INTRODUCTION:
ORAL SOLID DOSAGE FORMS
Most of drug formulations are administered orally by means of solid dosage forms such as tablets and capsules. Preparations of these solid dosage forms require the presence of other additives. These are included in the formulations to facilitate easy handling, enhance the physical appearance, and improve stability and aid in the delivery of the drug to the blood stream after administration.
GASTRO INTESTINAL ADMINISTRATION - THE ORAL ROUTE
Orally administered drug must be absorbed through the gut which depends on number of factors such as, gastric emptying, intestinal motility, mucosal surface area, degradation of drug in the stomach and first pass effect. The absorption rate varies from the stomach to the intestine owing to the increased surface area (about 4500 cm2), the intestinal mucosa and greater velocity of blood (1000 ml/min) through the intestinal capillaries compared to the gastric capillaries.
In the present study development of an enteric coated delayed release dosage form having one of the raft forming ingredient which is used to provide symptom relief from GERD by forming a physical barrier on top of the stomach contents in the form of neutral gel or raft. Proton pump inhibitor is indicated for the treatment of erosive esophagitis.
For centuries, neutralization of gastric acid with antacids provided only relief from the pain of ulcers. Studies of the physiological control of acid secretion demonstrated that anti-cholinergic agents would block this process. The development of an H2 antagonist that acts at H2 histaminergic receptors provided more specific class of inhibitors of gastric acid secretion. More recently the substituted benzimidazole inhibitors of H+ K+-ATPase (Proton pump) offers very effective means of selectively blocking the proton pump that is responsible for acid secretion by parietal cells3.
Gastroesophageal reflux disease, commonly referred to as GERD or acid reflux, is a condition in which the liquid content of the stomach regurgitates (backs up or refluxes) into the esophagus. The liquid can inflame and damage the lining (cause, causeesophagitis) of the esophagus although visible signs of inflammation occur in a minority of patients. The regurgitated liquid usually contains acid and pepsin that are produced by the stomach. (Pepsin is an enzyme that begins the digestion of proteins in the stomach.) The refluxed liquid also may contain bile that has backed-up into the stomach from the duodenum. (The duodenum is the first part of the small intestine that attaches to the stomach.) Acid is believed to be the most injurious component of the refluxed liquid. Pepsin and bile also may injure the esophagus, but their role in the production of esophageal inflammation and damage is not as clear as the role of acid.
GERD is a chronic condition. Once it begins, it usually is life-long. If there is injury to the lining of the esophagus (esophagitis), this also is a chronic condition. Moreover, after the esophagus has healed with treatment and treatment is stopped, the injury will return in most patients within a few months. Once treatment for GERD is begun, therefore, it usually will need to be continued indefinitely although it is argued that in some patients with intermittent symptoms and no esophagitis, treatment can be intermittent and done only during symptomatic periods.
In fact, the reflux of the stomach's liquid contents into the esophagus occurs in most normal individuals. One study found that reflux occurs as frequently in normal individuals as in patients with GERD. In patients with GERD, however, the refluxed liquid contains acid more often, and the acid remains in the esophagus longer. It has also been found that liquid refluxes to a higher level in the esophagus in patients with GERD than normal individuals.
As is often the case, the body has ways (mechanisms) to protect itself from the harmful effects of reflux and acid. For example, most reflux occurs during the day when individuals are upright. In the upright position, the refluxed liquid is more likely to flow back down into the stomach due to the effect of gravity. In addition, while individuals are awake, they repeatedly swallow, whether or not there is reflux. Each swallow carries any refluxed liquid back into the stomach. Finally, the salivary glands in the mouth produce saliva, which contains bicarbonate. With each swallow, bicarbonate-containing saliva travels down the esophagus. The bicarbonate neutralizes the small amount of acid that remains in the esophagus after gravity and swallowing have removed most of the liquid.
Gravity, swallowing, and saliva are important protective mechanisms for the esophagus, but they are effective only when individuals are in the upright position. At night duringsleep, gravity is not in effect, swallowing stops, and the secretion of saliva is reduced. Therefore, reflux that occurs at night is more likely to result in acid remaining in the esophagus longer and causing greater damage to the esophagus.
