Formulation and Evaluation of Controlled Release Drug Delivery System Containing Water Soluble Drug.

 

Pushpanjali C Ligade*, Kisan R Jadhav and Vilasrao J Kadam

Bharati Vidyapeeth’s College of Pharmacy, CBD Belapur, Sector-8, Navi Mumbai-400 614, India.

*Corresponding Author E-mail: ligadepushpanjali92@rediffmail.com, ligadepushpanjali@yahoo.com

 

ABSTRACT:

The objective of the present study was to develop controlled release tablet of water soluble drug (X) which can release the drug up to time of 12 hrs in predetermined rate. The drug release for extended duration, particularly for highly water soluble drug using a hydrophilic matrix system is restricted because of the rapid diffusion of the dissolved drug though the hydrophilic network. For such drug with high water solubility hydrophobic polymers are suitable, along with a hydrophilic matrix for developing sustained release dosage forms. Therefore in this study both the hydrophilic and hydrophobic polymer was used as matrix material to obtain a desirable drug release, patient compliance and cost–effectiveness. Hence in the present study work an attempt has been made to develop controlled release matrix tablet using hydrophobic and hydrophilic polymers. Matrix materials such as (HPMC) hydroxyl propyl methyl cellulose, hydroxyl propyl cellulose (HPC) and ethyl cellulose (EC), Na CMC, hydrogenated castor oil are tried. The in vitro drug release study and optimization studies revealed that low concentration of HPMC and high concentration of Ethyl Cellulose was able to control the simultaneous release of water soluble drug for 12 hours. Optimization was done using 32factorial design. The in vitro release data followed higuchi equation or matrix model, respectively. In conclusion, the in vitro release profile and the mathematical models indicate that release of drug can be effectively controlled from a single tablet using HPMC and EC matrix system.

 

KEYWORDS: Water soluble drug X, Hydrophobic and Hydrophilic Polymers, Optimization, In-vitro release mechanisms.

 


INTRODUCTION:

Water soluble drug X is an essential precursor for the synthesis of phosphatidylcholine, a key component of cell membranes. Although drug is a naturally occurring endogenous compound, the sodium salt of which is synthesized for clinical use. During ischemia, phosphatidylcholine is broken down into free fatty acids, which in turn are used to generate free radicals that potentiate ischemic injury. As it is a water soluble drug to maintain plasma level concentration (as it has 90% bioavailability) controlled release formulation is required, so the drug is suitable candidate for controlled release drug delivery system. Many of such highly water soluble pharmaceutical agents had not previously been susceptible to controlled-release as their high degree of solubility cause the entire dose of the compound to dissolve and thus be delivered immediately and achieve plateau. In long-term therapy for the treatment of chronic disease conditions, conventional formulations are required to be administered in multiple doses, and therefore have several disadvantages as they required the delivery of small doses many times per day which will maintain the plasma concentration.

 

Thus there remains a significant need for pharmaceutical carrier preparations that will make it possible to administer such highly water soluble pharmaceutical agents on a controlled-release basis as infrequently as once or twice a day.1 Traditionally, solid oral dosage forms are comprised of immediate release (IR) dosages in the form of tablets or capsules. these IR dosage form release the active drug substance into the body of a subject at a rate that is initially very high followed by a rapid decline. One potential result of an IR dosage form is that the subject may have very verifying degrees of blood level fluctuation, which may result in therapeutic overdose, followed by a period of therapeutic under dosing. Another disadvantage with regard to IR dosage form is frequent dosing which ultimately result in poor patient compliance. 2 The usual dose of drug X is 1000-2000mg per day in 2 divided doses. In order to meet this dose requirement tablets that are required should contain 500mg and 1000mg.For fulfilling these dosing requirements, doctors required only 500mg or 1000mg tablets. Thus availability of 1000mg tablet is a distinct need that is felt by the doctors and they would feel better equipped if the additional formulation of 1000mg tablet is made available.

 

MATERIALS AND METHODS:

Hydroxypropylcellulose, sodium carboxymethylcellulose, Hydroxy propylmethylcellulose, Ethyl cellulose, Isopropyl alcohol (IPA), hydrogenated vegetable oil, Magnesium stearate and Talc, all the ingredients used were of analytical grade.

