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Open Access  Full Text Article                                                                           Research Article

Formulation Development and Evaluation of New Albendazole Tablets with Integrated Quality by Design (QbD) Approach

Dnyaneshwar G. Sitre*, Ravindra K. Kamble

Bhupal Nobles University, Maharana Pratap Station Road, Udaipur 313001, Rajasthan, India

 

Article Info:

_________________________________________

Article History:

Received 07 Jan 2021;     

Review Completed 23 Feb 2021

Accepted 06 March 2021;  

Available online 15 March 2021 

___________________________________________________________

Cite this article as:

Sitre DG, Kamble RK, Formulation Development and Evaluation of New Albendazole Tablets with Integrated Quality by Design (QbD) Approach, Journal of Drug Delivery and Therapeutics. 2021; 11(2):123-134                                                                DOI: http://dx.doi.org/10.22270/jddt.v11i2.4782    ______________________________

*Address for Correspondence: 

Dnyaneshwar G. Sitre, Bhupal Nobles University, Maharana Pratap Station Road, Udaipur 313001, Rajasthan, India

Abstract

______________________________________________________________________________________________________

Hydatid disease occurs in most areas of the world and currently affects about one million people. Albendazole is an orally administered broad spectrum anthelmintic drug approved by US FDA in 1996. Literature review suggests Albendazole is low solubility compound and most of the studies were performed to improve the solubility with traditional approach of product development. The present study was aimed to apply Design of Experiments (DoE) in the development and optimization of drug release from new Albendazole tablets using three factor two level (23) full factorial designs with integrated Quality be Design (QbD) approach. New Albendazole tablets were formulated using micronized grade of the Albendazole active and excipients were selected inline with market reference product. Quality target product profile (QTPP) and Critical quality attributes (CQAs) were designed. Risk assessment was used to identify the Formulation variables impacting CQA dissolution. The amount of Formulation variables were optimized on the basis of drug release profiles at 15 minutes and 30 minutes of different formulation batches manufactured based on 23 full factorial design. Tablets were prepared by wet granulation technique and evaluated for various physicochemical parameters and in vitro drug release. Formulation trials dissolution results at 15 minutes and 30 minutes were evaluated to derive the concentration of Formulation variables which will achieve the release of more than 80%. Analysis of variance (ANOVA) analysis, Pareto chart and Contour plot were used to predict the values of formulation variables and their effect on dissolution.  Updated risk assessment of the Formulation Variables was performed and justification was provided for reduction of risk from medium to low level. Optimized formulation from DOE had comparable dissolution profile with market reference tablet. Stability studies of new Albendazole tablets 200 mg were conducted at ICH accelerated conditions and found to be stable. Thus studies revealed that full factorial experimental design could efficiently be applied for optimization of formulation variables affecting drug release. New Albendazole tablets 200 mg successfully formulated with application of the integrated quality by design (QbD) and design of experiment (DOE) approach and thereby achieved comparable release profile with market reference product.

Keywords: Albendazole, Experimental design, Full Factorial Design, Design of experiment & Dissolution

 


INTRODUCTION

Oral route is one of the most useful route for the systemic effect due to its ease of intake, convenient, non-invasive and most importantly, in terms of patient compliance. Sterile conditions are not required for the manufacturing of Solid oral delivery systems there by reducing the cost of production. Tablet dosage forms that are intended to be swallowed whole followed by disintegration and immediate release of medicaments in the gastrointestinal tract1.

Albendazole is an orally administered broad-spectrum anthelmintic. Albendazole is poorly absorbed from the gastrointestinal tract due to its low aqueous solubility2. Although the detailed mechanisms of action of albendazole are unclear, experimental evidence from exposure of intestinal helminths of several different species shows that the parasites suffer from metabolic disruption at a number of different sites, most of which are involved in energy production in the parasite3.

Quality by Design is the modern approach for quality of pharmaceuticals. QbD is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management4. DoE is a structured, organized method for determining the relationships among factors affecting a process and its output. It has been suggested that DoE can offer returns that are four to eight times greater than the cost of running the experiments in a fraction of the time that it would take to run one-factor-at-a-time experiments5.

Literature review suggests that Albendazole is low solubility compound and most of the studies were performed to improve the solubility of the Albendazole with traditional approach of product development. This scientific work comes with application design of experiments (DoE) in the development and optimization of drug release from new Albendazole tablets using three factor two level (23) full factorial designs with integrated Quality be Design (QbD) approach.

