development of asymmetric membrane capsules of metformin hydrochloride for oral osmotic controlled drug delivery

ORIGINAL ARTICLE Development of asymmetric membrane capsules of metformin hydrochloride for oral osmotic controlled drug delivery Venkatesh Teja Banala, Bharath Srinivasan, Deveswaran Rajamanickam, Basavaraj Basappa Veerbadraiah, Madhavan Varadharajan1 Departments of Pharmaceutics, and 1Pharmacognosy, M S Ramaiah College of Pharmacy, Bengaluru, Karnataka, India A symmetric membrane capsules are one of the novel osmotic delivery devices which offer the delivery of a wide range of drugs in a controlled manner In the present work, we developed a semi‑automatic process by fabricating a hydraulic assisted mechanical robotic arm for the manufacturing of asymmetric membrane capsules and the process was validated in comparison with the manual procedure of manufacturing The capsule walls were made by dip coating phase inversion process using cellulose acetate butyrate as polymer and propylene glycol as plasticizer/pore forming agent.The comparative examination of physical parameters in manual and semi‑automatic process confirmed the consistency, reproducibility and efficiency of the semi‑automatic process over manual procedure The resulting asymmetric membrane wall was evaluated by scanning electron microscopy studies revealed the thin dense region supported on a thicker porous region Fourier transform infrared studies showed phase inversion of the asymmetric membrane as compared to plain membrane Osmotic release study and in vitro behavior was studied for controlled delivery of metformin hydrochloride as a model drug In vitro release studies of the formulations showed that drug release was dependent on the concentration of pore forming agent, level of osmogents and independent of the media pH and agitation The effect of the process variables on the drug release was optimized using 23 full factorial design and the release kinetics of the optimized formulation confirmed zero order kinetics with a controlled drug delivery of 13 h and the mechanism of drug release was found to be super case II transport Key words: Asymmetric membrane capsules, cellulose acetate butyrate, metformin hydrochloride, osmotic controlled delivery, phase inversion, semi‑automatic process INTRODUCTION Despite tremendous advancements in the drug delivery, oral route remains the preferred route of administration due to high levels of patient compliance and simplicity In conventional oral drug delivery systems (DDSs), there is a little or no control over the release of the drug and effective concentration at the target site can be achieved by intermittent administration of excessive doses An ideal oral delivery system should steadily deliver a measurable and reproducible amount of the drug to the target site over a prolonged period of time.[1,2] Thus, there has been an increasing and remarkable interest in the concepts of controlled delivery of orally administered drugs This has also been due to various factors including prohibitive cost of developing new drug entities, expiration of existing patents, etc., Controlled delivery systems provide a uniform concentration of drug at the absorption site and thus after absorption allow the maintenance of plasma concentrations within the therapeutic range, thereby minimizing side‑effects and frequency of drug administration However, the drug release from the controlled release dosage forms may be affected by pH, gastrointestinal motility and presence of food.[3,4] An appropriately designed oral controlled delivery system can be a major advantage toward overcoming some of these problems One such controlled delivery system is the osmotic DDS (ODDS) which has been explored to a greater extent by pharmaceutical scientists Different types of oral osmotic delivery systems are elementary Access this article online Quick Response Code: Address for correspondence: Dr Bharath Srinivasan, Department of Pharmaceutics, M S Ramaiah College of Pharmacy, M S R Nagar, MSRIT Post, Bengaluru ‑ 560 054, Karnataka, India E‑mail: bharath1970in@yahoo.com Asian Journal of Pharmaceutics - January-March 2014 Website: www.asiapharmaceutics.info DOI: 10.4103/0973-8398.134088 Banala, et al.: Asymmetric membrane capsules for osmotic delivery osmotic pump, push pull osmotic pump, sand witched osmotic tablets, controlled porosity osmotic pumps etc., But these ODDS had some disadvantages like laser or mechanical drilling procedure and requirement of significant modifications for the scale up process thereby making the final product more expensive.