 

Solubility studies:3,4

The equilibrium solubility of drug X was measured at pH 1.2, 2, 4, 6, 8 buffer solutions Excess amounts of the drug was added to 5mL-stoppered glass vials (n = 2). The vials were shaken mechanically at 37ºC ± 0.5ºC for 24 hours. After another 2 days of equilibrium, aliquots were withdrawn and filtered (0.22-μm pore size filter paper). Then, the filtered samples were diluted with an appropriate amount of 0.1 M hydrochloric acid to obtain final solutions of pH 1.2. The final solutions were measured spectrophotometrically at 280 nm, adopting the peak height method (Shimadzu-UV 160A spectrophotometer, Shimadzu, Kyoto, Japan).

 

Drug-excipient compatibility studies

1)    By DSC: The physicochemical compatibilities of the drug (X) and the used excipients were tested by differential scanning calorimetric (DSC) analysis. DSC thermograms of the drug alone and drug-excipient physical mixtures (1:1 wt/wt) were derived from a DSC with a thermal analysis data station system, computer, and plotter interface. The instrument was calibrated with an indium standard. The samples (2-4 mg) were heated (50-C-300-C) at a constant scanning speed (10-C/min) in sealed aluminum pans, using nitrogen as purging gas.

 

2)    By FTIR: The physicochemical compatibilities of the drug and the used excipients were tested by FTIR analysis. IR spectra of the drug alone and drug-excipient physical mixtures (1:1 wt/wt) were compared and correlated. 

 

Formulation of tablets:

Drug (X) and excipients were passed separately through 40 mesh. Ethyl cellulose was sieved through 60 mesh. All the ingredients (except ethyl cellulose, magnesium stearate and talc) were mixed in increasing order of weights and blended for 5 mins. Ethyl cellulose was dissolved in required amount of IPA to make the granulating solution of desired concentration. The dry mixture was granulated by using above granulating solution. The wet mass was passed through 18 mesh. The granules were air dried for 1.5 hrs in maintained conditions in front of dehumidifier. The dried granules were passed through 18 mesh superimposed on 40 mesh. These granules were lubricated with sieved magnesium stearate and Talc. The granules ready for compression were compressed on single punch compression machine with 20.8 x 9.6 mm capsule shaped plain punch, respectively. The tablets were evaluated for appearance, hardness, friability, In-vitro drug release and drug content. Various formulation batches with their respective formula are shown in table no. 1(a) and (b).

 

In-vitro dissolution study:

The study was carried out using 0.01NHCL using the USP apparatus types II, the dissolution medium 1000 ml maintained at 37oc ± 0.5oc, The absorbance was measured at 280nm, the dissolution study were carried out for 8hrs.

 

Optimization studies:5-10

Statistical software, Statease Design-Expert® was utilized to evaluate the response. The expected responses were:

Release in 1 hr:       30-33%

Release in 8 hr:       80-85%

Optimization was done by using 32 factorial design in which two factors were evaluated each at 3 levels and experimental trials were performed on all 9 possible combinations.

 

In-vitro release studies:

The drug release data of optimization batches were evaluated by the model-dependent (curve fitting) method by PCP Disso V3 software developed by Bharati Vidyapeeths College of pharmacy, Pune.

 

Stability studies:11, 12

Final optimized formulation was kept for stability studies for 3 months under conditions recommended by ICH guidelines as 40ºC/75% RH, 30ºC/65% RH and checked for physical parameters and in vitro drug release profiles.

 

Evaluation of drug and tablet blend:-

Physical properties of powder:5,6

Drug was evaluated for the following powder characteristics.

i) Untapped Bulk Density:

Powder weighing 10 g was placed into 100 mL measuring cylinder. Volume occupied by the powder was noted without disturbing the cylinder and bulk density was calculated by the following equation:

 

Bulk density    =            Mass of bulk drug

                                     Volume of bulk drug

The experiment was done in triplicate.

