Formulation of methyldopa 250 mg Tablets by direct compression using a Quality by Design approach

 

Murungi Isaac Baguma1*, Mbali Luvuno-Keele1, Gauda Mahlatsi2, Nelesh Jaganath3

1Department of Pharmacy, Nelson Mandela University, Gqeberha, South Africa, 6031.

2School of Pharmacy, Sefako Makgatho Health Sciences University, Pretoria, South Africa, 0204.

3Aspen South Africa Operations (Pty) Limited, Gqeberha, South Africa, 6014.

*Corresponding Author E-mail: bagizaak@gmail.com

 

ABSTRACT:

Background: Despite being in use for over 50 years, the physicochemical challenges posed by methyldopa remain ever present. Methyldopa is not only significantly hygroscopic, but also prone to oxidative and hydrolytic degradation that can be accelerated by moisture. Poor compression behaviour, another limitation of methyldopa, leaves the formulation scientist with a constellation of formulation hurdles that must be faced, understood, and overcome. This is a task that can be tackled using elements of the Quality by Design (QbD) approach. Objective: The study aimed at developing an optimal formulation of methyldopa into 250 mg immediate release tablets by direct compression using elements of QbD. Method: Excipients of pharmaceutical grade were selected for the candidate formulation, preliminary concentrations set for each and settings for mixing and compression variables established. The risk posed by all these factors was evaluated using Failure Modes and Effects Analysis (FMEA). The preliminary experiment was executed using a 12 run Plackett Burman design. A 16 run Box-Behnken experimental design successfully aided in the identification of excipient concentrations and manufacturing conditions that yield tablets of optimal quality. Results: FMEA revealed that magnesium stearate, colloidal silica, sodium starch glycolate (SSG), citric acid monohydrate, mixing speed, duration of pre-lubrication mixing, duration of lubrication and compression speed were critical risk factors. The optimal formulation was achieved at the following settings: 1 % m/m magnesium stearate, 1 % m/m colloidal silica, 3.9 % m/m sodium starch glycolate, 1.7 % m/m citric acid monohydrate, mixing speed of 101 rpm, 6 minutes of pre-lubrication mixing, 2 minutes of lubrication and compression speed of 20 rpm. Conclusion: The QbD tools used in this study enabled, not only achievement of optimal quality, but also a better understanding of the impact of critical formulation variables on tablet quality. Challenges to pharmaceutical development can be effectively overcome using the QbD approach.

 

KEYWORDS: Hygroscopy, Methyldopa, Direct Compression, Quality by Design.

 

 


INTRODUCTION:

Methyldopa is a centrally acting antihypertensive agent approved for the treatment of essential hypertension and preeclampsia in South Africa1. Methyldopa is also known for being a hygroscopic material2 that is cohesive and poorly compactable3. The drug is also prone to oxidative and hydrolytic degradation, exhibiting a grayish black discolouration as a result2,4.

 

These properties make it important for a systematic proactive approach to be taken in the development of a methyldopa formulation. In 2006, the International Conference on Harmonisation (ICH) guidelines officially recommended Quality by Design (QbD) as a cornerstone for pharmaceutical development5. A sequential plan must be developed to employ such an approach using elements of the QbD framework5,6,7. Such a plan would culminate in the definition of excipient and process settings that yield optimal tablet quality8.

 

 

The manufacture of immediate release tablets is generally performed via the use of wet granulation, dry granulation or direct compression (DC) processes9. Both wet and dry granulation processes involve multiple steps and often more than one piece of equipment is utilized, which can make the manufacturing process costly and long10. Production time, production cost and tablet variation can be minimized by reducing the number of operations performed before tablet compression10. DC is a cheaper method where the powder mix is uniformly fed into a die cavity in its primary state and compressed into individual tablets11. The quality of a pharmaceutical product is an important factor to be considered during the product development process5. Aspects relating to quality must, therefore, be considered at every step of the process and quality attributes evaluated after the development work5.

 

The aim of this study was to develop a formulation of methyldopa into 250 mg immediate release tablets by direct compression using specific elements of the QbD approach.

 

MATERIALS AND METHODS:

Materials:

The following pharmaceutical-grade materials were selected for use in the tablet formulation: methyldopa sesquihydrate, microcrystalline cellulose, sodium starch glycolate (SSG), colloidal silica, magnesium stearate, citric acid monohydrate. All materials were kindly donated by Aspen South Africa Operations (Pty) Limited (Gqeberha, South Africa). Factors including performance12,13,14, compactability15, compatibility16, hygroscopicity5 and rheology17 were used as criteria during the excipient selection process.