[5,6] Thus to reduce the cost and also the process complications, the concept of asymmetric membranes for a controlled osmotic DDS was utilized Asymmetric membranes are normally used in a variety of membrane separation process such as reverse osmosis, ultra filtration and dialysis.[7] These are one of the single core osmotic delivery device consisting of a drug containing core surrounded by an asymmetric membrane which has an asymmetric structure (a relatively thin, dense region supported on a thicker, porous region) In the present work we described the fabrication of a semi‑automatic lab model capsule shell manufacturing equipment for the manufacture of asymmetric membrane capsules and its validation parameters had been discussed with cellulose acetate butyrate (CAB) polymer and metformin hydrochloride as a model drug Metformin hydrochloride, an anti‑diabetic drug from the biguanide class of oral antihyperglycemic agent improves glucose tolerance in Type‑II diabetes mellitus It has been reported that the absolute bioavailability of metformin when given orally is 50‑60% with biological half‑life of 1.5‑1.6 h Being an ideal drug candidate for controlled release, in the present study an osmotic controlled delivery system using asymmetric membrane capsules was planned to deliver metformin for a prolonged period of time.[8,9] MATERIALS AND METHODS Materials Metformin hydrochloride (a kind gift from Micro Labs, Bangalore, India), CAB (Hi Media Laboratories Ltd., Mumbai, India, mol.wt 30,000), propylene glycol (PG) (Ranbaxy Fine Chemicals Ltd., New Delhi, wt/ml 1.035 at 20°C), Fructose (Merck Specialties Pvt Ltd Mumbai, India) Potassium chloride (Qualigens Fine Chemicals, Mumbai, India) All other chemicals and reagents used were of analytical grade The hydraulic pressure required for the movement of arms facilitated by 15 ml and 20 ml syringes filled with water connected by rubber tubing Movement of one plunger result in the movement of water from one syringe to another result in the movement of the plunger of the second syringe in the opposite direction The original image of the fabricated instrument was shown in Figure 1 It consists of two arms a vertical arm and horizontal arm The horizontal arm was connected to the vertical arm with the help of a plunger of the syringe which facilitates the up and down movements, the vertical arm can be rotated at a certain angle with the help of disc connected at the bottom to one more syringe A removable mold setup was connected to the horizontal arm which holds the plate containing mold pins The entire mold setup was connected to one more syringe to the top of the horizontal arm to facilitate inversion of mold plate The mold plate was designed in such a way to remove and reinsert a new plate for every fresh batch For this equipment, a mold plate was prepared which can accommodate six molds at a time which can be detached and reattached a new set of mold pins each time The spinning of the mold pins can be facilitated by the two knobs which are arranged diagonally on the mold plate Each knob was connected and interlinked with three mold pins by which rotating one knob will facilitate the spinning of three mold pins Hence, the two knobs present will facilitates the spinning of six mold pins in either clockwise or anti clockwise direction according to the requirement For easy understanding of the design and specifications three‑dimensional sketch had been provided using CAD 2013 (AutoCAD LT, USA) software [Figure 2] Design specifications of the molds and mold plate Separate molds were fabricated for the cap and body of the capsule shell using teflon to facilitate smooth and easy removal Design description of the fabricated lab equipment for the manufacture of asymmetric membrane capsules A semi‑automatic hydraulic assisted lab model equipment was designed and fabricated simulating all the steps in usual hard gelatin capsule shell preparation process such as dipping, spinning, flipping, drying etc., for the manufacturing of asymmetric membrane capsule shells The design of the equipment was inspired by the mechanical