1. INTRODUCTION:

New drug delivery systems are being developed as per the needs of the health care system¹. Drug delivery system that give therapeutic levels of the drug for a long time, which also allow the dose of a drug as per the requirement and would be more effective in recent times. Nowadays, physicians have the choice to choose the delivery of a drug for local effect or instant systemic effect.

However, implantable drug delivery systems ensure adequate doses for the duration of treatment. These systems have several advantages which include, constant and predetermined release, reducing the amount of medication needed and the possible side effects, and increased therapeutic efficacy^2,3,4,5,6. These systems are used to treat ocular disease, tuberculosis, cancer, diabetes, cardiovascular disease, and chronic pain management which require medication for a long duration. Disulfiram has been the first choice of drug prescribed to discourage alcoholics from drinking alcohol because it produces many unpleasant experiences for the person such as hypotension, nausea, facial flushing, etc.^7,8,9,10.

The oral effectiveness of disulfiram is limited because of less patient compliance and poor bioavailability and patients don’t want to take the drug daily. During medication, patients stop the treatment as they may start to drink alcohol.

Thus, the failure of conventional drugs has stimulated interest in treatment with oral subcutaneous disulfiram pellets. Therefore, the present study aims to develop a clinically effective implant. The first method of preparing implantable pellets is to compress the plain disulfiram directly. The present study aimed to check the effect of agitation speed with three different in-vitro dissolution methods i.e., Vial Method (VM) (5mins Shaking at sampling time), Rotary Flask Shaker method (RFM) (25 RPM), and Intrinsic Dissolution method (IDM) on in-vitro release of disulfiram pellets. Finally, an attempt was made to interpret the kinetics and in-vitro mechanism of subcutaneously plain disulfiram implantable pellets release.

2. MATERIAL AND METHODS:

2.1Materials: Disulfiram USP, Methanol AR, Potassium dihydrogen phosphate, Copper (II) Chloride (dihydrate), Magnesium stearate, 0.2 M Sodium hydroxide, and Distilled water.

2.2Apparatus: Rotary Flask Shaker, U.V. spectrophotometer (Shimadzu UV-2501PC), I.R. press (Lab India),

2.3 Software: Sigma-stat version 2.03.

2.4 Drug Identification and Characterization:

Analysis of Disulfiram:

There was no purification applied when using the disulfiram and various physicochemical characteristics were studied.

a) Organoleptic properties and description:

The organoleptic characteristics of plain Disulfiram were studied.

b) Melting point:

The open capillary method was used to determine it.

c) Solubility:

The excess amount of disulfiram was added to the solvent and the supernatant was used for determination of equilibrium solubility by using UV-visible spectrophotometer.

d) UV Spectroscopy:

Disulfiram stock solution (20 µg/ml) was prepared in methanol. Methanolic solution (20 ml) of cupric chloride (0.1% w/v) was made and added to 5.0 ml of the disulfiram stock solution. After being well combined, it was stored for one hour. The UV-visible spectrophotometer was used to record the spectrum in the range of 300–600nm by using methanol and water as a solvent¹¹.

e) Construction of Beer - Lambert’s plot:

Methanol (20ml) was used to dissolve disulfiram (10 mg) and a standard curve was prepared. To prepare 5 to 40mg/ml of this solution, a solution of cupric chloride (0.1% w/v) in methanol was added. The absorbance was noted spectrophotometrically at 395.5nm^12,13.

2.5 Implants preparation:

The active ingredient (200mg of drug in each Implant) was directly compressed to get pellets. IR press and intrinsic Hydraulic Press equipped with 7.98 flat-faced die and punch set were used to prepare all the formulations. The applied compression force for 30 seconds was 550lb/cm², 1100lb/cm², 1650lb/cm²and 2200 lb/cm² for formulations S3, S7, S11, and S15 respectively.

2.6 Implants evaluation:

The implant matrix's hardness, thickness, weight variation, and drug content were assessed¹⁴.

a) Thickness and diameter variation: Micrometer Screw Gauge (Japan) was used for measuring implant thickness (n=6).

b) Hardness test: Monsanto hardness tester (Cadmach, Ahmedabad, India) was used for measuring the implant hardness (n=6).

c) Weight variation: Pellets (n=20), were used for studying weight variation¹⁵.

d) Drug content: The weight of 5 (five) prepared implants were taken to calculate the drug content, as per the below-mentioned procedure.