 

METHODOLOGY:

Application of Quality by Design:

A risk evaluation18 was performed on the physicochemical properties of methyldopa sesquihydrate, the excipients to be used, their ratios and the variables of the DC process to determine their individual impact on the critical quality attributes (cQAs) of methyldopa tablets.

 

Based on the QbD framework for risk management, Failure Mode and Effects Analysis (FMEA) was used to perform the evaluation exercise6,19. Factors with Priority Numbers (RPNs) ≥ 50 were considered as high risk. These factors were eligible for investigation in subsequent experiments.

 

A 12-batch Plackett-Burman design was used to perform the screening experiment20. The Box-Behnken design21 for optimization of the formulation followed a 16-batch model, including 4 centerpoint batches (D3, D4, D6 and D7). Knowledge from both experiments provided the basis for an understanding of the risk posed to the DC process and tablet quality. Material and process variables studied in the experiments included but were not limited to excipient concentrations and mixing times. The influence of these variables on tablet quality was quantitatively evaluated20. JMP 15® (SAS Institute, USA) software was used to create the experimental plans and analyze the data.

 

Powder handling and compression:

For each experimental batch, a Mettler Toledo® XPE205 analytical balance (Mettler Instruments, United Kingdom) was used to weigh raw materials below 200 g and an Astro® ASC 2001 compact scale (Adam Equipment, South Africa) used for heavier raw materials. The weighed materials were then assembled for mixing and transferred to a Erweka® KB15 cube mixer (Erweka GmbH, Germany). Each batch was mixed at the predefined speeds and durations.

 

The powder blends were transferred to the feeder hopper of an Erweka® EP1 single punch tablet press (Erweka GmbH, Germany). Convex unscored tablets of approximately 5 mm thickness and 12 mm diameter were produced at the respective compression speeds. In their respective batches, all manufactured tablets were placed in airtight closed glass containers stored at 25°C and kept within 30-50 % relative humidity. Tablet testing was performed after a duration of 28 days had elapsed.

 

Tablet testing:

Uniformity of weight tests were performed by randomly sampling tablets from each batch, weighing each individual tablet, and calculating the average weights per batch22. Weight measurements were performed using a Model XP205 Mettler Toledo® analytical balance (Mettler Instruments, Zurich, Switzerland). The standard deviations (SD) among the average weights were calculated. The optimal weight for tablets prepared in this study was 500 mg.

 

The hardness tests were performed using an Erweka® TBH 325 hardness tester (Erweka® GmbH, Germany), which provided a breaking force in Newtons (N). Randomly selected tablets from each batch were tested and average hardness values calculated. Friability was measured by rotational agitation of pre-weighed tablets in a Model TA3R friabilator (Erweka® GmbH, Germany), after which the tablets are weighed again and losses in individual tablet weights calculated. These values were used to calculate average percentage loss per sample, indicating the degree of tablet friability. The friability and hardness values were used as measures of mechanical strength10.

 

Loss on drying (LOD) tests23 were carried out on a sample of 8 randomly selected methyldopa tablets per batch. The tablets were crushed into a powder and each sample weighed using a Model XP205 Mettler Toledo® analytical balance (Mettler Instruments, Zurich, Switzerland), the mass (g) recorded, and the sample dried in a drying chamber at 100 to 105 ºС for 2 hours. The samples were then allowed to cool for 50 minutes, individually re-weighed and percentage losses in weight calculated to indicate the respective amounts of moisture gained.

 

Disintegration tests were performed in ZT 320 Series disintegration chambers (Erweka® GmbH, Germany) whose tubes oscillate vertically at a regular frequency. The glass chamber was filled with a medium of distilled water at 37 ± 0.5°C, within which 12 randomly selected tablets were agitated. The times taken for each tablet to completely disintegrate were recorded and averages for each batch calculated10.