robotic arm works on the principle of hydraulic pressure Some modifications have been made in the robotic arm, such a way to facilitate the manufacturing of the asymmetric membrane capsule shells with a capacity to manufacture 80‑100 capsules a day Figure 1: Original image of the fabricated equipment with labeled parts Asian Journal of Pharmaceutics - January-March 2014 Banala, et al.: Asymmetric membrane capsules for osmotic delivery In the semi‑automatic process same manufacturing procedure was followed using fabricated equipment by dipping the teflon mold containing cap and body hood dipped into the polymer solution followed by spinning Then the molds were taken out by moving the horizontal arm in the upward direction and inverted for 30 s for initial drying and then the mold plate was dipped into the quench bath containing 5% v/v aqueous PG for 3 min The mold plate was then dried at room temperature for 4 h and the capsule shells were stripped off and stored for further use Figure 2: (a) Three-dimensional sketch of the fabricated instrument for the preparation of the asymmetric membrane capsule shells (b) Top view showing the alignment of plunger connected for angular rotation Parts: (a) Vertical arm (b) Horizontal arm (c) Mold hood plate with mold pins (d) Two knobs on mold pins for spinning (e) Syringe plunger (1) Connected to horizontal arm for up/down movement (f) Syringe plunger (2) Connected to mold plate for flipping movement (g) Syringe plunger (3) Connected to disc for angular rotation of the dried capsule shells without any prior lubrication As the temperature used in the preparation of the asymmetric membrane capsule shells and the drying conditions required is below 40‑50°C teflon molds are found most suitable and convenient Proper care had been taken in the designing of the mold pins in such a way to snugly fit each other The dimensions of the cap and body were maintained at a ratio of length: diameter 35:9.85 and 55:9.5 mm respectively A rectangular mold plate was designed in such a way to accommodate six molds Provision has been made to remove the individual molds from the plate by unscrewing and a fresh batch of another six molds can be attached by screwing to the mold plate With this equipment the spinning step of the capsule shell preparation was designed by interlinking the three molds in a row by a pulley setup and the respective knobs are arranged diagonally at the positions of 1st and 6th mold on the top of mold plate to facilitate the spinning in clockwise and anti‑clockwise directions, the diagonal arrangement of the knobs gives ease in spinning operation Development of manual and semi‑automatic method for manufacture of asymmetric membrane capsules Asymmetric membrane capsules were prepared using phase inversion process Included dipping of the teflon mold pins in polymeric solutions of CAB (10, 12, 14 and 16% w/v) dissolved in a mixture of acetone and ethanol (3:7) and PG was added to the homogenous polymer solution as per the formula listed in Table 1, followed by quenching in a 5% w/v aqueous solution of PG for 3 min After quenching the pins were withdrawn and allowed to air dry for 4 h then the capsule shells were stripped off from the molds, trimmed to the required size and stored in a desiccator until further use.[10‑14] 10 With the aim of developing asymmetric membrane capsules of uniform thickness in a reproducible manner an optimum concentration of the CAB formulation (CAB‑12) was selected and validation of the instrument was performed to check the consistency and reproducibility of the capsule shells with the fabricated equipment Characterization of the CAB asymmetric membrane capsules of manual and semi‑automatic process Physical characteristics The physical characteristics of the CAB capsule shells like clarity, uniformity and intactness of cap and body were determined for all individual batches Solubility studies The solubility of the capsule shells was observed in different media (distilled water, simulated gastric fluid and simulated intestinal fluid) at 37°C ± 0.5°C for 24 h in a constant temperature water bath shaker Weight variation The average weight of the 20 capsules in each formulation was determined after trimming to the appropriate size and snugly fitting to each other Diameter The diameter of the cap and body of the capsule shells were determined of 10 capsules individually for all the formulations of CAB capsules by using Vernier calipers and the mean diameter was calculated Surface morphology The characterization of an asymmetric membrane capsule wall of CAB‑12 and the effect of plasticizer concentrations on the surface integrity were studied by observing the cross‑section of the capsule under the (Jeol – 840A) scanning microscope.