Standard solution: Disulfiram (40mg/ml)

Sample solution: Methanol (75.0ml) was used to dissolve 0.4 gm of precisely weighed disulfiram powder, and the volume was increased to 100.0ml using methanol. After taking 5.0ml of the solution, it was properly mixed and filtered after being diluted to 100 ml with methanol once more. To 5.0ml of this solution, a 0.1% w/v solution of cupric chloride in methanol was added, yielding 25ml. To create a blank solution, 5.0 ml of methanol was diluted with 25.0ml of cupric chloride solution. At 395.5nm, the extinction of standard and sample solutions was recorded.

2.7 Implant sterilization:

The gamma-ray was used for sterilization of all the formulations. The samples were sent to Bhaba Atomic Research Centre, Mumbai.

Time of exposure – 5 to 7 minutes

Radiation dose – 2.5 Mrad

Sterility test: Direct inoculation method was used. Thioglycollate medium was used in which 20 units were directly transferred and then incubated for 14 days at 30 to 35°C. After 14 days, the formation of turbidity and any microbial growth were observed¹⁶.

Study of In-vitro release:

It was completed via three different techniques, VM, ^{17,18,19,20,
21}RFM and IDM²².

2.8 Data treatment:

Various kinetic equations, including the square root law of kinetic equation, zero-order, first-order, and Korsmeyer Peppas kinetic equations were used for the interpretation of the release rate of all the formulations.

3. RESULTS:

Disulfiram was characterized using spectroscopic techniques as well as physicochemical characteristics. The drug was utilized in the trial without any purification because it was found to be pure. The entire effort involved the compendial approach for drug analysis.

The dissolution data of all the formulations by VM, RFM and IDM are shown in Tables no. 1, 2 and 3.

Table 1: Drug release cumulative percent by vial method (n=3) from formulation (S3, S7, S11, S15)

Time in days

S11

S15

12.88

(±1.11)

11.63

(±1.33)

9.12

(±1.07)

8.7

(±1.46)

16.94

(±0.98)

15.82

(±1.46)

14.32

(±1.62)

13.56

(±1.08)

23.01

(±1.43)

21.1

(±1.68)

19.21

(±0.63)

18.23

(±1.27)

31.87

(±0.96)

29.46

(±1.54)

26.33

(±1.49)

24.87

(±1.18)

40.21

(±0.77)

36.57

(±1.32)

33.45

(±1.53)

32.12

(±1.36)

48.08

(±1.32)

45.94

(±1.71)

40.61

(±1.37)

38.32

(±1.12)

58.98

(±1.22)

52.56

(±0.69)

46.18

(±1.22)

44.74

(±1.43)

65.6

(±1.05)

58.05

(±0.94)

51.93

(±1.74)

50.07

(±1.37)

75.97

(±1.36)

65.36

(±0.73)

57.63

(±1.23)

55.65

(±1.66)

100

97.28

(±0.67)

74.92

(±0.88)

65.32

(±1.37)

63.28

(±1.51)

110

86.63

(±1.29)

74.31

(±0.95)

71.69

(±1.61)

120

97.27

(±1.36)

86.13

(±1.38)

83.18

(±1.28)

130

97.63

(±1.12)

95.71

(±0.86)

Table 2: Drug release cumulative percent by RF method (n=3) from formulation (S3, S7, S11, S15)

Time in days

S11

S15

16.18

(±0.86)

13.23

(±1.16)

11.23

(±1.13)

9.79

(±1.16)

22.16

(±1.66)

19.56

(±1.23)

16.77

(±1.62)

15.67

(±1.23)

29.32

(±1.39)

25.63

(±1.64)

22.78

(±0.85)

21.36

(±1.66)

36.64

(±0.94)

34.23

(±1.32)

30.65

(±0.46)

28.69

(±1.47)

45.10

(±1.49)

42.23

(±0.64)

37.12

(±1.12)

36.98

(±1.32)

56.32

(±1.35)

52.32

(±1.16)

45.66

(±0.73)

43.26

(±0.59)

67.66

(±1.92)

61.96

(±1.38)

54.23

(±1.26)

51.36

(±1.22)

79.77

(±1.38)

73.23

(±0.77)

61.98

(±1.32)

57.23

(±1.37)

96.65

(±0.93)

85.11

(±1.11)

69.12

(±1.09)

62.77

(±1.68)

100

96.67

(±1.36)

77.27

(±1.66)

73.63

(±1.31)

110

86.91)

(±1.53)

84.32

(±1.28)

120

97.81

(±1.28)

96.21

(±1.19)

Table: 3 Drug release cumulative percent by ID method (n=3) from formulation (S3, S7, S11, S15)

Time in days

S11

S15

9.45

(±1.06)

8.61

(±1.21)

7.47

(±1.36)

7.32

(±1.01)

14.18

(±0.76)

13.12

(±1.18)

12.64

(±1.32)

