1. INTRODUCTION:

Osmotic pump tablets are the controlled release (CR) dosage form which offers advantages as minimum adverse reaction, improving patient compliance, in vivo predictability of release rate based on in vitro data etc.

An osmotic pump tablet utilizes the principal of osmotic pressure for controlled delivery of drugs¹. As the osmotic pump tablets can deliver pharmaceutical therapeutic agent at approximately zero-order rate over a long period of time, Pharmaceutical Industry has shown tremendous interest in it over last 2 and half decade.

In 1970s Theeuwes introduced the simplest form of osmotic pump in the form of elementary osmotic pump tablets ². The EOP tablets are formed by compressing a drug having a suitable osmotic pressure into a tablet using a tableting machine. The tablets are then coated with a semi-permeable membrane and a hole is drilled through the membrane coating.

When the tablet is placed in into an aqueous environment, the osmotic pressure of the soluble drug inside the tablet because of passage of water through the semi-permeable membrane is increased. Slight hydrostatic pressure inside the tablet is formed. The pressure is relieved by flow of saturated agent solution through drilled delivery orifice.

EOP tablets are suitable for the moderately water soluble drugs. Design of EOP tablets were modified to make it suitable for less soluble drugs by developing two-compartment ³, two-layer push-pull ⁴ and three layer ⁵ osmotic tablets system. Very limited attempts were made in characterizing of EOP tablets containing inorganic therapeutic agent. The present study was aimed toward verifying feasibility of development of EOP tablets for controlled delivery of inorganic therapeutics agent. The study was also aimed to characterize the EOP tablets regarding delivery orifice size, semi-permeable coating layer thickness/ weight gain. The developed EOP tablets were also tested for its behavioral change with change in pH of dissolution media and also for change in agitation intensity.

Sodium Fluoride was selected as an inorganic therapeutic agent as a model drug for the present study ^{6, 7, 8}. Sodium Fluoride has been used since long time as a dental caries preventing agent and also as therapeutic agent which can prevent bone fracture especially in post-menopause condition. The NaF prevents bone fracture by increasing bone density by virtue of its osteoblast stimulating activity. Immediate release of Sodium Fluoride from conventional tablet dosage form often induces various side effects such as irritation, ulceration or perforation of intestinal wall, mucosal damage, bleeding and gastroenteritis. The controlled slow release of NaF over a prolonged period for delivering therapeutic dose rationalizes its use in present study.

In the developed EOP tablets of NaF, NaCL was included in the core composition to verify the feasibility of sustaining the release of NaF for longer period of time by means of common ion effect. The NaCL offers Na⁺ ion as common ion with NaF salt.

2. MATERIAL AND METHODS:

2.1 Materials-

Sodium Fluoride was purchased from Research Lab. Mumbai (India). Cellulose Acetate-DS 39.8% was purchased from USA (Eastman Chemical INTL.)The other materials are purchased from commercial sources available in India and are used as it is are Sodium Chloride(Merck Ltd.), Potassium Chloride( Merck Ltd. ), Castor oil (Loba Chem.Pvt. Ltd.), Polyethylene Glycol 400 (Loba Chem.Pvt. Ltd., ), Polyvinyl Pyrrolidone (PVP K-30) (S.D.Fine Chemicals), Microcrystalline Cellulose (Research Lab.), Magnesium Stearate (Loba Chemie.Pvt. Ltd.) and Purified Talc (Loba Chemie Pvt. Ltd.). The Acetone and Isopropyl Alcohol used as a coating solvent were purchased from Merck Ltd.

2.2 Drug Analysis-

Sodium Fluoride content in assay test and its release in dissolution test was calculated by detecting fluoride ion (F⁺) by using Fluoride- specific indicating electrode and calomel reference electrode having pH meter capable of minimum reproducibility of 0.2 mV. Calibration curve were plotted by plotting Fluoride concentration in µg per ml. of the standard preparation versus potential in mV. in distill water and phosphate buffer pH 7.4 solutions.