 

ii) Tapped Bulk Density:

Powder weighing 10 g was placed into 100 mL measuring cylinder. The cylinder was then subjected to a fixed number of taps (˜100) until the powder bed volume had reached the minimum level. The final volume was recorded and the tap density was calculated by the following equation:

 

Tap density       =             Mass of bulk drug

                                   Volume of bulk drug on tapping

The experiment was done in triplicate.

 

iii) Compressibility:

Compressibility of the drug was found out using the following formula:

 

% Compressibility   =           ρt – ρu          x  100

                                                  ρt

 


Table 1- Composition of formulation batches

a)    Batch X1-X3 and A1-A5

Ingredient (in mg)

X1

X2

X3

A1

A2

A3

A4

A5

Drug  ‘X’

1098

1098

1098

1098

1098

1098

1098

1098

Avicel pH 101MKcoline sodium

18

8

18

9

8

8

8

8

HPCopyl

-

-

-

9

20

-

-

-

SCMC

-

-

-

-

-

20

25

30

EC

60

70

60

30

30

25

25

20

HCO

-

-

-

30

20

25

20

20

Magnesium stearate

12

12

12

12

12

12

12

12

Talcteesium

12

12

12

12

12

12

12

12

Total

1200

1200

1200

1200

1200

1200

1200

1200

 

 

 

 

 

 

 

 

 

 

 

(b) Batches A6 - A12

Ingredient (in mg)

A6

A7

A8

A9

A10

A11

A12

Drug  ‘X’

1098

1098

1098

1098

1098

1098

1098

Avicel pH 101MKcoline sodium

10

10

10

10

10

10

10

EC 

60

50

50

45

60

55

50

HPMC

20

30

-

-

-

-

-

HPMC K4M

-

-

30

35

-

-

-

HPMCK15M

-

-

-

-

20

25

30

Magnesium stearate

6

6

6

6

6

6

6

Talcteesium

6

6

6

6

6

6

6

Total

1200

1200

1200

1200

1200

1200

1200

 

 


 

 

 

 

 

 

 

 

iv) Angle of repose:

The angle of repose gives an indication of the flow ability of the substance. Funnel was adjusted such that the stem of the funnel lies 2 cm above the horizontal surface. The drug powder was allowed to flow from the funnel under the gravitational force till the apex of the pile just touched the apex of the funnel, so the height of the pile was taken as 2 cm. Drawing a boundary along the circumference of the pile and taking the average of six diameters determined the  diameter of the pile. These values of height and diameter were then substituted in the following equation.

 

               Angle of repose (θ) = tan -1(2h/d)

Where, h is height of the pile and d is the diameter of the pile. The experiment was done in triplicate.

 

v) Flow Rate:

The flow rate gives an indication of the flow ability of the substance. 5 g of drug powder was allowed to flow from the funnel under the gravitational force till complete emptying. The time required for complete removal of the drug from the funnel was determined.

The experiment was done in triplicate.

 

Evaluation of tablet:

Weight variation: Twenty tablets were randomly selected from each batch individually weighed, the average weight and standard deviation of 20 tablet calculated 13.

 

Thickness, length, width: The thickness, length, width of the tablet was measured by using digital vernire caliper, twenty tablets from each batch were randomly selected and respective parameters were measured 14.

 

Hardness: Hardness was measured using dolphin hardness tester, for each batch three tablets were tested 15.

 

Friability: Twenty tablets were weighed and placed in the Roche friabilator and apparatus was rotated at 25 rpm for 4 min. After revolution the tablets were dusted and again weighed 16.

 

Drug content uniformity: Weigh and pulverize not less than 20 tablets and transfer an accurately weighed quantity of powder equivalent to about 100 mg of drug ‘X’  in a 100 ml volumetric flask. Add about 60 ml water and sonicate for about 5 minutes. Dilute upto the mark with water and mix well. Transfer 5 ml of above solution to a 25 ml volumetric flask and dilute upto the mark with water. Mix well and filter through 0.45 µ filter paper, use the filtrate for chromatographic injection.

 

RESULTS AND DISCUSSION:

Solubility Studies:

The results of drug solubility studies in physiological solutions/buffers of pH 1.2, 2, 4, 6, 8 at 37ºC shows  higher solubility value of drug X  at pH 2.