[15,16] Each sample was coated with gold by an ion sputter (DMX‑220A, Beijing, China) at 50 mA for 120 s before scanning electron microscopy (SEM) observation Osmotic release study The capsule shells of CAB‑12 were filled with water soluble dye, erythrosine along with osmogents potassium chloride and fructose and then sealed using 12% w/v of CAB and Asian Journal of Pharmaceutics - January-March 2014 Banala, et al.: Asymmetric membrane capsules for osmotic delivery Table 1: Composition of asymmetric membrane capsules of CAB Ingredient Formulation code CAB‑10 CAB‑12 CAB‑14 CAB (% w/v) 10 12 14 Propylene glycol (% v/v) 10 15 20 10 15 20 10 15 20 Ethanol (% v/v) 30 30 30 Acetone (q.s) 100 100 100 Purified water ‑ ‑ ‑ CAB‑16 16 10 15 20 30 100 ‑ Quenching solution Sealing solution ‑ ‑ ‑ 95 12 ‑ ‑ 88 ‑ CAB: Cellulose acetate butyrate, q.s: Quantity sufficient acetone as sealant solution The capsules were then suspended separately in beakers containing 250 ml of water and 10% w/v sodium chloride solution The capsules were observed visually for release of any colored dye.[17,18] Preparation and comparative evaluation of plain and asymmetric membrane films of CAB Plain films of CAB in the concentration of 12% w/v were prepared with varying concentrations of PG such as 10%, 15% and 20% v/v in ethanol and acetone The polymer solution was then casted on three different petri dishes and dried at room temperature for 8 h Asymmetric membrane films of CAB‑12 were prepared with above concentrations and cast The cast solution after 10 min was treated with 5% v/v of aqueous PG and quenched with PG for 10 min Then quench solution was decanted and the formed films were further dried for 8 h at the room temperature Evaluation of films Determination of thickness Three film strips were selected from different portions of the membrane and the thickness was measured with the help of screw gauge and the average values were taken Water vapor transmission studies Clean, dried glass vials of identical dimension were used as transmission cells One gram of fused anhydrous calcium chloride was added to each cell and the polymer film was securely fixed over the brim with the help of an adhesive and accurately weighed The cells were stored in the humidity chamber (Tempo Instruments, India) at 85% relative humidity (RH) for 72 h At frequent time intervals, the cells were taken out and weighed The difference in the weight was noted and rate of water vapor transmission was calculated by the formula RWVT = g × 24 × L  t×a (1) Where g = weight change in grams, L = film thickness in cm, t = time in hours during which weight change occurred Formulation of asymmetric membrane osmotic capsules of metformin hydrochloride The formulation blend for osmotic delivery system consisted of metformin HCl with potassium chloride and fructose as osmogents in varying ratio Purified talc and magnesium stearate were used as glidant and lubricant [Table 2] A 23 full factorial design was employed to study the effect of process variables such as concentration of PG, amount of osmogents potassium chloride and fructose on the response time taken for 100% drug release Optimization of process variables were carried out using the software Design Expert V8.0‑Trial verion1 Accordingly eight formulations were formulated with varying concentrations of PG, potassium chloride and fructose [Table 3] The prepared formulations were evaluated for controlled release of metformin hydrochloride Evaluation of the dosage forms Fourier transform infrared (FT‑IR) spectral studies Infrared (IR) spectral studies were carried out for pure drug metformin hydrochloride, fructose and physical mixture of drug and excipient Samples were prepared in KBr disks (2 mg sample in 200 mg KBr) with a hydrostatic press at a force of 5.2 N/m2 for 3 min The samples were scanned in the range of 400‑4000/cm with the resolution 4/cm using computer mediated FT‑IR Spectroscopy (Shimadzu 8400S, Japan) In vitro dissolution studies In vitro drug release studies were carried out according to USP XXIII Type‑I method using 900 ml of distilled water as dissolution medium maintained at 37°C ± 0.5°C with an agitation speed of 100 RPM A volume of 5 ml samples were withdrawn at periodic intervals, diluted and analyzed spectrophotometrically using ultra violet‑visible spectrophotometer (Shimadzu 1700) at 233 nm In vitro drug release kinetics In vitro drug release data of the formulations was fitted to zero order, first order, Higuchi matrix, Hixson‑Crowell cube root law model and Korsmeyer–Peppas equations using PCP‑Disso V3 software.