MATERIALS AND METHODS

MATERIALS

API Albendazole USP grade manufactured by Enaltec Labs pvt. Ltd. Mumbai India was used for the formulation development. Selections of excipients was based on excipients commonly found in medications        available on the market and the inline with market reference product. Ingredients including Lactose monohydrate grade Pharmatose 200M (DFE Pharma), Microcrystalline cellulose grade Avicel PH 101 (FMC), Maize starch grade Maize starch B (Roquette), Polyvinyl pyrrolidone grade Povidone K-30 (ISP), Sodium lauryl sulfate grade Kolliphor SLS fine (BASF), Saccharin sodium (Spectrum), Sodium starch glycolate grade Primojel (DFE Pharma), Magnesium stearate grade Hyqual (Avantor) and Hypromellose E3 (Dow) were used for manufacturing of the product. Analytical grade and HPLC grade reagents were used for analytical part of this study during the pre-formulation and formulation stages.

The equipments including Analytical balance (Sartorius BT2245), Rapid mixer granulator (Sainath boilers & pneumatics), Dryer (Retsch dryer), Octagonal blender (Karnawati eng. Ltd.), Compression machine (Cadmach) & Tablet coating machine (Neocoata) were used to manufacture and coat tablets. In-process instruments used for the tablet evaluation includes Moisture analyzer (Sartorius MA150), Tablet hardness tester (Dr. Schleuniger), Disintegration test apparatus (Electrolab), Friability test apparatus (Electrolab), Density measurement apparatus (Electrolab). Analysis equipments including a Ultraviolet–visible spectrophotometer, Dissolution test apparatus (Electrolab) & High-performance liquid chromatography system (Agilent) with Column: Inertsil- ODS-3V, 250 x 4.6mm, 5µ & Rotatory shaker were used. The factorial design in the Minitab software was used to generate and evaluate the trial batches. A p-value less than 0.05 (typically ≤ 0.05) indicate result as statistically significant.

METHODS

Preformulation studies

Preformulation studies were designed to identify physicochemical properties of Albendazole and excipients that may influence formulation design and method of manufacture. Studies performed include Bulk density (BD), Tapped density (TD), Hausner’s ratio (HR) & Compressibility index (CI) of Albendazole. In addition Loss on drying, Melting point, Solubility study & Drug-Excipients interaction studies were performed. Analytical UV and HPLC methods were developed for the analysis of dissolution and assay6,7.

Formulation development with integrated QbD approach

Following steps are involved in the Formulation development of new Albendazole tablets with integrated QbD approach.

 

Preparation of Formulation batches of New Albendazole tablets 200 mg

Tablets were prepared by wet granulation technique13,14. Each batch of tablets (T1 – T9) has varied amount of Povidone K 30, Sodium Lauryl sulphate & Sodium starch glycolate. All ingredients were weighed accurately in required quantity. Albendazole, Lactose monohydrate, Microcrystalline cellulose and Maize starch were sifted through #40 mesh and blended for 10 minutes in rapid mixer granulator at impeller speed of 200 rpm and chopper off for 10 minutes. Granulation fluid was prepared by dissolving Povidone K30 in Purified water. Sodium lauryl sulfate was added under stirring to the binder solution. Binder Addition was performed at 200 rpm impeller speed and chopper off for 2 minutes and kneading for 1 minute at 200 rpm impeller speed and chopper speed of 200 rpm. Wet granules were dried at 60°C in  dryer till LOD reaches below 2%. Dried granules were sifted through #24 mesh. Sodium starch glycolate, sodium saccharin and Colloidal silicon dioxide were sifted through #40 mesh and mixed into the octagonal blender for 10 minutes. Magnesium stearate was sifted through ASTM #60 mesh & mixed with blend for 5 minutes. Lubricated blend was compressed into tablets by using 11.50 mm Round standard concave tooling using compression machine. HPMC E3 (Methocel E3 Premium LV) was dispersed in purified water to get the 10% dispersion. Core tablets were loaded into the coating pan and warm it for few minutes. Start spraying of solution and continue till the weight gain achieves to the 2%. Formulation of tablets batches of new Albendazole tablets are represented in table 1.