 

Drug-Excipient Interaction:

1)    FOR DSC: Figure 1 shows DSC chromatogram of drug (X) alone and Figure 2 and 3 shows DSC thermograms of  physical mixtures of drug  (1:1 ratio wt/wt) with the polymers EC and HPMC used in this study. Thus, it was thought to indicate that there was no evidence of interactions between drug X and the excipients used in study.

2)    FOR FTIR: Figure 4 shows FTIR spectrum of sample (drug excipient admixture) which was compared with std. spectrum of drug and groups assigned were checked. Thus it was concluded that there was no interaction between drug and excipients used.

 

Figure no. 1:- DSC chromatogram of DRUG.

 

Physical Properties of Starting Material and Granules:

The percent compressibility of the drug was 31.78 % indicating its poor flowability of powder suggesting that it should be granulated prior to compression. The high angle of repose also suggested poor flow properties of the drug. Physical properties of drug are as shown in Table 2 and properties of granules ready for compression (GRC) of respective batches are shown in Table 3.

 

Figure no. 2:- DSC chromatogram of DRUG and EC.

 

Figure no. 3:- DSC chromatogram of DRUG and HPMC.

 

Figure 4:- FTIR spectra comparison of drug-excipient sample with std. drug

 

 

Table no. 2:- - Physical properties of drug powder

No.

Test

Result

1.

Bulk density

0.455 gm/mL

2.

Tap density

0.667 gm/mL

3.

Compressibility

31.78 %

4.

Angle of Repose

37.56 °

5.

Flow Rate

1 g/60 secs

 

 

Physical Properties of Tablets:

The physical properties of the prepared tablets of formulation batches (A6-A12) are as shown in Table 4. The tablets of various batches formulated were evaluated for parameters such as hardness, friability and drug content, thickness, length, width and uniformity of weight. The weight variation tests were performed. The average percentage deviation of all tablet formulation was found to be within the pharmacopoeial limit and hence all formulation passed the test for uniformity of weight. The friability of all formulation was below the 1% limit shown in the pharmacopoeia indicating that the friability is within the standard limit. For all prepared tablets, the SDs of all tests was quite uniform.

 

In vitro dissolution results

In Formulation X1 tablets were prepared using drug, avicel pH101 as diluent and ethyl cellulose-20cps (5% w/v solution) as hydrophobic binder prepared in IPA, magnesium stearate (1% w/w) and talc (1%w/w) as a lubricant and glidant. The tablets did not remain intact and in-vitro dissolution studies showed 92.93% drug release in 1 hr which was unacceptable. Based on the observations from formulation X1, Formulation X2 tablets were prepared using drug, avicel pH101 as diluent and ethyl cellulose-20cps (6%w/v solution) as hydrophobic binder prepared in IPA. The tablets did not remain intact. In-vitro dissolution studies showed 85.25% drug release in 1 hr which was unacceptable. Based on the observations from formulation X2, Formulation X3 tablets were prepared using drug, avicel pH101 as diluent and ethyl cellulose-50cps (5% w/v solution) as hydrophobic binder prepared in IPA. The tablets remained intact but release rate was quite slow. The drug release was 68.88% in 1 hr and about 99.05% drug release in 4 hrs which shows EC alone couldn’t retard the release of drug for significant period of time. Therefore to achieve desirable control on release rate various polymers such as HPC, SCMC, HCO, HPMC, HPMCK4M and HPMCK15M were added one by one in various concentrations in various respective batches by trial and error as discussed below.

 

