Omeprazole is a potent proton pump inhibitor with powerful inhibition of secretion of gastric juice. Oral site-specific drug delivery systems have recently attracted a great interest for the local treatment of bowel disease and for improving systemic absorption of drugs which are unstable in the stomach. However, microenvironment in the gastrointestinal tract and varying absorption mechanisms cause hindrance for the formulation and optimization of oral drug delivery. The objective of the study was to develop and optimize enteric coating process for omeprazole tablets. Different batches of core tablets were sub coated, one set sub coated with opadry and another with a mixture of light magnesium oxide, magnesium stearate and absolute alcohol omeprazole magnesium. Seal coating was applied by using opadry to achieve certain weight gain and to protect omeprazole from acidic coating polymers. A comparative dissolution test was performed. The variation of thickness and diameter were observed to be minimal with a weight gain of 3% - 4% of enteric polymer. Disintegration test showed that in each tested batch the enteric coated layer remained intact in 0.1N HCl for 2 hours and when exposed to alkaline media of phosphate buffer pH 6.8, it dissolved within few minutes. Dissolution release was 98.8% to 102.4% within two hours when the product was exposed to phosphate buffer pH 6.8 after 2 hours. The similarity and dis-similarity factors were calculated and observed to be 54 to 61 and 4 to 5 respectively. Therefore a simple and good enteric coating process was developed and tested with potential for transfer this technology into local pharmaceutical industries using cheap and easily available materials.
Omeprazole, 5-methoxy-2(((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)sulfinyl)-1H-benzimidazole (Figure
1), is a potent inhibitor of gastric acid secretion. It shows powerful inhibitory action against secretion of gastric juice and is used in treatment of duodenal and gastric ulcers [
The in vitro degradation of omeprazole is catalyzed by acidic compounds and is stabilized in mixtures with alkaline compounds. Moisture and organic solvents also affect the stability of omeprazole. From the data of stability studies of omeprazole, it is obvious that an oral dosage form must be protected from contact with acid gastric juice in order to reach the small intestine without degradation [
Human pharmacological studies showed that the rate of release of omeprazole from solid dosage form could influence the total extent of absorption of omeprazole to the general circulation [
The pharmaceutical dosage form with property of protecting omeprazole from contact with gastric acid must be developed, that is core. The core must be enteric coated. The core developed must be alkaline in nature as most of available acid compounds will not favor stability of omeprazole [
Coating polymer, such as Eudragit L 30, hydroxyl propyl methyl cellulose phthalate, cellulose acetate phthalate and acryl EZE® (Aqueous Acrylic Enteric System), to achieve 5% weight gain may be considered [
It is expected that the diffused water of gastric juice will dissolve parts of the core in the close proximity of the enteric coating layer and form an alkaline solution in the coated dosage form. The alkaline solution is expected to interfere with the enteric coating and eventually dissolve it [
The equipments include: Tabular mixer (Analytical Technology, Bangalore, India), Korsh EK 01 tablet press machine (Germany), auto coater (Glatt, Germany), Monsanto type tablet hardness tester (IEC, Mumbai, India), Roche Fribilator (electro lab, Bangalore, India), single pan balance (Shimadzu,AX200, Japan), Disintegration Apparatus USP (Elecrolab, Bangalore, India), graduated cylinder (Fisher Scientific, Germany), sieve analyzer (Endecott’s, Germany), glass bottles (Fisher Scientific, Germany), HPLC (Shimazdu, Japan), ERWEKA TBH machine (Heusenstamm, Germany), Dissolution Test Apparatus (Elecro Lab, TDT-08L, Mumbai, India.