12.11

(±0.39)

20.10

(±0.69)

18.36

(±1.23)

17.12

(±1.02)

17.05

(±0.98)

26.71

(±1.33)

23.67

(±1.08)

23.74

(±0.87)

23.29

(±1.36)

34.32

(±1.40)

28.63

(±0.66)

28.63

(±1.18)

28.38

(±0.77)

41.56

(±1.23)

33.77

(±1.47)

33.45

(±0.40)

32.98

(±0.74)

48.07

(±1.14)

38.87

(±1.03)

38.93

(±0.49)

38.07

(±1.64)

55.31

(±1.61)

43.54

(±1.10)

43.56

(±1.07)

43.12

(±0.70)

63.36

(±1.11)

48.63

(±0.41)

48.67

(±0.49)

48.45

(±0.77)

100

70.23

(±0.40)

53.89

(±1.30)

53.86

(±1.22)

53.36

(±1.01)

110

79.37

(±0.56)

60.21

(±0.60)

59.21

(±1.31)

58.91

(±1.22)

120

87.65

(±1.33)

65.29

(±1.47)

65.11

(±1.03)

64.85

(±0.51)

130

95.78

(±0.77)

71.68

(±1.21)

71.36

(±0.60)

70.97

(±0.49)

140

78.36

(±1.06)

77.23

(±1.01)

77.09

(±1.20)

150

86.12

(±1.22)

82.69

(±1.34)

82.17

(±0.70)

160

96.32

(±1.43)

89.12

(±1.18)

88.61

(±0.63)

170

95.32

(±1.30)

95.04

(±1.07)

To analyze the outcomes of the prepared formulations of disulfiram implants for their in-vitro release, these data were subjected to various dissolution models^,23,24,25,26.

To comprehend the mechanism underlying the release of a drug from subcutaneous tissue and its function in the distribution of a drug into the systemic circulation, the release kinetics of the disulfiram implant were investigated. The results were put to the zero order, first order, Higuchi and Korsmeyer Peppas model, and the release rate constant (K), regression coefficient (R²), diffusion exponent (n) value, and kinetic rate constant (kkp) value, as calculated from zero order, first order, Higuchi and Korsmeyer Peppas equation, are shown in (Table 4 to 7).

Table 4: Zero order dissolution kinetic treatment to formulation (S3, S7, S11, S15) by all three methods

	Equation of Line	Regression Coefficient	Release Rate Constant
Vial Method
S3	y = 0.8844x - 1.4205	0.9788	0.8844
S7	y = 0.7457x + 0.4891	0.9942	0.7457
S11	y = 0.7025x - 1.2234	0.9885	0.7025
S15	y = 0.6529x - 0.3703	0.9936	0.6529
Rotary Flask Method
S3	y = 0.9891x + 0.4725	0.9828	0.9891
S7	y = 0.9297x - 0.6495	0.9914	0.9297
S11	y = 0.7835x + 0.0281	0.9966	0.7835
S15	y = 0.7568x - 0.697	0.9919	0.7568
Intrinsic Dissolution Method
S3	y = 0.7243x - 0.9320	0.9972	0.7243
S7	y = 0.5594x + 0.4867	0.9938	0.5594
S11	y = 0.5449x + 0.8042	0.9988	0.5449
S15	y = 0.544x + 0.5237	0.9988	0.5440

Table 5: First order dissolution kinetic treatment to formulation (S3, S7, S11, S15) by all three methods

		Equation of Line	Regression Coefficient	Release Rate Constant
Vial Method
S3		y = -0.0108x + 2.1796	0.6571	-0.0108
S7		y = -0.0096x + 2.1857	0.7164	-0.0096
S11		y = -0.0086x + 2.1843	0.6953	-0.0086
S15		y = -0.0075x + 2.1514	0.7389	-0.0075
Rotary Flask Method
S3		y = -0.0122x + 2.1693	0.7184	-0.0122
S7		y = -0.0115x + 2.1799	0.7625	-0.0115
S11		y = -0.0109x + 2.1912	0.7367	-0.0109
S15		y = -0.0087x + 2.1594	0.7533	-0.0087
Intrinsic Dissolution Method
S3	y = -0.0084x + 2.1629		0.8133	-0.0084
S7	y = -0.0063x + 2.145		0.7626	-0.0063
S11	y = -0.0061x + 2.1432		0.8388	-0.0061
S15	y = -0.006x + 2.1408		0.8425	-0.0060

Table 6: Higuchi square root dissolution kinetic treatment to formulation (S3, S7, S11, S15) by all three methods