 

As described in the USP monograph for methyldopa tablets, sample solutions containing powdered tablets were assayed using ultraviolet–visible spectrophotometry to determine potency22. The dissolution test listed in the monograph22 was used in the study. A Biobase® USP BK-RC8 paddle dissolution tester (Biobase, China) was selected for use. This apparatus has compartments that use a rotating paddle to agitate the tablets in a dissolution medium. Tablets were randomly selected from each batch and placed in a medium of 0.1M hydrochloric acid (900 ml) at 37 ± 0.5 °C. For each test session, the apparatus paddles were rotated at 50 rotations per minute, for 20 minutes22. Samples were withdrawn from the medium at regular intervals and each filtered sample analysed to calculate the quantity of drug contained. These assays were done using a Boeco® S-220 UV-VIS spectrophotometer (Boeco, Germany).

 

In an effort to control moisture gained by the tablets, the humidity in the storage chamber was controlled at all times2. The tablets were observed over 28 days, the number of discoloured tablets within each batch counted and expressed as a percentage of the batch size. These assessments, including degradation, are summarised in Table 1.

 

Table 1: A summary of the tests performed on the methyldopa tablets prepared22

Test

Specification

Weight variation (mg)

475 – 525

Hardness (N)

To be determined

Friability (% m/m)

< 1.0

Moisture content (% m/m)

To be determined

Disintegration time (seconds)

< 900

Potency (%)

90.0 – 110.0

Dissolution after 20 min (%)

> 80

Degradation (%)

0

 

RESULTS:

Risk evaluation:

FMEA revealed that, among others, the following factors posed considerable risk to methyldopa tablet quality: magnesium stearate concentration (X1), colloidal silica concentration (X2), SSG concentration (X3), citric acid monohydrate concentration (X4), mixing speed (X5), duration of mixing before adding magnesium stearate (X6), duration of lubrication (X7) and compression speed (X8). These factors were investigated in the experimental work.

 

Preliminary experiment:

The preliminary experimental data is displayed in Table 2. The mean tablet weights for all the batches were within the ± 5 % limit (475 – 525 mg). However, some batches such as batches B3 and B4 were within close range of the lower and upper weight limits. Batches B2 and B12 had the greatest number of discoloured tablets, while batches B5 and B8 showed negligible levels of tablet discolouration. Discoloured tablets accounted for over 1 % batch size in seven batches. Moisture content values above 6 % m/m were observed for each of these seven batches, increasing numbers of discoloured tablets being seen with higher moisture content. ANOVA results demonstrated the significant impact of citric acid monohydrate concentration on tablet stability (p = 0.0026, f ratio = 24.6076). The striking impact of powder mixing


 

Table 2: The 12-run preliminary Plackett Burman design and results of tablet testing for each batch prepared

Moisture content

(%  m/m)

6.2

6.3

7.2

5.4

5.8

5.6

6.2

6.0

6.1

5.7

6.4

6.5

Disintegration time (seconds)

241

380

51

260

339

79

125

371

410

104

311

349

Dissolution at 20 min (%)

103

85

101

99

108

101

87

82

65

105

108

77

Weight (mg ± SD)

502 ± 1.90

500 ± 2.60

482 ± 2.78

517 ± 3.94

488 ± 0.97

499 ± 1.93

510 ± 2.10

501 ± 0.96

480 ± 3.81

498 ± 3.82

509 ± 1.17

503 ± 1.13

Friability (% m/m)

0.56

0.18

0.81

0.41

0.42

0.88

0.89

0.11

0.20

0.91

0.19

0.38

Hardness (N)

85 ± 0.29

107 ± 1.40

55 ± 4.43

84 ± 2.10

91 ± 3.17

49 ± 0.11

71 ± 0.26

94 ± 2.48

105 ± 1.12

68 ± 1.26

90 ± 1.65

94 ± 1.00

Degradation (%)

0.5

2.4

2.0

0.2

0.1

0.2

1.5

0.1

1.6

2.0

1.4

2.2

Potency

(% ± SD)

