Sandip Chavan, Associate Manager-Technical Service and Application, Lubrizol Lifesciences, Kedar V Chikhalikar, Associate Head, Technical Service and Application, Lubrizol Lifesciences and Dr Elena Draganoiu, Global Technology Manager for Pharma Solutions, Lubrizol Lifesciences, in this study evaluate the multimedia release profiles of extended release matrix tablets containing carbopol polymers
A key aspect for development of extended release tablets is understanding the drug release under various testing conditions, especially the effect of dissolution medium on the release. The purpose of this study was to evaluate the multimedia release profiles of extended release matrix tablets containing carbopol polymers and to develop multimedia compliant formulations of selected model drugs.
Metformin hydrochloride USP (Wanbury, India), Guaifenesin USP (Synthokem Labs, India), carbomer homopolymers type A (Carbopol 971P NF polymer, Lubrizol Advanced Material, USA), sodium carboxymethylcellulose USP (Sodium CMC high viscosity, Cekol 100000 cellulose gum, CP Kelco, USA and sodium CMC medium viscosity, Blanose 7MF, Ashland, USA), citric acid monohydrate (citric acid) and sodium citrate (Merck, India), corn starch USP NF (Maize starch extra white, Roquette, USA), methacrylic acid copolymer type C USP NF (Eudragit L30D and Eudragit L100 55, Evonik Industries, Germany), colloidal silicon dioxide USP NF (Aerosil 200 fumed silica, Evonik Industries, Germany), magnesium stearate USP (Ferro, USA), hypromellose type 2208 of low viscosity K100 LVCR (hypromellose K100 LVCR, Benecel K100 LVCR, Ashland, USA), hypromellose K4M (Metolose 90SH-4000SR USP, Shin-Etsu Chemical Co, Japan), hypromellose E6 (Pharmacoat 606 USP, Shin-Etsu Chemical Co, Japan), sodium alginate low viscosity (Protanal CR 8133, FMC Biopolymer, USA) and sodium alginate high viscosity (Keltone HVCR, FMC Biopolymer, USA).
Two highly soluble, high dose drugs with pH independent solubility were selected as model drugs for the study: metformin hydrochloride (freely soluble in water; dose 500 mg/ tablet) and guaifenesin (soluble in water; dose 600 mg/ tablet) extended release matrix tablets of metformin hydrochloride and guaifenesin were manufactured containing 10 per cent and 20 per cent.
Carbopol 971P NF polymer by aqueous granulation process. Additional formulations containing combinations of Carbopol polymers with other co-ingredients were evaluated in order to improve f2 factor. The co-ingredients were selected based on their chemistry, suitability for oral administration (presence in the US FDA Inactive Ingredients Database) and potential to act synergistically with Carbopol polymers (See Table 1). The following classes of ingredients were selected:
- Cellulosic polymers like hypromellose and carboxymethylcellulose sodium.
- Non-cellulosic polymers such as Eudragit L100 55, Eudragit RSPO and sodium alginate.
- Buffers for modulation of micro-environmental pH like sodium citrate and citric acid.
- Diluents such as maize starch and dicalcium phosphate
In the case of guaifenesin, a different formulation approach was also tested: coating of the matrix tablets with an enteric film of Eudragit and hypromellose as a pore former. The release profiles were tested in three dissolution media 0.1N hydrochloric acid, pH 4.5 acetate buffer USP and pH 6.8 phosphate buffer USP) and the f2 similarity factors (similarity between dissolution profiles in different media) calculated.
Metformin hydrochloride and guaifenesin ER tablets had acceptable physical properties (mechanicalstrength 20–25 kP, friability less than one per cent). The extended release matrix tablets of metformin hydrochloride and guaifenesin manufactured with 10 per cent and 20 per cent Carbopol 971P NF showed faster release in 0.1N HCl than the other two media.
Metformin hydrochloride 500 mg ER tablets with Carbopol 971P NF polymer:
Multimedia dissolution compliance was achieved for Metformin hydrochloride extended release tablets formulated with combinations of:
- Carbopol polymer and Hypromellose K100 LVCR (ratio 2:1) – (See Figure 1)
- Carbopol polymer and Hypromellose K4M (ratio 2:1) – (See Figure 2)
- Carbopol polymer and Sodium CMC high viscosity (ratio 4:1) – (See Figure 3)
- Carbopol polymer and Sodium alginate low viscosity (ratio 2:1) – (See Figure 4)
- Carbopol polymer and Maize starch (ratio 1:1) – (See Figure 5)
- Carbopol polymer and Sodium citrate (ratio 4:1) – (See Figure 6)
The faster release in 0.1N HCl from tablets containing Carbopol polymers has been controlled by the synergistic combinations with co-ingredients that favour the hydration process.
Guaifenesin 600 mg ER tablets with Carbopol 971P NF polymer:
Guaifenesin release from tablets formulated with 20 per cent Carbopol and coexcipients is shown in Figure 7 – 9.
The following combinations provided multimedia compliant dissolution with calculated f2 factor above 50:
- Carbopol polymer and hypromellose K100 LVCR (ratio 2:1) – (See Figure 7)
- Carbopol polymer and hypromellose K4M (ratio 2:1) – (See Figure 8)
- Carbopol polymer and Sodium alginate low viscosity (ratio 2:1) – (See Figure 9)
Similar to metformin hydrochloride, the synergistic combination of Carbopol polymers with hydrophilic matrix forming excipients (hypromellose K4M, hypromellose K100 LVCR and sodium alginate low viscosity) at ratio 2:1 resulted in matrix tablets efficiently controlling the drug release in the three media.
Guaifenesin release from tablets formulated with 10 per cent Carbopol polymer and 10 per cent hypromellose K4M have shown f2 factor >50 in the three media. An alternative strategy of a porous enteric coating over matrix tablets was also successful in providing multimedia compliant release – (See Figure. 10). The tablet cores containing 10 per ent Carbopol polymer were coated with a porous enteric layer consisting of Eudragit L30D and hypromellose E6 (1:1) at three per cent weight gain.
The study demonstrated development of multimedia compliant extended release matrix tablets of Metformin HCl or guaifenesin by using synergistic combinations of Carbopol 971P NF polymer and co-ingredients. The findings from this study may be extended to other drugs on a case to case basis.
Carbopol is a registered trademark of The Lubrizol Corporation, USA.
Protanal and Keltone are registered trademarks of FMC Biopolymer, USA
Cekol is the registered trademark of CP Kelco US Inc, USA
Benecel and Blanose are registered trademarks of the Ashland Corporation, USA
Eudragi and Aerosil is the registered trademark of Evonik Industries, Germany
Metolose and Pharmacoat are the registered trademark of Shin-Etsu Chemical Co Ltd, Japan.