium in USP paddle type apparatus at 37ºC at 100 rpm. 

Ampicillin
(Sodium alginate)    For dissolution: 500 mL of distilled water, JP XII disintegration test medium No.1 (pH 1.2) and No.2 (pH 6.8) in JP XII dissolution apparatus with paddle stirrer at 50 rpm.  

Diclofenac
(HPC-L)    An aliquot of 0.1 g of granules was immersed in 40 mL of purified water in a vessel at 37°C. Dried granules were weighed and floating percentage of granules was calculated.
For dissolution: flow sampling system (dissolution tester: DT-300, triple flow cell) followed by 900 mL of distilled water in JP XII with paddles at 37 ºC ± 0.5ºC at 100 rpm.  

Sulphiride
(CP 934P)    For dissolution: 500 mL of each JP XII disintegration test medium No. 1 (pH 1.2) and No. 2 (pH 6.8) in JP XII dissolution apparatus at 37º C at 100 rpm.  

Amoxicillin trihydrate
(HPC)    For dissolution: 500–1000 mL (adequate to ensure sink conditions) of citrate/phosphate buffer of variable pH or solution of HCl (pH 1.2) in Erweka DT 6 dissolution tester fitted with paddles. 

Ibuprofen, Tranilast
(Eudragit S)    For dissolution: 900 mL dissolution medium (disintegration test medium No. 1 (pH 1.2) and No. 2 (pH 6.8) as specified in JP XI and as corresponding to USP XXI, paddle method at 37ºC at 100 rpm.

Isardipine
(HPMC)    For dissolution: Method 1:
300 mL of artificial gastric fluid in a beaker, which was suspended in water bath at 37ºC agitated by magnetic stirrer and by bubbling CO2 free air.
Method 2:
500/1000 mL of 0.1 M HCl and surfactant lauryl sulfate dimethyl ammonium oxide with rotating paddle at 50 rpm.

Potassium chloride
(Metolose S.M. 100, PVP)    For dissolution: tablet was mounted onto the perspex holder except one face of the matrix was set flush with one face of the holder at 37ºC and the other face of the tablet was prevented from the dissolution media by a rubber closure; good mixing was maintained in the receiver by a magnetic stirrer at 100 rpm.

Verapamil
(HPC-H, HPC-M, HPMC K15)    For dissolution: water in USP XXIII dissolution apparatus (method II) at 50 rpm.

PABA
(Ethyl cellulose
HPC-L)    70 mL of 50 mM acetate buffer with various pH (1–5) or viscosity (25–115 cps) in a 100-mL beaker at 37°C, 100 rpm.
% age of floating pills was calculated.
For dissolution: 50 mM acetate buffer (pH 4) in JP XI dissolution tester with paddles at 37ºC at 100 rpm.

Tetracycline, metronidazole, bismuth salt
(Polyox, HPMC K4)    900 mL of 0.1 M HCl (pH 1.8) in USP dissolution apparatus at 50 rpm. The duration of floatation was observed visually.    30

Tranilast
(Acrylic polymer, Eudragit RS)    Microballoons were introduced into 900 mL of disintegrating fluid solution no 1 (pH 1.2) containing Tween 20 (0.02% wt/vol) in USP XXII apparatus at 100 rpm . Percentage buoyancy was calculated.

Sotalol    Lag time required for the tablet to start floating on the top of the basket in dissolution apparatus was measured 

Furosemide    Tablet were placed in a 400-mL flask at pH 1.2 and both the time needed to go upward and float on surface of the fluid and floating duration were determined.    31

Calcium carbonate
(HPMC K4M, E4 M and Carbopol)    A continuous floating monitoring system was conceived. The upward floating force could be measured by the balance and the data transmitted to an online computer.
Test medium used was 900 mL simulated gastric fluid (pH 1.2) at 37ºC.  

Timmermans and Andre18 characterized the buoyancy capability of floating forms and sinking of nonfloating dosage forms using an apparatus to quantitatively measure the total force acting vertically on the immersed object. It was given by the vectorial sum of buoyancy F(b) and gravitational forces F(g) acting on the test object.
F   =   F ( b )   -   F ( g )     (1)
Equation 1 can be rewritten as,
F   =   ( d f   -   d s )   g V   =   ( d f   -   W / V )   g V     (2)
Where F is the resultant weight of the object, df and ds represent the fluid density and solid object density, g is the acceleration due to gravity and W and V are the weight and volume of the test objects. It can be seen from Equation 2 that if the resultant weight is more positive, better floating is exhibited by the object.
Li et al33,34 invented an online continuous floating monitoring system that was a modification of the system described by Timmermans and Andre.18 It was used to provide quantitative measurement of resultant floating force. The set-up consisted of an analytical balance connected with a computer. A tablets was inserted into the sample holder basket and the holder was immersed into the test medium (900 mL of simulated gastric fluid). A typical floating kinetic curve was obtained by plotting floating force vs time and 4 parameters were used to describe the floating properties of the capsules from this graph: F max, T max, Fr, and AUC f . Similar to Equation 2 conceived by Timmermans and Andre18 the overall force that the tablets is subjected can be given by
F   =   ( ρ m   -   ρ c )   g   V c     (3)
where ρm and ρc are the density of floating media and test object and Vc is the volume of the test object. In this equation, 2 parameters, ρc and Vc, are important for overall floating force. During the measurement of buoyancy, Vc increased due to swelling of polymer and ρc increased due to water uptake. This increase led to an upward rise in floating force curve, which reached a maximum (Fmax) and declined until an equilibrium was reached.
                     Table 2 gives dissolution tests generally performed using USP dissolution apparatus. USP 28 states “the dosage unit is allowed to sink to the bottom of the vessel before rotation of the blade is started. A small, loose piece of nonreactive material with not more than a few turns of a wire helix may be attached to the dosage units that would otherwise float.78 However standard USP or BP methods have not been shown to be reliable predictors of in vitro performance of floating dosage forms.24 Pillay and Fassihi79 applied a helical wire sinker to the swellable floating system of theophylline, which is sparingly soluble in water and concluded that the swelling of the system was inhibited by the wire helix and the drug release also slowed down. To overcome this limitation a method was developed in which the floating tablet was fully submerged under a ring or mesh assembly and an increase in drug release was observed. Also, it was shown that the method was more reproducible and consistent. However no significant change in the drug release was observed when the proposed method was applied to a swellable floating system of diltiazem, which is a highly water-soluble drug. It was thus concluded that the drug release from swellable floating systems was dependent upon uninhibited swelling, surface exposure, and the solubility of the drug in water.