2.3 Granulation and tablet preparation-

Core tablet of Sodium Fluoride was prepared by wet granulation method. The core composition of experimental batches prepared are mentioned in table: 1

Accurately weighed quantities of ingredients mentioned in table 1 were passed through sieve No. 85 (aperture size 180 micron, British standard). All the ingredient, except lubricant (magnesium stearate, talc) and binder polyvinylpyrrolidone (PVP), were manually blended homogeneously in a mortor by way of geometric dilution. The mixture was moistened with aqueous solution of 10% (w/v) PVP, and granulated through sieve No.18 (aperture size 1003 micron, US standard) and dried in a hot air oven at 60 C for sufficient time (3 to 4 hr) so that the moisture of the granules was 2-4 %. The dried granules were passed through sieve No.25 (aperture size 710 micron, US standard) and blended with talc and magnesium stearate. The homogeneous blend was then compressed into tablets (165 mg) using 8- mm diameter, deep concave punches. The compression was adjusted to give tablet with approximately 7-8 kg/cm² hardness on a Monsanto tablet hardness tester.

2.4 Coating of core tablet:

The coating operation was performed on 200-tablet batch in a conventional laboratory model stainless steel, 20 cm pear shaped, baffled coating pan. Baffled were three in number to allow free tumbling of tablet. The pan speed was 20 rpm and the coating solution was sprayed on tumbling bed of tablet with the help of spray gun manually.. The inlet air temperature was 40-45ºc and the manually coating procedure used was intermittent spraying and drying technique. The coat weight and thus was coating thickness was controlled by the volume of coating solution consumed in the coating process. Coated tablet were allowed to dry completely in a hot air oven at 60ºc and finished by standard polishing procedure. An appropriate orifice was drilled on one face of the tablet through the membrane by mechanical microdrill.

Table:1 Core composition of different EOP batches.

Ingredient(mg/tablet)	Batch code
	A1	A2	A3	A4	B1	B2	B3	B4	C1	D1
Sodium Fluoride	25	25	25	25	25	25	25	25	25	25
MCC	132	132	132	132	102	102	102	102	92	102
Potassium Chloride	__	__	__	__	30	30	30	30	40	__
Sodium Chloride	__	__	__	__	__	__	__	__	__	30
Purified Talc	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5
Magnesium Stearate	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5
PVP	5	5	5	5	5	5	5	5	5	5

MCC-microcrystalline cellulose, PVP-Polyvinyl Pyrrolidone

Table: 2. –Coating solution composition

Coating Formulation
Cellulose Acetate	2% w/v
Castor Oil OR	20% of total solid polymer
Polyethylene Glycol(400)	10% w/w
Isopropyl Alcohol	10% v/v
Acetone	q.s. to 100 v/v

2.5. in-vitro release:

In vitro release of sodium fluoride from various EOPs was investigated using the standard USP dissolution apparatus II at 50 rpm. One tablet was placed in 250ml of distilled water equilibrated to 37 +_ 0.1 C. Then 5-ml sample were withdrawn, from the point halfway between the surface of the dissolution medium and the top of the paddle, with pipette at different time interval, replacing with an equal volume of pre-warmed (37±0.1ºc) fresh dissolution medium.

2.6- Drug Release as a Function of Agitation Intensity:

To study the effect of agitation intensity, drug release studies were performed at a high (100 rpm) and low (50 rpm) agitation intensity and at static condition using the USP dissolution apparatus in distilled water. Under static conditions, samples at different times were taken after uniform mixing of the medium to preclude any possible sampling error.

2.7- Effect of pH of the Dissolution medium on Release rate:

Release rates of Sodium Fluorides from EOPs in phosphate buffer of pH 7.4 and in distilled water were compared using USP dissolution apparatus at 50 rpm.

3. RESULT AND DISCUSSION:

3.1: Uniformity of coating:

The uniformity of coating operation of batches were tested by calculating Coefficient of Variations as shown in table: 4

Comparison of CVs of tablet batch before and after coating indicates the uniformity of coating operation. Consistent CVs before and after coating guaranty about coating uniformity.⁹

Less magnitude of coefficient of weight variation, diameter variation, core weight variation and coat thickness variation assured the uniformity of all experimental EOP batches.

3.2. Effect of membrane thickness:

Membrane thickness has a profound effect over the release rate of drug from osmotic pump. To evaluate and quantify the effect of membrane thickness, batches of different membrane thickness was fabricated and their release profile is compared in Fig.1.

Table 3- Physical parameters of experimental EOP batches

No.