The materials include: Omeprazole magnesium (Metrochem API Private Limited, Hyderabad, India), Sodium laurl sulphate (LOBA Chemie Pvt. Ltd., Mumbai, India), Lactose (OXFORD Laboratories, Mumbai, India), Avicel ph 102 (Shandong Liaocheng Ehua Medicine Co. Ltd., Shandong, China), Maize starch (OXFORD Laboratories,
Mumbai, India), Water aerosil 200 (Shandong Liaocheng Ehua Medicine Co. Ltd., Shandong, China) and Magnesium stearate (Hozhou Zhanwang Pharmaceutical Co. Ltd., Huzhou, China), Kollicoat® MAE Polymers (BASF, Germany). Other reagents and solvents were procured commercially and were of pharmaceutical and analytical grade. Application of the entire materials (Active ingredient and excipients) has been described in
In vitro analysis of the prepared tablets was carried out as per the requirements of enteric coated tablets as specified in official pharmacopoeia [
Since omeprazole magnesium is moisture sensitive material, all the processing steps including weighing, mixing, direct compression and coating was carried out at 30˚C ± 2˚C and 60% ± 5% RH [
The materials for preparation of core tablets for three different as listed in
Category | Ingredients | Application |
---|---|---|
Core Tablets Ingredients | ||
Omeprazole Magnesium | Active | |
Sodium Lauryl Sulphate | Lubricant | |
Tablottose (Lactose) | Binder | |
Avicel ph 102 | Disintegrant | |
Maize starch | Diluent | |
Water Aerosil 200 | Glidant | |
Magnesium Stearate | Lubricant | |
Sub Coating I Ingredients | ||
OPADRY White (HPMC) | ||
Phosphate Buffer pH | ||
Sub Coating II Ingredients | ||
Cellular Powder | Water Insoluble Polymer | |
Light Magnesium Oxide | Stabilizer/Alkalizer | |
Magnesium Stearate | Anti-Sticking Agent | |
Absolute Alcohol | Solvent | |
Enteric Coating Ingredients | ||
Kollicoat MAE 30 DP* | Enteric Coating Polymer | |
Propylene Gycol | Plasticizer | |
Water | Solvent |
*Kollicoat MAE 30 DP is Methacrylic acid copolymer.
Before sub coating of core tablets, IPQC tests was conducted. The parameters tested were weight variation, thickness, diameter, hardness, friability and disintegration time as per USP Pharmacopoeia [
Sub coating was done for the purpose of acting as moisture barrier to core tablet and preventing interaction between acidic labile omeprazole and acidic enteric coating material. Two sets of sub coating materials were considered (Sub coating I and Sub coating II) as depicted in
Enteric coating of sub coated tablets was done after accurately weighed ingredients of coating materials as depicted in
Formulations | OME 001 | OME 002 | OME 003 | OME 004 | OME 005 | OME 006 |
---|---|---|---|---|---|---|
Core Tablets Ingredients (mg) | ||||||
Omeprazole Magnesium | 20.0 | 20.0 | 20.0 | 20.0 | 20.0 | 20.0 |
Sodium Lauryl Sulphate | 2.0 | 2.0 | 1.9 | 2.0 | 1.9 | 2.1 |
Tablottose (Lactose) | 76.0 | 76.0 | 76.0 | 76.0 | 76.0 | 76.0 |
Avicel ph 102 | 60.0 | 60.0 | 60.0 | 60.0 | 60.0 | 60.0 |
Maize starch | ||||||
Water Aerosil 200 | 0.6 | 0.6 | 0.6 | 0.6 | 0.6 | 0.6 |
Magnesium Stearate | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 |
Sub Coating 1 Ingredients | ||||||
OPADRY White (HPMC) | 0.008 | 0.008 | 0.008 | 0.008 | 0.008 | 0.008 |
Phosphate Buffer pH | QS | QS | QS | QS | QS | QS |
Sub Coating II Igredients | ||||||
Cellulose Powder | 0.96 | 0.96 | 0.96 | 0.96 | 0.96 | 0.96 |
Light Magnesium Oxide | 0.77 | 0.77 | 0.77 | 0.77 | 0.77 | 0.77 |
Magnesium Stearate | 0.77 | 0.77 | 0.77 | 0.77 | 0.77 | 0.77 |
Absolute Alcohol | QS | QS | QS | QS | QS | QS |
Enteric Coating Material | ||||||
Kollicoat MAE 30 DP* | 70% | 70% | 70% | 70% | 70% | 70% |
Propylene glycol | 4.2% | 4.2% | 4.2% | 4.2% | 4.2% | 4.2% |
Water | 25.8% | 25.8% | 25.8% | 25.8% | 25.8% | 25.8% |
*Kollicoat MAE 30 DP is Methacrylic acid copolymer.
Process Parameters | Formulation I | Formulation II |
---|---|---|
Pan speed | 2 RPM | 2 RPM |
Inlet air temperature | 40˚C ± 5˚C | 50˚C ± 5˚C |
Outlet air temperature | 30˚C ± 5˚C | 40˚C ± 5˚C |
Air volume | 360 m2/h | 360 m2/h |
Nozzle diameter | 1.0 mm | 1.0 mm |
Atomizing air pressure | 2.0 bar | 2.0 bar |
Spraying rate | 1.5 ml/min | 1 gm/min |
Coating level | 3% | 3% |
Process Parameters | Set Limit |
---|---|
Pan speed | 2 RPM |
Inlet air temperature | 50˚C ± 5˚C |
Outlet air temperature | 30˚C ± 5˚C |
Air volume | 360 m2/h |
Nozzle diameter | 1.0 mm |
Atomizing air pressure | 2.0 bar |
Spraying rate | 30 - 35 g/min (1.5 ml/Min) |
Coating level | 3% - 4% |
coated tablets were pre heated in coating pan for 10 minutes at 40˚C ± 5˚C. The tablets were coated in Glatt auto coater to achieve 3% to 4% weight gain.