94.1 ± 0.97

101.3 ±0.68

97.3 ±0.32

99.1 ± 1.00

99.7 ± 1.24

107.8 ± 0.07

102.3 ± 1.80

100.4 ± 0.04

95.8 ± 2.26

97.9 ± 0.75

103.6 ±1.95

100.9 ± 0.89

X8

20

80

80

20

20

80

80

80

80

20

20

20

X7

2

2

2

2

2

2

4

4

4

4

4

4

X6

6

3

6

3

6

3

6

6

3

3

3

6

X5

80

200

80

200

200

80

80

200

200

80

80

200

X4

0.3

0.3

0.3

2

2

2

2

2

0.3

0.3

2

0.3

X3

2

2

8

8

2

8

2

8

2

8

2

8

X2

1

0.5

0.5

0.5

1

1

0.5

1

1

1

0.5

0.5

X1

2

2

1

2

1

1

2

2

1

2

1

1

Batch code

B1

B2

B3

B4

B5

B6

B7

B8

B9

B10

B11

B12

X1 = magnesium stearate concentration (% m/m), X2 = colloidal silica concentration ( % m/m), X3 = SSG concentration (% m/m), X4 = citric acid monohydrate concentration (% m/m), X5 = powder mixing speed (rpm), X6 = duration of powder mixing before adding magnesium stearate (min), X7 = duration of powder lubrication (min), X8 = compression speed (rpm)

speed (X5) was also revealed during data analysis, as the factor had noteworthy influence on tablet hardness (p = 0.0021), friability (p = 0.0095), disintegration (p = 0.0006) and dissolution rate (p10

=0.0037). Using all the response values, MANOVA was performed in JMP 15® and the resulting p values interpreted24. The p values for the investigated factors are displayed in Table 3. SSG concentration (X3), citric acid monohydrate concentration (X4) and mixing speed (X5) were identified as the significant factors (p < 0.05) and selected for investigation in the subsequent definitive experiment.

 


Table 3: Levels of significance for each factor in the multivariate model of the preliminary experiment

Factor

p-value

X1

0.1099

X2

0.0679

X3

0.0414

X4

0.0304

X5

0.0186

X6

0.5060

X7

0.1015

X8

0.0992

 

The prediction profiler in JMP 15® was used to  identify the best settings  for the non-significant factors. These settings were held constant in the subsequent Box Behnken experiment, allowing the focus to be placed on the significant excipient and process factors. These settings were identified at a maximum desirability value of 0.8310 and were as follows: 1 % m/m magnesium stearate,  1 % m/m colloidal silica, 6 minutes of pre-lubrication mixing 2 minutes of powder lubrication and  a compression speed of 20 rpm.

 

Definitive experiment:

Despite the poor compressibility of the API, all the tablets manufactured were of satisfactory mechanical strength, before and throughout storage. This contrasted with the preliminary batches, where batch B3 had extensive tablet softening as a result of excess moisture. The results of tablet testing are displayed in Table 4. Tablet hardness values ranged between 68 – 87 N, and friability did not exceed 0.5 % m/m. The target mean weight of 500 mg was achieved for most tablets sampled from batches D1, D13 and D15. Deviation from the desired tablet weight of 500 mg was generally negligible, evidenced by the narrow standard deviation values. In contrast to the preliminary experiment, distinctly lower levels of degradation and reduced batch-to-batch variation was observed. The highest numbers of discoloured tablets were observed in batches D2 and D11, discoloured tablets accounting for over 1 % of the respective batches. On the other hand, percentage discolouration as low as 0.1 % was seen with batches D3, D7 and D14. Likewise, discoloured tablets constituted only 0.05 % of batch D9. Using regression analysis, it was learned that the rate of tablet discolouration decreases significantly with increasing concentrations of citric acid monohydrate.

 

The data from the definitive experiment was subjected to polynomial regression in JMP 15®. Using the prediction profiler tool in the software, the factor settings that yield the optimal methyldopa DC formulation were identified. An image of the profile predicted is displayed as Figure 1. The settings determined were as follows: 42.4 % m/m microcrystalline cellulose, 1.0 % m/m magnesium stearate, 1.0 % m/m colloidal silica, 3.9 % m/m SSG, 1.7 % m/m citric acid monohydrate, powder mixing at 101 rpm, 6 minutes of pre-lubrication mixing, 2 minutes of lubrication and tablet compression at 20 rpm. A confirmatory batch of methyldopa tablets was prepared at these settings and tested. The batch met all test specifications, achieving hardness values of 76 - 77 N and adsorbing only 5.05 % m/m moisture. Optimal weight, potency and dissolution results were also attained.