Certain conditions make a person susceptible to GERD. For example, GERD can be a serious problem during pregnancy. The elevated hormone levels of pregnancy probably cause reflux by lowering the pressure in the lower esophageal sphincter (see below). At the same time, the growing fetus increases the pressure in the abdomen. Both of these effects would be expected to increase reflux. Also, patients with diseases that weaken the esophageal muscles (see below), such as scleroderma or mixed connective tissue diseases, are more prone to develop GERD.
OBJECTIVE:
The stability of Rabeprazole sodium is a function of pH, it is rapidly degraded in acid media, and is more stable under alkaline condition. The degradation is catalyzed by acidic reacting compounds and Proton Pump Inhibitor (PPI) is usually stabilized in mixtures with alkaline reacting compounds. Therefore exposure of drug to the acidic content of the stomach would lead to significant degradation of the drug and hence, reduce bioavailability.
Delayed release dosage form is best formulation which is used for drugs that are destroyed in the gastric fluids, or cause gastric irritation, or are absorbed preferentially in the intestine. Such preparations contain an alkaline core material comprising the active substance, a separating layer and enteric coating layer.
The first aim of present work was to prepare delayed release i.e. enteric coated tablet to prevent degradation in the stomach due to the acidic environment or gastric enzymes and to study the factors affecting the film coating of tablets performed in a perforated pan coater. The second aim of present work was optimization of coating process parameters which implicate more significant effects on tablet coating process.
For the delayed release there is need of enteric coating on the core tablet, but the enteric coating is also an acidic medium. There is need to protect the drug from enteric coating layer, for this one more additional coating (seal coating) is required in between core tablet & enteric coating.
Main objective of the study:
1. Drug-Excipients compatibility studies to identify suitable excipients.
2. Selection of manufacturing formula on the basis of process development and formulation strategy.
3. Stability studies of final batch.
EXPERIMENTAL:
PREFORMULATION STUDIES:
Preformulation studies are the first step in the rational development of dosage form of a drug substance. The objective of preformulation studies are to develop a portfolio of information about the drug substance, so that this information useful to develop formulation. Preformulation can be defined as investigation of physical and chemical properties of drug substance alone and when combined with excipients.
Preformulation investigations are designed to identify those physicochemical properties and excipients that may influence the formulation design, method of manufacture, and pharmacokinetic-biopharmaceutical properties of the resulting product. Followings are the tests carried out for the preformulation study.
Micromeritic properties of API:
1. Organoleptic Characteristics:
The color, odor, and taste of the drug were characterized and recorded using descriptive terminology.
2. Particle Size:
Particle size analysis is done by analytical method or by sieve analysis. In analytical method particle size is measured by Malvern Mastersizer. In sieve analysis standard sieves of different meshes were available as per the specifications of USP; sieves were arranged in a nest with coarser at the top. This sieve set was fixed to the mechanical shaker apparatus and shaken for a certain period of times. The powder retained on each sieve was weighed and percentage of powder retained on each sieve was calculated using the initial weight taken.
3. Solubility of drug:
Add measured volumes of different media at physiological pH to 1 gm of Rabeprazole sodium until it dissolve and produce saturated solution. Calculate the mg of Rabeprazole sodium that goes into per ml of solvent or media. Solubility is carried out at temperature between RT.