 

 

 

 

 

 

 

 

 

Table 1: Formulation of batches of new Albendazole tablets

Ingredients

T1

T2

T3

T4

T5

T6

T7

T8

T9

Dry Mix

Albendazole

200.0

200.0

200.0

200.0

200.0

200.0

200.0

200.0

200.0

Lactose monohydrate

195.9

195.9

195.9

195.9

195.9

195.9

195.9

195.9

195.9

Microcrystalline cellulose

91.5

91.5

91.5

91.5

91.5

91.5

91.5

91.5

91.5

Maize starch

120.0

120.0

120.0

120.0

120.0

120.0

120.0

120.0

120.0

Binder

Povidone K30

20.0

20.0

10.0

10.0

20.0

10.0

15.0

10.0

20.0

Sodium lauryl sulfate

1.0

2.0

2.0

2.0

2.0

1.0

1.5

1.0

1.0

Purified water

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

Pre-lubricants

Sodium saccharin

1.5

1.5

1.5

1.5

1.5

1.5

1.5

1.5

1.5

Sodium starch glycolate

4.6

4.6

4.6

14.6

14.6

14.6

9.6

4.6

14.6

Colloidal silicon dioxide

3.2

3.2

3.2

3.2

3.2

3.2

3.2

3.2

3.2

Lubricant

Magnesium stearate

4.8

4.8

4.8

4.8

4.8

4.8

4.8

4.8

4.8

Total weight

640.0

640.0

640.0

640.0

640.0

640.0

640.0

640.0

640.0

Coating

Hypromellose 2910

12.8

12.8

12.8

12.8

12.8

12.8

12.8

12.8

12.8

Purified water

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

Total weight

652.8

652.8

652.8

652.8

652.8

652.8

652.8

652.8

652.8

 


Evaluation of the Lubricated blend15,16,17

Lubricated blend was evaluated for the following parameters

Bulk Density

Bulk density is used to determine the amount of drug that occupies the volume in g/mL.  The bulk density of the ingredients was evaluated using a graduated cylinder. It is the ratio of total mass of powder to the bulk volume of powder. It was measured by pouring the weighed quantity of powder into a graduated measuring cylinder and the volume was noted. It is expressed in g/mL and is calculated by using following formula

Bulk density

=

Mass of powder blend

Volume of powder blend

Tapped density

It is the ratio of total mass of powder to the tapped volume of powder. The tapped volume was measured by tapping the powder 10, 500, 1250 taps in tap density apparatus. The blend was subjected for 500 taps; % Volume variation was calculated and subjected for additional 1250 taps, % variation is calculated.

Tapped Density

=

Mass of powder blend

tapped volume of powder blend

Compressibility index (Carr’s index)

Compressibility index is an important measure that can be obtained from the bulk and tapped densities. A material having values of less than 20% is defined as the free flowing material.

Carr's index=

Tapped Density- Bulk Density

×100

 

 

                       Tapped Density

Hausner’s ratio

It indicates the flow properties of the granules and is measured by the ratio of tapped density to the bulk density.

Loss on drying

Loss on drying was carried out by using halogen moisture analyser at 105˚C for 5 minutes with 1.0 – 2.0 g powder samples18.

Evaluation of Core tablet Compression parameter19

Tablets are evaluated as per Pharmacopoeial specification 

Weight of tablet

Ten tablets were randomly selected from each batch and individually weighed. The average weight of ten tablets was calculated.

Tablet Dimensions

Thickness of the tablets was measured using a Vernier calliper. It was determined by checking ten tablets from each formulation batch. It is expressed in mm.

Hardness:

Hardness indicates the ability of a tablet to withstand mechanical shock while handling. For each formulation, ten hardness of tablet was determined by using hardness tester. It is expressed in N.

Friability

Sample of whole tablets corresponding to about 6.5 g was withdrawn. Dedust the tablets carefully and weigh accurately the required number of tablets. Place the tablet in the Roche friabilator. The friability was operated at 25 rpm at 100 revoluation then remove any loose dust from tablets and weigh them accurately. A maximum loss of weight not greater than 1.0 % is acceptable for tablet. The percent friability was calculated by using following equation.

% F=

1-

W

x 100

W0

Where, % F = friability in percentage

             W = weight of table after revolution

             W0 = Initial weight of tablet

Disintegration Time

In vitro disintegration time of tablets from each formulation was determined by using disintegration apparatus. In vitro disintegration test was carried out at 37  2˚C in 900 ml by using disintegration media water. Six tablets of each formulation were taken and placed in tubes of disintegration apparatus. The time taken for complete disintegration was noted.

In vitro drug release study20

In vitro dissolution study was carried out for all formulations of new Albendazole tablets and market reference product in 900 mL of 0.1N HCl, Apparatus II at 50 rpm and analyzed at 308 nm by UV spectrophotometer. Dissolution of the DOE batches was compared with market reference product using F2 (Similarity factor) criteria. Batch with F2 more than 50 is considered as comparable with market reference product.