In Formulation A1 tablets remained intact. Dissolution studies showed 48.30 % drug release in 1 hr and 86.41% drug release in 4th hr. From the above observations, Formulation A2 was planned by increasing concentration of HPC. The tablets remained intact. Dissolution studies showed 49.32 % drug release in 1 hr and 86.82% drug release in 4 hrs which is nearly similar as formulation A1 which was not applicable. In Formulation batch A3 Dissolution studies showed sustained release upto 6 hrs such as 45.04 % drug release in 1 hr and 100.48% drug release in 6th hrs.  From the above observations, Formulation A4 was planned by increasing concentration of SCMC. Dissolution studies showed drug release was sustained upto 8 hrs such as 42.18 % drug release in 1 hr and 98.03% in 8 hrs. From the above observations, Formulation A5 was planned by increasing concentration of SCMC. Dissolution studies showed drug release was sustained upto 8 hrs such as 41.57 % drug release in 1 hr and 97.01% in 8 hrs. The dissolution profile obtained was nearly as similar as formulation A4. Therefore, in Formulation batch A6 tablets were prepared using HPMC (1.66% w/w) as swellable polymer. Dissolution studies showed drug release was sustained upto 8 hrs such as 42.39 % drug release in 1 hr and 88.86% in 8 hrs. From the above observations, Formulation A7 was planned by increasing concentration of HPMC. Dissolution studies showed drug release was sustained upto 8 hrs such as 46.26 % drug release in 1 hr and 90.49% in 8 hrs. The dissolution profile obtained was nearly as similar as formulation A6. Therefore, in Formulation batch A8 tablets were   HPMCK4M (2.5%w/w) as swellable polymer. Dissolution studies showed drug release was sustained upto 8 hrs such as 38.92 % drug release in 1 hr and 84.99% in 8 hrs. From the above observations, Formulation A9 was planned by increasing concentration of HPMC. Dissolution studies showed drug release was sustained upto 8 hrs such as 39.13 % drug release in 1 hr and 87.62% in 8 hrs. The dissolution profile obtained shows increase in drug release as compared to formulation A8. Therefore, in Formulation batch A10 tablets were prepared using HPMCK15M (1.66% w/w) as swellable polymer. Dissolution studies showed drug release was sustained upto 8 hrs such as 37.70 % drug release in 1 hr and 85.19% in 8 hrs. From the above observations, Formulation A11 was planned by increasing concentration of HPMC. Dissolution studies showed drug release was sustained upto 8 hrs such as 33.83 % drug release in 1 hr and 83.56% in 8 hrs. From the above observations, Formulation A12 was planned by increasing concentration of HPMC.   Dissolution studies showed drug release was sustained upto 8 hrs such as 31.99 % drug release in 1 hr and 81.72% in 8 hrs. Dissolution studies or drug release profile obtained was as per specifications decided and matched with the marketed formulation profile.  Therefore this formula was chosen for of optimization study. In-vitro drug release profiles from all formulation batches are shown in Figure 5 (a) and (b).

 

Figure 5:- In-vitro drug release study from formulation batches (a) and (b) - Dissolution profile of batches (X1-X3,A1-A5)

 

(b) - Dissolution profile of batches (A6-A12)

 

 

Optimization results:

The expected responses decided were:

Release in 1 hr:       30-33%

Release in 8 hr:       80-85%

 

Optimization was done by using 32 factorial design. An overlay plot was obtained using Statease Design-Expert® software, to determine the total polymers amount i.e. EC and HPMC required for obtaining formulations having respective release profiles in 1 hr and 8 hrs. Optimization study also helped in finding significant factors and significant levels. Figure 6 (a) and (b) shows the response surface plots for EC and HPMC respectively. Dissolution profile of optimized batch is as shown in Figure 7.

 


Table 3:- Physical properties of GRC [Batch (A6-A12)]

Parameters

A6

A7

A8

A9

A10

A11

A12

Bulk density (gm/mL)

0.64±0.017

0.65±0.002

0.65±0.002

0.70±0.005

0.65±0.012

0.65±0.023

0.63±0.023

Tapped density (gm/mL)

0.72±0.007

0.73±0.005

0.75±0.006

0.81±0.019

0.74±0.016

0.75±0.031

0.73±0.034

Angle of

repose (degree)

20.30±0.04

20.15±0.04

19.80±0.03

20.02±0.07

19.53±0.034

19.2±0.034

19.12±0.034

Flow rate

1gm/30sec

1gm/30sec

1gm/30sec

1gm/30sec

1gm/30sec

1gm/30sec

1gm/30sec

 Compressibility

(% )

10.71±1.51

11.49±0.45

13.21±1.17

12.76±1.31

13.01±0.32

13.08±0.53

12.77±0.53

Moisture content (%)

4.56±0.020

4.48±0.080

4.24±0.035

4.27±0.025

4.16±0.040

4.16±0.015

4.11±0.036

 

Table 4 – Evaluation of tablets

Batch no.