4. Bulk Density:
An accurately weighed quantity of powder, which was previously passed through # 40 [USP] and carefully poured into graduated cylinder. Then after pouring the powder into the graduated cylinder the powder bed was made uniform without disturbing. Then the volume was measured directly from the graduation marks on the cylinder as ml. The volume measure was called as the bulk volume and the bulk density is calculated by following formula;
5. Tapped Density:
After measuring the bulk volume the same measuring cylinder was set into tap density apparatus. The tap density apparatus was set to 250 taps per minute and operated for 500 taps. Volume was noted as (Va) and again operated for 750 taps and volume was noted as (Vb). If the difference between Va and Vb not greater than 2% then Vb is consider as final tapped volume. The tapped density is calculated by the following formula;
Carr’s Index [Compressibility Index]:
It is one of the most important parameter to characterize the nature of powders and granules. It can be calculated from the following equation;
Table 1: Interpretation of Carr’s index for powder flow
|
% Compressibility |
Flow ability |
|
5-15 |
Excellent |
|
12-16 |
Good |
|
18-21 |
Fair-passable |
|
23-35 |
Poor |
|
33-38 |
Very poor |
|
>40 |
Very very poor |
6. Hausner’s Ratio:
Hausner’s ratio is an important character to determine the flow property of powder and granules. This can be calculated by the following formula;
Value < 1.25 indicate good flow (=20% Carr)
While > 1.50 indicate poor flow (=35% Carr)
7. Drug Excipients Compatibility Study:
Procedure:
Rabeprazole sodium and Excipients are to be thoroughly mixed in predetermined ratio mentioned in below table and passed through the # 40. The blend was to be filled in amber colored glass vials sealed with aluminum seal and charged at 40ºC/75% RH and 60°C. Similarly Rabeprazole sodium should also be kept at all condition and samples to be withdrawn for analysis within two day of sampling date as per the compatibility study plan.
Table 2: Protocol for drug-excipients compatibility
|
Sr. No |
Drug- Excipient combination |
Drug – Excipient Ratio |
|
1 |
Rabeprazole sodium |
NA |
|
2 |
Rabeprazole sodium : Mannitol |
1: 1 |
|
3 |
Rabeprazole sodium : Hydroxypropyl cellulose |
1: 1 |
|
4 |
Rabeprazole sodium : HPMC phthalate |
1: 1 |
|
5 |
Rabeprazole sodium : Magnesium Stearate |
1:0.25 |
|
6 |
Rabeprazole sodium : Ethyl cellulose |
1:1 |
|
7 |
Rabeprazole sodium : Iron oxide Yellow |
1:0.25 |
|
8 |
Rabeprazole sodium : Sodium hydroxide |
1:0.25 |
|
9 |
Rabeprazole sodium : Cros povidone |
1:0.25 |
|
10 |
Rabeprazole sodium : Propane-1,2 diol (Propylene glycol) |
1:0.25 |
|
11 |
Rabeprazole sodium : Titanium dioxide |
1:0.25 |
|
12 |
Rabeprazole sodium : Talc |
1:0.25 |
Condition: 4,7
1. 40° C / 75% RH
2. 60° C
Pack details: Amber colored glass vials with rubber stopper and aluminum seal.
Test to be performed:
1. Description (Physical Observation).
2. DSC of initial sample.
3. Degradation by UPLC (Related substances)
Testing Frequency:
Physical observation shall be done at every two week up to 4 week. Degradation by UPLC shall be done at every two week up to 4 week for 60°C sample and 40°C/75%RH sample.
8. Differential scanning calorimetry:
A differential scanning calorimeter was used for thermal analysis of drug and excipients. The drug and excipients were passed through the # 40 and mixed in ratio as shown in table no.21. The sample was weighed directly in the pierced DSC aluminum pan and scanned at the temperature range of 50-400°c at heating rate of 5°c/min - 10°c/min. and nitrogen purging rate 50ml/min. The thermo grams obtained were observed for any interaction.
9. X-Ray Diffraction Analysis:
The powder X-ray diffraction study was carried to check out change in the polymorphic forms of Rabeprazole sodium during stability. Data was collected in the continuous scan mode. The scanned range was 0-400.
4) Evaluation of tablets:
1. Appearance:
Twenty tablets of each formulation were taken to check any discoloration or degradation of drug in the tablets by visual method. If any discoloration or black spots appears, it shows the degradation or decomposition of the drug in the tablet formulation.
2. Weight variation test:
Every individual tablet in a batch should be in uniform weight and weight variation within permissible limits. Weight control is based on a sample of 20 tablets. Twenty tablets were randomly selected and accurately weighed using an electronic balance. The results are expressed as mean values of 20 determinations.