Stability Study

The final formulation from DOE studies was subjected to accelerated stability study (40ºC/75% RH) for the period of three months as per ICH guidelines. Physical stability was analyzed by recording the change in appearance and chemical stability was analyzed by the change in the assay, impurities, water by KF and in vitro drug dissolution at the end of three months21.

RESULTS

Preformulation studies

Albendazole was found to have very poor compressibility and flow properties ( BD: 0.196 g/mL, TD: 0.300 g/mL, Carr’s index of 34.66% and Hausner’s ratio of 1.53) hence wet granulation method was opted to achieve better compression and good flow property for the preparation of the new Albendazole tablets 200 mg. Albendazole is low solubility drug. The drug has pH dependent solubility nature. It has good solubility in strong acidic condition with 0.385 mg / ml. Melting point of Albendazole was found to be in range as given in literature (205-210˚C).

 Design of Quality target product profile (QTPP) for new Albendazole Tablets, 200 mg Based on the clinical and pharmacokinetic characteristics as well as the in vitro dissolution and physicochemical characteristics of the market reference product, a Quality target product profile (QTPP) was defined for new Albendazole Tablets, 200 mg and represented in below table 2.


 

Table 2: Quality target product profile (QTPP) for new Albendazole tablets 200 mg

QTPP Elements

Target

Justification

Dosage form

Tablet

Pharmaceutical equivalence requirement: same dosage form.

Dosage design

Immediate release tablet without a score

Immediate release design needed to meet label claims.

Route of administration

Oral

Pharmaceutical equivalence requirement: same route of administration

Dosage strength

200 mg

Pharmaceutical equivalence requirement: same strength

Pharmacokinetics

Bioequivalent to  Reference product

Bioequivalence requirement Needed to ensure rapid onset and efficacy

Stability

At least 24-month shelf-life at room temperature

Equivalent to or better than reference product shelf-life

Drug product quality attributes

 

Physical Attributes

Pharmaceutical equivalence requirement: Must meet the same compendial or other applicable (quality) standards (i.e., identity, assay, purity, and quality).

 

Identification

Assay

Content Uniformity

Dissolution

Degradation Products

Residual Solvents

Water Content

Microbial Limits

Container closure system

 

Container closure system qualified as suitable for this drug product

Needed to achieve the target shelf-life and to ensure tablet integrity during shipping

Administration / Concurrence with labeling

Similar food effect as reference product

The product can be taken without regard to food.

 

Identification of Critical Quality Attributes (CQAs) of New Albendazole Tablets, 200 mg

Critical Quality Attributes (CQAs) of New Albendazole Tablets, 200 mg are represented in the following table 3.

Table 3: Critical quality attributes (CQA) for new Albendazole tablets 200 mg

Quality Attributes

Target

 

Is this

CQA?

Justification

 

Appearance

Color and shape acceptable to the patient.

No

Color, shape and appearance are not directly linked to safety and efficacy. Therefore, they are not critical. The target is set to ensure patient acceptability.

Size

Similar to reference product

No

For comparable ease of swallowing as well as patient acceptance and compliance with treatment regimens, the target for tablet dimensions is set similar to the reference product.

Score configuration

Unscored

No

The reference product is an unscored tablet; therefore, the new tablet will be unscored.

Friability

NMT 1.0% w/w

No

A target of NMT 1.0% w/w of mean weight loss assures a low impact on patient safety and efficacy and minimizes customer complaints

Identification

Positive for Albendazole

Yes*

Formulation and process variables do not impact identity. Therefore, this CQA will not be discussed during formulation and process development.

Assay

100% w/w of label claim

Yes

Assay variability will affect safety and efficacy. Process variables may affect the assay of the drug product. Thus, assay will be evaluated throughout product and process development.

Content Uniformity

(CU)

Conforms to USP <905> Uniformity of Dosage Units

Yes

Variability in content uniformity will affect safety and efficacy. Both formulation and process variables impact content uniformity, so this CQA will be evaluated throughout product and process development.

Dissolution

Not less than 80% (Q)

Yes

Failure to meet the dissolution specification can impact bioavailability. Both formulation and process variables affect the dissolution profile. This CQA will be investigated throughout formulation and process development.

Degradation Products

As per ICH guidance

Yes

Formulation and process variables can impact degradation products. Therefore, degradation products will be assessed during product and process development.