[19‑21] The best‑fit model was selected based on the highest r2‑values obtained from different models Effect of pH and agitation rate on drug release The effect of media pH and agitation rate on the drug release were investigated for the optimized formulation (OPT) using different media (distilled water, 0.1 N HCl, phosphate buffer pH 6.8 and 7.4) at 100 RPM,[22,23] as well as in varied agitation intensities (50, 100 and 150 RPM) by using distilled water as dissolution media, maintaining 900 ml as the volume at 37°C ± 0.5°C.[24,25] Asian Journal of Pharmaceutics - January-March 2014 11 Banala, et al.: Asymmetric membrane capsules for osmotic delivery Table 2: Levels of independent variables taken for optimization of metformin hydrochloride formulations Independent variables Levels used Low High A ‑ Propylene glycol (plasticizer) (% v/v) 15 20 B ‑ Potassium chloride (osmogent) (mg) 75 125 C ‑ Fructose (osmogent) (mg) 75 125 Metfromin HCl (drug) (mg) 500 Purified talc (glidant) (mg) Magnesium stearate (glidant) (mg) Table 3: Experimental design summary of the metformin hydrochloride formulations A B C Formulation code Concentration Concentration Concentration of propylene of potassium of glycol (% v/v) chloride (mg) fructose (mg) 15.00 125.00 75.00 F1M1 15.00 75.00 125.00 F1M2 15.00 125.00 125.00 F1M3 15.00 75.00 75.00 F1M4 20.00 125.00 75.00 F2M1 20.00 75.00 125.00 F2M2 20.00 125.00 125.00 F2M3 20.00 75.00 75.00 F2M4 Effect of osmotic pressure on the drug release To assess the effect of osmotic pressure on drug release, the OPT was subjected to dissolution studies at 100 RPM with 900 ml of dissolution media varying at the pre‑determined time alternately with magnesium sulfate solution ‑ 2.4% w/v (6 atm osmotic pressure) and distilled water having atm osmotic pressure.[26] Stability studies Based on the International Conference on Harmonization guidelines[27] the stability studies were carried out in an environmental chamber (Tempo Instruments, India) The OPT was stored at 40°C ± 2°C and 75% ±5% RH for a period of 6 months At intervals of 0, 2, and 6 months for accelerated storage condition, the samples were tested for changes in physical appearance and drug content RESULTS AND DISCUSSION Although the manual process was suitable for providing a relatively small number of asymmetric membrane capsules that could be used to demonstrate the feasibility of prolonged release and to allow early preformulation and formulation development, an automated approach was desired to supply asymmetric membrane capsules of consistent quality and quantities typically required for the for full scale formulation development and for providing supplies for clinical, toxicity, and stability testing In the present work, we successfully designed and fabricated semi‑automatic lab model capsule shell manufacturing 12 equipment with an output of 80‑100 units/day CAB asymmetric membrane capsule shells were prepared by the phase inversion technique of dip coating process manually using polymer concentration between 10 and 16% w/v with PG of 10, 15 and 20% v/v concentrations as plasticizer/pore forming agent The asymmetric membrane capsule shell with 10% w/v concentration (CAB‑10) was found to be very thin, delicate and fragile The capsule shell with 12% w/v concentration (CAB‑12) was intact with snugly fitting body and cap with good uniformity, mechanical strength and reproducibility The capsule shell with 14% and 16% w/v concentration (CAB‑14 and CAB‑16) was found to be very hard, rigid and brittle The flexibility of the capsule shells increased with the increase in plasticizer concentration Hence, further studies had been carried out with CAB‑12 with varying concentrations