B) Surface Morphology
                   Surface morphology was observed by SEM, which serves to confirm qualitatively a physical observation relating to surface area. In preparation of SEM analysis, the sample was exposed to high vacuum during the gold-coating process, which was needed to make the sample conductive.

C) Particle size
Sakuma et al81 prepared radiolabeled anionic poly metha acrylic acid nanoparticles and the particle size of nonlabeleled nanoparticles was measured by dynamic spectrophotometry.

D) In vivo gastric residence time
In vivo gastric residence time of a floating dosage form is determined by X-ray diffraction studies, gamma scintigraphy,22 or roentgenography
 In Vivo Evaluation
Drug (Polymer)    Method    Ref
Tranilast
(Eudragit S (BaSo4))    Two healthy male volunteers administered hard gelatin capsules packed with microballons (1000 mg) with 100 mL water. X-ray photographs at suitable intervals were taken.

Isardipine
(HPMC)    Two phases:
Phase I (fasted conditions):
Five healthy volunteers (3 males and 2 females) in an open randomized crossover design, capsules ingested in sitting position with 100 mL of tap water.
Phase II (fed states):
Four subjects received normal or MR capsules in a crossover design after standard breakfast.
Venous blood samples were taken in heparinized tubes at predetermined time intervals after dosing.  

PABA+ Isosorbide dinitrate    Six healthy beagle dogs fasted overnight, then administered with capsules with 50 mL of water at 30 minutes after the meal.
Control study: same amount of control pills without the effervescent layer were administered in the same protocol.
The experimental design:
Crossover design, 1-week washout time, plasma samples were taken by repeated venipuncture at upper part of the leg.

Hydrogel composites    Dogs (50 lbs) kept fasted and fed conditions.
In each experiment (fed or fasted) 300 mL of water was given before administration of the capsules; X-ray pictures were taken.  

Amoxycillin trihydrate    Six healthy fasted male subjects were selected; serum drug levels were compared in a single-dose crossover study following administration of tablets/capsules.

Floating beads    Gamma scintigraphy:
In vivo behavior of coated and uncoated beads was monitored using a single channel analyzing study in 12 healthy human volunteers of mean age 34 yrs (22–49).

Pentoxyfillin    Four healthy beagle dogs (fasted for 24 hours). Tablet was administered with 100 mL of water for radiographic imaging. The animal was positioned in a right lateral/ventrodorsal recumbency.

Furosemide    Six purebred young male beagle dogs (9.6 to 14.3 kg), a 4-period crossover study balanced by residual effects was employed.
Dogs were fasted overnight (water ad libitum), a catheter was inserted into right and left cephalic vein with 0.3 mL heparin lock, blood sampling was done at appropriate intervals.   

Polystyrene nanoparticles    Dosing solution was administered to male SD strain rats fasted overnight
The radioactivity was measured with a gamma counter or a β counter (small intestine was cut into 10-cm portions).  

Piroxicam    Nine healthy male albino rabbits weighing 2.2–2.5 kg were divided into 3 groups and were fasted for 24 hours.
First batch: fed with 20 mg of Piroxicam powder in a gelatin capsule.
Second batch: 67% piroxicam loaded piroxicam microspheres (~20mg of drug).
Third batch: 7 mg of piroxicam and 67% piroxicam-loaded piroxicam microspheres (~20 mg of drug). 

Calcium alginate multiple units floating beads    Seven healthy males (21–55 years). After fasting from midnight the night before the subjects consumed cereal (30 g) with milk (150 ml) to which was added ~20 Ci .99 m Tc-DTPA?
An anterior image of stomach was obtained with γ camera.
Static 120-second anterior images were acquired at suitable intervals and subjects remained standing/sitting for the duration of the study.

Furosemide    Six healthy males (60–71 kg) aged between 25 and 32 years for X-ray detection. Labeled tablets were given to subjects with 200 mL of water after a light breakfast, following ingestion. Gastric radiography revealed the duration for which the tablet stayed in stomach was determined.

Sulphiride    Three 3.5-kg white male rabbits
10 mg of the drug/kg body weight was administered in a crossover manner with a 14-day washout period between dosing.
Both IV and oral dosage form were given.