Water Content

NMT 4.0% w/w

No

Albendazole is not sensitive to hydrolysis and moisture will not impact stability.

 

The physicochemical characterization of the Market reference product tablet

The physicochemical characterization of the Market reference product tablet was performed and results are summarized in Table 4.

Table 4: Market reference product evaluation

Brand Name

Albenza® Albendazole tablets USP 200 mg

Lot No.

F4003

Manufacturer

GlaxoSmithKine

Appearance

White to off-white, circular, biconvex, bevel-edged, film coated TILTAB tablet debossed "ap" and "550"

Average Weight of 10 tablets (mg)

671.40

Diameter (mm)

11.59, 11.60, 11.58, 11.60, 11.62

Thickness (mm)

6.79, 6.89, 6.88, 6.87, 6.83

Disintegration test

6 minutes 1 second

Hardness (N)

196

 

 


Initial Risk Assessment of the Formulation Variables

Initial Risk Assessment of the Formulation Variables was performed to determine the critical Formulation Variables which may impact the CQA dissolution of the new Albendazole Tablets. The initial risk assessment of the formulation variables is compiled in Table 5.


 

Table 5: Initial risk assessment of the new Albendazole Tablets


Drug Product CQA’s

Albendazole PSD

Microcrystalline cellulose

Lactose monohydrate

Maize starch

Povidone K30

Sodium Saccharin

Sodium lauryl sulfate

Sodium starch glycolate

Magnesium Stearate

Methocel

E3 LV

 

Dissolution

Low

Low

Low

Low

Medium

Low

Medium

Medium

Low

Low

 

Justification for initial risk assessment of formulation variables of the new Albendazole Tablets is represented in below table 6.

Table 6: Justification for initial risk assessment of the new Albendazole Tablets

Formulation Variables

Drug Products CQAs

Justification

Drug Substance PSD

Dissolution

 

The drug substance micronized grade material is used for formulation development thus particle size distribution has low impact on dissolution. The risk is low.

Microcrystalline cellulose

(Avicel PH 101)

Microcrystalline cellulose can impact dissolution via tablet hardness. However, hardness can be controlled during compression. The risk is low.

Lactose monohydrate

(Pharmatose 200M)

Lactose monohydrate is a water soluble diluent and will not impact the dissolution of the drug product. The risk is low.

Sodium saccharin dihydrate

Sodium saccharin doesn’t have any impact on dissolution of the drug product. The risk is low.

Maize starch

(Maize starch B)

The concentration of maize starch used will not impact dissolution of the drug product. The risk is low.

Povidone K30

 

Povidone K-30 is used as binder and levels of binder may impact the disintegration and in turn, the dissolution of drug product. Thus the risk is considered as medium.

Sodium lauryl sulfate (Kolliphor SLS Fine)

As it is a BCS class II drug substance, the surfactant concentration will have impact on dissolution profile of the drug product. Hence the risk is considered as medium.

Sodium Starch glycolate Type A

(Primojel)

As it is a class II drug substance, the disintegrant concentration will have significant impact on dissolution of the drug product. The risk is considered as medium.

Magnesium Stearate

(Hyqual, vegetable source)

Magnesium stearate is used at very low concentration in formulation and thus it will not impact the dissolution of the drug product. The risk is low.

Hypromellose 2910 (Methocel E3 Premium LV)

Hypromellose 2910 is used as coating polymer in film coating system; the concentration used for coating does not affect dissolution of the drug product. The risk is low.

 

Initial formulation variable risk assessment indentified PVP, SLS and SSG level as medium risk for the CQA dissolution of the new Albendazole tablets 200 mg.

 


 


DOE Design:

Three factor two level (23) full factorial design was employed for development of new Albendazole tablets. A translation of coded values of formulation variables and experimental design is executed is represented in table 7.


 

Table 7: Execution of experimental design of the new Albendazole Tablets

Factors: Formulation Variables

Levels (mg/tablet)

-1

0

+1

Povidone K 30

10

15

20

Sodium Lauryl sulfate

1

1.5

2

Sodium starch glycolate

4.6

9.6

14.6

Response (Goal)

Acceptable Ranges

Dissolution at 15 min (%) (Maximize)

≥ 70%

Dissolution at 30 min (%)  (Maximize)

≥ 80%

 


Formulation DOE batches were manufactured and evaluated for the following parameters.