Specification

Batches of EOPs

A1, A2 & A3^a

EOPs weight

(mg)

174.3

(5.124)

174.52

(4.274)

169.83

(3.728)

170.8

(3.824)

172.47

(4.123)

171.21

(3.863)

171.21

(4.522)

170.66

(3.872)

Thickness

(mm)

3.9803

(0.048)

4.330

(0.028)

4.9201

(0.046)

4.0420

(0.026)

4.0277

(0.048)

4.2907

(0.048)

3.9212

(0.029)

3.9437

(0.026)

Diameter

(mm)

8.4221

(0.025)

8.4234

(0.026)

8.4242

(0.023)

8.4421

(0.026)

8.4432

(0.023)

8.4023

(0.024)

8.4241

(0.026)

8.4437

(0.036)

Drug Content

(%)

98.6

(1.04)

94.8

(1.4)

96.1

(1.08)

97.4

(1.07)

97.4

(1.07)

95.9

(1.5)

96.4

(1.43)

97.6

(1.24)

Surface area^b

(cm²)

1.361

1.408

1.491

1.375

1.373

1.397

1.355

1.363

Volume ^b

(cm³)

0.119

0.131

0.151

0.121

0.129

0.117

0.118

^a-Formulation variable in orifice diameter only ^b-Calculated from geometry of the tablet

Table 4: Membrane characteristic of experimental EOPs batches

Batches of EOPs
No	Item	A1	A2	A3	A4	B1	B2	B3	B4	C1	D1
1	Coat Nature	SP	SP	SP	MP	SP	SP	SP	MP	SP	SP
2	Coat weight^a(mg)(±SD)	4.5 (0.3)	4.5 (0.25)	4.5 (0.25)	4.5 (0.3)	4.5 (0.25)	7 (0.3)	9 (0.22)	6.5 (0.23)	4.5 (0.3)	4.5 (0.22)
3	Coat Thickness^a (μm)(+-SD)	40 (4)	40 (4)	40 (6)	75 (4)	40 (6)	50 (5)	60 (4)	75 (6)	40 (4)	40 (4)
4	Orifice diameter^a(mm)(+-SD)	__	0.3 (0.1)	0.5 (0.2)	__	0.3 (0.2)	0.3 (0.2)	__	0.3 (0.1)	0.3 (0.1)

MP- Microporous Cellulose Acetate coat with propylene glycol plasticizer, SP- semipermeable membrane with castor oil as plasticizer.

^a–mean of 20 determinations

Table: 5- Percentage drug release per hour (S.D) (n=3)

Time

(hours)

Batch code

0.347

(0.514)

0.915

(0.821)

1.072

(1.203)

11.357

(1.240)

2.800

(0.821)

1.167

(0.231)

1.104

(0.531)

31.009

(0.812)

1.198

(0.812)

0.347

(1.402)

1.482

(0.819)

2.870

(0.861)

3.122

(1.942)

16.536

(1.130)

8.389

(1.010)

7.159

(0.534)

5.841

(2.413)

44.475

(2.743)

10.502

(1.402)

2.239

(2.801)

2.618

(1.654)

5.046

(1.023)

5.456

(0.983)

20.601

(1.324)

16.400

(2.431)

13.499

(3.564)

11.045

(2.768)

54.921

(2.908)

21.667

(2.781)

3.879

(2.943)

3.091

(0.781)

7.098

(0.483)

7.538

(1.230)

24.078

(1.820)

24.726

(2.616)

20.216

(3.728)

16.186

(2.864)

63.789

(2.829)

33.147

(2.684)

5.172

(2.781)

4.037

(1.284)

9.388

(0.846)

9.840

(1.203)

27.175

(2.947)

32.705

(2.130)

26.871

(2.487)

21.989

(2.310)

71.642

(3.158)

45.005

(3.458)

6.844

(2.317)

4.668

(1.953)

11.543

(1.283)

11.795

(0.873)

29.998

(3.451)

41.662

(1.425)

33.115

(2.687)

27.287

(3.481)

78.771

(3.219)

56.012

(3.180)

8.232

(3.573)

5.645

(2.741)

13.845

(1.548)

14.287

(1.364)

32.612

(2.716)

50.241

(2.653)

39.865

(2.786)

33.027

(0.781)

87.001

(3.942)

67.745

(2.482)

9.903

(3.782)

6.497

(3.724)

16.021

(1.873)

16.242

(2.187)

35.060

(1.956)

58.220

(2.104)

45.825

(3.159)

38.452

(4.187)

91.489

(3.124)

78.815

(2.651)

11.669

(3.954)

Figure 1. Effect of membrane thickness on release profile of NaF from EOPs in distill water. Bars represent SD (n=3)

The membrane thickness is inversely proportional to the release rate and eventually with the overall release profile which can express by following equation¹³:

dm/dt = (AS/h) LpσΔπ ------2

Where dm/dt is the zero-order release rate of the drug, A is the surface area of the film coating membrane, h is the membrane thickness, Δπ is the osmotic pressure difference across the membrane at saturation, S is the solubility, Lp is the hydraulic permeability of the membrane and σ is the reflection coefficient having the value of one for an ideal SPM like cellulose acetate and zero for a non-selective membrane.