Friability (%)

Hardness (Kg/cm2)

Length (mm)

Width (mm)

Thickness (mm)

  Weight uniformity (mg)

A6

0.025±0.004

12.7±0.208

20.79+0.005

  9.60+0.08

7.14 +0.03

1214 + 3.5

A7

0.023±0.004

12.5±0.566

20.80 +0.02

9.60+0.04

6.29 +0.02

1207 + 4.2

A8

0.014±0.003

12.2±0.305

20.78+0.005

9.62 +0.02

6.28+0.008

1215 + 5.0

A9

0.016±0.004

12.8±0.351

20.80+ 0.02

9.63 +0.01

6.26 + 0.01

1208 + 4.2

A10

0.025±0.003

12.3±0.346

20.80 +0.01

9.62 +0.01

6.26 + 0.01

1212 + 4.1

A11

0.025±0.002

12.5±0.208

20.80 +0.01

9.62 +0.01

6.26 + 0.01

1212 + 3.3

A12

0.017±0.002

12.5±0.251

20.80 +0.01

9.60+0.05

6.25    + 0.01

1218 + 4.5

 

Figure 6:- Response surface plots (a) and (b)

(a)          For 1 hr

 

 (b) For 8 hrs

 

In vitro release mechanism studies: 17-24

The release data of optimization batches were evaluated by the model-dependent (curve fitting) method by PCP Disso V3 software developed by Bharati Vidyapeeths College of pharmacy, Pune. Different kinetic equations (zero-order, first-order, and Higuchi’s equation) were applied to interpret the release rate of the drug from matrix systems. The optimized formulation follows Higuchi model as it has higher value of correlation coeffient (r =0.9971). Therefore, Higuchi equation primarily governed the drug release from the optimized formulation as model applicable to systems with drug dispersed in uniform swellable polymer matrix as in case of matrix tablets with water soluble drug.

It can be described by the equation;

 

Qt =KH ½ or   %R= Kt 0.5

Higuchi describes drug release as a diffusion process based in the Fick’s law, square root time dependant. This relation can be used to describe the drug dissolution from several types of modified release pharmaceutical dosage forms, as in the case of some transdermal (Costa et al., 1996) and matrix tablets with water (heterogeneous) matrix to study the dissolution from water soluble drugs.

 

Stability studies result:

Physical parameters and in vitro drug release profiles within 3 month of stability period was found to be in within permissible limits. % drug content of batch kept for stability studies after respective time interval is as shown in table 5 respectively.

 

Table no. 5:- - Percent drug content of different formulations subjected to stability studies

Time Interval

(days)

% Drug content

40ºC/75% RH

30ºC/65% RH

0

98.58

98.50

30

98.49

98.23

60

98.37

98.17

90

98.25

98.15

 

Figure 7:- In-vitro drug release from optimized batch

 

CONCLUSION:

In vitro release studies demonstrated that the release of water soluble drug X from all prepared matrix tablet formulations was generally sustained.  In addition, in vitro release profiles of the drug from the above-mentioned matrix tablet formulation did not alter significantly upon storage at ambient conditions. Optimization studies helped to find out   the significant factors at significant levels. The release data of optimization batches were evaluated by the model-dependent (curve fitting) method by PCP Disso V3. The drug release pattern of optimized formulation was found primarily governed by higuchi model or by matrix. Higuchi equation applicable to systems with drug dispersed in uniform swellable polymer matrix as in case of matrix tablets with water soluble drug. Drug content analyzed by HPLC was found within limits during 3 month stability period, also dissolution profiles obtained are in acceptable limits. According to stability study data, shelf life (2 years) from the formulation during the three month period of stability testing was calculated as per ICH guidelines. Therefore, these polymers can be used to modify release rates of water soluble drug X in matrix tablets.

 

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Received on 26.10.2009                             Modified on 21.12.2009

Accepted on 23.01.2010                            © RJPT All right reserved

Research J. Pharm. and Tech. 3(2): April- June 2010; Page 468-474