Evaluation of the Formulation DOE batches of the new Albendazole Tablets

Lubricated blend was evaluated for the BD, TD, CI and H.R. Compressed core tablets were tested for weight variation, thickness, hardness, friability and Disintegration Time. Coated tablets were evaluated for the weight variation and Disintegration Time. Parameter results are represented in below table 8.


 

Table 8: Core tablet physical parameters of the new Albendazole Tablets

Batch

T1

T2

T3

T4

T5

T6

T7

T8

T9

B.D. (g/ml)

0.54

0.51

0.57

0.60

0.57

0.46

0.59

0.52

0.53

T.D. (g/ml)

0.67

0.70

0.72

0.74

0.68

0.67

0.80

0.76

0.79

C.I. (%)

19.50

27.02

21.70

18.49

15.38

31.03

26.35

31.43

32.91

H.R.

1.24

1.37

1.27

1.22

1.18

1.45

1.35

1.45

1.49

Core tablets

Weight (mg)

640.1 -646.0

638.9  -643.4

642.0  -647.0

637.0  -643.0

638.0  -644.0

637.0  -642.0

637.0  -646.0

636.7  -646.7

640.0 -645.0

Thickness (mm)

5.90   -  5.92

5.79  -5.94

5.98  -6.00

5.83  -

5.86

5.90  -

5.92

6.93  -6.01

5.98  - 6.05

5.89  -

5.94

6.00

- 6.04

Hardness

(N)

153  -

166

143  -

164

141  -

160

143-

155

146 -

164

143  -

159

147  - 160

143

- 168

144  -

145

Friability (%w/w)

0.25

0.22

0.32

0.21

0.10

0.15

0.37

0.27

0.12

Disintegration Time

6:25  -  7:00

7:05  -7:59

4:08  -  4:49

7:10  to8:10

7:20  -8:30

5:37  -6:35

4:25  -4:40

4:20  -5:20

6:30 -7:05

Coated tablets

Weight (mg)

646.0 -657.0

646.0  -656.0

646.0  -659.0

643.0  -658.0

646.0  -659.0

646.0  -659.0

646.0  -658.0

648.0  -654.7

642.0  -650.0

Disintegration Time (min)

8:18  - 9:13

9:12  -9:37

5:59  - 8:46

6:50  - 8:35

5:45  -7:46

8:09  - 8:58

5:26  -6:39

5:25  - 6:51

9:15  - 9:37

 


Flow of the batches was acceptable and powder was flowing through hopper properly. Tablets were compressed with weight range of 640±10 mg, Thickness of 6.00±0.4 mm, Hardness of 150±20N, Friability of 0.10 to 0.37 and Disintegration time of less than 8 minutes 30 seconds. Coated tablets showed Weight of 653±10 mg and DT was 9 min 37 seconds.


 

 

Dissolution study

Final coated tablets were studies for the dissolution and results are represented in below table 9.

Tablet 9: In vitro drug release studies of new Albendazole tablets 200 mg

Dissolution

RLD

T1

T2

T3

T4

T5

T6

T7

T8

T9

Time (minutes)

% Drug release

5

29.0

16.0

25.0

23.0

48.0

41.0

50.0

21.0

20.0

26.0

10

62.0

24.0

30.0

51.0

68.0

45.0

64.0

58.0

39.0

31.0

15

77.0

35.0

38.0

60.0

79.0

48.0

78.0

74.0

55.0

37.0

20

84.0

65.0

68.0

82.0

90.0

75.0

88.0

83.0

78.0

79.0

30

89.0

80.0

82.0

90.0

100.0

85.0

100.0

95.0

94.0

85.0

45

95.0

96.0

95.0

97.0

104.0

101.0

100.0

98.0

100.0

101.0

F2

 

30

33

53

49

41

50

66

43

34

DOE trials dissolution profiles were represented in below figure 1.

 


 

Figure 1: Comparative % drug release profile of formulations

Dissolution of Formula composition of T7 new albendazole tablets was comparable with innovator with F2 more than 60. Hence this batch was studies for stability evaluation. Dissolution data of the batches was analyzed with DOE to derive the optimized composition with DOE and to study the impact of formulation variables on the CQA drug dissolution.

 

Statistical Analysis of DOE trials

15 minutes and 30 minutes dissolution data obtained from the DOE studies were evaluated using DOE analysis to identify the perfect concentration ranges of formulation variables to achieve target dissolution and to study the impact of formulation variables on the CQA drug dissolution.

 

Significant factors for tablet dissolution (at 15 minutes)

15 minutes dissolution was studied and statistics of the model used was represented in below table 10.