of PG to check the consistency and reproducibility of the fabricated equipment The polymer and plasticizer concentration had a remarkable effect on the physical parameters like thickness, weight variation and diameter The concentration of polymer had shown positive and the plasticizer concentration had a negative effect on the physical parameters such as thickness, weight variation and diameter The thickness of the different concentrations of asymmetric membrane capsules of CAB‑10, CAB‑12, CAB‑14, CAB‑16 was in the range of 0.445 ± 0.0096‑0.457 ± 0.0094, 0.532 ± 0.0078‑0.739 ± 0.0034, 0.632 ± 0.0054‑0.810 ± 0.0075 and 0.843 ± 0.0057‑0.895 ± 0.0066 mm, respectively [Figure 3] The individual and average weights of the capsule were found to be increasing with an increase in the concentrations of polymer, but in an individual concentration the weight of the capsules was decreasing with an increase in the concentration of the PG due to the decrease in the thickness The average weights of the different formulations of CAB were in the range of 285 ± 32.253‑525 ± 35.537 mg [Figure 4] The increase in the thickness of the formulations containing higher concentrations of the polymer (CAB‑14 and CAB‑16) directly affected the diameter of the capsule shells resulting in poor intactness of the capsules The formulations with a higher concentration of the polymer and lower concentration of PG resulting the rough structure and poor snugly fitting properties Based on the physical characteristics CAB‑12 was selected for the further studies The equipment validation, formulation optimization and other studies had been performed with CAB‑12 capsules with varied concentrations of PG The dye test (osmotic release study) and SEM revealed the fact of semi permeable nature of the prepared capsule shells The dye release from the capsules placed in distilled water and release prevention in the 10% w/v sodium chloride solution attributed the fact of solvent movement based on osmotic pressure and also confirms the fact of semi permeable nature of the capsule shells [Figure 5] The cross‑sectional view of the Asian Journal of Pharmaceutics - January-March 2014 Banala, et al.: Asymmetric membrane capsules for osmotic delivery membrane by SEM [Figure 6a] revealed a distinct asymmetric wall in the structure with denser continuous imperforate outer surface below which were thick interconnected porous membrane and the surface view of the asymmetric membranes [Figure 6b‑d] revealed the increased pore number and size with higher concentration of PG in the capsule shells The consistency reproducibility and efficiency of the fabricated equipment was performed with CAB‑12 formulation at varying concentrations of PG (10%, 15% and 20%) and compared with the manual process Slight reduction in the thickness was observed in the semi‑automatic process compared to the manual manufacturing procedure, but there is a significant reduction in the deviation in the semi‑automatic process compared to the manual process revealed the fact of consistency and reproducibility of the capsule shells [Figure 7] No significant variations in the thickness of capsules of individual mold pins [Figure 8] in different batches confirming the fact of robustness of the fabricated equipment Evaluation of plain and asymmetric films of CAB The thickness of the asymmetric membranes was slightly higher than the plain membranes, which may be due to the phase inversion of the polymer during its manufacturing process The thickness of the plain films was found in the range of 0.371 ± 0.023‑0.513 ± 0.025 mm and asymmetric membrane films were in the range between 0.492 ± 0.034 and 0.739 ± 0.078 mm [Figure 9] The thickness of the plain membranes was found to increase with the increase in the concentration of PG whereas the thickness of the asymmetric membranes was found to decrease with an increase in concentration of PG may be due to miscibility of plasticizer from the polymer with the quench solution during the phase inversion process Figure 4: Average weight of the cellulose acetate butyrate capsule shells (n = 20) Figure 3: Thickness of asymmetric membrane capsule shells of cellulose acetate butyrate (n = 3) Figure 5: Dye test (osmotic release study) showing release of dye in distilled water and intactness in 10% w/v NaCl a b c d Figure 6: Scanning electron