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

Development of asymmetric membrane capsules of metformin hydrochloride for oral osmotic controlled drug delivery Venkatesh Teja Banala, Bharath Srinivasan, Deveswaran Rajamanickam, Basa

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 Varadharajan 1

Departments of Pharmaceutics, and 1 Pharmacognosy, M S Ramaiah College of Pharmacy, Bengaluru, Karnataka, India

Asymmetric 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

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

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

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DOI:

10.4103/0973-8398.134088

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

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

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

Figure 1: Original image of the fabricated equipment with labeled parts

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]

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

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

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

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

t a

×

24

(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 r 2-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]

Table 1: Composition of asymmetric membrane capsules of CAB

solution solution Sealing

-CAB: Cellulose acetate butyrate, q.s: Quantity sufficient

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 0 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, 4 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

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

Table 2: Levels of independent variables taken for 

optimization of metformin hydrochloride formulations

A - Propylene glycol (plasticizer) (% v/v) 15 20

B - Potassium chloride (osmogent) (mg) 75 125

Table 3: Experimental design summary of the metformin 

hydrochloride formulations

code Concentration

of propylene

glycol (% v/v)

Concentration

of potassium

chloride (mg)

Concentration

of fructose (mg)

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 3: Thickness of asymmetric membrane capsule shells of

cellulose acetate butyrate (n = 3)

Figure 4: Average weight of the cellulose acetate butyrate capsule

shells (n = 20)

Figure 5: Dye test (osmotic release study) showing release of dye in

distilled water and intactness in 10% w/v NaCl

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

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

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 r 2 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

Figure 7: Comparison of thickness between manual and

semi-automatic process (n = 3)

Figure 9: Thickness of plain and asymmetric membranes (n = 3)

Figure 8: Variation in the thickness in different mold pins of the mold

plate (n = 3)

Figure 10: Water vapor transmission rate of plain and asymmetric membranes

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 r 2 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 6 and 9 h in distilled water (114.96 mg/h) This revealed that the drug release was completely dependent on the osmotic pressure gradient

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

Table 4: Levels of variables of the OPT

level High level Standard  deviation

OPT: Optimized formulation

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

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 adjuvants,

cost-effective and industrially feasible The semi-automatic

process improved the reproducibility and allowed to

manufacture a sufficient number of capsules in less time

to support formulation development

ACKNOWLEDGMENTS

The authors are thankful to the Gokula Education Foundation, Bangalore

for providing necessary facilities to carry out the research work and

Indian Institute of Science, Bangalore for providing SEM facility.

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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.