	Equation of Line		Regression Coefficient	Release Rate Constant
Vial Method
S3	y = 0.0915x - 0.1631		0.8676	0.0915
S7	y = 0.0894x - 0.1783		0.8975	0.0894
S11	y = 0.0853x - 0.1885		0.8900	0.0853
S15	y = 0.0830x - 0.1870		0.8844	0.0830
Rotary Flask Method
S3	y = 0.0968x - 0.1412		0.8821	0.0968
S7	y = 0.0967x - 0.1666		0.8889	0.0967
S11	y = 0.0914x - 0.1796		0.9075	0.0914
S15	y = 0.0879x - 0.1785		0.8969	0.0879
Intrinsic Dissolution Method
S3		y = 0.0883x - 0.1938	0.9053	0.0883
S7		y = 0.0771x - 0.1856	0.9111	0.0771
S11		y = 0.0782x - 0.1961	0.9258	0.0782
S15		y = 0.078x - 0.1980	0.9241	0.0780

Table 7: Korsmeyer Peppas model dissolution kinetic treatment to formulation (S3, S7, S11, S15) by all three methods

	Equation of Line	Regression Coefficient	n	kkp
Vial Method
S3	y = 0.7993x - 4.0436	0.9581	0.7933	0.017534235
S7	y = 0.8200x - 4.1932	0.9699	0.8200	0.015097894
S11	y = 0.8714x - 4.5013	0.9902	0.8714	0.011075719
S15	y = 0.8784x - 4.5734	0.9889	0.8784	0.010322802
Rotary Flask Method
S3	y = 0.6851x - 3.4836	0.9703	0.6851	0.030696704
S7	y = 0.7608x - 3.8522	0.9786	0.7608	0.021232972
S11	y = 0.8152x - 4.1585	0.9831	0.8152	0.015630987
S15	y = 0.8720x - 4.4170	0.9909	0.872	0.012070389
Intrinsic Dissolution Method
S3	y = 0.8757x - 4.4908	0.9857	0.8757	0.11211671
S7	y = 0.8263x - 4.4517	0.9941	0.8263	0.01165873
S11	y = 0.8765x - 4.6718	0.9975	0.8765	0.009355415
S15	y = 0.885x - 4.7196	0.9974	0.885	0.008918745

Effect of all three in-vitro release methods (RFM, VM and IDM) on in-vitro release of formulation S3, S7, S11 and S15

Effect of method on S3 formulation

Table 8: ANOVA for RFM, VM and IDM method effect on release of formulation S3

ANOVA Table	SS (Type III)	DF	MS	F (DFn, DFd)	P value
Row Factor	28334	13	2180	F (13, 19) = 64.93	P<0.0001
Column Factor	1104	2	552.2	F (2, 19) = 16.45	P<0.0001
Residual	637.7	19	33.56

P (< 0.0001) value summary: Method Effect: Significant

% Cumulative drug released data of formulation S3 (a plain drug with compression force 550 lb/cm²) by all three methods were put through Tukey's multiple comparison test after a two-way analysis of variance, showing there was a significant effect of three different methods on release with p value <0.0001 (Inference no. 1).

Method effect on S7 formulation:

Table 10: ANOVA for Effect of Method (RFM, VM and IDM) on release of formulation S7

ANOVA Table	SS (Type III)	DF	MS	F (DFn, DFd)	P value
Row Factor	31963	16	1998	F (16, 22) = 33.03	P<0.0001
Column Factor	2204	2	1102	F (2, 22) = 18.22	P<0.0001
Residual	1331	22	60.48

P (< 0.0001) value summary: Method Effect: Significant

Table 11: Tukey's multiple comparisons test S7

Tukey's multiple comparisons test	Mean Diff.	95.00% CI of diff.	Below threshold?	Summary	Adjusted P Value
RFM (S7) vs. VM (S7)	9.898	-1.271 to 15.07	Yes	**	0.0032
RFM (S7) vs. IDM (S7)	19.09	10.92 to 27.26	Yes	****	<0.0001
VM (S7) vs. IDM (S7)	12.19	4.527 to 19.85	Yes	**	0.0017

% Cumulative drug released data of formulation S7 (plain drug with compression force 1100 lb/cm²) by all three methods were put through Tukey's multiple comparison test after a two-way analysis of variance, showing there was a significant effect of three different methods on release with p value < 0.0001 (Inference no. 2).