 

DISCUSSION:

Several batches including but not limited to B5, B8, B12, D3 and D9 were mixed at speeds over 100 rpm for over 6 minutes. As shown in the experimental data (Tables 2 and 4), these batches generally had potency values closest to 100 % and showed relatively less variance than other batches. Cohesive forces exist between particles of pharmaceutical powders, arising from various surface phenomena25. Surface liquid films, for example, can exert tensional forces between particles of a hygroscopic powder, giving rise to increased cohesion26. Cohesive forces hinder powder flow, creating the need for prolonged mixing at high velocities25. It can thus be noted that the higher mixing speeds employed during the manufacture of these batches may have contributed to decreasing cohesive forces between particles which subsequently improved powder rheology. This stabilised die fill rate and resultant tablet potency, as substantiated by the low standard deviation values recorded for these batches during uniformity of weight testing.

 

In the preliminary experiment, some batches were prepared using colloidal silica at a concentration of 0.5 % m/m. Several of these batches, including B3, B4, B7 and B11 showed relatively significant variation in tablet weight and potency. These inconsistencies can be attributed to erratic flow that may have occurred as the respective powders were  fed into the hopper. On the other hand, low standard deviation values were recorded for batches such as B1, B6 and B8 that were formulated using the higher 1 % m/m concentration of colloidal silica. Despite the statistical insignificance of the factor, these observations demonstrate the flow enhancing the impact of colloidal silica. Colloidal silica exists as loose agglomerates which are broken down into small aggregates during powder blending. These aggregates adsorb to the surfaces of powder particles to form an interactive mix, which increases particle coarseness and overcomes the van der Waal’s attraction between cohesive particles25. The flow of such powder blends is improved due to reduced cohesion. The generally improved weight and potency results achieved in the definitive experiment are a testament to the excellent glidant properties of colloidal silica. Colloidal silica also has desiccant properties10, which could be exploited when handling significantly hygroscopic materials. The moisture gained by a material such as methyldopa can be adsorbed by colloidal silica, consequently protecting it from oxidation and the associated discolouration.


 

Table 4: The 16-run Box Behnken design for the definitive experiment and results of tablet testing for each batch prepared

Moisture content (%m/m)

4.9

5.6

5.2

5.3

5.1

5.2

5.2

4.6

4.8

4.7

5.5

4.7

5.0

4.7

5.4

4.9

Disintegration time (sec)

61

63

128

134

101

131

130

171

95

105

64

206

69

181

70

159

Dissolution at 20 min (%)

100

100

100

100

100

100

100

100

100

99

100

92

100

91

100

93

Weight

(mg ± SD)

500 ± 0.05

499 ± 3.03

501 ± 2.05

498 ± 2.60

491 ± 4.72

497 ± 1.92

501 ± 2.38

503 ± 1.50

502 ± 2.20

496 ± 2.71

502 ± 0.04

494 ± 3.30

500 ± 0.22

505 ± 4.17

500 ± 0.72

504 ± 3.92

Friability

(% m/m)

0.1

0.33

0.18

0.18

0.36

0.21

0.19

0.07

0.15

0.4

0.1

0.07

0.12

0.09

0.47

0.26

Hardness (N)

77 ± 1.00

68 ± 0.03

76 ± 1.12

78 ± 0.97

77 ± 0.04

75 ± 2.51

77 ± 1.72

84 ± 0.80

73 ± 0.04

69 ± 1.76

73 ± 1.08

87 ± 2.81

74 ± 0.01

86 ± 3.23

72 ± 1.26

81 ± 0.60

Degradation (%)

0.6

1.3

0.1

0.15

0.4

0.15

0.1

0.45

0.05

0.9

1.05

0.45

0.8

0.1

0.25

0.1

Potency

(% ± SD)

100.2 ± 0.45

100.9 ± 1.88

101.2 ± 0.02

101.8 ± 1.50

102.7 ± 2.01

99.5 ± 1.10

99.6 ± 1.40

103.4 ± 1.14

99.6 ± 0.04

101.0 ± 2.50

99.7 ± 0.07

98.1 ± 2.52

100.5 ± 0.98

97.8 ± 1.00

100.4 ± 0.10

102.9 ± 0.15

X5

120

80

100

100

80

100

100

100

120

80

120

120

100

100

100

80

X4

1.5

1.5

1.5

1.5

2

1.5

1.5

1

2

1

1

1.5

1

2

2

1.5

X3

6

6

4

4

4

4

4

2

4

4

4

2

6

2

6

2

B

atch code

D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

D16

X3 = SSG concentration (% m/m), X4 = citric acid monohydrate concentration (% m/m), X5 = powder mixing speed (rpm)