 

Table 10: Model data for 15 minutes dissolution

Source

DF

Adj SS

Adj MS

F-Value

P-Value

Model

7

2526.00

360.86

20.05

0.170

Linear

3

2039.00

679.67

37.76

0.119

PVP

1

1624.50

1624.50

90.25

0.067

SLS

1

50.00

50.00

2.78

0.344

SSG

1

364.50

364.50

20.25

0.139

2-Way Interactions

3

122.50

40.83

2.27

0.446

PVP*SLS

1

8.00

8.00

0.44

0.626

PVP*SSG

1

112.50

112.50

6.25

0.242

SLS*SSG

1

2.00

2.00

0.11

0.795

Curvature

1

364.50

364.50

20.25

0.139

Error

1

18.00

18.00

 

 

Total

8

2544.00

 

 

 

 

P-Value observed for the model was 0.170 and for the formulation variables values were PVP: 0.067, SLS: 0.344 and SSG: 0.139.

 

Pareto chart of dissolution at 15 min

Pareto chart of the formulation variable effects on dissolution at 15 min is represented in below Figure 2.

 


Pareto chart Results showed that significant factors impacting the dissolution of the new Albendazole Tablets, USP 200 mg tablet formulation at 15 min were identified as concentration of the PVP & SSG.

Contour Plot of Dissolution 15 minutes

Contour Plot of the formulation variable effects on dissolution at 15 min is represented in below Figure 3.


 

 


Contour Plot Results showed that concentration of the PVP 10-13 mg per tablet & SSG 11-14 mg / tab will give dissolution more than 70% of the new Albendazole Tablets, USP 200 mg.

Significant factors for tablet dissolution (at 30 minutes)

30 minutes dissolution was studied and statistics of the model used was represented in below table 11.


 

 

 

 

 

Table 11: Model data for 30 minutes dissolution

Source

DF

Adj SS

Adj MS

F-Value

P-Value

Model

7

450.389

64.341

14.30

0.201

Linear

3

410.500

136.833

30.41

0.132

PVP

1

338.000

338.000

75.11

0.073

SLS

1

0.500

0.500

0.11

0.795

SSG

1

72.000

72.000

16.00

0.156

2-Way Interactions

3

13.000

4.333

0.96

0.617

PVP*SLS

1

4.500

4.500

1.00

0.500

PVP*SSG

1

8.000

8.000

1.78

0.410

SLS*SSG

1

0.500

0.500

0.11

0.795

Curvature

1

26.889

26.889

5.98

0.247

Error

1

4.500

4.500

 

 

Total

8

454.889

 

 

 

 

P-value for the model was 0.201 and values obtained for the formulation variable were PVP:0.073 SLS:0.795 and SSG:0.156.

Pareto chart of dissolution at 30 min

Pareto chart of the formulation variable effects on dissolution at 30 min is represented in below Figure 04.


Pareto chart Results showed that significant factors impacting the dissolution of the new Albendazole Tablets, USP 200 mg tablet formulation at 30 min were identified as concentration of the PVP & SSG.

Contour Plot of Dissolution 30 minutes

Contour Plot of the formulation variable effects on dissolution at 30 min is represented in below Figure 5.


 

 

 image

Figure 2: Pareto chart of the formulation variable effects on dissolution at 15 min

image

Figure 3: Contour Plot of Dissolution 15 minutes vs PVP vs SSG

image

Figure 4: Pareto chart of the formulation variable effects on dissolution at 30 min

 

image

Figure 5: Contour Plot of Dissolution 30 minutes vs PVP vs SSG


Contour Plot Results showed that concentration of the PVP below 14 mg per tablet & SSG 5 mg / tab will give dissolution more than 80% of the new Albendazole Tablets, USP 200 mg.

Updated Risk Assessment of the Formulation Variables

The updated risk assessment of the formulation variables was performed based on the DOE experiment outcome and compiled in Table 12.


 

Table 12: Updated Risk assessment of formulation variables


Drug Product CQA’s

Drug PSD

Avicel

PH 101

Pharmatose 200 M

Maize starch

Kollidon

K-30

Sodium Saccharin

Kolliphor     SLS  Fine

Primojel

Magnesium Stearate

Methocel

E3 LV

 

Dissolution

Low

Low

Low

Low

*Low

Low

*Low

*Low

Low

Low

*Updated

Justification for updated Risk Assessment of formulation variables is represented in below table 13.