photomicrographs (a) cross sectional view (b) Surface view of cellulose acetate butyrate (CAB)-12% w/v, propylene glycol (PG)-10% v/v (c) Surface view of CAB-12% w/v, PG-15% v/v (d) Surface view of CAB-12% w/v, PG-20% v/v Asian Journal of Pharmaceutics - January-March 2014 13 Banala, et al.: Asymmetric membrane capsules for osmotic delivery Figure 7: Comparison of thickness between manual and semiautomatic process (n = 3) Figure 8: Variation in the thickness in different mold pins of the mold plate (n = 3) Figure 9: Thickness of plain and asymmetric membranes (n = 3) The water vapor transmission studies which were carried out to study the permeability and to estimate the extent of porosity in plain and asymmetric membranes also help in determining the effect of concentration of pore forming agent on the porosity of the membrane The rate of water vapor transmission was found to be more in asymmetric membranes compared to plain membranes The concentration of the pore forming agent had a significant positive effect on the rate of water vapor transmission in the asymmetric membranes [Figure 10] Evaluation of asymmetric membrane osmotic capsules containing metformin HCl From Figure 11a‑c, it was observed that there were no changes in the main peaks in the IR spectra of drug and osmogents mixture when compared with the pure sample indicating no physical interactions Thus it can be concluded that the drug was compatible with the formulation components The results of in vitro studies [Figure 12] showed distinguishable difference in the release rate of metformin hydrochloride depending on the concentration of the osmogents in the 14 Figure 10: Water vapor transmission rate of plain and asymmetric membranes formulation blend and the plasticizer concentration in the asymmetric membrane capsule shells The prepared formulations showed a 6‑18 h controlled delivery of metformin hydrochloride From the results obtained, it was clear that the increased concentration of the osmogents and the pore forming agent are affecting positively on the drug release patterns In vitro drug release kinetics studies revealed the best fit model with the r2 and k values for all the formulations The best fit model for the formulations F1M2, F1M3, F1M4, F2M1, F2M3 were found to be Peppas model and other formulations F1M1, F2M3 and F2M4 were following zero order kinetics of drug release It was found that marketed product had followed the matrix model of drug release kinetics The 23 full factorial design which was adopted to study the effect of the independent variable concentration of PG, fructose and potassium chloride on the release of metformin HCl from the asymmetric membrane capsules Based on the results Asian Journal of Pharmaceutics - January-March 2014 Banala, et al.: Asymmetric membrane capsules for osmotic delivery obtained from the experimental runs statistical analysis was performed to find out the optimum levels of variables required for the desired response time taken for 100% drug release The rank order contribution revealed that the concentration of fructose was the key variable having the percentage of contribution of 59.25%, KCl 26.33% and concentration of PG 10.28% From the three dimensional‑response surface graph it was demonstrated that as the concentration of fructose and potassium chloride increased the drug release [Figure 13] A target of 100% drug release in 12 h was fixed and optimization was carried out, from the possible solutions generated by the software, one of the solution was selected randomly and formulated and subjected to evaluation studies [Table 4] The in vitro drug release studies of the OPT showed that complete drug release was achieved at the end of 13th h, which was found to be closer to the predicted response of 12 h The release kinetics of the OPT revealed that it was following zero order kinetics with r2 and k values of 0.9981 and 7.8941 respectively and n value of 0.9187 From the study of the effect of external factors on the drug release conducted on OPT it had been observed that drug release was independent of pH and agitation intensities [Figure 14] The study conducted at different osmotic environments revealed the significance of osmotic pressure on the drug release [Figure 15] In the study at initial 3 h in distilled water had a significant amount of drug release (68.856 mg/h) compared