 


Figure 1: An image of the prediction profiler in JMP 15® indicating factor settings that yield optimal tablet quality

 


Several attributes of tablet quality such as hardness, are dependent on the moisture content of the formulation16. During processing and storage, a strict range of equilibrium moisture levels must be maintained to ensure that tablet quality is not compromised. This is  specifically true for a hygroscopic formulation that is being directly compressed16. The risk to tablet moisture content was substantially mitigated by implementing 30 - 50 % humidity control during the experimental work. As demonstrated by the definitive experimental results, humidity regulation can ensure that the moisture content of resulting tablets will remain within an acceptable range.

 

It is important that factors affecting the absorption and ensuing bioavailability of a BCS Class III drug such as methyldopa are contemplated before product development. Potency is one of these factors27. As seen in this study, oxidative and hydrolytic degradation of an API can lower the potency of the pharmaceutical product. This would manifest in reduced bioavailability, a phenomenon which is detrimental for a BCS Class III drug such as methyldopa. However, it is expected that methyldopa tablets manufactured at the optimal settings shown in Figure 1 will be free of degradative activity and thus maintain acceptable potency levels during storage. 

 

CONCLUSION:

Formulation development involving physicochemically challenging drugs can be a daunting task. However, this study has demonstrated the benefits of taking a proactive experimental approach to formulation design. The QbD paradigm has become the standard framework for pharmaceutical development globally, ensuring quality is instilled in the developed product before attempts to scale up are made.

 

ACKNOWLEDGEMENTS:

The authors are grateful to Aspen South Africa Operations (Pty) Limited for funding this study. We also extend our gratitude to the staff of the pharmaceutics laboratory at Nelson Mandela University where the laboratory work was performed.

 

ETHICAL DECLARATION:

The authors would like to state that this research did not involve any human or animal subjects, therefore ethical clearance was not required. Furthermore, no financial or any other conflicts of interest were identified in this work.

 

REFERENCES:

1.      Rossiter D. Blockman M. Barnes K. South African Medicines Formulary. Health and Medical Publishing Group, 2019.

2.      Stewart B. α-methyldopa. In Chemical Stability of Pharmaceuticals: A Handbook for Pharmacists, John Wiley & Sons, 1986; 2nd ed: pp. 573-579.

3.      Yujing L. Xiaoyan X. Cheng, X. Methyldopa composition and methyldopa tablets as well as preparation methods thereof: Patent CN108379233A. Applicant: Nanjing Zeheng Pharmaceutical Science & Tech Company Ltd. European Patent Office, 2018.

4.      Connors KA. Amidon GL. Stella, VJ. Oxidation and photolysis. In Chemical Stability of Pharmaceuticals: A Handbook for Pharmacists. John Wiley & Sons, 1986; 2nd ed: pp. 82-114.

5.      Aditee M and Rathod S. Quality by Design: A New Era of Development of Quality in Pharmaceuticals. Research Journal of Pharmacy and Technology 2014; 7(5): 581-591.

6.      Kadam VR. Patil MP. Pawar VV. Kshisagar S. A Review on: Quality by Design (QbD). Asian Journal of Research in Pharmaceutical Sciences 2017; 7(4): 197-204. doi.org/10.5958/2231-5659.2017.00030.3

7.      Vyas AJ. Visana N. Patel AI. Patel AB. Patel NK. Shah S. Analytical Quality by Design in Stress Testing or Stability - Indicating Method. Asian Journal of Pharmaceutical Analysis 2021; 11(2):170-178. doi.org/10.52711/2231-5675.2021.00029

8.      Gibson M. Carmody A. Weaver R. Development and Manufacture of Drug Product. In Pharmaceutical Quality by Design: A practical approach, Edited by Schlindwein WS and Gibson M. John Wiley & Sons, 2018; 1st ed: pp. 117-156.

9.      Al-Achi A. Tablets: A Brief Overview. Journal of Pharmacy Practice and Pharmaceutical Sciences 2019; 1: 49-52. doi.org/10.33513/PPPS/1901-10

10.   Alderborn G and Frenning G. Tablets and compaction. In Aulton’s Pharmaceutics: The Design and Manufacture of Medicines, Edited by Taylor KMG and Aulton ME. Elsevier: Churchill Livingstone, 2022; 6th ed: pp. 501-541.