3. Hardness:
The hardness of the tablets was determined using a Dr. Schleuniger hardness tester.
4. Thickness and diameter:
The thickness of ten randomly selected tablets was determined using a digital vernier caliper. The results are expressed as mean values of 10 determinations. 5.
Friability:
The friability of the tablets was measured in a Roche friabilator. Tablets of a known weight (W0) or a sample of 10 tablets are dedusted in a drum for a fixed time (100 revolutions) and weighed (W) again. Percentage friability was calculated from the loss in weight as given in equation as below. The weight loss should not be more than 1 % w/w with no breakage of any tablet.
6. Disintegration time:
It was performed using USP disintegration test apparatus. One tablet is placed in each tube, and the basket rack is positioned in a 1-L beaker of water at 37°C ± 2°C.
7. Assay of prepared tablet:
Assay of prepared tablet was carried out by Chromatographic method using UPLC.
Mobile Phase:
Prepare a mixture of Buffer*, Methanol in the ratio 55:45v/v, mixed well and degassed by sonication.
*Buffer preparation:
Dissolve 2.5ml Triethylamine into 550 ml Milli-Q water and adjust the pH to 6.9 ± 0.5 with dilute Orthophosphoric acid and mix well, filter through 0.45µ membrane filter.
Standard solution:
Weigh accurately about 50 mg of Rabeprazole sodium working standard in to 200 ml volumetric flask, add about 150 ml of diluent, sonicate to dissolve. Make the volume up to the mark with diluent and mix well.
5 ml of solution diluted to 250 ml with diluents.
(Concentration of Rabeprazole sodium is about 5.0 µg/ml)
Test solution:
For Acid Stage (Back Assay):
Transfer one tablet into a 250 ml volumetric flask, add to it about 150 ml of diluents and sonicate to disintegrate the tablet for about 15 minutes. Dilute up to the mark with diluent. Dilute 10 ml of solution to 200 ml using diluent. Filter through 0.45µ syringe filter discarding first few ml of filtrate.
Chromatographic systems:
Column : Kromasil C18, 250 × 4.6 mm, 5µ
Flow rate : 1.0ml/min
Detection Wavelength : 275nm
Injection volume : 40µl
Column oven temperature : 45°C
Sample cooler temperature : 25°C
Run time : 30 minutes
Procedure:
Equilibrate the column with mobile phase till the stable baseline obtained. Inject blank in single, standard solution in five replicates and each test preparation into the chromatographic system and record the chromatograms. The retention time of Rabeprazole sodium peak is about 6.5 minutes. Evaluate the system suitability parameters from standard chromatograms.
System suitability parameters:
In the chromatograms obtained with standard preparation; the %RSD of Rabeprazole sodium peak area in five replicate injections shall be not more than 5.0%.
USP Tailing for Rabeprazole sodium peak shall be not more than 2.0.
USP plate count for Rabeprazole sodium peak shall be not less than 2000.
Calculations:
AT WS 5 250 200 P
% content = ------ x ------ x ----- x ------- x ------- x------ x 100
AS 200 250 LC 10 100
Where,
AT= Average area of Rabeprazole sodium in test preparations
AS= Average area of Rabeprazole sodium in standard preparations
WS= Weight of Rabeprazole sodium working standard taken in mg
P= Potency of Rabeprazole sodium working standard in % w/w
LC = Label claim of Rabeprazole sodium in mg
Report the average results.
8. In-Vitro Dissolution Testing:
Given anti-psychotic drug is not official in any pharmacopoeia. Dissolution of developmental batches and optimized batches was carried out as below.
Preparation of standard solution:
For Acid Stage:
Weigh accurately about 50 mg of Rabeprazole sodium working standard in to 200 ml volumetric flask, add about 150 ml of diluent, sonicate to dissolve. Make the volume up to the mark with diluent and mix well.
5 ml of solution diluted to 250 ml with diluents.