to next 3 h in magnesium sulfate solution (26.36 mg/h) followed by again a significant raise in drug release between and 9 h in distilled water (114.96 mg/h) This revealed that the drug release was completely dependent on the osmotic pressure gradient Table 4: Levels of variables of the OPT Factor Name Level Low High Standard level level deviation A Propylene glycol 15.09 15 20 0.00 conc (% v/v) B Potassium 75.47 75 125 0.00 chloride (mg) C Fructose (mg) 116.17 75 125 0.00 OPT: Optimized formulation Figure 11: Infrared spectra of (a) metformin hydrochloride (b) Fructose (c) Physical mixture of metformin HCl with fructose Figure 12: Comparative in vitro release profiles of the formulations containing metformin HCl with marketed product Figure 13: Three-dimensional surface showing the effect of fructose and KCl on the drug release Figure 14: Effect of osmotic pressure on drug release profile Asian Journal of Pharmaceutics - January-March 2014 15 Banala, et al.: Asymmetric membrane capsules for osmotic delivery REFERENCES Figure 15: Effect of dissolution medium pH on drug release profile Stability studies The OPT of metformin hydrochloride (OPT) when subjected to accelerated stability testing showed a slight change in the physical appearance of the capsule shell with a drug content loss of 1.2% at the end of 6 months The comparative stability in vitro drug release profile of the OPT at specified time intervals was carried out and compared using a model independent pairwise approach of similarity factor f2 The initial sample (0 month) was considered as a reference to calculate f2 values and it was observed that f2 value was found to be 69.87, which confirmed that the drug release profile were similar 10 11 12 13 14 CONCLUSION CAB asymmetric membrane capsule shells were successfully scaled up using designed model lab scale equipment using the phase inversion technique with an output of 80‑100 capsules/day The physical parameters of the capsule walls are more consistent and reproducible in the semi‑automatic process compared to manual procedure The developed system was able to control metformin hydrochloride release for an extended period of time and the process variables were successfully optimized to deliver the drug over a period of 13 h by osmotic mechanism The developed system was independent of external factors like pH and agitation intensity The process employed in the preparation was simple, makes use of limited 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January-March 2014 Banala, et al.: Asymmetric membrane capsules for osmotic delivery 25 Choudhury PK, Ranawat MS, Pillai MK, Chauhan CS Asymmetric membrane capsule for osmotic delivery of flurbiprofen Acta Pharm 2007;57:343‑50 26 Wang GM, Chen CH, Ho HO, Wang SS, Sheu MT Novel design of osmotic chitosan capsules characterized by asymmetric membrane structure for in situ formation of delivery orifice Int J Pharm 2006;319:71‑81 27 Grimm W Extension of the international conference on harmonization tripartite guideline for stability testing of new drug substances and products to countries of climatic zones III and IV Drug Dev Ind Pharm 1998;24:313‑25 How to cite this article: Banala VT, Srinivasan B, Rajamanickam D, Veerbadraiah BB, Varadharajan M Development of asymmetric membrane capsules of metformin hydrochloride for oral osmotic controlled drug delivery Asian J Pharm 2014;8:8-17 Source of Support: Nil Conflict of Interest: None declared Asian Journal of Pharmaceutics - January-March 2014 17 Copyright of Asian Journal of Pharmaceutics is the property of Medknow Publications & Media Pvt Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission However, users may print, download, or email articles for individual use  ... weight change occurred Formulation of asymmetric membrane osmotic capsules of metformin hydrochloride The formulation blend for osmotic delivery system consisted of metformin HCl with potassium... membrane capsules of metformin hydrochloride for oral osmotic controlled drug delivery Asian J Pharm 2014;8:8-17 Source of Support: Nil Conflict of Interest: None declared Asian Journal of Pharmaceutics... Journal of Pharmaceutics - January-March 2014 11 Banala, et al.: Asymmetric membrane capsules for osmotic delivery Table 2: Levels of independent variables taken for optimization of metformin hydrochloride