Table 12: In-vitro release of formulation S11

ANOVA Table	SS (Type III)	DF	MS	F (DFn, DFd)	P value
Row Factor	36162	17	2127	F (17, 25) = 65.68	P<0.0001
Column Factor	1409	2	704.4	F (2, 25) = 21.75	P<0.0001
Residual	809.6	25	32.38

P (< 0.0001) value summary: Method Effect: Significant

Table 13: Tukey's multiple comparisons test S11

Tukey's multiple comparisons test	Mean diff.	95.00% CI of diff.	Below threshold?	Summary	Adjusted P Value
RFM (S11) vs. VM (S11)	6.006	0.4966 to 11.52	Yes	*	0.0307
RFM (S11) vs. IDM (S11)	14.47	8.955 to 19.97	Yes	****	<0.0001
VM (S11) vs. IDM (S11)	8.459	3.101 to 13.82	Yes	**	0.0016

% Cumulative drug released data of formulation S11 (a plain drug with compression force 1650 lb/cm²) by all three methods were put through Tukey's multiple comparison test after a two-way analysis of variance, showing there was a significant effect of three different methods on release with p value < 0.0001(Inference no. 3).

Effect of method on S15 formulation

Table 14: ANOVA for RFM, VM and IDM method effect on release of formulation S15

ANOVA Table	SS (Type III)	DF	MS	F (DFn, DFd)	P value
Row Factor	34981	17	2058	F (17, 25) = 73.47	P<0.0001
Column Factor	1046	2	522.9	F (2, 25) = 18.67	P<0.0001
Residual	700.2	25	28.01

P (< 0.0001) value summary: Method Effect: Significant

Table 15: Tukey's multiple comparisons test S15

Tukey's multiple comparisons test	Mean Diff.	95.00% CI of diff.	Below threshold?	Summary	Adjusted P value
RFM (S15) vs. VM (S15)	5.239	0.1149 to 10.36	Yes	*	0.0444
RFM (S15) vs. IDM (S15)	12.47	7.348 to 17.60	Yes	****	<0.0001
VM (S15) vs. IDM (S15)	7.233	2.251 to 12.22	Yes	**	0.0036

% Cumulative drug released data of formulation S15 (a plain drug with compression force 2200 lb/cm²) by all three methods were put through Tukey's multiple comparison test after a two-way analysis of variance, showing there was a significant effect of three different methods on release with p value <0.0001(Inference no. 4).

4. DISCUSSION:

It is obvious from the regression coefficient that all the formulations exhibited zero-order kinetics. Therefore, zero-order release constants were used for all the statistical interpretations.

There were a few things that made the zero-order equation less applicable. So, the diffusion exponent (n) value was calculated from the Korsmeyer Peppas equation to comprehend the mechanism of release.

In case I, n = 0.45: Fickian diffusion was a first-order and diffusion is the main release mechanism.

In case II, n = 1: Non-Fickian transport showed zero-order kinetic.

n>1: Supercase II: It showed when modifications in the matrix were severe.

For Intrinsic Dissolution Method: Formulations S3, S7, S11 and S15 have n value in between 0.45< n<1 which represents Anomalous Transport, these formulations release was characterized by diffusion and dissolution.

For Vial Method: Formulations S3, S7, S11 and S15 have n value between 0.45<n<1 which represents Anomalous Transport, these formulations' release was characterized by diffusion and dissolution.

For R.F. Method: Formulations S3, S7, S11 and S15 have n value in between 0.45<n<1 which represents Anomalous Transport, these formulations release was characterized by diffusion and dissolution.

From (Inference no. 1,2,3 and 4), the formulations S3, S7, S11 and S15 (Plain drug with compression force 550 cm², 1100 lb/cm², 1650cm² and 2200 cm² respectively) showed significant effects of three different methods on release with p value<0.0001.

The dissolving volume medium and agitation speed of the three previously described procedures employed in this investigation are different. Therefore, as can be seen from Tables 1, 2, and 3, the rotary flask approach produced a greater amount of drug release than the vial method for the identical formulation (in the case of formulations S3, S7, S11, and S15). The higher release of a drug could be because of agitation in the Rotary Flask method. In the Rotary Flask method increase in the hydrodynamics causes a reduction of diffusional distance, hence a rise in the rate of disintegration. When the Vial method and RF method release were compared with the Intrinsic Dissolution method it showed a significant difference in release. This may be due to two reasons first may be the volume of the dissolution medium is 900ml and the second reason may be the intrinsic dissolution apparatus ensures the constant surface area i.e., only one end of the formulation was exposed to the dissolution media so that the release was affected or delayed as less surface area was in contact. Thus, suggesting exposed surface area to the dissolution medium had a marked effect on the dissolution rate of the disulfiram implant.

5. CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

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Received on 23.09.2023 Modified on 15.01.2024

Research J. Pharm. and Tech 2024; 17(7):3163-3168.

DOI: 10.52711/0974-360X.2024.00494