The weight of the membrane (W) was shown to be related with the membrane thickness as follow:

W=ρmAh ------3

Where. ρm is membrane density. Consequently, the release rate can be expressed s a function of the membrane weight (W) by substituting Eq.3 into Eq.2.

Dm/dt = (A2)S/W) ρm Lpσ π. ------4

From Eq.4 it can be inferred that the release rate is inversely related to the weight of the membrane and also can be observed from the Figure 1.Increase in membrane weight/thickness has shown decrease in release rate of NaF.

3.3 Effect of Delivery orifice size:

Delivery orifice serves as a port through which the drug gets released as a result of build-up of osmotic pressure inside the osmotic pump. The delivery orifice should be sufficiently large enough to release the drug and should not allow the build-up of any hydrostatic pressure as hydrostatic pressure may hinder the zero-order release rate. At the same time it should not be larger so that it will allow release of drug by diffusion and not merely by convection for required zero-order rate.

Hence the delivery orifice size should be within upper and lower limit in order to have zero-order release rate without any hindrance. To observe and get assured of size of delivery orifice of being within limit, batches of different orifice diameter was fabricated and their release rate is plotted in Fig.3.

The delivery orifice size of 0.225 mm and 0.3 mm batches i.e. A2 and A3, has not shown any significant difference in release rate (p=0.01) as can be inferred from the graph plotted comparing the release rate of this two batches in Fig. 2. and also from the release rate comparison from table 6.

Therefore it can inferred that the delivery size of range 0.225 to 0.3 mm has exhibited perfect zero order release rate and has not allowed the diffusion to play a role in release and has also not allowed to build-up the hydrostatic pressure. The pump has maintained its shape during the operating period of 8 hours. Hence it can be inferred that the range of size of delivery orifice is well within limit as described by Theeuwes ¹⁰ and Ramadan and Tawashi ¹¹.

Figure 2. Effects of orifice diameter on release of NaF from EOPs in distill water. Bars represent SD (n=3)

3.4 Effect of Agitation Intensity:

Osmotic pump drug delivery system is such a delivery system which is un affected by environmental condition as agitation intensity. To characterize this feature of osmotic pump the batches coded with A2 and B1 were stirred at 50 and 100 rpm and their release profile was followed. The release profile has not shown any significant changes even on increase of stirring rate, which can be observed from the graph plotted. fig 3 (p=0.01).

Figure 3. Effect of agitation intensity on release of NaF from EOPs in distill water. Bars represent SD (n=3).

3.5 Effect of pH of the Dissolution Medium:

To verify that the drug delivery profile from EOP tablets are independent of the other environmental factor as pH of dissolution medium, the dissolution test was carried out in distill water and in Phosphate Buffer pH 7.4 solution.

This is one of the important test to mark the distinguishing characteristic of osmotic pump and advantage over other delivery system The semi permeable membrane is truly ion selective, ion are not allowed to diffuse through the membrane, while solvent molecule is allowed to pass through it.

The release profiles are plotted in Fig.4 of the batches whose release profile was tested in different pH dissolution medium. The average release rate in different pH media were tested for a statistically significant difference and has resulted in no significant difference.(p=0.05).

Figure 4. Effect of pH of the dissolution medium on release rate of NaF from EOPs Bars represent SD (n=3)

3.6 Kinetics of drug release:

For comparison of In-vitro drug release profile of sodium fluoride from osmotic pump tablets of different membrane type i.e. semi permeable and microporous are shown in Fig.5.

Figure 5. Release profile of NaF from EOPs coated with different membranes in distill water. Bars represent SD (n=3)

To explain the kinetics of drug release, release data were fitted to the modified Korsmeyer equation

Q(t) = K t ⁿ ------1

Where Q(t) is the fraction of the drug released after time t, K is a constant, and n is the time exponent that characterizes the drug transport mechanism¹². When the logarithm of the cumulative percentage released (CPR) is plotted against the logarithm of the time in minutes, the slope of the graph will give the value of the time exponent n. Calculated values of n, along with other release characteristics such as lag time, average release rate, and CPR at 8 hr, for various batches of EOPs are listed in table 7 for comparison.