Enteric coated tablets of omeprazole were evaluated for weight variation, Thickness, Diameter, Hardness, Friability and Disintegration time as per USP Pharmacopoeia. The formulations assessed by content uniformity test and dissolution testing by USP Type I Basket apparatus at 100 RPM in 900 ml of 0.1 N HCl for 120 minutes and afterwards in phosphate buffer of 6.8 for 60 minutes [
All of the studied physical properties were within the acceptable range with narrow variation and complied with the pharmacopoeia specifications for both core and coated tablets. The parameters tested were diameter, hardness, friability and weight variation. The shape and the size of tablets for all batches were found to be within the acceptable limit. For core tablets diameter for all tablets range between 9.37 to 9.39 mm and hardness of all formulations lies within the range of 66 to 68 N. All formulations passes friability test as the percentage weight loss was within pharmacopeia limit, i.e. NMT 1%. The weight variation and drug content of all the formulations were found to be within the acceptable limit.
For coated tablets, three batches were taken and each was divided into two batches, i.e. OME 001, OME 002 & OME 003 divided into OME 001A, OME 001B, OME 002A, OME 002B, OME 003A and OME 003B. Where the A ones were of sub-coated I and of B were of sub-coated II. There was a weight gain of 3% - 4% of the enteric polymer. The thickness and diameter of 20 coated tablets from each formulation was determined using ERWEKA TBH machine and average value were calculated and evaluated as per USP 30. The hardness of tablets ranges from 67 N to 73 N. The variation of thickness and diameter was observed to be minimal. The percentage of friability of tablets ranges from 0.339% to 0.468% which was in acceptable range. The percentage of drug content of the formulated tablets when assayed was 100.1% to 105.9% which is within specification. Results showed no significant differences. Results for evaluation of core tablets are summarized in
Tablets were prepared by direct compression technique. The results of in process quality control tests are listed in
The friability results of coated tablets indicate good mechanical resistance of tablets. Results showed no significant differences. Results for evaluation of coated tablets are summarized in
Disintegration Test show that in all six tablets in each tested batch the enteric coated layer remained intact in 0.1N HCl for 2 hours but there were few signs of cracking and little swelling observed. The enteric coating layer of tablets started to imbibe the alkaline media of phosphate buffer pH 6.8 and completely removed approximately at 30 minutes and afterwards tablets were completely dissolved within 50 minutes.
The in vitro dissolution of all formulated batches (i.e. OME 001A, OME 002A, OME 003A, OME 001B, OME 002B & OME 003B) was studied in 0.1N HCl for 2 hours and 1 hour in phosphate buffer pH 6.8. The results observed showed that for all batches there was physical resistance to the acid medium with few signs of cracking and swelling and the drug released after two hours was found to be within specified limit (
Batches | Diameter (mm) | Thickness (mm) | Friability (%) | Hardness (N) | Weight uniformity (mg) | Assay (%) | Disintegration time (Min) |
---|---|---|---|---|---|---|---|
OME 001 | 9.37 ± 0.03 | 4.28 ± 0.11 | 0.369 | 66.75 | 221.55 ± 6 | 105.2 ± 1.1 | NMT 5 |
OME 002 | 9.37 ± 0.03 | 4.28 ± 0.14 | 0.387 | 59.9 | 221.55 ± 5 | 104.5 ± 1.1 | NMT6 |
OME 003 | 9.38 ± 0.05 | 4.28 ± 0.11 | 0.339 | 67 | 221.55 ± 5 | 105.2 ± 1.1 | NMT 5 |
OME 004 | 9.38 ± 0.05 | 4.28 ± 0.11 | 0.350 | 70 | 221.55 ± 5 | 105.9 ± 0.1 | NMT 7 |
OME 005 | 9.37 ± 0.03 | 4.28 ± 0.11 | 0.386 | 68 | 221.55 ± 6 | 99 ± 1.1 | NMT6 |
OME 006 | 9.37 ± 0.03 | 4.28 ± 0.11 | 0.370 | 60 | 221.55 ± 7. | 99 ± 1.1 | NMT 5 |
NB: All values are expressed as mean ± SD (n = 20).