Table 13: Justification for updated Risk Assessment of formulation variables

Formulation Variables

Drug Products CQAs

Justification

PVP

Dissolution

Formulation variables PVP, SLS and SSG concentrations were identified, optimized and analyzed with DOE studies to achieve comparable release profile with market reference product and final composition was derived.

Thus risk of these factors is reduced from medium to low.

SLS

SSG

 

ICH Stability studies results of Albendazole Tablets, USP 200 mg

Stability data of new Albendazole Tablets, USP 200 mg (T7) results are represented in below table 14.

Table 14: Stability results of new Albendazole Tablets, USP 200 mg

Packaging configuration

150 CC HDPE bottle with PP closure

Stability Conditions

40ºC/ 75% RH

Tests

Specification

Initial

1 month

 2 months

3 months

Assay (% w/w)

NLT 90.0% and NMT 105.0%

91.9

100.8

99.6

99.9

Related Substances (% w/w)

Impurity B

NMT 0.2%

0.05

0.06

0.04

0.04

Impurity C

NMT 0.2%

ND

ND

ND

ND

Any other individual impurity

NMT 0.2%

ND

0.02

0.03

0.04

Total Impurities

NMT 1.0%

0.05

0.08

0.09

0.11

Water by KF (%w/w)

NMT 7.0%

3.7

3.4

3.7

3.9

Dissolution: USP II, 900 mL, 0.1 N HCl and 50 rpm

Time

NLT 80% (Q) in 30 minutes

% Drug Release

30 minutes

95

97

95

95

ND: Not detected

 


Results showed that the initial analytical results of new Albendazole tablets 200 mg were found to be satisfactory and meeting designed specification. During accelerated stability studies assay, related substances, dissolution and water content meets product specification with no significant changes.

SUMMARY

Albendazole was found to have very poor compressibility and flow properties ( BD: 0.196 g/mL, TD: 0.300 g/mL, Carr’s index of 34.66%, Hausner’s ratio of 1.53) hence wet granulation method was opted for better compression and good flow property for the preparation of the new Albendazole tablets 200 mg. Albendazole is low solubility drug. The drug has pH dependent solubility nature. It has good solubility in strong acidic condition with 0.385 mg / ml in acidic media. Melting point of Albendazole was found to be in range as given in literature (205-210˚C).

Quality target product profile (QTPP) and Critical quality attributes (CQAs) were designed for the new Albendazole tablets 200 mg which showed that dissolution is critical CQA. Market Reference product characterization was performed. Risk assessment showed that formulation variable PVP, SLS and SSG has medium impact on CQA dissolution. Experiments were designed with DOE software for this formulation variable with 23 full factorial design and batches (T1-T9) were executed in the lab. Dissolution data was analyzed with DOE software to achieve drug release comparable with market reference product and studies impact of these formulation variables on CQA dissolution. Flow of the batches was acceptable and power was flowing through hopper properly. Tablets were compressed  with weight range of 640±10 mg,  Thickness of 6.00±0.4 mm, Hardness of 150±20N, Friability of  0.10 to 0.37 and Disintegration time of less than 8 minutes 30 seconds. Coated tablets showed Weight of 653±10 mg and DT was 9 min 37 seconds.Dissolution of Formula composition of T7 new albendazole tablets was comparable with innovator with F2 more than 60. Pareto chart Results showed that significant factors impacting the dissolution of the new Albendazole Tablets, USP 200 mg tablet formulation at 30 min were identified as concentration of the PVP & SSG.Contour Plot Results showed that concentration of the PVP below 14 mg per tablet & SSG 5 mg / tab will give dissolution more than 80% of the new Albendazole Tablets, USP 200 mg. Updated risk assessment was performed to justify the risk level of low from DOE studies for these variables. Results showed that the initial analytical results of new Albendazole tablets 200 mg were found to be satisfactory and meeting designed specification. During accelerated stability studies assay, related substances, dissolution and water content meets product specification with no significant changes.

CONCLUSION

Tablets were manufactured by wet granulation technique with application of the QbD and DoE approach. The tablets exhibited drug release comparable to the market reference product. The amount of Povidone K 30, Sodium Lauryl sulfate & Sodium starch glycolate was optimized by 23 full factorial design based on the drug release. The accelerated stability studies suggested no significant change in the drug content, physical properties and drug release. The developed generic albendazole tablet was found to be similar to the reference product on the market in terms of quality parameters, therefore can be produced as a generic formulation by an interested local pharmaceutical industry in the country.

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