(Concentration of Rabeprazole sodium is about 5.0 µg/ml)
For Buffer Stage:
Weigh accurately about 50.0 mg of Rabeprazole sodium working standard in to 200 ml volumetric flask, add about 50 ml prepared OGD media, sonicate to dissolve. Make the volume up to the mark with dissolution media and mix well.
(Concentration of Rabeprazole sodium is about 3.125 µg/ml)
Dilute 5.0 ml of prepared solution to 100 ml with dissolution medium. Mix it well. Add 10 ml of above solution in to the testube containing 2 ml of 0.5N NaOH solution, mixed well.
Dilute 5 ml of solution to 20 ml using diluents, filter it through syringe filter.
(Concentration of Rabeprazole sodium is about 3.125 µg/ml)
Test solution:
For Acid Stage (Back Assay): Transfer one tablet in each of the dissolution vessel containing 700 ml of 0.1N hydrochloric acid, and run the dissolution apparatus as per the dissolution conditions. After the specified time interval stop the instrument, remove each tablet or the major portion thereof if the tablet is not intact. Transfer it into a 250 ml volumetric flask, add to it about 150 ml of diluents and sonicate to disintegrate the tablet for about 15 minutes. Dilute up to the mark with diluent. Dilute 10 ml of solution to 200 ml using diluent. Filter through 0.45µ syringe filter discarding first few ml of filtrate.
For Buffer Stage:
Step:1 Transfer one tablet in each of the dissolution vessel containing 700 ml of 0.1N hydrochloric acid; and run the dissolution apparatus as per the dissolution conditions. After the specified time interval stop the instrument.
Step:2 Add 300 ml of prepared Tris buffer into each of the dissolution vessel, pH adjusted to 8.0 using 5N NaOH solution. At the specified time interval, withdraw the sample aliquot from each of the dissolution vessel and replace with fresh dissolution media. Add withdrawals in to the centrifuge tubes containing 2 ml of 0.5N NaOH solution, mixed well. Dilute 5 ml of solution to 20 ml with diluents. Filter it using 0.45 µ syringe filter discarding first few ml of filtrate.
Procedure: Equilibrate the column with mobile phase till the stable baseline obtained. Inject blank in single, standard solution in five replicates and each test preparation into the chromatographic system and record the chromatograms. The retention time of Rabeprazole sodium peak is about 6.5 minutes. Evaluate the system suitability parameters from standard chromatograms.
Media: As per OGD
For Acid stage: 0.1N HCl
For buffer stage: 0.6N Tris buffer pH 8.0.
Apparatus and Speed: USP II (Paddle) at 100 RPM
Time points: 120 min in acid stage followed by 45 min in buffer stage.
Temperature: 37 °C ± 0.5 °C
Withdrawal volume: 10 ml
Calculations:
Calculation for acid stage: Calculation % drug release from the measured area of standard and test preparation by the formula:
% drug release in acid stage = % Assay of the tablet - % content of acid stage tablets.
AT WS 5 250 200 P
% content = ------ x ------ x ----- x ------- x ----- x ----- x 100
AS 200 250 LC 10 100
Calculation for buffer stage: Calculate % drug release from the measured area of standerd and test preparation by the formula:
AT WS 5 10 5 1000 12 20 P
% drug = ----- x -----x ---- x-----x ----- x ------- x ----- x ---- x ---- x 100 release AS 100 100 2 20 LC 10 5 100
Where,
AT= Average area of Rabeprazole sodium in test preparations
AS= Average area of Rabeprazole sodium in standard preparations
WS= Weight of Rabeprazole sodium working standard taken in mg
P= Potency of Rabeprazole sodium working standard in % w/w
LC = Label claim of Rabeprazole sodium in mg
Further calculate % of label claim of Rabeprazole sodium present using following formula
Assay (mg/tablet) x 100
% Label Claim = ----------------------------------
Label claim (mg/tablet)
Report the average results.
4.5 FORMULATION DESIGN:
Delayed release tablet will be designed as Immediate release tablet coated with modified release polymer to produce a seal coat followed by enteric coat.