11.   Iqubal MK. Singh PK. Shuaib M. Iqubal A. Singh M. Recent Advances in Direct Compression Technique for Pharmaceutical tablet formulation. International Journal of Pharmaceutical Research and Development 2014, 6(1): 49-57.

12.   Kengar MD. Tamboli JA. Magdum CS. Quality by Design in Pharmaceutics. Research Journal of Pharmaceutical Dosage Forms and Technology 2019; 11(3): 235-238. doi.org/10.5958/0975-4377.2019.00039.9

13.   Reddy K. Divakar K. Reddy B. Shruti P. Pharmaceutical Excipients- Their Mechanisms. Research Journal of Pharmaceutical Dosage Forms and Technology 2013; 5(6): 355-360.

14.   Debnath S. Yadav C. Nowjiya N. Prabhavathi M. SaiKumar A. Sai-Krishna P. Babu M. A Review on Natural Binders used in Pharmacy. Asian Journal of Pharmaceutical Research 2019; 9(1): 55-60. doi.org/10.5958/2231-5691.2019.00009.1

15.   McCormick D. Evolutions in direct compression. Pharmaceutical Technology, Special Report 2005, 29(4): 52–62.

16.   Kader M. Mitigating the Risks of Generic Drug Product Development: An Application of Quality by Design (QbD) and Question based Review (QbR) Approaches. Journal of Excipients and Food Chemicals 2016, 7(2): 35-75.

17.   Somnache S. Godbole A. Gajare P. Kashyap S. Significance of Pharmaceutical Excipients on Solid Dosage form Development: A Brief Review. Asian Journal of Pharmaceutical Research 2016; 6(3): 193-202. doi.org/10.5958/2231-5691.2016.00028.9

18.   Baker N. Quality Risk Management (QRM). In Pharmaceutical Quality by Design: A practical approach, Edited by Schlindwein WS and Gibson M. John Wiley & Sons, 2018; 1st ed: pp. 97-116.

19.   Chavan SD. Pimpodkar NV. Kadam AS. Gaikwad PS. Quality by Design. Journal of Pharmaceutical Quality Assurance 2015; 1(2): 18-24.

20.   Beg S. Saquib-Hasnain M. Rahman M. Imam SS. Pharmaceutical Quality by Design: Principles and Applications. Academic Press, 2019.

21.   Chettupalli AK. Padmanabha-Rao A. Kuchukuntla M. Bakshi V. Development and Optimization of Aripiprazole ODT by using Box-Behnken Design. Research Journal of Pharmacy and Technology 2020; 13(12): 6195-6201. doi.org/10.5958/0974-360X.2020.01080.X

22.   United States Pharmacopeial Convention. Methyldopa tablets. United States Pharmacopeia 43, National Formulary 38 Formulary [USP 43 – NF 38]. Rockville, MD; 2019. pp. 2878.

23.   United States Pharmacopeial Convention. <731> Loss on Drying. United States Pharmacopoeia - National Formulary [USP 35 – NF 30]: Stage 6 Harmonisation. Rockville, MD; 2012. pp. 317-318.

24.   Frost JD. Hypothesis Testing: An Intuitive Guide for Making Data Driven Decisions. James D. Frost, 2020.

25.   Deveswaran R. Bharath S. Basavaraj B. Abraham S. Furtado S. Madhavan V. Concepts and Techniques of Pharmaceutical Powder Mixing Process: A Current Update. Research Journal of Pharmacy and Technology 2009; 2(2): 245-249.

26.   Florence AT and Atwood D. Physicochemical Principles of Pharmacy: In Manufacture, Formulation and Clinical Use. Pharmaceutical Press, 2015.

27.   Byrn SR and Haskell RJ. Efficient Laboratory Methods to Assess Risk and Design Formulations. In Discovering and Developing Molecules with Optimal Drug-Like Properties, Volume 15 of AAPS Advances in the Pharmaceutical Sciences Series, Edited by Templeton AC. Byrn SR. Haskell RJ. Prisinzano TE. Springer Verlag, 2015; pp. 251-254.

 

 

 

Received on 16.11.2021            Modified on 06.02.2022

Accepted on 03.04.2022           © RJPT All right reserved

Research J. Pharm. and Tech 2022; 15(9):4151-4157.

DOI: 10.52711/0974-360X.2022.00697