IPQC Parameters | OME 001A | OME 001B | OME 002A | OME 002B | OME00 3A | OME 00 3B |
---|---|---|---|---|---|---|
Diameter (mm) | 9.4 ± 0.05 | 9.42 ± 0.05 | 9.38 ± 0.05 | 9.3 ± 0.05 | 9.41 ± 0.06 | 9.48 ± 0.06 |
Thickness (mm) | 5.77 ± 0.11 | 5.78 ± 0.11 | 6.02 ± 0.10 | 6.0 ± 0.10 | 5.97 ± 0.11 | 5.90 ± 0.11 |
Friability (5) | 0.369 | 0.387 | 0.339 | 0.350 | 0.468 | 0.384 |
Hardness (N) | 69 | 70 | 67 | 73 | 68 | 72 |
Weight uniformity | 229.6 ± 10 | 231.3 ± 10 | 231.1 ± 10 | 231.9 ± 10 | 231.8 ± 10 | 231.7 ± 10 |
Assay (%) | 105.2 ± 1.1 | 104.5 ± 0.0 | 105.5 ± 0.1 | 105.9 ± 0.1 | 100.1 ± 0.3 | 100.1 ± 0.3 |
NB: All values are expressed as mean ± SD (n = 20).
% Drug Release | OME 001A | OME 002A | OME 003A | OME 001B | OME 002B | OME 003B |
---|---|---|---|---|---|---|
0.1N HCl within 2 Hrs | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
Phosphate buffer pH 6.8 after 2 Hrs | ||||||
02:10 | 34.07 | 22.18 | 23.08 | 68.9 | 70.2 | 93.0 |
02:20 | 52.99 | 35.88 | 37.07 | 78.8 | 79.23 | 95.0 |
02:40 | 72.03 | 52.78 | 53.57 | 90.25 | 91.45 | 98.3 |
02:50 | 86.5 | 77.05 | 78.68 | 98.9 | 99.1 | 101.3 |
03:00 | 98.8 | 99.1 | 99.1 | 100.82 | 101.3 | 102.4 |
Therefore all batches were selected as optimized batches because they have shown better drug release even though the formulation sub coated with opadry solution has a better dissolution profile i.e. OME 001 - 003A and consumed less concentration of enteric coating polymer.
The selected batches i.e. OME 001 and OME 002 were compared with Pilorsec capsules 20 mg and Losec Mups 20 mg. Pilorsec capsules was dropped from the study after the capsules dissolved immediately in the acid and noted that omeprazole powder and sodium bicarbonate was present in the capsules without any protection. The disintegration time and release profile of selected formulations and Losec is given in
The Similarity Factor (F2 value) and Dissimilarity Factor (F1) were calculated using equation of similarity by using a simple model independent approach to compare dissolution profile between Formulated products OME 001A & OME 002B and marketed product Losec MUPS 20 mg [
Time (Minutes) | 0 | 30 | 60 | 90 | 120 | 130 | 140 | 150 | 160 | 180 | 190 |
---|---|---|---|---|---|---|---|---|---|---|---|
OME 001A | 0 | 0 | 0 | 0 | 0 | 58 | 85.9 | 94.5 | 98.4 | 99.8 | 101.1 |
OME 001B | 0 | 0 | 0 | 0 | 0 | 45 | 87 | 96 | 99 | 99.5 | 100.82 |
Losec Mups | 0 | 0 | 0 | 0 | 0 | 72 | 88.2 | 96 | 98.7 | 99.3 | 100 |
1)
2)
By using the formula [
A simple and good enteric coated omeprazole magnesium tablets with potential for transfer into local industries in Tanzania was developed and tested. Opadry white coating (HPMC) (Sub-coating I) and a mixture of cellulose powder, light magnesium oxide, magnesium stearate and absolute alcohol (Sub-coating II) were used for sub-coating. The enteric coating was successfully done by using Kollicoat® Methacrylic acid AE 30 DP (Methacrylic acid/ethyl acrylate copolymers) which is an aqueous dispersion.
Migoha C.O is thankful to Tanzania Food & Drugs Authority for sponsoring the programme and for providing necessary facilities to carry out analysis work at its laboratory, also the School of Pharmacy for providing required facilities to carry out formulation development of the product.
The authors declare that they have no conflict of interests regarding the publication of this article.
Christopher OswaldMigoha,EliangiringaKaale,GodliverKagashe, (2015) Formulation Development of Generic Omeprazole 20 mg Enteric Coated Tablets. Pharmacology & Pharmacy,06,293-301. doi: 10.4236/pp.2015.67031