The category of batches for which the release kinetics was compared is semi permeable and microporous membrane coated batches. The semi permeable membrane was formed by using water in soluble plasticizer, castor oil, and microporous membrane by using soluble plasticizer, polyethylene glycol (400).

The microporous membrane is formed by water soluble plasticizer as it gets in contact with water get soluble and form porous, sponge like membrane. This is evident from the release profile of A4 and B4 coded batches. The drug release is almost diffusion controlled as can be observed by following their curve and can also be confirmed by the value of time exponent. The observance of non-significant zero lag time is attributed to the same reason of nature of membrane i.e. microporous.

On the other hand, the semi permeable membrane coated EOP batches such as A2 and B1 formed by using castor oil as a plasticizer exhibited zero order release pattern¹³. The release was mainly through the delivery orifice and has shown a lag time.

Thus the drug release from the microporous coated EOPs is diffusion controlled while drug release from semi permeable coated EOPs is controlled by convection resulting in consistent linear release.

Increase in quantity of Potassium Chloride from 30 mg to 40 mg in batches coded with A2 & B1 respectively increased NaF release rate (ref. Table: 6 & Fig.1)

Table: 7- Comparison of release characteristic and time exponents of different batches :

Batch code	Average(n=3) Lag time(hr)	Average(n=3) Release rate(mg/hr)	Mean CPR^a±SD At 8 hr	Time Exponent(n)	Coefficient of Determination
A1	1.02	0.812	6.497±1.602	0.998	0.98664
A2	1.01	2.003	16.021±1.864	0.962	0.9651
A3	1.01	2.030	16.242±2.025	0.9754	0.9872
A4	Zero	4.383	35.060±1.946	0.5423	0.9948
B1	1.00	7.278	58.220±0.987	0.9983	0.9986
B2	1.01	5.728	45.825±2.405	0.9482	0.9897
B3	0.97	4.806	38.452±2.721	0.9847	0.9929
B4	Zero	11.436	90.815±2.388	0.5724	0.9937
C1	1.01	9.852	78.815±2.338	1.001	0.9978
D1	1.02	1.459	11.669±2.769	0.9683	0.9980

^a- Cumulative percentage release.

An important feature of any osmotic drug delivery system is that to maintain its mechanical stability and resistance of the film coating to rupture during passage through the gastrointestinal tract. None of the tablet ruptured during the dissolution studies. Empty polymeric shell retained their original shape and floated on the dissolution medium after completion of drug release

Release rate of semi permeable membrane coated osmotic pump were unaffected by hydrodynamic condition and as well by the pH of dissolution medium, confirms the nature of membrane as a semi permeable which is in addition confirmed by release rate is inversely proportional to the membrane thickness. The semi permeable membrane coated batches as A1, A2, A3, B1, B2, B3, C1 and D1 behaved as a true semi permeable. The semi permeable nature of the membrane believed to involve the passage of solvent through the membrane by a diffusion process or by dissolving the material of the membrane in which the solute is insoluble ¹⁴. The kinetics of drug release remain linear as long as the transport mechanism is unidirectional.¹⁵

NaCL was included in batch D1 for offering common ion effect for sustaining the drug action. The drug sodium fluoride drug was incorporated in core formulation along with sodium chloride, which serves as a source of common ion (Na-) for sodium ions of sodium fluoride which has resulted in a decrease in solubility of sodium Fluoride eventually in a sustain action with decreased controlled release rate as evident from fig.6.

Figure 6. Graph showing the effect of common ion on release

of NaF from EOPs in distill water. Bars represent SD (n=3)

4. CONCLUSION

The Elementary Osmotic Pump (EOP) tablets prepared for controlled delivery of inorganic therapeutic agent has behaved in similar manner as EOP for organic therapeutics. It deliver the inorganic agent at approximate zero order and is independent of dissolution pH and agitation intensity. The common ion effect can be utilized to have more sustained delivery in EOP design.

5. REFERENCES:

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Received on 13.12.2012 Accepted on 28.12.2012

Int. J. Tech. 2(2): July-Dec. 2012; Page 42-48